Psychological Medicine (2010), 40, 557567.

f Cambridge University Press 2009

doi:10.1017/S0033291709990821 Printed in the United Kingdom

O R I G I N A L AR T I C LE

Evidence for structural abnormalities of the human

habenular complex in aective disorders but not
in schizophrenia
K. Ranft1,2, H. Dobrowolny1, D. Krell1, H. Bielau3, B. Bogerts1 and H.-G. Bernstein1*
1

Department of Psychiatry, University of Magdeburg, Magdeburg, Germany

Department of Neurology, University of Magdeburg, Magdeburg, Germany
3
Walter-Friedrich-Krankenhaus Olvenstedt, Magdeburg, Germany
2

Background. The habenular complex is composed of important relay nuclei linking the limbic forebrain to the
midbrain and brain stem nuclei. Based on clinical observations, experiments with animals and theoretical considerations, it has been speculated that this brain area might be involved in psychiatric diseases (i.e. schizophrenia
and depression). However, evidence in favour of this hypothesis is still lacking because the human habenular complex has rarely been studied with regard to mental illness.
Method. We examined habenular volumes in post-mortem brains of 17 schizophrenia patients, 14 patients with depression (six patients with major depression and eight patients with bipolar depression) and 13 matched controls. We
further determined the neuronal density, cell number and cell area of the medial habenular nuclei of the same cohorts using a counting box and a computer-assisted instrument.
Results. Signicantly reduced habenular volumes of the medial and lateral habenula were estimated in depressive
patients in comparison to normal controls and schizophrenia patients. We also found a reduction in neuronal cell
number and cell area in depressive patients for the right side compared to controls and schizophrenia patients. No
such changes were seen in schizophrenia.
Conclusions. Our anatomical data argue against prominent structural alterations of the habenular nuclei in schizophrenia but demonstrate robust alterations in depressive patients. We are currently applying immunohistochemical
markers to better characterize neuronal subpopulations of this brain region in schizophrenia and depression.
Received 10 December 2008 ; Revised 28 April 2009 ; Accepted 5 June 2009 ; First published online 12 August 2009
Key words : Aective disorder, habenula, human brain, morphometry, neuronal density, schizophrenia.

Introduction
The habenula is a paired diencephalic structure,
positioned below the pineal gland in the dorsal
diencephalon, adjacent to the posterior and dorsal part
of the thalamus. It was commonly regarded as consisting of two parts, the medial and lateral habenula (Marburg, 1944). However, a detailed anatomical
analysis of the rodent habenula revealed a much more
complex subnuclear structure with up to 15 subdivisions (Andres et al. 1999 ; Geisler et al. 2003). Medial
and lateral habenular nuclei are cytoarchitectonically
distinct, with very dierent input and output connections. According to Nauta and others, the habenula
is one of a few brain structures where limbic and

* Address for correspondence : Prof. Dr H.-G. Bernstein,

Department of Psychiatry, University of Magdeburg, Leipziger Str. 44,
D-39120 Magdeburg, Germany.
(Email : Hans-Gert.Bernstein@med.ovgu.de)

striatal mechanisms intermix directly (Nauta, 1958 ;

Herkenham & Nauta, 1977, 1979 ; Sutherland, 1982 ;
Haun et al. 1992 ; Andres et al. 1992, 1999). Because of
its structural complexity and numerous connections
with other brain areas, the habenular complex is implicated in many dierent neurotransmitter and modulator systems including biogenic amines (dopamine,
serotonin and acetylcholine : Wang & Aghajanian, 1977 ;
Herkenham & Nauta, 1979 ; Lisoprawski et al. 1980 ;
Wooten et al. 1981 ; Reisine et al. 1982 ; Contestabile &
Fonnum, 1983 ; London et al. 1985 ; Thornton et al. 1985 ;
Christoph et al. 1986 ; Caldecott-Hazard et al. 1988;
Mori et al. 1999), amino acids [glutamate/aspartate :
Kiss et al. 2002 ; gamma-aminobutyric acid (GABA) :
Gallager, 1976 ; Gottesfeld et al. 1977 ; Contestabile &
Fonnum, 1983], neuropeptides (substance P, vasopressin : Ronnekleiv, 1988 ; Lucas et al. 1992) and purines [adenosine triphosphate (ATP) : Pankratov et al.
2006]. Functionally, numerous reports have linked
the habenular complex with avoidance learning,

