A morphometric analysis of the septal nuclei in schizophrenia and affective disorders: reduced neuronal density in the lateral septal nucleus in bipolar disorder.

The septal nuclei are assumed to play a significant role in the pathophysiology of schizophrenia and affective disorders. The aim of this study was to morphometrically characterize the septal nuclei in patients with schizophrenia, bipolar disorder, and major depressive disorder, when compared with healthy control subjects. We analyzed the septal nuclei by determining the density and size of the neurons in postmortem brains in 17 patients with schizophrenia, 8 patients with bipolar disorder, 7 patients with major depressive disorder, and 14 control subjects matched for age and gender. There was a significant reduction in the neuronal density, but not in the mean cross-sectional area, in the lateral septal nucleus (P = 0.013) in patients with bipolar disorder when compared with control subjects. There were no significant changes in the neuronal density of the septal nuclei of the medial and lateral cell groups in patients with schizophrenia and major depressive disorder when compared with control subjects. There was a significant negative correlation between neuronal density in the lateral septal nucleus and disease duration in patients with major depressive disorder (P = 0.037, r = -0.9). The histopathological abnormality of the decreased neuronal density in the lateral septal nucleus, which is an important limbic region involved in emotions, might be a neuropathological correlate of bipolar disorder.

Demonstration of decreased activity of dorsal raphe nucleus neurons in depressed suicidal patients by the AgNOR staining method.

BACKGROUND: Suicide and depression are closely related yet distinct phenomena. In both these phenomena, research has focused on central serotonergic system disturbances. The dorsal raphe nucleus (DRN) is the main source of serotonergic innervation of limbic structures crucial for the regulation of emotionally influenced behaviour. METHODS: The study was carried out on paraffin-embedded brains from 23 depressed patients (12 suicides and 11 non-suicides) and 26 matched controls without mental disorders. The karyometric parameters of DRN neurons were evaluated by the AgNOR silver staining method. RESULTS: The significant effect of suicide on the nuclear area was found in the cumulative analysis of all DRN subnuclei (ANOVA, P=0.032). A decreased mean value of this parameter was observed in the suicides group versus controls (t-test, P=0.032). This effect was especially pronounced in the violent suicide victims (t-test, P=0.001), who also demonstrated a decreased AgNOR area versus controls (t-test, P=0.007). No significant effect of depression or polarity on AgNOR parameters was found. LIMITATIONS: A major limitation of this study is relatively small case number. A further limitation is given by the lack of data on drug exposure across the whole life span. CONCLUSION: Our findings suggest that hypoactivity of DRN neurons is a distinct phenomenon in depression, specific only for suicidal subgroup of depressed patients.

The volumes of the fornix in schizophrenia and affective disorders: a post-mortem study.

Structural and functional pathology of limbic structures including the hippocampus are frequently replicated in schizophrenia. Although the fornix is the main afferent system of the hippocampus to the septal nuclei and the hypothalamus (especially the mammillary bodies), relatively few studies have investigated structural changes of the fornix in schizophrenia. We measured the volume of the fornix in post-mortem brains in 19 patients with schizophrenia, 9 patients with bipolar disorder, 7 patients with unipolar depression, and 14 control subjects by planimetry of serial sections. The volumes, the mean cross-sectional areas, and the anterior to posterior distances of the fornix did not differ among patients with schizophrenia, bipolar disorder, unipolar depression, and control subjects. No lateralization existed between the right and the left fornices in among patients in the diagnostic groups and the control subjects. The fornix does not show morphometrical abnormalities in patients with schizophrenia, bipolar disorder and unipolar depression compared with control subjects, which might indicate that the fornix is not a primary focus of structural changes in these diseases.

Tyrosine hydroxylase immunoreactivity in the locus coeruleus is elevated in violent suicidal depressive patients.

