WINDOWS TO THE BRAIN

Robin A. Hurley, M.D., L. Anne Hayman, M.D., Katherine H. Taber, Ph.D.

Section Editors

Neuroimaging in Schizophrenia: Misattributions and Religious Delusions

Katherine H. Taber, Ph.D., Robin A. Hurley, M.D.
Cover and Figure 1. In healthy individuals, there is a clear
difference between event-related potentials (ERPs) recorded from
the area of the temporal lobe, containing the auditory cortex when
listening silently to sounds (dark green, N1) compared with talking
while listening to sounds (light green). This indicates a suppression
of auditory cortical activity during self-generated speech, a clear
difference that is not found in subjects with schizophrenia. Note
that the ERP generated by listening silently to sounds (dark purple)
is very similar to that generated while talking (light purple). The
larger N1 peak seen in healthy individuals during listening is not
seen.1

Figure 2. In healthy individuals, activation of the anterior insula

(pink) is associated with attribution of an action to self, whereas
inferior parietal lobe activation (orange) is associated with
attributing the action to another.2 Subjects with schizophrenia who
were experiencing delusions of control over-activated areas in the
inferior parietal (yellow) and cingulate cortices during a motor
control task. This is compared with a state of remission, patients
with schizophrenia who had never experienced delusions of
control, and healthy individuals.3 It has been suggested that this
high level of parietal activation during self-generated action may
result in a predisposition to misattribute the source of control.

Figure 3. Alterations in white matter have been implicated as a mechanism for altered connectivity in schizophrenia. Two recent studies
used diffusion tensor magnetic resonance imaging to assess the integrity of white matter in schizophrenia patients during their first
episode.4,5 One study found areas of both increased (red) and decreased (blue) intervoxel coherence. The other found only areas of
decreased fractional anisotropy (green). Both found localized areas of abnormality in the prefrontal and temporal white matter.

http://neuro.psychiatryonline.org J Neuropsychiatry Clin Neurosci 19:1, Winter 2007


