Alterations in white matter network dynamics in patients with schizophrenia and bipolar disorder

Emerging evidence suggests white matter network abnormalities in patients with schizophrenia (SZ) and bipolar disorder (BD), but the alterations in dynamics of the white matter network in patients with SZ and BD are largely unknown. The white matter network of patients with SZ (n = 45) and BD (n = 47) and that of healthy controls (HC, n = 105) were constructed. We used dynamics network control theory to quantify the dynamics metrics of the network, including controllability and synchronizability, to measure the ability to transfer between different states. Experiments show that the patients with SZ and BD showed decreasing modal controllability and synchronizability and increasing average controllability. The correlations between the average controllability and synchronizability of patients were broken, especially for those with SZ. The patients also showed alterations in brain regions with supercontroller roles and their distribution in the cognitive system. Finally, we were able to accurately discriminate and predict patients with SZ and BD. Our findings provide novel dynamic metrics evidence that patients with SZ and BD are characterized by a selective disruption of brain network controllability, potentially leading to reduced brain state transfer capacity, and offer new guidance for the clinical diagnosis of mental illness.     

No change to grey and white matter volumes in bipolar I disorder patients

BACKGROUND: Structural brain imaging is assumed to be a key method to elucidate the underlying neuropathology of bipolar disorder. However, magnetic resonance imaging studies using region of interest analysis and voxel-based morphometry (VBM) revealed quite inconsistent findings. Hence, there is no clear evidence so far for core regions of cortical or subcortical structural abnormalities in bipolar disorder. The aim of this study was to investigate grey and white matter volumes in a large sample of patients with bipolar I disorder. METHODS: Thirty-five patients with bipolar I disorder and 32 healthy controls matched with respect to gender, handedness and education participated in the study. MRI scanning was performed and an optimized VBM analysis was conducted. RESULTS: We could not observe any significant differences of grey or white matter volumes between patients with bipolar disorder and healthy control subjects. Additional analyses did not reveal significant correlations between grey or white matter volume with number of manic or depressive episodes, duration of illness, existence of psychotic symptoms, and treatment with lithium or antipsychotics. CONCLUSIONS: With this VBM study we were not able to identify core regions of structural abnormalities in bipolar disorder.     

Combined analysis of grey matter voxel-based morphometry and white matter tract-based spatial statistics in late-life bipolar disorder

Background

Previous magnetic resonance imaging (MRI) studies in young patients with bipolar disorder indicated the presence of grey matter concentration changes as well as microstructural alterations in white matter in various neocortical areas and the corpus callosum. Whether these structural changes are also present in elderly patients with bipolar disorder with long-lasting clinical evolution remains unclear.

Methods

We performed a prospective MRI study of consecutive elderly, euthymic patients with bipolar disorder and healthy, elderly controls. We conducted a voxel-based morphometry (VBM) analysis and a tract-based spatial statistics (TBSS) analysis to assess fractional anisotropy and longitudinal, radial and mean diffusivity derived by diffusion tensor imaging (DTI).

Results

We included 19 patients with bipolar disorder and 47 controls in our study. Fractional anisotropy was the most sensitive DTI marker and decreased significantly in the ventral part of the corpus callosum in patients with bipolar disorder. Longitudinal, radial and mean diffusivity showed no significant between-group differences. Grey matter concentration was reduced in patients with bipolar disorder in the right anterior insula, head of the caudate nucleus, nucleus accumbens, ventral putamen and frontal orbital cortex. Conversely, there was no grey matter concentration or fractional anisotropy increase in any brain region in patients with bipolar disorder compared with controls.

Limitations

The major limitation of our study is the small number of patients with bipolar disorder.

Conclusion

Our data document the concomitant presence of grey matter concentration decreases in the anterior limbic areas and the reduced fibre tract coherence in the corpus callosum of elderly patients with long-lasting bipolar disorder.     

Premorbid adjustment in bipolar disorder: comparison with schizophrenia

Knowledge that poor premorbid adjustment (PMA) precedes illness onset in many schizophrenia cases can facilitate early detection. Increasing consideration is being given to a similar early detection strategy for bipolar disorder (BPD). Results of this preliminary investigation comparing PMA in BPD (N = 53) and schizophrenia (N = 39) outpatients revealed a significant difference at the late adolescent (F[1,58] = 4.499, p = 0.038) stage only, with specific differences in two areas of PMA: adaptation to school (t [58] = 1.83, p = 0.036) and social sexual functioning (t [58] = 2.441, p = 0.009). However, mood state may affect some PMA ratings in BPD. Depression ratings were not correlated with reported late adolescent PMA, but a significant, positive correlation was found for the childhood stage (r = 0.32, p = 0.02). Findings fail to support a trend similar to schizophrenia of deteriorating PMA in BPD; however, the approach to investigations of PMA in BPD may need to be reconsidered.     

