University of Iowa

Iowa Research Online

Theses and Dissertations

2011

Beyond the cortex: implications of white matter

connectivity for depression, cognition, and vascular
disease
Kelly Cathryn Rowe
University of Iowa

Follow this and additional works at: http://ir.uiowa.edu/etd

Part of the Neuroscience and Neurobiology Commons
Copyright 2011 Kelly Rowe
Recommended Citation
Rowe, Kelly Cathryn. "Beyond the cortex: implications of white matter connectivity for depression, cognition, and vascular disease."
dissertation, University of Iowa, 2011.
http://ir.uiowa.edu/etd/2765.

This dissertation is available at Iowa Research Online: http://ir.uiowa.edu/etd/2765

BEYOND THE CORTEX:

IMPLICATIONS OF WHITE MATTER CONNECTIVITY FOR
DEPRESSION, COGNITION, AND VASCULAR DISEASE

by
Kelly Cathryn Rowe

An Abstract
Of a thesis submitted in partial fulfillment of the
requirements for the
Doctor of Philosophy degree in Neuroscience in the Graduate
College of
The University of Iowa
December 2011

Thesis Supervisor: Professor David Moser

ABSTRACT
The current study investigates the effects of vascular disease on white matter
health by comparing participants with atherosclerotic vascular disease (AVD) to healthy
control participants (HC). The comparison between groups will help elucidate the
differences between early-stage mild vascular disease and normal aging processes in
terms of their effects on white matter health as measured by diffusion tensor imaging
(DTI). Relationships between white matter health and depression, attention, and
processing speed are studied by the application of a variety of DTI neuroimaging
techniques, which will allow investigation of these relationships at the levels of global,
lobe-wise, and subregional analysis. The specific subregion of interest in the depression
study is Brodmann Area 25, which has shown significant relationships with depressive
symptomatology in patients with treatment refractory depression, but has not been
studied in the context of aging, vascular disease, or subthreshold depressive symptoms.
Results indicate that there are significant differences between AVD and HC participants
in global and regional FA measures. Within the AVD group, significant relationships of
FA with depressive symptoms and attentional function have been observed in the current
study. Several unexpected findings emerged, most important of which was the
observation that there is a significant relationship between FA in Brodmann Area 25 and
depressive symptoms in AVD participants which is specific to the right hemisphere.
These findings have implications for the treatment of depressive symptoms in older
adults and participants with vascular disease.

Abstract Approved:
Thesis Supervisor
Title and Department
Date

BEYOND THE CORTEX:

IMPLICATIONS OF WHITE MATTER CONNECTIVITY FOR
DEPRESSION, COGNITION, AND VASCULAR DISEASE

by
Kelly Cathryn Rowe

A thesis submitted in partial fulfillment of the

requirements for the Doctor of Philosophy degree in
Neuroscience in the Graduate College of
The University of Iowa
December 2011

Thesis Supervisor: Professor David Moser

Copyright by
KELLY CATHRYN ROWE
2011
All Rights Reserved

Graduate College
The University of Iowa
Iowa City, Iowa

CERTIFICATE OF APPROVAL
PH.D. THESIS
This is to certify that the Ph.D. thesis of
Kelly Cathryn Rowe
has been approved by the Examining Committee for the thesis requirement for the Doctor
of Philosophy degree in Neuroscience at the December 2011 graduation.
Thesis Committee:
David Moser, Thesis Supervisor
Vincent Magnotta
Peg Nopoulos
Stephan Arndt
Sergio Paradiso

ACKNOWLEDGMENTS
At the start of this compendium of facts and findings, it is fitting to begin with a brief
word of thanks, not only to those who have directly helped me get my bearings in the dizzying
process of researching and writing, but also to those great minds who have lived and pondered
and toiled before me in search of answers to these same questions. The old adage there are no
new ideas, just new combinations of old ideas is especially true in my current work. Here I
am, applying a new methodology to the study of centuries-old ideas with the hopes of
shedding new light on the function of the brain. As someone great once told me, all we can do
is stand on the shoulders of giants in the hopes that we might get a clearer view of this
beautiful system.

ii

TABLE OF CONTENTS
LIST OF TABLES ................................................................................................................vi
LIST OF FIGURES.............................................................................................................viii
CHAPTER I: THEORETICAL BASIS...................................................................................1
History of Connectionism and the Associationist Movement......................................1
Application to the current research...........................................................................6
CHAPTER II: VASCULAR DISEASE..................................................................................7
What is atherosclerosis?.............................................................................................8
Effects of atherosclerosis on the brain.....................................................................9
Summary and implications for the current research................................................13
CHAPTER III: EMOTIONAL CHANGE IN VASCULAR DISEASE:
DEPRESSIVE SYMPTOMS................................................................................................14
Late-onset vs. early-onset depression......................................................................26
Summary..................................................................................................................29
Implications for treatment and research strategies..................................................32
CHAPTER IV: COGNITIVE OUTCOMES IN VASCULAR DISEASE...........................33
Attention function....................................................................................................33
Processing Speed.....................................................................................................36
Relationship of cognition to depression..................................................................39
Summary..................................................................................................................40
CHAPTER V: NEUROIMAGING TECHNIQUES.............................................................41
White matter hyperintensity measures.....................................................................41
Diffusion Tensor Imaging........................................................................................42
DTI techniques: region-of-interest, atlas-based, and voxel-based
morphometry.......................................................................................................46
Summary..................................................................................................................52
CHAPTER VI: A NOTE ON CONTEXT: THE AGING BRAIN.......................................54
Vascular changes during normal aging....................................................................54
Structural changes in normal aging.........................................................................54
Cognitive changes in normal aging.........................................................................57
Summary and implications......................................................................................58
CHAPTER VII: SUMMARY OF THE LITERATURE, ADVANTAGES OF THE
CURRENT STUDY, AND HYPOTHESES.......................................................................60
CHAPTER VIII METHODS...................................................66
iii

Participants..............................................................................................................66
Demographics......................................................................................................67
Neuropsychological Measures................................................................................68
SCL-90-R............................................................................................................68
RBANS...............................................................................................................69
WAIS-III.............................................................................................................70
Trail-making Test A............................................................................................71
Stroop test: color-naming and word-reading.......................................................72
Composite measures............................................................................................72
Imaging Measures.....................................................................................................72
Analyses...................................................................................................................77
General approach.................................................................................................77
Power analyses....................................................................................................79
CHAPTER IX RESULTS ...................................................................................................81
Preliminary Analyses ..............................................................................................81
Reliability............................................................................................................81
Group-wise performance on cognitive and psychiatric measures.......................81
Specific Aim 1: Structure........................................................................................85
Hypotheses..........................................................................................................86
Effects of sex on FA values by group.................................................................88
Effects of education on FA values by group.......................................................89
Effects of handedness on FA values by group....................................................89
Covariate interactions..........................................................................................89
Friedmans One-way ANOVA............................................................................89
Specific Aim 2: Structure-Function Relationships...............................................90
Hypotheses......................................................................................................91
Relationship of global and regional FA with depressive symptoms on the SCL90-R.................................................................................................................92
Relationship of FA with Brodmann Area 25 with SCL-90-R depression........94
Bilateral Analyses................................................................................94
Unilateral Analyses..............................................................................96
Specific Aim 3: Structure-Function Relationships...............................................98
Hypotheses......................................................................................................98
Relationship of global and regional FA with composite scores of attention and
processing speed..............................................................................................99
Attention............................................................................................100
Speed..................................................................................................101
Specific Aim 4: Voxel-based Morphometry......................................................102
CHAPTER X DISCUSSION ............................................................................................103
Summary of critical findings...................................................................................103
Cognitive and emotional findings..........................................................................104
Structural Findings.................................................................................................105
Depression Findings...............................................................................................111
Attention Findings.................................................................................................123
Processing Speed Findings....................................................................................127
iv

VBM Findings.......................................................................................................129
Limitations and future directions...........................................................................130
Conclusions and implications................................................................................134
APPENDIX A SUBGENUAL CINGULATE TRACING PROTOCOL..........................136
APPENDIX B INDIVIDUAL DEPRESSION ITEMS FROM SCL-90-R.......................141
REFERENCES..................................................................................................................142

LIST OF TABLES
Table 1.

Demographics of participants with DTI......................................................67

Table 2.

Demographics of participants without DTI.................................................67

Table 3.

Power analyses for means comparison........................................................79

Table 4.

Power analyses for correlations...................................................................79

Table 5:

Reliability calculations for composite measures.........................................81

Table 6:

Performance difference between AVD and HC participants on

cognitive and psychiatric measures.............................................................82

Table 7:

Differences between AVD and HC participants on total composite

scores...........................................................................................................83

Table 8:

Differences between AVD and HC participants who received DTI on

cognitive and psychiatric measures............................................................83

Table 9:

Range of SCL-90-R depression scores in AVD and HC participants

who received DTI........................................................................................84

Table 10:

Differences between AVD participants with and without DTI on

cognitive and psychiatric measures.............................................................85

Table 11:

Comparison of AVD to HC participants in terms of FA globally, by

lobe, and by hemisphere..............................................................................87

Table 12:

Sex differences in AVD group (n = 35)......................................................88

Table 13:

Sex differences in HC group (n = 22).........................................................88

Table 14:

AVD group Friedmans One-way ANOVA................................................90

Table 15:

HC group Friedmans One-way ANOVA...................................................90

Table 16:

Depression T-score vs. FA by lobe in AVD group covarying for age........93

vi

Table 17:

Depression T-score vs. FA by lobe in AVD + HC group covarying for

age................................................................................................................94

Table 18:

Comparison of AVD to HC on mean FA measured in BA25 bilaterally....94

Table 19:

Partial correlation between bilateral BA25 FA and depression T-scores in

AVD group covarying for age....................................................................95

Table 20:

Partial correlation between BA25 FA and depression T-score in AVD

group controlling for age.............................................................................96

Table 21:

Partial correlation between BA25 FA and depression T-score in AVD

group controlling for age and contralateral BA25 FA.................................97

Table 22:

Paired sample t-test in AVD group ............................................................97

Table 23:

Z-test for the significance of differences between two correlation

coefficients..................................................................................................98

Table 24:

Attention composite score vs. FA by lobe in AVD group covarying

for age and education.................................................................................100

Table 25:

Attention composite score vs. FA boxes in AVD group covarying for

age, education, and SCL-90-R depression T score....................................101

vii

LIST OF FIGURES
Figure 1:

Schematic representation of connectionist model of neural

dysfunction.................................................................................................5

Figure 2:

Cross-sectional view of an artery showing adventitia (outermost

layer), media (middle layer), and intima (thin inner lining)
of an artery ................................................................................................9

Figure 3:

White matter hyperintensities as they appear on a proton density

image in a participant with late-life major depression.............................20

Figure 4:

Anatomical locations of key brain regions implicated in Major

Depressive Disorder.................................................................................28

Figure 5:

Neural substrates of three attention networks..........................................34

Figure 6:

Images from Diffusion Tensor data.........................................................43

Figure 7:

Diffusion tensor imaging of a patient with multiple sclerosis lesions

to white matter.........................................................................................45

Figure 8:

Left lateral views from three-dimensional depictions of fiber

pathways, which were developed from normal DTI images...................51

Figure 9:

Example of partial volume artifact in DTI...............................................52

Figure 10:

White matter + lesion mask (pink) overlay on T1 images of the

same brain................................................................................................73

Figure 11:

Subject tissue classified image presented in axial (upper left), sagittal

(right), and coronal (lower left) views in BRAINS2 image viewer.........74

Figure 12:

Left panel shows AC-PC aligned, b-spline transformed FA scalar

map in subject anatomical space.............................................................75

Figure 13:

Images from Figure 12 left and right panels overlaid on each other.......76
viii

Figure 14:

Overlay of Mori et al. (2005) white matter atlas on participant

anatomical scan........................................................................................77

Figure 15:

Areas (red) of significantly higher FA in men than women...................107

Figure 16:

Anterior (Frontal) white matter shows preferential vulnerability to

the effects of aging.................................................................................108

Figure 17:

Limbic-cortical dysregulation model.....................................................114

Figure 18:

Converging evidence implicating BA 25 in Major Depressive

disorder...................................................................................................116

Figure 19:

Simplified neural circuitry of depression...............................................119

Figure 20:

Cortical areas involved in three attention networks...............................125

Figure A1:

Figure adapted from McCormick et al. (2006)......................................136

Figure A2:

Example traces in coronal and sagittal view..........................................138

Figure A3:

Example of surface view with all region-of-interest traces overlaid

in purple.................................................................................................139

ix

CHAPTER I
THEORETICAL BASIS
History of Connectionism and the Associationist Movement
In tracing the lineage of the connectionist model to be applied to the current
research, one is led all the way back to two separate and basic tenets which were
eventually fused and appear to represent the simplest version of the theory. The first,
localization of function to discrete cortical areas, is primarily attributed to the work of
Franz Joseph Gall (1758-1828), who recognized the specific importance of the cortex.
Gall established the functional divisions between gray and white matter, demonstrating
that white matter consisted of ascending and descending conducting fibers originating in
or projecting to the cortex (Zola-Morgan, 1995). In England, Galls ideas developed into
the dubious practice of phrenology and fell into disrepute, but in France they went on to
influence later clinicopathological studies of Paul Broca and Jean Martin Charcot, among
others (Catani & ffytche, 2005). The second element of the theory states that higher
cognitive functions are not composed of the action of singular cortical areas, but rather
exist as concerted patterns of neuronal firing in disparate brain regions, linked together
through white matter connection pathways and associative areas of cortex. Theodore
Meynert, (1833-1892), a Viennese anatomist, took the critical step of identifying the roles
played by different types of white matter fibers by categorizing them into projection
fibers (ascending or descending pathways), commissural fibers (interhemispheric), and
association fibers (intrahemispheric).
These two elements independently informed droves of neurologists and scientists,
but it was Karl Wernicke (1848-1904) who is credited with fusing the ideas together into
a theory of connectionism, thus earning the title, The Father of Connectionism. He
conceived of the brain as a mosaic of areas containing fundamental psychic elements

2
related to motor or sensory experiences. Wernicke was convinced that higher functions
could not be localized within specific regions, but instead were the result of the
associative connections between related areas. Wernicke said, Any higher psychic
process [] could not be localized, but rested on the mutual interaction of these
fundamental psychic elements mediated by means of their manifold connections via the
association fibers (Wernicke, published 1994).
Connectionism lost some of its popularity during the move against localized brain
theories in the early 1900s, but was revitalized in the 1950s by the work of Ronald Myers
and Roger Sperry on the consequences of callosal sectioning, which provided evidence
for hemispheric specialization of brain functions (Sperry, 1982). The findings of Myers
and Sperry inspired the young Norman Geschwind to re-examine the older clinical
literature and to re-assess the patients with disturbances of the higher functions (Catani
& ffytche, 2005). The outcome was to be his 1965 manifesto on the topic. Geschwind
added two important components to the associationist view (Geschwind, 1965a). First,
based on Flechsigs rule (Flechsig, 1901), Geschwind suggested that the association
cortex acted in effect as a relay station between different brain regions and that any
damage to association cortex would serve to disconnect them. Second, Geschwind added
the concept that the evolution of association cortex underlies the evolution of higher
function, such that higher functions in human beings are more reliant on white matter and
association areas than analogous functions in monkeys or rabbits. Geschwind outlined a
variety of disconnection syndromes affecting language, motor and sensory functions,
though he stopped short of proposing any disconnection for affective disorders
(Geschwind, 1965a).
This theory ruled neurology until the late 1980s, when it was de-emphasized and
incorporated into more general models of higher cognitive dysfunction. The primary

3
objections raised against the pure connectionist model were based on Geschwinds
hypothesis that the association cortex was merely a homogeneous relay station between
primary sensory and motor areas. Furthermore, Geschwinds 1965 theory was
predominantly focused on the feed-forward, serial nature of information processing,
which did not adequately consider the extremely recursive and reciprocal connections
between most brain regions. The contributions of recursive and reciprocal connections to
higher function were later emphasized by Damasio and Mesulam in the retroactivation
model (Damasio & Damasio, 1994; Damasio, 1989) and the large-scale network model
respectively (Mesulam, 1990).
The modern framework for clinicopathological correlations that evolved from
Geschwinds 1965 model consists of a network of specialized cortical areas grouped into
territories which are connected through parallel, bidirectional pathways (see Figure 1
above). Thus, two primary mechanisms can underlie deficits in higher cognitive and
emotional functions: loss of function in a specific cortical area, or damage to its
underlying white matter connecting pathways. In humans, the former is much better
understood, primarily because of brain lesion and functional neuroimaging studies.
However, there is criticism of the lesion method in that most brain lesions damage not
only the cortical gray matter but also the underlying white matter. In this case it can be
problematic to ascribe deficits of higher cognitive functions to specific cortical regions
because it remains unknown whether the driving force is in the white matter or gray
matter damage. By comparison, anatomical knowledge of white matter pathways has
until recently relied on primate tracing studies using histological brain specimens
(Mesulam, 2005), and functional knowledge of the contributions of white matter to
higher cognitive functions has been extremely limited. One way to further understand
these complex higher-order functions would be to study them in patients with damage

4
only to the white matter connecting fibers while sparing the gray matter structures. Doing
so would clarify the degree to which cognitive and emotional deficits are related to
damage to the white matter, as opposed to studies in participants with cortical lesions that
involve both white and gray matter structures.
Today, new techniques such as diffusion tensor imaging and tractography (Basser,
Mattiello, & Lebihan, 1994; Lebihan & Breton, 1985; Moseley et al., 1990) allow
scientists to study the physical connectivity of white matter non-invasively in living
human brain tissue to test the classical theory directly. The application of these
methodologies is critical, as disconnection syndromes have been implied in various cases
of patients with stroke in the neurology clinic (Geschwind, 1965a; Geschwind, 1965b) as
well as outside it in disorders ranging from schizophrenia (Bullmore, Frangou, & Murray,
1997) to autism (Frith, 2001), and dyslexia (Demonet, Taylor, & Chaix, 2004). One
further consideration in the study of these disorders, proposed by Catani and ffychte
(2005), holds that disease states can arise not only from the disconnection, but also from
the hyperconnection of functionally coordinated cortical units. These so-called
hodological mechanisms (dysfunction of connecting pathways arising from
disconnection, hyperconnection, or a combination of the two) have been implicated in a
range of disorders, from the classic disconnection syndrome of conduction aphasia
arising from pure subcortical lesions (Naeser et al., 1982) to the combination of frontofrontal hyperconnectivity with frontal disconnection from the rest of the brain found in
autism (Courchesne & Pierce, 2005). Given the recent findings by Mayberg et al. (2005),
a similar hyperconnectivity model may be useful for the study of early-onset depression,
where participants depressive symptoms were immediately alleviated by downregulating the firing rate in a network of associated brain regions. In contrast, perhaps the
elevation of depressive symptoms in participants with so-called Vascular Depression

5
(Alexopoulos, 1997; Krishnan et al., 1997) may be related to the accumulation of white
matter lesions interrupting these same pathways.

Figure 1: Schematic representation of connectionist model of neural dysfunction

A) The contemporary view of the cortex and its connections. Territories have different
functions, and within each territory each specialized region has a different sub-function
within the overall function (for example, in the occipital territory, all areas are involved
in visual processing, but one region is involved with detection of edges and another
region is used to differentiate among colors). Regions are connected with each other via
short intra-territorial connections, and territories are connected to each other through
long inter-territorial connections. B) The consequence of white matter pathology; when
the dashed pathway is either hyper- or hypo-functional, the associated cortical areas
also become dysfunctional. C) The consequence of cortical pathology; when the area of
cortex indicated by the red arrow becomes dysfunctional, some distantly connected
cortical areas may also become dysfunctional because they lose feedback from the
affected area. D) The consequence of combined cortical and white matter pathology;
widespread cortical regions are affected by this type of damage. Feedback and
connectivity with associated brain regions are diminished. (Figure and caption adapted
from Catani and ffychte (2005)).

6
Application to the current research
In the current research, the theoretical framework of connectionism is applied to
cognitive and emotional dysfunction in participants with vascular disease. We believe
this is an appropriate application of the theory, based on the critical finding that even in
relatively early-stage vascular disease, there is a dramatic elevation in the frequency and
severity of white matter lesions. In the current study we hypothesize that widely
distributed cognitive processes such as attention and processing speed may be sensitive to
subtle white matter pathology precisely because they are widely distributed and may
depend on coordination through the white matter. We hypothesize that effects of white
matter disease on depressive symptoms are likely to be observed in the current sample,
given that the areas of white matter vulnerability in vascular disease largely overlap with
areas containing depression-associated white matter tracts. It is proposed in the current
thesis that depressive symptoms in participants with vascular disease and associated
white matter damage may be caused by underlying disconnection of the white matter
tracts involved in mood regulation. Under these circumstances, the current research may
be interpreted as further evidence that depression arising from white matter damage
should be considered a disconnection syndrome.
Studying the effects of vascular disease on the brain in participants who have not
had cortical stroke affords a unique opportunity to study the effects of impaired white
matter function with predominantly intact cortical function. Thus, the cognitive and
affective changes noted in this participant group can be interpreted to be driven by
hodologically-based dysfunction which may be amenable to inspection via new methods
for white matter assessment such as diffusion tensor imaging (DTI).

CHAPTER II
VASCULAR DISEASE
The brain has a tremendous capacity for vascular autoregulation, and for this
reason cardiovascular disease was once thought to convey little risk to the brain (Lassen
et al., 1964; Cohen et al., 2009). However, it has since been observed that patients with
cardiovascular disease frequently show cognitive and emotional dysfunction in the
absence of clinically identified stroke (Elias, Elias, Sullivan, Wolf, & D'Agostino, 2003;
Moser et al., 1999; Paul et al., 2005; Rao, 2002; Wang, van Belle, Kukull, & Larson,
2002). Further studies have demonstrated that the likely neural substrate for these
changes is the dramatic increase in ischemic damage to the white matter fibers in the
brain, as the following chapters will outline. These findings are important because they
suggest that even in the absence of damage to cortical gray matter tissue, people with
vascular disease have clinically meaningful, measurable cognitive and emotional
changes, which may help researchers to delineate the discrete effect of white matter
damage to cognitive and emotional functioning.
Within cardiovascular disease, the current research focuses on early-stage
atherosclerotic vascular disease (atherosclerosis or AVD) prior to the development of
stroke. In addition to the scientific relevance of studying cognition and emotion in
people with white matter disease, the rigorous scientific study of early-stage AVD is
critical because this condition frequently precedes more severe cardiovascular and
cerebrovascular events. In this sense, early-stage AVD may represent a prodromal state
with measurable cognitive, emotional, and structural brain changes during which medical
interventions may be more likely to ameliorate symptoms and prevent exacerbation of the
illness. Gaining a clearer understanding of what takes place in early vascular disease will
shed light on the later outcomes of the disease as well as what therapeutic interventions

8
are most likely to be helpful for the various cognitive and emotional changes that take
place.
What is atherosclerosis
Atherosclerosis is thought to be implicated in roughly half of all deaths in the
developed world. This condition is characterized by lesions of the intima called
atheromas, or atherosclerotic plaques, which protrude into the vessel lumen (Mitchell &
Schoen, 2010). The primary dangers associated with atherosclerotic plaque formation are
the possibility of plaque rupture (leading to thrombosis or embolism), secondary
hypoperfusion of tissue, and reduction of the vascular dilation and constriction capacity
necessary to maintain hemodynamically stable tissue perfusion.
AVD is strongly related to abnormalities in lipoprotein levels, inflammation, and
endothelial dysfunction. Common lipoprotein abnormalities include increased lowdensity lipoprotein (LDL) and lipoprotein A, as well as decreased high-density
lipoprotein (HDL). Lipoprotein abnormalities can directly impair vessel function by
increasing local oxygen free radical production, and by causing oxidized lipoproteins to
accumulate in the intima. Oxidized LDL is cytotoxic to endothelial cells and causes cell
dysfunction (Roman, 2004).
Risk factors for AVD are multiplicative; having one risk factor doubles patient
risk while having two risk factors quadruples patient risk (Wilson et al., 1998). These
risk factors include non-modifiable (older, male, family history, genetics) and modifiable
(hyperlipidemia, hypertension, smoking, diabetes, obesity, lack of physical activity, poor
diet, high C-reactive protein) elements (Wilson et al., 1998). Importantly, many of the
risk factors for atherosclerosis are common in the general population, thus explaining the
high incidence of the disease.

Figure 2: Cross-sectional view of an artery showing adventitia

(outermost layer), media (middle layer), and intima (thin inner lining)
of an artery. During atherosclerotic vascular disease, damage (such as
tearing) to artery walls leads to the deposition of cholesterol,
macrophage foam cells and fatty deposits between the intima and
media layers. In advanced atherosclerosis, the deposition extends into
the lumen of the vessel, impeding blood flow. Figure adapted from
the National Library of Medicine website (http://www.nlm.nih.gov).

Effects of atherosclerosis on the brain

Eventually, the smooth muscle cells lining blood vessels affected by
atherosclerosis are replaced by fibroblasts and vessels become elongated, tortuous,
narrow, calcified, and less reactive to vasoactive agents. The relative lack of reactivity of
the vessels is catastrophic for the compensatory autoregulatory changes, which typically
take place when cerebral perfusion pressure drops. Vessels need to dilate to increase
blood volume and maintain flow to the brain, and the effects of aging and atherosclerosis
limit these responses. If the decline in perfusion pressure exceeds the vascular

10
compensatory mechanisms, oxygen metabolism will become compromised leading to
oxidative stress. During oxidative stress, the interaction of neurons with glia is lost, their
metabolism is decoupled, and DNA and protein synthesis is altered. This alteration often
takes place via up-regulation of apoptotic mRNA signals such as caspase and tumor
necrosis factor-alpha in oligodendroglia, leading to DNA fragmentation and eventually
white matter degeneration with incomplete necrosis. In addition, partial occlusion of the
vessels by atherosclerotic plaques directly decreases perfusion of tissue. If the perfusion
cannot provide the necessary oxygen and glucose to support cellular metabolism,
ischemic damage develops in the tissue. According to Poiseuilles law, a major decrease
in blood flow follows from either a decrease in radius or an increase in length in small
vessels. Thus, both vessel elongation and deposition of plaque on the vessel walls are risk
factors for hypoperfusion and partial ischemia of brain tissues. Atherosclerotic effects on
vessels are most prominent in the frontal lobes, followed by parietal, occipital, and
temporal lobes (Mitchell & Schoen, 2010).
Relentless and prolonged hypoperfusion due to severe and extensive
atheromatous stenoses (areas of narrowing) of the cerebral arteries produces incomplete
white matter infarction, which is histologically similar to that observed in the penumbra
of large cerebral infarcts (Pantoni, Garcia, & Gutierrez, 1996). These lesions are often
noted in watershed or boundary zones such as the center of white matter between the
deep territories of the anterior and middle cerebral arteries, as well as in periventricular
white matter which is vascularized by long penetrating end-arterioles. These areas are
highly sensitive to hypoperfusion, particularly in the elderly. Moody et al. (1990)
propose that brain areas irrigated by short-penetrating arteries can better tolerate
hypotension and hypoperfusion, explaining the relative sparing of the cortex, subcortical
arcuate fibers, and the corpus callosum (Moody, Bell, & Challa, 1990). Ischemic damage

11
to white matter appears on MRI imaging as bright areas, or hyperintensities, in the
midst of normal-appearing white matter. These white matter hyperintensities (WMH) are
the most common neuroradiological finding in participants with vascular disease. While a
certain extent of white matter lesion development is to be expected in normal aging
(Awad, Spetzler, Hodak, Awad, & Carey, 1986), there are notable increases in white
matter lesion severity in participants with vascular disease and hypertension (Fazekas,
Chawluk, Alavi, Hurtig, & Zimmerman, 1987; Taylor et al., 2003). WMH can result from
a variety of pathologic conditions including infarction, gliosis, demyelination, or
occasionally from cysts (Braffman et al., 1988). In a study by Raz and colleagues in
2007, white matter hyperintensity volume and regional brain volume were correlated with
age in a sample of participants with vascular disease (Raz, Rodrigue, Kennedy, & Acker,
2007). At 5-year follow-up, the white matter hyperintensity volume more than doubled in
the vascular disease participants but not in the healthy comparison group. The
hyperintensities tended to predominantly affect the frontal lobes at baseline and followup, while the parietal lobes showed the greatest rate of lesion expansion. In a study of
peripheral vascular function relative to white matter hyperintensity development, Hoth
and colleagues (2007) showed that endothelial-dependent vasodilation measured in the
forearm is significantly and inversely related to white matter hyperintensity volume,
while endothelial-independent vasodilation and total brain volume were not associated
(Hoth et al., 2007). Thus, endothelial dysfunction in vascular disease may drive the
development of white matter hyperintensities in the brain.
In addition to the independent effects of ischemic damage and vessel damage,
there is likely an interaction between the two effects as well. Cholinergic structures in
basal forebrain and their projections in deep white matter are highly vulnerable to
ischemic damage (Selden, Gitelman, Salamon-Murayama, Parrish, & Mesulam, 1998;

12
Swartz, Sahlas, & Black, 2003). These regions are critical hubs of the sympathetic
nervous system, and their destruction can lead to dysregulation of vasodilation in the
cortex, thereby exacerbating an already sensitive hemodynamic situation.
Unfortunately, changes in brain structure and function following long-term
hypoperfusion or ischemic injury are not likely to be restored if normal blood flow
returns to the tissue. Vandenburg and colleagues (1985) showed that patients with
atherosclerosis of the carotid artery, which was surgically repaired via carotid
endarterectomy, did not show an improvement of cognitive function post-surgery
(Vandenburg, 1985). Participants with carotid atherosclerosis performed worse than agematched healthy controls on measures of intelligence, memory, fluency, and decision
speed prior to the surgery and again post-surgically. In a series of later studies by
Bossema and colleagues (2005) and Grunwald and colleagues (2010), these findings were
extended to show that there were no specific restorative effects of carotid endarterectomy
on cognitive abilities, with the possible exception of processing speed.
One difficulty in the study of vascular disease is the preponderance of
neuropsychologically relevant covariates such as age, gender, and education (Breteler et
al., 1994) as well as common comorbid conditions including diabetes, hypertension, lipid
disorders, obesity, and malignant neoplasms (Desmond, Tatemichi, Paik, & Stern, 1993;
Moser et al., 1999). Each covariate or comorbid condition is likely related to a slightly
different pattern of structural and cognitive change in participants with vascular disease,
so they must be carefully controlled when possible. It is also critical to note that
participants with atherosclerosis often use a variety of medications including cholesterollowering agents, anti-hypertensives, statins, and antidepressants, and these medications
are also likely to interact with structural and cognitive health. The rate of comorbid
conditions and medication use in this population makes the causality of relationships very

13
difficult to establish in the patient population, though clarifying correlations among
vascular disease, demographic and risk factors, and structural and cognitive changes can
shed light on the outcomes of vascular compromise.
Summary and implications for the current research
Atherosclerotic vascular disease is pervasive in the population and its effects on
cognition and brain structure remain mysterious. By studying participants with AVD, we
stand to gain insight into the function of cerebral white matter and into the cognitive
changes associated with the very earliest stages of cardiovascular disease. AVD appears
to have a significant relationship with psychiatric illness and depression in particular
(which will be described in greater detail below). We hope that by studying the
relationship of depressive symptoms to the health of white matter tissue in participants
with AVD, we will be able to further elucidate the underlying structural mechanism
driving the manifestation of the depressive symptoms. AVD participants are possibly the
best population for this type of study because they are likely to have a range of white
matter damage as well as a range of depressive symptomatology, from which correlations
with function are more likely to be significant. By comparison, studies of this relationship
in healthy older adults may prove less fruitful because participants may lack the range of
white matter damage necessary to reveal any relationships.

14

CHAPTER III
EMOTIONAL CHANGE IN VASCULAR DISEASE:
DEPRESSIVE SYMPTOMS
The significant relationship between vascular disease and psychiatric disturbance
has been well established:
Psychiatrists, pathologists, and internists who have been
affiliated with psychiatric institutions have recognized for
many years that atherosclerotic coronary artery disease always
has been a major risk factor in relation to the occurrence of
sudden deaths among adults whose principal disability is some
form of mental illness (Wendkos, 1979).

Patients with cardiac disease are known to be at elevated risk for depression, and
those who develop depressive symptoms are more likely to have poor cardiac outcomes
than those without (Carney et al., 1988; Littman, 1993). Risk for subsequent
cardiovascular disease-related death is generally higher in participants with affective
disorders than in those without, and the risk is greater for men than women (Murphy,
Monson, Olivier, Sobol, & Leighton, 1987). In addition, a review of the current evidence
by Lett and colleagues (2004) revealed that depression confers a relative risk between 1.5
and 2.0 for the onset of coronary artery disease in healthy individuals, and that depression
in patients with existing coronary artery disease presents a relative risk of 1.5 to 2.5 for
cardiac morbidity and mortality (Lett et al., 2004).
The study of depressive symptoms in participants with vascular disease is
particularly important because of the significant relationship between depressive
symptomatology and vascular health, though the causality of the relationship remains
unclear. While there is a convergence of evidence that depressive symptoms can arise
from white matter changes in the brain caused by hypoperfusion in participants with
vascular disease (as will be reviewed in the following chapter), there is also a

15
preponderance of evidence suggesting that depression can cause cardiovascular
abnormalities as well. It has been hypothesized, for example, that hypothalamic-pituitaryadrenal (HPA) axis dysregulation can induce hypercholesterolemia, hypertriglyceridemia
and hypertension (all of which are known precursors of atherosclerosis) (Musselmann et
al., 1998). Furthermore, psychological stress has been shown to induce an enhanced
platelet response (Markovitz, 1991), which may trigger adverse coronary artery ischemic
events. Platelets interact with components of damaged vessel walls and plasma
coagulation factors to produce atherosclerosis, thrombosis, and acute coronary
syndromes. Circulating catecholamines bind with adrenergic, serotonergic, and
dopaminergic receptors on platelets, initiating platelet responses such as secretion and
aggregation. The platelet activation effect may be triggered by depression, as evidenced
by the finding that depressed participants show enhanced baseline platelet activation and
responsiveness compared to normal controls (Musselman et al., 1996; Laghrissi-Thode et
al., 1997).
Symptoms in a triad of domains are considered in the formulation of depression
diagnoses by the Diagnostic and Statistical Manual-IV (DSM-IV-TR). The broadest
domain encompasses all vegetative signs and symptoms including changes in appetite
and weight, sleep disturbances, fatigue and loss of energy, observed psychomotor
slowing or agitation, trouble concentrating, and indecisiveness. The second domain
includes the emotional symptoms of depression such as sad mood, loss of pleasure in
normally pleasurable activities (anhedonia), and loss of sexual interest. The final domain
(ideational) includes thoughts of worthlessness and self-deprecation, thoughts of death or
suicidal plans, and general hopelessness. For clinical diagnosis of Major Depressive
Disorder, a person must have a clinical course characterized by one or more Major
Depressive Episodes without a history of Manic, Mixed, or Hypomanic Episodes. A

16
Major Depressive Episode is characterized as the presence of depressed mood or the lost
of interest in nearly all activities, in addition to at least four additional symptoms drawn
from a list that includes the vegetative, emotional, and ideational symptoms outlined
above for most of the day every day for a minimum of 2 weeks (DSM-IV-TR) and
vocational, social, or family impairment (loss of function). However, less severe
depressive disorders, such as Dysthymic Disorder and Depressive Disorder Not
Otherwise Specified (including premenstrual dysphoric disorder, minor depressive
disorder, and recurrent brief depressive disorder) require different combinations of
symptoms and often for a shorter minimum period of time for diagnosis. The
manifestation of depressive symptoms is highly variable, giving rise to a broad range of
depressive syndromes, though research has shown that depressive symptoms of any level
of severity or frequency can contribute to medical morbidity and mortality (Judd et al.,
1994; Meeks et al., 2010). The current study includes participants with vascular disease
and damage to white matter, but who are not specifically recruited based on any
manifestation, number, or duration of depressive symptoms. Because of the constraints
imposed by the type of participants we study and the likelihood that depression exists on
a spectrum, we will focus on the presence and severity of depressive symptoms, rather
than focusing on the diagnostic entities Major Depressive Disorder or Major Depressive
Episode.
The theoretical basis for increased depressive symptoms in vascular disease is
rooted in connectionism (Wernicke, 1994). Ischemic white matter lesions are thought to
represent cerebrovascular injury to the brain that impairs its ability to regulate mood,
increasing the risk of developing depression. Primarily, this is thought to occur via
disruption of fronto-striatal circuitry (Alexopoulos et al., 1997; Tekin & Cummings,
2002; Thomas, Perry, Barber, Kalaria, & O'Brien, 2002; Alexander, DeLong, & Strick,

17
1986) and/or via interruption of the connections with limbic structures (Mayberg, 1997;
Mayberg et al., 2005; Nestler et al., 2002; Seminowicz et al., 2004). Imbalance favoring
indirect inhibitory inputs in these pathways has been hypothesized in depression (Baxter,
1990; Baxter, Schwartz, Guze, Bergman, & Szuba, 1990) (see Figure 19 in Discussion).
In general there are two competing hypotheses about the relationship of lesion
location to depressive symptoms (Alexopoulos et al., 1997). The first dictates that small
lesions may disrupt critical pathways that, once damaged, precipitate depressive
symptoms (Astrom, Adolfson, & Asplund, 1993; Starkstein & Robinson, 1993; Steffens,
Taylor, & Krishnan, 2003). The alternative hypothesis states that the accumulation of
lesions past a threshold of lesion burden predisposes a person to depressive symptoms
(Boone et al., 1992; Churchill, Priolo, Nemeroff, Krishnan, & Breitner, 1991; Figiel,
Krishnan, Doraiswamy, Rao, Nemeroff, Boyko, 1991; Krishnan et al., 1993; Zubenko,
Sullivan, & Nelson, 1990). In reality, as with many competing hypotheses, the truth
probably lies somewhere between the two.
Vascular disease is so frequently associated with increased depressive symptoms
that George Alexopoulos (Cornell University Medical College) and K. Ranga Rama
Krishnan (Duke University) independently arrived at hypotheses implicating vascular
disease and risk factors as a potential mechanism underlying the depressive symptoms
they observed in older adults. Krishnan called the phenomenon Subcortical Ischemic
Depression (SID) (Krishnan, Hays, & Blazer, 1997). Patients were considered to have
SID if they had depressive symptoms and elevated levels of white matter hyperintensity
or subcortical gray matter lesions, as measured on a modified Fazekas rating scale (See
Chapter V for a description of the scale) (Fazekas et al., 1987; Krishnan et al., 1993).
Participants with SID were generally characterized by having greater age, more lassitude,
and more frequent history of hypertension relative to depressed people without SID. SID

18
was therefore considered to be a subtype of vascular late-life depression (Krishnan et al.,
1997; Krishnan et al., 2004; Steffens & Krishnan, 1998). Alexopoulos et al. further
described the relationship of vascular disease to depressive symptoms in the Vascular
Depression Hypothesis:
Cerebrovascular disease may predispose, precipitate, or
perpetuate some geriatric depressive symptoms. There is significant
comorbidity of depression, vascular disease, and vascular risk
factors. Additionally there is a strong association of ischemic lesions
to distinct behavioral symptoms. The central mechanism for vascular
depression is proposed to be the disruption of prefrontal systems and
their modifying pathways by the accumulation of lesions.
(Alexopoulos et al., 1997).

