White matter density in patients with schizophrenia, bipolar disorder and their unaffected relatives.

BACKGROUND: This study sought to assess white matter density in patients and relatives with histories of bipolar disorder and/or schizophrenia. METHODS: Subjects included those with schizophrenia from families affected by schizophrenia alone, those with bipolar disorder from families affected by bipolar disorder alone and those with bipolar disorder from families affected by both bipolar disorder and schizophrenia. Unaffected relatives of the three patient groups were also recruited. Subjects underwent an MRI brain scan which was analyzed using a white-matter optimized technique. RESULTS: Subjects with schizophrenia and bipolar disorder showed reduced white matter density in the anterior limb of the internal capsule which was not found in unaffected relatives. Reductions were found in frontal subgyral white matter density in affected subjects with a family history of schizophrenia only. CONCLUSIONS: Abnormal anterior internal capsule white matter may provide a structural substrate for both disorders.     

Regional brain morphometry in patients with schizophrenia or bipolar disorder and their unaffected relatives

OBJECTIVE: Schizophrenia and psychotic bipolar disorder have a number of overlapping symptoms and risk factors, but it is not yet clear if the disorders are characterized by similar deviations in brain morphometry or whether any such deviations reflect the impact of shared susceptibility genes on brain structure. The authors used region-of-interest morphometry to volumetrically assess brain structures frequently implicated in psychotic illness in families affected with schizophrenia or psychotic bipolar disorder. METHOD: Magnetic resonance imaging brain scans were obtained from 243 subjects, comprising 42 patients with schizophrenia or schizoaffective disorder, 57 of their unaffected first-degree relatives, 38 patients with psychotic bipolar disorder, 52 of their unaffected first-degree relatives, and 54 healthy comparison subjects. Most of the families affected with schizophrenia and all of the families affected with bipolar disorder were multiply affected with the illness. Volumetric measurements of the cerebrum, lateral ventricles, third ventricle, and hippocampus were completed with stereological methods. RESULTS: Patients with schizophrenia had increased volume of the lateral and third ventricles and reduced hippocampal volume. None of these volumetric abnormalities was present in psychotic bipolar disorder. Unaffected relatives of patients with schizophrenia from multiply affected families had enlarged lateral ventricles but no other volumetric deviations. Unaffected relatives of patients with bipolar disorder showed preservation of ventricular and hippocampal volume. CONCLUSIONS: Schizophrenia and psychotic bipolar disorder are characterized by morphometric distinctions in ventricular and hippocampal regions. Lateral ventricular enlargement represents a potential morphometric endophenotype for schizophrenia.     

Auditory P300 in patients with bipolar disorder and their unaffected relatives

Objectives: There is evidence that genetic susceptibility may be shared between bipolar disorder (BD) and schizophrenia, but electrophysiological phenotypes which have been extensively used in studies of genetic susceptibility for schizophrenia remain far less explored in bipolar illness. This study assesses whether auditory P300 latency delays and amplitude reductions, which have been demonstrated in patients with schizophrenia and their unaffected first‐degree relatives, are associated with familial liability to psychotic bipolar illness. Methods: The P300 auditory evoked potential was obtained using an oddball task from 37 participants with BD who had a history of psychotic symptoms, 38 of their unaffected first‐degree relatives and 42 healthy unrelated comparison subjects. Patients and relatives came from families multiply affected with BD or another functional psychotic disorder. P300 amplitude and latency at midline sites were compared between the groups, using linear regression analyses and robust variance estimators for clustered data, including age and gender as covariates. Results: Bipolar disorder patients with a history of psychosis and their unaffected relatives showed significantly delayed P300 latency at Pz compared to controls. The groups did not differ in P300 amplitude. Conclusions: P300 latency delays are associated with both psychotic BD and familial liability for this illness. Sample size limited our ability to test for multimodal distribution of P300 measures among relatives, which might be expected if only a subgroup inherits any deficits. In future it will be of interest to directly compare groups of families with psychotic and non‐psychotic forms of BD to explore further the role of psychotic symptoms with regard to P300 measures in the disorder. Our results indicate that delayed P300 latency is a promising candidate endophenotype for psychotic BD, as well as schizophrenia, and may reflect the impact of shared susceptibility genes for both types of psychosis.     