Evidence for morphological alterations in prefrontal white matter glia in schizophrenia and bipolar disorder

Background

Brain imaging studies suggest that volume reductions and compromised white matter integrity occur in schizophrenia and bipolar disorder (BD). However, the cellular correlates have not yet been identified. To address this issue we assessed oligodendrocyte, astrocyte and microglial populations in postmortem white matter from schizophrenia, BD and nonpsychiatric control samples.

Methods

The density, areal fraction and spatial distribution of glial fibrillary acidic protein (GFAP)-expressing astrocytes and ionized calcium-binding adaptor molecule-1 (IBA-1)-expressing microglia as well as the density, nuclear size and spatial distribution of Nissl-stained oligodendrocytes were quantified in postmortem white matter adjacent to the dorsolateral prefrontal cortex (Brodmann area 9) in schizophrenia, BD and control samples (n = 20). In addition, the oligodendrocyte-associated proteins myelin basic protein and 2′,3′-cyclic-nucleotide 3′-phosphodiesterase (CNPase) were quantified in the same samples by enzyme-linked immunosorbent assay and immunoblotting.

Results

Oligodendrocyte density (p = 0.012) and CNPase protein levels (p = 0.038) differed between groups, being increased in BD compared with control samples. The GFAP area fraction (p = 0.05) and astrocyte spatial distribution (p = 0.040) also differed between groups, reflecting decreased area fraction and increased cell clustering in both schizophrenia and BD samples.

Limitations

Oligodendrocytes were identified using morphological criteria.

Conclusion

This study provides evidence for glial pathology in prefrontal white matter in schizophrenia and BD. Changes in oligodendrocyte and astrocyte populations in white matter in the major psychiatric disorders may reflect disruptions in structural or metabolic support of axons.     

Tract-specific white matter structural disruption in patients with bipolar disorder

Benedetti F, Absinta M, Rocca MA, Radaelli D, Poletti S, Bernasconi A, Dallaspezia S, Pagani E, Falini A, Copetti M, Colombo C, Comi G, Smeraldi E, Filippi M. Tract‐specific white matter structural disruption in patients with bipolar disorder. Bipolar Disord 2011: 13: 414–424. © 2011 The Authors. Journal compilation © 2011 John Wiley & Sons A/S. Objectives: A growing body of evidence suggests that, independent of localized brain lesions, mood disorders can be associated with dysfunction of brain networks involved in the modulation of emotional and cognitive behavior. We used diffusion tensor (DT) tractography to quantify the presence and extent of structural injury to the connections between the amygdala and other brain regions, which included the subgenual, the supragenual and posterior cingulate, the parahippocampal, the orbitofrontal and dorsolateral prefrontal cortices, as well as the insula. Methods: Using a 3.0 Tesla scanner, conventional and DT magnetic resonance imaging sequences of the brain were acquired from 15 adult patients with major depressive disorder (MDD), 15 with bipolar disorder (BD), and 21 age‐matched healthy controls. Using FSL software, diffusivity changes of the white matter (WM) fiber bundles belonging to the emotional network were measured. Results: Compared to controls and MDD patients, BD patients had significantly decreased average fractional anisotropy, increased average mean diffusivity, and increased average axial and radial diffusivity values in the majority of the WM fiber bundles connecting structures of the anterior limbic network (p‐values ranging from 0.002 to 0.040). Medication load did not influence the results with the exception of lithium, which was associated with normal diffusivity values in tracts connecting the amygdala with the subgenual cingulate cortex. Conclusions: We detected specific WM abnormalities, suggestive of disrupted integrity of fiber bundles in the brains of patients with BD. These abnormalities might contribute to understanding both mood dysregulation and cognitive disturbances in BD, and might provide an objective marker to monitor treatment efficacy in this condition.     

Gray matter volume in schizophrenia and bipolar disorder with psychotic features

There is growing evidence that schizophrenia (SZ) and bipolar disorder (BD) overlap significantly in risk factors, neurobiological features, clinical presentations, and outcomes. SZ is characterized by well documented gray matter (GM) abnormalities in multiple frontal, temporal and subcortical structures. Recent voxel-based morphometry (VBM) studies and meta-analyses in BD also report GM reductions in overlapping, albeit less widespread, brain regions. Psychosis, a hallmark of SZ, is also experienced by a significant proportion of BD patients and there is evidence that psychotic BD may be characterized by specific clinical and pathophysiological features. However, there are few studies comparing GM between SZ and psychotic BD. In this study we compared GM volumes in a sample of 58 SZ patients, 28 BD patients experiencing psychotic symptoms and 43 healthy controls using whole-brain voxel-based morphometry. SZ patients had GM reductions in multiple frontal and temporal regions compared to healthy controls and in the subgenual cortex compared to psychotic BD patients. GM volume was increased in the right posterior cerebellum in SZ patients compared to controls. However, psychotic BD patients did not show significant GM deficits compared to healthy controls or SZ patients. We conclude that GM abnormality as measured by VBM analysis is less pronounced in psychotic BD compared to SZ. This may be due to disease-specific factors or medications used more commonly in BD.     