The primary features of Vascular Depression include clinical evidence of vascular

disease or significant risk factors (stroke or transient ischemic attack, atrial fibrillation,
angina pectoris, history of myocardial infarction, carotid bruit, hypertension, or
hyperlipidemia) or laboratory evidence of structural changes in brain tissue indicative of
vascular compromise (white matter hyperintensity in area of perforating arteries, infarcts,
evidence of occlusion, stenosis of carotid arteries or in the circle of Willis). Also,
depression onset must take place at or above a certain age that varies with specific
diagnostic criteria, or a change in depression course must be noted after the onset of
vascular disease. This is often seen as the development of more frequent and persistent
depressive episodes. Patients with Vascular Depression often present with cognitive
impairments including but not limited to executive functioning, psychomotor retardation,
and poor insight, all of which culminate in high levels of disability in the absence of
family history of mood disorders (Alexopoulos et al., 1997). It should be noted, there are
some studies that do not support the Vascular Depression hypothesis. Primarily, these
studies have failed to support a specific relationship between vascular disease and

19
incident depression in longitudinal community-based populations (Cervilla, Prince, &
Rabe-Hesketh, 2004; Lyness, King, Conwell, Cox, & Caine, 2000; Versluis et al., 2006).
However, in support of the Vascular Depression hypothesis is a confluence of
research from a variety of participant groups, brain regions, and measurement techniques.
Studies of depressive symptoms in the context of white matter damage have used a
variety of techniques; the earliest was to use white matter hyperintensity volumes, then
total white matter volumes, and finally using diffusion tensor imaging (DTI) parameters
such as fractional anisotropy (FA) as indices for white matter health. It is important to
note that while white matter disease is observed to increase with normal aging, it tends to
develop earlier and progress more rapidly in participants with vascular disease.
Subcortical white matter hyperintensities of ischemic origin (Thomas et al., 2002) are
observed to be more common among older adults with depressive symptoms than in
those without (see Figure 3 below) (Coffey et al., 1988; Coffey, Figiel, Djang, Saunders,
& Weiner, 1989; Coffey, Figiel, Djang, & Weiner, 1990; Coffey et al, 1993b; Krishnan et
al., 1993; Krishnan et al., 1988; Kumar, Bilker, Jin, & Udupa, 2000; Taylor et al., 2005).
These lesions correspond with areas of arteriolar ectasia, enlargement of
perivascular spaces, and myelin pallor associated with arteriosclerotic changes in
perforating arteries. While these white matter lesions are most frequent in elderly people
with both depression and vascular disease, it remains unclear whether white matter
lesions can cause depression (Alexopoulos et al., 1997; Fazekas et al., 1987; Lesser,
Hillgutierrez, Miller, & Boone, 1993; Miller, Kumar, Yousem, & Gottlieb, 1994; Rao,
2000; Steffens, Bosworth, Provenzale, & MacFall, 2002; Thomas et al., 2002; Carney et
al., 1987; Rabkin, Charles, & Kass, 1983; Sulzer, Levin, Mahler, High, & Cummings,
1993). Many studies have shown a significant positive association between late-onset

20

Figure 3: White matter hyperintensities as they appear

on a proton density image in a participant with latelife major depression. Note areas of abnormal
brightness around the anterior and posterior horns of
the lateral ventricles. Figure and caption adapted
from Kumar et al. (2000).

depression and the size and number of subcortical white matter (and to a lesser extent
gray matter) lesions (de Groot et al., 2000; Firbank, Lloyd, Ferrier, & O'Brien, 2004;
Firbank et al., 2005; Greenwald et al., 1998; Krishnan et al., 1988; Krishnan et al., 2002;
Krishnan, 2002; Lesser et al., 1996; MacFall et al., 2006; OBrien & Ames, 1996; Taylor
et al., 2005; Versluis et al., 2006). Silent or non-symptomatic strokes have often been
noted in participants with depressive symptoms; infarctions with diameters greater than
five millimeters were found in 83% of patients with major depression who were older
than 65, and in 94% of those with depression onset after 65 (Ebrahim, Barer, & Nouri,
1987; Folstein, Malberger, & McHugh, 1971; Fujikawa, Yamawaki, & Touhouda, 1993;
Mendez, Adams, & Lewandoski, 1989; Starkstein & Robinson, 1993). In addition, some
studies have found the number of gray matter lesions in the basal ganglia and severe
white matter lesions to be associated with subsequent exacerbation of depressive

21
symptom severity in persons who were already depressed (Steffens, Helms, Krishnan, &
Burke, 1999; Steffens et al., 2002).
Localization studies have found that the frontal lobes, frontal subcortical areas,
and frontostriatal pathways are particularly vulnerable to vascular injury, and that lesions
in these areas are related to the development of late-onset depression (Coffey et al., 1989;
Coffey et al., 1990; Coffey, Wilkinson, Weiner, Parashos, Djang, Webb, Figiel, &
Spritzer, 1993a; de Groot et al., 2000; Firbank et al., 2004; Greenwald et al., 1998). The
prefrontal cortex and amygdala are of particular interest given their interconnections and
role in mood regulation (Phillips, 2003). Structural differences in prefrontal cortex have
been reported between patients with late-onset depression and healthy controls (Bae et
al., 2006; Ballmaier et al., 2004; Taylor et al., 2007). These differences likely reflect an
upset in the limbic-cortical balance (Drevets, 2000; Mayberg, Westmacott, & McIntosh,
2001), contributing to the persistence of depressive symptoms, poor affective control, and
impaired executive functioning (Alexopoulos et al., 2008; Sheline et al., 2008).
Additionally it has been noted that depressed elders have compromised white matter
integrity in the anterior cingulate cortex as well as in some temporal regions (Nobuhara et
al., 2006; Taylor et al., 2004). Diffusion tensor imaging studies have corroborated the
findings of white matter hyperintensity studies by showing low FA (thought to indicate
poor white matter health) in a variety of regions, but particularly in the frontal and
temporal lobes (Murphy et al., 2007; Nobuhara et al., 2006; Taylor et al., 2004; Yang,
Huang, Hong, & Yu, 2007; Yuan et al., 2007) in participants with depression.
The findings on laterality of brain structural damage relative to depressive
symptoms have been mixed. Cortical lesions of the left hemisphere are often seen to
result in severe major depression (Starkstein & Robinson, 1993), while damage to the
right hemisphere is seen to result in apathy and a loss of emotional awareness

22
(Alexopoulos, Meyers, Young, Abrams, & Shamolan, 1988; Paradiso et al., 2008). In left
hemisphere cortical stroke, anterior lesions are more frequently associated with
depression than posterior lesions (Starkstein & Robinson, 1993), and especially in the
case where white matter connections between the prefrontal cortex and amygdala are
damaged (Taylor et al., 2007). However, other researchers have shown that in right
hemisphere stroke, posterior lesions were associated with immediate manifestation of
depressive symptoms, while posterior lesions were associated with depression severity
measured 3-6 months after the event (House, Dennis, Warlow, Hawton, & Molyneux,
1990; Robinson, Starr, Lipsey, Rao, & Price, 1984). The finding from a study by Taylor
et al., (2004) is particularly applicable to the current analysis. Taylor and colleagues
found that reduced FA in the right dorsolateral prefrontal white matter was significantly
related to late-life depression, while FA in the corresponding area in the left hemisphere
was not. The mixed findings with regards to laterality effects on depressive symptoms
may reflect the lack of structural specificity attained in the studies, or alternatively they
may suggest that the two hemispheres have divergent roles in the manifestation of
depression.
Magnetic resonance spectroscopy studies in older depressed subjects report
increased frontal lobe concentrations of myo-inositol, choline (involved in membrane
phospholipid metabolism), and glutamine (Binesh, Kumar, Hwang, Mintz, & Thomas,
2004; Kumar et al., 2002). These changes are thought to be related to cerebral white
matter hyperintensities (Murata et al., 2001). In corroboration, post-mortem studies of
people with late-life depression also show changes in choline and creatine, which can
change glutamate regulation (Rajkowska & Miguel-Hidalgo, 2007). Late-life depression
has also been associated with decreased neuronal size and density in frontal regions

23
(Cotter, Mackay, Landau, Kerwin, & Everall, 2001; Rajkowska, Miguel-Hidalgo, Dubey,
Stockmeier, & Krishnan, 2005).
Functional neuroimaging studies have shown that participants with late-life
depression exhibit less prefrontal activation and greater caudate activation during the
explicit learning of a sequence compared to healthy controls (Aizenstein et al., 2005),
which may reflect the disconnection of those two structures by white matter lesions.
From studies of white matter hyperintensities, it has been shown that white matter
health has a significant relationship with the outcomes of late-life depression. First, it has
been postulated that interruption of the cortico-striato-limbic networks by white matter
damage interferes with their reciprocal regulation, and leads to poor antidepressant
response (Alexopoulos et al., 2002; Alexopoulos et al., 2008; O'Brien et al., 1998). More
severe and progressive lesions are predictive of poor treatment response, longer
chronicity of illness, and worse long-term outcome in late-onset depression (Hickie et al.,
1995; Hickie, Scott, Wilhelm, & Brodaty, 1997; Lavretsky, Lesser, Wohl, Miller, &
Mehringer, 1999; O'Brien et al., 1998; Taylor et al., 2003). Furthermore, Sheline et al.
(2010) showed that cognitive function and white matter hyperintensity rating at baseline
were able to predict depressive symptomatology measured by the Montgomery-Asberg
Depression Rating Scale (MADRS) prospectively over a 12-week treatment course with
sertraline (Sheline et al., 2010). Baseline neuropsychological function differentiated
remitters from non-remitters. In addition, poor white matter health (manifested as low
FA) predicted poor remission rates in participants with depression (Alexopoulos, 2002;
Alexopoulos et al., 2008). This finding may reflect the role of white matter abnormalities
in disrupting the limbic-cortical balance and leading to chronic depression. Non-remitters
had lower FA in multiple frontal limbic areas including rostral and dorsal anterior

24
cingulate cortex, dorsolateral prefrontal cortex, genu and posterior corpus callosum, and
white matter adjacent to hippocampus and insula.
Depressive symptoms are associated with more medical morbidity than any other
psychiatric disorder in late life (Lacro & Jeste, 1994). Furthermore, disability from
medical illness is a risk factor for onset of depressive disorders in late life (Kennedy,
Kelman, & Thomas, 1990). There also appears to be a significant relationship between
cognitive disorders and depressive symptoms. Elderly subjects with mild cognitive
impairment have shown higher rates of comorbid depression than the general elderly
population (Alexopoulos, 1995). Conversely, older adults with elevated depressive
symptoms are at approximately doubled risk for cognitive decline and dementia
compared to older non-depressed people (Reding, Haycox, & Blass, 1985; Barnes,
Alexopoulos, Lopez, Williamson, & Yaffe, 2006; Jorm, 2001; Lopez et al., 2003). These
findings suggest depressive disorders may predispose to the development of Alzheimers
disease and other dementing disorders. It remains unclear whether depressive symptoms
are risk factors for dementia, early symptoms of neurodegeneration, or an early
psychological reaction to cognitive deficits.
Interestingly, Oulis and colleagues (2010) found that women with current and
severe major depressive symptoms had significantly more arterial stiffness (measured via
pulse-wave velocity) than women with no significant depressive symptoms (Oulis et al.,
2010). This is important because arterial stiffness is a risk factor and/or early sign of
cardiovascular disease in both normo- and hyper-tensive patients. When participants were
treated for depression (SSRI/SNRI, ECT, antipsychotics), the participants whose
depressive symptoms responded completely showed more relief of arterial stiffness than
those who only partially responded. This suggests that current and severe depressive

25
symptoms in women lead to acute aggravation of arterial stiffness, which is reversible
upon effective treatment.
Depressive symptoms are of further interest in studies of aging and vascular
disease because of their strong relationship with cognitive functions. Previous research
shows that elevated depressive symptoms are associated with reduced cognitive functions
including memory, attention, executive functions, and psychomotor speed (Chodosh,
Kado, Seeman, & Karlamangla, 2007; Dotson et al., 2009; Panza et al., 2009; SachsEricsson, Joiner, Plant, & Blazer, 2005; Wilson, de Leon, Bennett, Bienias, & Evans,
2004). There are several possible explanations for these observations. First, severely
depressed elderly patients may be unable to participate fully in cognitive tests because of
apathy and sad mood (Alexopoulos et al., 1993). An alternative explanation holds that
cognitive dysfunction may be a primary sign in depression rather than an indirect
behavioral consequence. In support of that idea, improvement in memory appears to
correlate with improved symptoms and signs of depression (Sternberg & Jarvik, 1976).
A third explanation maintains that the neural substrate of depression in late life is similar
to the substrate for the cognitive impairments observed. In the case of late-life
depression, it appears that the relationship between depression and cognitive impairment
may be worsened by white matter lesion burden. An MRI study by Kramer-Ginsberg and
colleagues (1999) showed that deficits in executive functioning and memory were
observed in depressed elders with deep white matter hyperintensities, but not in
depressed elders without deep white matter hyperintensities or healthy comparison
participants without deep white matter hyperintensities (Kramer-Ginsberg et al., 1999).
In summary, depression in late life is critical because of its functional outcomes
for disability and disease. Patients with late onset depression have more
neuropsychological (Alexopoulos, Meyers, Young, Mattis, & Kakuma, 1993;

26
Alexopoulos, Young, & Meyers, 1993; Lesser et al., 1991) and neuroradiological
(Alexopoulos, Young, & Shindledecker, 1992; Coffey et al., 1988; Jacoby & Levy, 1980;
Janssen et al., 2007; Taylor et al., 2008) abnormalities, greater disability (Alexopoulos,
1996) poorer treatment response (Alexopoulos et al., 2008), more medical morbidity and
mortality (Jacoby, Levy, & Bird, 1981; Roth & Kay, 1956), and lower familial
prevalence of mood disorders (Baron, Mendlewicz, & Klotz, 1981) than elderly patients
with early-onset depression.
Late-onset depression vs. early-onset depression
While early-onset and late-onset depression share similar profiles in terms of
symptom manifestation, accumulating evidence suggests they may be caused by disparate
neural abnormalities. Studies of early-onset depression have recently focused on a
specific network of brain regions as described by Mayberg (2003) in the Limbic-cortical
model of depression. The regions implicated in the network have been studied in a
variety of contexts, including depression with concomitant neurological disease, primary
depression, likelihood to recover from depression, likelihood of various treatments to be
effective, and efficacy of deep brain stimulation in the region to cause remission of
symptoms in patients whose depression has been treatment refractory (Ketter et al., 1996;
Mayberg, 1994; Baxter et al., 1989; Bench et al., 1992; Malone et al., 2009; Jimenez et
al., 2005; Sartorius et al., 2010; Bewernick et al., 2010; Pardo et al., 2008; Lozano et al.,
2008, Hamani et al., 2009; Kennedy et al., 2011).
Based on the studies of the network structures in a variety of contexts, the limbiccortical circuit is hypothesized to include cortical sites such as the medial and ventral
prefrontal and parietal cortices, limbic and paralimbic structures including the amygdala,
insula, cingulate, hippocampus and subcortical structures such as the striatum, thalamus,
hypothalamus, and brainstem. Improvement in depressive symptoms is seen to correlate

27
most commonly with increases in blood flow in the prefrontal cortical regions (Brodmann
areas 9 and 46) and with blood flow decreases in the subgenual cingulate (Brodmann area
25) in participants being treated for Major Depressive Disorder (see Mayberg 2009 for a
review). Paradoxically, evidence from patients undergoing limbic leucotomy to alleviate
treatment refractory Major Depressive Disorder suggests that the disruption of afferent
and efferent pathways in the subgenual cingulate is related to the improvement of
depressive symptoms (Kelly and Mitchell-Heggs, 1973).
The applicability of the limbic-cortical network to participants with Major
Depressive Disorder was tested by Seminowicz and colleagues in 2004, when they
applied a seven-region model of depression including lateral prefrontal cortex (BA 9),
anterior thalamus, anterior cingulate (BA 24), subgenual cingulate (BA 25), orbitofrontal
cortex (BA 11), hippocampus, and medial frontal cortex (BA 10) derived from FDG PET
data using Structural Equation Modeling. The model was stable in three separate groups
of depressed patients at different institutions. Limbic-cortical connections between BA9 BA25 - BA11 - hippocampus differentiated treatment responders from non-responders.
Nonresponders also showed abnormalities in the activity of a limbic-subcortical path
(anterior thalamus - BA24 - BA25 - BA11 - hippocampus). The network was further
elaborated by Gutman et al. (2009), when DTI tractography showed ipsilateral
connections of BA25 to the medial frontal cortex, the full extent of anterior and posterior
cingulate, medial temporal lobe, dorsal medial thalamus, hypothalamus, nucleus
accumbens, and dorsal brainstem using a 1.5T scanner with 60 directions. This study
provided convincing further evidence that BA 25 functions as a physical white matter
hub among many cortical and subcortical areas involved in the depression network.
BA25 (see Figure 4 below) is an ideal region of interest in the study of depressive
symptoms in participants with vascular disease, based on evidence implicating region in

28
depressive symptom manifestation. For example, decreases in blood flow or glucose
metabolism in the region are noted in response to various interventions (including
antidepressant medication and placebo treatments, and electro-convulsive therapy).
Elevated blood flow in BA25 is noted in treatment non-responders, currently depressed,
and transiently sad participants compared to healthy controls (Mayberg et al., 1999;
Mayberg et al., 2005; Kennedy et al., 2007; Dougherty et al., 2003; Greicius et al., 2007;
Nobler et al., 2001; Mayberg et al., 2002; see Mayberg 2009 for a review).

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structural findings across studies, not a
pattern. Differences among patient sub
with familial, bipolar, unipolar, neurologi
(reviewed in ref. 13), provided an early anatomical perspective, con- sion) as well as heterogeneous expression
sistently identifying clear abnormalities in both the frontal cortex as illness severity, cognitive impairment,
and basal ganglia. Studies in individuals with primary depression, reactivity, and psychomotor slowing, are
BA25 is known
to be metabolically overactive in treatment-resistant depression,
on the other hand, have indicated that structural abnormalities are the described variance, but there is not y
more subtle, generally necessitating more advanced image acquisi- replicated behavioral correlate of a rest
is that of an inverse relationsh
andcolleagues
analytic approaches.
Such studies
have
identified
volume depression
2005, Maybergtion
and
demonstrated
that
chronic
stimulation
(at a slower
changes in the amygdala, hippocampus, and anterior cingulate, ven- the prefrontal cortex and the severity of d
tromedial, and prefrontal cortices but with considerable variability cortex activity has also been correlated w
(8, 2022) (Figure 1). Postmortem studies further identify glial cell and impairment in cognitive functions su
loss in primary depression but the findings are also not localized to ing memory; low parietal and parahippo
any one brain region (2326). Unlike depression following a selective associated with anxiety; medial frontal
brain lesion or injury, in which causal inferences can be reasonably ity has been associated with impairment
asserted, volume changes reported in MDD appear to be more com- detection and set-shifting tasks; ventral
BOE
#"
SFE

W.'
WFOUSPNFEJBM
GSPOUBM
DPSUFY
#"

but in

29
firing-rate than normal) of the white matter tracts within BA25 led to a striking remission
of depression in four out of six patients. Positive effects were associated with reduced
blood flow to BA25 and changes in downstream limbic and cortical sites observed on
positron emission tomography. Later, the study was expanded to include twenty
participants with short-term follow-up. Lozano and colleagues (2008) reported that at one
month follow-up, 35% of participants had improvement of depressive symptoms
(response), and 10% were considered remitted from Major Depressive Disorder. At sixmonth follow-up, 60% of participants were considered responders and 35% were in
remission (Lozano et al., 2008). Long-term follow-up of deep brain stimulation in BA25
showed a 75% response rate after three years in addition to improved social and work
function and physical health in all participants.
Of note for the current study, BA25 appear to play a major role in the
manifestation of Major Depressive Disorder or early-onset depression, in that it is
metabolically overactive. We hypothesize that the opposite may be true of the region in
older participants with vascular disease, given their proclivity toward white matter
damage. If it is true that BA25 is less active in older adults with vascular disease, as has
been suggested by the literature on late-life depression (Bae et al., 2006), the functional
outcomes for depressive symptom manifestation remain to be seen.
Implications for treatment and research strategies
The differences between early- and late-onset depression, in terms of baseline
brain structure and activity, course of depressive illness, and treatment responsiveness,
suggest that while the primary outcomes are similar in both (manifestation of depressive
symptoms), the etiologies of late- and early- onset depression may be very different.
Effective treatment for vascular (or late-onset) depression will likely need to be different
from existing treatment protocols, which were likely designed with the early-onset

30
depression mechanism in mind. Several drugs have demonstrated tentative efficacy in
treating post-stroke depression outcomes including trazodone, nortriptyline,
amphetamine, and methylphenidate (Finkelstein et al., 1987; Lazarus, Moberg, Langsley,
& Lingam, 1994; Lipsey, Spencer, Rabins, & Robinson, 1986; Masand, Murray, &
Pickett, 1991; Reding et al., 1986; Robinson, 2003) (see Robinson, 2003 for a review),
though the results from these studies must be taken with a grain of salt because several
were based on single cases or included no randomized control group. Further study is
required to determine whether antihypertensive, anticholesterolemic, or antiplatelet
agents improve outcomes in vascular depression. Antiplatelet treatment may be useful for
preventing further damage during depressive episodes, when serotonin mediated
thrombogenic platelet response is enhanced (Kusumi, Koyama, & Yamashita, 1991;
Mikuni, Kagaya, Takahashi, & Meltzer, 1992). We hope that the current research will
help elucidate the mechanism of late-life vascular depression by merging the current
literature on late-life depression with a specific region of interest from studies of earlyonset depression. This will help inform research on exactly which treatments for earlyonset depression may be applicable to the late-life vascular depression etiology (for
example, electrosurgical techniques and pharmacological treatments may need to be
altered to fit a hypo-connectivity model of depression rather than the hyperactivity model
that has been previously proposed by Mayberg and colleagues).
Studies of white matter health in relation to depressive symptoms have not been
limited to participants with diagnosed Major Depressive Disorder. It appears that even
subthreshold depressive symptoms are related to structural brain abnormalities and
cognitive changes. In a study by Dotson and colleagues (2009), participants with a
history of elevated depressive symptoms had smaller frontal volumes, including total
gray matter, cingulate and orbitofrontal cortical volumes; participants also showed long-

31
term declines in memory, cognitive status, and left frontal white matter volume as
compared with participants without elevated depressive symptoms (Dotson, Zonderman,
Davatzikos, Kraut, & Resnick, 2009). These findings were consistent with other studies
of structural abnormalities in the frontal lobes in major (Ballmaier et al., 2004; Drevets et
al., 1997; Lai et al., 2000) or minor depression (Kumar et al., 1997; Kumar, Jin, Bilker,
Udupa, & Gottlieb, 1998; Taki et al., 2005).
Further study of minor or subthreshold depression is critical, especially in the
older adult population. Data from 181 studies suggest that in older adults, subthreshold
depression occurs at least 2-3 times more frequently than major depression, where the
median community point prevalence was 9.8% (Meeks et al., 2010). Of the older adults
with subthreshold depression, approximately 8-10% will go on to develop major
depression each year. Additionally, these studies showed that subthreshold depression
leads to increased disability, greater healthcare utilization, and increased suicidal ideation
(Broadhead et al., 1990; Hybels et al., 2001; Xavier et al., 2002; Koenig, 1998; Judd et
al., 1994).
As yet, studies of subthreshold depression have not included analyses of white
matter health using diffusion tensor imaging. The current study stands to expand our
understanding of depressive symptom manifestation in older adults with vascular disease,
but not only in the context of comorbid major depressive disorder. We believe that any
elevation in depressive symptomatology in this population carries with it the possibility
of a vascular mechanism. Furthermore, the current study is uniquely suited to test the
relationships between cognitive function, depression, and white matter health because the
participants with atherosclerotic vascular disease in the current study have a wide range
of all three traits, which facilitates analysis.

32
Summary
Depression is an overwhelmingly common outcome of vascular disease in the
elderly, but most studies on the topic have focused on white matter lesion quantification.
Recent advances in our understanding of the neural substrates of depression (independent
of vascular disease) have helped inform the current study of depression in vascular
disease, specifically by focusing our attention on Brodmann Area 25. The current study
also stands to advance the understanding of depressive symptomatology because of the
use of a dimensional symptom approach, which is more likely to capture the full range of
medically significant depressive symptoms than previous analyses that focused solely on
diagnosed Major Depressive Disorder.

33

CHAPTER IV
COGNITIVE OUTCOMES OF VASCULAR DISEASE
While depression is a critical consideration in participants with vascular disease, a
host of other cognitive functions are also compromised by the development of white
matter damage. Attention/working memory and processing speed are the primary
capacities that are adversely affected. In addition, some studies have shown memory and
executive functioning impairments in participants with vascular disease, though these
studies have reported somewhat mixed findings and seem to be more related to severe
cardiovascular events or may be outcomes of more basic impairments such as in
processing speed (Moser et al., 1999; Muller, Grobbee, Aleman, Bots, & van der
Schouw, 2007; Sheline et al., 2006). In this introduction, the focus will be on
attention/working memory and processing speed because these two faculties are affected
in the early and less severe stages of cardiovascular disease, which is consistent with the
participants available in the current study.
Attention function
As with the study of depressive symptoms in these participants, our hypothesized
mechanism underlying cognitive dysfunction is based in connectionism and the
importance of white matter health for the function of distributed networks. The neural
circuitry underlying attention function has been thoroughly characterized by studies using
a variety of neuroimaging modalities (see Posner et al., 2006 for a review). Posner and
colleagues contend that specific networks underlie three primary attentional functions:
alerting, orienting to sensory stimuli, and executive control of attention (see Figure 5).

34

Figure 5: Neural substrates of three attention networks. The alerting

network (squares) includes thalamic and cortical sites, which are
implicated in the brains noradrenergic system. The orienting
network (circles) includes predominantly parietal sites, and the
executive network (triangles) includes the anterior cingulate and
other frontal cortical areas. Figure adapted from Posner et al. (2006).

Alertness, which includes acquiring and maintaining the alert state, depends on
the activation of the locus coeruleus in the brainstem, which supplies norepinephrine to
the rest of the brain. Activation of the noradrenergic system in turn activates other brain
regions, including regions in the frontal and superior parietal lobes, though there is some
evidence to suggest that the right and left hemispheres play divergent roles in the
maintenance of alertness (Fan et al., 2005). Orienting to sensory events is hypothesized to
arise from activation in the frontal eye fields in conjunction with superior and inferior
parietal areas, working as the cortical hubs of the network. Additionally, some studies
have implicated the pulvinar of the thalamus and the superior colliculus in this network.
Executive control over attention is thought to involve activations of the anterior cingulate
gyrus and lateral prefrontal areas (see Posner et al., 2006 for a review). Based on these

35
patterns of cortical involvement with attentional function, we hypothesize that all three
systems will be involved with performance on attention measures in the current study.
Studies of cognitive impairments in vascular disease have used a variety of
techniques, ranging from the rating or calculation of white matter hyperintensity volumes
to the measurement of white matter tissue integrity using diffusion tensor imaging (DTI).
While white matter damage is observed to increase with normal aging, it is also known to
develop earlier and progress more rapidly in participants with vascular disease.
Boone and colleagues (1992) found that digit span forward, an attention measure,
was poorest among a group of individuals with the highest volume of white matter
lesions (greater than 10 cm2) in a study of otherwise healthy elderly participants.
However, verbal memory and semantic fluency were not shown to be related to white
matter disease in these participants (Boone et al., 1992). The finding that poorer
performance on digit span forward was related to more white matter hyperintensity
volume was later reproduced in a group of middle-aged hypertensive patients in a study
by Sierra et al. (2004). In studies by Gunning-Dixon and Raz (2000), it was noted that
greater volume of subcortical white matter hyperintensity was related to slower
processing speed as well as deficits on attention and executive functioning measures in
healthy aging participants (Gunning-Dixon & Raz, 2000). Further studies demonstrated
that higher loads of white matter lesions in participants with vascular disease were
associated with poorer performance on measures of attention and executive function (Raz
et al., 2007; Jurnica, Leitten, & Mattis, 2001; Cook et al., 2004; Kramer et al., 2007).
Numerous studies have examined the relationship of attention with FA measures
from DTI, where lower FA values indicate poorer white matter health. All of the studies
identified in the current literature review appear to have been conducted in conditions
with known effects on DTI measures, including schizophrenia (Kubicki et al., 2003),

36
attention deficit hyperactivity disorder (Ashtari et al., 2005), breast cancer after
chemotherapy treatment (Deprez et al., 2011), major depressive disorder (Schermuly et
al., 2010), and aging (Charlton et al., 2006; Deary et al., 2006; Grieve et al., 2007;
OSullivan et al., 2001). The studies in these participant populations have included a
variety of neuropsychological indices of attention and working memory such as the
Bourdon-Wiersma dot cancellation test, computerized versions of digit-span and trailmaking tests, Wisconsin Card Sorting Task, Digit-Span Backward from the WMS-III,
Letter-Number Sequencing from the WAIS-III, a divided attention task, and a test of
attentional set shifting. The findings that are most applicable to the current study were
generated by Charlton et al., who found that FA in manually generated regions of interest
bilaterally in the centrum semiovale (the dorsal core of white matter in the frontal and
parietal lobes) was significantly correlated with performance on the Digit Span
Backwards test from the WMS-III and Letter-Number Sequencing from the WAIS-III.
Another study that used similar attention measures to those currently reported was Deary
et al., (2006), who reported significant correlations between FA in the centrum semiovale
and performance on Letter-Number Sequencing and Verbal Fluency subtests.
Processing Speed
The neural correlates of processing speed have been primarily conceptualized in
terms of white matter disease burden as a direct predictor of cognitive slowing. Because
processing speed is not a cognitive process per-se, but rather a measure of the speed of a
particular cognitive process, it is not hypothesized to have a specific neural network
associated with it. However studies of predictors of slowed processing speed have
converged on a pattern of cardiovascular components that likely contribute. Cohen (2008)
demonstrated via principal components analysis that there are two primary components
of vascular disease related to cognitive performance and structural brain changes. Cardiac

37
function and atherosclerotic plaque burden were significantly associated with cognitive
function and white matter hyperintensity volume. In particular, reduced systolic
variability and increased intima-media thickness were strongly related to reduced
attention, executive function, and processing speed performance in 88 outpatients with
treated, stable cardiovascular disease (Cohen et al., 2009). Saczynski (2009) showed in a
study of 4,030 non-demented participants that the number and location of white matter
lesions have different effects on cognition. Participants with multiple infarcts had slower
processing speed and poorer memory and executive function relative to those with
singular lesions. Participants with lesions in multiple different locations were more likely
to have poor performance in those three domains regardless of cardiovascular disease
burden, white matter lesion volume, and overall brain atrophy (Saczynski et al., 2009).
Additionally, Kluger et al. (1988) showed a relationship between frontal lobe white
matter hyperintensities and deficits on psychomotor tests (Kluger, Glanutsos, Leon, &
George, 1988). Moser (2001) showed a significant relationship between subcortical
hyperintensity volume and attention and processing speed variables, while seeing no
significant correlation with abstraction and problem-solving in vascular dementia patients
(Moser et al., 2001).
FA relationships with processing speed have been widely variable across studies.
As with the studies of attention, the existing literature on relationships of FA to
processing speed have been conducted in a variety of participant populations including
women treated with chemotherapy for breast cancer (Abraham et al., 2008; Deprez et al.,
2011), patients with multiple sclerosis (Rovaris et al., 2002), and participants
experiencing normal aging (Madden et al., 2004; Tuch et al., 2005; Deary et al., 2006;
Charlton et al., 2006).

38
Tuch and colleagues (2005) noted that behavioral reaction time, often measured in
terms of choice reaction time or CRT, is a widely-used measure of processing speed. In
their sample, CRT was found to have significant positive correlations with FA in small
segments of projection and association fibers in the temporal, parietal and occipital lobes
(right optic radiation, right posterior thalamus, right medial precuneus, left superior
temporal sulcus and parietal operculum). The pattern of lateralization of the findings
suggested specialization of the effect for the right visual and parietal pathways, which are
understood to be critical mediators of visuospatial attention. A direct relationship
between FA in the anterior limb of the internal capsule and shorter response time was
further noted in a visual target detection task (Madden et al., 2004). In 2006, Deary and
colleagues found that FA in the centrum semiovale correlated with two of three
information-processing measures administered to older adults. In particular, significant
relationships were found between simple and choice reaction time measures and FA.
Additionally, a significant relationship was found in women who had been treated with
chemotherapy for breast cancer, where FA in the genu, but not the splenium of the corpus
callosum, had a significant correlation with performance on the Digit-Symbol modalities
test (Abraham et al., 2008).
Finally, there are several examples of non-significant relationships between
processing speed and measures of FA in the literature (Rovaris et al., 2002; Charlton et
al., 2006; Deary et al., 2006). Rovaris and colleagues computed mean diffusivity and FA
measures in normal-appearing white and gray matter as well as within lesions from
multiple sclerosis, and discovered non-significant correlations of these FA measures with
performance on the Symbol-Digit Modalities Test, despite significant relationships with
diffusivity measures from the same regions. Later, Charlton and colleagues found that a
composite measure of processing speed including the WAIS-R Digit-Symbol test was not

39
significantly correlated with FA in any region when controlled for age. They did find
significant relationships with attention composite score and FA, following the same
pattern of results as those identified in the current study. Deary et al. (2006) found that in
addition to significant relationships between FA in centrum semiovale and two measures
of processing speed, there were non-significant relationships of simple and choice
reaction time as well as inspection time on a two-alternative forced-choice task with FA
in the frontal and parieto-occipital regions, a non-significant relationship of FA in the
centrum semiovale with inspection time, and non-significant relationships of frontal and
parieto-occipital white matter with performance on the Symbol-Digit Modality Test.
Relationship of cognition to depression
There appears to be an interaction of attention with the vascular risk factors
implicated in the hypotheses of vascular-based depression advanced by Alexopoulos and
Krishnan. The neuropsychological performance of participants with vascular risk factors
is consistent with a subcortical dysfunction syndrome, particularly affecting the
attentional systems and executive functions (Potter, McQuoid, Steffens, Welsh-Bohmer,
& Krishnan, 2009). Sheline and colleagues hypothesize (in the context of late-life
depression) that impairments on higher order cognitive abilities may stem from an
impairment of the more basic functions, particularly processing speed, which is
significantly associated with white matter lesion burden (Sheline et al., 2006). Another
study (echoing the hypotheses advanced by Sheline and colleagues in 2006) suggested
that age-related reductions in FA in the pericallosal frontal regions and in the genu of the
corpus callosum mediate the relationship between processing speed and episodic retrieval
(Bucur et al., 2008).