H allucinations (subjective perceptions of an external
event or object that do not correspond to sensory
input) and delusions (strongly held beliefs or judgments
not justified by objective evidence) are hallmarks of
schizophrenia. Both are considered to be Schneiderian
or first-rank positive symptoms of schizophrenia.6 The
delusions and hallucinations of schizophrenia are simi-
lar across cultures, although cultural context is impor-
tant to specific content and interpretation of experiences
(e.g., whether sensing a presence outside of oneself is
labeled as an angel, devil, counselor, alien). An intrigu-
ing theory for the genesis of both delusions and hallu-
cinations is that they may arise from misattribution of
one’s own actions or thoughts to an external agent.7–10
This presumably results, in part, from impairment in the
system(s) that allows a person to differentiate an inter-
nally generated event from an externally generated
event. On an intermittent basis, individuals with schizo-
phrenia appear to experience an impaired sense of
agency, a diminished ability to recognize actions or
thoughts as self-generated (e.g.,“I am making my body
move”).9 The sense of ownership of one’s own actions
(e.g., “My body is moving”) appears to be intact. It has
been suggested that schizophrenia, as a disorder affect-
ing the sense of self, may be uniquely human.
It has been shown that internal self-monitoring
dampens neuronal responses to actions that are self-
generated. Normal healthy individuals report stronger
somatosensory sensations (e.g., tickle) when touched by
another compared to their own touch, and much less
activity is evoked in the primary sensory cortex by self-
touch than by other-touch.11 Psychiatric patients (e.g.,
with schizophrenia, bipolar affective disorder) who re-
ported auditory hallucinations and/or passivity expe-
riences rated both self-touch and other-touch as simi-
larly intense.12 The authors of this study suggest that
these results support a breakdown in self-monitoring in
this population. Electroencephalographic (EEG) and
event-related potential (ERP) studies have shown that
Drs. Taber and Hurley are affiliated with the Veterans Affairs Mid-
Atlantic Mental Illness Research, Education, and Clinical Center, and
the Mental Health Service Line, Salisbury Veterans Affairs Medical
Center, Salisbury, North Carolina. Dr. Taber is also affiliated with the
Department of Physical Medicine and Rehabilitation, Baylor College
of Medicine, Houston, Texas. Dr. Hurley is also affiliated with the De-
partments of Psychiatry and Radiology, Wake Forest University School
of Medicine, Winston-Salem, North Carolina, and the Menninger De-
partment of Psychiatry and Behavioral Sciences, Baylor College of
Medicine, Houston, Texas. Address correspondence to Dr. Hurley,
Hefner VA Medical Center, 1601 Brenner Avenue, Salisbury, NC 28144;
Robin.Hurley@med.va.gov (e-mail).
Copyright 䉷 2007 American Psychiatric Publishing, Inc.
J Neuropsychiatry Clin Neurosci 19:1, Winter 2007
TABER and HURLEY
in normal healthy individuals there is less activity in the
auditory cortex during both speaking out loud and in-
ner speech compared with listening to speech. This re-
sults from an inhibitory influence (“corollary dis-
charge”) from the area of frontal cortex generating
speech onto auditory cortex. In subjects with schizo-
phrenia, the clear difference in auditory cortex activity
between the perception of self-generated speech and
other-generated speech is not seen (Figure 1).1 In addi-
tion, this study found that measures of coherence of
electrical activity between frontal and temporal speech-
related areas were high during talking in normal healthy
individuals, but not in subjects with schizophrenia. The
authors of this study noted that these results suggest
that speech-generating frontal areas are not “alerting”
temporal areas that the speech is self-generated. As a
result, the patient misattributes inner speech to external
sources, and experiences an auditory hallucination. Sup-
porting this interpretation are studies that have found
that patients with schizophrenia, particularly those who
currently have auditory hallucinations, are more likely to
misattribute the source of speech (self/other/unsure)
during a verbal self-monitoring task.13
Recent studies support the therapeutic efficacy of low-
level, repetitive transcranial magnetic stimulation
(rTMS) in the region of the temporoparietal junction for
auditory hallucinations.14,15 This type of stimulation is
believed to decrease neuronal excitability, and thus
might be acting by supplementing the impaired “cor-
ollary discharge” in these patients. This interpretation is
supported by a case study in which fluorodeoxyglucose
positron emission tomography (FDG-PET) was acquired
prior to and during treatment with rTMS in a patient
with auditory hallucinations resistant to both drug ther-
apy and electroconvulsive treatments.16 rTMS was ap-
plied to the region of increased metabolic activity in the
temporal cortex on the baseline PET scan. The hyper-
activity of this region was decreased on the follow-up
PET scans at 2 and 5 weeks of treatment. In a different
study, rTMS to the temporoparietal area decreased au-
ditory hallucinations and improved performance on a
verbal self-monitoring task, suggesting a relationship
between defective source monitoring and auditory hal-
lucinations.17
As noted above, patients with schizophrenia appear
to have an impaired sense of individual agency such
that they misattribute the source of self-generated
thoughts or actions. One approach to delineating areas