558

K. Ranft et al.

regulation of feeding behaviour, maternal behaviour

and stress (Gonzalez-Lima & Scheich, 1986 ; Wilcox
et al. 1986 ; Thornton & Bradbury, 1989 ; Chastrette et al.
1991 ; Corodimas et al. 1993 ; Matthews-Felton et al.
1995 ; Vale-Martinez et al. 1997 ; Amat et al. 2001). As
the habenular complex seems to serve as a crucial
modulatory relay between limbic forebrain structures
and the midbrain, regulating levels of dopamine and
serotonin utilization in the telencephalon and diencephalon, it is reasonable to consider the habenula a
candidate brain area involved in the development of
schizophrenic and aective disorders (Scheibel, 1997).
Indeed, there are both good theoretical arguments
and experimental evidence in favour of a putative
role of the habenula in processes with relevance
for neuropsychiatric disorders (i.e. aective disorder
and schizophrenia). Thus, the habenular complex is
implicated in a variety of processes known to be disrupted in depression, such as disturbed motor and
cognitive behaviour, nociception, anxiety, reward,
behavioural inhibition and sleep (Ronnekleiv et al.
1980 ; Sutherland & Nakajima, 1981 ; Goldstein, 1985 ;
Mahieux & Benabid, 1987 ; Benabid & Jeaugey, 1989 ;
Haun et al. 1992 ; Murphy et al. 1996 ; Valjakka et al.
1998 ; Carlson et al. 2001 ; Ellison, 2002 ; Ullsperger &
von Cramon, 2003 ; Hikosaka et al. 2008). A variety of
drugs have been demonstrated to induce degeneration
within the lateral habenula (e.g. by amphetamine or
cocaine) and the medial habenula (nicotine), and in the
fasciculus retroexus when given continuously (for an
overview, see Carlson et al. 2000, 2001 ; Ellison, 2002).
Neuronal activity in the lateral habenula is strongly
inhibited by dopamine agonists and disinhibited by
dopamine antagonists such as haloperidol, an antipsychotic drug (McCulloch et al. 1980 ; CaldecottHazard et al. 1988 ; Ellison, 1994). Moreover, Shumake
et al. (2003, 2004) studied congenitally helpless rats
(a widely used animal model of depression) and found
an elevated metabolism within the habenula and the
interpeduncular nucleus. These authors also revealed
an almost complete decoupling of limbic forebrain
regions from midbrain and diencephalic regions in
newborn congenitally helpless rats. In three other rat
models of depression an elevated metabolism in the
lateral habenula was shown that was accompanied
by reduced exploratory behaviour (Caldecott-Hazard
et al. 1988). Lesions of the habenula have also been
shown to eliminate the induction of learned helplessness (Amat et al. 2001 ; Klemm, 2004). In a neuroimaging study using positron emission tomography
(PET), a strong correlation between habenula activity
and depression severity was demonstrated in human
subjects (Morris et al. 1999).
Accumulating evidence from experiments with
animals led Sartorius & Henn (2007) to suggest that an

overactivation of the habenula might play a crucial

role in human depression, and that functional inhibition of the lateral habenula by deep brain stimulation might have antidepressive eects.
Unlike depression, there is only little evidence in
favour of an involvement of the habenular complex in
schizophrenia. It has been shown that in rats bilateral
lesions of the structure induces schizophrenia-like
behaviour (Lecourtier et al. 2004). Human functional
imaging studies have demonstrated that the habenula
is activated following receipt of unexpected negative
feedback or the absence of expected positive feedback.
In patients with schizophrenia, a lack of appropriate
modulation of habenula activity in response to feedback has been described (Kelly, 1998; Shepard et al.
2006). Hence, the habenula might play an important
role in mediating the feedback-processing decits in
schizophrenia.
All these ndings give good reason to investigate
the habenula in human neuropsychiatric disorders.
Surprisingly, the habenular complex has been largely
overlooked by neuropsychiatric research, except for
the above-mentioned study of Morris et al. (1999) and a
computed tomography (CT) study by Sandyk (1992)
that demonstrated an increased prevalence of habenular calcication in schizophrenia. One reason for that
might be our limited knowledge on this brain structure in normal human brains with regard to its anatomy and physiology. To our knowledge, there is only
one paper dealing with this topic (Marburg, 1944). The
aim of the current study was therefore to investigate
the morphology of the human habenular complex at a
light microscopic level in patients with schizophrenia
and depression and in normal control subjects.