40
Summary
These findings provide preliminary support for the hypothesis that the
deterioration of white matter microstructural integrity may contribute to poorer
performance in attention, working memory, and processing speed (Gunning-Dixon et al.,
2009). The vast majority of studies on cognitive functioning relative to white matter
health have been conducted in populations of healthy older adults, but in many of these
studies, participants are not screened for mild vascular disease. Because of this lack of
specificity within the literature (whether changes are age-related or vascular diseaserelated), we suggest that an important dimension of the current study will be to clarify the
relationships between early vascular disease, cognitive impairment, and changes in white
matter health. Further study in this area is critical in order to identify the earliest vascular
and cognitive risk factors for cognitive decline, which in some cases proceeds to become
dementia.

41

CHAPTER V
NEUROIMAGING TECHNIQUES
White matter hyperintensity measures
As is probably evident from the review of current literature on the structural and
functional outcomes of vascular disease on the brain, the vast majority of research studies
to date have utilized measures of white matter hyperintensities (see Figure 3), which are
thought to be ischemic in origin and have demonstrated relationships with cognitive and
emotional variables in vascular disease. There are many techniques for measuring and
analyzing white matter hyperintensities (Bryan et al., 1994; Scheltens et al., 1993),
though the most common and perhaps the simplest is the semi-quantitative Fazekas scale
(Fazekas et al., 1987). This technique relies on the researchers overall visual impression
of white matter lesion severity in a few specific areas. The scale ranges from 0 to 3,
where 0 reflects zero or one punctate white matter lesion, 1 reflects several punctate
lesions, 2 reflects more lesions that are beginning confluency, and 3 reflects large,
confluent lesions in the deep white matter. Additionally, a similar scale from 0 to 3 is
used in rating the severity of white matter lesions that appear to be capping the lateral
ventricles (termed periventricular capping) in the Fazekas method (Zarei et al., 2009).
This method has demonstrated sensitivity in detecting functionally meaningful white
matter disease as reported in many of the measures in the preceding two sections.
However, the Fazekas scale is categorical nature and is somewhat qualitative in terms of
its dependence on rater impressions of lesion severity. To overcome those obstacles with
white matter lesion rating scales, a different technique of white matter lesion
quantification was born: white matter lesion volumetry. This technique involves the
generation of traces around areas of white matter lesion on each slice of an MRI image
from an individual subject, and subsequent quantification of the total volume of lesion

42
traced in the whole brain. This technique is considered to be more sensitive to the range
of possible white matter structural change in the brain, as well as being more resistant to
issues of inter-rater variability. However, as seen with the more crude methods of white
matter lesion quantification, this technique has significant limitations. It requires a
thorough understanding of normal human neuroanatomy in order for the rater to reliably
differentiate between ischemic white matter damage, normal subcortical gray matter
structures, and dilated perivascular spaces, rendering it an extremely time-intensive
process, which thus far has been relatively impervious to automation. In addition, both of
these methodologies are limited by their reliance on the physical properties of the
damaged tissue to reach the threshold for appearing as hyperintense on T2 or fluidattenuated inversion recovery (FLAIR) MRI images. This dependence means that white
matter hyperintensity studies are not well suited to detect more subtle changes to white
matter tissue, which are known to take place upstream and downstream of the area that
appears hyperintense.
Diffusion Tensor Imaging
While the previous measures of white matter health have demonstrated sensitivity
to the effects of vascular disease, a more complete understanding of these effects may be
gained by the addition of analyses using Diffusion Tensor Imaging (DTI). According to
Salat and colleagues (2005), DTI is one technique that can, at the very least, be used to
measure alterations in tissue structure but it may additionally be able to differentiate
among pathologies and specify affected fiber pathways.
DTI is used to quantify the molecular motion of water in the brain, which is
constrained by neuron and myelin integrity in living tissue (Basser et al., 1994; Beaulieu,
2002; Taylor et al., 2008). The properties of each voxel of a DTI image are calculated by
vector or tensor math from six or more different diffusion weighted image acquisitions,

43
each obtained after applying a different orientation of diffusion sensitizing gradient.
Image intensities at each voxel are attenuated depending on the strength (b-value) and
direction of the diffusion gradient, as well as depending on local microstructure. More
attenuation is interpreted to reflect more diffusion in the direction of the gradient. DTI
analysis provides rotationally invariant measurements, meaning the magnitude will be
the same regardless of the orientation of the tract relative to the gradient axes.

Figure 6: Images from Diffusion Tensor data. a-b) Axial and coronal T1
weighted anatomical images. c-d) Mean diffusivity maps in the same
slices. e-f) Fractional anisotropy maps where high intensity reflects high
diffusivity. g-h) Color-coded FA maps: blue represents fibers traveling
primarily along a super-inferior axis, red represents fibers in primarily
left-right axis orientation, and green represents primarily anterior-posterior
axis orientation. Figure adapted from Assaf and Pasternak, 2008.

44
A variety of measures are generated by diffusion tensor imaging, though the most
commonly utilized is fractional anisotropy (FA), which ranges from 0 to 1 (see Figure 6,
panels E and F). Anisotropy refers to the degree to which diffusion is directionally
constrained. Anisotropy is typically high in healthy white matter because water tends to
diffuse parallel to fiber bundles. The degree of anisotropy depends on the microstructural
components such as the integrity of cell membranes and the organization of fiber tracts
and more generally on the health and integrity of the white matter (Alexopoulos et al.,
2008; Taylor et al., 2008).
Standardization studies have shown that areas of white matter hyperintensity have
decreased FA as well as increased mean diffusivity (see Figure 7), meaning that water is
able to diffuse further, potentially because the fibers are less dense and more disorganized
owing to the ischemic damage to the tissue (DeCarli, Fletcher, Ramey, Harvey, & Jagust,
2005; Kubicki et al., 2003; Taylor et al., 2001). Additionally, these analyses have shown
alterations on FA and diffusivity even in white matter that appears normal on T2 MRI
imaging which is typically used for white matter hyperintensity ratings and quantification
methods (Beaulieu, 2002; Taylor et al., 2007).
Changes in FA are known to occur in a variety of conditions, not all of which
overlap with those that cause white matter hyperintensities; normal aging, cognitive
dysfunction, multiple sclerosis, schizophrenia, HIV, cerebral ischemia, head trauma,
development, dementia, and vascular disease (Alexopoulos et al., 2008; Grieve et al,
2007; see Assaf and Pasternak, 2008 for a review).
The issue of white matter lesions in DTI analyses has been a thorny one for many
researchers, and techniques to mitigate the problem have been widely varied. Typically,
region-of-interest analyses (see below for description) tend to avoid lesioned white

45

Figure 7: Diffusion tensor imaging of a patient with multiple sclerosis lesions to white
matter. A) Fluid-attenuated inversion recovery image showing lesions (bright spots
marked by yellow frame). B) Mean diffusivity map in same slice as in A, showing that
diffusivity in the lesion is increased compared to normal-appearing white matter. C)
Fractional anisotropy map showing significantly reduced anisotropy within lesions. D)
Color-coded FA map showing same observation as in C. Image and caption adapted from
Assaf and Pasternak, 2008.
matter, whereas voxel-based morphometry analyses (see below) do not make any
adjustments for lesions. One possible reason for avoiding lesions has to do with the
concern that they do not represent the same type of tissue as the normal-appearing white
matter and may thus present too much additional variance to the DTI measures. However,
the mere visual avoidance of lesions in ROI analyses may not adequately address the
problem because the appearance of lesions can vary dramatically in intensity and extent
among MRI and quantification protocols based on image contrast and intensity, magnetic
strengths, and thresholding parameters applied to the data. Because these aspects of
lesion imaging are not adequately standardized across studies, there is likely to be
extraneous variability in the appearance of lesions produced by various imaging
protocols. We propose that instead, including all white matter regardless of lesion status
is likely to produce data that are free from systematic bias on the basis of neuroimaging

46
protocol parameters, as well as producing data that are more consistent across postprocessing methodologies.
DTI techniques: Region-of-interest, atlas-based, and
voxel-based morphometry
Studies of DTI data have used a wide variety of post-processing techniques,
ranging from the analysis of FA values within circumscribed regions of interest to more
global studies of FA using voxel-based morphometry (Ashburner and Friston, 2001), to
the application of probabilistic white matter atlases (Mori et al., 2008 for example) to
reveal FA values within specific white matter tracts of interest.
The most common technique of DTI analysis to date has been the region-ofinterest (ROI) analysis. As the name suggests, in ROI-based analyses, DTI scalar
measures are gathered from specific regions in each participant. These regions can be
segmented manually or through semi-automated means; in the former, manual tracing
based on landmarks can yield a segmented region that can be anatomically variable
among participants, whereas in the latter, regions of interest can be placed by hand, but
the shape and volume will be uniform. For example, in Taylor et al., (2004), semiautomated oval regions of interest were placed in the prefrontal cortex with care to avoid
lesions, but semi-automated oval control regions of interest were placed in the occipital
lobes without regard for lesions. In this study, the volumes of ROIs in the frontal lobe
were constant across participants (55mm2.) as were the occipital ROIs (78.2mm2). By
comparison, a study focused on the cingulate fasciculus (Kubicki et al., 2003) used
manually placed regions of interest defined by local landmark structures which were
viewed with more detail by generating a color-coded FA map (as in Figure 6g) to help
discriminate the white matter structure of interest from surrounding white matter
structures. ROI analyses are advantageous in the sense that they do not involve multiple

47
comparisons in most cases, so they do not need to have strong adjustments that reduce
their power. In addition, they allow greater structural specificity of hypothesized group
differences and correlations with external variables. Limitations of ROI analyses include
concerns that regions are not anatomically or functionally identical across participants,
and that in many psychiatric disorders, specific regions of interest may not be known.
Voxel-based morphometry (VBM) was originally developed for use in studies of
gray matter structure, but has in recent years been applied to the study of white matter
scalar maps generated by diffusion tensor imaging (Ashburner and Friston, 2001). VBM
is designed to be sensitive to structural differences within groups while discounting
positional and other large-scale individual differences in gross brain anatomy. It does this
by removing positional and volume differences through its process of spatial
normalization, wherein scans from each participant are warped to a template image so
that they are all co-registered with each other. The images are then smoothed with a
user-defined smoothing kernel, which removes some of the inter-subject variability in
morphology and registration from the images. While the registration and smoothing
processes remove some of the macroscopic shape differences between brains, VBM has
been designed to maintain local volume differences between brains, which are retained in
the data even after smoothing. An additional step is then run to compensate for the effects
of spatial normalization, which takes into account the relative proportion of cerebrospinal
fluid (CSF), gray, and white matter-labeled voxels in a series of partitions in each brain
before and after the registration steps, and adjusting the intensity of those voxels
accordingly. The procedure has the effect of preserving the total signal of each tissue type
in the normalized partitions (Goldszal et al., 1998). The final step in VBM is to perform
voxel-wise statistical analyses, the results of which are rendered on a statistical
parametric map (SPM) (Friston et al., 1995). These maps can be generated to show

48
significant regional differences among samples included in the study after correction for
multiple dependent comparisons using the theory of Gaussian random fields (Friston et
al., 1995, Worsley et al., 1996). In addition to group-wise comparisons, correlations can
also be calculated between regional voxel-wise attributes and independent measures such
as those of depressive symptoms or processing speed in the current study. VBM analysis
has the advantage that it requires no a-priori hypothesis with regards to structural regions
that are likely to be different between groups or related to an external variable of interest.
However, because VBM considers the possible relationship of each voxel as an
individual statistical test, there are significant issues of type 1 error due to multiple
comparisons. Correction for multiple comparisons leaves the method with significantly
reduced power. In addition, there is evidence that the use of differently sized smoothing
kernels can produce very different patterns of results within the same data set, and there
are as yet no firm parameters defining which size of kernel is appropriate for which type
of analysis (Jones et al., 2005).
Voxel-based morphometry has been applied to DTI scalar maps with notable
success in previous studies both in terms of comparing groups of participants and in
correlating DTI data with cognitive performance measures. For example, in 2001
Nusbaum and colleagues investigated the effects of aging on white matter health and
found that the primary differences between older and younger adults were in the
periventricular and frontal white matter, as well as in the genu and splenium of the corpus
callosum. Notably, these findings were made in the absence of any observable
abnormality on the T1 structural image, and are in line with similar findings detected in
DTI studies of aging using region-of-interest based analyses. Klingberg and colleagues
did a comparison study followed by a correlational study using data from a 1.5T scanner
with 12 diffusion-sensitizing gradients (similar to the current study), and found that

49
participants with reading difficulties show decreased FA bilaterally in the temporoparietal
white matter, and that reading scores correlated with only the left temporoparietal region.
Atlas-based techniques operate on the principle that one can build a white matter
atlas based on fiber tracking conducted in a large sample and averaged across participants
to produce a probability map reflecting the most likely white matter structures to be
present at each voxel. The most widely-used white matter atlas has been developed by
Mori and colleagues across the United States and Canada (Mori et al., 2008). This atlas
was built using tensor maps obtained from 81 normal subjects recruited at the Montreal
Neurological Institute (24 cases) and the University of California, Los Angeles (57
cases), whose average age was 38.63 (18-59 years old), including 42 men and 39 women
all of whom were right-handed. DTI imaging on all participants used 1.5T MR units and
single-shot echo-planar imaging, which produced 2.5mm slices parallel to the anteriorposterior commissure line. Thirty diffusion-sensitizing gradients were applied in addition
to the use of a b-value of 1000s/mm2. Based on the tensor images generated by this
protocol, fractional anisotropy maps were created. Eigenvectors associated with the
largest eigenvalues for each voxel were used as indicators of the fiber orientation in that
voxel. Based on fiber orientation information from the color-coded FA maps, white
matter was segmented into a White Matter Parcellation Map (WMPM), where deep white
matter regions were manually segmented into various anatomic regions. The partitions
were based on histological atlases (Carpenter, 1976, Crosby et al., 1962; Nieuwenhuys et
al., 1983), using tractography-based tract identification as a secondary source of white
matter parcellation (see Figure 8 below). The use of atlas-based DTI data generated by
use of the Mori et al. (2008) atlas has several limitations. First, the atlas is built on a
relatively young and normal participant group, which may not be a good approximation
of the experimental groups the atlas is applied to. In addition, the atlas requires extremely

50
accurate registration algorithms to be applied in order to obtain an appropriate fit of the
atlas to participant data. The development and use of these algorithms can be extremely
burdensome and time-intensive. However, atlas-based analyses can be an excellent
alternative to manually generating regions of interest for DTI analyses because it is more
standardized across participants that ROI analyses can be. In addition, in cases when the
DTI data are not amenable to fiber tracking, the use of a white matter atlas may achieve a
reasonable approximation of tract anatomy from which FA values can be calculated. To
date, the Mori et al. (2008) atlas has not been widely reported, probably due to its novelty
and the limitations outlined above, though we expect it will become one of the most
common techniques in DTI analysis in the future.
As with any methodology, there are limitations to DTI. First, DTI analyses by
definition characterize all tissue within a given voxel as a single tensor (ie. a threedimensional vector), which may not provide an accurate representation of all the tissues
present in that voxel. This can be highly problematic at tissue interfaces (such as between
gray and white matter or white matter and CSF) and in regions where multiple fiber
systems converge or branch (Tuch et al., 2002) (see Figure 9 below). DTI also assumes
that diffusion of water follows a Gaussian distribution (Basser, 1995), which is unlikely
to be true in tissue that is compartmentalized or diffusion-restricted (as is the case with
white matter) (Beaulieu, 2002). Studies of DTI data have further shown that alterations of
anisotropy can occur under a variety of circumstances including but not limited to edema
and inflammation (Sotak, 2002), demyelination (Huppi et al., 1998), and gliosis, which
suggests that FA is not a specific measure, but rather that FA reflects dysfunction at the
cellular level without exact identification of the cause (Assaf and Pasternak, 2008).

51

Figure 8: Left lateral views from three-dimensional depictions of fiber pathways, which
were developed from normal DTI images. The thalamus, caudate, and putamen and
globus pallidus are depicted for anatomic orientation. In box A (projection and thalamic
fibers), the anterior, superior, and posterior thalamic radiation derive from the thalamus.
The corticobulbar and corticospinal tracts form the projection system. In box B
(association fibers), the superior and inferior longitudinal fasciculus and the superior and
inferior frontooccipital fasciculus are organized around the basal ganglia. In box C
(limbic system fibers), the cingulum, fornix, and stria terminalis fibers are depicted; the
ventricular system around which limbic fibers are organized is dark gray. In box D
(callosal fibers), corticocortical connections pass through the corpus callosum. The subset
of these tracts that project to the temporal lobe are pink. Images were generated using a
white matter atlas (Mori S, Wakana S, Nagae-Poetscher LM, van Zijl PCM: MRI Atlas of
Human White Matter. Amsterdam, Elsevier, 2005), and caption is adapted from Mori and
Van Zijl, 2007.

52

Figure 9: Example of partial volume artifact in DTI. A) T1 anatomical image with right
frontal area enlarged in panel D, including line drawings of the fiber systems passing
through the region: one arrives from the genu of the corpus callosum and the other from
the thalamic radiation of the internal capsule, both projecting to the frontal lobe. B) FA
image enlarged at E showing an area of low anisotropy (marked by yellow circle) in the
area of the crossing fiber systems. C) Color-coded FA image showing the same
observation as in B. Figure and caption adapted from Assaf and Pasternak, 2008.

Summary
As yet, DTI findings remain unreported in atherosclerotic vascular disease. DTI
analyses are an ideal follow-up for a literature dominated by white matter hyperintensity
studies, especially because it is not limited by the dichotomous nature of signal
hyperintensity. DTI provides us with the opportunity to study the health of white matter
with more regional specificity, even down to specific tracts of interest in various
disorders. Through the use of a combination of DTI analytical approaches (Global and

53
lobe-wise, VBM, and region-of-interest), the current study is likely to yield clearer
picture of white matter dysfunction in AVD than has ever been reported before. These
studies will lay the groundwork for a future of analysis specific tracts of interest in
vascular disease for their relationship with depressive and cognitive measures.

54

CHAPTER VI
A NOTE ON CONTEXT: THE AGING BRAIN
There has been some mention of the effects of normal aging on the brain in
terms of white matter hyperintensity studies and effects on cognition. However, it
becomes necessary to delve a bit deeper into the concept of normal aging to more
clearly define the expected neuroanatomical and cognitive characteristics of the healthy
control participants in this study, as well as to describe what may likely be taking place in
the background of the vascular-based cerebral pathology observed in the participants with
atherosclerotic vascular disease. It remains unclear what relationship, if any, normal
aging has with the development of vascular pathology. For the purposes of this chapter,
normal aging will refer to the aging process in the absence of any concomitant
neurologically relevant disorders.
Vascular changes during normal aging
Aging causes lengthening and tortuosity of medullary and cortical arterioles,
leading to formation of Virchow-Robin spaces (dilated perivascular spaces). The
formation of these spaces interferes with metabolic exchanges between blood and neural
tissue. These cavities show no necrosis, macrophages or tissue debris, and have a small
vessel inside. In addition, during normal aging, the vessels progressively thicken and
become more vulnerable to atherosclerosis. The relationship of these vascular
abnormalities with structural changes in brain tissue has not been firmly established,
though there is reason to believe the two are inextricably linked (Mitchell & Schoen,
2010).
Structural changes in normal aging
Studies of structural changes in the brain during normal aging have shown a
general pattern of gray matter tissue loss and atrophy as well as changes in white matter

55
integrity and morphology. Several studies have noted general decreases in total brain
volume, cortical thickness, and gyral thickness as a function of increasing age (Raz et al.,
2004; Uylings & de Brabander, 2002). Anterior brain regions seem to be preferentially
affected by age-related degeneration, especially including the gray matter of the
prefrontal cortex (Pfefferbaum et al., 1994), orbitofrontal and inferofrontal cortices
(Beason-Held, Kraut, & Resnick, 2008; Dotson et al., 2009), cingulate and insular
cortices (Resnick, Pham, Kraut, Zonderman, & Davatzikos, 2003), as well as
inferoparietal and mesial temporal regions (Jack & Petersen, 2000). Changes in white
matter also appear to preferentially affect the anterior regions (Davis et al., 2009; Head,
Buckner, Shimony, Williams, Akbudak, Conturo, McAvoy, Morris, & Snyder, 2004b;
Nusbaum, Tang, Buchsbaum, Wei, & Atlas, 2001; O'Sullivan et al., 2001; Raz et al.,
2005; Salat, Kaye, & Janowsky, 1999; Salat et al., 2005; Sullivan & Pfefferbaum, 2003).
For example, volume loss in the prefrontal cortex in a study by Salat and colleagues
(2005) was shown to affect white matter more strongly than gray matter, and was
primarily manifest as a decrease in myelin density and change in its microstructure, as
well as a gross decrease in the number of myelinated fibers present. These findings
follow the patterns of observed white matter degradation and volume loss as well as
increased white matter hyperintensity volume observed in other studies (Taylor et al.,
2005; Taylor et al., 2008; Thomas et al., 2002; Ylikoski et al., 1995). Finally, a
longitudinal study by Raz and colleagues (2005) showed that the caudate nucleus,
cerebellum, hippocampus, and association cortices decreased in volume substantially
over 5-year follow-up, though there were minimal changes in the entorhinal and primary
visual cortices. Atrophy of hippocampus, entorhinal cortex, inferotemporal cortex,
cerebellum and prefrontal white matter accelerated with age. The individual differences
in volume reduction were correlated across some regions, suggesting common causes.

56
There was no evidence of neuroprotection from a larger brain or higher education level.
Age-related increases in rate of decline observed in this study are consistent with the
notion of non-linear regional brain aging. Further studies have revealed that anterior
portions of corpus callosum decrease in volume with increasing age, where splenium and
posterior sections are relatively preserved (Cowell, Allen, Zalatimo, & Denenberg, 1992;
Doraiswamy et al., 1991; Janowsky, Kaye, & Carper, 1996; Salat, Ward, Kaye, &
Janowsky, 1997; Weis, Jellinger, & Wenger, 1991), possibly because the anterior corpus
callosum is most susceptible to alteration in tissue microstructure (Abe et al., 2002; Head,
Buckner, Shimony, Williams, Akbudak, Conturo, McAvoy, Morris, & Snyder, 2004a;
Pfefferbaum et al., 2000), supporting the view that anterior tissue is preferentially
affected by age.
Studies utilizing diffusion tensor imaging methods have produced marginally
clearer results as seen in the study by Pfefferbaum and colleagues (2005), where a broad
frontal distribution of low FA and high mean diffusivity was noted in older participants
compared to younger ones. Pfefferbaum interprets this finding as a relative preservation
of posterior white matter systems with aging, and suggests that the selective disruption of
frontally-based fibers is a likely substrate of the age-related cognitive declines noted in
other studies (Pfefferbaum, Adalsteinsson, & Sullivan, 2005). However, Salat and
colleagues (2005) showed that while there were significant age-related declines in the
frontal white matter, the posterior limb of the internal capsule is also strongly affected by
normal aging. It is presumed that these areas are particularly vulnerable to age-related
structural change, while the temporal and more posterior white matter regions are
relatively preserved. Prefrontal white matter anisotropy was directly correlated with
prefrontal white matter volume in participants over 40 years old, meaning that
participants with higher FA values (healthier white matter) also had greater white matter

57
volume (Salat et al., 2005). The changes in FA observed with aging are thought to be due
to microstructural alterations that precede and coincide with the formation of white
matter hyperintensities and volume loss noted in previous studies.
Later, it was shown by Zarei and colleagues in 2009 that FA is reduced in forceps
minor (anterior corpus callosum) to a significantly larger extent in Vascular Dementia
than it is in Alzheimers disease (Zarei et al., 2009). This was interpreted by Zarei and
colleagues as support for the hypothesis that DTI scalar measures such as FA may be
useful in distinguishing Vascular Dementia from Alzheimers disease. Regional
anisotropy measures further demonstrated statistically significant relationships with
cognitive performance even in young healthy participants (Tuch et al., 2005). Zhang and
colleagues (2006) showed that white matter lesion severity is not significantly different
between participants with Alzheimers disease, Mild Cognitive Impairment (MCI), and
healthy comparison participants. However, when comparing the FA measures among
those groups, FA of the cingulum was significantly reduced in MCI, and even more in
AD. Conversely, FA was significantly reduced in splenium of the corpus callosum in AD
but not in MCI. This suggested that using DTI can improve the accuracy of the
distinctions between Alzheimers disease, mild cognitive impairment, and healthy normal
aging (Zhang et al., 2007).
Cognitive changes in normal aging
The common cognitive outcomes of normal aging have been exhaustively studied and the
point will not be belabored in this introduction. The primary impairments observed in
cognitive studies of aging have included memory and executive functions (for reviews,
see (Albert, 1997; Buckner, 2004; Hedden & Gabrieli, 2004). Additionally, Pfefferbaum
et al. in 2005 noted poorer problem solving, working memory, and dual tasking

58
performance in a group of older adults compared to younger adults (Pfefferbaum et al.,
2005).
Studies of the relationships between age-related structural changes and cognitive
changes in normal aging have produced mixed results. In normal populations, white
matter hyperintensity volume correlates most strongly with impaired global functioning
and processing speed, delayed memory, executive functions, attention, and immediate
memory, although negative findings exist. (Astrom & Stoner, 1990; Harrell et al., 1991;
Vanswieten et al., 1991) but see (Fein et al., 1990; Tupler, Coffey, Logue, Djang, &
Fagan, 1992) for a review see (Gunning-Dixon & Raz, 2000). In general, these studies
have shown no significant link between white matter degeneration and indices of
intelligence (fluid or crystallized) or fine motor performance. The results from these
studies demonstrate that the presence and extent of age-related white matter changes are
related to global cognitive declines. However, certain domains of cognitive function
(processing speed, executive functioning, and explicit memory) appear especially
sensitive to white matter deterioration (Gunning-Dixon & Raz, 2000). Studies in older
adults with declining memory have shown decreased hippocampal volume as well as
decreased FA in the anterior corpus callosum when compared with older adults with
stable episodic memory over a decade (Persson et al., 2006). Anterior corpus callosum
FA also showed a negative correlation with activity in the right ventral prefrontal cortex
during an episodic encoding task, possibly indicating a pathological increase in activity.
This activity has previously been show to be elevated in participants with the greatest
memory decline.
Summary and implications
Studies of normal aging show an enhanced likelihood of developing vascular
disease because of physical changes in the blood vessels. Aging has been consistently

59
linked with white matter damage that seems to preferentially affect the anterior portions
of the brain, particularly focused on the frontal and temporal lobes. This pattern of
structural change in aging is consistent with the pattern of neuropsychological change
that occurs in old age; memory impairment, slowing of processing speed, executive
dysfunction, and attentional difficulties.
Typically, studies of diseases that predominantly manifest in older adults use
control groups composed of normal older adults for comparisons, and studies of aging
often recruit these types of participants as well. However, this choice of participant group
may be a poor one in that it is not particularly representative of the population at large,
but rather it skews the results toward a sort of super-healthy participant group that does
not accurately represent the typical course of life in old age. One advantage of the
current study is that it includes participants with a range of concomitant disorders (such
as diabetes, obesity, history of cancer) as healthy controls, which renders the findings
more generalizeable to the contemporary population of older adults. In addition, it is
experimentally helpful to be studying vascular disease and white matter health in older
adults because they are more likely to have a range of structural tissue health and
neuropsychological function that will allow us to detect significant relationships.

60

CHAPTER VII
SUMMARY OF THE LITERATURE, ADVANTAGES OF
THE CURRENT STUDY, AND HYPOTHESES
In the current research, the theoretical framework of connectionism is being
applied to cognitive and emotional dysfunction in participants with vascular disease. We
believe this is an appropriate application of the theory, based on the critical finding that
even in relatively early-stage vascular disease, there is sometimes a dramatic elevation in
the size and number of white matter lesions. In the current study we hypothesize that
widely distributed cognitive processes such as attention and processing speed may be
more sensitive to subtle white matter pathology precisely because they are widely
distributed and may depend heavily on coordination through the white matter to work.
We further hypothesize that effects of white matter disease on depressive symptoms are
likely to be observed in the current sample, given that the areas of white matter
vulnerability in vascular disease largely overlap with areas containing depressionassociated white matter tracts. It is proposed in the current thesis that depressive
symptoms in participants with vascular disease and associated white matter damage may
be caused by underlying disconnection of the white matter tracts involved in mood
regulation. Under these circumstances, the current research may be interpreted as further
evidence that depression arising from white matter damage should be considered a
disconnection syndrome.
Studying the effects of vascular disease on the brain (in participants who have not
had cortical stroke) affords a unique opportunity to study the effects of impaired white
matter function in the context of predominantly intact cortical function. Thus, the
cognitive and affective changes noted in this participant group are very likely driven by

61
hodologically-based dysfunction, which may be amenable to inspection via new methods
for white matter assessment.
Atherosclerotic vascular disease (AVD) is pervasive in the population and its
effects on cognition and brain structure remain relatively mysterious. By studying
participants with AVD, we stand to gain a great deal, both in terms of insight into the
function of cerebral white matter, and insight into the cognitive and emotional changes
associated with the very earliest stages of cardiovascular disease.
As demonstrated by the review of literature, depression is an overwhelmingly
common outcome of vascular disease in the elderly, though most studies on the topic
have focused on white matter lesion quantification. Recent advances in our understanding
of the neural substrates of depression (independent of vascular disease) could help inform
the study of depression in vascular disease, specifically by focusing our attention on
Brodmann Area 25. The current study also stands to advance our understanding of
depressive symptomatology because of the use of a dimensional symptom approach,
which is more likely to capture the full range of medically significant depressive
symptoms than previous analyses that focused specifically on Major Depressive Disorder
alone. In addition, it should be noted that studies of the Vascular Depression hypothesis
recruit participants with Major Depressive Disorder and then obtain and analyze
neuroimaging data to see if there are vascular-based brain changes that could underlie the
development of depressive symptoms. The current study can be viewed as replication
study with a twist, in that the current study follows an opposite recruitment strategy by
enrolling participants with vascular disease and then testing to see if there is a
relationship between vascular-based white matter damage and depressive symptoms. In
addition, the current study is well equipped to look for effects of laterality with regards to
depressive symptoms, a topic which has not been thoroughly investigated to date. Most

62
of the literature on laterality effects on depressive symptoms has utilized post-stroke
populations who likely have damage to both white and gray matter structures. The study
of depressive symptoms in a relatively clean sample of participants with white matter
damage is also advantageous.
Findings from studies on the relationship of cognitive performance and white
matter health provide preliminary support for the hypothesis that the deterioration of
white matter microstructural integrity may contribute to poorer performance in
processing speed, working memory, and attention (Gunning-Dixon et al., 2009).
However, the vast majority of these studies have been conducted in populations of
healthy older adults who are not screened for mild-to-moderate vascular disease. Because
of this lack of specificity within the literature (whether changes are age-related or
vascular disease-related), we suggest that an important dimension of the current study
will be to clarify the relationships between relatively early-stage vascular disease,
cognitive impairment, and changes in white matter health. Further study in this area is
critical in order to identify the earliest vascular and cognitive risk factors for later
cognitive decline, which in many cases proceeds to become dementia.
Studies of atherosclerotic vascular disease to date have not reported data from
diffusion tensor imaging, though the technique may be an ideal follow-up for a literature
dominated by white matter hyperintensity studies. DTI is not limited by the dichotomous
nature of signal hyperintensity, and it provides us with the opportunity to study the health
of white matter with more regional specificity, even down to specific tracts of interest in
various disorders. Through the use of three DTI analytical approaches (global and lobewise analysis, VBM, and region-of-interest), we will be able to get a clearer picture of
white matter dysfunction in AVD than has ever been reported before. These studies will

63
lay the groundwork for a future of analysis specific tracts of interest in vascular disease
for their relationship with depressive and cognitive measures.
Aging has been consistently linked with white matter damage that seems to
preferentially affect the anterior portions of the brain, particularly focused on the frontal
and temporal lobes. This pattern of structural change in aging is consistent with the
pattern of neuropsychological change that occurs in old age; memory impairment,
slowing of processing speed, executive dysfunction, and attentional difficulties.
Typically, studies of diseases that predominantly manifest in older adults use control
groups composed of normal older adults for comparisons, and studies of aging often
recruit these types of participants as well. However, this choice of participant group may
be a poor one in that it is not particularly generalizeable to the population at large, but
rather it skews the results toward a sort of super-healthy participant group that does not
accurately represent the typical course of life in old age. One advantage of the current
study is that it includes participants with a range of concomitant disorders as healthy
controls, which renders the findings more generalizeable to the contemporary population
of older adults. In addition, it is experimentally helpful to be studying vascular disease
and white matter health in older adults because they are more likely to have a range of
structural tissue health and neuropsychological function that will allow us to detect
significant relationships.

The specific aims of the project are summarized as follows, and stated explicitly
in the Results section starting on page 85:
1.) To compare the participants with Atherosclerotic Vascular Disease (AVD) to healthy
control participants on their regional brain attributes, utilizing Fractional Anisotropy
values from Diffusion Tensor Imaging. To examine FA measures for effects of

64
laterality, sex, age, education, and handedness. To characterize what lobe has lowest
FA (most vulnerability to white matter damage) across AVD participants only.
2.) To characterize the relationship of white matter integrity with depressive symptoms in
AVD participants utilizing global and regional measures from Diffusion Tensor
Imaging and depressive symptom endorsement from the Symptom Checklist 90Revised (SCL-90-R). To further determine whether a region-of-interest based
diffusion tensor analysis of the confluence of white matter tracts of interest in
depression (BA 25) shows a relationship with depressive symptoms measured on the
SCL-90-R. To explore effects of laterality on the relationship of depressive symptoms
with white matter health.
3.) To characterize the relationship of attention and processing speed composite measures
with white matter integrity as measured by Fractional Anisotropy measures from
Diffusion Tensor Imaging. To further examine the effects of laterality and depressive
symptoms on this relationship.
4.) To characterize the differences in white matter integrity between AVD and HC
participants and to characterize the relationship of depression, attention and
processing speed measures with white matter integrity using Voxel-based
Morphometry (VBM).

The formal hypotheses of the study follow from the literature previously
presented:
1.) FA will be significantly lower globally and in all subregions analyzed between AVD
and HC participants. Within each group there are likely to be effects of age and
education on FA, where older and less educated participants are likely to have lower

65
FA. We further hypothesize that deep white matter in the frontal lobes is likely to be
the most vulnerable to damage in both groups but especially in the AVD participants.
2.) Elevated depressive symptoms will be significantly related to lower cerebral and
frontal lobe FA values, particularly in the right hemisphere. In addition, elevated
depressive symptoms will be significantly related to lower FA values in Brodmann
Area 25, particularly in the right hemisphere, and this relationship will remain
significant when controlled for global white matter health.
3.) Lower cerebral and lobar FA will be significantly related to poorer performance on
attention and processing speed measures, but these relationships will weaken to a
level of non-significance when controlled for the effects of depressive symptoms.
4.) AVD participants will have lower FA values in a variety of regions when compared to
healthy comparison participants, and lower FA will be related to poorer performance
on the attention and processing speed measures, as well as with elevated depressive
symptoms.

66

CHAPTER VIII
METHODS
Participants
As a part of the parent study, Aging, Vascular Disease, and Cognition (grant number
RO1AG030417-01A2 from the National Institute on Aging), elderly individuals were recruited
from University of Iowa Heart and Vascular Care clinic and from newspaper and magazine
advertisements. All participants ere between 55 and 90 years old and were recruited into two
groups: Atherosclerotic Vascular Disease group (AVD) and Healthy Comparison group (HC).
Participants in the AVD group were required to have an unequivocal diagnosis of
Atherosclerotic Vascular Disease and a history of one or more of the following: angina pectoris,
myocardial infarction, percutaneous transluminal coronary angioplasty, placement of coronary
artery stent, or peripheral vascular disease (claudication). Exclusion criteria include coronary
artery bypass grafting, valve replacement, carotid endarterectomy, stroke, head injury with a loss
of consciousness >30 minutes, other neurological or systemic illness unrelated to vascular
disease that is likely to affect cognition, focal neurological signs, diagnosis of dementia, or
severe and uncontrolled psychiatric illness (current or past) (Moser et al., 2007). HC participants
were required to be between 55 and 90 years old and otherwise met none of the AVD inclusion
criteria. The criteria for exclusion from the AVD group were applied to the HC group as well.
All participants used in the current study were recruited and received neuroimaging between
May 15, 2003 and July 12, 2011. It is important to note that while participants with a clinical
history of stroke are excluded from the study, no neuroimaging was done at the time of screening
to overtly exclude participants with damage to the gray matter.

67

Demographics
Participants were asked to fill out a brief demographic questionnaire which asked them to
identify their current age, highest education level, sex, and handedness (which could be entered
as dominant left- or right-handedness or ambidextrous).

Table 1. Demographics of participants with DTI

AVD
HC
Statistic
p-value
Mean (SD)
Mean (SD)
Age
66.83 (7.60)
69.27 (7.41)
t = 1.193
.238
Education
14.83 (3.25)
13.95 (2.63)
t = -1.061
.293
Sex
40% F (14 f : 21 m) 55% F (12 f : 10 m ) X2 = 1.152
.283
Handedness (29 R : 5 L : 1 A)*
(18 R : 3 L : 1 A)*
Fishers exact p =1.000
Note: Based on 22 HC and 35 AVD participants with usable DTI data. Age and education
reported in years. * R = right handed, L = left handed, A = ambidextrous. Comparison of
handedness uses Fishers exact test.

