Two-dimensional assessment of cytoarchitecture in the anterior cingulate cortex in major depressive disorder, bipolar disorder, and schizophrenia: evidence for decreased neuronal somal size and increased neuronal density.

BACKGROUND: Abnormalities of cortical neuronal organization and reductions in neuronal somal size have been reported in schizophrenia. The purpose of this investigation was to assess patterns of neuronal and glial distribution in the anterior cingulate cortex (ACC) in major depressive disorder (MDD), schizophrenia, bipolar disorder (BPD), and normal control subjects (15 subjects per group). METHODS: Estimates for neuronal somal and glial nuclear size and density were obtained. We employed two-dimensional morphometric analysis to examine the location of neurons and glia in a 1000-microm-wide strip of cortex. RESULTS: A decreased clustering of neurons was seen in BPD (p =.001). No other group differences were observed in the clustering of neurons, glia, or of neurons about glia. Neuronal somal size was reduced in layer 5 in schizophrenia (18%, p =.001), BPD (16%, p <.001), and MDD (9%, p =.01). Neuronal density was increased in layer 6 in BPD (63%, p =.004) and schizophrenia (61%, p =.006) and in layer 5 in MDD (24%, p =.018) and schizophrenia (33%, p =.003). CONCLUSIONS: The results of this study indicate that reduced neuronal somal size and increased neuronal density in cortical layers 5 and 6 of the ACC may be key features of schizophrenia, MDD, and BPD.     

Reductions in neuronal and glial density characterize the dorsolateral prefrontal cortex in bipolar disorder.

BACKGROUND: Bipolar disorder (BPD) is a mental illness in which depression and mania typically alternate, and both phases can present with psychotic features. The symptomatology of BPD, therefore, resembles major depressive disorder (MDD) and schizophrenia (SCHZ), posing diagnostic dilemmas. Distinct alterations in cellular architecture of the dorsolateral prefrontal cortex distinguish SCHZ and MDD, whereas the cellular neuropathology of BPD has not been studied. METHODS: Dorsolateral prefrontal area 9 was analyzed using a three-dimensional morphometric method in postmortem brains from 10 BPD patients and 11 matched nonpsychiatric control subjects. RESULTS: Area 9 in BPD was characterized by reduced neuronal density in layer III (16%-22%) and reduced pyramidal cell density in layers III and V (17%-30%). A 19% reduction in glial density was found in sublayer IIIc coupled with enlargement and changes in shape of glial nuclei spanning multiple layers. CONCLUSIONS: The morphologic signature of BPD, i.e., decreased neuronal and glial density in association with glial hypertrophy, is distinct from previously described elevations in neuronal density in SCHZ, instead resembling the reductions in cell density found in MDD. Thus, the neuropathologic distinctions between BPD and SCHZ are indicative of separate mental illnesses, each with a unique morphologic disturbance of specific neural circuits.     

Deficit of perineuronal oligodendrocytes in the prefrontal cortex in schizophrenia and mood disorders

OBJECTIVE: A deficit of oligodendrocytes has been reported in the prefrontal cortex (PFC) in schizophrenia (SCH), bipolar disorder (BPD) and major depression (MDD). Also, a decreased size of pyramidal neurons has been detected in layer III in SCH and in mood disorders. Since oligodendrocytes have a trophic influence on neurons, reduced neuronal size reported in these disorders might be associated with the deficit in subpopulation of perineuronal oligodendrocytes. We hypothesized that deficit of perineuronal oligodendrocytes might occur in SCH and mood disorders. METHOD: We estimated the number of oligodendroglial satellites of pyramidal neurons and the size of pyramidal neurons in layer III (Brodmann's area 9) in Nissl stained sections in SCH, BPD, MDD and normal controls. The Stanley Foundation Neuropathology Consortium brain collection consisted of 15 cases in each of four groups was used. RESULTS: We detected a prominent and significant reduction in the number of perineuronal oligodendrocytes in the sublayers IIIa, IIIb and IIIc in SCH, BPD and MDD as compared to controls. The BPD group differed significantly from SCH group and from MDD group. There were no significant differences in somal sizes of pyramidal neurons in the sublayers IIIa, IIIb, IIIc between each of the psychiatric groups and the control group. Only BPD group showed significantly smaller neuronal size in sublayer IIIc as compared to controls. CONCLUSIONS: Our data provide evidence for a deficit of perineuronal oligodendrocytes in severe mental disorders that may play a key role in the pathophysiology of SCH, BPD and MDD.     

