Impaired Cerebellar Functional Connectivity in Schizophrenia Patients and Their Healthy Siblings

The long-standing notion of schizophrenia as a disorder of connectivity is supported by emerging evidence from recent neuroimaging studies, suggesting impairments of both structural and functional connectivity in schizophrenia. However, investigations are generally restricted to supratentorial brain regions, thereby excluding the cerebellum. As increasing evidence suggests that the cerebellum contributes to cognitive and affective processing, aberrant connectivity in schizophrenia may include cerebellar dysconnectivity. Moreover, as schizophrenia is highly heritable, unaffected family members of schizophrenia patients may exhibit similar connectivity profiles. The present study applies resting-state functional magnetic resonance imaging to determine cerebellar functional connectivity profiles, and the familial component of cerebellar connectivity profiles, in 62 schizophrenia patients and 67 siblings of schizophrenia patients. Compared to healthy control subjects, schizophrenia patients showed impaired functional connectivity between the cerebellum and several left-sided cerebral regions, including the hippocampus, thalamus, middle cingulate gyrus, triangular part of the inferior frontal gyrus, supplementary motor area, and lingual gyrus (all p < 0.0025, whole-brain significant). Importantly, siblings of schizophrenia patients showed several similarities to patients in cerebellar functional connectivity, suggesting that cerebellar dysconnectivity in schizophrenia might be related to familial factors. In conclusion, our findings suggest that dysconnectivity in schizophrenia involves the cerebellum and that this defect may be related to the risk to develop the illness

Regional brain volumes and antidepressant treatment resistance in major depressive disorder

Major depressive disorder (MDD) is a heritable and highly debilitating condition with antidepressants, first-line treatment, demonstrating low to modest response rates. No current biological mechanism substantially explains MDD but both neurostructural and neurochemical pathways have been suggested. Further explication of these may aid in identifying subgroups of MDD that are better defined by their aetiology. Specifically, genetic stratification provides an array of tools to do this, including the intermediate phenotype approach which was applied in this thesis. This thesis explores genetic overlap with regional brain volume and MDD and the genetic and non-genetic components of antidepressant response. The first study utilised the most recent published data from ENIGMA (Enhancing Neuroimaging Genetics through Meta-analysis) Consortium’s genome-wide association study (GWAS) of regional brain volume to examine shared genetic architecture between seven subcortical brain volumes and intracranial volume (ICV) and MDD. This was explored using linkage disequilibrium score regression (LDSC), polygenic risk scoring (PRS) techniques, Mendelian randomisation (MR) analysis and BUHMBOX (Breaking Up Heterogeneous Mixture Based On Cross-locus correlations). Results indicated that hippocampal volume was positively genetically correlated with MDD (rg= 0.46, P= 0.02), although this did not survive multiple comparison testing. Additionally, there was evidence for genetic subgrouping in Generation Scotland: Scottish Family Health Study (GS:SFHS) MDD cases (P=0.00281), however, this was not replicated in two other independent samples. This study does not support a shared architecture for regional brain volumes and MDD, however, provided some evidence that hippocampal volume and MDD may share genetic architecture in a subgroup of individuals, albeit the genetic correlation did not survive multiple testing correction and genetic subgroup heterogeneity was not replicated. To explore antidepressant treatment resistance, the second study utilised prescription data in (GS:SFHS) to define a measure of (a) treatment resistance (TR) and (b) stages of resistance (SR) by inferring antidepressant switching as non-response. GWAS were conducted separately for TR in GS:SFHS and the GENDEP (Genome-based Therapeutic Drugs for Depression) study and then meta-analysed (meta-analysis n=4,213, cases=358). For SR, a GWAS on GS:SFHS only was performed (n=3,452). Additionally, gene-set enrichment, polygenic risk scoring (PRS) and genetic correlation analysis were conducted. No significant locus, gene or gene-set was associated with TR or SR, however power analysis indicated that this analysis was underpowered. Pedigree-based correlations identified genetic overlap with psychological distress, schizotypy and mood disorder traits. Finally, the role of neuroticism, psychological resilience and coping styles in antidepressant resistance was investigated. Univariate, moderation and mediation models were applied using logistic regression and structural equation modelling techniques. In univariate models, neuroticism and emotion-orientated coping demonstrated significant negative association with antidepressant resistance, whereas resilience, task-orientated and avoidance-orientated coping demonstrated significant positive association. No moderation of the association between neuroticism and TR was detected and no mediating effect of coping styles was found. However, resilience was found to partially mediate the association between neuroticism and TR. Whilst the first study does not indicate a genetic overlap between regional brain volumes and MDD, it demonstrates the utility of the intermediate approach in complex disease. Antidepressant resistance was associated with neuroticism both genetically and phenotypically, indicating its role as an intermediate phenotype. Nonetheless, larger sample sizes are needed to adequately address the components of antidepressant resistance. Further work in antidepressant non-response may help to identify biological mechanisms responsible in MDD pathology and help stratify individuals into more tractable groups