Table 2. Demographics of participants without DTI

Age
Education
Sex

AVD
Mean (SD)
68.01 (8.36)
14.28 (3.00)

HC
Mean (SD)
65.59 (15.24)
14.57 (3.69)

Statistic

p-value

Z = -.230
t= .419

.818
.676

41% F (31f : 45m)

86% (25f : 4m)

X2 = 17.396

.001

Handedness
(63 R : 7 L : 1 A)
(27 R : 1 L : 1 A)
Fishers exact p = .378
Note: Based on 29 HC and 76 AVD participants with usable DTI data. Age and education
reported in years. * R = right handed, L = left handed, A = ambidextrous. Comparison of
handedness uses Fishers exact test. Comparison of age uses Mann-Whitney U-test.

T-tests were conducted within participant groups (AVD and HC) to determine if there
were systematic differences in age, sex, education, or handedness between participants who
received DTI analyses and those who did not. There were no differences between AVD
participants with and without DTI on any of the included parameters. The only significant

68

difference between HC participants with and without DTI is the sex make-up of the samples,
where those without DTI included more women (86.2%) compared to the group with DTI
(54.5%) (X2 = 6.297, df = 1, p = .012). There were no other differences between HC participants
with and without DTI on any of the included parameters.
Neuropsychological measures
SCL-90-R
The Symptom Checklist 90-Revised (SCL-90-R) (Derogatis & Melisaratos, 1983) was
used to assess psychological symptoms. The SCL-90-R is an established self-report measure that
asks participants to rate the extent to which they have been distressed by specific psychological
symptoms over the past week on a scale from 0 (not at all) to 4 (extremely). It provides an
overall severity index T-score reflecting the level of general psychological distress (Global
Severity Index) as well as T-scores for nine individual symptom domains including depression.
This measure has some detractors; for example, Clark and Friedman (1983) showed that
in a population of veterans, the SCL-90 did not have the requisite sensitivity to discriminate
between participants with major depressive disorder, clinically diagnosed anxiety disorders, and
schizophrenia. The researchers contended instead that the measure works best as an overall
indicator so psychological distress, which did vary among those three symptom groups.
However, a follow-up study by Steer, Clark, and Ranieri (1994) went on to demonstrate that
depression is still sensitively detected by the SCL-90-R after controlling for overall
psychological distress. The Depression Dimension was shown to have a strong correlation with
Beck Depression Inventory Scales after controlling for psychological distress, suggesting
convergent and discriminant validity of the Depression Dimension.

69

RBANS
The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)
(Randolph, Tierney, Mohr, & Chase, 1998) is a widely used and well-validated measure of
neuropsychological function composed of 12 subtests including List Learning, Story Memory,
Figure Copy, Line Orientation, Picture Naming, Semantic Fluency, Digit Span, Coding, List
Recall and Recognition, Story Recall, and Figure Recall. Scores from these subtests are often
collapsed into index scores of Immediate Memory, Delayed Memory, Visuospatial /
Constructional, Language, and Attention. However, for our purposes we prefer to use the scores
from the subtests individually for a purer measure of the cognitive abilities of interest. We have
used RBANS Digit Span as a measure of attention and Coding as a measure of processing speed
as supported by several studies (McKay, Casey, Wertheimer, & Fichtenberg, 2007; Randolph et
al., 1998).
RBANS Digit Span consists of a series of strings of numbers increasing in length which
are read to the participant at a steady speed and which are repeated back by the participant. This
digit span measure includes only digits repeated back in the same order they were read, while
WAIS-III Digit Span (see below) includes both digits repeated forward and backward.
RBANS Coding involves presenting the participant with a series of symbols and a key
which shows each symbol with a corresponding number (1-9). Participants are familiarized with
the key briefly and then asked to translate the symbols to their corresponding numbers as quickly
as possible during a 90 second time period. This test is scored in terms of the number of items
completed correctly within the time limit.

70

WAIS-III
The Wechsler Adult Intelligence Scale-Third Edition (WAIS-III, Copyright 1997 NCS
Pearson, Inc.) is a battery of tests including Picture Completion, Vocabulary, Digit SymbolCoding, Similarities, Block Design, Arithmetic, Matrix Reasoning, Digit Span, Information,
Picture Arrangement, Comprehension, Symbol Search, Letter-Number Sequencing, and Object
Assembly. For the purposes of the current research, WAIS-III Digit Span and Letter-Number
Sequencing have been used as measures of attention and working memory, while the WAIS-III
Digit Symbol-Coding test was used as a measure of processing speed as supported by several
studies (Gevins & Smith, 2000; Jones, Sahakian, Levy, Warburton, & Gray, 1992).
WAIS-III Digit Span consists of a series of strings of numbers increasing in length which
are read to the participant at a steady speed and which are repeated back by the participant. The
first set of number strings are to be repeated back in the same order that they were read, and the
second set of number strings are to be repeated back in reverse order.
WAIS-III Letter-Number Sequencing requires that the examinee listen to a mixture of
letters and number and then recall the numbers first in ascending order and then the letters in
alphabetical order. Each item consists of three trials and each trial is a different combination of
numbers and letters. Letter-Number Sequencing is scored in terms of correct responses for each
trial, with a total possible for each item of three points (perfect on all three trials).
WAIS-III Digit Symbol-Coding involves presenting the participant with a series of
numbers and a key which shows each number (1-9) with a corresponding symbol. Participants
are familiarized with the key briefly and then asked to translate the numbers to their
corresponding symbols as quickly as possible during a 120 second time period. This test is
scored in terms of the number of correct responses generated within the time limit.

71

WAIS-III Digit Span and Digit Symbol-Coding are included in the current analysis
because while they are similar to the versions included in the RBANS, they do have some key
differences. First, WAIS-III Digit Span is more likely to be tapping both attention and working
memory processes than the version included in RBANS because it requires that the numbers be
repeated back in reverse order. This can be much more difficult for participants and gives the
added advantage of making the test much less susceptible to ceiling effects in this studys
population of participants who are by-and-large cognitively intact. The WAIS-III Digit SymbolCoding subtest is significantly longer than the one included in RBANS and requires that
participants translate digits into symbols rather than the other way around. These differences are
large enough to justify the inclusion of both the RBANS and WAIS-III versions of these
subtests. Additionally, the Letter-Number Sequencing subtest of the WAIS-III requires the
participant to hold the stimuli in working memory and manipulate them to provide the correct
response. This subtest provides a different type of data on working memory and attention, which
significantly diversifies our coverage of the topic in the composite score.
Trail-Making Test A
During the Trail-Making Test A (Reitan, 1958), participants are asked to draw a
continuous line connecting dime-sized circles on a sheet of paper in ascending order with
reference to the numbers contained in each circle. The participants are instructed to complete this
task as quickly as possible. Then, participants are timed on their completion of this task and
scored for errors. For the purposes of the current study, time to complete Trail-Making-Test A is
used as a measure of cognitive processing speed (Blanchard et al., 2010; Sacktor et al., 2010; R.
Ylikoski et al., 1993).

72

Stroop Test: Color-Naming and Word-Reading

Two of the three constituent parts of the Stroop test (Golden, 1978) were used in the
current study. In the first condition, the participant names the colors of rectangles (red, blue, or
green) presented on a stimulus sheet. In the second, the participant reads names of those same
colors printed on a stimulus sheet in black ink.
In the color naming and word reading conditions, scoring is based on the total number of
colored blocks or words read correctly in the time allotted (45 seconds). Scores on the Stroop
color naming and word reading tests are used in the current study as measures of processing
speed as supported in the literature (Lo, Cottinghain, Aretsen, Boone, & Goldberg, 2010).
Composite measures
The previously mentioned neuropsychological tests were formed into composite scores
based on the cognitive skills. These composite scores were aimed at two primary capacities;
attention/working memory, and processing speed. These composites consist of the following:
Attention: RBANS Digit Span, WAIS-III Digit Span, WAIS-III Letter-Number
Sequencing.
Processing Speed: RBANS Coding, WAIS-III Digit Symbol-Coding, Trail-Making Test
A, Stroop Word-Reading and Color-Naming.
Imaging Measures
Participants underwent high resolution anatomical and diffusion tensor imaging using
Siemens Avanto 1.5T scanner (Erlangen, Germany). DTI data were gathered on 56 slices, slice
thickness of 2.5mm, spacing between slices of 2.5mm, in a 320mm x 320mm field of view. The
acquisition matrix is 128 x 128, using 12 directions and a b-value of 1000. TR/TE = 9500/94 ms,
flip angle is 90, pixel bandwidth is 1347Hz, and the imaging frequency is 63.623624 MHz.

73

Automated processing of the T1, T2, and FLAIR images was performed using BRAINS2
(Brain Research: Analysis of Images, Networks, and Systems) software (Magnotta et al., 2002).
It was determined that all white matter tissue should be included in the DTI analysis regardless
of whether it was categorized as lesioned or not based on T1/T2 and FLAIR image review.
This determination was based on the idea that the threshold used in the tissue classifier in
BRAINS2 to categorize white matter as lesioned (appearing gray) or not lesioned (appearing
white) is not consistent across studies and in some ways represents an arbitrary division between
healthy and unhealthy which could confound our results (as discussed in the introduction).
For this reason, manual traces of white matter lesions were generated for each participant in the
study. The traces were converted to a mask and were added to the existing white matter mask
from BRAINS2 automated workup, thus yielding a mask that included white matter and lesions.
Because of this step, all subsequent DTI analyses include both healthy-appearing and unhealthyappearing white matter for FA calculations. See Figure 10 below for an example of the white
matter + lesion mask that was used in the FA analyses.

Figure 10: White matter + lesion mask (pink) overlay on T1 images of the same brain. Left panel
shows coronal slice with white matter + lesion mask showing the extent of periventricular lesion
which was included in the analysis of white matter health. Middle and right panels show sagittal
slices to demonstrate the extent of white matter included in the mask.

74

The diffusion tensor data were first processed using GTRACT software (Cheng et al.,
2006). The diffusion tensor images were co-registered to eliminate motion. Once the images
were co-registered, diffusion tensor decomposition was performed and scalar maps including
fractional anisotropy (FA) were generated. The FA maps were then aligned with each subjects
anatomical scan. Each participants neuroimaging data were subsequently visually inspected for
quality to verify that the co-registration of DTI data to anatomical scans was appropriate, as well
as to check for artifacts such as head motion, table vibration, RF noise, and susceptibility
artifacts. Measures of FA were then obtained in each Talairach box region (see Figure 11
below) in white matter defined by the white matter plus lesion mask in voxels where the FA was
greater than 0.1.

Figure 11: Subject tissue classified image presented in axial (upper left), sagittal
(right), and coronal (lower left) views in BRAINS2 image viewer. Standard
Talairach boxes are overlaid on the brain to show fit of each box to the brain.

Because of poor coverage in the raw DTI scans, analysis of the cerebellum and brainstem
was considered unreliable and any significant findings in those regions have been excluded from

75

the results reported in the current study. Evidence of the poor coverage is presented in Figures
12 and 13 below.

Figure 12: Left panel shows AC-PC aligned, b-spline transformed FA scalar map in
subject anatomical space. Right panel shows AC-PC aligned anatomical T1 image
from corresponding slice in same participant.

Talairach box analyses presented in the current study are based on one of the most widely
used brain atlases, which used the histological data from a single participant (Talairach and
Tournoux, 1988) to define a broad range of cortical and subcortical structures. In the current
study, stereotaxic boxes based on the histological properties that define the borders of each lobe
were applied to each scan. Based on the application of the Talairach boxes, tissue can be
analyzed from any lobe or the subcortical box (which primarily includes tissue of the basal
ganglia) from either hemisphere.

76

Figure 13: Images from Figure 12 left and right panels overlaid on each
other. Note the apparent ghosting around the pons and brainstem, showing
that the brainstem in the anatomical image is poorly registered with the
brainstem in the FA scalar map.

Atlas-based analyses of Brodmann Area 25 (subgenual cingulate) utilized a combination

of manually-traced regions of interest and the Mori white matter atlas. First, a hand-tracing
protocol was developed based on existing studies of this area by McCormick et al (2005) and
Johansen-Berg et al (2008) to isolate the region of interest (Appendix 1). Traces were generated
using coronal slices in the T1 image acquisition using BRAINS2 software. Subsequently, these
traces were integrated into the pre-existing white matter atlas developed by Mori and colleagues
at Johns Hopkins University. Next, the Mori Atlas was registered to the anatomical images and
scalar maps generated by the GTRACT software and FA values were generated for BA25 ROIs
bilaterally, as well as for a variety of white matter tracts throughout the brain. Figure 14 below
shows the coverage of BA25 bilaterally achieved by its application through the Mori et al. atlas.

77

Figure 14: Overlay of Mori et al. (2005) white matter atlas on participant anatomical scan. Left
panel shows Mori label map outlines, where subgenual cingulate regions of interest are colored
peach (left) and off-white (right). Right panel shows a sagittal slice of the left hemisphere with
opaque Mori atlas label map overlay, showing the extent of the masked subgenual cingulate
region of interest (peach mass below the violet genu of the corpus callosum).

Analyses
General approach
Because of the constrained number of participants in this study and the continuous nature
of the variables, we utilized correlational analyses frequently to determine whether there were
relationships between structural variables of interest and emotional/cognitive variables of
interest. We used the standard levels for determination of statistical significance with an alpha
level < .05 for all comparisons of means and correlational analyses. Comparisons were made
across multiple brain regions, and correlations were run between cognitive variables and a
variety of brain regions, so the risk for type 1 error is somewhat elevated in the current study.
We suggest caution in interpreting the clinical relevance of results with significance values
greater than p = .01. One adjustment made for multiple comparisons in the current study was the
formation of composite scores for attention and processing speed measures, which reduced the

78

number of comparisons being made across cognitive tests and potentially reduced the type 1
error rate.
Visual inspection of the histograms of structural, emotional, and cognitive data revealed
normal distributions in all these measures. Levenes test for equality of variances during means
comparisons in the structural, emotional, and cognitive data showed all data to have nonsignificant differences in variance between groups. Because the data showed normality of
distribution and equality of variances, parametric statistical analyses were used. In this case,
students t-tests were used to compare means, and Pearson correlations were used when
analyzing the correlations of variables with each other.
We used raw scores from neuropsychological tests in order to facilitate the formation of
Z-scores and composites of the attention and processing speed variables. We analyzed the
composite scores, depression T-scores, and FA measurements for statistically significant
covariates and controlled for them accordingly. The depression dimension T-scores from the
SCL-90-R were adjusted for sex during scoring, so no further adjustment for sex was necessary
during later stages of analysis.
A somewhat uncommon analysis was used to assess the vulnerability of different cortical
regions to FA changes. We used Friedmans One-way ANOVA to rank the FA values for each
cortical region (frontal, temporal, parietal, occipital, and subcortical) within each participant
from lowest FA (ranked 1) to highest FA (ranked 5). Then the mean ranking for each cortical
region was calculated within the AVD group and the HC group. A chi-square test was
subsequently run on the mean ranks of the data to test whether that the pattern that emerged was
statistically significant.

79

Power Analyses
36 AVD and 22 HC participants were recruited and diffusion tensor scans were acquired.
All of these scans passed initial quality control for overt head motion, RF noise, table vibration,
and susceptibility artifacts. However, one AVD participants scan was later assessed to be
unsuitable for DTI analyses because of subtle warping of the brain shape in the posterior parietal
and occipital lobes. While this warping seemed to only affect the posterior portions of the brain,
we assessed that the risk inappropriate fitting of the Talairach boxes and Mori atlas to this
abnormally warped brain was too high, so the participants scan was excluded from further
analysis. The table below reflects the power available with the included participants to detect mean
differences between the two groups.

Table 3. Power analyses for means comparison

Power
0.439
0.823

AVD HC
35
22
35
22

Ratio
1.591
1.591

Alpha
0.05000
0.05000

Cohens d
0.5
0.8

For correlational analyses, we see that a sample of 35 AVD participants has 80% power to
detect a medium-to-large size effect (r = .453), and the sample of 22 healthy comparison
participants 80% power to detect a large-sized effect (r = 0.556) (see Table below).

Table 4. Power analyses for correlations

Power
0.80000
0.80000

N
22
35

Alpha
0.05000
0.05000

Beta
0.2000
0.2000

R
0.556
0.453

80

In addition, it is important to note that these analyses of power do not account for the
inclusion of any significant covariates. The inclusion of significantly associated covariates will
lend additional power to the comparisons and correlations presented in this study.
While there have not been any published studies of diffusion tensor imaging in
atherosclerotic vascular disease to date, existing reports from studies of white matter
hyperintensity severity in late-life depression suggest that our expected power will be adequate
to reveal statistically significant differences in means between groups. A meta-analysis of 24 of
these studies revealed effect sizes (Cohens d) ranging from 0.36 to 0.87 for means comparisons
between groups (Hermann, Masurier, and Ebmeier, 2008). One study of diffusion tensor imaging
reported correlations between regional anisotropy measures and processing speed in a group of
75 depressed and 23 control participants reported significant findings with correlations between r
= .26 and r = .32, suggesting that we may be slightly underpowered for correlational analysis
(Shimony et al., 2009). However, the study by Shimony and colleagues was conducted in
participants with late-life depression without any screening for vascular disease. We hypothesize
that our AVD participants may be more likely to have white matter damage and thus that the
DTI analyses will be more sensitive in this population than in the one used by Shimony and
colleagues.

81

CHAPTER IX
RESULTS
Preliminary Analyses
Reliability
Reliability was assessed prior to the recruitment of the final study sample, to assess the
feasibility of forming composite scores from attention and processing speed neuropsychological
measures, based on scores for 102 AVD and 47 HC for all tests except Stroop, in which 99AVD
and 47 HC participants were included.
Table 5: Reliability calculations for composite measures
Composite
Speed Composite

Attention Composite

Components
RBANS Coding
WAIS-III Digit Symbol-Coding
Trail-Making Test A
Stroop Color-Naming
Stroop Word-Reading
RBANS Digit Span
WAIS-III Digit Span
WAIS-III Letter-Number
Sequencing

Item-Total
Correlation
0.639
0.701
0.400
0.503
0.560
0.614
0.683

Cronbach's
Alpha
0.781

0.767

0.516

Group-wise performance on cognitive and psychiatric measures

First we characterized the performance of all the participants in the parent study on the
composite measures and their constituent tests prior to moving forward to look at correlations
between performance on these tests and brain structure. In order to form composite scores, first
we calculated means and standard deviations for 51 healthy control participants on all cognitive
variables of interest. Based on these means and standard deviations, Z-scores were calculated for
each participant on each variable of interest. The Z-scores were then inverted in cases where

82

higher scores signified worse performance (so all positive Z-scores now indicate better
performance than the mean for healthy controls). Next, performance differences between AVD
and HC participants were tested via t-tests on all the Z-scores (see Table 6 below). Finally, for
each participant, the Z-scores for each constituent measure were averaged to yield composite
scores for attention/working memory, and processing speed. Differences between AVD and HC
participants on composite scores were tested using t-tests (Table 7 below).

Table 6: Performance difference between AVD and HC participants on cognitive and

psychiatric measures
AVD Mean
HC Mean
Tests
t
DF
p
(SD)
(SD)
SCL-90-R Depression Dimension
55.18
50.67
2.466
160 .015
T-score
(11.15)
(10.06)
-.579
.000
RBANS Coding Z-score
-3.465 160 .001
(.982)
(1)
WAIS-III Digit Symbol-Coding
-.520
.000
-2.750 160 .007
Z-score
(1.170)
(1)
-.351
.000
Trail-Making Test A Z-score
-1.902 160 .059
(1.132)
(1)
.034
.000
Stroop Color-Naming Z-score
.229
156 .819
(.811)
(1)
-.011
.000
Stroop Word-Reading Z-score
-.064
156 .949
(.901)
(1)
-.104
.001
RBANS Digit Span Z-score
-.576
160 .565
(1.080)
(1)
-.199
.001
WAIS-III Digit Span Z-score
-1.273 160 .205
(.878)
(1)
WAIS-III Letter-Number
.009
.001
.050
160 .960
Sequencing Z-score
(.951)
(1)
Note: Sample sizes were 111 AVD and 51 HC for all tests except Stroop, in which 107
AVD and 51 HC participants were included. Two-tailed test of significance was used.

83

Table 7: Differences between AVD and HC participants on total composite scores

AVD Mean (SD) HC Mean (SD) t
DF
p
Attention Composite
-.100 (.814)
.005 (.837)
-.753
160
.453
Speed Composite
-.296 (.780)
.000 (659)
-2.353 160
.020
Note: All measures included 111 AVD and 51 HC participants. When participants
lacked one or more constituent tests within a composite score, the remaining tests Zscores were averaged and used as the composite score. This occurred in 6 participants,
none of whom had DTI data collected. Two-tailed tests of significance were used.

Table 8: Differences between AVD and HC participants who received DTI on cognitive
and psychiatric measures
AVD Mean
HC Mean
t
DF
p
(SD)
(SD)
SCL-90-R Depression Dimension
53.11
51.59
-.528
55
.600
T-score
(9.37)
(12.36)
-.254
-.233
RBANS Coding Z-score
.090
55
.928
(.838)
(.818)
WAIS-III Digit Symbol-Coding Z-.075
-.238
-.562
55
.576
score
(1.133)
(.939)
.042
.252
Trail-Making Test A Z-score
.981
55
.331
(.791)
(.783)
.172
.074
Stroop Color-Naming Z-score
-.391
54
.697
(.703)
(1.168)
.117
-.168
Stroop Word-Reading Z-score
-1.126
54
.265
(.704)
(1.192)
-.102
-.008
RBANS Digit Span Z-score
.281
55
.780
(1.259)
(1.182)
-.149
.035
WAIS-III Digit Span Z-score
.694
55
.491
(.798)
(1.207)
WAIS-III Letter-Number
.234
.100
-.525
54
.601
Sequencing Z-score
(.791)
(1.113)
Note: Sample sizes were 35 AVD and 22 HC for all tests except Stroop, in which 34 AVD
and 22 HC participants were included, and WAIS-III Letter-Number Sequencing which
included 21 HC and 35 AVD. Two-tailed test of significance was used.
Tests

84

Table 9: Range of SCL-90-R depression scores in AVD and HC participants who received DTI

In the AVD group, 25 participants had scores below 60, 4 participants had scores of 6064, 5 participants had scores of 65-69, and 1 participant had a score of 72. In the HC group, 18
participants had scores below 60, 1 participant had a score of 60-65, 2 participants had scores of
66-70, and 1 participant had a score of 80.
For reference, the normative mean for SCL-90-R is a T-score of 50, and the Standard
Deviation is 10. Based on the distribution of samples above 65 (1.5 standard deviations above
the normative mean, assuming this is a reasonable approximation of the threshold between

85

subsyndromal depression and Major Depressive Disorder), 6 AVD and 3 HC participants may
meet criteria for diagnosis with MDD.

Table 10: Differences between AVD participants with and without DTI on cognitive
and psychiatric measures
With DTI
Without DTI
Tests
Mean (SD)
Mean (SD)
t
DF
p
SCL-90-R Depression
53.11
56.13
1.329 109
.187
Dimension T-score
(9.37)
(11.82)
-.254
-.729
RBANS Coding Z-score
-2.422 109
.017
(.838)
(1.012)
WAIS-III Digit Symbol-.073
-.725
-2.806 109
.006
Coding Z-score
(1.133)
(1.134)
Trail-Making Test A Z.042
-.532
-2.542 109
.012
score
(.791)
(1.221)
Stroop Color-Naming Z.172
-.030
-1.197 105
.234
score
(.703)
(.854)
Stroop Word-Reading Z.117
-.070
-.997
105
.321
score
(.704)
(.979)
RBANS Digit Span Z-.102
-.104
-.009
109
.993
score
(1.259)
(.997)
WAIS-III Digit Span Z-.149
-.222
-.403
109
.687
score
(.798)
(.916)
WAIS-III Letter-Number
.234
-.095
-1.703 109
.091
Sequencing Z-score
(.791)
(1.004)
Note: Sample sizes were 76 participants without DTI and 35 participants with DTI
for all tests except Stroop, in which 73 without and 34 with DTI were included.
Two-tailed test of significance was used. No significant differences were detected
between HC participants with and without DTI.

Specific Aim 1: Structure

To compare the participants with Atherosclerotic Vascular Disease (AVD) to healthy
control participants on their regional white matter integrity, utilizing Fractional Anisotropy
values from Diffusion Tensor Imaging.
1a). Compare FA in each of the Talairach boxes between participant groups:
i) Whole cerebrum

86

ii) Frontal, temporal, parietal, occipital, subcortical regions

1b). Examine FA measures for effects of laterality, sex, age, education, and handedness.
1c). Characterize what lobe has lowest FA (most vulnerability to white matter damage)
across AVD participants only.
Hypotheses
1a). FA will be significantly lower globally and in all regional parcellations in the AVD
participants than in the healthy comparison participants.
1b). Within the AVD and HC groups, the older, less educated participants are expected
to have significantly lower FA than the younger participants. Based on existing literature,
we make no a-priori hypotheses about the effects of sex, handedness, and laterality in the
AVD participants because these effects have not yet been examined in DTI analyses in
this population to date. There is relatively weak evidence in the literature on DTI in
normal aging to suggest that women will have lower FA values than men (Hsu, Leemans,
Bai, Lee et al., 2008), but this may be due to an interaction of sex with age.
1c). Because of the observed vulnerability of the deep white matter in the frontal lobes
to ischemic damage, we expect to see the lowest FA values here in the AVD participants.

87

Table 11: Comparison of AVD to HC participants in terms of FA globally, by lobe, and by

hemisphere
Region
Cerebrum
Left
Right
Frontal
Left
Right
Temporal
Left
Right
Parietal
Left
Right
Occipital
Left
Right
Subcortical
Left
Right

Mean FA (SD)
AVD

HC

.253
(.016)
.252
(.016)
.254
(.016)
.262
(.020)
.261
(.019)
.262
(.020)
.251
(.015)
.251
(.016)
.251
(.016)
.266
(.019)
.264
(.019)
.267
(.019)
.194
(.013)
.193
(.013)
.196
(.015)
.366
(.023)
.366
(.024)
.366
(.024)

.261
(.015)
.260
(.015)
.263
(.015)
.270
(.017)
.269
(.018)
.270
(.017)
.255
(.015)
.254
(.015)
.257
(.016)
.277
(.017)
.277
(.017)
.278
(.017)
.203
(.014)
.202
(.016)
.203
(.014)
.381
(.022)
.380
(.025)
.382
(.022)

Main Effects and

Interaction Terms (p-values)
Sex

Age

Group

Sex *
Group

Age *
Group

2.015

0.548

.049

.189

.005

.007

.377

.871

1.984

0.540

.052

.194

.004

.007

.441

.681

1.983

0.540

.052

.200

.006

.008

.336

.942

-1.566

0.431

.123

.044

.015

.021

.268

.631

-1.497

0.432

.140

.039

.014

.024

.266

.540

-1.584

0.431

.119

.060

.018

.022

.282

.726

-1.077

0.267

.286

.661

.001

.097

.776

.858

-.768

0.193

.446

.569

.001

.187

.990

.799

-1.290

0.375

.202

.793

.003

.074

.610

.596

2.426

0.660

.019

.371

.020

.004

.319

.970

2.699

0.734

.009

.322

.027

.002

.356

.893

2.083

0.567

.042

.435

.019

.011

.293

.837

2.294

0.624

.026

.232

.098

.008

.758

.738

2.250

0.612

.028

.367

.108

.011

.697

.728

1.949

0.530

.056

.170

.171

.021

.817

.331

2.436

0.663

.018

.074

.411

.006

.503

.811

2.140

0.582

.037

.111

.293

.014

.598

.772

2.617

0.712

.011

.059

.592

.004

.441

.871

Note: Samples included 35 AVD and 22 HC participants. Comparison of AVD to HC in

terms of mean FA used the students T-test with a two-tailed test of significance and had 55
degrees of freedom. Cohens d presented in the table as d. Main effects and interaction
terms are calculated using univariate general linear models with each region as a dependent
variable, group (AVD vs. HC) as the fixed factor, age and sex as covariates. Interactions

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- Table 11 continued were tested in the context of the full model. Main effects were tested removing the nonsignificant interactions. R2 values for the general linear models range from .155 to .258
across all regions.

Effects of sex on FA values by group

An ANCOVA analysis was computed using frontal lobe FA as the dependent variable,
group (AVD vs. HC) as the fixed factor, and sex as a covariate. An interaction term was added to
the model, and the test of between-subjects effects showed that the model was significant (F =
2.96, p = .040), and that the interaction term of group*sex was non-significant (F = .202, p =
.655).

Table 12: Sex differences in AVD group (n = 35)

Female FA
Male FA
DF
t
p-value
mean (SD)
mean (SD)
Frontal
.254 (.021)
.267 (.017)
33
2.117
.042
Left
.253 (.021)
.267 (.016)
33
2.163
.038
Right
.254 (.021)
.268 (.018)
33
2.017
.052
Note: No significant sex differences in any other region. Analysis used a two-tailed
test of significance. Sample included 14 women and 21 men. Non-significant
correlations are presented for comparison between groups only.

Table 13: Sex differences in HC group (n = 22)

Female FA
Male FA
DF
t
p-value
mean (SD)
mean (SD)
Frontal
.266 (.015)
.275 (.019)
20
-1.276
.216
Left
.265 (.014)
.274 (.021)
20
-1.307
.206
Right
.267 (.016)
.275 (.018)
20
-1.175
.254
Note: No significant sex differences were detected in any other region. Analysis
used a two-tailed test of significance. Sample included 12 women and 10 men.
Non-significant comparisons are presented for comparison between groups only.

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Sex differences were significant in the combined AVD + HC group for the frontal lobe as
well (t = 2.163, p = .035), predominantly driven by the left hemisphere (t = 2.229, p = .030).
Effects of education on FA values by group
No significant relationships were detected between education and FA globally or in any
subregion in the AVD group. No significant relationship was detected between education and
global FA in the HC group, though significant relationships were detected in the occipital lobe (p
= .033), right occipital lobe (p = .008), and right subcortical box (p = .048).
Effects of handedness on FA values by group
Students T-tests comparing left-handers to right-handers in the AVD and HC
participants showed no significant differences in global or regional FA between the groups.
Covariate interactions
Interestingly, a significant relationship was noted between education and SCL-90 T score
in the AVD group, where more education was related to more depressive symptom endorsement
(r = .218, p = .011). This relationship was non-significant in the HC group.
Friedmans One-way ANOVA
This analysis tests for a significant pattern of FA values across cortical regions by first
ranking the FA values in each participant where the region with lowest FA is ranked 1 and the
region with highest FA is ranked 5. Mean ranks for all regions are calculated and compared to
the hypothetical distribution given the null hypothesis. The significance of the chi-square tests
suggests that the pattern of FA health in the cortical regions is significantly replicated in each
participant in the group.

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Table 14: AVD group Friedmans One-way ANOVA

Frontal
Temporal
Parietal
Occipital
Subcortical

Mean Rank
3.03
2.37
3.60
1.00
5.00

N
35
Chi-square
122.58
DF
4
Asymp. Sig.
<.001
Note: Analysis used a two-tailed test of
significance.

Table 15: HC group Friedmans One-way ANOVA

Frontal
Temporal
Parietal
Occipital
Subcortical

Mean Rank
3.18
2.09
3.73
1.00
5.00

N
22
Chi-square
82.62
DF
4
Asymp. Sig.
<.001
Note: Analysis used a two-tailed test of
significance.

Specific Aim 2: Structure-Function Relationships

To characterize the relationship of white matter integrity with depressive symptoms in
AVD participants utilizing measures from Diffusion Tensor Imaging and depressive symptom
endorsement from the Symptom Checklist 90-Revised (SCL-90-R). To further determine

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whether a region-of-interest based diffusion tensor analysis of the confluence of white matter
tracts of interest in depression (BA25) shows a relationship with depressive symptoms measured
on the SCL-90-R. The network comprised of the white matter tracts emanating from BA25
shows ipsilateral connections to the medial frontal cortex, the full extent of anterior and posterior
cingulate, medial temporal lobe, dorsal medial thalamus, hypothalamus, nucleus accumbens, and
dorsal brainstem (Gutman et al (2009).
2a). Determine the relationship of total cerebral FA and regional FA with depressive
symptoms.
Exploratory Aim: Explore the effects of laterality on this relationship.
2b). Determine the relationship of depressive symptoms to local FA inside BA 25
(average of both sides).
Exploratory Aim: Explore the relationship of depressive symptoms and FA in
BA25 by hemisphere.
2c). Determine the relationship of depressive symptoms to FA in BA25 while
controlling for FA in all cerebral white matter excluding BA25.
Hypotheses
2a). Increased depressive symptoms will be significantly related to decreased cerebral
and frontal FA values.
Exploratory Hypothesis: Increased depressive symptoms will be more strongly
related to decreased FA in the right hemisphere.
2b). Increased depressive symptoms will be significantly related to decreased FA in
BA25 bilaterally.

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Exploratory Hypothesis: Increased depressive symptoms will be more strongly

related to decreased FA in the right hemisphere.
2c). The significant relationship between FA in BA25 and depressive symptoms will
remain significant even when controlling for global FA (all cerebral white matter
excluding BA25).
Alternative approach: It is important to note that while BA25 represents a major
area of confluence for five depression-associated tracts, the tracts themselves
extend well beyond this area. Therefore, controlling for cerebral FA outside of
BA25 could result in controlling for FA in large parts of those depressionassociated tracts, which could reduce the correlation between BA25 FA and
depressive symptoms to a level of non-significance. If that occurs, we will
employ an alternative control approach. We will determine the relationship
between BA25 FA and depressive symptoms after controlling for FA in a control
region-of-interest which we do not anticipate to have a relationship with
depressive symptoms (potentially in the parietal or occipital lobes). Ideally this
control region would be comprised of tissue with similar anatomical properties
and a similar total white matter volume to the BA25 region of interest.
Relationship of global and regional FA with depressive
symptoms on the SCL-90-R
FA values defined by Talairach boxes have shown significant relationships with age,
while depression T-scores on SCL-90 have already been adjusted for sex and show no
relationship with age or education. Therefore, all partial correlations between FA and depression
T-scores are adjusted for age only.

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Table 16: Depression T-score vs. FA by lobe in AVD

group covarying for age (n = 35)
DF
r
p-value
Cerebrum
32
-.222
.208
Left
32
-.193
.274
Right
32
-.242
.167
Frontal
32
-.254
.146
Left
32
-.250
.154
Right
32
-.251
.152
Temporal
32
-.018
.917
Left
32
.028
.875
Right
32
-.054
.763
Parietal
32
-.224
.204
Left
32
-.210
.232
Right
32
-.233
.186
Occipital
32
-.025
.886
Left
32
.028
.874
Right
32
-.082
.646
Subcortical
32
-.046
.797
Left
32
.009
.960
Right
32
-.098
.580
Note: Analysis used a two-tailed test of significance.
Non-significant correlations are presented for
comparison between groups only.

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Table 17: Depression T-score vs. FA by lobe in

AVD+HC group covarying for age (n = 57)
DF
r
p-value
Cerebrum
54
-.283
.035
Left
54
-.263
.050
Right
54
-.294
.028
Frontal
54
-.261
.052
Left
54
-.253
.060
Right
54
-.262
.051
Temporal
54
-.191
.158
Left
54
-.141
.301
Right
54
-.209
.122
Parietal
54
-.320
.016
Left
54
-.301
.024
Right
54
-.330
.013
Occipital
54
-.100
.463
Left
54
-.081
.553
Right
54
-.101
.460
Subcortical
54
-.160
.240
Left
54
-.124
.363
Right
54
-.189
.163
Note: Analysis used a two-tailed test of significance.
Non-significant correlations are presented for
comparison between groups only.

Relationship of FA within Brodmann Area 25

(subgenual cingulate) with SCL-90-R depression
Bilateral Analyses
Table 18: Comparison of AVD to HC on mean FA measured in BA25
bilaterally
AVD FA
HC FA
Sample
t
p-value
Mean (SD) Mean (SD)
35 AVD, 22 HC
.270 (.045) .273 (.043)
-.245
.807
Note: Analysis used a two-tailed test of significance.

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Covariates
Preliminary analysis revealed no significant relationship between SCL-90-R depression
T-scores and age, sex, or education (p > .10 for each).
Bivariate correlation of bilateral BA25 FA and age reveals a significant relationship (r = .526, p <.001). Because of the marginal relationship of education with FA by lobe (reported in
Aim 1), we analyzed the relationship of FA in bilateral BA25 with education and detected no
significant relationship (r = .118, p = .191). Based on these relationships, we deemed it
appropriate to control for the effects of age but not education in the following correlational
analyses.
Because of concerns that the relationship of BA25 FA with depressive symptoms may be
reflecting global white matter processes (rather than a process specific to the region of interest),
we also calculated partial correlations controlling for age and FA in the contralateral BA25
region. This control structure is ideal because it includes approximately the same amount of
white matter as the region of interest in addition to having similar anatomy and similar
likelihood to reflect the effects of aging and vascular disease.

Table 19: Partial correlation between bilateral BA25

FA and depression T-scores in AVD group
covarying for age
DF
r
p-value
Bilateral BA25
32
-.122
.493
Note: Analysis used a two-tailed test of significance.

