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Contains fulltext : 291574.pdf (Publisher’s version ) (Open Access) Left-right asymmetry is an important organizing feature of the healthy brain that may be altered in schizophrenia, but most studies have used relatively small samples and heterogeneous approaches, resulting in equivocal findings. We carried out the largest case-control study of structural brain asymmetries in schizophrenia, with MRI data from 5,080 affected individuals and 6,015 controls across 46 datasets, using a single image analysis protocol. Asymmetry indexes were calculated for global and regional cortical thickness, surface area, and subcortical volume measures. Differences of asymmetry were calculated between affected individuals and controls per dataset, and effect sizes were meta-analyzed across datasets. Small average case-control differences were observed for thickness asymmetries of the rostral anterior cingulate and the middle temporal gyrus, both driven by thinner left-hemispheric cortices in schizophrenia. Analyses of these asymmetries with respect to the use of antipsychotic medication and other clinical variables did not show any significant associations. Assessment of age- and sex-specific effects revealed a stronger average leftward asymmetry of pallidum volume between older cases and controls. Case-control differences in a multivariate context were assessed in a subset of the data (N = 2,029), which revealed that 7% of the variance across all structural asymmetries was explained by case-control status. Subtle case-control differences of brain macrostructural asymmetry may reflect differences at the molecular, cytoarchitectonic, or circuit levels that have functional relevance for the disorder. Reduced left middle temporal cortical thickness is consistent with altered left-hemisphere language network organization in schizophrenia.

ObjectiveSchizophrenia is associated with widespread brain-morphological alterations, believed to be shaped by the underlying connectome architecture. This study tests whether large-scale structural reorganization in schizophrenia relates to normative network architecture, in particular regional centrality/hubness and connectivity patterns. We examine network effects in schizophrenia across different disease stages, and transdiagnostically explore consistency of such relationships in patients with bipolar and major depressive disorder.MethodsWe studied anatomical MRI scans from 2,439 adults with schizophrenia and 2,867 healthy controls from 26 ENIGMA sites. Case-control patterns of structural alterations were evaluated against two network susceptibility models: 1) hub vulnerability, which examines associations between regional network centrality and magnitude of disease-related alterations; 2) epicenter models, which identify regions whose typical connectivity profile most closely resembles the disease-related morphological alteration patterns. Both susceptibility models were tested across schizophrenia disease stages and compared to meta-analytic bipolar and major depressive disorder case-control maps.ResultsIn schizophrenia, regional gray matter reductions co-localized with interconnected hubs, in both the functional (r=0.58, pspinspin=0.01). Epicenters were identified in temporo-paralimbic regions, extending to frontal areas. We found unique epicenters for first-episode and early stages, and a shift from occipital to temporal-frontal epicenters in chronic stages. Transdiagnostic comparisons revealed shared epicenters in schizophrenia and bipolar, but not major depressive disorders.ConclusionsCortical reorganization over the course of schizophrenia closely reflects brain network architecture, emphasizing marked hub susceptibility and temporo-frontal epicenters. The observed overlapping epicenters for schizophrenia and bipolar disorder furthermore suggest shared pathophysiological processes within the schizophrenia-bipolar-spectrum.

Schizophrenia (SZ) is associated with an increased risk of life-long cognitive impairments, age-related chronic disease, and premature mortality. We investigated evidence for advanced brain ageing in adult SZ patients, and whether this was associated with clinical characteristics in a prospective meta-analytic study conducted by the ENIGMA Schizophrenia Working Group. The study included data from 26 cohorts worldwide, with a total of 2803 SZ patients (mean age 34.2 years; range 18-72 years; 67% male) and 2598 healthy controls (mean age 33.8 years, range 18-73 years, 55% male). Brain-predicted age was individually estimated using a model trained on independent data based on 68 measures of cortical thickness and surface area, 7 subcortical volumes, lateral ventricular volumes and total intracranial volume, all derived from T1-weighted brain magnetic resonance imaging (MRI) scans. Deviations from a healthy brain ageing trajectory were assessed by the difference between brain-predicted age and chronological age (brain-predicted age difference [brain-PAD]). On average, SZ patients showed a higher brain-PAD of +3.64 years (95% CI: 3.01, 4.26; I2 = 55.28%) compared to controls, after adjusting for age and sex (Cohen’s d = 0.50). Among SZ patients, brain-PAD was not associated with specific clinical characteristics (age of onset, duration of illness, symptom severity, or antipsychotic use and dose). This large-scale collaborative study suggests advanced structural brain ageing in SZ. Longitudinal studies of SZ and a range of mental and somatic health outcomes will help to further evaluate the clinical implications of increased brain-PAD and its ability to be influenced by interventions.