Cognitive functions in bipolar affective disorder and schizophrenia: comparison

Aims: Earlier comparisons of cognitive impairment among patients with bipolar disorder and schizophrenia have found a largely similar profile of deficits, but results have varied between studies. This prompted the current attempt at another such comparison. Methods: Executive functions, memory, IQ, attention–concentration and perceptuomotor function were assessed in 48 bipolar disorder patients with operationally defined euthymia, and compared with 32 schizophrenia patients in remission, and 23 normal controls. Comparisons were re‐attempted after controlling for years of schooling and residual affective symptoms. Results: Uncontrolled comparisons indicated that, compared to controls, both bipolar disorder and schizophrenia patients were significantly impaired on different tests of executive function, memory, IQ and perceptuomotor functions. Controlling for years of schooling and residual affective symptoms, however, served to remove most of the differences between patients and controls, apart from some aspects of executive function in schizophrenia and memory impairment in both schizophrenia and bipolar disorder. Patients with schizophrenia consistently performed worse than patients with bipolar disorder, but none of the differences between schizophrenia and bipolar disorder were significant. Conclusions: Patients with bipolar disorder exhibit cognitive difficulties that are very similar to schizophrenia in terms of their profile, although patients with schizophrenia may have more severe and widespread impairments. The resemblance in cognitive profiles has important implications for the etiology and treatment of both disorders.     

Frontal and temporal volume size of grey and white matter in patients with schizophrenia

We previously performed a magnetic resonance imaging (MRI) parcellation study that showed smaller grey and white matter volumes of the temporal lobes and increased CSF volumes in the frontal and temporal lobe in men with schizophrenia. One question that arose from this earlier study was whether similar structural changes in the brain are found in a large group of schizophrenic patients consisting of both men and women. In the present study, MRI scans were acquired from 94 patients of both genders with schizophrenia and 101 healthy subjects. After the automatic segmentation of grey matter, white matter, and cerebrospinal fluid, the frontal, temporal, parietal, and occipital lobes were automatically parcellated according to the Talairach atlas. Compared with healthy subjects, schizophrenic patients showed significantly smaller volumes of grey matter in the temporal lobe and white matter in the frontal lobe. Schizophrenic patients had a greater CSF volume in the frontal and temporal lobes. These results suggest that volume reduction in the cerebrum is prominent in the frontal and temporal lobes in both men and women with schizophrenia.     

ApoE genotype in relation to AD and cholesterol: a study of 2,326 Chinese adults.

OBJECTIVE: To calculate the frequencies of apolipoprotein E (apoE) alleles in a large Chinese community sample and to compare the serum cholesterol levels of epsilon2, epsilon3, and epsilon4 carriers. BACKGROUND: In comparison with Western populations, a lower frequency of the apoE epsilon4 allele among the Chinese has been proposed as one factor for the lower prevalence of AD found in Chinese populations, but there are insufficient Chinese data on epsilon4 frequency that are based on large community samples. In addition, although Western studies have repeatedly found a lower cholesterol level in epsilon2 carriers and a higher cholesterol level in epsilon4 carriers in comparison with epsilon3 homozygotes, two Chinese studies have yielded inconsistent findings between them. METHODS: During the incidence phase of an epidemiologic survey of several neurologic disorders in a Chinese community, the authors took blood samples from 2,326 participants to determine the apoE genotypes and to measure cholesterol levels. RESULTS: The allelic frequencies of epsilon2, epsilon3, and epsilon4 were 11.8%, 76.4%, and 11.8% among 17 AD patients, and 7.8%, 84.1%, and 8.1% for the entire sample. The mean cholesterol level of the epsilon2 carriers was significantly lower, and that of the epsilon4 carriers significantly higher, than that of the epsilon3 homozygotes. CONCLUSIONS: The obtained epsilon4 rate of 8.1% is lower than most of the Western findings, and this may account in part for the lower prevalence of AD found among the Chinese. The associations between the apoE genotype and serum cholesterol level are similar between Chinese and white populations.     