Executive functioning in familial bipolar I disorder patients and their unaffected relatives

Schulze KK, Walshe M, Stahl D, Hall MH, Kravariti E, Morris R, Marshall N, McDonald C, Murray RM, Bramon E. Executive functioning in familial bipolar I disorder patients and their unaffected relatives.
Bipolar Disord 2011: 13: 208–216. © 2011 The Authors.
Journal compilation © 2011 John Wiley & Sons A/S. Objective: To compare the executive function of patients with familial bipolar I disorder (BP‐I) with a history of psychotic symptoms to their first‐degree relatives and normal controls. Methods: Three domains of executive function: response inhibition, working memory, and cognitive set shifting were assessed in 44 familial patients with a lifetime diagnosis of BP‐I who had experienced psychotic symptoms, 42 of their unaffected first‐degree relatives, and 47 controls. Results: Bipolar disorder patients and their unaffected relatives had significantly worse scores for response inhibition compared to healthy controls. The groups did not differ in working memory or cognitive set shifting. Conclusions: Impairments in response inhibition are associated with both psychotic bipolar disorder and genetic liability for this illness. Our results indicate that deficits in this specific domain of executive functioning are a promising candidate endophenotype for psychotic bipolar disorder.     

Anterior cingulate volumes associated with trait impulsivity in individuals with bipolar disorder

Objective:  Impulsivity is associated with the clinical outcome and likelihood of risky behaviors among bipolar disorder (BD) patients. Our previous study showed an inverse relationship between impulsivity and orbitofrontal cortex (OFC) volume in healthy subjects. We hypothesized that BD patients would show an inverse relationship between impulsivity and volumes of the OFC, anterior cingulate cortex (ACC), medial prefrontal cortex, and amygdala, which have been implicated in the pathophysiology of BD.
Methods:  Sixty-three BD patients were studied (mean ± SD age = 38.2 ± 11.5 years; 79% female). The Barratt Impulsiveness Scale (BIS), version 11A, was used to assess trait impulsivity. Images were processed using SPM2 and an optimized voxel-based morphometry protocol. We examined the correlations between BIS scores and the gray matter (GM) and white matter (WM) volumes of the prespecified regions.
Results:  Left rostral ACC GM volume was inversely correlated with the BIS total score ( t  =   3.95, p_corrected = 0.003) and the BIS motor score ( t  =   5.22, p_corrected < 0.001). In contrast to our hypothesis, OFC volumes were not significantly associated with impulsivity in BD. No WM volume of any structure was significantly correlated with impulsivity. No statistical association between any clinical variable and the rostral ACC GM volumes reached significance.
Conclusions:  Based on our previous findings and the current results, impulsivity may have a different neural representation in BD and healthy subjects, and the ACC may be involved in the pathophysiology of abnormal impulsivity regulation in BD patients.     

Neurocognitive function in unaffected first-degree relatives of patients with bipolar disorder: a preliminary report

OBJECTIVE: Patients with remitted bipolar disorder (BD) have persistent impairments in neuropsychological function, particularly in the domains of executive control and declarative memory [Br J Psychiatry 180 (2002) 293]. If these were the phenotypic expression of genetic vulnerability to BD, then healthy subjects with a genetic predisposition to BD would be expected to display the same deficits. This study, therefore, examined neuropsychological function in healthy first-degree relatives of patients with BD. METHOD: A cross-sectional design was employed to compare the performance of 17 unaffected first-degree relatives of BD patients and 17 demographically matched controls on a range of neuropsychological tests. RESULTS: Relatives were significantly impaired on Backward Digit Span, Spatial Span and on tasks of visuospatial declarative memory in comparison with controls. Psychomotor performance and verbal declarative memory were intact, as were non-working memory aspects of executive performance. CONCLUSION: The selective deficits in executive control and declarative memory exhibited by relatives in this study have previously been reported in euthymic BD patients suggesting they may be useful endophenotypic markers of genetic vulnerability to BD.     