Method
Subject characteristics
All brains were from the Magdeburg Brain Collection.
Sampling of the human brain material and asservation
was carried out in accordance with the Declaration of
Helsinki (1964), German law and approval by the local
ethics commission.
Brains were collected from 14 patients with mood
disorder (eight women, six men). The age range was
26 to 69 years (mean 48.612.8 years). Of these 14,
nine had died by suicide, including ve women and
four men ; six patients displayed major depression and
eight bipolar depression. We also investigated brains
of 17 patients with schizophrenia (nine women and
eight men) with an age range of 39 to 66 years (mean
52.67.5 years). Control brains were collected from
ve women and eight men with an age range of 38 to
66 years (mean 55.98.9 years). All control subjects

Habenula in schizophrenia and aective disorders

559

Table 1. Characteristics of subjects

No./sex/
age (years)
Controls
1/M/56
2/M/64
3/F/52
4/M/47
5/M/38
6/F/48
7/M/47
8/M/56
9/F/64
10/F/61
11/M/63
12/F/65
13/M/66
MeanS.D.
55.98.9
Schizophrenia
1/M/49
2/F/66
3/M/46
4/F/53
5/F/60
6/M/50
7/M/47
8/M/39
9/F/52
10/F/40
11/F/55
12/F/61
13/M/61
14/M/48
15/M/58
16/F/59
17/F/56
MeanS.D.
52.97.6
Depression
1/F/46
2/M/69
3/F/62
4/F/60
5/M/39
6/F/49
7/M/42
8/F/39
9/F/53
10/F/26
11/M/42
12/F/61
13/M/35
14/M/47
MeanS.D.
48.612.4

Brain
weight (g)

Post-mortem
delay (h)

Cause of death

1450
1310
1200
1200
1550
1170
1450
1470
1190
1350
1200
1100
1550

30
35
24
24
19
48
24
24
24
24
48
24
24

Acute pancreatitis
Cardiac insuciency
Cardiac insuciency
Respiratory insuciency
Myocardial infarction
Status asthmaticus
Myocardial infarction
Myocardial infarction
Peritonitis
Heart failure
Acute cardiac failure
Cardiac insuciency
Myocardial infarction

1322157

28.69.4

1325
Unknown
1450
1110
1470
1350
Unknown
1170
1240
1290
Unknown
1300
Unknown
1300
Unknown
1060
Unknown

24
24
48
48
48
48
24
12
24
48
48
24
24
48
24
48
24

1279128

34.613.3

1300
1320
1300
1140
1520
1274
Unknown
1400
1340
1320
1320
1240
1240
1670

4
24
48
24
14
72
5
48
48
22
12
70
24
24

1337133

31.924.8

F, Female ; M, male ; S.D., standard deviation.

Cardiac insuciency
Coronary thrombosis
Pulmonary embolism
Myocardial infarction
Cardiac insuciency
Sudden cardiac death
Ventricular brillation
Ventricular brillation
Drowning
Cardiac insuciency
Suicide (pills)
Pulmonary embolism
Cardiac insuciency
Bolus death
Pulmonary embolism
Cardiac insuciency
Pulmonary embolism

Duration
(years)

Diagnosis
(DSM-III-R)

Psychopathology

18
23
18
20
16
25
24
22
28
19
6
3
35
32
25
7
15

295.32
295.0
295.3
295.3
295.3
295.1
295.3
295.3
295.3
295.0
295.32
295.2
295.3
295.2
295.3
295.3
295.2