Our postmortem study aimed to determine the impact of suicide on the number of noradrenergic neurons of the locus coeruleus (LC) in suicidal depressive patients. Noradrenergic neurons were shown by immunostaining tyrosine hydroxylase in the LC of 22 non-elderly patients with mood disorders compared to 21 age- and sex-matched normal controls. Eleven patients were suicide victims and the other eleven died of natural causes. Seven violent suicide victims revealed an increased number of tyrosine hydroxylase immunoreactive (TH-ir) neurons compared with non-violent suicide victims and controls. No difference was found between the number of TH-ir neurons in all suicidal patients and controls and between non-suicidal patients and controls. The differences of TH-immunoreactivity could neither be attributed to medication nor to the polarity of depressive disorder (unipolar/bipolar). The numbers of TH-ir neurons in suicidal patients correlated negatively with the mean doses of antidepressants. The study suggested a presynaptic noradrenergic dysregulation in the LC related to the level of self-aggression. Traditional antidepressants may, therefore, regulate noradrenergic activity of the LC in suicide patients, however, without demonstrating the suicide-preventing effect.

Strongly reduced number of parvalbumin-immunoreactive projection neurons in the mammillary bodies in schizophrenia: further evidence for limbic neuropathology.

The mammillary bodies (MB) are important relay nuclei within limbic and extralimbic connections. They are known to play important roles in memory formation and are affected in alcoholism and vitamin B1 deficiency. Their strategic position linking temporo-limbic to cortico-thalamic brain structures make the MB a candidate brain structure for alterations in schizophrenia. We studied 15 postmortem brains of schizophrenics and 15 matched control brains. Brain sections were stained either with Heidenhain-Woelcke, glutamic acid decarboxylase (GAD), calretinin, or parvalbumin. We determined the volumes of the MB and performed cell countings using stereological principles and a computerized image analysis system. The volumes of MB do not differ between schizophrenics and controls. However, in schizophrenia the number of neurons as well as the resulting neuronal densities was significantly reduced on both sides (on left side by 38.9%, on right side by 22%). No changes were seen in the number of GAD-expressing or calretinin-containing neurons, whereas the number of parvalbumin-immunoreactive MB neurons was reduced by more than 50% in schizophrenia. This cell loss (as a result of developmental malformation and/or neurodegeneration) points to a prominent involvement of the MB in the pathomorphology of schizophrenia. Parvalbumin-immunoreactive GABAergic interneurons have been reported to be diminished in schizophrenia. However, in the MB parvalbumin labels a subpopulation of glutamate/aspartate-containing neurons projecting mainly to the anterior thalamus. Thus, our data provide new evidence for impaired limbic circuits in schizophrenia.

The changes of AgNOR parameters of anterior cingulate pyramidal neurons are region-specific in suicidal and non-suicidal depressive patients.

The anterior cingulate cortex (AC) is consistently implicated in the pathophysiology of depression. While suicide has been shown in previous reports to be closely related to depression, it is still a distinct phenomenon. The aim to differentiate between depression and suicide was approached by the karyometric analysis of AC pyramidal neurons. The study was performed on paraffin-embedded brains from 20 depressive patients (10 of whom had committed suicide) and 24 matched controls. The karyometric parameters of the layer III and V pyramidal neurons of the dorsal and ventral AC were evaluated bilaterally by Argyrophilic Nucleolar Organiser (AgNOR) silver staining method. Control-specific was the increased nuclear area in ontogenetically younger pyramidal neurons layer III in the left dorsal compared with ventral AC (Wilcoxon test, P<0.01). The decreased AgNOR number per nucleus in these cells in the right ventral AC was depression-specific compared with controls (t-test, P=0.047). On the other hand, the diffuse decrease in AgNOR ratio throughout pyramidal neurons on the left side was specific for suicidal depressive patients compared with non-suicidal patients and controls (ANOVA, P=0.028). The results suggest that regionally differentiated depression- and suicide-specific disturbed function of the most important AC output cells exists in depressive patients.

The changes in AgNOR parameters of dorsal raphe nucleus neurons are related to suicide.

Depression has been established as the main cause of suicide and the research has concentrated on disturbed central serotonergic system in both disorders. The dorsal raphe nucleus (DRN) of brain stem is the main source of serotonergic innervation of limbic structures fundamental in the regulation of emotionally influenced behavior. The study was carried out on paraffin-embedded brains from 10 depressive patients, among them 5 suicides and 5 non-suicides and 13 matched mentally healthy controls. The karyometric parameters of DRN neurons were evaluated by AgNOR (Argyrophilic Nucleolar Organizer) silver staining method. The significant effect of suicide on nuclear area and AgNOR-ratio found in the cumulative analysis of all DRN subnuclei could be relevant for forensic diagnostic. The results suggest DRN neurons hypoactivity specific for suicide. Whether observed phenomenon is a "common trait" existing also in other diagnostic groups of mental disorders remains an open question.