Reduced glial cell density and neuronal size in the anterior cingulate cortex in major depressive disorder

BACKGROUND: Glial cells are more numerous than neurons in the cortex and are crucial to neuronal function. There is evidence for reduced neuronal size in schizophrenia, with suggestive evidence for reduced glial cell density in mood disorders. In this investigation, we have simultaneously assessed glial cell density and neuronal density and size in the anterior cingulate cortex in schizophrenia, major depressive disorder, and bipolar disorder. METHODS: We examined tissue from area 24b of the supracallosal anterior cingulate cortex in 60 postmortem brain specimens from 4 groups of 15 subjects, as follows: major depressive disorder, schizophrenia, bipolar disorder, and normal controls. Glial cell density and neuronal size and density were examined in all subjects using the nucleator and the optical disector. RESULTS: Glial cell density (22%) (P =.004) and neuronal size (23%) (P =.01) were reduced in layer 6 in major depressive disorder compared with controls. There was some evidence for reduced glial density in layer 6 (20%) (P =.02) in schizophrenia compared with controls, before adjusting for multiple layerwise comparisons, but there were no significant changes in neuronal size. There was no evidence for differences in glial density or neuronal size in bipolar disorder compared with controls. Neuronal density was similar in all groups to that found in controls. CONCLUSION: These findings suggest that there is reduced frontal cortical glial cell density and neuronal size in major depressive disorder.     

Evidence for altered neuronal organisation within the planum temporale in major psychiatric disorders

Reductions in neuronal size and glial cell density have been described in the frontal cortex in major psychiatric disorders. In this investigation, we performed a cytoarchitectural assessment within the planum temporale (PT), an auditory association region located within the superior temporal gyrus, using two-dimensional (2D) measures of cell size and density and spatial point pattern analysis. In sections of the PT from subjects with schizophrenia, bipolar disorder, major depressive disorder and controls (15 subjects per group), the laminar distribution and size of all neurons and glial cell nuclei was recorded. Spatial point pattern investigation demonstrated reduced neuronal clustering in bipolar disorder (p=0.033) and schizophrenia (p=0.027) compared with controls. Statistical analyses comparing each of the patient groups with the control group failed to identify differences in neuronal density between groups. Neuronal size was reduced in cortical layer 3 (p=0.02) and glial cell density reduced in cortical layer 6 (p=0.05) in bipolar disorder relative to controls but these findings did not remain significant after adjusting for six layer-wise comparisons. We propose that alterations in cortical cytoarchitecture within this region are subtle and involve reduced clustering of neurons, which may be due to altered neuronal organisation within cortical mini-columns or within cortical layers.     

Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression.

BACKGROUND: This report provides histopathological evidence to support prior neuroimaging findings of decreased volume and altered metabolism in the frontal cortex in major depressive disorder. METHODS: Computer-assisted three-dimensional cell counting was used to reveal abnormal cytoarchitecture in left rostral and caudal orbitofrontal and dorsolateral prefrontal cortical regions in subjects with major depression as compared to psychiatrically normal controls. RESULTS: Depressed subjects had decreases in cortical thickness, neuronal sizes, and neuronal and glial densities in the upper (II-IV) cortical layers of the rostral orbitofrontal region. In the caudal orbitofrontal cortex in depressed subjects, there were prominent reductions in glial densities in the lower (V-VI) cortical layers that were accompanied by small but significant decreases in neuronal sizes. In the dorsolateral prefrontal cortex of depressed subjects marked reductions in the density and size of neurons and glial cells were found in both supra- and infragranular layers. CONCLUSIONS: These results reveal that major depression can be distinguished by specific histopathology of both neurons and glial cells in the prefrontal cortex. Our data will contribute to the interpretation of neuroimaging findings and identification of dysfunctional neuronal circuits in major depression.     