Chronic schizophrenia
Chronic schizophrenia
Chronic schizophrenia
Chronic schizophrenia
Chronic schizophrenia
Schizophrenia
Chronic schizophrenia
Chronic schizophrenia
Chronic schizophrenia
Schizophrenia
Schizophrenia
Catatonic schizophrenia
Schizophrenia
Catatonic schizophrenia
Chronic schizophrenia
Chronic schizophrenia
Catatonic schizophrenia

296.53
296.53
296.53
296.53
296.53
296.53
296.34
296.34
296.34
296.34
296.53
296.34
296.34
296.53

Bipolar depression
Bipolar depression
Bipolar depression
Bipolar depression
Bipolar depression
Bipolar depression
Major depression
Major depression
Major depression
Major depression
Bipolar depression
Major depression
Major depression
Bipolar depression

19.59.1
Suicide by overdose
Cardiac insuciency
Pulmonary embolism
Bronchopneumonia
Pulmonary embolism
Suicide by overdose
Suicide by hanging
Suicide by overdose
Suicide by hanging
Suicide by falling
Suicide by hanging
Cardiac insuciency
Suicide by bleeding
Suicide

13
17
11
10
1.5
24
Unknown
7
Unknown
Unknown
16
11
2
9
11.16.6

560

K. Ranft et al.

died of natural causes. The demographic data for all

subjects are summarized in Table 1.
All patients were matched for age, gender and postmortem delay. The matching processes were carried
out before the experimental procedures and quantitative analyses. Information for clinical diagnosis was
obtained by the careful study of clinical records and by
structured interviews with people who either lived
with, or had frequent contact with, the subjects before
death. Structured interviews were carried out to collect information to determine the presence or absence
of psychiatric disorders. Data on lifetime and current
mental illness were gathered with the Lifetime Version
of the Schedule for Aective Disorders and Schizophrenia (SADS-L ; Spitzer & Endicott, 1978). Final
Axis I diagnoses were assigned in consensus meetings
of two psychiatrists using all available information
from informants and clinical charts. The nal diagnosis was compatible with DSM-III-R (APA, 1987).
In the same way, neuropsychiatric disorders were
excluded in the control subjects. There was no current
or lifetime psychoactive substance disorder (abuse or
dependence according to DSM-III-R) in any of the
subjects. All patients suering from depressive syndrome had received long-term treatment with antidepressants. In addition, one of them had received
neuroleptic drugs. All bipolar patients but one had
received lithium. All schizophrenia patients had been
treated with typical neuroleptics (haloperidol).
Qualitative neuropathological changes due to
neurodegenerative disorders (such as Alzheimers
disease, Parkinsons disease, Picks disease), tumours,
inammatory, vascular or traumatic processes were
ruled out by an experienced neuropathologist (for
demographical, histological and clinical data see
Table 1).
Tissue processing and histology
All brains were obtained from pathologists or medical
examination ocers. Tissue preparation was performed as described previously (Bernstein et al. 1998,
1999). Brains were removed within 4 to 72 h after
death and xed in toto in 8 % phosphate-buered formaldehyde for at least 2 months. Frontal and occipital
poles were separated by coronal cuts anterior to the
genu and posterior to the splenium of the corpus
callosum. After embedding all parts of the brains in
paran, serial coronal sections of the middle block
were cut on a microtome at 20 mm and mounted. Every
50th section was stained for anatomical orientation
and morphometric investigations with a combined cell
and bre staining according to Nissl (Cresyl Violet)
and HeidenhainWoelcke procedures (Zech et al. 1986).
Volume shrinkage was determined for each brain

Fig. 1. Overview of the medial (MHB) and lateral (LHB)

habenula of the right and left side with adjacent structures.
Aq, aqueduct, ant, anterior, pc, posterior commissure,
hbc, habenular commissure. Combined cell and bre with
Nissl (Cresyl Violet) and HeidenhainWoelcke procedures
(magnicationr1.25).

before and after dehydration and embedding of tissue.