White matter (WM) abnormalities have implicated schizophrenia (SZ) and bipolar disorder (BD) as disconnection syndromes, yet the extent to which these abnormalities are shared versus distinct remains unclear. Diffusion tensor imaging (DTI) studies yield a putative measure of WM integrity while neuropathological studies provide more specific microstructural information. We therefore systematically reviewed all neuropathological (n = 12) and DTI (n = 11) studies directly comparing patients with SZ and BD. Most studies (18/23) reported no difference between patient groups. Changes in oligodendrocyte density, myelin staining and gene, protein and mRNA expression were found in SZ and/or BD patients as compared to healthy individuals, while DTI studies showed common alterations in thalamic radiations, uncinate fasciculus, corpus callosum, longitudinal fasciculus and corona radiata. Altogether, findings suggest shared disconnectivity in SZ and BD, which are likely related to their considerable overlap. Above all, neuroimaging findings corroborated neuropathological findings in the prefrontal cortex, demonstrating the utility of integrating multiple methodologies. Focusing on clinical dimensions over disease entities will advance our understanding of disconnectivity and help inform preventive medicine.

Background There is growing evidence for complement system involvement in the pathophysiology of schizophrenia, although the extent and magnitude of complement factor disturbances has not been fully reported. It also remains unclear whether complement abnormalities are characteristic of all patients with schizophrenia or whether they are representative of a subgroup of patients who show signs of heightened inflammation. The aim of the present study was to quantify and compare the levels of a range of complement factors, receptors and regulators in healthy controls and people with schizophrenia and to determine the extent to which the levels of these peripheral molecules relate to measures of brain structure, particularly cortical thickness. Method Seventy-five healthy controls and 90 patients with schizophrenia or schizoaffective disorder were included in the study. Peripheral blood samples were collected from all participants and mRNA expression was quantified in 20 complement related genes, four complement proteins, as well as for four cytokines. T1-weighted structural MRI scans were acquired and analysed to determine cortical thickness measures. Results There were significant increases in peripheral mRNA encoding receptors (C5ar1, CR1, CR3a), regulators (CD55, C59) and protein concentrations (C3, C3b, C4) in people with schizophrenia relative to healthy controls. C4a expression was significantly increased in a subgroup of patients displaying elevated peripheral cytokine levels. A higher inflammation index score derived from mRNA expression patterns predicted reductions in cortical thickness in the temporal lobe (superior temporal gyrus, transverse temporal gyrus, fusiform gyrus, insula) in patients with schizophrenia and healthy controls. Conclusions Analysis of all three major complement pathways supports increased complement activity in schizophrenia and also shows for the first time that peripheral C4a up-regulation is related to increased peripheral pro-inflammatory cytokines in schizophrenia. Our region-specific, neuroimaging findings linked to an increased peripheral complement mRNA expression pattern suggests a role for complement in cortical thinning. Further studies are required to further clarify clinical and neurobiological consequences of aberrant complement levels in schizophrenia and related psychoses.