The density and spatial distribution of GABAergic neurons, labelled using calcium binding proteins, in the anterior cingulate cortex in major depressive disorder, bipolar disorder, and schizophrenia.

BACKGROUND: There is strong evidence for the presence of a deficit in cortical gamma aminobutyric acid (GABA) neurotransmission in schizophrenia. In this investigation we have used the calcium binding proteins (CBPs) parvalbumin (PV), calretinin (CR), and calbindin-D28K (CB) as markers of these neuronal populations, and have characterized their pattern and density in schizophrenia, bipolar disorder (BPD), and major depressive disorder (MDD). METHODS: We examined the anterior cingulate cortex (ACC) in four groups of 15 brains each from subjects with schizophrenia, MDD, and BPD, and from control subjects. Using immunocytochemistry to identify these distinct neuronal populations, we quantified their areal density and spatial pattern organization. RESULTS: There were reductions in the density of CB-labeled neurons in layer 2 in schizophrenia (34%; p =.04) and BPD (33%; p =.05) compared with control subjects; however, after correction for multiple comparisons these findings no longer attained formal statistical significance. We observed no differences in the density of the neuronal populations labeled by CR or PV in any layer of the cortex in any disorder compared with control subjects. There was increased clustering among PV-labeled neurons in BPD compared with control subjects but no significant differences in the spatial organization of the other neuronal subpopulations in any disorder. CONCLUSIONS: The study provides some support for the presence of a deficit in GABAergic neurons in schizophrenia and shows that these changes are not specific to schizophrenia. The findings indicate that there may be a pathophysiological condition, shared by subjects with schizophrenia and BPD, which operates to selectively reduce the number or protein expression of CB-immunoreactive neurons.     

Comparison of prefrontal cell pathology between depression and alcohol dependence

Chronic alcohol abuse is often co-morbid with depression symptoms and in many cases it appears to induce major depressive disorder. Structural and functional neuroimaging has provided evidence supporting some degree of neuropathological convergence of alcoholism and mood disorders. In order to understand the cellular neuropathology of alcohol dependence and mood disorders, postmortem morphometric studies have tested the possibility of alterations in the number and size of cells in the prefrontal cortex and other brain regions. The present review compares the cell pathology in the prefrontal cortex between alcohol dependence and depression, and reveals both similarities and differences. One of the most striking similarities is that, although pathology affects both neuronal and glial cells, effects on glia are more dramatic than on neurons in both alcohol dependence comorbid with depression and idiopathic depression. Moreover, prefrontal cortical regions are commonly affected in both depression and alcoholism. However, the cellular changes are more prominent and spread across cortical layers in alcohol dependent subjects than in subjects with mood disorders, and changes in glial nucleus size are opposite in alcoholism and depression. It could be argued that one defining factor in the manifestation of the depressive pathology is a reduction in the glial distribution in the dlPFC that is reflected in a reduced glial density. In alcoholism reduced glial nuclear size might be related to the cytotoxic effects of prolonged alcohol exposure, while in MDD, in the absence of alcohol abuse, other processes might be responsible for the increase in average size of glial nuclei. In either case abnormal function related to glial reduction would be associated with depression due to insufficient glial support to the surrounding neurons.     

Decreased prefrontal Myo-inositol in major depressive disorder.

BACKGROUND: Postmortem studies have shown robust prefrontal cortex glial losses and more subtle neuronal changes in major depressive disorder (MDD). Earlier proton magnetic resonance spectroscopy (1H-MRS) studies of the glial marker myo-inositol in MDD were subject to potential confounds. The primary hypothesis of this study was that MDD patients would show reduced prefrontal/anterior cingulate cortex levels of myo-inositol. METHODS: Thirteen nonmedicated moderate-severe MDD patients and 13 matched control subjects were studied (six male, seven female per group). Proton magnetic resonance spectroscopy stimulated echo acquisition mode spectra (3.0 T; echo time=168 msec; mixing time=28 msec; repetition time=3000 msec) were obtained from prefrontal/anterior cingulate cortex. Metabolite data were adjusted for tissue composition. RESULTS: Patients with MDD showed significantly lower myo-inositol/creatine ratios (.94+/-.23) than control subjects (1.32+/-.37) [F(1,23)=6.9; p=.016]. CONCLUSIONS: These data suggest a reduction of myo-inositol in prefrontal/anterior cingulate cortex in MDD, which could be a consequence of glial loss or altered glial metabolism. Additional in vivo studies of glial markers could add to the understanding of the pathophysiology of MDD.     

