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Background: Diffusion tensor imaging studies show reductions in fractional anisotropy (FA) in individuals with bipolar disorder and their unaffected siblings. However, the use of various analysis methods is an important source of between-study heterogeneity. Using tract-based spatial statistics, we previously demonstrated widespread FA reductions in patients and unaffected relatives. To better interpret the neuroanatomical pattern of this previous finding and to assess the influence of methodological heterogeneity, we here applied tractography to the same sample., Methods: Diffusion-weighted images were acquired for 96 patients, 69 unaffected siblings and 56 controls. We applied TRACULA, an extension of a global probabilistic tractography algorithm, to automatically segment 18 major fiber tracts. Average FA within each tract and at each cross-section along each tract was compared between groups., Results: Patients had reduced FA compared to healthy controls and their unaffected siblings in general, and in particular in the parietal part of the superior longitudinal fasciculus. In unaffected siblings, FA was nominally reduced compared to controls in the corpus callosum. Point-wise analyses indicated that similar effects were present along extended sections, but with variable effect sizes. Current symptom severity negatively correlated with FA in several fronto-limbic association tracts., Conclusions: The differential sensitivity of analysis techniques likely explains between-study heterogeneity in anatomical localization of FA reductions. The present tractography analysis confirms the presence of overall FA reductions in patients with bipolar disorder, which are most pronounced in the superior longitudinal fasciculus. Unaffected siblings may display similar, albeit more subtle and anatomically restricted FA reductions. Hum Brain Mapp 37:3474-3485, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Objective: Several lines of evidence indicate that white matter integrity is compromised in bipolar disorder, but the nature, extent, and biological causes remain elusive. To determine the extent to which white matter deficits in bipolar disorder are familial, the authors investigated white matter integrity in a large sample of bipolar patients, unaffected siblings, and healthy comparison subjects., Method: The authors collected diffusion imaging data for 64 adult bipolar patients, 60 unaffected siblings (including 54 discordant sibling pairs), and 46 demographically matched comparison subjects. Fractional anisotropy was compared between the groups using voxel-wise tract-based spatial statistics and by extracting mean fractional anisotropy from 10 regions of interest. Additionally, intraclass correlation coefficients were calculated between the sibling pairs as an index of familiality., Results: Widespread fractional anisotropy reductions in bipolar patients (>40,000 voxels) and more subtle reductions in their siblings, mainly restricted to the corpus callosum, posterior thalamic radiations, and left superior longitudinal fasciculus (>2,000 voxels) were observed. Similarly, region-of-interest analysis revealed significant reductions in most white matter regions in patients. In siblings, fractional anisotropy in the posterior thalamic radiation and the forceps was nominally reduced. Significant between-sibling correlations were found for mean fractional anisotropy across the tract-based spatial statistic skeleton, within significant clusters, and within nearly all regions of interest., Conclusions: These findings emphasize the relevance of white matter to neuropathology and familiality of bipolar disorder and encourage further use of white matter integrity markers as endophenotypes in genetic studies.

In the rodent forebrain GABAergic neurons are generated from progenitor cells that express the transcription factors Dlx1 and Dlx2. The Rap-1 guanine nucleotide exchange factor, MR-GEF, is turned on by many of these developing GABAergic neurons. Expression of both Dlx1/2 and MR-GEF is retained in both adult mouse and human forebrain where, in human, decreased Dlx1 expression has been associated with psychosis. Using in situ hybridization studies we show that MR-GEF expression is significantly down-regulated in the forebrain of Dlx1/2 double mutant mice suggesting that MR-GEF and Dlx1/2 form part of a common signalling pathway during GABAergic neuronal development. We therefore compared MR-GEF expression by in situ hybridization in individuals with major psychiatric disorders (schizophrenia, bipolar disorder, major depression) and control individuals. We observed a significant positive correlation between layers II and IV of the dorso-lateral prefrontal cortex (DLPFC) in the percentage of MR-GEF expressing neurons in individuals with bipolar disorder, but not in individuals with schizophrenia, major depressive disorder or in controls. Since MR-GEF encodes a Rap1 GEF able to activate G-protein signalling, we suggest that changes in MR-GEF expression could potentially influence neurotransmission.

There is considerable evidence for cognitive dysfunction in schizophrenia and affective disorders, but the pattern of potential similarities or differences between diagnostic groups remains uncertain. The objective of this study was to conduct a quantitative review of studies on cognitive performance in schizophrenia and affective disorders. Relevant articles were identified through literature search in major databases for the period between January 1980 and December 2005. Meta-analytic treatment of the original studies revealed widespread cognitive deficits in patients with schizophrenia and affective disorders in intellectual ability and speed of information processing, in encoding and retrieval, rule discovery and in response generation and response inhibition. Differences between diagnostic groups were quantitative rather than qualitative.