While high levels of glucocorticoids are generally neuro-damaging, a related adrenal steroid, dehydroepiandrosterone (DHEA), has anti-glucocorticoid and neuroprotective properties. Previous work has shown increased circulating levels of DHEA and abnormal cortisol/DHEA ratios in people with schizophrenia, however reports are limited and their relationship to neuropathology is unclear. We performed the largest study to date to compare levels of serum DHEA and cortisol/DHEA ratios in people with schizophrenia and healthy controls, and investigated the extent to which cortisol/DHEA ratios predict brain volume. Serum cortisol and DHEA were assayed in 94 people with schizophrenia and 81 healthy controls. T1-weighted high-resolution anatomical scans were obtained using a 3 T Achieva scanner on a subset of 59 people with schizophrenia and 60 healthy controls. Imaging data were preprocessed and analyzed using SPM12. People with schizophrenia had significantly increased serum DHEA levels (p = 0.002), decreased cortisol/DHEA ratios (p = 0.02) and no difference in cortisol levels compared to healthy controls. Cortisol/DHEA ratios were inversely correlated with hippocampal (r = -0.33 p = 0.01) and dorsolateral prefrontal cortex (r = -0.30, p = 0.02) volumes in patients. Our findings suggest that the cortisol/DHEA ratio may be a molecular blood signature of hippocampal and cortical damage. These results further implicate the role of DHEA and hypothalamic-pituitary-adrenal axis dysfunction in the pathophysiology of schizophrenia.

According to global neuronal workspace (GNW) theory, conscious access relies on long-distance cerebral connectivity to allow a global neuronal ignition coding for conscious content. In patients with schizophrenia and bipolar disorder, both alterations in cerebral connectivity and an increased threshold for conscious perception have been reported. The implications of abnormal structural connectivity for disrupted conscious access and the relationship between these two deficits and psychopathology remain unclear. The aim of this study was to determine the extent to which structural connectivity is correlated with consciousness threshold, particularly in psychosis. We used a visual masking paradigm to measure consciousness threshold, and diffusion MRI tractography to assess structural connectivity in 97 humans of either sex with varying degrees of psychosis: healthy control subjects (n = 46), schizophrenia patients (n = 25), and bipolar disorder patients with (n = 17) and without (n = 9) a history of psychosis. Patients with psychosis (schizophrenia and bipolar disorder with psychotic features) had an elevated masking threshold compared with control subjects and bipolar disorder patients without psychotic features. Masking threshold correlated negatively with the mean general fractional anisotropy of white matter tracts exclusively within the GNW network (inferior frontal-occipital fasciculus, cingulum, and corpus callosum). Mediation analysis demonstrated that alterations in long-distance connectivity were associated with an increased masking threshold, which in turn was linked to psychotic symptoms. Our findings support the hypothesis that long-distance structural connectivity within the GNW plays a crucial role in conscious access, and that conscious access may mediate the association between impaired structural connectivity and psychosis.

Schizophrenia (SZ) and bipolar disorder (BD) are often conceptualized as “disconnection syndromes”, with substantial evidence of abnormalities in deep white matter tracts, forming the substrates of long-range connectivity, seen in both disorders. However, the study of superficial white matter (SWM) U-shaped short-range tracts remained challenging until recently, although findings from post-mortem studies suggest they are likely integral components of SZ and BD neuropathology. This diffusion weighted imaging (DWI) study aimed to investigate SWM microstructure in vivo in both SZ and BD for the first time. We performed whole brain tractography in 31 people with SZ, 32 people with BD and 54 controls using BrainVISA and Connectomist 2.0. Segmentation and labelling of SWM tracts were performed using a novel, comprehensive U-fiber atlas. Analysis of covariances yielded significant generalized fractional anisotropy (gFA) differences for 17 SWM bundles in frontal, parietal and temporal cortices. Post hoc analyses showed gFA reductions in both patient groups as compared with controls in bundles connecting regions involved in language processing, mood regulation, working memory and motor function (pars opercularis, insula, anterior cingulate, precentral gyrus). We also found increased gFA in SZ patients in areas overlapping the default mode network (inferior parietal, middle temporal, precuneus), supporting functional hyperconnectivity of this network evidenced in SZ. We thus illustrate that short U-fibers are vulnerable to the pathological processes in major psychiatric illnesses, encouraging improved understanding of their anatomy and function.