Reductions in cholesterol and synaptic markers in association cortex in mood disorders

OBJECTIVES: Cholesterol forms an integral part of cell membranes and is a major component of myelin. Furthermore, cholesterol also plays a vital role in the development, function and stability of synapses. While low serum cholesterol has previously been associated with mood disorders, cholesterol levels have yet to be quantified within the brain in these disorders. The aim of this study was to quantify sterol levels in the brains of patients with major psychiatric disorders and further to relate these levels to markers of myelin and synapses. METHODS: Samples of visual association cortex were obtained postmortem from subjects with bipolar disorder (BPD), major depressive disorder (MDD) and schizophrenia (SCZ) and from controls (all n = 15). Concentrations of brain cholesterol, its precursors lathosterol, desmosterol and lanosterol and its metabolite 24S-hydroxycholesterol were determined by gas-liquid chromatography. Immunoreactivity for myelin basic protein (MBP), synaptophysin and VAMP was quantified by enzyme-linked immunosorbent assay. RESULTS: Cholesterol levels were 13% lower in MDD (p = 0.018) and 10% lower in BPD (p = 0.052) compared with controls. Cholesterol precursor or metabolite concentrations did not differ between groups. Synaptophysin immunoreactivity was 20% lower in BPD (p = 0.025) and VAMP immunoreactivity 37% lower in MDD (p = 0.032) and 45% lower in BPD (p = 0.009). MBP immunoreactivity was not altered in any disorder. CONCLUSIONS: Our data suggest that lower brain cholesterol levels and a reduction in synapses may be features of mood disorders.     

Glial fibrillary acidic protein immunoreactivity in the prefrontal cortex distinguishes younger from older adults in major depressive disorder.

BACKGROUND: Recent postmortem studies in major depressive disorder (MDD) provide evidence for a reduction in the packing density and number of glial cells in different regions of the prefrontal cortex; however, the specific types of glia involved in those morphologic changes are unknown. METHODS: The territory occupied by the astroglial marker glial fibrillary acidic protein (GFAP) was measured as an areal fraction in cortical layers III, IV, and V in sections from the dorsolateral prefrontal cortex (dlPFC) of MDD and control subjects. In addition, the packing density of GFAP-immunoreactive somata was measured by a direct three-dimensional cell counting method. RESULTS: The mean areal fraction and packing density of GFAP-immunoreactive astrocytes in the dlPFC of MDD subjects were not significantly different from those in control subjects; however, in MDD there was a significant strong positive correlation between age and GFAP immunoreactivity. When the MDD group was divided into younger (30-45 years old) and older (46-86) adults, in the five younger MDD adults, areal fraction and packing density were smaller than the smallest values of the control subjects. In contrast, among older MDD subjects these parameters tended to be greater than in the older control subjects. CONCLUSIONS: The present results suggest that the GFAP-immunoreactive astroglia is differentially involved in the pathology of MDD in younger compared with older adults.     

Glial reduction in amygdala in major depressive disorder is due to oligodendrocytes.