Evidence for altered cell membrane lipid composition in postmortem prefrontal white matter in bipolar disorder and schizophrenia

Brain imaging suggests that white matter abnormalities, including compromised white matter integrity in the frontal lobe, are shared across bipolar disorder (BD) and schizophrenia (SCZ). However, the precise molecular and cellular correlates remain to be elucidated. Given evidence for widespread alterations in cell membrane lipid composition in both disorders, we sought to investigate whether lipid composition is disturbed in frontal white matter in SCZ and BD. The phospholipids phosphatidylethanolamine (PE) and phosphatidylcholine (PC) were quantified in white matter adjacent to the dorsolateral prefrontal cortex in subjects with BD (n = 34), SCZ (n = 35), and non-psychiatric controls (n = 35) using high-pressure liquid chromatography. Individual fatty acid species and plasmalogens were then quantified separately in PE and PC fractions by gas liquid chromatography. PC was significantly lower in the BD group, compared to controls. The fatty acids PE22:0, PE24:1 and PE20:2n6 were higher, and PC20:4n6, PE22:5n6 and PC22:5n6 lower in the BD group, relative to the control group. PE22:1 was higher and PC20:3n6, PE22:5n6 and PC22:5n6 lower in the SCZ group, compared to the control group. These data provide evidence for altered lipid composition in white matter in both BD and SCZ. Changes in white matter lipid composition could ultimately contribute to dysfunction of frontal white matter circuits in SCZ and BD.     

Increased presence of white matter hyperintensities in adolescent patients with bipolar disorder

Several reports have noted an increase in white matter hyperintensities (WMH) on MRI scans of adult patients with bipolar disorder. We investigated whether this increase was also evident in a group of adolescent patients with bipolar disorder. The sample consisted of 15 bipolar patients, 19 patients with schizophrenia and 16 healthy comparison subjects. All subjects were adolescents. WMH were blindly rated on T2-weighted and PD-weighted MRI scans using our own scale with documented inter-rater reliability. WMH were present in 10 of 15 bipolar patients (67%), seven of 19 patients with schizophrenia (37%) and five of 16 comparison subjects (31%). The bipolar adolescent group had a statistically significant increased presence of WMH compared both with healthy comparison subjects and the schizophrenic group. The association between WMH and bipolar disorder appears to extend to the adolescent years.     

Diffusion imaging studies of white matter integrity in bipolar disorder

Diffusion tensor imaging (DTI) is a neuroimaging technique with a potential to elucidate white matter integrity. Recently, it has been used in the field of psychiatry to further understand the pathophysiology of major diseases, including bipolar disorder (BD). This review sought to focus on existing DTI findings on white matter organization in BD.     

Cognitive dysfunctions and white matter lesions in patients with bipolar disorder in remission

OBJECTIVE: To compare cognitive functioning in relation to white matter lesions in bipolar disorder in remission and schizophrenia. METHOD: Cognitive performance and the occurrence of white matter lesions on MRI images of the brain were assessed in 22 patients with bipolar disorder in remission, 22 patients with schizophrenia and 22 healthy volunteers. RESULTS: Performance of tests of memory, speed and cognitive flexibility was significantly impaired in both patient groups. The frequency of white matter lesions did not differ significantly between the three groups. No differences in cognitive performance were found between patients with white matter lesions and patients without such lesions. CONCLUSION: White matter lesions apparently do not underlie cognitive deficits that are found in patients with bipolar disorder in remission and in patients with schizophrenia.     

Increased rates of white matter hyperintensities in late-onset bipolar disorder

Objectives: Magnetic resonance imaging (MRI) studies have reported an increased frequency of white matter hyperintensities (WMH) in association with late-onset (LO) depression, and this has supported the notion that vascular-related mechanisms may be implicated in the pathophysiology of LO mood disorders. Recent clinical studies have also suggested a link between LO bipolar disorder (LO-BD) and cerebrovascular risk factors, but this has been little investigated with neuroimaging techniques. In order to ascertain whether there could be a specific association between WMH and LO-BD, we directly compared WMH rates between LO-BD subjects (illness onset ≥ 60 years), early-onset BD subjects (EO-BD, illness onset <60 years), and elderly healthy volunteers. Methods: T2-weighted MRI data were acquired in LO-BD subjects (n = 10, age = 73.60 ± 4.09), EO-BD patients (n = 49, age = 67.78 ± 4.44), and healthy subjects (n = 24, age = 69.00 ± 7.22). WMH rates were assessed using the Scheltens scale. Results: There was a greater prevalence of WMH in LO-BD patients relative to the two other groups in the deep parietal region (p = 0.018) and basal ganglia (p < 0.045). When between-group comparisons of mean WMH scores were conducted taking account of age differences (ANCOVA), there were more severe scores in LO-BD patients relative to the two other groups in deep frontal and parietal regions, as well as in the putamen (p < 0.05). Conclusions: Our results provide empirical support to the proposed link between vascular risk factors and LO-BD. If extended in future studies with larger samples, these findings may help to clarify the pathophysiological distinctions between bipolar disorder emerging at early and late stages of life.