Lower testosterone levels are associated with greater negative symptoms in men with schizophrenia. Testosterone signals via androgen receptor (AR). A functional variant in the AR gene (CAG trinucleotide repeat polymorphism) is associated with circulating testosterone and mood-related symptoms in healthy people. Raloxifene increases testosterone in healthy males and reduces symptom severity and improves cognition in schizophrenia; however, whether raloxifene increases testosterone in men with schizophrenia is unknown. We assessed the interaction of a functional AR gene variant and adjunctive raloxifene on peripheral testosterone and symptom severity in schizophrenia. Patients with schizophrenia (59 males and 38 females) participated in a randomized, double-blind, placebo-controlled, crossover trial of adjunctive raloxifene (120 mg/day). Healthy adults (46 males and 41 females) were used for baseline comparison. Baseline circulating testosterone was decreased in male patients compared to male controls and positively correlated with CAG repeat length in male controls and female patients. Male patients with short, compared to long, CAG repeat length had higher stress scores. Raloxifene treatment increased testosterone in male patients, but was unrelated to AR CAG repeat length, suggesting that raloxifene’s effects may not depend on AR activity. Sex-specific alterations of the relationship between AR CAG repeat length and testosterone suggest that altered AR activity may impact perceived stress in men with schizophrenia.

Growing evidence suggests that testosterone may play a role in the pathophysiology of schizophrenia given that testosterone has been linked to cognition and negative symptoms in schizophrenia. Here, we determine the extent to which serum testosterone levels are related to neural activity in affective processing circuitry in men with schizophrenia. Functional magnetic resonance imaging was used to measure blood-oxygen-level-dependent signal changes as 32 healthy controls and 26 people with schizophrenia performed a facial emotion identification task. Whole brain analyses were performed to determine regions of differential activity between groups during processing of angry versus non-threatening faces. A follow-up ROI analysis using a regression model in a subset of 16 healthy men and 16 men with schizophrenia was used to determine the extent to which serum testosterone levels were related to neural activity. Healthy controls displayed significantly greater activation than people with schizophrenia in the left inferior frontal gyrus (IFG). There was no significant difference in circulating testosterone levels between healthy men and men with schizophrenia. Regression analyses between activation in the IFG and circulating testosterone levels revealed a significant positive correlation in men with schizophrenia (r=.63, p=.01) and no significant relationship in healthy men. This study provides the first evidence that circulating serum testosterone levels are related to IFG activation during emotion face processing in men with schizophrenia but not in healthy men, which suggests that testosterone levels modulate neural processes relevant to facial emotion processing that may interfere with social functioning in men with schizophrenia.

Background Alterations in brain connectivity are strongly implicated in the pathophysiology of schizophrenia (SZ). Very recently, evidence is mounting to suggest that changes in superficial white matter (SWM) U-shaped short range fibers are integral components of disease neuropathology, a theory that is supported by findings from postmortem studies and less often in vivo in patients with SZ. This diffusion weighted imaging (DWI) study aimed to investigate SWM microstructure in the frontal cortex in people with SZ. Methods Whole brain tractography was performed in 31 people with SZ and 54 healthy controls using BrainVISA and Connectomist 2.0 software. Segmentation and labelling of superficial white matter tracts were performed using a novel atlas characterizing 100 bundles. Principal Components Analysis (PCA) using a varimax orthogonal rotation was performed on mean generalised fractional anisotropy (gFA) of bundles located in the frontal cortex. Composites scores were computed for each subject, reflecting a linear combination of mean gFA values. Results PCA revealed three components explaining 19.7 %, 5.8 %, and 5.4 % of the total variance. The mean score of the second component was significantly lower in the people with SZ compared with controls (p = 0.01) and included 13 bundles connecting regions in the pars orbitalis, insula, pars triangularis, pars opercularis, orbitofrontal cortex, anterior cingulate, superior frontal cortex and middle frontal cortex. Discussion Our results support findings of reduced white matter integrity in the frontal cortex in people with SZ. Moreover, PCA may be helpful in identifying specific networks as the deficits do not appear to be widespread. Identifying patterns of superficial white matter dysconnectivity may be helpful in understanding the prominent symptoms and cognitive deficits and observed in SZ.