Localization of neuregulin-1alpha (heregulin-alpha) and one of its receptors, ErbB-4 tyrosine kinase, in developing and adult human brain.

Using immunohistochemistry, Western blot analysis, and RT-polymerase chain reaction, we studied the distribution of neuregulin-1 splice variant alpha (NRG-1alpha) and one of its putative receptors, ErbB-4 tyrosine kinase, in human brain. In the pre- and perinatal human brain immunoreactivity was confined to numerous neurons, with the highest cell density found in cortical gray matter, hypothalamus and cerebellum. In the adult brain, single cortical gray and white matter neurons showed NRG-1alpha immunoreactivity. Occasionally, immunoreactive oligodendrocytes were observed. NRG-1alpha-expressing neurons were also found in the hypothalamus, hippocampus, basal ganglia and brain stem. Application of two antibodies recognizing alpha and beta isoforms revealed a different distribution pattern in that many cortical and hippocampal pyramidal neurons were labeled. ErbB-4 immunoreactivity was expressed in both neurons and oligodendrocytes. Our data show that NRG-1alpha expression is lower in the adult human brain than in the developing brain, and, therefore, support a role for NRG-1alpha in brain development.

Differences in activation of the dorsal raphe nucleus depending on performance of suicide.

The serotonergic system has been implicated in the pathogenesis of mood disorders as well as in suicidal behavior. It is unknown, however, whether raphe neurons, which are mostly serotonergic, show altered activity in patients with mood disorders who complete suicide as compared to those without suicidal behavior. In order to measure cellular markers of serotonergic activity in the dorsal raphe nucleus in brains of 12 people with mood disorders and of 12 controls (C), stereological measurements were carried out of nucleolar organizer regions (AgNORs) and of serotonergic neuron numbers. Six patients died from suicide (S) and the other six patients died from natural causes (NS). Results were assessed using ANOVA and post hoc Tukey-HSD tests looking for effects of diagnostic group (S, NS, C). Results show that in the rostral subnuclei of the dorsal raphe there was a significant effect of diagnostic group on the ratios of the nucleolar organizer regions to nuclear area (NOR ratio) and a nearly significant effect on numbers of serotonergic neurons. Post hoc tests revealed larger values for those dependent variables in S compared to NS. Dose equivalents of antidepressants correlated positively with NOR ratios and numbers of serotonergic neurons in the rostral part of the dorsal raphe. In conclusion, the present data suggest that there are functional differences in the dorsal raphe of patients with mood disorders depending on suicidal behavior. Antidepressants appear to contribute to cellular activation in the rostral part of the dorsal raphe.

Volume and neuron number of the mediodorsal thalamic nucleus in schizophrenia: a replication study.

Previous neuropathological studies on the mediodorsal thalamic nucleus (MD) in schizophrenia have yielded conflicting results. While some studies suggested that patients with schizophrenia have a pronounced reduction of the volume and neuron number in the MD, more recent data have not found anatomical alterations in this thalamic nucleus. However, most studies have considerable methodological shortcomings. In the present study, we investigated the volume, neuron density and neuron number in the left and right MD in patients with schizophrenia (n=20) and normal control subjects without neuropsychiatric disorders (n=18). Patients with schizophrenia showed no significant difference in neuron density and total neuron number in the MD. Compared with the control group, patients with schizophrenia had a smaller MD volume in both hemispheres, a difference that approached significance in the left MD (-7.3%) when the whole brain volume was included as a covariate. No significant main group effect of diagnosis was found for the right MD volume. There were no significant correlations between MD volume, neuron density, total neuron number and the duration of illness or the age of the patients. Taken together, the present results suggest that schizophrenia is associated with a moderate volume reduction in the left mediodorsal thalamic nucleus, while the neuron density and the total neuron number are unchanged.

Calretinin and parvalbumin in schizophrenia and affective disorders: a mini-review, a perspective on the evolutionary role of calretinin in schizophrenia, and a preliminary post-mortem study of calretinin in the septal nuclei.