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Unilateral Analyses
Covariates
Preliminary analysis revealed no significant relationship between SCL-90-R depression
T-scores and age, sex, or education (p > .10 for each).
Bivariate correlation between FA in unilateral BA25 regions and age revealed significant
relationships (p <.001 in left and right). Because of the marginal relationship detected in Aim 1
between education and FA, we analyzed this relationship using bivariate correlations with FA
values for unilateral BA25 regions. We found no significant relationship in the right BA25, but a
significant relationship with the left (r = .251, p =.030).
Because of the possibility that any relationship detected between depressive symptoms
and FA within the region of interest may be reflecting a global white matter process rather than
one specific to the region of interest, we also calculated all correlations controlling for both age
and FA in the occipital lobe (which is assumed to be relatively unrelated to depressive symptom
manifestation).

Table 20: Partial correlation between BA25 FA and

depression T-score in AVD group controlling for age
DF
r
p-value
Left BA25 FA
32
.082
.645
Right BA25 FA
32
-.290
.096
Note: Analysis used two-tailed test of significance.

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Table 21: Partial correlation between BA25 FA and

depression T-score in AVD group controlling for age and
contralateral BA25 FA
DF
r
p-value
Left BA25 FA
31
.287
.105
Right BA25 FA
31
-.392
.024
Note: Analysis used two-tailed test of significance.

Follow-up analysis comparing BA25 FA in left and right hemispheres showed no

significant differences.

Table 22: Paired sample t-test in AVD group

Left BA25 FA
Right BA25 FA

Mean
.2734
.2657

SD
.0475
.0536

Sample
35
35

r
p
Comparison (t) Comparison p
Left vs. Right BA25 FA .594 <.001 .985
.332
Note: Analyses used two-tailed tests of significance. Left two panels are based
on Pearson correlation, right two panels are based on a students T-test.

Comparison of correlations shows relationship of right BA25 FA with SCL-90

depression to be significantly stronger than left BA25FA with SCL-90 depression.

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Table 23: Z-test for the significance of differences between two correlation
coefficients (using correlation of BA25 FA with SCL-90 depression adjusted
for age)
Z
p (two-tailed)
Left vs. Right BA25 FA
2.310
.021
Source: Meng, X.L., Rosenthal, R., & Rubin, D.B. (1992) Comparing
Correlated Correlation Coefficients. Psychological Bulletin, 111(1), 172-175.

Specific Aim 3: Structure-Function Relationships

To characterize the relationship of attention and processing speed measures with white
matter integrity as measured by Fractional Anisotropy measures from Diffusion Tensor Imaging
3a). Correlate cerebral and regional FA with composite scores on:
i). Attention/Working Memory: RBANS Digit Span, WAIS-III Digit Span and
Letter-Number Sequencing.
ii). Processing Speed: RBANS Coding, Trail-Making Test A, Stroop Word
Reading and Color Naming, WAIS Digit Symbol-Coding.
Exploratory Aim: Examine effects of laterality on this relationship.
3b). Examine the effects of depressive symptoms on attention and processing speed
variables.
Hypotheses
3a). Lower cerebral FA will be significantly related to poorer performance on attention
and processing speed measures.
3b). The relationship of attention and processing speed to FA will weaken to a level of
non-significance when controlled for the effects of depressive symptoms.

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Relationship of global and regional FA with composite

scores of attention and processing speed
Preliminary analysis showed that the attention composite has significant correlations with
age and education (p = .003; p = .018 respectively), while speed shows significant correlations
with age, education and sex (p = .008; p = .029; p = .001 respectively). FA values by lobe show
significant relationships with age (as demonstrated in Aim 1). Therefore, when correlating
attention with FA values, we controlled for age and education. When correlating speed with FA
we controlled for age, education, and sex. In order to test the hypothesis that attention and
processing speed dysfunction in vascular disease is an outcome of depressive symptom
manifestation, partial correlations were also calculated controlling for the covariates stipulated
above in addition to SCL-90-R depression T-score.

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Attention
Table 24: Attention composite score vs. FA by lobe in AVD group covarying for age and
education
DF
r
p-value
Cerebrum
31
.303
.087
Left
31
.336
.056
Right
31
.263
.140
Frontal
31
.318
.071
Left
31
.349
.046
Right
31
.280
.115
Temporal
31
-.056
.758
Left
31
-.035
.845
Right
31
-.070
.699
Parietal
31
.376
.031
Left
31
.393
.024
Right
31
.348
.047
Occipital
31
.145
.422
Left
31
.102
.572
Right
31
.165
.360
Subcortical
31
.272
.126
Left
31
.284
.109
Right
31
.248
.165
Note: Analysis used a two-tailed test of significance. Non-significant correlations are
presented for comparison between groups only.

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Table 25: Attention composite score vs. FA boxes in AVD group covarying for age,
education, and SCL-90-R depression T score
DF
r
p value
Cerebrum
30
.299
.096
Left
30
.333
.062
Right
30
.258
.153
Frontal
30
.316
.078
Left
30
.348
.051
Right
30
.276
.126
Temporal
30
-.057
.758
Left
30
-.034
.853
Right
30
-.073
.692
Parietal
30
.375
.034
Left
30
.392
.027
Right
30
.347
.052
Occipital
30
.144
.433
Left
30
.104
.571
Right
30
.161
.378
Subcortical
30
.270
.135
Left
30
.285
.113
Right
30
.244
.178
Note: Analysis used a two-tailed test of significance. Non-significant correlations are
presented for comparison between groups only.

Speed
Analysis of the processing speed composite revealed no significant relationships with FA
by lobe and hemisphere. There were no significant relationships detected during the bivariate
correlation of those two variables in the AVD group.
Follow-up analysis was conducted using only WAIS-III coding as the index of speed.
WAIS-III coding and FA by lobe and hemisphere showed non-significant relationships in
bivariate correlation as well as in partial correlation controlled for age, sex, and education in the
AVD group.

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Specific Aim 4: Voxel-Based Morphometry

Follow-up whole-brain analyses using voxel-based morphometry techniques did not
reveal anything beyond the findings reported from the lobe-wise and global FA analyses.

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CHAPTER X
DISCUSSION
Summary of critical findings
Structural differences were found between AVD and HC participants on global and select
subregional FA measures, which were further analyzed to characterize significant effects of sex
and aging on FA values in each group. The overall landscape of FA values in the brain was then
described for each group using Friedmans one-way ANOVA, which showed that AVD and HC
participants showed the same pattern of FA values across lobes, where the occipital lobe
consistently had the lowest FA, followed by the temporal, frontal, and parietal lobes, and the
subcortical white matter consistently showed the highest FA values.
Significant relationships of FA with depressive symptoms were characterized in global
and subregional FA measures, which were found to be significant only in the combined AVD +
HC group. A significant relationship between FA in Brodmann Area 25 in the right hemisphere
and SCL-90-R depression T-score was observed in the AVD group, when controlled for age and
FA in the contralateral BA25 region. Follow-up analysis revealed this relationship to be specific
to the right hemisphere.
Significant relationships of FA globally and lobe-wise with attention composite scores
were found in the AVD group. When controlled for SCL-90-R depression T-score, these
relationships remained significant. Findings from global and lobe-wise analysis were
corroborated by the findings from the voxel-based morphometry analysis.
An equivocal relationship of FA globally and regionally with processing speed was
observed in both participant groups. These relationships remained non-significant when analyzed

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in the AVD and HC groups combined, when covaried for depressive symptom endorsement, and
when analyzed using only one processing speed index rather than the composite score.
The voxel-based morphometry analysis served to replicate the findings from the global
and lobe-wise analyses of depression, attention and processing speed.
All significant results will be discussed and contextualized with regards to the current
literature in the paragraphs to follow.
Cognitive and emotional findings
The most significant differences between AVD and HC participants in the parent study
were in RBANS Coding and WAIS-III Digit-Symbol Coding (p =.001 and p = .007 respectively)
and in the SCL-90-R Depression scale T-score (p = .015). This trend is interesting in that while
there were very strong relationships identified later between attention measures and FA value,
these relationships do not appear to be specific to the AVD condition. In addition, while there
were strong and significant differences between AVD and HC participants on processing speed
measures, these did not translate into relationships with white matter health that were detectable
in global and lobe-wise analysis. AVD participants have been previously shown to have mean
RBANS Attention index scores of 95.68 (SD = 13.97, 39th percentile) and mean SCL-90-R
Depression scale T-scores of 56.06 (SD = 9.67, 73rd percentile) (Moser et al., 2004). The current
analysis adds to the previously reported literature by including a control group of age-matched
healthy older adults, and by reporting on composite scores of attention and processing speed.
Follow-up analysis comparing the parent study participants to the subgroup who received
DTI scans revealed interesting results. First, the comparison of AVD and HC participants with
DTI scans on the attention, processing speed, and depression measures used in the study
revealed no significant group-wise differences (p < .30 for each), which we interpret to be

105

related to the smaller sample with lower power included in the DTI analysis. However, we
suggest that this lack of significant difference biases our analysis toward the null hypothesis,
rather than increasing the risk of finding spurious significant relationships. Second, comparison
of HC participants with and without DTI scans showed no differences on any measures of
attention, processing speed, or depression (p < .12 for each). Comparison of AVD participants
with and without DTI scans showed no differences in attention or depression measures (p < .09
for each), but significant differences in RBANS Coding, WAIS-III Digit-Symbol Coding, and
TMT-A time (p = .017, p = .006, and p =.012 respectively), where participants who received
DTI scans performed significantly better than those without scans. We suggest that the
recruitment bias toward AVD participants with better processing speed and less depressive
symptoms receiving DTI scans may partially explain the lack of significant correlations we were
able to detect between these variables and FA values in the global and lobe-wise analyses.
Structural findings
The comparison of AVD and HC participants on global and lobe-wise FA shows subtle
differences between groups (whole cerebrum, parietal, occipital, and subcortical), though the
frontal and temporal lobes did not show significant group-wise differences. Follow-up analysis
showed a significant main effect of group (AVD vs. HC) in all regions except the temporal
lobes.
DTI analyses of the differences between AVD and HC participants on white matter
health have never been previously reported, though to some extent they could be inferred from
the studies of white matter lesions and hyperintensities in vascular disease. Raz and colleagues
(2007) showed that at 5-year follow-up, the white matter hyperintensity volume (affecting
predominantly the frontal lobes at both time points) more than doubled in vascular disease

106

participants but not in healthy control participants. In addition, Hoth et al. (2007) showed that
the extent of endothelial dysfunction likely drives the formation of white matter hyperintensities
in atherosclerotic vascular disease. Interestingly, even though the current analysis included white
matter lesions in the analyses of white matter health via FA measurements, the differences
between groups were still equivocal in the temporal lobes. Our best guess for why these lobes
did not yield significant differences between groups is related to the pattern of white matter
damage that is commonly noted in studies of normal aging. The anterior portion of the brain is
reported to be adversely affected by advancing age at a much higher level than the rest of the
brain, which could be significantly reducing our ability to detect significant inter-group
differences in FA. Further analyses of white matter health at longitudinal follow-up should help
clarify these issues.
Global and lobe-wise analysis showed a significant main effect of sex in the frontal
lobes, which appears to have been driven by the left hemisphere. While the interaction test was
non-significant, there was an interesting relationship between lower FA in the frontal lobes and
female sex in the AVD group, which was not found to be statistically significant in the HC
group. This finding may not be specific to vascular disease, but it suggests that frontal lobe white
matter may be particularly vulnerable to the effects of aging in women. In corroboration of that
point, the relationship becomes more significant when including both the AVD and HC groups
in the analysis. This may suggest issues of sample size and power in the HC group, or that the
combination of groups provided a wider range of FA values within which to detect the sex
difference.
Reports on sex differences in DTI measures have been mixed. Oh and colleagues (2007)
reported that men had significantly higher FA than women in a global measure of corpus

107

callosum, while women had significantly higher FA than men in the rostrum, genu, and splenium
of the corpus callosum. A voxel-based morphometry analysis (Haut et al., 2007) revealed small
regions of significant FA difference between men and women where men had higher FA (see
Figure 15 below), primarily affecting frontal and parietal white matter. However, reports of nonsignificant differences between sexes have also been made (Abe, 2002; Sullivan, 2001). The
possible reasons for these inconsistencies include differences in sample sizes, DTI
methodologies, and the possibility that other demographic characteristics are more strongly
related to FA than sex.

Figure 15: Areas (red) of significantly higher FA in men than women.

Background is smoothed average of all FA volumes. Figure adapted
from Haut et al., 2007.

In the current analysis, the main effect of age was significant in the global measure of FA
as well as in the frontal, temporal, and parietal lobes. The test of interaction between age and
group (AVD and HC) was non-significant, suggesting that the relationship of lower FA with
older age was not specific to either the AVD or healthy control conditions. The significant

108

relationship of lower FA with older age is an established finding, but it underscores the necessity
to adequately control for the effects of age in studies of white matter health.
As reviewed by Buckner (2004), while declines in FA values are observable in all
regions of the brain, the largest age-related changes in white matter health are observed in the
frontal lobes and anterior corpus callosum (Pfefferbaum et al., 2000, OSullivan et al., 2001,
Sullivan et al., 2001; Nusbaum et al., 2001; Head et al., 2004; Madden et al., 2004; Abe et al,
2002; OSullivan et al., 2004; Pfefferbaum and Sullivan, 2003; Charlton et al., 2006; Grieve et
al., 2007). These patterns of longitudinal FA change have been taken to indicate an anteriorposterior gradient of white matter degeneration in aging.

Figure 16: Anterior (Frontal) white matter shows preferential vulnerability to the
effects of aging. (Left) Regional DTI measures of anterior and posterior callosal
tracts plotted for young (black bars) and non-demented old (gray bars) adults.
Significant effects are detected in anterior but not posterior regions. Data adapted
from OSullivan et al. (2001). (Right) A map of white matter integrity plotted as a
direct comparison of old and young adults. Brighter colors illustrate areas of
greatest difference between groups, and preferential degeneration of anterior
white matter structures is clearly observed. Data adapted from Head et al. (2004),
Figure adapted from Buckner (2004).

109

Given that our participants are older adults with vascular disease, we predicted that the
region with the lowest FA would be the frontal lobes. Our correlational analysis between age and
FA by lobe showed significant relationships of lower FA values in older healthy control
participants wherein the most significant finding was detected in the frontal lobe. However, in
the AVD participant group we found that the temporal lobe produced the most significant
relationship between FA and age. Longitudinal follow-up analysis will be necessary to
demonstrate the rate of degeneration across the lobes.
White matter abnormalities are associated with poor processing speed, executive
functioning, immediate and delayed memory in the context of normal aging. The preferential
loss of white matter integrity in the prefrontal cortex is thought to underlie a loss of connectivity
between the prefrontal cortex and the hippocampus and striatum. Damage to this network is
consistent with the pattern of neuropsychological deficits most often noted in older age:
difficulty encoding new memory, abnormal working memory, executive dysfunction, and
processing speed impairments (see Hedden 2011 for a review). In addition, a study of interhemispheric transfer demonstrates that participants with lower FA in the corpus callosum have
slower interhemispheric processing speed (Schulte et al., 2005).
Findings from Friedmans One-way ANOVA in both groups characterizes a standard
landscape of FA values which systematically differs across Talairach-defined regions, with
lowest FA being in the occipital lobes in every participant in both groups (AVD mean = .1943,
SD = .0128; HC mean = .2027, SD = .0142), while the highest FA was found to be in the
subcortical box in every participant in both groups (AVD mean = .3659, SD = .0234; HC mean =
.3811, SD = .0225). Interestingly, the pattern does not seem to differ between AVD and HC

110

participants, suggesting that underlying regional differences in structure may exert a stronger
effect on FA than any vascular disease process.
Because of the inherent difficulties with image registration and masking with DTI data,
our first thought was to check that the white matter mask and DTI data overlay on the anatomical
image to exclude the possibility that this pattern was the result of registration error or
abnormalities in the mask. After the validity of the registration and masking were confirmed, a
follow-up analysis was run on DTI data that excluded the white matter lesions, based on the idea
that perhaps there were regional differences in lesion burden which were driving this pattern of
FA values across regions. However, the exact same pattern emerged from the follow-up analysis
as well. Based on these internal validity checks, we believe the findings represent real
anatomical differences in FA across regions, especially due to our use of a DTI-based scalar
value (FA), which is relatively resistant to the effects of noise in the image.
There has been a great deal of variability in the literature with regards to the regional
landscape of FA values, as well as in the absolute values of the regional mean FA values. Head
et al. (2004), reported that no regional pattern was detected but all the absolute values for mean
FA by region ranged between .21 and .26. By contrast, in Taylor et al. (2004), the FA of an oval
ROI placed in the left occipital lobe white matter was reported to be 0.408 in a group of
depressed elders and 0.416 in an elderly healthy control group. One explanation for the
variability in absolute values reported could be differences in DTI methodologies or participant
populations being reported, where Head et al. (2004) used different sized regions of interest
manually placed in white matter tracts in each lobe in healthy older adults, while Taylor et al.
(2004) used oval ROIs of matching sizes in their regions of interest in participants with late-life
depression. The same general regional landscape of FA values as the one identified by the

111

current study was reported by Grieve et al. (2007), wherein the global average FA was 0.320 +
0.017, the occipital lobe had the lowest FA (0.268 + 0.017) and parietal lobe had the highest FA
(0.324 + 0.020) (the subcortical box was not reported).
An additional unexpected relationship was noted between education level and depression
in the current study. It was noted that in the AVD participant group, more education was related
to elevated depressive symptom endorsement on the SCL-90. In addition, age was noted to be
positively correlated with education in both participant groups, which is unusual given the age
range of participants involved. While these relationships were somewhat bizarre and
unanticipated, we suggest that the covariate structures used in the current analyses have
adequately controlled for these effects of education.
Depression findings
No significant relationships between SCL-90-R depression T-scores and FA values were
detected in any of the global or lobe-wise analyses in the AVD participants. However, the
restricted range of FA values in the AVD group may have limited the power of the analyses to
detect significant correlations. A follow-up analysis looking at the correlation of global and lobewise FA with SCL-90-R depression T-scores in all participants (including both AVD and HC
participants) revealed significant relationships in the whole cerebrum as well as in the frontal,
temporal, and parietal lobes. In all cases, correlations are in the expected direction, where higher
(healthier) FA values are related to lower (healthier) SCL-90-R depression scores.
In addition, a significant relationship between FA in BA25 and depression was observed
in the AVD participants. Importantly, this finding appears to be unique to the right hemisphere
because the finding remains significant when controlled for FA in the contralateral BA25 region
in addition to controlling for the effects of age. Ostensibly, this covariate structure controls for

112

the contributions of global white matter health to depressive symptom variability. It was
important to choose a control region that did included a similar volume of white matter as the
region of interest, as well as one that had similar anatomical properties. The directionality of the
finding suggests that participants with healthier white matter in BA25 are less likely to endorse
of depressive symptoms on the SCL-90-R, which is consistent with the Vascular Depression
hypothesis (Alexopoulos 1997; Krishnan 1997) as well as the hypotheses set out in this study.
There was an unexpected laterality effect where the significant relationship between BA25 FA
and depression only appeared on the right side. Follow-up analysis showed that the relationship
of right hemisphere BA25 FA was not reflecting gross differences between left and right on
absolute FA values, but rather that the white matter integrity of BA25 may be more important
for depressive symptom manifestation than the integrity of the region on the left side. .
The findings that global and regional FA values correlate with depressive symptoms is
taken as support for the hypothesis that white matter health in the tracts underlying a network of
depression-associated structures significantly contributes to the function or dysfunction of the
network. As such, we would anticipate relationships between FA in other network-associated
structures and depressive symptoms in addition to the relationship in BA25 noted in the current
study. Many regions have been implicated in this network, as described by Mayberg (2003) in
the Limbic-cortical model of depression. In that model, it is proposed that depression is
unlikely to arise from the dysfunction of a single brain region or neurotransmitter system, but
rather it is better conceptualized as a multidimensional, systems-level disorder affecting discrete
and functionally integrated pathways.
The regions implicated in the network have been studied in a variety of contexts,
including depression with concomitant neurological disease, primary depression, likelihood to

113

recover from depression, likelihood of various treatments to be effective, and efficacy of deep
brain stimulation in the region to cause remission of depressive symptoms in patients whose
depression has been treatment refractory (Ketter et al., 1996; Mayberg, 1994; Baxter et al., 1989;
Bench et al., 1992; Malone et al., 2009; Jimenez et al., 2005; Sartorius et al., 2010; Bewernick et
al., 2010; Pardo et al., 2008; Lozano et al., 2008, Hamani et al., 2009; Kennedy et al., 2011).
Based on the studies of the network structures mentioned above, the limbic-cortical
circuit is hypothesized to include cortical sites such as the medial and ventral prefrontal and
parietal cortices, limbic and paralimbic structures including the amygdala, insula, cingulate,
hippocampus and subcortical structures such as the striatum, thalamus, hypothalamus, and
brainstem as depicted in Figure 17.
Importantly, improvement in depressive symptoms is seen to correlate most commonly
with increases in blood flow in the prefrontal cortical regions (Brodmann areas 9 and 46) and
with blood flow decreases in the subgenual cingulate (Brodmann area 25) in participants being
treated for major depressive disorder (see Figure 18 below). Additionally, evidence from patients
undergoing limbic leucotomy to alleviate treatment-refractory major depressive disorder
suggests that the disruption of afferent and efferent pathways in the subgenual cingulate is
related to the improvement of depressive symptoms (Kelly & Mitchell-Heggs, 1973).
The applicability of the limbic-cortical network to participants with major depressive
disorder was tested by Seminowicz and colleagues in 2004, where they applied a seven-region
model of depression including lateral prefrontal cortex (BA 9), anterior thalamus, anterior
cingulate (BA 24), subgenual cingulate (BA 25), orbitofrontal cortex (BA 11), hippocampus, and
medial frontal cortex (BA 10), based on PET data using Structural Equation Modeling.

Imaging neuroscience: clinical frontiers for diagnosis and management

114

Plate XI Limbic-cortical dysregulation model. Regions with known anatomical interconnections2729, that also show
synchronized changes using PET in 3 behavioural states base-line depressed (unipolar and Parkinsons disease patients),
post-treatment
(medication, cognitivedysregulation
therapy, placebo, model.
surgery), and
transientincluded
induced sadness
(controls,
patients, have
Figure
17: Limbic-cortical
Regions
in this
schematic
neurotics) form the basis of this schematic. Failure of this regional network is hypothesized to explain the combination
known
anatomical interconnections and synchronized changes using PET in three
of clinical symptoms seen in depressed patients (i.e. mood, motor, cognitive, vegetative). Regions are grouped into 3 main
behavioral
states:(blue),
baseline
depression,
post-treatment,
and transient
induced
sadness.
compartments, cortical
limbic (red)
and subcortical
(green). The frontal-limbic
(dorsal-ventral)
segregation
additionally
identifies
those
brain
regions
where
an
inverse
relationship
is
seen
across
the
different
PET
paradigms.
Regions are grouped into three main compartments, cortical (blue), limbic (red), and
Sadness and depressive illness are both associated with decreases in dorsal neocortical regions and relative increases in
subcortical
(green).
The The
model
proposes
that
remission
occurs
when the
ventral limbic and
paralimbic areas.
model, in
turn, proposes
that illness
illness remission
occurs when
there is appropriate
modulation
of
dysfunctional
limbic-cortical
interactions
(solid
black
arrows)

an
effect
facilitated
by
various
forms of by
dysfunctional limbic-cortical interactions are modulated appropriately (either
treatment. It is further postulated that initial modulation of unique subcortical targets by specific treatments facilitates
medication,
placebo, cognitive therapy, or surgery). Abbreviations: mF, medial
adaptive changes in particular pathways necessary for network homeostasis and resulting clinical recovery. Dorsal medial
prefrontal;
dF, anterior
prefrontal;
pm,
premotor;
aCg,
anterior
cingulate;
frontal (mF9), rostral
cingulate
(rCg24)
and medial par,
orbitalparietal;
frontal cortex
(oF11)dorsal
are separated
from their
respective
compartments
in the model
highlightcingulate;
their critical primary
within and
between levels
in
pCg,
posterior
cingulate;
rCg,torostral
thal, interactions
thalamus;both
bstem,
brainstem;
mOF,
the integration self-referential, emotionally salient, exogenous stimuli relevant to reward, punishment and learning in
medial
cortex;
Cg25,
subgenual
Hth,
hypothalamus;
Hc,
the healthyorbitofrontal
and depressed state.
Abbreviations:
mF, medial
prefrontal;cingulate;
dF, prefrontal; pm,
premotor;
par, parietal; aCg,
dorsal
anterior
cingulate;
pCg,
posterior
cingulate;
rCg,
rostral
cingulate;
thal,
thalamus;
bstem,
brainstem;
mOF,
medial
hippocampus; a-ins, anterior insula, amyg, amygdala; p-ins, posterior insula. Numbers
orbital frontal; Cg25, subgenual cingulate; Hth, hypothamus; Hc, hippocampus; a-ins, anterior insula; amyg, amygdala; pare
Brodmann
Figure
adapted from Mayberg et al., 2003.
ins, posterior
insula.designations.
Numbers are Brodmann
designations.

The model was stable in three separate groups of depressed patients at different institutions.
Limbic-cortical connections between BA9 - BA25 - BA11 - hippocampus differentiated
treatment responders from non-responders. Nonresponders also showed abnormalities in a
*208

British Medical Bulletin 2003;65

limbic-subcortical path (anterior thalamus - BA24 - BA25 - BA11 - hippocampus). The network
was further elaborated by Gutman et al (2009), where probabilistic tractography showed

115

ipsilateral connections of BA25 to the medial frontal cortex, the full extent of anterior and
posterior cingulate, medial temporal lobe, dorsal medial thalamus, hypothalamus, nucleus
accumbens, and dorsal brainstem using a 1.5T scanner with 60 directions. This study provided
convincing further evidence that BA 25 functions as a physical white matter hub among many
cortical and subcortical areas involved in the depression network.
Our choice to focus on BA 25 as the region of interest in the study of depressive
symptoms in the current study was based on the preponderance of evidence implicating the
white matter tracts converging there with depressive symptom manifestation. For example,
decreases in blood flow or glucose metabolism in the region are noted in response to various
interventions, and elevated blood flow is noted in depressed or transiently sad participants
compared to healthy controls, as depicted in Figure 18 below.
The finding that depressive symptoms were significantly related to BA 25 FA in the right
hemisphere but not the left could be related to subtle differences between the ROIs in terms of
volume of white matter included, inter-participant variability in gyral and sulcal structure in this
region, or inherent differences in white matter structure between right and left hemispheres.
Previous studies have demonstrated that the right frontal lobe has a more regular organization of
axons than the left frontal lobe in both children and adults (p = .0001, paired t-test) (Klingberg et
al., 1999), as estimated by comparing the direction of the primary eigenvector of one voxel to the
primary eigenvectors of its eight neighboring voxels. However, in the study by Klingberg and
colleagues, a significant difference between the right and left hemispheres FA (p = .0004) was
also noted with higher values in the right than left. In the current study, there was no difference
between right and left hemisphere BA 25 FA, suggesting that perhaps the difference in relation
to depressive symptoms is related to real functional differences between the hemispheres.

116
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Figure 18: Converging evidence implicating BA 25 in Major Depressive disorder.

(A-E) Common pattern of change in glucose metabolism or blood flow in
response to treatment. Images reflect group changes relative to depressed baseline
depressive state. (F-J) Images demonstrate elevated resting state activity in
various participants with treatment-refractory Major Depressive Disorder
compared to healthy controls. (F) Elevated metabolic activity in cognitive
behavioral therapy + venlafaxine non-responders compared to healthy controls
and treatment responders. (G) Elevated resting-state fMRI in pharmaceutical
therapy non-responders compared to healthy controls. (H) Baseline metabolic
activity in patients who did not respond to cingulotomy compared to those who
did
respond.
(I)
Treatment-refractory
patients
prior
tomaladaptive
receiving
deep proexplicit cognitions,
affective
bias, and
information
serotonin
reuptake
inhibitor
(SSRI)
fluoxetine were differentiateddepression
by theirbrain
pattern of
glucose metabolism
observed
six weeks afterto
the healthy
cessing, all
of which are(J)
putatively
localized
to orbital,
medial fronstimulation
surgery
compared
controls.
Blood
flow
increases
initiation of therapy, with clinical improvement associated with tal, prefrontal, and anterior cingulate regions of the cortex (82, 83).
in healthy control participants asked to recall a personal sad memory. Red
limbic-paralimbic and striatal decreases and dorsal cortical increase Imaging studies examining brain changes following interpersonal
indicates
activity
(white
arrows),
and blue
decreased
activity
in glucose
metabolism.increased
Failed response
was associated
with persispsychotherapy
andindicates
CBT report substantial
regional
effects most
tence of the pattern of glucose metabolism observed one week after prominently decreased glucose metabolism and blood flow in the
(black
arrows).
Image
and
caption
adapted
from
Mayberg
et
al.,
2009.
the initiation of therapy (when the same pattern was seen in both prefrontal cortex (62, 71, 84, 85), but with differential nonfrontal

groups) and absence of either SCC (specifically BA25) or prefrontal cortex changes depending on the specific therapeutic intervention
cortex changes. This combination of reciprocal dorsal cortical and employed. For example, using CBT, remission was associated with
ventral limbic changes appears to be a common pattern in individ- not only prefrontal cortex changes but also decreased metabolism
uals that respond to treatment with SSRIs (72), placebo medication in posterior cingulate, dorsomedial frontal, and orbital frontal cor(79), and combination serotonin-norepinephrine reuptake inhibi- tices as well as increased metabolism in anterior mid-cingulate cortors (SNRIs) (62). The change in the glucose metabolism pattern in tex and parahippocampal regions (71). This CBT-specific change
only those
patients who
clinical improvement
suggests
a pattern
was generally
in a follow-up,
Findings
in showed
the current
depression
literature
suggest
that replicated
the finding
in therandomized
right study
process of neural plasticity or adaptation in specific brain regions comparing treatment with CBT and the SNRI venlafaxine (62).
with chronic treatment. These responder-nonresponder differences Interestingly, this second study identified both a common decrease
are also consistent
time
course and location
of changes multiple
in dorsomedial
frontal
cortical
activity with that
both treatments
hemisphere
maywith
notthebe
spurious.
For example,
studies
have
contended
patients as
identified in animal studies of antidepressant medications, which well as reciprocal changes in subgenual cingulate cortex activity
emphasize early brainstem and hippocampal changes and late (increased with CBT, decreased, as seen previously, with medicawith
stroke
damage
to the left
hemisphere
tend totion),
develop
more severe
than
patients
cortical
effects,
involving presynaptic
autoregulatory
desensitizafurther suggesting
a criticaldepression
role for this region
in mediating
tion, up- and downregulation of multiple postsynaptic receptor remission from depression across treatments.
sites, and receptor-mediated second messenger and neurotrophic
with
strokesignaling
damage
to (80,
the81).
right hemisphere, but that
the patients with right hemisphere strokes
intracellular
effects
$SJUJDBM
SPMF
GPS
UIF
4$$
Psychotherapy. In contrast to pharmacological treatments, CBT is Among the series of treatment studies surveyed, the involvement
thought to retrain brain activity by modifying attention and mem- of the SCC is especially prominent (Figure 3, AE). Not only do
tended
to present
more consistentchanges
with in
a this
non-dysphoric
type
region appear criticalor
forsubsyndromal
antidepressant response
ory functions
involvedwith
in thesymptoms
mediation of depression-relevant
The Journal of Clinical Investigation
http://www.jci.org
Volume 119
Number 4
April 2009
of 
depression, including
apathy and poor emotional
awareness
(Gainotti,
1972; Ross and Rush,

1981; Robinson et al., 1984; see Pearlson and Robinson, 1982 for a review). This

117

characterization of depressive symptoms with right hemisphere damage makes sense given that
the participants in the current study were not patients of major depressive disorder, and given
that we elected to measure depressive symptoms using a dimensional approach rather than a
dichotomous depressed or non-depressed characterization. The current study is not the first
to look at changes in brain structure or activity in the case of subthreshold depressive symptoms.
For example, Zald and colleagues (2002) showed that brain activity in the ventromedial
prefrontal cortex is correlated with differences in post-hoc self report of negative affect periods,
in which participants were asked to report rate how many negative affect mood states they had
experienced in the past month.
In corroboration of the laterality effect in our data, Taylor et al., (2004) found a
significant relationship of superior frontal gyrus white matter FA in the right hemisphere with
depressive symptoms in late-life depression patients, despite a non-significant relationship in the
left hemisphere. The study by Taylor et al was similar to the current analysis in that they
controlled for age and occipital lobe FA in order to demonstrate the regional specificity of their
findings. Right-lateralized findings have also been described in terms of hypometabolism in PET
studies of depressed patients and those experiencing transient sadness or the suppression of
sadness (Baxter et al., 1989; Mayberg 1997; Mayberg et al., 1999; Levesque et al., 2003).
We propose that in the context of participants with white matter damage (as is seen in
vascular disease and normal aging), the neural correlate of depressive symptoms is a
disconnection of the limbic-cortical mood regulatory structures (Mayberg, 2003; Seminowicz et
al., 2004). This proposition stands opposed to the proposed neural abnormality underlying
depressive symptom development in younger participants and those without vascular disease.
Mayberg and colleagues found that by implanting an electrode in the region and down-regulating

118

the firing rate of the neurons entering and leaving the region, depressive symptoms resolve in
60% of patients with treatment refractory depression, suggesting that in those participants, the
problem was over-activity of the network. We suggest that the current finding lends credence to
the idea that the network dysfunction in depression is not necessarily related to being hyperactive as opposed to normal, but instead that the network is either firing in the correct range of
frequencies, or at an abnormal rate (where abnormal can be defined as either hyper-active or
hypo-active). The current findings represent the first evidence that damage to this region is
significantly related to depressive symptoms. If the problem were simply that the network was
hyperactive, one would expect that lesions in this region could help to down-regulate the activity
of the network, potentially resulting in less severe or frequent depressive symptoms than
observed in participants with healthy white matter in the area.
An additional point about the depressive network needs to be acknowledged; the network
is made up of cortical and subcortical regions, which include both excitatory and inhibitory
neurons (see Figure 19 for an extremely simplified summary). Thus there are several ways in
which the activity of the network can be altered, including changes in physical connection,
activity of individual neurons and regions, and changes in the balance between excitatory and
inhibitory inputs. For example, in the current study we hypothesize that the observed depressive
symptoms may be related to a decrease in the number of axons reaching their target structures
due to mechanical white matter damage. However, a similar phenotype might be observed in
participants whose neuronal inputs fire at a hypoactive frequency or in those who have an upregulation of inhibitory interneuron firing in the network.

119

Figure 19: Simplified neural circuitry of depression. The schematic

depicts the inhibitory and excitatory neural circuitry underlying
depression, including connections between the hippocampus and
prefrontal cortex (PFC), which are hypothesized to underlie the cognitive
aspects of depression including the ideational symptom domain (guilt,
worthlessness, doom, hopelessness, suicidality), as well as the memory
impairments classically associated with depression. Research has more
recently turned to the study of several subcortical structures such as the
nucleus accumbens (NAc), amygdala, and hypothalamus, which have
been implicated in reward, motivation, and fear. In addition to these
critically involved brain regions, the schematic also includes
neurotransmitter support from the locus coeruleus (LC), raphe nucleus
(DR) which provide norepinephrine and serotonin respectively to all
regions in the schematic. In addition, the ventral tegmental area (VTA)
provides dopaminergic support to the NAc, amygdala, PFC, and other
limbic structures. Figure and caption adapted from Nestler et al., 2002).