BACKGROUND: A previous study reported reductions in glial density and glia/neuron ratio in the amygdala of individuals with major depressive disorder (MDD), without a change in neuronal density. It is not known, however, whether this glial loss is due to astrocytes, oligodendrocytes, or microglia. METHODS: Tissue samples, equally from the right and left hemispheres, were obtained from subjects diagnosed with MDD (n = 8), bipolar disorder (BD) (n = 9), or no psychiatric disorders (n = 10). Sections were stained immunohistochemically for S-100beta (for astrocytes) and human leukocyte antigen (for microglia), and with the Nissl method. In Nissl-stained sections, oligodendrocytes have more compact, darker-stained nuclei, whereas astrocytes and microglia have larger, lighter-stained nuclei, with more granular chromatin. Neurons are larger, with a nucleolus and stained cytoplasm. The density of glia was determined with stereologic methods. RESULTS: The density of total glia and oligodendrocytes in the amygdala was significantly lower in MDD than in control subjects, but not significantly lower in BD compared with control subjects. The decreases were largely accounted for by differences in the left hemisphere. There was no significant decrease in astrocyte or microglia density in MDD or BD subjects. CONCLUSIONS: The glial cell reduction previously found in the amygdala in MDD is primarily due to oligodendrocytes.     

Through the looking glass: Examining neuroanatomical evidence for cellular alterations in major depression

Alterations in brain plasticity are increasingly thought to play important roles in major depressive disorder (MDD) and suicide. To gain a better understanding of the gross structural changes observed in the brains of major depressed and suicide subjects, a number of recent investigations have scrutinized the cellular integrity of brain regions implicated in mood disorders. The purpose of this review is to summarize the current knowledge on the microscopic features of neuronal and glial cell populations in these different brain regions, namely the prefrontal cortex, hippocampus, amygdala, raphe nucleus and locus coeruleus. In general, evidence from this burgeoning field supports the hypothesis of altered cell plasticity in MDD and suicide occurring mainly in key fronto-limbic areas. Interestingly, reported morphometric and cell density alterations are generally region-specific and implicate several neuromodulatory systems, notably GABAergic, serotonergic, noradrenergic and glutamatergic pathways. Cell-specific changes involve reductions in densities of astrocytes and oligodendrocytes, while increases in microglial densities have also been reported. Furthermore, increases in neuronal densities have been found in subcortical regions. The implication of such findings for our understanding of the cellular and molecular underpinnings of MDD and suicide are discussed, and the strengths and weaknesses of morphological approaches used to analyse human postmortem brain tissues are evaluated.     

Enhanced rostral anterior cingulate cortex activation during cognitive control is related to orbitofrontal volume reduction in unipolar depression

Objective

In patients with major depressive disorder (MDD), enhanced activation of the rostral anterior cingulate cortex (rACC) during conflict resolution has been demonstrated with the use of functional magnetic resonance imaging (fMRI), which suggests dysregulation of the affective compartment of the ACC associated with error monitoring and cognitive control. Moreover, several previous studies have reported disrupted structural integrity in limbic brain areas and the orbitofrontal cortex in MDD. However, the relation between structural and functional alterations remains unclear. Therefore, the present study sought to investigate whether structural brain aberrations in terms of grey matter decreases directly in the medial frontal regions or in anatomically closely connected areas might be related to our previously reported functional alterations.

Methods

A sample of 16 female, drug-free patients with an acute episode of MDD and 16 healthy control subjects matched for age, sex and education were examined with structural high-resolution T₁-weighted MRI; fMRI images were obtained in the same session.

Results

Voxel-based morphometry (VBM) revealed grey matter decreases in the orbitofrontal and subgenual cortex, in the hippocampus-amygdala complex and in the middle frontal gyrus. The relative hyperactivation of the rACC in terms of inability to deactivate this region during the Stroop Color-Word Test showed an inverse correlation with grey matter reduction in the orbitofrontal cortex.

Conclusion

The present study provides strong evidence for an association between structural alterations in the orbitofrontal cortex and disturbed functional activation in the emotional compartment of the ACC in patients with MDD during cognitive control.Medical subject headings: magnetic resonance imaging, depressive disorder, depression     

Glial fibrillary acidic protein in late life major depressive disorder: an immunocytochemical study