OBJECTIVE: The septal nuclei are important limbic regions that are involved in emotional behavior and connect to various brain regions such as the habenular complex. Both the septal nuclei and the habenular complex are involved in the pathology of schizophrenia and affective disorders. METHODS: We characterized the number and density of calretinin-immunoreactive neurons in the lateral, medial, and dorsal subregions of the septal nuclei in three groups of subjects: healthy control subjects (N = 6), patients with schizophrenia (N = 10), and patients with affective disorders (N = 6). RESULTS: Our mini-review of the combined role of calretinin and parvalbumin in schizophrenia and affective disorders summarizes 23 studies. We did not observe significant differences in the numbers of calretinin-immunoreactive neurons or neuronal densities in the lateral, medial, and dorsal septal nuclei of patients with schizophrenia or patients with affective disorders compared to healthy control subjects. CONCLUSIONS: Most post-mortem investigations of patients with schizophrenia have indicated significant abnormalities of parvalbumin-immunoreactive neurons in various brain regions including the hippocampus, the anterior cingulate cortex, and the prefrontal cortex in schizophrenia. This study also provides an explanation from an evolutionary perspective for why calretinin is affected in schizophrenia.

Volumes of association thalamic nuclei in schizophrenia: a postmortem study.

The major association thalamic nuclei, the mediodorsal nucleus (MD) and the medial pulvinar nucleus (PUM) are regarded as important parts of the circuits among association cortical regions. Association cortical regions of the frontal, parietal and temporal lobes have been repeatedly implicated in the neuropathology of schizophrenia. Thus, the aim of the present postmortem study was to investigate the volumes of association thalamic nuclei in this disease. The volumes of the whole thalamus (THAL), MD and PUM were measured in each hemisphere of brains of 12 patients with schizophrenia and 13 age-matched and gender-matched normal control subjects without neuropsychiatric disorders. Patients with schizophrenia exhibited significant volume reductions in both the MD and the PUM, the reductions being more pronounced in the PUM. The volume of the PUM in the left (-19.7%, P=0.02) and right (-22.1%, P=0.01) hemispheres was significantly reduced in the schizophrenia group. The volume of the MD was reduced in both hemispheres in the schizophrenia group. However, the volume reduction was only significant in the left hemisphere (-9.3%, P=0.03). Patients with schizophrenia also exhibited a decreased volume of the THAL in the left (-16.4%, P=0.003) and right (-15.2%, P=0.006) hemispheres. There were no significant correlations between thalamic volumes and duration of illness or age of the patients. In conclusion, the present data indicate volume reductions of association thalamic nuclei in schizophrenia. These anatomical findings are consistent with the view that schizophrenia may be associated with disturbances of association cortical networks. However, the findings of a substantial volume reduction of the THAL suggest that the volumes of additional thalamic nuclei may be also reduced in schizophrenia.

The ventral lateral posterior nucleus of the thalamus in schizophrenia: a post-mortem study.

The ventral lateral posterior thalamic nucleus (VLp) is an integral part of both the cerebello-thalamocortical and the basal ganglia-thalamocortical circuit. Although both circuits are thought to be involved in the pathophysiology of schizophrenia, the VLp has not yet been examined in schizophrenia. Using stereological techniques in the brains of eight patients with schizophrenia and in eight age- and sex-matched controls, we measured the nuclear volume of the VLp and obtained estimates of the total number of neurons in this nucleus. Whole brain volume did not differ between the schizophrenia group and the control group and was not correlated to the volume of the right VLp or left VLp. The volume (minus sign25%) and the total neuron number (minus sign27%) of the left VLp were significantly reduced in the schizophrenia group. There were no significant differences in the nuclear volume, neuron density and total neuron number in the right VLp between the schizophrenia group and the control group. There were no significant correlations between length of illness and the nuclear volume, neuron density and total neuron number of the left and right VLp. The present results suggest that the total neuron number of the left VLp is reduced in the schizophrenia group, which may reflect disturbed cerebello-thalamocortical and basal ganglia-thalamocortical circuits in this disease.

Ribosomal DNA transcription in the anterior cingulate cortex is decreased in unipolar but not bipolar I depression.