The hypothesis advanced above, based on the neural network underlying the
manifestation of depressive symptoms, is not meant to bypass or minimize the critical
contributions of genetics, early childhood experiences, hormonal abnormalities, and stress to the

120

development of depressive symptoms in the participants in our study. Instead, we hope to that
future studies will allow these variables to be included in the network construct at the level of
their effects on the brain. One excellent example is a study done in 2009 by Choi and
colleagues, which compared healthy young adults who had experienced parental verbal abuse in
childhood and those who experienced no parental verbal abuse in terms of FA values. Group
differences were found in the left arcuate fasciculus, left cingulum bundle near posterior tail of
hippocampus, and left body of fornix. These changes suggest that early childhood experiences
may affect the health of white matter tracts associated with depression and language
development. However, we advise caution in interpreting these results because the study
included no mechanism to assess differences in depression history between abused and nonabused participants.
It is likely that future analyses of the proposed limbic-cortical network will need to take
myriad genetic and non-genetic factors into account. Epidemiologic studies show roughly 4050% of risk for depression is genetic (Sanders, 1999; Fava and Kendler, 2000). Effects of stress,
emotional trauma, viral infections, random processes during brain development have also shown
significant relationships with the development of depressive symptoms (Akiskal, 2000; Fava and
Kendler, 2000; see Nestler et al., 2002 for a review).
In particular, the hippocampus and the hypothalamic-pituitary-adrenal (HPA) axis appear
to be critically involved in the development of depression. Briefly, neurons in paraventricular
nucleus of the hypothalamus excrete corticotropin-releasing factor (CRF), which stimulates the
synthesis and release of adrenocorticotropin from the anterior pituitary, which stimulates the
synthesis and release of glucocorticoids from the adrenal cortex. This process is controlled by
several pathways including the hippocampus (inhibitory) and amygdala (excitatory). The whole

121

process is relatively circular in that glucocorticoids regulate hippocampal and paraventricular

hypothalamic neurons but also provide feedback to regulate the HPA axis. These glucocorticoids
get elevated during prolonged and severe stress, which can damage hippocampal neurons
(especially CA3 pyramidal cells). In addition, stress and hypercortisolemia have been shown to
reduce the rate of neurogenesis in the granular cell layer of the adult hippocampal dentate gyrus
(Sheline, 1999; Bremner, 2000). This process may underlie the memory impairment noted in
depression. Damage to the hippocampus potentially also underlies the reduction of inhibitory
control the hippocampus exerts on the HPA axis, thus exacerbating the issue of elevated
glucocorticoids. Treatment with selective serotonin reuptake inhibitors has been shown to
reverse these effects. It is important to note the overlap in behaviors between the stress response
and depression, which includes increased arousal and vigilance, decreased appetite and sexual
behavior, and elevated heart rate and blood pressure (Arborelius, 1999; Holsboer; 2001). The
proposal is that the hyperactive HPA axis may contribute to depression by inducing
hypercortisolism and enhancing CRF transmission in the hypothalamus and other brain regions
innervated by these neurons.
Furthermore, the release of excessive glucocorticoids can alter the expression of
neurotrophic factors, which are critical for neuronal growth and differentiation. Excess
glucocorticoids can cause reduced expression of brain-derived neurotrophic factor (BDNF) via
interference with the CREB transcriptional mechanism. The hypothesized mechanism is that a
deficiency in neurotrophic support may lead to hippocampal pathology in depression
pathogenesis, and reversal of the deficiency by antidepressant treatments may contribute to their
efficacy.

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In the current study, the choice to study depressive symptoms in participants with
vascular disease was made due to the significant interaction of depressive brain changes with
vascular health and vice versa. However, the causality in the relationship of vascular disease
with depression remains unclear. While there is a convergence of evidence that depressive
symptoms can arise from white matter changes in the brain caused by hypoperfusion participants
with vascular disease, there is also a preponderance of evidence suggesting that depression can
cause cardiovascular abnormalities as well. For example, Musselmann and colleagues (1998)
review the evidence that HPA axis dysregulation can induce hypercholesterolemia,
hypertriglyceridemia and hypertension (all of which are known to induce atherosclerosis).
Excessive release of glucocorticoids is also known to cause injury to vascular endothelial cells
(Bjorkerud, 1973) and intima (Nahas et al., 1958; Valigorsky, 1969; Kemper, Baggenstoss, and
Slocumb, 1957), and cause inhibition of normal healing (Ross and Harker, 1976). In addition,
sympathoadrenal dysregulation has been proposed as a critical intermediary between depression
and vascular disease. Hypersecretion of norepinephrine (NE) in depression has been documented
in terms of elevated plasma NE and NE metabolite concentrations (Wyatt et al., 1971; Louis,
Doyle, and Anavekar, 1975; Roy et al., 1988; Veith et al., 1994). Depressed patients show higher
basal plasma concentrations of NE, and this sympathoadrenal hyperactivity contributes to
cardiovascular disease via effects NE on the heart, vessels, and platelets. Furthermore,
psychological stress has been shown to induce an enhanced platelet response (Markovitz, 1991),
which may trigger adverse coronary artery ischemic events. Platelets interact with subendothelial
components of damaged vessel walls and plasma coagulation factors to produce atherosclerosis,
thrombosis, and acute coronary syndromes. Circulating catecholamines bind with adrenergic,
serotonergic, and dopaminergic receptors on platelets, initiating platelet responses such as

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secretion and aggregation. The platelet activation effect may be triggered by depression, as
evidenced by the finding that depressed participants show enhanced baseline platelet activation
and responsiveness compared to normal controls (Musselman et al., 1996; Laghrissi-Thode et
al., 1997).
Attention findings
Significant relationships were found globally and in a variety of brain regions (frontal,
temporal, parietal, and occipital) with attention composite scores in the AVD group, which were
in the expected direction where higher FA was correlated with better attention functioning. We
hypothesized that the relationship between FA and attention could be driven by depressive
symptom manifestation in the sample, but when partial correlations controlling for significant
covariates and depressive score were run, nearly all the significant correlations remained
significant.
Numerous studies have examined the relationship of attention with FA measures from
DTI. All of the studies identified in the current literature review appear to have been conducted
in conditions with known effects on DTI measures, including schizophrenia (Kubicki et al.,
2003), attention deficit hyperactivity disorder (Ashtari et al., 2005), breast cancer after
chemotherapy treatment (Deprez et al., 2011), major depressive disorder (Schermuly et al.,
2010), and aging (Charlton et al., 2006; Deary et al., 2006; Grieve et al., 2007). The studies in
these participant populations have included a variety of neuropsychological indices of attention
and working memory such as the Bourdon-Wiersma dot cancellation test, computerized versions
of digit-span and trail-making tests, Wisconsin Card Sorting Task, Digit-Span Backward from
the WMS-III, Letter-Number Sequencing from the WAIS-III, and a divided attention task.
Findings from these studies have been consistent with those generated by the current analysis, in

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that a wide variety of brain regions have shown significant correlations with attentional function
or dysfunction. The findings that are most applicable to the current study were generated by
Charlton et al., who found that FA in manually generated regions of interest in the centrum
semiovale (the dorsal core of white matter in the frontal and parietal lobes) bilaterally was
significantly correlated with performance on the Digit Span Backwards test from the WMS-III
and Letter-Number Sequencing from the WAIS-III. Another study that used similar
neuropsychological measures to those currently reported was Deary et al., (2006), who reported
significant correlations between FA in the centrum semiovale and performance on LetterNumber sequencing and verbal fluency subtests. Other studies reveal different patterns of
positively correlated FA values, including the parietal portion of the superior longitudinal
fasciculus correlated with dot cancellation, left cingulum correlated with the Wisconsin Card
Sorting Test, and the negative finding that FA in the frontal, temporal, parietal, and occipital
lobes (whole-lobe ROIs) were not related to computerized digit span performance. Finally, the
VBM comparison of children with ADHD to healthy control children revealed significantly
lower FA in the ADHD participants in the right premotor area, right striatum, right cerebral
peduncle, left cerebellum and left parieto-occipital area compared to control children.
The neural circuitry underlying attention function has been relatively thoroughly
elucidated by the current neuroimaging methodologies. Posner et al. (2006) contend that specific
networks have shown involvement with three primary attentional functions: alerting, orienting to
sensory stimuli, and executive control of attention (see Figure 20).

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Figure 20: Cortical areas involved in three attention networks. The alerting
network (squares) includes thalamic and cortical sites, which are implicated in the
brains noradrenergic system. The orienting network (circles) includes
predominantly parietal sites, and the executive network (triangles) includes the
anterior cingulate and other frontal cortical areas. Figure and caption adapted
from Posner et al. (2006).

Alertness, which includes acquiring and maintaining the alert state, appears to begin with
activation of the locus coeruleus, the source of norepinephrine in the brain. Alertness depends
heavily on the function of the right hemisphere, based on the finding that of lesions to the right
hemisphere profound difficulty in responding to unexpected targets (Posner and Petersen 1990).
By comparison, response to warning signals seems to be influenced more strongly by the left
hemisphere (Coull et al., 2000; Fan et al., 2005). Orienting to sensory events is hypothesized to
arise from activation in the frontal eye fields in conjunction with superior and inferior parietal
areas, working as the cortical hubs of the network. Additionally, some studies have implicated
the pulvinar of the thalamus and the superior colliculus in this network. Executive control over
attention is thought to involve activations of the anterior cingulate gyrus and lateral prefrontal

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areas (see Posner et al., 2006 for a review). Based on these patterns of cortical involvement with
attentional function, the current data are interpreted to suggest that all three attention systems
were involved with performance on the measures included in the attention composite score:
RBANS Digit-Span, WAIS-III Digit-Span, and WAIS-III Letter-Number Sequencing. These
tasks require that the participant remain alert and focused on the task, which would require both
the alerting and executive networks. While the tasks used to measure attention did not include
visual stimuli (excluding the involvement of the frontal eye fields), participants needed to remain
attentive and oriented to the task at hand, which may have implicated the rest of the orienting
network suggested by Posner and colleagues.
The interplay between depressive symptoms and attention function are important to
identify because ADHD and MDD co-occur between 9-37% of cases of ADHD (Biederman,
1998; Downey et al., 1997), possibly due to overlapping brain regions which are thought to be
involved in both disorders.
The relationship of depressive symptoms with attentional dysfunction has been studied
most eloquently by Armengol and colleagues in 2003, who found that comorbidity of depression
and ADHD in college students was related to elevated omission and commission errors in the
continuous performance task in both the cued and uncued conditions, compared to students with
ADHD without comorbid depression. Furthermore, Schermuly et al. (2010) demonstrated that
FA in the middle anterior and middle posterior cingulum bundle (left only) was significantly
associated with the performance of a divided attention task in participants with major depressive
disorder. In view of the finding that cingulum fibers are significantly connected with cingulate,
dorsolateral, and dorsomedial prefrontal cortices (Croxson et al., 2005), the finding by

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Schermuly and colleagues is taken to suggest that a disconnection within the limbic-cortical
depression networks may underlie attentional problems in major depression.
Processing speed findings
Surprisingly, there were no relationships identified between the processing speed
composite and FA globally or by lobe in either group under any covariance structure. We
completed follow-up analysis using only one processing speed measure (WAIS-III Coding) and
again no significant relationships were found.
FA relationships with processing speed have been widely variable across studies. Such
variation is likely due to methodological differences among studies including the
neuropsychological measure used, covariate structures, strength of DTI data, and parameters of
VBM analyses used. As with the studies of attention, the existing literature on relationships of
FA to processing speed have been conducted in a variety of participant populations including
women treated with chemotherapy for breast cancer (Abraham et al., 2008; Deprez et al., 2011),
patients with multiple sclerosis (Rovaris et al., 2002), and participants experiencing normal
aging (Madden et al., 2004; Tuch et al., 2005; Deary et al., 2006; Charlton et al., 2006).
Tuch and colleagues (2005) note that behavioral reaction time (often measured in terms
of choice reaction time or CRT) is a widely-used measure of processing speed, and in their
sample, CRT was found to have significant positive correlations with FA in small segments of
projection and association fibers in the temporal, parietal and occipital lobes (right optic
radiation, posterior thalamus, and medial precuneus, left superior temporal sulcus and parietal
operculum). The pattern of lateralization of the findings suggested specialization of the effect for
the right visual and parietal pathways, which are understood to be critical mediators of
visuospatial attention. A direct relationship between FA in the anterior limb of the internal

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capsule and shorter response time was further noted in a visual target detection task (Madden et
al., 2004). In 2006, Deary and colleagues found that FA in the centrum semiovale correlated
with two of three information processing measures administered to older adults. In particular,
significant relationships were found between simple and choice reaction time measures and FA.
Additionally, a significant relationship was found in women who had been treated with
chemotherapy for breast cancer, where FA in the genu, but not the splenium of the corpus
callosum, had a significant correlation with performance on the Digit-Symbol modalities test
(Abraham et al., 2008).
Finally, there are several examples of non-significant relationships between processing
speed and measures of FA in the literature (Rovaris et al., 2002; Charlton et al., 2006; Deary et
al., 2006). Rovaris and colleagues computed mean diffusivity and FA measures in normalappearing white and gray matter as well as within lesions from multiple sclerosis, and discovered
non-significant correlations of these FA measures with performance on the Symbol-Digit
Modalities Test, despite significant relationships with diffusivity measures from the same
regions. Later, Charlton and colleagues found that a composite measure of processing speed
including the WAIS-R Digit-Symbol test was not significantly correlated with FA in any region
when controlled for age. They did find significant relationships with attention composite score
and FA, following the same pattern of results as those identified in the current study. Deary et al.
(2006) found that in addition to significant relationships between FA in centrum semiovale with
two measures of processing speed, there were non-significant relationships of simple and choice
reaction time as well as inspection time on a two-alternative forced-choice task with FA in the
frontal and parieto-occipital regions, a non-significant relationship of FA in the centrum

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semiovale with inspection time, and non-significant relationships of frontal and parieto-occipital
white matter with performance on the Symbol-Digit Modality Test.
A VBM analysis of the correlations between processing speed measures and FA scalar
maps from a 3T scanning protocol found regions of significant correlation, predominantly in the
parietal and temporal lobes (Deprez et al., 2011) in women treated with chemotherapy for breast
cancer. In particular, time to complete the Trail-Making Test part A (TMT-A) was directly
correlated with voxel clusters in the parietal lobe, while performance on the WAIS-III DigitSymbol test was directly correlated with a cluster of voxels in the temporal lobe within the
superior and inferior longitudinal fasciculi. Interestingly, an inverse relationship was also
identified between TMT-A time and FA in the cingulum bundle.
Based on the mixed findings of relationships between processing speed and white matter
FA in the literature, we interpret our non-significant findings in the global and lobe-wise
regional FA analysis to mean that the regions which are likely to be strongly involved in
processing speed may be too small to emerge in analyses of larger regions of interest.
Alternatively, the relationship of white matter health with processing speed may be more subtle
than the current study is powered to detect, in which case a follow-up analysis including a
greater number of participants could help clarify our findings.
VBM findings
In general, the findings from the current VBM analysis are seen to corroborate the
findings reported from the global and lobe-wise FA analyses. It appears that relationships
between depressive symptoms and FA may be too subtle or nuanced to be readily identified by a
VBM analysis, though follow-up studies could improve on the current study by adding control
mechanisms for significant covariates like age or vascular disease burden. The VBM findings on

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attention seem to corroborate the strong relationships with FA that were identified in the global
and lobe-wise analyses, wherein it was apparent that attentional function was largely dependent
on healthy white matter in the frontal, parietal, and temporal lobes. We find that the significant
regions identified in the correlation with processing speed were likely too small to influence the
FA of their entire region, but they were identified in the VBM analysis. Careful follow-up
analysis is necessary to exclude the possibility that these findings are related to demographic or
medical covariates.
Limitations and Future Directions
As with any research study, there are significant limitations to be reported with the
current project, which range from specific aspects of the DTI method used in the current study to
global concerns about the meaning of DTI data in general.
Because of the constrained number of participants in the current study, the subtlety of the
relationships between brain structure and function, and the fact that comparisons were made
across multiple brain regions, we suggest caution in interpreting the clinical relevance of results
with significance values greater than p = .01. Future studies employing larger samples are
needed to clarify the clinical significance of the relationships reported here.
One would be remiss to ignore the short-comings of DTI data generated by a 1.5T
scanner using only 12 diffusion sensitizing gradients. The current data have been generated as a
product of a long-term study, which has been ongoing since 2003. As such, the DTI method
which was perfectly state-of-the-art at the beginning of the study has since become antiquated
and even archaic by comparison to the common 3T and 7T DTI protocols used today. That being
said, the use of a lower magnetic strength and fewer gradient directions is not likely to produce
spurious significant findings, but rather would be likely to produce non-significant findings

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because of a lack of spatial sensitivity and low signal-to-noise ratio. The fact that regional and
global findings were detectable in this somewhat constrained sample suggests that it is possible
with further study using a stronger DTI protocol to maximize the signal-to-noise ratio, stronger
relationships with better spatial resolution may be obtained. In addition, it is likely that the health
of white matter in the brainstem and/or cerebellum have relationships with depressive symptoms
as well as attention and processing speed, though they could not be measured in the current
analysis for technical reasons. In future analyses, thorough and accurate imaging of these regions
is needed to characterize the role these regions play in the emotional and cognitive processes we
have reported in the current study.
The laterality effect in the study of BA25 FA relative to depressive symptoms could be
related to subtle differences in coverage between the left and right subgenual cingulate cortex or
the inclusion of different absolute volumes of white matter on either side. However, this
difference would be small and is not expected to explain the fact that FA was significantly
related to depressive symptoms in the right hemisphere but not in the left. Future analyses will
be needed to further test the reliability of the BA25 segmentation protocol used in the current
study, and to compare the results produced by applying the ROI via a standardized atlas to what
would be seen if the region were manually traced in each participant based on landmarks.
Future investigations of DTI parameters relative to depressive symptoms should plan to
use better psychiatric measures, such as the Beck Depression Inventory, the MontgomeryAsberg Depression Rating Scale, the Hamilton Depression Scale, or the Structured Clinical
Interview for the diagnosis of Depression from the DSM-IV. While the SCL-90 is an adequate
index of depressive symptoms, it would be very helpful to be able to break down the symptoms
into their constituent domains such as vegetative, ideational, and emotive. By focusing on

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specific subsections of the depressive syndrome, it may be possible to detect relationships

between specific types of depressive symptoms and FA in associated white matter tracts. In
addition, it is important to note that the majority of the depression literature reported here comes
from analyses of participants with diagnosed Major Depressive Disorder, though on average
neither the AVD nor the HC participants showed an elevated depressive burden (AVD average
T-scores = 53.11, HC average T-scores = 51.59). We hypothesize that depression exists on a
spectrum ranging from mild or subsyndromal symptoms up to clinically intractable Major
Depressive Disorder; however, it is possible that subsyndromal depression is mediated by a
different neural substrate entirely and that the Major Depressive Disorder research is not
applicable to the current research.
It will be critical for future analyses to complete longitudinal follow-up on the matters
investigated in the current study, especially the finding in depression. It remains completely
unknown how subthreshold depressive symptoms evolve over time in participants with vascular
disease, and the comparison between AVD and HC participants longitudinally would go a long
way toward clarifying these relationships. Longitudinal analysis would also be critical to
demonstrate which regions of the brain are most susceptible to white matter degeneration across
the lifespan. In addition, it may become critical to include measures of premorbid IQ as
covariates in studies of FA with cognition because of a reported relationship of FA with IQ at
age 11 (Deary et al., 2006).
There have been many questions raised about the validity of interpreting DTI data in
terms of anisotropy within voxels, where the questions mainly focused on the cellular structure
of the brain and implications for water diffusivity. For example, FA has been reported to be
reduced in edema, demyelination, gliosis, and inflammation, and under those circumstances it is

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difficult to describe the exact contribution of any particular cellular aspect (such as myelin
integrity) to FA because so many other factors can contribute to the signal (Assaf and Pasternak,
2008). Diffusion tensor imaging also makes several assumptions about the type of data it is
applied to which may not necessarily be accurate. For example, the method assumes that the
diffusion of water molecules follows a Gaussian distribution, but this may not be true in
compartmentalized and diffusion-restricted regions (like white matter). In addition, DTI analysis
assumes it is appropriate to characterize an entire voxel with a single diffusion tensor, which
may not be accurate because within each voxel are tens of thousands of axons and glial cells
which are unlikely to form a single, unified structure. This can be especially problematic at
tissue interfaces where a voxel may contain multiple types of tissue, such as gray and white or
white and CSF, or at branching points where two or more fiber tracts may converge or cross
within a single voxel. With increased magnetic strengths used for DTI data acquisition, it may be
possible to gain greater spatial sensitivity by reducing the voxel size, which could address these
problems to some degree.
Future analyses of the neural networks underlying depressive symptoms, attention, and
processing speed will need to include data across a variety of methodologies. One approach to
studying connectivity uses fMRI to study the time course of activations and correlations among
areas of activity. In response to the relatively long time course involved in the BOLD response
measured by fMRI, temporal connections between brain areas can also be measured using
electrical or magnetic signals such as EEG or ERP. These methods in conjunction with DTI
analyses of structural connectivity will be able to shed further light on the specific interactions of
neural networks underlying these complex cognitive and emotional processes.

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An additional limitation must be raised about the participants recruited to the AVD
group. While medically they resemble a normal sample of participants with atherosclerotic
vascular disease, they vary from the average population in terms of their willingness and interest
to participate in research, their education level, their ethnicity, and the fact that all are under
close medical care. These issues are inherent recruiting biases that occur due to the geographical
location of the study and the pragmatics of enrolling participants who have been identified as
potential research participants via their recent contact with a cardiologist. Future studies
including participants with AVD would do well to use alternative enrollment strategies to
maximize their sampling of a more diverse group of participants.
Conclusions and implications
The current research has served to characterize the differences in white matter health
between healthy older adults and their age-matched counterparts with atherosclerotic vascular
disease. Findings of diffuse differences in white matter health between the two groups may help
explain the observed neuropsychological deficits in participants with atherosclerosis. These
findings may be of further use in motivating clinical patients with atherosclerotic vascular
disease to seek out appropriate treatments or interventions to reverse these effects. Significant
relationships of global and regional white matter health with depression, attention, and
processing speed have been further characterized in both healthy older adults and participants
with atherosclerosis. These relationships are important to consider because they arise in people
without overt stroke or damage to the gray matter and cortical structures. These findings
corroborate the sentiment that white matter health is critical for the effective function of neural
networks, some of which have been outlined in the above discussion and some of which have yet
to be identified. The finding that depressive symptoms are significantly related to lower FA in

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BA25 on the right side is novel in several ways. It is the first report that impaired connectivity in
BA25 region is related to elevated depressive symptoms, since reports to date have been focused
on treating hyperactivity of the network converging on the region. Second, the finding helps
shed some light on laterality effects in depression, in that the health of BA25 white matter on the
right side may be uniquely important for depressive symptom manifestation in older adults with
vascular disease. The BA25 finding may help inform participant recruitment strategies for deep
brain stimulation studies in major depressive disorder. Currently, DBS results in improvement or
remission from depressive symptoms in approximately 60% of cases. Depression is considered
to be a multi-factorial disorder with different causes and etiologies in different cases, which
likely correspond to different sensitivities to treatment protocols. It is possible that patients with
comorbid major depressive disorder and vascular disease are unlikely to respond to deep brain
stimulation treatment, and that by excluding these patients from DBS studies, some of the
variation in response could be reduced. In addition, the targeting of BA25 in DBS in patients
with vascular disease could be informed by the current findings, which suggest that the right
hemisphere may be a better target than the left.

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APPENDIX A
SUBGENUAL CINGULATE TRACING PROTOCOL
Introduction
The region to be traced in the current protocol will include all cingulate gyrus material below
the corpus callosum from the beginning of the corpus callosum anteriorly until the most
posterior limit of the paraterminal gyrus. There are two distinct subregions included in this trace,
which will be called subcallosal and subgenual for the purpose of this protocol (Figure A1).
Both subregions appear to have relationships with depressive symptom manifestation, as well as
having white matter outputs to cortical and subcortical regions of interest for depression. For
more information on these two subregions and how they will be handled in the protocol, please
see the note on subgenual and subcallosal region definition at the end.

Figure A1: Figure adapted from McCormick et al. (2006)

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Tracing Protocol
The anterior and posterior boundary definitions are directly taken from those laid out by
McCormick et al. (2006). The rules for tracing each individual coronal slice were adapted from
McCormick et al. (2006) in that the current protocol is trying to isolate white matter in these
regions, where McCormick and colleagues were seeking to analyze volumes of gray matter. As
such, new rules had to be generated to stipulate the amount of underlying white matter to be
included in the traces. I decided to use a system of cross-referencing with other views and gross
anatomical land-marking to generate a reproducible protocol for the inclusion of a fixed amount
of subgenual white matter.
Anterior and Posterior boundary definitions
1). Most anterior trace should be on the coronal slice after the first one in which the corpus
callosum is seen to join the two hemispheres together.
2). Most posterior coronal slice should be when the white matter tissue below the basal ganglia
appears to fade away or become dilute with gray matter. This is the ending of the paraterminal
gyrus.
3). The division between the subcallosal and subgenual compartments of the cingulate should be
made in the first coronal slice in which the putamen becomes visible.
Tracing per Coronal Slice
1). Define the superior boundary of the trace by cross-referencing to the sagittal view to be sure
the corpus callosum white matter fibers are excluded in the first five slices to the left and right of
the mid-sagittal plane. After the fifth slice, trace directly over to the medial wall of the ventricle.
2). Trace down the wall of the ventricle and in more posterior slices and include the globus
pallidus in this line. Continue inferiorly until you reach the most inferior point of the ventricle
(in more anterior slices) or the globus pallidus (in more posterior slices).
3). Drop a line straight down from the most inferior point of the ventricle/GP, to the level of the
cingulate sulcus. Trace medially (including all white matter underlying cingulate gray) to the
medial limit of the brain (should be gray matter).
4). Connect the lower medial line to the top, where the trace began.

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Figure A2: Example traces in coronal and sagittal view. Note that small yellow x marks on
vertical crosshairs indicate where the red trace intersects with the sagittal plane shown. Tracing
is careful to exclude corpus callosum fibers on superior aspect and straight gyrus fibers on
inferior aspect.
Cross-referencing points
1). Generate surface views for each hemisphere individually to help define the ventral border of
the trace and to settle any issues arising from atypical paracingulate gyrus morphology. Be sure
that any gyral tissue included in a trace becomes cingulate as it travels anteriorly (rather than
becoming medial frontal gyrus). Using the surface view is especially helpful because it can be
rotated in any direction to yield a more sophisticated view of the mid-sagittal sulcal and gyral
morphometry than what is available in the regular sagittal view in Brains2.

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Figure A3: Example of surface view with all region of interest traces overlaid in
purple. This view is used to verify that the traces exclude all corpus callosum and
non-cingulate material on the ventral border.

A note on Subgenual vs. Subcallosal region definition

Helen Mayberg (Emory) and Wayne Drevets (Oklahoma) disagree about which portion
of the anterior cingulate gyrus below the genu is most important for depressive symptom
manifestation. Drevets appears to favor the more anterior portion, in this protocol termed
subcallosal, which begins at the front of the corpus callosum and continues posteriorly to the
level of the putamen. Mayberg tends to favor the literal Brodmann Area 25, which is termed
subgenual for the purposes of this protocol and which starts when the putamen becomes
apparent in the coronal slices and continues posteriorly until the end of the paraterminal gyrus. A
tractography study of these regions and the rostral anterior cingulate was completed in 2008 by
Johansen-Berg and colleagues (a group affiliated with Mayberg). This study showed that the
patients who received effective deep brain stimulation for depression had their electrodes placed
close to the border between the two areas (subcallosal and subgenual). Additionally, the study
showed that both regions were likely to have strong connections with the orbitofrontal cortex,
fornix, medial temporal lobe in the vicinity of the amygdala and anterior hippocampus. Because
it is unclear which sub-region of the ACC is most important for depressive symptoms, I have
chosen to include both in the trace. This way we can look at the relationship of the entire region
with depressive symptoms and then compare the two subregions as necessary.

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Sources
Fornito, A., et al. (2006). The influence of sulcal variability on morphometry of the human
anterior cingulate and paracingulate cortex. NeuroImage, 33, 843-854.
Johansen-Berg, H. et al. (2008). Anatomical Connectivity of the Subgenual Cingulate Region
Targeted with Deep Brain Stimulation for Treatment-Resistant Depression. Cerebral Cortex, 18,
1374-1383.
McCormick, L.M., Ziebell, S., Nopoulos, P., Cassell, M., Andreasen, N.C., Brumm, M. (2006).
Anterior cingulate cortex: an MRI-based parcellation method. NeuroImage, 32, 1167-1175.
Personal Communications with Michael Brumm and Laurie McCormick.

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Appendix B
Individual Depression Scale Items from the
Symptom Checklist 90 Revised
Participant instructions: Blacken the circle that best describes how much each problem
has distressed or bothered you during the past 7 days including today. Circles indicate 0 = not at
all, 1 = a little bit, 2 = moderately, 3 = quite a bit, 4 = extremely.

Item 5- Loss of sexual interest or pleasure

Item 14- Feeling low in energy or slowed down
Item 15- Thoughts of ending your life
Item 20- Crying easily
Item 22- Feelings of being trapped or caught
Item 26- Blaming yourself for things
Item 29- Feeling lonely
Item 30- Feeling blue
Item 31- Worrying too much about things
Item 32- Feeling no interest in things
Item 54- Feeling hopeless about the future
Item 71- Feeling everything is an effort
Item 79- Feelings of worthlessness.

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REFERENCES
Abe, O., Aoki, S., Hayashi, N., Yamada, H., Kunimatsu, A., Mori, H., et al. (2002). Normal
aging in the central nervous system: Quantitative MR diffusion-tensor analysis.
Neurobiology of Aging, 23(3), 433-441.
Abraham, J., Haut, M. W., Moran, M. T., Filburn, S., Lemiuex, S., & Kuwabara, H. (2008).
Adjuvant chemotherapy for breast cancer: Effects on cerebral white matter seen in
diffusion tensor imaging. Clinical Breast Cancer, 8(1), 88-91.
Aizenstein, H. J., Butters, M. A., Figurski, J. L., Stenger, V. A., Reynolds, C. F., & Carter, C.
S. (2005). Prefrontal and striatal activation during sequence learning in geriatric
depression. Biological Psychiatry, 58(4), 290-296.
Akiskal, H. S. (2000). Mood disorders: Introduction and overview. In B. J. Sadock, & V. A.
Sadock (Eds.), Comprehensive textbook of psychiatry (pp. 1284-1298). New York:
Lippincott, Williams, & Wilkins.
Albert, M. S. (1997). The ageing brain: Normal and abnormal memory. Philosophical
Transactions of the Royal Society of London Series B-Biological Sciences,
352(1362), 1703-1709.
Alexander, G. E., DeLong, M. R., & Strick, P. L. (1986). Parallel organization of
functionally segregated circuits linking basal ganglia and cortex. Annual Review of
Neuroscience, 9, 357-381.
Alexopoulos, G. S. (1995). Methodology of treatment studies in geriatric depression.
American Journal of Geriatric Psychiatry, 3(4), 280-289.
Alexopoulos, G. S. (2002). Frontostriatal and limbic dysfunction in late-life depression.
American Journal of Geriatric Psychiatry, 10(6), 687-695.
Alexopoulos, G. S., Meyers, B. S., Young, R. C., Abrams, R. C., & Shamolan, C. A. (1988).
Brain changes in geriatric depression. International Journal of Geriatric Psychiatry,
3(3), 157-161.
Alexopoulos, G. S., Meyers, B. S., Young, R. C., Campbell, S., Silbersweig, D., & Charlson,
M. (1997). 'Vascular depression' hypothesis. Archives of General Psychiatry, 54(10),
915-922.
Alexopoulos, G. S., Meyers, B. S., Young, R. C., Mattis, S., & Kakuma, T. (1993). The
course of geriatric depression with "reversible dementia": A controlled study. The
American Journal of Psychiatry, 150(11), 1693-1699.
Alexopoulos, G. S., Murphy, C. F., Gunning-Dixon, F. M., Latoussakis, V., Kanellopoulos,
D., Klimstra, S., et al. (2008). Microstructural white matter abnormalities and
remission of geriatric depression. The American Journal of Psychiatry, 165(2), 238244.

143

Alexopoulos, G. S., Young, R. C., & Meyers, B. S. (1993). Geriatric depression: Age of
onset and dementia. Biological Psychiatry, 34(3), 141-145.
Alexopoulos, G. S., Young, R. C., & Shindledecker, R. D. (1992). Brain computed
tomography findings in geriatric depression and primary degenerative dementia.
Biological Psychiatry, 31(6), 591-599.
Arborelius, L., Owens, M. J., Plotsky, P. M., & Nemeroff, C. B. (1999). The role of
corticotropin-releasing factor in depression and anxiety disorders. Journal of
Endocrinology, 160(1), 1-12.
Armengol, C. G. (2003). Effect of co-morbid depression on continuous performance test
(CPT) tasks in college students with attention deficit hyperactivity disorder
(ADHD). Revista Espaola De Neuropsicologa, 5(1), 33-48.
Ashburner, J., & Friston, K. J. (2000). Voxel-based morphometry - the methods.
NeuroImage, 11(6), 805-821.
Ashtari, M., Kumra, S., Bhaskar, S. L., Clarke, T., Thaden, E., Cervellione, K. L., et al.
(2005). Attention-deficit/hyperactivity disorder: A preliminary diffusion tensor
imaging study. Biological Psychiatry, 57(5), 448-455.
Assaf, Y., & Pasternak, O. (2008). Diffusion tensor imaging (DTI)-based white matter
mapping in brain research: A review. Journal of Molecular Neuroscience, 34(1), 5161.
Astrom, M., Adolfson, R., & Asplund, K. (1993). Major depression in stroke patients: A
three-year longitudinal study. Stroke, 24, 976-982.
Astrom, K. E., & Stoner, G. L. (1990). Asymptomatic progressive multifocal
leukoencephalopathy with early lesions discovered at autopsy. Journal of
Neuropathology and Experimental Neurology, 49(3), 302-302.
Awad, I. A., Spetzler, R. F., Hodak, J. A., Awad, C. A., & Carey, R. (1986). Incidental
subcortical lesions identified on magnetic-resonance-imaging in the elderly (1)
correlation with age and cerebrovascular risk-factors. Stroke, 17(6), 1084-1089.
Bae, J. N., MacFall, J. R., Krishnan, K. R. R., Payne, M. E., Steffens, D. C., & Taylor, W. D.
(2006). Dorsolateral prefrontal cortex and anterior cingulate cortex white matter
alterations in late-life depression. Biological Psychiatry, 60(12), 1356-1363.
Ballmaier, M., Toga, A. W., Blanton, R. E., Sowell, E. R., Lavretsky, H., Peterson, J., et al.
(2004). Anterior cingulate, gyrus rectus, and orbitofrontal abnormalities in elderly
depressed patients: An MRI-based parcellation of the prefrontal cortex. American
Journal of Psychiatry, 161(1), 99-108.
Barnes, D. E., Alexopoulos, G. S., Lopez, O. L., Williamson, J. D., & Yaffe, K. (2006).
Depressive symptoms, vascular disease, and mild cognitive impairment: Findings
from the cardiovascular health study. Archives of General Psychiatry, 63(3), 273

144

Baron, M., Mendlewicz, J., & Klotz, J. (1981). Age-of-onset and genetic transmission in
affective-disorders. Acta Psychiatrica Scandinavica, 64(5), 373-380.
Basser, P. J., Mattiello, J., & Lebihan, D. (1994). MR diffusion tensor spectroscopy and
imaging. Biophysical Journal, 66(1), 259-267.
Basser, P. J. (1995). Inferring microstructural features and the physiological state of tissues
from diffusion-weighted images. NMR in Biomedicine, 8(7-8), 333-344.
Baxter, L. R. (1990). Brain imaging as a tool in establishing a theory of brain pathology in
obsessive-compulsive disorder. Journal of Clinical Psychiatry, 51 (supplement), 2225.
Baxter, L. R., Schwartz, J. M., Phelps, M. E., Mazziotta, J. C., Guze, B. H., Selin, C. E., et
al. (1989). Reduction of prefrontal cortex glucose metabolism common to three
types of depression. Archives of General Psychiatry, 46, 243-250.
Baxter, L. R., Schwartz, L. M., Guze, B. H., Bergman, K., & Szuba, M. P. (1990). PET
imaging in obsessive-compulsive disorder with and without depression. Journal of
Clinical Psychiatry, 51 (supplement), 61-69.
Beason-Held, L. L., Kraut, M. A., & Resnick, S. M. (2008). Temporal patterns of
longitudinal change in aging brain function. Neurobiology of Aging, 29(4), 497-513.
Beaulieu, C. (2002). The basis of anisotropic water diffusion in the nervous system - a
technical review. NMR in Biomedicine, 15(7-8), 435-455.
Bench, C. J., Friston, K. J., Brown, R. G., Scott, L. C., Frackowiak, R. S. J., & Dolan, R. J.
(1992). The anatomy of melancholia - focal abnormalities of cerebral blood-flow in
major depression. Psychological Medicine, 22(3), 607-615.
Bewernick, B. H., Hurlemann, R., Matusch, A., Kayser, S., Grubert, C., Hadrysiewicz, B., et
al. (2010). Nucleus accumbens deep brain stimulation decreases ratings of
depression and anxiety in treatment-resistant depression. Biological Psychiatry,
67(2), 110-116.
Biederman, J. (1998). Attention-deficit/hyperactivity disorder: A life-span perspective.
Journal of Clinical Psychiatry, 59, 4-16.
Binesh, N., Kumar, A., Hwang, S., Mintz, J., & Thomas, M. A. (2004). Neurochemistry of
late-life major depression: A pilot two-dimensional MR spectroscopic study.
Journal of Magnetic Resonance Imaging, 20(6), 1039-1045.
Bjorkerud, S. (1973). Effect of adrenocortical hormones on the integrity of rat aortic
endothelium. In G. Schettler, & A. Weizel (Eds.), Proceedings of the 3rd
international symposium on atherosclerosis (pp. 245). Berlin, Germany: SpringerVerlag.