Objectives: There is evidence for differential neural alterations within the prefrontal cortex (PFC) in bipolar disorder I (BDI) and schizophrenia that may translate into different cognitive deficits. Our objective was to compare the cognitive profile of stable BDI and schizophrenic patients using neuropsychological tasks which utilize frontal systems but differ in terms of the exact neural circuits and cognitive processes involved., Methods: We studied 43 patients with BDI, 54 with schizophrenia and 46 matched healthy participants. All participants completed (i) the Wisconsin Card Sorting Test (WCST) which is known to recruit the dorsal and ventral PFC, (ii) the verbal fluency task (VFT), which engages frontal-temporal regions, and (iii) the Stroop Colour Word Test (SWCT) which depends on the integrity of the cingulo-frontal network. A series of multivariate analyses examined differences between the cognitive profiles of BD and schizophrenic patients relative to that of healthy participants controlling for general intellectual ability and gender., Results: Bipolar disorder I patients showed minimal verbal fluency impairment while schizophrenic patients demonstrated marked deficits on this task relative to the control and BDI groups. The two patient groups had comparable performance on the WCST. In the SWCT, schizophrenic patients showed impairment in both congruent and incongruent conditions while BD patients had deficits only in the latter., Conclusions: Absence of significant verbal fluency abnormalities and by inference dysfunction in the associated fronto-temporal circuitry may distinguish BDI from schizophrenia. Both disorders may show impairment in tasks involving cingulo-frontal networks with evidence of greater cingulate dysfunction in schizophrenia.

Background: Cognitive abnormalities are increasingly recognized as a feature of bipolar I disorder (BDI,) but there is limited information regarding the pattern and severity of cognitive impairment during remission and its relationship with clinical variables., Methods: Forty-four remitted BDI patients recruited from a representative treatment sample and an equal number of matched healthy volunteers underwent comprehensive clinical and cognitive assessments. Cognitive evaluation covered the domains of IQ, memory, and executive function. The profile of cognitive deficits in patients was examined, and the correlation of executive function with clinical features and treatment variables was explored., Results: Remitted BDI patients were impaired in tests of executive function compared with healthy participants. Within the patient group, current antipsychotic treatment predicted worse performance across all executive function tests, whereas duration of illness predicted loss of inhibitory control. Residual mood symptoms, regardless of polarity, had a negative impact primarily on measures of attentional interference., Conclusions: These results suggest that impaired executive function might be an important feature of BDI. Antipsychotic treatment, duration of illness, and level of symptoms are the most significant contributors to the observed impairment.

Background: The orbitofrontal cortex is involved in the monitoring of reward and in judgement. Lesion studies and functional neuroimaging investigations implicate this region in affective disorders, and altered neuronal and glial cell composition have been observed in this region in subjects with major depressive disorder (MDD)., Aims: Stereologically based investigation of caudal orbitofrontal cortex (cOFC), in 60 postmortem brains from four groups of 14 subjects each with bipolar disorder (BPD), schizophrenia and MDD., Methods: Glial cell and neuronal size and density were examined in all subjects using stereological probes such as the nucleator and the optical disector., Results: We found statistical evidence for a neuronal size reduction in BPD in layer 1 (21%, p=0.007) and a trend for a reduction in layer 5 (20%, p=0.05). There was a significant interaction effect of brain hemisphere and group on neuronal size in layer 3 (p=0.001), with evidence for reduced layer 3 neuronal sizes in MDD (30%, p<0.001). We found no evidence for group differences in glial cell size nor for differences in glial or neuronal density., Conclusions: These findings provide preliminary evidence that neuronal size reduction in cOFC is a component of the pathology of BPD. Overall, the data implicate this cortical region in affective disorders, but provide no evidence for neuronal or glial pathology in this region in schizophrenia.

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.

There is evidence that the superior temporal gyrus and Heschl's gyrus within it are implicated in schizophrenia. We investigated neuronal and glial cell density and cortical thickness within Heschl's gyrus, using the optical disector to estimate cell density within cortical layers 3 and 5 in tissue derived postmortem from people with diagnoses of major depressive disorder, schizophrenia and bipolar disorder, compared with normal controls (n=15 per group). No significant difference in neuronal or glial cell density or in cortical thickness was observed between the groups; our findings therefore provide no support for the presence of cellular pathology within Heschl's gyrus in schizophrenia.

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.

Background: Despite the growing recognition of the importance of cognitive impairment in psychiatric disorders, the effect of clinical factors, such as medication use and family history of affective disorders, on cognition in bipolar I disorder patients still remains unclear. This study examines the contribution of known and potential predictors to both general intellectual function and memory in a representative population of bipolar I disorder patients., Method: Of the 425 patients receiving treatment within a defined catchment area, 63 were identified as having bipolar I disorder. Of these patients, 43 were enrolled in the study and participated in a personal interview by a psychiatrist. All patients were invited to participate in a personal interview by a psychiatrist, and information on family history, past psychiatric history, past and current treatments, duration of illness, and age at onset was collected, in addition to demographic data. Cognitive performance was assessed using the Wechsler Adult Intelligence Scale-Revised, the National Adult Reading Test, and the Wechsler Memory Test III., Results: Forty-three patients with DSM-IV bipolar I disorder were enrolled into the Maudsley Bipolar Disorder Project. Patients on treatment with antipsychotic drugs had a lower current full scale IQ, lower general memory scores, and lower working memory scores. A family history of affective disorders was associated with a higher full scale IQ, but not with either general or working memory measures. Duration of illness was negatively associated with general memory scores, but had no effect on either IQ or working memory measures., Conclusion: Current antipsychotic medication, duration of illness, and family history of affective disorder were the most significant predictors of IQ and memory function in bipolar I disorder patients.

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.