OBJECTIVES: Depression is a common psychiatric disorder in late life. Cerebrovascular disease has been postulated as an important aetiological factor in many cases (the "vascular depression" hypothesis). Consistent with this, an inflammatory response, most probably representing ischaemia, has been reported with increases in intercellular adhesion molecule 1 (ICAM-1), in the dorsolateral prefrontal cortex (DLPFC) in postmortem tissue from elderly depressed subjects. As ischaemia is known to cause astrogliosis, this study has further tested the "vascular depression hypothesis" by investigating the distribution of the astrocytic marker glial fibrillary acidic protein (GFAP) in the DLPFC and in the anterior cingulate cortex (ACC). METHODS: Postmortem tissue was obtained from 20 elderly patients with a history of major depressive disorder (MDD) and 20 control subjects. Sections were stained for GFAP using standard immunocytochemistry. Sets of images were obtained from all cortical layers in the DLPFC and ACC with the exception of layer IV in the ACC, and from gyral and deep white matter in both regions. The percentage of the area of each image occupied by GFAP was calculated using true colour image analysis, and mean values obtained for each region examined. RESULTS: Immunoreactivity for GFAP was low in grey matter (for example, Mean (SEM) 0.76 (0.2)% in DLPFC layer V in depressed subjects), but higher in white matter (for example, 12.02 (2.2)% in DLPFC deep white matter in depressed subjects). Pronounced gliosis was observed within grey matter in a few cases only. GFAP immunoreactivity was significantly higher in layer I of the DLPFC in depressed subjects 15.8 (2.6)% than in controls 9.7 (1.3)% (t=2.2; df=27.5, p=0.04). No difference was detected in any other region. CONCLUSIONS: The data suggest any increase in GFAP in elderly MDD patients is limited to layer 1 of the DLPFC. These results provide some support for the vascular depression hypothesis and further implicate DLPFC abnormalities in depression.     

Borderline personality-bipolar spectrum relationship

BACKGROUND: The relationship between borderline personality disorder (BPD) and bipolar disorders, especially bipolar-II disorder (BP-II), is unclear. Several reviews on the topic have come to opposite conclusions, i.e., that BPD is a bipolar spectrum disorder or instead that it is unrelated to bipolar disorders. Study aim was to find which items of BPD were related to BP-II, and which instead had no relationship with BP-II. METHODS: Study setting: An outpatient psychiatry private practice, more representative of mood disorders usually seen in clinical practice in Italy. INTERVIEWER: A senior clinical and mood disorder research psychiatrist. PATIENT POPULATION: A consecutive sample of 138 BP-II and 71 major depressive disorder (MDD) remitted outpatients. ASSESSMENT INSTRUMENTS: The Structured Clinical Interview for DSM-IV Axis I Disorders-Clinician Version (SCID-CV) was used for diagnosing, the SCID-II Personality Questionnaire was used by patients to self-assess borderline personality traits. Interview methods: Patients were interviewed with the SCID-CV to diagnose BP-II and MDD. The questions of the Personality Questionnaire relative to borderline personality were self-assessed by patients. As clinically significant distress or impairment of functioning was not assessed by the questionnaire, a diagnosis of borderline personality disorder could not be made, but borderline personality traits (BPT) could be assessed (i.e., all DSM-IV BPD items but not the impairment criterion). RESULTS: BPT items were significantly more common in BP-II versus MDD. The best combination of sensitivity and specificity for predicting BP-II was found by using a cutoff number of BPT items > or =5: specificity was 71.4%, sensitivity was 45.9%. BPT (defined by > or =5 items) was present in 29.5% of MDD and in 46.3% of BP-II (p=0.019). Logistic regression of BP-II versus BPT items number found a significant association. Principal component factor analysis of BPT items found two orthogonal factors: "affective instability" including unstable mood, unstable interpersonal relationships, unstable self-image, chronic emptiness, and anger, and "impulsivity" including impulsivity, suicidal behavior, avoidance of abandonment, and paranoid ideation. "Affective instability" was associated with BP-II (p=0.010), but "impulsivity" was not associated with BP-II (p=0.193). Interitem correlation was low. There was no significant correlation between the two factors. DISCUSSION: Study findings suggest that DSM-IV BPD may mix two sets of unrelated items: an affective instability dimension related to BP-II, and an impulsivity dimension not related to BP-II, which may explain the opposite conclusions of several reviews. A subtyping of BPD according to these dimensions is supported by the study findings.     