双相障碍患者及其一级亲属认知功能损害的研究

目的:探讨双相障碍(BD)患者及其健康一级亲属认知功能损害的特点。方法:采用持续操作测验(CPT)和威斯康星卡片分类测验(WCST)对51例BD-I型患者(BD-I组)、51例BD-II型患者(BD-II组)、50名健康一级亲属(亲属组)及51名正常对照者(对照组)进行认知功能评估。结果:BD-I组、BD-II组及亲属组CPT中正确数评分明显低于对照组,且BD-I组明显低于BD-II组及亲属组(P均0.05)。BD-I组、BD-II组及亲属组WCST中的错误应答数、正确率和非持续性错误数与对照组比较差异有统计学意义,且BD-I组及亲属组与BD-II组间差异有统计学意义(P均0.05)。BD-I组及亲属组WCST完成分类数、完成第一个分类所需应答数、不能维持完整分类数评分与对照组及BD-II组比较差异有统计学意义(P均0.05)。结论:BD患者及其健康一级亲属存在多维度认知功能损害,BDI患者任务管理能力损害较明显,BD-II患者注意力损害较明显。     

The relationship of structural alterations to cognitive deficits in schizophrenia: a voxel-based morphometry study.

BACKGROUND: Region of interest studies have identified a number of structure-cognition associations in schizophrenia and revealed alterations in structure-cognition relationship in this population. METHODS: We examined the relationship of structural brain alterations, identified using voxel-based morphometry, to cognitive deficits in 45 schizophrenia patients relative to 43 healthy control subjects and tested the hypothesis that structure-cognition relationship is altered in schizophrenia. RESULTS: Patients had smaller total brain, gray matter, and white matter volumes. Regional alterations were left-hemisphere specific, including: gray matter reduction of inferior frontal, lingual, and anterior superior temporal gyri; white matter reduction of posterior and occipital lobes; and gray matter increase of the putamen and the precuneus. Smaller whole brain and gray matter volumes were associated with lower premorbid intelligence quotient (IQ) and poorer performance on IQ-dependent cognitive measures in patients and to a similar extent in control subjects. Larger precuneus was associated with better immediate verbal memory in patients, whereas verbal and nonverbal memory were positively associated with inferior frontal gyrus volume in control subjects. Smaller occipital white matter volume was associated with slower information processing speed in patients but not in control subjects. CONCLUSIONS: Regional volume alterations are associated with specific cognitive deficits in schizophrenia. Some structure-cognition relationships differentiate this population from healthy control subjects.     

Pituitary volume in unaffected relatives of patients with schizophrenia and bipolar disorder

BACKGROUND: Hypothalamic-pituitary-adrenal (HPA) axis hyperactivity has been demonstrated in both schizophrenia and bipolar disorder, but the mechanisms underlying this abnormality are still unclear. Enlarged pituitary volume has been recently reported in patients with first episode psychosis and been interpreted as a consequence of an increased activation of the HPA axis. The aim of this study was to assess the contribution of familial liability to pituitary volume in schizophrenia and bipolar disorder. Pituitary volume may be an indirect measure of HPA axis activity. METHODS: MRI brain scans and measurements of pituitary volumes were obtained for 183 subjects: 26 patients with established schizophrenia or schizoaffective disorder, 44 of their unaffected first-degree relatives (22 familial schizophrenia, 22 non-familial schizophrenia), 29 patients with established bipolar disorder, 38 of their unaffected first-degree relatives, and 46 healthy comparison subjects. RESULTS: We found a significantly larger pituitary volume (effect size=0.7) in unaffected relatives of patients with schizophrenia compared with controls (p=0.002); the pituitary was even larger in relatives of patients with familial schizophrenia (effect size=0.8, p=0.005). We did not find a significant difference in pituitary volume when comparing the relatives of bipolar patients with controls. Among patients, those with schizophrenia who were receiving prolactin-elevating antipsychotics had an increased pituitary volume compared with controls (effect size=1.0, p=0.006). CONCLUSIONS: These results suggest that the larger pituitary volume previously reported in first episode schizophrenia could be partly due to a genetic susceptibility to over-activate the HPA axis.     

Voxel-based study of structural changes in first-episode patients with bipolar disorder.