Volume shrinkage factors were calculated using the
formula : VF=(A1/A2)3/2, where VF is the volume
shrinkage factor, A1 the cross-sectional area before
processing the tissue, and A2 the cross-sectional area
after processing the tissue. Sections were taken at intervals of 400 mm (according to Cavalieris principle ;
Mayhew, 1992).
Morphometry and stereology
Seven sections per case were selected randomly for the
analysis of the habenular complex. A computerized
image analysis system (Digitrace1 , Imatec, Germany)
was used. It was attached to a high-resolution video
camera on a Leica microscope, equipped with a
motorized scanning stage. For the identication and
delineation of the habenular, complex images of each
side were taken using a fourfold magnication. These
composed images were scanned by a digital camera
and loaded by the analysis system. At a higher magnication the entire area of the habenular complex
on the right or the left side was visible and allowed
delineation of the medial and lateral habenular nuclei
(Fig. 1). Volumes of both subnuclei were calculated
from areas measured on the videoscreen, performing
morphometrical operations described previously in
detail (Bogerts et al. 1990).
All further investigations (cell countings) were
performed within the medial habenular nucleus only
(see limitations of the study). The area of the medial
habenular nucleus was divided into boxes of 250r
250 mm using a counting grid. Every 20th box was
selected randomly and all neurones within these boxes

Habenula in schizophrenia and aective disorders

were counted manually. In each section, neurones of
the medial habenular nucleus were counted by the
optical dissector method using a r40 objective in the
dissector elds, which were selected using a systematic random sampling along the whole cross-sectional
area of the medial habenular nucleus (Bernstein et al.
1998). Application of the optical dissector made it
necessary to measure movements in the z axis, which
was performed by using a microcator as an integral
part of the microscope. Only neurones in which a
nucleolus was clearly visible were counted. Measurements of volumes and neurone counts were performed blind to the diagnosis.
Statistical analyses
All data are presented as meanstandard deviation
(S.D.). A single-factor analysis of variance (ANOVA)
was performed using diagnostic groups as a threelevel independent variable (mood disorder patients
versus schizophrenia patients versus non-psychiatric
controls) and measured and calculated parameters
(e.g. mean cell area) as dependent variables. Post-hoc
Tukey HSD tests were performed to detect two-group
dierences. Pearsons correlation coecients were calculated to determine the inuence of demographic,
histological and clinical variables such as age at time
of death, brain weight, post-mortem delay, duration of
illness or psychiatric medication, which might confound the results of the dependent variables. p values
<0.05 were dened as statistically signicant.

Results
Volumetry
Medial habenula
When estimating the volumes of habenular nuclei,
we found in the medial habenula of the depressive
patients a volume of 2.760.90 mm3 for the right side
and 2.650.65 mm3 for the left side. There was a
signicant dierence (p=0.025) for the right side in
comparison to controls, which displayed a volume of
3.640.97 mm3 for the right side and 3.351.33 mm3
for the left side. There was a signicant reduction
of 24.1 % on the right side (and 20.9 % with a trend
towards signicance on the left, see Fig. 2 a).
There was no dierence between schizophrenia
patients and controls with regard to habenular volumes (determined volumes in schizophrenia were
3.690.91 mm3 for the right side and 3.270.81 mm3
for the left side). However, the habenula as a whole
had a dierent shape in schizophrenia compared to
controls, in that it was plumper (shorter in the rostrocaudal dimension and larger in diameter). However,