of the brain important for the sense of agency has been
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MISATTRIBUTIONS AND DELUSIONS IN SCHIZOPHRENIA
to compare the areas activated when an individual be-
lieves they control an action (e.g., movement of a circle
on a computer screen) with the areas activated when
control is attributed to another. Using event-related
functional magnetic resonance imaging (fMRI), a study
of normal healthy individuals found that activation of
the anterior insula was associated with attribution of an
action to self, whereas inferior parietal lobe activation
was associated with attributing the action to another
(Figure 2).2 When the visual feedback provided during
a task was distorted to manipulate subjects’ attribution
of control (self, self-distorted, other), rCBF (H2O15-PET)
increased in the inferior parietal lobe with increasing
distortion of movement.18 Conversely, rCBF increased in
the anterior insula with decreasing distortion of move-
ment. This clear separation was not found in patients
with schizophrenia who were experiencing first-rank
symptoms, such as auditory hallucinations or delusions
of control.19 There were no areas in which rCBF covaried
with the degree of movement distortion. However,
when the extreme conditions were compared, increased
rCBF was found in the inferior parietal lobe. This was
also positively correlated with the severity of first-rank
symptoms. Comparison of the patients with normal
healthy individuals revealed higher than normal rCBF
in this area, even in the 0⬚ (undistorted) condition. The
authors of this study noted that this high level of parietal
activation during action that is clearly self-generated
may result in a predisposition to misattribute the source
of control.
A study of the brain areas activated (H2O15-PET)
when subjects manipulated a joystick found that pa-
tients with schizophrenia and active delusions of control
over-activated areas in the inferior parietal and cingu-
late cortices and cerebellum compared with themselves
when they had recovered from delusions of control and
normal healthy individuals and schizophrenia patients
who had never had delusions of control (Figure 2).3 This
suggests that these areas of overactivation may relate
more to “state” than to “trait.”
In addition, both patient groups failed to activate the
prefrontal cortex during this task when compared with
normal healthy individuals. The authors of this study
commented that the inferior parietal area is important
for spatial memory and orientation in space. Injury to
this region has been implicated previously in giving rise
to feelings of alienation, spatial dislocation, and control
by external forces. Thus, misattribution of internally
generated acts to external entities might be a result of
2 http://neuro.psychiatryonline.org
impaired communication between frontal brain areas
initiating action and parietal regions monitoring move-
ment in space. Interestingly, the severity of first-rank
symptoms correlated positively with rCBF (O-PET) in
the parietal cortex (BA 7/40) and inversely with rCBF in
the posterior cingulate cortex (BA 30) when scans were
acquired under resting (eyes closed) conditions.20
Both electrophysiological and anatomical studies sug-
gest that long-range functional connectivity between ce-
rebral regions is altered in patients with schizophrenia
compared with normal healthy individuals.21,22 Diffu-
sion tensor imaging-based measurements provide a way
to directly assess white matter integrity. Local changes
in the structural integrity of white matter are believed
to indicate areas of altered connectivity. There has been
considerable variation in the results of diffusion tensor
imaging studies of schizophrenia, some of which are
likely to be due to methodological differences.23 Most
studies have been of medicated patients with chronic
schizophrenia, which may also contribute to variabil-
ity.24,25 In addition, a recent study26 assessed fractional
anisotropy and mean diffusivity in specific white matter
tracts as a function of age in patients with schizophrenia
and age-matched healthy individuals. They concluded
that there are age-related differences in brain maturation
between these groups, particularly in the fronto-temporal
pathways, which complicate comparisons.
Several recent studies have used diffusion tensor im-
aging in patients with schizophrenia during their first
episode in order to avoid the confounding effects of dis-
ease progression and medications. One utilized very
strong gradients (maximum b⳱ 14,000 s/mm2) in an ef-
fort to more clearly isolate the intra-axonal compart-
ment.27 All patients were within 1 month of initial hos-
pitalization. Histogram analysis identified fewer pixels
consistent with white matter in the patient group, sug-
gesting an overall decrease in the white matter com-
partment. Symptom severity was negatively correlated
with this measure (more severe symptoms, less white
matter). Two studies used voxel-based analysis in order
to localize areas of abnormality (Figure 3).4,5 In one, av-
erage illness duration was 116 days (range⳱14 to 270).
Intervoxel coherence maps were constructed to identify
clusters (minimum of six voxels) of altered white matter.
Three clusters of increased intervoxel coherence and 11
clusters of decreased intervoxel coherence were identi-
fied in the subcortical white matter, corpus callosum,
and internal capsule. In the other, average illness dura-
tion was 10.3 months (range⳱6 to 24).5 Fractional aniso-
J Neuropsychiatry Clin Neurosci 19:1, Winter 2007