145

Blanchard, M. M., Jacobson, S., Clarke, M. C., Connor, D., Kelleher, I., Garavan, H., et al.
(2010). Language, motor and speed of processing deficits in adolescents with
subclinical psychotic symptoms. Schizophrenia Research, 123(1), 71-76.
Boone, K. B., Miller, B. L., Lesser, I. M., Mehringer, C. M., Hill-Gutierrez, E., Goldberg, M.
A., et al. (1992). Neuropsychological correlates of white-matter lesions in healthy
elderly subjects. A threshold effect. Archives of Neurology, 49(5), 549-554.
Bossema, E. R., Brand, N., Moll, F. L., Ackerstaff, R. G. A., & van Doornen, L. J. P. (2005).
Does carotid endarterectomy improve cognitive functioning? Journal of Vascular
Surgery, 41(5), 775-781.
Braffman, B. H., Zimmerman, R. A., Trojanowski, J. Q., Gonatas, N. K., Hickey, W. F., &
Schlaepfer, W. W. (1988). Brain MR: Pathologic correlation with gross and
histopathology (2) hyperintense white-matter foci in the elderly. American Journal
of Roentgenology, 151(3), 559-566.
Bremner, J. D., Narayan, M., Anderson, E. R., Staib, L. H., Miller, H. L., & Charney, D. S.
(2000). Hippocampal volume reduction in major depression. American Journal of
Psychiatry, 157(1), 115-117.
Bremner, J. D., Vythilingam, M., Vermetten, E., Vaccarino, V., & Charney, D. S. (2004).
Deficits in hippocampal and anterior cingulate functioning during verbal declarative
memory encoding in midlife major depression. American Journal of Psychiatry,
161(4), 637-645.
Breteler, M. M. B., Vanswieten, J. C., Bots, M. L., Grobbee, D. E., Claus, J. J., Vandenhout,
J. H. W., et al. (1994). Cerebral white-matter lesions, vascular risk-factors, and
cognitive function in a population-based study - the Rotterdam study. Neurology,
44(7), 1246-1252.
Broadhead, W. E., Blazer, D. G., George, L. K., & Chiu, K. T. (1990). Depression, disability
days, and days lost from work in a prospective epidemiologic survey. Journal of the
American Medical Association, 264(19), 2524-2528.
Bryan, R. N., Manolio, T. A., Schertz, L. D., Jungreis, C., Poirier, V. C., Elster, A. D., et al.
(1994). A method for using MR to evaluate the effects of cardiovascular-disease on
the brain - the cardiovascular health study. American Journal of Neuroradiology,
15(9), 1625-1633.
Buckner, R. L. (2004). Memory and executive function in aging and AD: Multiple factors
that cause decline and reserve factors that compensate. Neuron, 44(1), 195-208.
Bucur, B., Madden, D.J., Spaniol, J., et al. (2008). Age-related slowing of memory retrieval:
Contributions of perceptual speed and cerebral white matter integrity. Neurobiology
of Aging, 29, 1070-1079.

146

Bullmore, E. T., Frangou, S., & Murray, R. M. (1997). The dysplastic net hypothesis: An
integration of developmental and dysconnectivity theories of schizophrenia.
Schizophrenia Research, 28(2-3), 143-156.
Carney, R. M., Rich, M. W., Freedland, K. E., Saini, J., Tevelde, A., Simeone, C., et al.
(1988). Major depressive disorder predicts cardiac events in patients with coronaryartery disease. Psychosomatic Medicine, 50(6), 627-633.
Carney, R. M., Rich, M. W., Tevelde, A., Saini, J., Clark, K., & Jaffe, A. S. (1987). Major
depressive disorder in coronary-artery disease. American Journal of Cardiology,
60(16), 1273-1275.
Carpenter, M. (1976). Human neuroanatomy. Baltimore: Williams & Wilkins.
Catani, M., & Ffytche, D. H. (2005). The rises and falls of disconnection syndromes. Brain,
128, 2224-2239.
Cervilla, J., Prince, M., & Rabe-Hesketh, S. (2004). Vascular disease risk factors as
determinants of incident depressive symptoms: A prospective community-based
study. Psychological Medicine, 34(4), 635-641.
Charlton, R. A., Barrick, T. R., McIntyre, D. J., Shen, Y., O'Sullivan, M., Howe, F. A., et al.
(2006). White matter damage on diffusion tensor imaging correlates with age-related
cognitive decline. Neurology, 66(2), 217-222.
Cheng, P., Magnotta, V. A., Wu, D., Nopoulos, P., Moser, D. J., Paulsen, J., et al. (2006).
Evaluation of the GTRACT diffusion tensor tractography algorithm: A validation
and reliability study. NeuroImage, 31(3), 1075-1085.
Chodosh, J., Kado, D. M., Seeman, T. E., & Karlamangla, A. S. (2007). Depressive
symptoms as a predictor of cognitive decline: MacArthur studies of successful
aging. American Journal of Geriatric Psychiatry, 15(5), 406-415.
Choi, J., Jeong, B., Rohan, M. L., Polcari, A. M., & Teicher, M. H. (2009). Preliminary
evidence for white matter tract abnormalities in young adults exposed to parental
verbal abuse. Biological Psychiatry, 65(3), 227-234.
Churchill, C. M., Priolo, C. V., Nemeroff, C. B., Krishnan, K. R. R., & Breitner, J. C. S.
(1991). Occult subcortical magnetic resonance imaging in elderly depressives.
International Journal of Geriatric Psychiatry, 243, 41-46.
Clark, A., & Friedman, M. J. (1983). Factor structure and discriminant validity of the SCL90 in a veteran psychiatric population. Journal of Personality Assessment, 47(4),
396-404.
Coffey, C. E., Figiel, G. S., Djang, W. T., Cress, M., Saunders, W. B., & Weiner, R. D.
(1988). Leukoencephalopathy in elderly depressed patients referred for ECT.
Biological Psychiatry, 24(2), 143-161.

147

Coffey, C. E., Figiel, G. S., Djang, W. T., Saunders, W. B., & Weiner, R. D. (1989). White
matter hyperintensity on magnetic resonance imaging: Clinical and neuroanatomic
correlates in the depressed elderly. J Neuropsychiatry Clin Neurosci, 1(2), 135-44.
Coffey, C. E., Figiel, G. S., Djang, W. T., & Weiner, R. D. (1990). Subcortical
hyperintensity on magnetic-resonance-imaging - a comparison of normal and
depressed elderly subjects. American Journal of Psychiatry, 147(2), 187-189.
Coffey, C. E., Wilkinson, W. E., Weiner, R. D., Parashos, I. A., Djang, W. T., Webb, M. C.,
et al. (1993a). Quantitative cerebral anatomy in depression - a controlled magneticresonance-imaging study. Archives of General Psychiatry, 50(1), 7-16.
Coffey, C. E., Wilkinson, W. E., Weiner, R. D., Parashos, I. A., Djang, W. T., Webb, M. C.,
et al. (1993b). Quantitative cerebral anatomy in depression - a controlled magneticresonance-imaging study. Archives of General Psychiatry, 50(1), 7-16.
Cohen, R. A., Poppas, A., Forman, D. E., Hoth, K. F., Haley, A. P., Gunstad, J., et al. (2009).
Vascular and cognitive functions associated with cardiovascular disease in the
elderly. Journal of Clinical and Experimental Neuropsychology, 31(1), 96-110.
Conners, C. K., & MHS Staff. (2004). Conners' continuous performance test (CPT II) (5th
ed.). Canada: Multi-Health Systems, Inc.
Cook, I.A., Leucheter, A.F., Morgan, M.L. et al. (2004). Longitudinal progression of
subclinical structural brain disease in normal aging. American Journal of Geriatric
Psychiatry, 12, 190-200.
Cotter, D., Mackay, D., Landau, S., Kerwin, R., & Everall, I. (2001). Reduced glial cell
density and neuronal size in the anterior cingulate cortex in major depressive
disorder. Archives of General Psychiatry, 58(6), 545-553.
Coull, J. T., Frith, C. D., Buchel, C., & Nobre, A. C. (2000). Orienting attention in time:
Behavioural and neuroanatomical distinction between exogenous and endogenous
shifts. Neuropsychologia, 38(6), 808-819.
Courchesne, E., & Pierce, K. (2005). Why the frontal cortex in autism might be talking only
to itself: Local over-connectivity but long-distance disconnection. Current Opinion
in Neurobiology, 15(2), 225-230.
Cowell, P. E., Allen, L. S., Zalatimo, N. S., & Denenberg, V. H. (1992). A developmental
study of sex and age interactions in the human corpus callosum. Brain Res Dev
Brain Res, 66(2), 187-192.
Crosby, E., Humphrey, T., & Lauer, E. (1962). Correlative anatomy of the nervous system.
New York: MacMillan.

148

Croxson, P. L., Johansen-Berg, H., Behrens, T. E. J., Robson, M. D., Pinsk, M. A., Gross, C.
G., et al. (2005). Quantitative investigation of connections of the prefrontal cortex in
the human and macaque using probabilistic diffusion tractography. Journal of
Neuroscience, 25(39), 8854-8866.
Damasio, A. R., & Damasio, H. (1994). Cortical systems for retrieval of concrete
knowledge: The convergence zone framework. In C. Koch (Ed.), Large-scale
neuronal theories of the brain (pp. 61-74). Cambridge, MA: MIT Press.
Damasio, A. R. (1989). Time-locked multiregional retroactivation - a systems-level proposal
for the neural substrates of recall and recognition. Cognition, 33(1-2), 25-62.
Davis, S. W., Dennis, N. A., Buchler, N. G., White, L. E., Madden, D. J., & Cabeza, R.
(2009). Assessing the effects of age on long white matter tracts using diffusion
tensor tractography. NeuroImage, 46(2), 530-541.
de Asis, J. M., Stern, E., Alexopoulos, G. S., Pan, H., Van Gorp, W., Blumberg, H., et al.
(2001). Hippocampal and anterior cingulate activation deficits in patients with
geriatric depression. American Journal of Psychiatry, 158(8), 1321-1323.
de Groot, J. C., de Leeuw, F. E., Oudkerk, M., Hofman, A., Jolles, J., & Breteler, M. M. B.
(2000). Cerebral white matter lesions and depressive symptoms in elderly adults.
Archives of General Psychiatry, 57(11), 1071-1076.
Deary, I. J., Bastin, M. E., Pattie, A., Clayden, J. D., Whalley, L. J., Starr, J. M., et al. (2006).
White matter integrity and cognition in childhood and old age. Neurology, 66(4),
505-512.
DeCarli, C., Fletcher, E., Ramey, V., Harvey, D., & Jagust, W. J. (2005). Anatomical
mapping of white matter hyperintensities (WMH) - exploring the relationships
between periventricular WMH, deep WMH, and total WMH burden. Stroke, 36(1),
50-55.
Demonet, J. F., Taylor, M. J., & Chaix, Y. (2004). Developmental dyslexia. Lancet,
363(9419), 1451-1460.
Deprez, S., Amant, F., Yigit, R., Porke, K., Verhoeven, J., Van den Stock, J., et al. (2011).
Chemotherapy-induced structural changes in cerebral white matter and its
correlation with impaired cognitive functioning in breast cancer patients. Human
Brain Mapping, 32(3), 480-493.
Derogatis, L. R., & Melisaratos, N. (1983). The brief symptom inventory - an introductory
report. Psychological Medicine, 13(3), 595-605.
Desmond, D. W., Tatemichi, T. K., Paik, M., & Stern, Y. (1993). Risk factors for
cerebrovascular disease as correlates of cognitive function in a stroke-free cohort.
Archives of Neurology, 50(2), 162-166.

149

Doraiswamy, P. M., Figiel, G. S., Husain, M. M., Mcdonald, W. M., Shah, S. A., Boyko, O.
B., et al. (1991). Aging of the human corpus callosum magnetic resonance imaging
in normal volunteers. Journal of Neuropsychiatry and Clinical Neurosciences, 3(4),
392-397.
Dotson, V. M., Zonderman, A. B., Davatzikos, C., Kraut, M. A., & Resnick, S. M. (2009).
Frontal atrophy and attention deficits in older adults with a history of elevated
depressive symptoms. Brain Imaging and Behavior, 3(4), 358.
Dougherty, D. D., Weiss, A. P., Cosgrove, G. R., Alpert, N. M., Cassem, E. H., Nierenberg,
A. A., et al. (2003). Cerebral metabolic correlates as potential predictors of response
to anterior cingulotomy for treatment of major depression. Journal of Neurosurgery,
99(6), 1010-1017.
Drevets, W. C. (2000). Functional anatomical abnormalities in limbic and prefrontal cortical
structures in major depression. Cognition, Emotion and Autonomic Responses: The
Integrative Role of the Prefrontal Cortex and Limbic Structures, 126, 413-431.
Drevets, W. C., Price, J. L., Simpson, J. R., Todd, R. D., Reich, T., Vannier, M., et al.
(1997). Subgenual prefrontal cortex abnormalities in mood disorders. Nature,
386(6627), 824-827.
Ebrahim, S., Barer, K., & Nouri, F. (1987). Affective illness after stroke. British Journal of
Psychiatry, 154, 170-182.
Elias, M. F., Elias, P. K., Sullivan, L. M., Wolf, P. A., & D'Agostino, R. B. (2003). Lower
cognitive function in the presence of obesity and hypertension: The Framingham
heart study. International Journal of Obesity, 27(2), 260-268.
Fan, J., McCandliss, B. D., Fossella, J., Flombaum, J. I., & Posner, M. I. (2005). The
activation of attentional networks. NeuroImage, 26(2), 471-479.
Fava, M., & Kendler, K. S. (2000). Major depressive disorder. Neuron, 28(2), 335-341.
Fazekas, F., Chawluk, J. B., Alavi, A., Hurtig, H. I., & Zimmerman, R. A. (1987). MR signal
abnormalities at 1.5 T in Alzheimers dementia and normal aging. American
Journal of Roentgenology, 149(2), 351-356.
Fein, G., Vandyke, C., Davenport, L., Turetsky, B., Brantzawadzki, M., Zatz, L., et al.
(1990). Preservation of normal cognitive-functioning in elderly subjects with
extensive white-matter lesions of long duration. Archives of General Psychiatry,
47(3), 220-223.
Figiel, G. S., Krishnan, K. R. R., Doraiswamy, P. M., & Rao, V.P., Nemeroff, C.B., Boyko,
O.B. (1991). Subcortical hyperintensities on brain magnetic resonance imaging: A
comparison between late onset and early onset elderly depressed subjects.
Neurobiology of Aging, 12, 245-247.

150

Finkelstein, S. P., Weintraub, R. J., Karmouz, N., Askinazi, C., Davar, G., & Baldessarini, R.
J. (1987). Antidepressant drug treatment for poststroke depression: A retrospective
study. Archives of Physical Medicine and Rehabilitation, 6, 772-776.
Firbank, M. J., Lloyd, A. J., Ferrier, N., & O'Brien, J. T. (2004). A volumetric study of MRI
signal hyperintensities in late-life depression. American Journal of Geriatric
Psychiatry, 12(6), 606-612.
Firbank, M. J., O'Brien, J. T., Pakrasi, S., Pantoni, L., Simoni, M., Erkinjuntti, T., et al.
(2005). White matter hyperintensities and depression - preliminary results from the
LADIS study. International Journal of Geriatric Psychiatry, 20(7), 674-679.
First, M. B., & Pincus, H. A. (Eds.). (2000). American psychiatric association: Diagnostic
and statistical manual of mental disorders, text revision (4th ed.). Washington, D.C.:
American Psychiatric Association.
Flechsig, P. (1901). Developmental (myelogenic) localisation of the cerebral cortex in the
human subject. Lancet, 2, 1027-1029.
Fleck, D. E., Shear, P. K., & Strakowski, S. M. (2002). A reevaluation of sustained attention
performance in temporal lobe epilepsy. Archives of Clinical Neuropsychology,
17(4), 399-405.
Folstein, M. F., Malberger, R., & McHugh, P. R. (1971). Mood disorders as a specific
complication of stroke. Journal of Neurology, Neurosurgery, and Psychiatry, 40,
1018-1020.
Fornito, A., et al. (2006). The influence of sulcal variability on morphometry of the human
anterior cingulate and paracingulate cortex. NeuroImage, 33, 843-854.
Friston, K. J., Frith, C. D., Liddle, P. F., & Frackowiak, R. S. J. (1991). Comparing
functional (pet) images - the assessment of significant change. Journal of Cerebral
Blood Flow and Metabolism, 11(4), 690-699.
Friston, K.J. (1995). Commentary and opinion (2) Statistical parametric mapping ontology
and current issues. Journal of Cerebral Blood Flow and Metabolism, 15(3), 361370.
Frith, U. (2001). Mind blindness and the brain in Autism. Neuron, 32(6), 969-979.
Fujikawa, T., Yamawaki, S., & Touhouda, Y. (1993). Incidence of silent cerebral infarction
in patients with major depression. Stroke, 24, 1631-1634.
Gainotti, G. (1972). Emotional behavior and hemispheric side of the lesion. Cortex; a
Journal Devoted to the Study of the Nervous System and Behavior, 8(1), 41-55.
George, M. S., Ketter, T. A., & Post, R. M. (1994). Prefrontal cortex dysfunction in clinical
depression. Depression, 2, 59.
Geschwind, N. (1965a). Disconnexion syndromes in animals and man. Brain, 88, 237-294.

151

Geschwind, N. (1965b). Disconnexion syndromes in animals and man. Brain, 88, 585-644.
Gevins, A., & Smith, M. E. (2000). Neurophysiological measures of working memory and
individual differences in cognitive ability and cognitive style. Cerebral Cortex,
10(9), 829-839.
Golden, CJ (1978). Stroop Color and Word Test: A Manual for Clinical and Experimental
Uses. Chicago, Illinois: Skoelting. pp. 132.
Goldszal, A. F., Davatzikos, C., Pham, D. L., Yan, M. X. H., Bryan, R. N., & Resnick, S. M.
(1998). An image-processing system for qualitative and quantitative volumetric
analysis of brain images. Journal of Computer Assisted Tomography, 22(5), 827837.
Greenwald, B. S., Kramer-Ginsberg, E., Krishnan, K. R. R., Ashtari, M., Auerbach, C., &
Patel, M. (1998). Neuroanatomic localization of magnetic resonance imaging signal
hyperintensities in geriatric depression. Stroke, 29(3), 613-617.
Greicius, M. D., Flores, B. H., Menon, V., Glover, G. H., Solvason, H. B., Kenna, H., et al.
(2007). Resting-state functional connectivity in major depression: Abnormally
increased contributions from subgenual cingulate cortex and thalamus. Biological
Psychiatry, 62(5), 429-437.
Grieve, S.M., Williams, L.M., Paul, R.H., et al. (2007). Cognitive aging, executive function,
and fractional anisotropy: a diffusion tensor MR imaging study. AJNR: American
Journal of Neuroradiology, 28, 226-235.
Grunwald, I. Q., Papanagiotou, P., Reith, W., Backens, M., Supprian, T., Politi, M., et al.
(2010). Influence of carotid artery stenting on cognitive function. Neuroradiology,
52(1), 61-66.
Gunning-Dixon, F. M., & Raz, N. (2000). The cognitive correlates of white matter
abnormalities in normal aging: A quantitative review. Neuropsychology, 14(2), 224232.
Gunning-Dixon, F.M., Brickman, A.M., Cheng, J.C., Alexopoulos, G.S. (2009). Aging of
cerebral white matter: a review of MRI findings. International Journal of Geriatric
Psychiatry, 24, 109-117.
Gutman, D. A., Holtzheimer, P. E., Behrens, T. E. J., Johansen-Berg, H., & Mayberg, H. S.
(2009). A tractography analysis of two deep brain stimulation white matter targets
for depression. Biological Psychiatry, 65(4), 276-282.
Hamani, C., Mayberg, H., Snyder, B., Giacobbe, P., Kennedy, S., & Lozano, A. M. (2009).
Deep brain stimulation of the subcallosal cingulate gyrus for depression: Anatomical
location of active contacts in clinical responders and a suggested guideline for
targeting clinical article. Journal of Neurosurgery, 111(6), 1209-1215.

152

Harrell, L. E., Duvall, E., Folks, D. G., Duke, L., Bartolucci, A., Conboy, T., et al. (1991).
The relationship of high-intensity signals on magnetic-resonance images to cognitive
and psychiatric state in Alzheimers disease. Archives of Neurology, 48(11), 11361140.
Haut, M. W., Moran, M. T., Lancaster, M. A., Kuwabara, H., Parsons, M. W., & Puce, A.
(2007). White matter correlates of cognitive capacity studied with diffusion tensor
imaging: Implications for cognitive reserve. Brain Imaging and Behavior, 1(3-4),
83-92.
Head, D., Buckner, R. L., Shimony, J. S., Williams, L. E., Akbudak, E., Conturo, T. E., et al.
(2004a). Differential vulnerability of anterior white matter in non-demented aging
with minimal acceleration in dementia of the Alzheimer type: Evidence from
diffusion tensor imaging. Cerebral Cortex, 14(4), 410-423.
Head, D., Buckner, R. L., Shimony, J. S., Williams, L. E., Akbudak, E., Conturo, T. E., et al.
(2004b). Differential vulnerability of anterior white matter in non-demented aging
with minimal acceleration in dementia of the Alzheimer type: Evidence from
diffusion tensor imaging. Cerebral Cortex, 14(4), 410-423.
Hedden, T., & Gabrieli, J. D. E. (2004). Insights into the ageing mind: A view from
cognitive neuroscience. Nature Reviews Neuroscience, 5(2), 87-U12.
Hermann, L.L., Le Masurier, M., & Ebmeier, E.B. (2008). White matter hyperintensities in
late life depression: a systematic review. Journal of Neurology, Neurosurgery, and
Psychiatry, 79, 619-624.
Hickie, I., Scott, E., Mitchell, P., Wilhelm, K., Austin, M. P., & Bennett, B. (1995).
Subcortical hyperintensities on magnetic-resonance-imaging - clinical correlates and
prognostic-significance in patients with severe depression. Biological Psychiatry,
37(3), 151-160.
Hickie, I., Scott, E., Wilhelm, K., & Brodaty, H. (1997). Subcortical hyperintensities on
magnetic resonance imaging in patients with severe depression - A longitudinal
evaluation. Biological Psychiatry, 42(5), 367-374.
Holsboer, F. (2001). Stress, hypercortisolism and corticosteroid receptors in depression:
Implicatons for therapy. Journal of Affective Disorders, 62(1-2), 77-91.
Hoth, K. F., Tate, D. F., Poppas, A., Forman, D. E., Gunstad, J., Moser, D. J., et al. (2007).
Endothelial function and white matter hyperintensities in older adults with
cardiovascular disease. Stroke; a Journal of Cerebral Circulation, 38(2), 308-312.
House, A., Dennis, M., Warlow, C., Hawton, K., & Molyneux, A. (1990). Mood disorders
after stroke and their relation to lesion location - a ct scan study. Brain, 113, 11131129.

153

Hsu, J.L., Leemans, A., Bai, C.H., Lee, C.H., Tsai, Y.F., Chiu, H.C., & Chen, W.H. (2008).
Gender differences and age-related white matter changes of the human brain: A
diffusion tensor imaging study. NeuroImage 39, 566-577.
Huppi, P. S., Maier, S. E., Peled, S., Zientara, G. P., Barnes, P. D., Jolesz, F. A., et al.
(1998). Microstructural development of human newborn cerebral white matter
assessed in vivo by diffusion tensor magnetic resonance imaging. Pediatric
Research, 44(4), 584-590.
Hybels, C. F., Blazer, D. G., & Pieper, C. F. (2001). Toward a threshold for subthreshold
depression: An analysis of correlates of depression by severity of symptoms using
data from an elderly community sample. Gerontologist, 41(3), 357-365.
Jack, C. R., & Petersen, R. C. (2000). Structural imaging approaches to Alzheimers disease.
In M. Scinto, & K. R. Daffner (Eds.), Early diagnosis and treatment of Alzheimers
disease (pp. 127-148). Totowa, NJ: Humana Press.
Jacoby, R. J., & Levy, R. (1980). Computed tomography in the elderly. 3. affective disorder.
The British Journal of Psychiatry : The Journal of Mental Science, 136, 270-275.
Jacoby, R. J., Levy, R., & Bird, J. M. (1981). Computed tomography and the outcome of
affective disorder: A follow-up study of elderly patients. The British Journal of
Psychiatry : The Journal of Mental Science, 139, 288-292.
Janowsky, J. S., Kaye, J. A., & Carper, R. A. (1996). Atrophy of the corpus callosum in
Alzheimer's disease versus healthy aging. Journal of the American Geriatrics
Society, 44(7), 798-803.
Janssen, J., Hulshoff Pol, H. E., de Leeuw, F. E., Schnack, H. G., Lampe, I. K., Kok, R. M.,
et al. (2007). Hippocampal volume and subcortical white matter lesions in late life
depression: Comparison of early and late onset depression. Journal of Neurology,
Neurosurgery, and Psychiatry, 78(6), 638-640.
Jimenez, F., Velasco, F., Salin-Pascual, R., Hernandez, J. A., Velasco, M., Criales, J. L., et
al. (2005). A patient with a resistant major depression disorder treated with deep
brain stimulation in the inferior thalamic peduncle. Neurosurgery, 57(3), 585-592.
Johansen-Berg, H. et al. (2008). Anatomical Connectivity of the Subgenual Cingulate
Region Targeted with Deep Brain Stimulation for Treatment-Resistant Depression.
Cerebral Cortex, 18, 1374-1383.
Jones, G. M. M., Sahakian, B. J., Levy, R., Warburton, D. M., & Gray, J. A. (1992). Effects
of acute subcutaneous nicotine on attention, information-processing and short-termmemory in Alzheimers disease. Psychopharmacology, 108(4), 485-494.
Jones, D. K., Symms, M. R., Cercignani, M., & Howard, R. J. (2005). The effect of filter size
on VBM analyses of DT-MRI data. NeuroImage, 26(2), 546-554.

154

Jorm, A. F. (2001). History of depression as a risk factor for dementia: An updated review.
Australian and New Zealand Journal of Psychiatry, 35(6), 776-781.
Judd, L. L., Rapaport, M. H., Paulus, M. P., & Brown, J. L. (1994a). Subsyndromal
symptomatic depression - a new mood disorder. Journal of Clinical Psychiatry, 55,
18-28.
Jurica, P. J., Leitten, C. L., & Mattis, S. M. (2001). In Lutz F. L. (Ed.), Dementia rating
scale-2. Professional Manual. PAR, Inc.
Kasahara, H., Yamada, H., Tanno, M., Kobayashi, M., Karasawa, A., Endo, K., et al. (1995).
Magnetic resonance imaging study of the brain in aged volunteers: T2 high intensity
lesions and higher order cortical function. Psychiatry and Clinical Neurosciences,
49(5-6), 273-279.
Kelly, D., & Mitchell-Heggs, N. (1973). Stereotactic limbic leucotomy a follow-up study
of thirty patients. Postgraduate Medical Journal, 49, 865-882.
Kennedy, G. J., Kelman, H. R., & Thomas, C. (1990). The emergence of depressive
symptoms in late life: The importance of declining health and increasing disability. J
Community Health, 15(2), 93-104.
Kennedy, S. H., Konarski, J. Z., Segal, Z. V., Lau, M. A., Bieling, P. J., McIntyre, R. S., et
al. (2007). Differences in brain glucose metabolism between responders to CBT and
venlafaxine in a 16-week randomized controlled trial. American Journal of
Psychiatry, 164(5), 778-788.
Kennedy, S. H., Giacobbe, P., Rizvi, S. J., Placenza, F. M., Nishikawa, Y., Mayberg, H. S.,
et al. (2011). Deep brain stimulation for treatment-resistant depression: Follow-up
after 3 to 6 years. American Journal of Psychiatry, 168(5), 502-510.
Ketter, T. A., George, M. S., Kimbrell, T. A., Benson, B. E., & Post, R. M. (1996).
Functional brain imaging, limbic function, and affective disorders. Neuroscientist,
2(1), 55-65.
Klingberg, T., Hedehus, M., Temple, E., Salz, T., Gabrieli, J. D. E., Moseley, M. E., et al.
(2000). Microstructure of temporo-parietal white matter as a basis for reading
ability: Evidence from diffusion tensor magnetic resonance imaging. Neuron, 25,
493-500.
Klingberg, T., Vaidya, C. J., Gabrieli, J. D. E., Moseley, M. E., & Hedehus, M. (1999).
Myelination and organization of the frontal white matter in children: A diffusion
tensor MRI study. Neuroreport, 10(13), 2817-2821.
Kluger, A., Glanutsos, J., Leon, M. J., & George, A. E. (1988). Significance of age-related
white matter lesions. Stroke, 19, 1054-1055.
Koenig, H. G. (1998). Depression in hospitalized older patients with congestive heart failure.
General Hospital Psychiatry, 20(1), 29-43.

155

Kramer, J.H., Mungas, D., Reed, B.R., et al. (2007). Longitudinal MRI and cognitive change
in healthy elderly. Neuropsychology, 21, 412-418.
Kramer-Ginsberg, E., Greenwald, B. S., Krishnan, K. R. R., Christiansen, B., Hu, J., Ashtari,
M., et al. (1999). Neuropsychological functioning and MRI signal hyperintensities in
geriatric depression. American Journal of Psychiatry, 156(3), 438-444.
Krishnan, K. R. R., McDonald, W. M., Doraiswamy, P. M., Tupler, L. A., Husain, M.,
Boyko, O. B., et al. (1993). Neuroanatomical substrates of depression in the elderly.
European Archives of Psychiatry and Clinical Neuroscience, 243, 41-46.
Krishnan, K. R., Hays, J. C., & Blazer, D. G. (1997). MRI-defined vascular depression. The
American Journal of Psychiatry, 154(4), 497-501.
Krishnan, K. R. R. (2002). Biological risk factors in late life depression. Biological
Psychiatry, 52(3), 185-192.
Krishnan, K. R. R., Delong, M., Kraemer, H., Carney, R., Spiegel, D., Gordon, C., et al.
(2002). Comorbidity of depression with other medical diseases in the elderly.
Biological Psychiatry, 52(6), 559-588.
Krishnan, K. R. R., Goli, V., Ellinwood, E. H., France, R. D., Blazer, D. G., & Nemeroff, C.
B. (1988). Leukoencephalopathy in patients diagnosed as major depressive.
Biological Psychiatry, 23(5), 519-522.
Krishnan, K. R. R., Mcdonald, W. M., Doraiswamy, P. M., Tupler, L. A., Husain, M.,
Boyko, O. B., et al. (1993). Neuroanatomical substrates of depression in the elderly.
European Archives of Psychiatry and Clinical Neuroscience, 243(1), 41-46.
Krishnan, K. R. R., Taylor, W. D., McQuoid, D. R., MacFall, J. R., Payne, M. E.,
Provenzale, J. M., et al. (2004). Clinical characteristics of magnetic resonance
imaging-defined subcortical ischemic depression. Biological Psychiatry, 55(4), 390397.
Kubicki, M., Westin, C. F., Nestor, P. G., Wible, C. G., Frumin, M., Maier, S. E., et al.
(2003). Cingulate fasciculus integrity disruption in schizophrenia: A magnetic
resonance diffusion tensor imaging study. Biological Psychiatry, 54(11), 1171-1180.
Kumar, A., Bilker, W., Jin, Z. S., & Udupa, J. (2000). Atrophy and high intensity lesions:
Complementary neurobiological mechanisms in late-life major depression.
Neuropsychopharmacology, 22(3), 264-274.
Kumar, A., Jin, Z. S., Bilker, W., Udupa, J., & Gottlieb, G. (1998). Late-onset minor and
major depression: Early evidence for common neuroanatomical substrates detected
by using MRI. Proceedings of the National Academy of Sciences of the United
States of America, 95(13), 7654-7658.

156

Kumar, A., Schweizer, E., Jin, Z. S., Miller, D., Bilker, W., Sean, L. L., et al. (1997).
Neuroanatomical substrates of late-life minor depression - A quantitative magnetic
resonance imaging study. Archives of Neurology, 54(5), 613-617.
Kumar, A., Thomas, A., Lavretsky, H., Yue, K., Huda, A., Curran, J., et al. (2002). Frontal
white matter biochemical abnormalities in late-life major depression detected with
proton magnetic resonance spectroscopy. American Journal of Psychiatry, 159(4),
630-636.
Kusumi, I., Koyama, T., & Yamashita, I. (1991). Serotonin-stimulated Ca2+ response is
increased in the blood-platelets of depressed-patients. Biological Psychiatry, 30(3),
310-312.
Lacro, J. P., & Jeste, D. V. (1994). Physical comorbidity and polypharmacy in older
psychiatric-patients. Biological Psychiatry, 36(3), 146-152.
Lai, T., Payne, M. E., Byrum, C. E., Steffens, D. C., & Krishnan, K. R. (2000). Reduction of
orbital frontal cortex volume in geriatric depression. Biological Psychiatry, 48(10),
971-975.
Laghrissi-Thode, F., Wagner, W. R., Pollock, B. G., Johnson, P. C., & Finkel, M. S. (1997).
Elevated platelet factor 4 and beta-thromboglobulin plasma levels in depressed
patients with ischemic heart disease. Biological Psychiatry, 42(4), 290-295.
Lassen, N. (1964). Autoregulation of cerebral blood flow. Circulation Research, 15(2S1),
201.
Lavretsky, H., Lesser, I. M., Wohl, M., Miller, B. L., & Mehringer, C. M. (1999). Clinical
and neuroradiologic features associated with chronicity in late-life depression.
American Journal of Geriatric Psychiatry, 7(4), 309-316.
Lazarus, L. W., Moberg, P. J., Langsley, P. R., & Lingam, V. R. (1994). Methylphenidate
and nortriptyline in the treatment of poststroke depression - a retrospective
comparison. Archives of Physical Medicine and Rehabilitation, 75(4), 403-406.
Lebihan, D., & Breton, E. (1985). In-vivo magnetic-resonance imaging of diffusion.
Comptes Rendus De L Academie Des Sciences Serie Ii, 301(15), 1109-1112.
Lesser, I. M., Boone, K. B., Mehringer, C. M., Wohl, M. A., Miller, B. L., & Berman, N. G.
(1996). Cognition and white matter hyperintensities in older depressed patients.
American Journal of Psychiatry, 153(10), 1280-1287.
Lesser, I. M., Hillgutierrez, E., Miller, B. L., & Boone, K. B. (1993). Late-onset depression
with white-matter lesions. Psychosomatics, 34(4), 364-367.
Lesser, I. M., Miller, B. L., Boone, K. B., Hill-Gutierrez, E., Mehringer, C. M., Wong, K., et
al. (1991). Brain injury and cognitive function in late-onset psychotic depression.
Journal of Neuropsychiatry and Clinical Neuroscience, 3(1), 33-40.

157

Lett, H. S., Blumenthal, J. A., Babyak, M. A., Sherwood, A., Strauman, T., Robins, C., et al.
(2004). Depression as a risk factor for coronary artery disease: Evidence,
mechanisms, and treatment. Psychosomatic Medicine, 66(3), 305-315.
Levesque, J., Eugene, F., Joanette, Y., Paquette, V., Mensour, B., Beaudoin, G., et al. (2003).
Neural circuitry underlying voluntary suppression of sadness. Biological Psychiatry,
53(6), 502-510.
Lipsey, J. R., Spencer, W. C., Rabins, P. V., & Robinson, R. G. (1986). Phenomenological
comparison of poststroke depression and functional depression. American Journal of
Psychiatry, 143(4), 527-529.
Littman, A. B. (1993). Review of psychosomatic aspects of cardiovascular-disease.
Psychotherapy and Psychosomatics, 60(3-4), 148-167.
Lo, T., Cottinghain, M., Aretsen, T., Boone, K., & Goldberg, H. (2010). Stroop color-word
test as a symptom validity test for processing speed: Sensitivity and specificity.
Archives of Clinical Neuropsychology, 25(6), 501-501.
Lopez, O. L., Jagust, W. J., Dulberg, C., Becker, J. T., DeKosky, S. T., Fitzpatrick, A., et al.
(2003). Risk factors for mild cognitive impairment in the cardiovascular health study
cognition study part 2. Archives of Neurology, 60(10), 1394-1399.
Lozano, A. M., Mayberg, H. S., Giacobbe, P., Hamani, C., Craddock, R. C., & Kennedy, S.
H. (2008). Subcallosal cingulate gyrus deep brain stimulation for treatment-resistant
depression. Biological Psychiatry, 64(6), 461-467.
Lyness, J. M., King, D. A., Conwell, Y., Cox, C., & Caine, E. D. (2000). Cerebrovascular
risk factors and 1-year depression outcome in older primary care patients. American
Journal of Psychiatry, 157(9), 1499-1501.
MacFall, J. R., Taylor, W. D., Rex, D. E., Pieper, S., Payne, M. E., McQuoid, D. R., et al.
(2006). Lobar distribution of lesion volumes in late-life depression: The biomedical
informatics research network (BIRN). Neuropsychopharmacology, 31(7), 15001507.
Madden, D.J., Whiting, W.L., Huettel, S.A., et al. (2004). Diffusion tensor imaging of adult
age differences in cerebral white matter: relation to response time. NeuroImage, 21,
1174-1181.
Magnotta, V. A., Harris, G., Andreasen, N. C., O'Leary, D. A., Yuh, W. T. C., & Heckel, D.
(2002). Structural MR image processing using the BRAIN2 toolbox. Computerized
Medical Imaging and Graphics, 26(4), 251-264.
Malone, D. A.,Jr., Dougherty, D. D., Rezai, A. R., Carpenter, L. L., Friehs, G. M., Eskandar,
E. N., et al. (2009). Deep brain stimulation of the ventral capsule/ventral striatum for
treatment-resistant depression. Biological Psychiatry, 65(4), 267-275.