The anterior cingulate cortex (AC) is consistently implicated in the pathophysiology of depression. However, it is not clear whether unipolar and bipolar depression display distinct neuropathological features. Therefore, the objective of this post-mortem study was to re-evaluate this important issue. Brains from 9 patients with major depressive disorder (MDD) and 11 patients with bipolar disorder (BD) subtype I depression as well as 24 matched controls were analysed. The argyrophilic nucleolar organiser region (AgNOR) silver-staining method was applied on paraffin-embedded brain sections in order to assess the transcriptional activity of ribosomal DNA (rDNA) in layer III and V pyramidal neurons of the dorsal and ventral AC in both hemispheres. An AgNOR area decrease suggestive of a diminished transcriptional activity of rDNA was found in the MDD group both versus controls and versus the BD group. The effect was specific for the right hemisphere and dorsal AC and was restricted to layer V pyramidal neurons. The results suggest that only patients with MDD display region-specific chronic hypoactivity of these output neurons, which are critical for mood regulation. Furthermore, in our cohort, unipolar and bipolar I depression could be differentiated relative to the presumed AC hypoactivity and psychotropic medication did not counteract the observed effect.

Demonstration of disturbed activity of the lateral amygdaloid nucleus projection neurons in depressed patients by the AgNOR staining method.

BACKGROUND: The aim to find a morphological biomarker of disturbed activity of the lateral amygdaloid nucleus in depression was approached by a karyometric analysis of projection neurons. METHODS: The study was performed on paraffin-embedded brains from 19 depressed patients from both the major depressive disorder (MDD) and the bipolar disorder (BD) diagnostic groups, including 10 suicides, and 24 matched controls. The karyometric parameters of the lateral amygdaloid nucleus (La) projection neurons bilaterally were evaluated by the argyrophilic nucleolar organiser region (AgNOR) silver staining method. RESULTS: An increased AgNOR number was found in the right La in suicides compared to controls. The intra-group comparisons between the hemispheres suggest a disturbed amygdaloid lateralisation in depressed patients. The effects were independent from psychotropic medication. There was a strong positive correlation between the nuclear area in La projection neurons and prefrontal limbic areas pyramidal neurons in the right hemisphere specific for suicide and MDD. LIMITATIONS: A major limitation of this study is the relatively small number of cases. A further limitation is given by the lack of data on drug exposure across the entire lifespan. CONCLUSION: The results suggest that depressed patients from both the MDD and BD diagnostic groups exhibit an increased activity of the La output neurons specific for suicidal patients. The distinctness of the diagnostic groups of mood disorders was accentuated in the correlation analysis. This putative hyperactivity was specific for the right hemisphere and psychotropic medication most likely did not counteract it.

Demonstration of disturbed activity of external globus pallidus projecting neurons in depressed patients by the AgNOR staining method.

BACKGROUND: The external globus pallidus (EGP) is thought to play the most important integrating and conveying role in the striatopallidal system involved in the transfer from motivation to action. The aim to find a morphological biomarker of disturbed EGP activity in depression was approached by the karyometric analysis of large projecting neurons. METHODS: The study was performed on paraffin-embedded brains from 19 depressed patients from both the major depressive disorder (MDD) and the bipolar disorder (BD) diagnostic groups encompassing 10 suicides and from 24 controls. The karyometric parameters of EGP neurons bilaterally were evaluated by argyrophilic nucleolar organiser (AgNOR) silver staining method. RESULTS: A significantly decreased AgNOR area was found in the left EGP neurons in depressed patients compared to controls. The distinctness of the diagnostic groups and suicidal vs non-suicidal patients was not shown in the statistical comparisons. The AgNOR parameter which was decreased correlated positively with the mean dose of benzodiazepines in non-suicidal patients. LIMITATIONS: A major limitation of this study is the relatively small number of cases. A further limitation is given by the lack of data on drug exposure across the whole lifespan of patients. CONCLUSION: The results suggest disturbed, most likely decreased, activity of the left EGP projecting neurons in depressed patients, a disturbed activity that should hypothetically be counteracted by the applied pharmacotherapy in non-suicidal patients.

Demonstration of disturbed activity of orbitofrontal pyramidal neurons in depressed patients by the AgNOR staining method.