tropy maps were constructed to identify clusters (min-
imum of 30 voxels) of altered white matter. Eleven
clusters of decreased fractional anisotropy were identi-
fied in the subcortical white matter and cerebral pedun-
cles. Thus, all three studies support altered white matter
connectivity in schizophrenia, with some overlap of
areas.
One of the perplexing aspects of schizophrenia, which
has a strong genetic component, is its continual exis-
tence in the human species. The presence of schizophre-
nia in groups that are known to have been genetically
isolated for a very long time (e.g., Australian aborigines)
suggests that its origin may be very far back in time. A
great variety of hypotheses have been developed related
to evolutionary pressures that might have maintained
susceptibility genes for schizophrenia in the human
gene pool, either as a byproduct of selection for other
traits or due to adaptive advantages.28–30 Several of
these contend that schizophrenia, as a uniquely human
brain disorder, could most logically be linked to char-
acteristics that separate the human species from other
animals, such as intelligence, language, and highly de-
veloped social cognition.
Two such theories posit the evolutionary advantages
of having a few individuals prone to delusions/halluci-
nations by linking schizophrenia with a uniquely human
cultural trait—religion.30 Both are based on perceived
similarities between schizophrenia and shamanism. One
focuses on the evolutionary adaptive benefit to tribal
units of spiritual ceremonies, and the value of having at
least one individual within the group prone to “spirit
possession” to serve as shaman.31 The other concentrates
on the charismatic traits of schizophrenia-prone individ-
uals, and their possible important role as leaders provid-
ing a mechanism for splitting tribal communities that are
growing too large.30
Most of what is known about the neural substrates of
religious experiences is based on clinical observations.32
Only a few studies have explored the brain areas that
are active during a religious, spiritual or mystical ex-
perience. In one, Carmelite nuns were instructed to “re-
member and relive the most intense mystical experience
ever felt in their lives.”33 The brain areas activated while
they reexperienced this mystical state include medial or-
bital, medial prefrontal, anterior cingulate, and inferior
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TABER and HURLEY
and superior parietal cortices. In another study, Francis-
can nuns were imaged during religious meditation that
had the goal of “opening themselves to being in the
presence of God.”34 Increased blood flow was found in
the prefrontal, inferior frontal, and inferior parietal cor-
tices. In addition, there was an inverse correlation be-
tween cerebral blood flow in prefrontal and superior
parietal cortices. In the third study, members of an evan-
gelical fundamentalist community were imaged during
religious meditation.35 Areas activated included the dor-
solateral prefrontal cortex, dorsomedial prefrontal cor-
tex, medial parietal cortex, and cerebellum. No blood
flow changes were found in the orbitofrontal cortex or
amygdala.
One group has done extensive research exploring in-
duction of a quasi-religious experience, that of the ex-
perience of the sensed presence of a “sentient being.”36
They have found that application of weak (1 to 5 micro
tesla) complex magnetic field stimulation to the tem-
poroparietal area reliably evokes such experiences in
normal individuals. The proposed mechanism is that the
sense of self and sense of other depend upon the left and
right hemispheres, respectively, and that any process
that disrupts the normal reciprocal inhibition between
the hemispheres should increase the incidence of a
sensed presence. Two case reports are interesting in this
context. In one, a patient with uncontrolled epilepsy
who experienced a “sensed presence” during the aura
had markedly increased perfusion in the frontoparietal
region. The authors of this article postulated that the left
temporal spike spread to the right-sided mirror area to
create the clinical picture.37 In the other, a patient with
schizophrenia with active “florid religious delusions”
had increased perfusion in frontal and temporal regions
that normalized during remission of symptoms.38 The
authors of this case report note significance to the lat-
eralization of these changes to the left side.
In conclusion, these preliminary imaging studies in
patients with schizophrenia support the theory that the
misattribution of self-generated thoughts or actions to
outside entities/forces may contribute to the psychotic
state. The inferior parietal cortex has been implicated.
The few studies that have been completed in healthy
individuals suggest that this region may also be impor-
tant to normal religious experience.
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MISATTRIBUTIONS AND DELUSIONS IN SCHIZOPHRENIA
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