BACKGROUND: Although morphometric studies of bipolar disorder (BD) suggest that neurofunctional abnormalities reflect underlying structural changes, it remains unclear whether abnormalities are present at illness onset or reflect disease progression. Previous voxel-based morphometry (VBM) findings suggest that ventrolateral prefrontal cortex (VLPFC) changes develop over time, whereas morphologic abnormalities elsewhere in the anterior limbic network (ALN) are present early in BD. In this study, we used VBM to explore structural brain changes in first-episode bipolar patients. METHODS: First-episode bipolar (n = 33) and healthy (n = 33) subjects underwent magnetic resonance imaging. Images were normalized and compared on a voxel-by-voxel basis. RESULTS: Bipolar subjects showed no change in VLPFC density or volume. We observed increased volume in left thalamus and fusiform and cerebellum bilaterally; increased gray matter density in anterior cingulate and posterior parietal structures; and increased gray matter volume and density in middle/superior temporal and posterior cingulate gyri. No areas of decreased volume or density were observed. CONCLUSIONS: These data indicate that structural changes are absent from VLPFC early in the course of BD. Morphologic abnormalities are present in other portions of the ALN and in structures previously observed to mediate neurofunctional changes in BD, suggesting that dysfunctional neuronal proliferation or pruning may occur in bipolar patients.     

Cognitive regulation of emotion in bipolar I disorder and unaffected biological relatives

Green MJ, Lino BJ, Hwang E‐J, Sparks A, James C, Mitchell PB. Cognitive regulation of emotion in bipolar I disorder and unaffected biological relatives. Objective: We examined the use of particular cognitive strategies for regulating negative emotion in relation to mood and temperament in BD‐I, unaffected relatives of bipolar patients (UR), and healthy controls (HC). Method: Participants were 105 patients with BD‐I, 124 UR, and 63 HC; all participants completed the Cognitive Emotion Regulation Questionnaire (CERQ), the Depression Anxiety Stress Scales (DASS), and the Hypomanic Personality Scale (HPS). Results: The BD‐I group reported more frequent use of rumination, catastrophizing and self‐blame, and less frequent use of putting into perspective, in response to negative life events, relative to the UR and HC groups. In BD‐I, more frequent use of rumination was associated with increased DASS and HPS scores. By contrast, within the UR group, more frequent use of catastrophizing and self‐blame were associated with increased DASS and HPS scores. In all participants, less frequent use of adaptive cognitive reframing strategies (e.g. putting into perspective) were associated with increased DASS scores. Conclusion: Both BD‐I and UR groups reported more frequent use of maladaptive regulatory strategies previously associated with depression. Emotion regulation strategies of catastrophizing, self‐blame, and cognitive reframing techniques may be associated with vulnerability for mood disorders, with the latter active within the general population regardless of biological vulnerability to disorder.     

Grey matter volume abnormalities in patients with bipolar I depressive disorder and unipolar depressive disorder:a voxelbased morphometry study

Bipolar disorder and unipolar depressive disorder(UD) may be different in brain structure. In the present study,we performed voxel-based morphometry(VBM) to quantify the grey matter volumes in 23 patients with bipolar I depressive disorder(BP1) and 23 patients with UD,and 23 age-,gender-,and educationmatched healthy controls(HCs) using magnetic resonance imaging. We found that compared with the HC and UD groups,the BP1 group showed reduced grey matter volumes in the right inferior frontal gyrus and middle cingulate gyrus,while the UD group showed reduced volume in the right inferior frontal gyrus compared to HCs. In addition,correlation analyses revealed that the grey matter volumes of these regions were negatively correlated with the Hamilton depression rating scores. Taken together,the results of our study suggest that decreased grey matter volume of the right inferior frontal gyrus is a common abnormality in BP1 and UD,and decreasedgrey matter volume in the right middle cingulate gyrus may be specifi c to BP1.     

Grey matter differences in bipolar disorder: a meta-analysis of voxel-based morphometry studies

Selvaraj S, Arnone D, Job D, Stanfield A, Farrow TFD, Nugent AC, Scherk H, Gruber O, Chen X, Sachdev PS, Dickstein DP, Malhi GS, Ha TH, Ha K, Phillips ML, McIntosh AM. Grey matter differences in bipolar disorder: a meta‐analysis of voxel‐based morphometry studies. Bipolar Disord 2012: 14: 135–145. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S. Objective: Several neuroimaging studies have reported structural brain differences in bipolar disorder using automated methods. While these studies have several advantages over those using region of interest techniques, no study has yet estimated a summary effect size or tested for between‐study heterogeneity. We sought to address this issue using meta‐analytic techniques applied for the first time in bipolar disorder at the level of the individual voxel. Methods: A systematic review identified 16 voxel‐based morphometry (VBM) studies comparing individuals with bipolar disorder with unaffected controls, of which eight were included in the meta‐analysis. In order to take account of heterogeneity, summary effect sizes were computed using a random‐effects model with appropriate correction for multiple testing. Results: Compared with controls, subjects with bipolar disorder had reduced grey matter in a single cluster encompassing the right ventral prefrontal cortex, insula, temporal cortex, and claustrum. Study heterogeneity was widespread throughout the brain; though the significant cluster of grey matter reduction remained once these extraneous voxels had been removed. We found no evidence of publication bias (Eggers p = 0.63). Conclusions: Bipolar disorder is consistently associated with reductions in right prefrontal and temporal lobe grey matter. Reductions elsewhere may be obscured by clinical and methodological heterogeneity.     