Older adults who experience loneliness have an increased risk of all-cause mortality and morbidity [1], and among the biological mechanisms implicated, increases in inflammation might contribute. In older adults reporting high levels of loneliness and/or psychological stress, nuclear factor (NF)-κB shows increased activity [2]. NF-κB is a transcription factor that may be an important mediator for the translation of social stress into inflammation [3] as NF-κB controls the expression of genes that code for multiple inflammatory cytokines [4], and stress activation of the sympathetic nervous system stimulates NF-κB [3]. A meditation technique, Tai Chi Chih (TCC), is thought to act on stress response pathways [5] that may be sensitized in lonely individuals due to hypervigilance for social threat and feelings of vulnerability. TCC is a multidimensional behavioral therapy that integrates moderate physical activity, deep breathing and meditation to promote regulation of emotional and affective responses to stress, with downregulation of sympathetic nervous system outflow [6]. Findings show that TCC and other meditation forms also reduce markers of inflammation [6, 7] and the expression of genes bearing NF-κB response elements [8]. However, the effect of TCC on levels of the NF-κB transcription factor has not been examined. Given evidence that chronic stress leads to a progressive rise in inflammation in older adults [9], and that both stress and increased expression of genes bearing NF-κB response elements are associated with loneliness, we hypothesized that TCC would reduce stress and slow the rate of increase in NF-κB levels in lonely older adults, as compared to those who receive a stress and health education (SHE) intervention. Twenty-six older adults (≥ 60 years), naive to Tai Chi, who scored ≥ 40 on the UCLA Loneliness Scale, participated in this study approved by the UCLA Institutional Review Board (NCT01204021). Excluded were those with current psychotherapy, behavioral therapy and/or use of antidepressants, current DSM-IV (SCID-IV) psychiatric disorder, body mass index >33, cognitive impairment (Mini-Mental State Examination 3 standard deviations from the mean were dropped from analysis. One subject refused blood sampling and all NF-κB values were missing for this single case. The TCC intervention consisted of 20 guided meditative movements under the instruction of a certified teacher as previously detailed [11]. SHE controlled for nonspecific treatment effects of time, attention, expectancy and group support, similar to prior protocols [11]. The session format was didactic, with guest presenters lecturing on health (e.g. stress, aging, exercise and nutrition). Intention-to-treat analyses were performed in SPSS version 20 (IBM Corp., Armonk, N.Y., USA). Changes in PSS and levels of NF-κB from pre- to postintervention time points were tested using linear mixed modeling, adjusted for pre-intervention levels. Twenty-six enrollees were evenly randomized to treatment and provided pre-intervention data, 22 (85%) completed the postintervention visit (10 in TCC and 12 in SHE). The two treatment groups showed similar demographic and clinical characteristics (table 1). Psychological stress as indexed by the PSS significantly differed between the two groups after intervention [F(1, 23.92) = 4.49, p = 0.04] covarying for pre-intervention levels. From pre- to postintervention visits, decreases in PSS were observed in the TCC group (p < 0.01) but not in the SHE control (p = 0.75; fig. 1 a). NF-κB significantly differed between the two groups after intervention [F(1, 106.79) = 5.24, p = 0.02] covarying for pre-intervention levels. From pre- to postintervention visits, increases in NF-κB levels were observed in the SHE group (p < 0.05), but not in the TCC group (p = 0.34; fig. 1 b). The pre- to postintervention changes in PSS levels were correlated with changes in NF-κB levels (Spearman's r = 0.46, p = 0.05, n = 19, fig. 2). Fig. 1 a Estimated PSS levels (±SE), covarying for pre-intervention PSS score. b Estimated NF-κB activation (±SE), covarying for pre-intervention NF-κB; * p < 0.05 for difference between groups. Fig. 2 Correlation between changes from pre- to postintervention visits in PSS and NF-κB activation for the participants in the TCC and SHE control groups, Spearman's r = 0.46, p = 0.05, n = 19. Table 1 Pre-intervention characteristics of the lonely older adult sample Our findings show that among lonely older adults who received a health education control, levels of psychological stress persisted, and these elderly showed significant increases in nuclear levels of activated NF-κB from pre- to postintervention time points. Conversely, among lonely older adults who received TCC, psychological stress decreased, while NF-κB levels remained constant. Further, change in psychological stress was correlated with change in NF-κB activation from pre- to postintervention examinations, which together suggests that treatment-induced reduction in stress may attenuate increases in NF-κB activation. Previous work indicates that chronic stress in older adults is associated with an accelerated rate of increase in inflammatory markers such as interleukin-6 [9]. Lonely adults show elevated psychological stress scores as well as physiological indicators of stress, and they have been conceptualized as a chronically stressed population [12]. Ours is the first study to show that TCC has the capacity to alter stress levels in lonely older adults and to attenuate the rate of increase in a key transcription factor, NF-κB, involved in the upstream inflammatory cascade. Limitations of this study include its small sample size and the predominance of women, which limit the generalizability of our results; hence, these findings require future replication. A larger sample would enable more appropriate tests of whether changes in stress mediate the changes in NF-κB. History of loneliness was not assessed, so the chronic nature of stress in the sample was unknown. Future studies should account for a previous history of loneliness. Levels of NF-κB were only measured in peripheral blood mononuclear cells, and it is possible that the changes in NF-κB reported here are due to changes in lymphocyte subset distribution. However, such changes in immune cell trafficking occur primarily in the context of acute stress manipulation, and chronic stress has not been associated with changes in immune cell numbers. The meditation intervention TCC significantly reduced psychological stress and attenuated the rise of NF-κB activation that is otherwise found in lonely older adults.