BACKGROUND: The aim to find the morphological biomarker of disturbed activity of the orbitofrontal cortex (OFC) in depression was approached by the karyometric analysis of pyramidal neurons. METHODS: The study was performed on paraffin-embedded brains from 19 depressed patients from both major depressive disorder (MDD) and bipolar disorder (BD) diagnostic groups, including 9 suicides, and 24 matched controls. The karyometric parameters of medial OFC layer III and V pyramidal neurons bilaterally were evaluated by argyrophilic nucleolar organiser region (AgNOR) silver staining method. RESULTS: The enlarged nuclear area was found in layer V pyramidal neurons in the right OFC in non-suicides compared to suicides and controls, which was most likely the effect of neuroleptics. The intra-group comparisons between the hemispheres suggest the disturbed orbitofrontal lateralisation in depressed patients (predominantly in suicides) with moderate distinctness of the MDD and the BD diagnostic groups. LIMITATIONS: A major limitation of this study is a relatively small number of cases. A further limitation is given by the lack of data on drug exposure across the whole lifespan. CONCLUSION: The results suggest disturbed activity of OFC pyramidal neurons in depression, distinct in suicide and the diagnostic groups of mood disorders. The non-suicidal patients seem to benefit from neuroleptics, which most likely increase the activity of the subpopulation of OFC pyramidal neurons.

Dopamine-glutamate abnormalities in the frontal cortex associated with the catechol-O-methyltransferase (COMT) in schizophrenia.

Catechol-O-methyltransferase (COMT) plays an important role in brain catecholamine metabolism. Several studies point to the involvement of COMT in schizophrenia. We applied COMT immunohistochemistry to paraffin-embedded brain sections and assessed the cell density of COMT expressing glial cells and COMT expressing neurons in the gray matter of the frontal cortex of patients with schizophrenia compared with control subjects. We found a significantly increased cell density of COMT expressing glial cells (p=0.003), but an unchanged cell density of COMT expressing neurons (p=0.778) in the gray matter of the frontal cortex of patients with schizophrenia compared with control subjects. Our study demonstrates that schizophrenia might involve increased COMT expression in glial cells in the frontal cortex, which might be associated with a neuronal-glial abnormality and a disturbed dopamine-glutamate interaction.

Volumetric analysis of septal region in schizophrenia and affective disorder.

MRI and post-mortem studies indicate an increased prevalence of cavum septi pellucidi (CSP) in schizophrenia and affective disorder. The aim of this study was to characterize the CSP and the septal tissue among patients with schizophrenia, patients with affective disorder, and control subjects. The volumes of CSP and septal tissue were measured in post-mortem brains in 42 patients with schizophrenia, 14 patients with affective disorder, and 17 normal control cases by planimetry of serial sections. Enlargements of CSP (>100 mm(3)) were found in eight of the 42 (19%) patients with schizophrenia. There were no significant differences in CSP volumes between patients with affective disorder and controls. Enlarged CSP in schizophrenia were not associated with reduced septal tissue volumes. By contrast, a significant positive correlation between volumes of CSP and septal tissue volumes in patients with schizophrenia (P = 0.03) and in control cases (P < 0.01) was found, but not in patients with affective disorder (P = 0.53). The finding of enlarged CSP in schizophrenia strongly supports the hypothesis of an early developmental abnormality in this key structure of the limbic system.

Volume deficits of subcortical nuclei in mood disorders A postmortem study.

Structural changes in subcortical nuclei may underlie clinical symptoms of mood disorders. The goal was to determine whether macrostructural changes exist in brain areas assumed to be involved in regulation of mood and whether such changes differ between major depressive disorder and bipolar disorder. A case-control design was used to compare volumes of all major subcortical nuclei. Brains of patients with major depressive disorder (n = 9) or bipolar disorder (n = 11) or of individuals without a neuropsychiatric disorder (n = 22) were included. Exclusion criteria were a history of substance abuse or histological signs of neurodegenerative disorders. Volumes of the striato-pallidal nuclei, of the hypothalamus, thalamus, amygdala, hippocampus and basal limbic forebrain were determined in the right and left hemisphere by planimetry of 20 mum whole brain serial paraffin sections. Comparisons between patients with bipolar disorder, major depressive disorder and controls showed a significant (Lambda = 0.35, F(20,56) = 1.93, P = 0.028) overall difference in volumes of all investigated regions with strong effect sizes ( f > 0.40) contributed by the hypothalamus, external pallidum, putamen and thalamus. As compared to controls, a strong effect size (f > 0.40) was found in the bipolar group for smaller volumes of the hypothalamus, external pallidum, putamen and thalamus,whereas in patients with major depressive disorder a strong effect size was only found for a smaller volume of the external pallidum. In conclusion our data suggest that pathways presumably involved in mood regulation have structural pathology in affective disorders with more pronounced abnormalities in bipolar disorder.