Structural changes in the gray matter of unmedicated patients with obsessive-compulsive disorder: a voxel-based morphometric study

The aim of the current study was to use whole brain voxel-based morphometry（VBM）to assess the gray matter（GM）changes in unmedicated patients with obsessive-compulsive disorder（OCD）compared with normal controls.We compared the GM volumes in28 patients with 22 matched healthy controls using a1.5T MRI.Three-dimensional T1-weighted magnetic resonance images were obtained from all participants.VBM was performed to detect GM volume differences between the two groups.We detected increased regional GM volumes in the bilateral middle temporal gyri,bilateral middle occipital gyri,bilateral globus pallidus,right inferior parietal gyrus,left superior parietal gyrus,right parahippocampus,right supramarginal gyrus,right medial superior frontal gyrus,and left inferior frontal opercular cortex in the OCD patients relative to controls（P〈0.001,uncorrected,cluster size〉100 voxels）.No decreased GM volume was found in the OCD group compared with normal controls.Our findings suggest that structural changes in the GM are not limited to fronto-striato-thalamic circuits in the pathogenesis of OCD.Temporo-parietal cortex may also play an important role.     

Gut microbiota composition in patients with newly diagnosed bipolar disorder and their unaffected first-degree relatives

ObjectiveAn aberrant gut microbiota may be associated with a broad spectrum of diseases including mental illness. The gut microbiota is scarcely studied in bipolar disorder (BD). We examined the gut microbiota composition in patients with newly diagnosed BD, their unaffected first-degree relatives and healthy individuals.MethodsStool samples were collected from 113 patients with BD, 39 unaffected first-degree relatives and 77 healthy individuals and the microbiota was profiled using 16S rRNA gene amplicon sequencing.ResultsThe gut microbiota community membership of patients with BD differed from that of healthy individuals (R² = 1.0%, P = 0.008), whereas the community membership of unaffected first-degree relatives did not. Flavonifractor was present in 61% of patients with BD, 42% of their unaffected relatives and 39% of healthy individuals. Presence of Flavonifractor was associated with an odds ratio of 2.9 (95%CI: 1.6–5.2, P = 5.8 × 10⁻⁴, Q = 0.036) for having BD. When excluding smokers, presence of Flavonifractor was associated with an odds ratio of 2.3 (95%CI: 1.1–5.3, P = 0.019) for having BD. However, when considering the subsample of non-smokers only, BD and presence of Flavonifractor were no longer associated when adjusted for all possible tests at genus level (Q = 0.6). Presence of Flavonifractor in patients with BD was associated with smoking and female sex, but not with age, waist circumference, exercise level, high-sensitive C-reactive protein, current affective state, subtype of BD, illness duration or psychotropic medication, respectively.ConclusionFlavonifractor, a bacterial genus that may induce oxidative stress and inflammation in its host, was associated with BD. Higher prevalence of smoking among patients with BD contributed to our findings, and it cannot be excluded that findings are influenced by residual confounding.     

精神分裂症患者及其一级亲属性格特征的对照研究

目的探讨精神分裂症患者及其一级亲属的性格特征。方法选取住我院治疗处于缓解期的精神分裂症患者48例和一级亲属与正常组各79人，进行MMPI测查分析。结果精神分裂症患者及其一级亲属Hs、D、Hy、Pd、Pa、Pt、Sc量表分高于正常人，而患者和一级亲属间各量表分接近。结论精神分裂症患者及一级亲属具有明显的分裂性人格，两者的性格特征可能有着共同的遗传学基础。