561

when comparing the volumes of the aective disorder group with those of schizophrenia patients, a
signicant reduction for both sides (p=0.01 and
p=0.029) was revealed for the depressed patients. We
failed to detect any dierences of the left and right side
within the groups (Table 2).
Lateral habenula
As shown in Fig. 2b, we found a signicant dierence
of the right side between depressive patients (right
side 23.666.61 mm3 and left side 24.915.23 mm3)
and controls (right side 29.594.83 mm3 and left
side 27.575.05 mm3), with a reduction of 20.0 % (p=
0.014). There was also a signicant reduction of the
right side between schizophrenia and depressive patients of 26.7%, but no signicant dierence of schizophrenia patients in comparison to controls (right side
29.985.03 mm3, left side 28.565.70 mm3).
Cell number, cell area and cell density
Neuronal cell numbers
The estimated total cell numbers were 21073154972
(right side) and 18714288447 (left side) in controls,
13788634729 (right side) and 12909125945 (left
side) in patients with aective disorder, and 206751
68261 (right side) and 16898467978 (left side) in
schizophrenia patients. Signicant dierences were
found for the depressive patients in comparison to
controls, with a reduction of 34.6 % (p=0.000) and
31.0 % (p=0.027) for the right and left side respectively, and between patients with aective disorder
and schizophrenia, with a reduction of 49.9 % (p=
0.003) of the right side and 30.9 % (p=0.047) of the left
side. No dierences were seen between schizophrenia
patients and controls (Fig. 2 c).
Neuronal cell areas
We found an area of 0.236r106 mm2 on the right and
0.206r106 mm2 per 1 mm3 tissue on the left of controls,
0.142r106 mm2 on the right and 0.135r106 mm2 per
1 mm3 tissue on the left of the depressive patients,
and 0.218r106 mm2 and 0.189r106 mm2 of the schizophrenia patients respectively. There was a signicant
reduction on both sides in depressive patients in
comparison to controls of 39.6 % (p=0.000) and 34.4 %
(p=0.016) for right and left respectively, and between
patients with aective disorder and schizophrenia
patients with 53.5 % (p=0.002) and 39.8 % (p=0.018)
(see Fig. 2 d).
Neuronal cell densities
No signicant dierences were found between the
groups. We could not detect any dierences between

562

Repeated-measures ANOVA

Tukey-HSD post-hoc tests, group diagnosis

Hemisphere

Hemisphere

Diagnosis

Subnucleus,
hemisphere
Diagnosis
Con v. Dep

Con v. Sz

Dep. v. Sz

Statistical factors by repeated-measures ANOVA

Within-subject
Between-subject
Control
Lateral habenula
Volume (mm3)
Left
Right
Medial habenula
Volume (mm3)
Left
Right

27.575.05
29.594.83

3.351.33
3.640.97

Depressive

24.144.54
22.785.96

Diagnosis

Schizophrenia

28.915.73
30.265.03

Interaction partr
diagnosis
F(2, 41)=5.832 ;
p = 0.006

Main eect diagnosis

F(2, 41)=6.545 ;
p = 0.003

Con>Dep
p= 0.026

Con<Sz
p=0.836

Dep<Sz
p = 0.003

Main eect
diagnosis
F(2, 41)=6.914 ;
p = 0.003

Main eect diagnosis

F(2, 41)=4.065 ;
p = 0.025

Con>Dep
p= 0.046

Con>Sz
p=0.991

Dep<Sz
p = 0.040

2.640.67
2.710.88

3.240.80
3.670.89

Estimated number of cells

Left
187.14288.447
Right
210.73154.972

130.71626.253
139.69034.114

165.59467.498
201.72369.574

Main eect diagnosis

F(2, 41)=5.244 ;
p = 0.009

Con>Dep
p= 0.010

Con>Sz
p=0.709

Dep<Sz
p = 0.040

Estimated area of cells (mm2)

Left
206.36697.579
Right
235.53473.225

136.31431.929
142.96635.119

185.61374.954
213.64973.876

Main eect diagnosis

F(2, 41)=6.130 ;
p = 0.005

Con>Dep
p= 0.005

Con>Sz
p=0.614

Dep<Sz
p = 0.029

Estimated cell density (cells/mm3)

Left
59.35723.525
Right
60.46817.331

50.46813.240
54.90014.816

Main eect diagnosis

F(2, 41)=0.622 ;
p=0.542

53.72224.146
57.18722.323

Con, Control ; Dep, depressive ; Sz, Schizophrenia.

Values given as meanstandard deviation. Signicant p values are in bold.
All interactions hemisphererdiagnosis were non-signicant, therefore no single test per hemisphere was performed.

K. Ranft et al.

Table 2. Summary of results

Habenula in schizophrenia and aective disorders

(b)
5

Volume of lHb (mm3)

Volume of mHb (mm3)

(a)
*

4
3
2
1
0
Left

40
35
30
25
20
15
10
5
0

Left

Right

(c)

**

Right

(d)

200000
150000
100000
50000

Cell area (mm2)

0.300
*** ***

250000
Cell number

563

0.200
0.150
0.100
0.050
0.000

0
Left

Right

*** ***

0.250

Left

Right

Fig. 2. Volumes of the (a) medial (mHb) and (b) lateral (lHb) habenular complex ; (c) neuronal cell number and (d) neuronal
cell areas of the medial habenula. Signicant reductions of all parameters measured were found only in depressive patients
(right side). %, Controls ; , depressive patients ; &, schizophrenia patients. * pf0.05, ** pf0.01, *** pf0.001.

patients with major depression and bipolar depression.