158

Markovitz, J., & Matthews, K. (1991). Platelets and coronary heart-disease - potential
psychophysiological mechanisms. Psychosomatic Medicine, 53(6), 643-668.
Masand, P., Murray, G. B., & Pickett, P. (1991). Psychostimulants in post-stroke depression.
Journal of Neuropsychiatry and Clinical Neurosciences, 3(1), 23-7.
Mayberg, H. S. (2003). Modulating dysfunctional limbic-cortical circuits in depression:
Towards development of brain-based algorithms for diagnosis and optimised
treatment. British Medical Bulletin, 65, 193-210.
Mayberg, H. S., Lewis, P. J., Regenold, W., & Wagner, H. N. (1994). Paralimbic
hypoperfusion in unipolar depression. Journal of Nuclear Medicine, 35(6), 929-934.
Mayberg, H. S., Liotti, M., Brannan, S. K., McGinnis, S., Mahurin, R. K., Jerabek, P. A., et
al. (1999). Reciprocal limbic-cortical function and negative mood: Converging PET
findings in depression and normal sadness. American Journal of Psychiatry, 156(5),
675-682.
Mayberg, H. S., Silva, J. A., Brannan, S. K., Tekell, J. L., Mahurin, R. K., McGinnis, S., et
al. (2002). The functional neuroanatomy of the placebo effect. American Journal of
Psychiatry, 159(5), 728-737.
Mayberg, H. S. (2009). Targeted electrode-based modulation of neural circuits for
depression. Journal of Clinical Investigation, 119(4), 717-725.
Mayberg, H., Westmacott, R., & McIntosh, A. (2001). Network analysis of trait and state
abnormalities in depression. NeuroImage, 13(6), S1071-S1071.
Mayberg, H. S. (1997). Limbic-cortical dysregulation: A proposed model of depression.
Journal of Neuropsychiatry and Clinical Neurosciences, 9(3), 471-481.
Mayberg, H. S., Lozano, A. M., Voon, V., McNeely, H. E., Seminowicz, D., Hamani, C., et
al. (2005). Deep brain stimulation for treatment-resistant depression. Neuron, 45(5),
651-660.
McCormick, L.M., Ziebell, S., Nopoulos, P., Cassell, M., Andreasen, N.C., Brumm, M.
(2006). Anterior cingulate cortex: an MRI-based parcellation method. NeuroImage,
32, 1167-1175.
McKay, C., Casey, J. E., Wertheimer, J., & Fichtenberg, N. L. (2007). Reliability and
validity of the RBANS in a traumatic brain injured sample. Archives of Clinical
Neuropsychology, 22(1), 91-98.
Meeks, T. W., Vahia, I. V., Lavretsky, H., Kulkarni, G., & Jeste, D. V. (2011). A tune in "a
minor" can "b major": A review of epidemiology, illness course, and public health
implications of subthreshold depression in older adults. Journal of Affective
Disorders, 129(1-3), 126-142.

159

Mendez, M. F., Adams, N. L., & Lewandoski, K. S. (1989). Neurobehavioral changes

associated with caudate lesions. Neurology, 39, 349-354.
Meng, X.L., Rosenthal, R., & Rubin, D.B. (1992) Comparing Correlated Correlation
Coefficients. Psychological Bulletin, 111(1), 172-175.
Mesulam, M. (2005). Imaging connectivity in the human cerebral cortex: The next frontier?
Annals of Neurology, 57(1), 5-7.
Mesulam, M. M. (1990). Large-scale neurocognitive networks and distributed-processing for
attention, language, and memory. Annals of Neurology, 28(5), 597-613.
Mikuni, M., Kagaya, A., Takahashi, K., & Meltzer, H. Y. (1992). Serotonin but not
norepinephrine-induced calcium mobilization of platelets is enhanced in affectivedisorders. Psychopharmacology, 106(3), 311-314.
Miller, D. S., Kumar, A., Yousem, D. M., & Gottlieb, G. L. (1994). MRI high-intensity
signals in late-life depression and Alzheimers-disease. American Journal of
Geriatric Psychiatry, 2(4), 332-337.
Mitchell, R. N., & Schoen, F. J. (2010). Blood vessels: Atherosclerosis. In V. K. Kumar, A.
K. Abbas, N. Fausto & J. C. Aster (Eds.), Robbins and Cotran pathologic basis of
disease (8th ed., pp. 496-507). Philadelphia, PA: Saunders Elsevier.
Moody, D. M., Bell, M. A., & Challa, V. R. (1990). Features of the cerebral vascular pattern
that predict vulnerability to perfusion or oxygenation deficiency - an anatomic study.
American Journal of Neuroradiology, 11(3), 431-439.
Mori, S., Oishi, K., Jiang, H., Jiang, L., Li, X., Akhter, K., et al. (2008). Stereotaxic white
matter atlas based on diffusion tensor imaging in an ICBM template. Neuroimage,
40(2), 570-582.
Mori, S., Wakana, S., Nagae-Poetscher, L. M., & van Zijl, P. C. M. (2005). MRI atlas of
human white matter. Amsterdam: Elsevier.
Mori, S., & Van Zijl, P. (2007). Human white matter atlas. American Journal of Psychiatry,
164(7), 1005
Moseley, M. E., Cohen, Y., Kucharczyk, J., Mintorovitch, J., Asgari, H. S., Wendland, M. F.,
et al. (1990). Diffusion-weighted MR imaging of anisotropic water diffusion in cat
central-nervous-system. Radiology, 176(2), 439-445.
Moser, D. J., Cohen, R. A., Paul, R. H., Paulsen, J. S., Ott, B. R., Gordon, N. M., et al.
(2001). Executive function and magnetic resonance imaging subcortical
hyperintensities in vascular dementia. Neuropsychiatry, Neuropsychology, and
Behavioral Neurology, 14(2), 89-92.

160

Moser, D. J., Cohen, R. A., Clark, M. M., Aloia, M. S., Tate, B. A., Stefanik, S., et al.
(1999). Neuropsychological functioning among cardiac rehabilitation patients.
Journal of Cardiopulmonary Rehabilitation, 19(2), 91-97.
Moser, D. J., Robinson, R. G., Hynes, S. M., Reese, R. L., Arndt, S., Paulsen, J. S., et al.
(2007). Neuropsychological performance is associated with vascular function in
patients with atherosclerotic vascular disease. Arteriosclerosis, Thrombosis, and
Vascular Biology, 27(1), 141-146.
Muller, M., Grobbee, D. E., Aleman, A., Bots, M., & van der Schouw, Y. T. (2007).
Cardiovascular disease and cognitive performance in middle-aged and elderly men.
Atherosclerosis, 190(1), 143-149.
Murata, T., Kimura, H., Omori, M., Kado, H., Kosaka, H., Iidaka, T., et al. (2001). MRI
white matter hyperintensities, H-1-MR spectroscopy and cognitive function in
geriatric depression: A comparison of early- and late-onset cases. International
Journal of Geriatric Psychiatry, 16(12), 1129-1135.
Murphy, C. F., Gunning-Dixon, F. M., Hoptman, M. J., Lim, K. O., Ardekani, B., Shields, J.
K., et al. (2007). White-matter integrity predicts Stroop performance in patients with
geriatric depression. Biological Psychiatry, 61(8), 1007-1010.
Murphy, J. M., Monson, R. R., Olivier, D. C., Sobol, A. M., & Leighton, A. H. (1987).
Affective-disorders and mortality - a general-population study. Archives of General
Psychiatry, 44(5), 473-480.
Musselman, D., Evans, D., & Nemeroff, C. (1998). The relationship of depression to
cardiovascular disease - epidemiology, biology, and treatment. Archives of General
Psychiatry, 55(7), 580-592.
Musselman, D., Tomer, A., Manatunga, A., Knight, B., Porter, M., Kasey, S., et al. (1996).
Exaggerated platelet reactivity in major depression. American Journal of Psychiatry,
153(10), 1313-1317.
Naeser, M. A., Alexander, M. P., Helmestabrooks, N., Levine, H. L., Laughlin, S. A., &
Geschwind, N. (1982). Aphasia with predominantly sub-cortical lesion sites.
Archives of Neurology, 39(1), 2-14.
Nestler, E. J., Barrot, M., DiLeone, R. J., Eisch, A. J., Gold, S. J., & Monteggia, L. M.
(2002). Neurobiology of depression. Neuron, 34(1), 13-25.
Nieuwenhuys, R., Voogd, J., & van Huijzen, C. (1983). The human central nervous system
Springer-Verlag.
Nobler, M. S., Oquendo, M. A., Kegeles, L. S., Malone, K. M., Campbell, C., Sackeim, H.
A., et al. (2001). Decreased regional brain metabolism after ECT. American Journal
of Psychiatry, 158(2), 305-308.

161

Nobuhara, K., Okugawa, G., Sugimoto, T., Minami, T., Tamagaki, C., Takase, K., et al.
(2006). Frontal white matter anisotropy and symptom severity of late-life
depression: A magnetic resonance diffusion tensor imaging study. Journal of
Neurology Neurosurgery and Psychiatry, 77(1), 120-122.
Nusbaum, A. O., Tang, C. Y., Buchsbaum, M. S., Wei, T. C., & Atlas, S. W. (2001).
Regional and global changes in cerebral diffusion with normal aging. American
Journal of Neuroradiology, 22(1), 136-142.
O'Brien, J., Ames, D., Chiu, E., Schweitzer, I., Desmond, P., & Tress, B. (1998). Severe
deep white matter lesions and outcome in elderly patients with major depressive
disorder: Follow up study. British Medical Journal, 317(7164), 982-984.
OBrien, J. T., & Ames, D. (1996). White matter lesions in depression and Alzheimers
disease. British Journal of Psychiatry, 169(5), 671-671.
O'Sullivan, M., Jones, D. K., Summers, P. E., Morris, R. G., Williams, S. C. R., & Markus,
H. S. (2001). Evidence for cortical "disconnection" as a mechanism of age-related
cognitive decline. Neurology, 57(4), 632-638.
O'Sullivan, M., Morris, R. G., Huckstep, B., Jones, D. K., Williams, S. C. R., & Markus, H.
S. (2004). Diffusion tensor MRI correlates with executive dysfunction in patients
with ischaemic leukoaraiosis. Journal of Neurology Neurosurgery and Psychiatry,
75(3), 441-447. doi:10.1136/jnnp.2003.014910
Oulis, P., Kouzoupis, A., Kyrkou, K., Masdrakis, V. G., Georgiopoulos, G., Karapoulios, E.,
et al. (2010). Reversal of increased arterial stiffness in severely depressed women
after 6-week antidepressant treatment. Journal of Affective Disorders, 122(1-2), 164166.
Pantoni, L., Garcia, J. H., & Gutierrez, J. A. (1996). Cerebral white matter is highly
vulnerable to ischemia. Stroke, 27(9), 1641-1646.
Panza, F., D'introno, A., Colacicco, A. M., Capurso, C., Del Parigi, A., Caselli, R. J., et al.
(2009). Temporal relationship between depressive symptoms and cognitive
impairment: The Italian longitudinal study on aging. Journal of Alzheimers Disease,
17(4), 899-911.
Paradiso, S., Vaidya, J., Tranel, D., Cosier, T., & Robinson, R. G. (2008). Nondysphoric
depression following stroke. Journal of Neuropsychiatry and Clinical
Neurosciences, 20(1), 52-61.
Pardo, J. V., Sheikh, S. A., Schwindt, G. C., Lee, J. T., Kuskowski, M. A., Surerus, C., et al.
(2008). Chronic vagus nerve stimulation for treatment-resistant depression decreases
resting ventromedial prefrontal glucose metabolism. NeuroImage, 42(2), 879-889.
Paul, R. H., Gunstad, J., Poppas, A., Tate, D. F., Foreman, D., Brickman, A. M., et al.
(2005). Neuroimaging and cardiac correlates of cognitive function among patients
with cardiac disease. Cerebrovascular Diseases, 20(2), 129-133.

162

Pearlson, G. D., & Robinson, R. G. (1982). Lateralization of emotional or behavioral

responses in intact and hemisphere-damaged humans and rats. In R. L. Isaacson, &
N. E. Spear (Eds.), The expression of knowledge (pp. 339-390). New York: Plenum
Press.
Persson, J., Nyberg, L., Lind, J., Larsson, A., Nilsson, L. G., Ingvar, M., et al. (2006).
Structure-function correlates of cognitive decline in aging. Cerebral Cortex, 16(7),
907-915.
Pfefferbaum, A., Mathalon, D. H., Sullivan, E. V., Rawles, J. M., Zipursky, R. B., & Lim, K.
O. (1994). A quantitative magnetic-resonance-imaging study of changes in brain
morphology from infancy to late adulthood. Archives of Neurology, 51(9), 874-887.
Pfefferbaum, A., Sullivan, E. V., Hedehus, M., Lim, K. O., Adalsteinsson, E., & Moseley,
M. (2000). Age-related decline in brain white matter anisotropy measured with
spatially corrected echo-planar diffusion tensor imaging. Magnetic Resonance in
Medicine, 44(2), 259-268.
Pfefferbaum, A., & Sullivan, E. V. (2003). Increased brain white matter diffusivity in normal
adult aging: Relationship to anisotropy and partial voluming. Magnetic Resonance in
Medicine, 49(5), 953-961.
Pfefferbaum, A., Adalsteinsson, E., & Sullivan, E. V. (2005). Frontal circuitry degradation
marks healthy adult aging: Evidence from diffusion tensor imaging. NeuroImage,
26(3), 891-899.
Phillips, M. L., Drevets, W. C., Rauch, S. L., & Lane, R. (2003). Neurobiology of emotion
perception I: The neural basis of normal emotion perception. Biological Psychiatry,
54(5), 504-514.
Pizzagalli, D. A., Peccoralo, L. A., Davidson, R. J., & Cohen, J. D. (2006). Resting anterior
cingulate activity and abnormal responses to errors in subjects with elevated
depressive symptoms: A 128-channel EEG study. Human Brain Mapping, 27(3),
185-201.
Posner, M. I., & Petersen, S. E. (1990). The attention system of the human brain. Annual
Review of Neuroscience, 13, 25-42.
Posner, M. I., Sheese, B. E., Odludas, Y., & Tang, Y. (2006). Analyzing and shaping human
attentional networks. Neural Networks, 19(9), 1422-1429.
Potter, G. G., McQuoid, D. R., Steffens, D. C., Welsh-Bohmer, K. A., & Krishnan, K. R.
(2009). Neuropsychological correlates of magnetic resonance imaging-defined
subcortical ischemic depression. International Journal of Geriatric Psychiatry,
24(3), 219-225.
Rabkin, J. G., Charles, E., & Kass, F. (1983). Hypertension and DSM-III depression in
psychiatric outpatients. American Journal of Psychiatry, 140(8), 1072-1074.

163

Rajkowska, G., & Miguel-Hidalgo, J. J. (2007). Gliogenesis and glial pathology in

depression. CNS Neurol Disord Drug Targets, 6(3), 219-233.
Rajkowska, G., Miguel-Hidalgo, J. J., Dubey, P., Stockmeier, C. A., & Krishnan, K. R. R.
(2005). Prominent reduction in pyramidal neurons density in the orbitofrontal cortex
of elderly depressed patients. Biological Psychiatry, 58(4), 297-306.
Randolph, C., Tierney, M. C., Mohr, E., & Chase, T. N. (1998). The Repeatable Battery for
the Assessment of Neuropsychological Status (RBANS): Preliminary clinical
validity. Journal of Clinical and Experimental Neuropsychology, 20(3), 310-319.
Rao, R. (2000). Cerebrovascular disease and late life depression: An age old association
revisited. International Journal of Geriatric Psychiatry, 15(5), 419-433.
Rao, R. (2002). The role of carotid stenosis in vascular cognitive impairment. Journal of the
Neurological Sciences, 203, 103-107.
Raz, N., Gunning-Dixon, F., Head, D., Rodrigue, K. M., Williamson, A., & Acker, J. D.
(2004). Aging, sexual dimorphism, and hemispheric asymmetry of the cerebral
cortex: Replicability of regional differences in volume. Neurobiology of Aging,
25(3), 377-396.
Raz, N., Lindenberger, U., Rodrigue, K. M., Kennedy, K. M., Head, D., Williamson, A., et
al. (2005). Regional brain changes in aging healthy adults: General trends,
individual differences and modifiers. Cerebral Cortex, 15(11), 1676-1689.
Raz, N., Rodrigue, K. M., Kennedy, K. M., & Acker, J. D. (2007). Vascular health and
longitudinal changes in brain and cognition in middle-aged and older adults.
Neuropsychology, 21(2), 149-157.
Reding, M., Haycox, J., & Blass, J. (1985). Depression in patients referred to a dementia
clinic: a three-year prospective study. Archives of Neurology, 42, 894-896.
Reding, M. J., Orto, L. A., Winter, S. W., Fortuna, I. M., Diponte, P., & Mcdowell, F. H.
(1986). Antidepressant therapy after stroke - a double-blind trial. Archives of
Neurology, 43(8), 763-765.
Reitan R. M. (1958). Validity of the Trail Making test as an indicator of organic brain
damage. Perceptual and Motor Skills, 8, 271-276
Resnick, S. M., Pham, D. L., Kraut, M. A., Zonderman, A. B., & Davatzikos, C. (2003).
Longitudinal magnetic resonance imaging studies of older adults: A shrinking brain.
Journal of Neuroscience, 23(8), 3295-3301.
Robinson, R. G., Starr, L. B., Lipsey, J. R., Rao, K., & Price, T. R. (1984). A 2-year
longitudinal-study of post-stroke mood disorders - dynamic changes in associated
variables over the 1st 6 months of follow-up. Stroke, 15(3), 510-517.

164

Robinson, R. G. (2003). Poststroke depression: Prevalence, diagnosis, treatment, and disease

progression. Biological Psychiatry, 54(3), 376-387.
Roman, G. C. (2004). Brain hypoperfusion: A critical factor in vascular dementia.
Neurological Research, 26(5), 454-458.
Ross, R., & Harker, L. (1976). Hyperlipidemia and atherosclerosis. Science, 193(4258),
1094-1100.
Ross, E. D., & Rush, A. J. (1981). Diagnosis and neuroanatomical correlates of depression in
brain-damaged patients - implications for a neurology of depression. Archives of
General Psychiatry, 38(12), 1344-1354.
Rosvold, H. E., Mirsky, A. F., Sarason, I., Bransome, E. D., & Beck, L. H. (1956). A
continuous performance-test of brain-damage. Journal of Consulting Psychology,
20(5), 343-350.
Roth, M., & Kay, D. W. K. (1956). Affective-disorder arising in the senium (2) physicaldisability as an aetiological factor. Journal of Mental Science, 102(426), 141-150.
Rovaris, M., Iannucci, G., Falautano, M., Possa, F., Martinelli, V., Comi, G., et al. (2002).
Cognitive dysfunction in patients with mildly disabling relapsing-remitting multiple
sclerosis: An exploratory study with diffusion tensor MR imaging. Journal of the
Neurological Sciences, 195(2), 103-109.
Sachs-Ericsson, N., Joiner, T., Plant, E. A., & Blazer, D. G. (2005). The influence of
depression on cognitive decline in community-dwelling elderly persons. American
Journal of Geriatric Psychiatry, 13(5), 402-408.
Sacktor, N., Skolasky, R. L., Cox, C., Selnes, O., Becker, J. T., Cohen, B., et al. (2010).
Longitudinal psychomotor speed performance in Human Immunodeficiency Virusseropositive individuals: Impact of age and serostatus. Journal of Neurovirology,
16(5), 335-41.
Saczynski, J. S., Sigurdsson, S., Jonsdottir, M. K., Eiriksdottir, G., Jonsson, P. V., Garcia, M.
E., et al. (2009). Cerebral infarcts and cognitive performance: Importance of location
and number of infarcts. Stroke; a Journal of Cerebral Circulation, 40(3), 677-682.
Salat, D., Ward, A., Kaye, J. A., & Janowsky, J. S. (1997). Sex differences in the corpus
callosum with aging. Neurobiology of Aging, 18(2), 191-197.
Salat, D. H., Kaye, J. A., & Janowsky, J. S. (1999). Prefrontal gray and white matter volumes
in healthy aging and Alzheimer disease. Archives of Neurology, 56(3), 338-344.
Salat, D. H., Tuch, D. S., Hevelone, N. D., Fischl, B., Corkin, S., Rosas, H. D., et al. (2005).
Age-related changes in prefrontal white matter measured by diffusion tensor
imaging. White Matter in Cognitive Neuroscience: Advances in Diffusion Tensor
Imaging and its Applications, 1064, 37-49.

165

Sanders, A. R., Detera-Wadleigh, S. D., & Gershon, E. S. (1999). Molecular genetics of

mood disorders. In E. J. Charney, E. J. Nestler & B. S. Bunney (Eds.), Neurobiology
of mental illness (). New York: Oxford.
Sartorius, A., Kiening, K. L., Kirsch, P., von Gall, C. C., Haberkorn, U., Unterberg, A. W., et
al. (2010). Remission of major depression under deep brain stimulation of the lateral
habenula in a therapy-refractory patient. Biological Psychiatry, 67(2), e9-e11.
Schechter, M. D., & Timmons, G. D. (1985). Objectively measured hyperactivity .2. caffeine
and amphetamine effects. Journal of Clinical Pharmacology, 25(4), 276-280.
Scheltens, P., Barkhof, F., Leys, D., Pruvo, J. P., Nauta, J. J. P., Vermersch, P., et al. (1993).
A semiquantitative rating-scale for the assessment of signal hyperintensities on
magnetic-resonance-imaging. Journal of the Neurological Sciences, 114(1), 7-12.
Schermuly, I., Fellgiebel, A., Wagner, S., Yakushev, I., Stoeter, P., Schmitt, R., et al. (2010).
Association between cingulum bundle structure and cognitive performance: An
observational study in major depression. European Psychiatry, 25(6), 355-360.
Schulte, T., Sullivan, E. V., Muller-Oehring, E. M., Adalsteinsson, E., & Pfefferbaum, A.
(2005). Corpus callosal microstructural integrity influences interhemispheric
processing: A diffusion tensor imaging study. Cerebral Cortex, 15(9), 1384-1392.
Selden, N. R., Gitelman, D. R., Salamon-Murayama, N., Parrish, T. B., & Mesulam, M. M.
(1998). Trajectories of cholinergic pathways within the cerebral hemispheres of the
human brain. Brain, 121, 2249-2257.
Seminowicz, D. A., Mayberg, H. S., McIntosh, A. R., Goldapple, K., Kennedy, S., Segal, Z.,
et al. (2004). Limbic-frontal circuitry in major depression: A path modeling metaanalysis. NeuroImage, 22(1), 409-418.
Sheline, Y. I., Sanghavi, M., Mintun, M. A., & Gado, M. H. (1999). Depression duration but
not age predicts hippocampal volume loss in medically healthy women with
recurrent major depression. Journal of Neuroscience, 19(12), 5034-5043.
Sheline, Y. I., Barch, D. M., Garcia, K., Gersing, K., Pieper, C., Welsh-Bohmer, K., et al.
(2006). Cognitive function in late life depression: Relationships to depression
severity, cerebrovascular risk factors and processing speed. Biological Psychiatry,
60(1), 58-65.
Sheline, Y. I., Pieper, C. F., Barch, D. M., Welsh-Bohmer, K., McKinstry, R. C., MacFall, J.
R., et al. (2010). Support for the vascular depression hypothesis in late-life
depression: Results of a 2-site, prospective, antidepressant treatment trial. Archives
of General Psychiatry, 67(3), 277-285.
Sheline, Y. I., Price, J. L., Vaishnavi, S. N., Mintun, M. A., Barch, D. M., Epstein, A. A., et
al. (2008). Regional white matter hyperintensity burden in automated segmentation
distinguishes late-life depressed subjects from comparison subjects matched for
vascular risk factors. American Journal of Psychiatry, 165(4), 524-532.

166

Shimony, J. S., Sheline, Y. I., D'Angelo, G., Epstein, A. A., Benzinger, T. L., Mintun, M. A.,
et al. (2009). Diffuse microstructural abnormalities of normal-appearing white
matter in late life depression: A diffusion tensor imaging study. Biological
Psychiatry, 66(3), 245-252.
Sierra, C., de la Sierra, A., Salamero, M., Sobrino, J., Gomez-Angelats, E., & Coca, A.
(2004). Silent cerebral white matter lesions and cognitive function in middle-aged
essential hypertensive patients. American Journal of Hypertension, 17(6), 529-534.
Sotak, C. H. (2002). The role of diffusion tensor imaging in the evaluation of ischemic brain
injury - a review. NMR in Biomedicine, 15(7-8), 561-569.
Sperry, R. (1982). Some effects of disconnecting the cerebral hemispheres. Science,
217(4566), 1223-1226.
Starkstein, S. E., & Robinson, R. G. (1993). Depression in neurological disease (pp. 28-49).
Baltimore, MD: The Johns Hopkins University Press.
Steer, R. A., Clark, D. A., & Ranieri, W. F. (1994). Symptom dimensions of the SCL-90-R:
A test of the tripartite model of anxiety and depression. Journal of Personality
Assessment, 62(3), 525-536.
Steffens, D. C., Bosworth, H. B., Provenzale, J. M., & MacFall, J. R. (2002). Subcortical
white matter lesions and functional impairment in geriatric depression. Depression
and Anxiety, 15(1), 23-28.
Steffens, D. C., Helms, M. J., Krishnan, K. R. R., & Burke, G. L. (1999). Cerebrovascular
disease and depression symptoms in the cardiovascular health study. Stroke, 30(10),
2159-2166.
Steffens, D. C., & Krishnan, K. R. R. (1998). Structural neuroimaging and mood disorders:
Recent findings, implications for classification, and future directions. Biological
Psychiatry, 43(10), 705-712.
Steffens, D. C., Taylor, W. D., & Krishnan, K. R. R. (2003). Progression of subcortical
ischemic disease from vascular depression to vascular dementia. American Journal
of Psychiatry, 160(10), 1751-1756.
Sternberg, D. E., & Jarvik, M. E. (1976). Memory functions in depression - improvement
with antidepressant medication. Archives of General Psychiatry, 33(2), 219-224.
Sullivan, E. V., Adalsteinsson, E., Hedehus, M., Ju, C., Moseley, M., Lim, K. O., et al.
(2001). Equivalent disruption of regional white matter microstructure in ageing
healthy men and women. Neuroreport, 12(1), 99-104.
Sullivan, E. V., & Pfefferbaum, A. (2003). Diffusion tensor imaging in normal aging and
neuropsychiatric disorders. European Journal of Radiology, 45(3), 244-255.

167

Sulzer, D. L., Levin, H. S., Mahler, M. E., High, W. M., & Cummings, J. L. (1993). A
comparison of psychiatric symptoms in vascular dementia and Alzheimer's disease.
American Journal of Psychiatry, 150, 1806-1812.
Swartz, R. H., Sahlas, D. J., & Black, S. E. (2003). Strategic involvement of cholinergic
pathways and executive dysfunction: Does location of white matter signal
hyperintensities matter? Journal of Stroke and Cerebrovascular Disease, 12(1), 2936.
Taki, Y., Kinomura, S., Awata, S., Inoue, K., Sato, K., Ito, H., et al. (2005). Male elderly
subthreshold depression patients have smaller volume of medial part of prefrontal
cortex and precentral gyrus compared with age-matched normal subjects: A voxelbased morphometry. Journal of Affective Disorders, 88(3), 313-320.
Taylor, W. D., Bae, J. N., MacFall, J. R., Payne, M. E., Provenzale, J. M., Steffens, D. C., et
al. (2007). Widespread effects of hyperintense lesions on cerebral white matter
structure. American Journal of Roentgenology, 188(6), 1695-1704.
Taylor, W. D., Kuchibhatla, M., Payne, M. E., Macfall, J. R., Sheline, Y. I., Krishnan, K. R.,
et al. (2008). Frontal white matter anisotropy and antidepressant remission in latelife depression. PloS One, 3(9), e3267.
Taylor, W. D., MacFall, J. R., Payne, M. E., McQuoid, D. R., Provenzale, J. M., Steffens, D.
C., et al. (2004). Late-life depression and microstructural abnormalities in
dorsolateral prefrontal cortex white matter. American Journal of Psychiatry, 161(7),
1293-1296.
Taylor, W. D., MacFall, J. R., Payne, M. E., McQuoid, D. R., Steffens, D. C., Provenzale, J.
M., et al. (2005). Greater MRI lesion volumes in elderly depressed subjects than in
control subjects. Psychiatry Research-Neuroimaging, 139(1), 1-7.
Taylor, W. D., MacFall, J. R., Provenzale, J. M., Payne, M. E., McQuoid, D. R., Steffens, D.
C., et al. (2003). Serial MR imaging of volumes of hyperintense white matter lesions
in elderly patients: Correlation with vascular risk factors. American Journal of
Roentgenology, 181(2), 571-576.
Taylor, W. D., Payne, M. E., Krishnan, K. R. R., Wagner, H. R., Provenzale, J. M., Steffens,
D. C., et al. (2001). Evidence of white matter tract disruption in MRI
hyperintensities. Biological Psychiatry, 50(3), 179-183.
Tekin, S., & Cummings, J. L. (2002). Frontal-subcortical neuronal circuits and clinical
neuropsychiatry - an update. Journal of Psychosomatic Research, 53(2), 647-654.
The Psychological Corporation. (1991). Vigil continuous performance test. San Antonio, TX:
Pearson.
Thomas, A. J., Perry, R., Barber, R., Kalaria, R. N., & O'Brien, J. T. (2002). Pathologies and
pathological mechanisms for white matter hyperintensities in depression.
Alzheimer's Disease: Vascular Etiology and Pathology, 977, 333-339.

168

Tuch, D. S., Reese, T. G., Wiegell, M. R., Makris, N., Belliveau, J. W., & Wedeen, V. J.
(2002). High angular resolution diffusion imaging reveals intravoxel white matter
fiber heterogeneity. Magnetic Resonance in Medicine, 48(4), 577-582.
Tuch, D. S., Salat, D. H., Wisco, J. J., Zaleta, A. K., Hevelone, N. D., & Rosas, H. D. (2005).
Choice reaction time performance correlates with diffusion anisotropy in white
matter pathways supporting visuospatial attention. Proceedings of the National
Academy of Sciences of the United States of America, 102(34), 12212-12217.
Tucker, D. M., Luu, P., Frishkoff, G., Quiring, J., & Poulsen, C. (2003). Frontolimbic
response to negative feedback in clinical depression. Journal of Abnormal
Psychology, 112(4), 667-678.
Tupler, L. A., Coffey, C. E., Logue, P. E., Djang, W. T., & Fagan, S. M. (1992).
Neuropsychological importance of subcortical white matter hyperintensity. Archives
of Neurology, 49(12), 1248-1252.
Uylings, H. B. M., & de Brabander, J. M. (2002). Neuronal changes in normal human aging
and Alzheimer's disease. Brain and Cognition, 49(3), 268-276.
Valigorsky, J. M. (1969). Metaplastic transformation of aortic smooth muscle cells in
cortisone-induced dissecting aneurysms in hamsters. Federation Proceedings, 28(2),
802.
Vandenburg, W. (1985). Carotid endarterectomy - does it improve cognitive or motor
functioning? Psychological Medicine, 15(2), 341-346.
Vanswieten, J. C., Geyskes, G. G., Derix, M. M. A., Peeck, B. M., Ramos, L. M. P.,
Vanlatum, J. C., et al. (1991). Hypertension in the elderly is associated with white
matter lesions and cognitive decline. Annals of Neurology, 30(6), 825-830.
Veith, R. C., Lewis, N., Linares, O. A., Barnes, R. F., Raskind, M. A., Villacres, E. C., et al.
(1994). Sympathetic nervous-system activity in major depression - basal and
desipramine-induced alterations in plasma norepinephrine kinetics. Archives of
General Psychiatry, 51(5), 411-422.
Versluis, C. E., van der Mast, R. C., van Buchem, M. A., Bollen, E. L., Blauw, G. J., Eekhof,
J. A., et al. (2006). Progression of cerebral white matter lesions is not associated
with development of depressive symptoms in elderly subjects at risk of
cardiovascular disease: The PROSPER study. International Journal of Geriatric
Psychiatry, 21(4), 375-381.
Wang, L., Krishnan, K. R., Steffens, D. C., Potter, G. G., Dolcos, F., & McCarthy, G. (2008).
Depressive state- and disease-related alterations in neural responses to affective and
executive challenges in geriatric depression. The American Journal of Psychiatry,
165(7), 863-871.

169

Wang, L., van Belle, G., Kukull, W. B., & Larson, E. B. (2002). Predictors of functional
change: A longitudinal study of nondemented people aged 65 and older. Journal of
the American Geriatrics Society, 50(9), 1525-1534.
Weis, S., Jellinger, K., & Wenger, E. (1991). Morphometry of the corpus-callosum in normal
aging and Alzheimers-disease. Journal of Neural Transmission-General Section, 3538.
Wendkos, M. H. (1979). Sudden death and psychiatric illness. New York, NY: SP Medical
and Scientific Books.
Wernicke, K. (1994). Some new studies on aphasia. Reader in the history of aphasia. (Eling
P Trans.). (4th ed., pp. 90-98). Amsterdam: John Benjamins.
Wilson, P. W. F., D'Agostino, R. B., Levy, D., Belanger, A. M., Silbershatz, H., & Kannel,
W. B. (1998). Prediction of coronary heart disease using risk factor categories.
Circulation, 97(18), 1837-1847.
Wilson, R. S., de Leon, C. F. M., Bennett, D. A., Bienias, J. L., & Evans, D. A. (2004).
Depressive symptoms and cognitive decline in a community population of older
persons. Journal of Neurology Neurosurgery and Psychiatry, 75(1), 126-129.
Worsley, K. J., Marrett, S., Neelin, P., Vandal, A. C., Friston, K. J., & Evans, A. C. (1996).
A unified statistical approach for determining significant signals in images of
cerebral activation. Human Brain Mapping, 4(1), 58-73.
Wyatt, R. J., Portnoy, B., Kupfer, D. J., Snyder, F., & Engelman, K. (1971). Resting plasma
catecholamine concentrations in patients with depression and anxiety. Archives of
General Psychiatry, 24(1), 65.
Xavier, F. M. F., Ferraza, M. P. T., Argimon, I., Trentini, C. M., Poyares, D., Bertollucci, P.
H., et al. (2002). The DSM-IV 'minor depression' disorder in the oldest-old:
Prevalence rate, sleep patterns, memory function and quality of life in elderly people
of Italian descent in southern brazil. International Journal of Geriatric Psychiatry,
17(2), 107-116.
Yang, Q., Huang, X., Hong, N., & Yu, X. (2007). White matter microstructural abnormalities
in late-life depression. International Psychogeriatrics, 19(4), 757-766.
Ylikoski, A., Erkinjuntti, T., Raininko, R., Sarna, S., Sulkava, R., & Tilvis, R. (1995). Whitematter hyperintensities on MRI in the neurologically nondiseased elderly - analysis
of cohorts of consecutive subjects aged 55 to 85 years living at home. Stroke, 26(7),
1171-1177.
Ylikoski, R., Ylikoski, A., Erkinjuntti, T., Sulkava, R., Raininko, R., & Tilvis, R. (1993).
White-matter changes in healthy elderly persons correlate with attention and speed
of mental processing. Archives of Neurology, 50(8), 818-824.

170

Yuan, Y. G., Zhang, Z. J., Bai, F., Yu, H., Shi, Y. M., Qian, Y., et al. (2007). White matter
integrity of the whole brain is disrupted in first-episode remitted geriatric
depression. Neuroreport, 18, 1845-1849.
Yuan, Y., Zhang, Z., Bai, F., Yu, H., Shi, Y., Qian, Y., et al. (2008). Abnormal neural
activity in the patients with remitted geriatric depression: A resting-state functional
magnetic resonance imaging study. Journal of Affective Disorders, 111(2-3), 145152.
Zald, D. H., Mattson, D. L., & Pardo, J. V. (2002). Brain activity in ventromedial prefrontal
cortex correlates with individual differences in negative affect. Proceedings of the
National Academy of Sciences of the United States of America, 99(4), 2450-2454.
Zarei, M., Damoiseaux, J. S., Morgese, C., Beckmann, C. F., Smith, S. M., Matthews, P. M.,
et al. (2009). Regional white matter integrity differentiates between vascular
dementia and Alzheimer disease. Stroke; a Journal of Cerebral Circulation, 40(3),
773-779.
Zhang, Y., Schuff, N., Jahng, G. H., Bayne, W., Mori, S., Schad, L., et al. (2007). Diffusion
tensor imaging of cingulum fibers in mild cognitive impairment and Alzheimer
disease. Neurology, 68(1), 13-19.
Zola-Morgan, S. (1995). Localization of brain function - the legacy of Franz Joseph Gall
(1758-1828). Annual Review of Neuroscience, 18, 359-383.
Zubenko, G. S., Sullivan, P., & Nelson, J. P. (1990). Brain imaging abnormalities in mental
disorders of late life. Archives of Neurology, 47, 1107-1113.