Estrogen has been implicated in the development and course of schizophrenia with most evidence suggesting a neuroprotective effect. Treatment with raloxifene, a selective estrogen receptor modulator, can reduce symptom severity, improve cognition and normalize brain activity during learning in schizophrenia. People with schizophrenia are especially impaired in the identification of negative facial emotions. The present study was designed to determine the extent to which adjunctive raloxifene treatment would alter abnormal neural activity during angry facial emotion recognition in schizophrenia. Twenty people with schizophrenia (12 men, 8 women) participated in a 13-week, randomized, double-blind, placebo-controlled, crossover trial of adjunctive raloxifene treatment (120 mg per day orally) and performed a facial emotion recognition task during functional magnetic resonance imaging after each treatment phase. Two-sample t-tests in regions of interest selected a priori were performed to assess activation differences between raloxifene and placebo conditions during the recognition of angry faces. Adjunctive raloxifene significantly increased activation in the right hippocampus and left inferior frontal gyrus compared with the placebo condition (family-wise error, P<0.05). There was no significant difference in performance accuracy or reaction time between active and placebo conditions. To the best of our knowledge, this study provides the first evidence suggesting that adjunctive raloxifene treatment changes neural activity in brain regions associated with facial emotion recognition in schizophrenia. These findings support the hypothesis that estrogen plays a modifying role in schizophrenia and shows that adjunctive raloxifene treatment may reverse abnormal neural activity during facial emotion recognition, which is relevant to impaired social functioning in men and women with schizophrenia.

This study examined differences between Asians and non-Hispanic Whites (Whites) in pain sensitivity, and its relationship to mean arterial pressure (MAP) and heart rate (HR). In 30 Whites (50% female) and 30 Asians (50% female), experimental pain sensitivity was assessed with a hand cold pressor task, yielding measures of pain threshold, tolerance, intensity, and unpleasantness. Mean arterial pressure and HR measurements taken at rest and in response to speech stress were assessed. Perceived stress, anxiety, perfectionism, parental criticism, parental expectations and depressive symptoms were also measured. The results indicated that for the cold pain test, Asians demonstrated significantly lower pain threshold and tolerance levels than Whites. Although no ethnic differences were seen for MAP or HR responses to stress, for Whites higher stress MAP levels were correlated with reduced pain sensitivity, while for Asians higher baseline and stress HR levels were correlated with reduced pain sensitivity. Asians reported higher parental expectations and greater parental criticism than Whites. For Asians only, higher levels of perfectionism were related to more depressive symptoms, anxiety and perceived stress. These results indicate that Asian Americans are more sensitive to experimental pain than Whites and suggest ethnic differences in endogenous pain regulatory mechanisms (e.g. MAP and HR). The results may also have implications for understanding ethnic differences in clinical pain.