Confounding factors
Variables that could inuence neurone numbers and
volumes, such as brain weight, age at time of death,
post-mortem delay or times of xation, and duration
of medication did not correlate with the parameters
measured.
Methodical limitations
A limitation of this study is the lack of data about cell
densities in the lateral habenula. Although we are
aware that knowledge of cell numbers from the lateral
habenula would be extremely interesting and helpful,
we had to restrict ourselves on the medial part for
methodical reasons. To properly determine volumes
we had to delineate the habenula and its subdivisions
(Herkenham & Nauta, 1977). This can be done best
using a combined cellbre staining technique. Unfortunately, a consequence of this approach was a
partial masking of stained neuronal cell bodies in the
lateral habenula (but not in the medial part) by very
dense bre tracts, which hampered correct countings.
Studies are in progress to overcome this problem.
A second important issue is the long-term treatment
of the patients with antipsychotics (schizophrenia)
or antidepressants (depression). Although our own
calculations did not reveal signicant correlations
between the duration and/or dose of medication

and volumes or cell numbers, others have found that

haloperidol (Dorph-Petersen et al. 2005 ; Lieberman
et al. 2005) and antidepressants (Young et al. 2008)
may aect brain volumes and should be taken into
account as possible confounding factors in postmortem studies.
Discussion
The limbic system has long been implicated in the
pathogenesis of schizophrenia and aective disorders,
and structural abnormalities have been found in
many limbic areas (for reviews, see Falkai et al. 1988 ;
Campbell & MacQueen, 2004 ; Dietrich et al. 2007 ;
Geisler & Trimble, 2008 ; White et al. 2008 ; Schmitt et al.
2009). Very little is known about the limbic habenular nuclei in neuropsychiatric disorders, however.
Although the need for studies on the habenula in the
context of psychiatric diseases such as schizophrenia
and depression has clearly been recognized (Sandyk,
1992 ; Scheibel, 1997 ; Deutsch et al. 2000; Klemm, 2004 ;
Sartorius & Henn, 2007 ; Hikosaka et al. 2008), there are
only two studies on this topic (Morris et al. 1999 ;
Shepard et al. 2006). The current study is, to our
knowledge, the rst morphometric study on the
human habenular complex in schizophrenia and depression. Our data show reduced habenular volumes
and cell numbers in patients with aective disorder,
indicating distinct disease-related structural alterations of this brain region. This is in agreement with
previous data of the human neuroimaging (PET)

564

K. Ranft et al.

study that found a strong correlation between habenula activity and severity of depression (Morris et al.
1999). Recent investigations show that depression is
associated with an increase in the activation of the
lateral habenular nucleus, which is accompanied by
down-regulation of monaminergic systems. Deep
brain stimulation is being applied increasingly to cure
treatment-resistant depressive patients by reducing
this overactivation (reviewed in Hauptman et al. 2008).
This increased habenular activity in patients with affective disorder is dicult to explain on grounds of
reduced volumes and cell numbers only. Rather,
changes in the chemical composition of the habenula
would be expected to contribute signicantly to this
altered activity pattern in depression. Unfortunately,
very little is known about the regional distribution and
cellular localization of neurotransmitters and modulators in the human habenula. Our own unpublished
data on altered cellular expression of choline acetyltransferase and glutamate decarboxylase in habenular
neurones of depressive patients are in favour of this
assumption.
Almost all available data for the habenular complex
originate from animal studies. In animal models
of depression tested so far, an abnormally elevated
habenular metabolism was found (Caldecott-Hazard
et al. 1988 ; Shumake et al. 2003).
Stress experiments demonstrate a role of the habenular complex in mediating the neurochemical and
behavioural responses to chronic stress. Moreover, the
habenula seems to be necessary for the induction of
learned helplessness/behavioural depression (Amat
et al. 2001).
The raphe nuclei are implicated in the pathophysiology of depression (Bielau et al. 2005). Morris
et al. (1999) and Hikosaka et al. (2008) proposed that
the habenula represents a point of convergence in a
feedback loop that controls raphe activity. A recently
published lesion experiment suggests that the lateral
habenula might be a necessary structure for the induction of behavioural depression in the rat, and that
activities of the lateral habenula are involved in depressive disorders (Yang et al. 2008). Lateral habenula
lesions improved behavioural responses of depressed
rats most probably by increasing serotonin levels in
the dorsal raphe nucleus (Hikosaka et al. 2008 ; Yang
et al. 2008).
Mainly based on genetic ndings, bipolar depression is currently discussed as a more distinct
disease that is possibly more closely related to schizophrenia than to major depressive disorder (for a review on this topic, see Moller, 2003). However, in the
case of the habenula, bipolar patients show structural
alterations that are similar to those in unipolar depression, but not to schizophrenia. Most of our results