Expression of hippocampal brain-derived neurotrophic factor and its receptors in Stanley consortium brains

Several lines of evidence implicate BDNF in the pathophysiology of psychiatric illness. BDNF polymorphisms have also been associated with the risk of schizophrenia and mood disorders. We therefore investigated whether levels of (pro)BDNF and receptor proteins, TrkB and p75, are altered in hippocampus in schizophrenia and mood disorder and whether polymorphisms in each gene influenced protein expression. Formalin-fixed paraffin-embedded hippocampal sections from subjects with schizophrenia, major depressive disorder (MDD), bipolar disorder (BPD) and non-psychiatric controls were obtained from the Stanley Foundation Neuropathology Consortium. (pro)BDNF, TrkB(T1) and p75 protein densities were quantified by immunoautoradiography and DNA extracted from each subject was used to determine the effect of genotype on protein expression. In MDD, reductions in (pro)BDNF were seen in all layers of the right but not the left hippocampus with no changes in the dentate gyrus. The pattern was similar but less marked for BPD. In addition, BPD but not MDD patients, had bilateral reductions in p75 in hippocampal layers but not in dentate gyrus. No changes in TrkB(T1) density were seen in any diagnosis. These findings suggest MDD and BPD may share impairment in (pro)BDNF expression. However, BPD may involve impairments of both (pro)BDNF and p75 receptor, whereas MDD may involve impaired (pro)BDNF alone. Moreover, the lateralisation of changes may indicate a role of asymmetry in vulnerability to MDD. Hippocampal (pro)BDNF and receptor levels were also affected by genotype, suggesting that allelic variations are important in the hippocampal abnormalities seen in these psychiatric disorders.     

Neuron somal size is decreased in the lateral amygdalar nucleus of subjects with bipolar disorder

OBJECTIVE: Morphometric studies of postmortem brains from subjects with mood disorders have reported altered density of glial cells in the amygdala; however, the nuclear regions have not been examined individually. METHODS: We assessed the size and density of both neuronal and glial cells in discrete amygdalar nuclei in postmortem sections from subjects with major depressive disorder, bipolar disorder (BD) and schizophrenia and from nonpsychiatric control subjects. Three adjacent Nissl-stained sections were examined from each individual. RESULTS: We report significantly decreased neuron somal size in the lateral amygdalar nucleus (LAN) and the accessory basal parvocellular nucleus (ABPC) in subjects with BD, relative to control subjects. These changes in cellular morphology were most prominent in the LAN in sections obtained from the left hemisphere. CONCLUSIONS: These findings add to increasing evidence for neuropathological changes in the amygdala of subjects with BD and specifically implicate the LAN and ABPC in this disorder.     

Selective deficits in the omega-3 fatty acid docosahexaenoic acid in the postmortem orbitofrontal cortex of patients with major depressive disorder.

BACKGROUND: Epidemiological surveys and peripheral tissue (red blood cells/plasma) fatty acid composition studies suggest that omega-3 fatty acid deficiency is associated with major depressive disorder (MDD) and suicide. It was hypothesized that patients with MDD would exhibit lower frontal cortical concentrations of docosahexaenoic acid (DHA), the principal omega-3 fatty acid in brain, relative to normal controls. METHODS: We determined the total fatty acid composition of postmortem orbitofrontal cortex (Brodmann's Area 10) from patients with DSM-IV-defined MDD (n = 15) and age-matched normal controls (n = 27) by gas chromatography. RESULTS: After correction for multiple comparisons, the omega-3 fatty acid DHA was the only fatty acid that was significantly different (-22%) in the postmortem orbitofrontal cortex of MDD patients relative to normal controls. Deficits in DHA concentrations were greater in female MDD patients (-32%) than in male MDD patients (-16%), and could not be wholly attributed to lifestyle factors or postmortem tissue variables. CONCLUSIONS: These results demonstrate a selective deficit in the omega-3 fatty acid DHA in the orbitofrontal cortex of patients with MDD. This finding adds to a growing body of evidence implicating omega-3 fatty acid deficiency as well as the orbitofrontal cortex in the pathophysiology and potentially pathogenesis of MDD.