were obtained from the medial habenula, which

plays an important role in the septo-habenulointerpeduncular pathway. Eerences of the medial
habenula are travelling primarily to the interpeduncular nucleus (Ramon y Cajal, 1911 ; Nauta, 1958 ;
Akagi & Powell, 1968 ; Herkenham & Nauta, 1977),
which is reciprocally connected to many midbrain
areas. The medial habenula itself has some minor
connections with the median raphe, the ventral tegmental area (VTA) and some other areas. In congenitally helpless rats the medial and lateral habenular
nuclei were metabolically hyperactive and the VTA
activity was diminished, which suggests that the
habenula might play a role in depression and reect a
defective dopamine innervation (Shumake et al. 2003).
In general, most interest is directed to the lateral
habenula (reviewed in Geisler & Trimble, 2008). We
found a strongly reduced volume of the lateral habenula, but additional investigations at the cellular
level are necessary to learn more about the structural
impact of this part of the habenular complex in
neuropsychiatric disorders, especially because the
lateral habenula has a very complex subnuclear
structure with abundant input and output patterns
(Andres et al. 1999 ; Geisler et al. 2003).
We would have expected more dierences in
schizophrenia patients compared to controls according to the often mentioned changes in the dopamine
system. In a motion prediction test (a human MRI
study) with positive and negative feedback, blood
ow to the habenula decreased following successful
trials and increased following failures. This again
indicates that the habenula might inhibit dopamine
activity in response to failure (Ullsperger & von
Cramon, 2003).
The habenular complex seems to include a wide
range of neurotransmitters in its trajectory, from its
septalbasal forebrain origins to the habenula, interpeduncular nucleus and midbrain tegmentum. These
neurotransmitters include glutamate, aspartate, acetylcholine, GABA, and opioid peptides. However,
on the morphological basis we could only detect subtle
but not signicant dierences in schizophrenia patients in comparison to controls. More interesting,
we found robust and statistical signicant dierence
between schizophrenia and depressive patients. We
assume there might be disturbances on other levels,
for example within subnuclei or certain neuronal
groups. Further immunohistochemical investigations
are necessary to relate dierent neurotransmitter to
those alterations or search for targets in schizophrenia.
The basic picture that emerges is that of a robust
feedback control system regulating levels of dopamine
and serotonin utilization in the telencephalon and
diencephalon, unique in combining and directing

Habenula in schizophrenia and aective disorders

striatal and limbic output caudally on major midbrain
sources of monaminergic and cholinergic innervation
of forebrain structures (Nauta, 1974 ; Scheibel, 1997).
These neurotransmitter systems are crucial in the
modulation of aect and behaviour and have been
implicated in schizophrenia and aective psychoses
(Scheibel, 1997).
In summary, we have shown a reduced volume of
the medial and lateral habenular complex and a reduced cell number and area of the medial habenula
in patients with aective disorder in comparison to
controls and schizophrenia patients.

Acknowledgements
We thank S. Funke and R. Stauch for excellent
technical assistance. This study was supported
by The Stanley Foundation and Graduiertenkolleg
der Deutschen Forschungsgemeinschaft Biologische
Grundlagen von Erkrankungen des Nervensystems .

Declaration of Interest
None.
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