Association of IQ changes and progressive brain changes in patients with schizophrenia

Although schizophrenia is characterized by impairments in intelligence and the loss of brain volume, the relationship between changes in IQ and brain measures is not clear. In the current study, we aimed to investigate the association between IQ and brain measures in patients with schizophrenia across time. Participants were recruited at the University Medical Center Utrecht, the Netherlands, and included 84 patients with schizophrenia (mean illness duration, 4.35 years) and 116 age-matched healthy controls. MRI of the brain and IQ scores were obtained for them at baseline and the 3-year follow-up. This study was approved by the University Medical Center Utrecht Medical Ethics Committee for Research in Humans. Written informed consent was obtained from all participants. Cerebral gray matter volume (p = 0.006) and cortical volume (p = 0.03) and thickness (p = 0.02) decreased more in patients with schizophrenia across time compared with control participants. Patients showed additional loss in cortical volume and thickness of the right supramarginal, posterior superior temporal, left supramarginal, left postcentral, and occipital regions (p values were between <0.001 and 0.03 after clusterwise correction). Although IQ increased similarly in patients with schizophrenia and control participants, changes in IQ were negatively correlated with changes in lateral ventricular volume (p = 0.05) and positively correlated with changes in cortical volume (p = 0.007) and thickness (p = 0.004) only in patients with schizophrenia. Positive correlations between changes in IQ and cortical volume and thickness were found globally and in widespread regions across frontal, temporal, and parietal cortices (p values were between <0.001 and 0.03 after clusterwise correction). These findings were independent of symptom severity at follow-up, cannabis use, and the use of cumulative antipsychotic medications during the 3 years of follow-up. These results suggest that progressive brain tissue loss in schizophrenia is related to relative cognitive decline during the early course of illness.日本統合失調症学

Association of IQ Changes and Progressive Brain Changes in Patients With Schizophrenia.

IMPORTANCE:Although schizophrenia is characterized by impairments in intelligence and the loss of brain volume, the relationship between changes in IQ and brain measures is not clear.OBJECTIVE:To investigate the association between IQ and brain measures in patients with schizophrenia across time.DESIGN, SETTING, AND PARTICIPANTS:Case-control longitudinal study at the Department of Psychiatry at the University Medical Center Utrecht, Utrecht, the Netherlands, comparing patients with schizophrenia and healthy control participants between September 22, 2004, and April 17, 2008. Magnetic resonance imaging of the brain and IQ scores were obtained at baseline and the 3-year follow-up. Participants included 84 patients with schizophrenia (mean illness duration, 4.35 years) and 116 age-matched healthy control participants.MAIN OUTCOMES AND MEASURES:Associations between changes in IQ and the total brain, cerebral gray matter, cerebral white matter, lateral ventricular, third ventricles, cortical, and subcortical volumes; cortical thickness; and cortical surface area.RESULTS:Cerebral gray matter volume (P = .006) and cortical volume (P = .03) and thickness (P = .02) decreased more in patients with schizophrenia across time compared with control participants. Patients showed additional loss in cortical volume and thickness of the right supramarginal, posterior superior temporal, left supramarginal, left postcentral, and occipital regions (P values were between <.001 and .03 after clusterwise correction). Although IQ increased similarly in patients with schizophrenia and control participants, changes in IQ were negatively correlated with changes in lateral ventricular volume (P = .05) and positively correlated with changes in cortical volume (P = .007) and thickness (P = .004) only in patients with schizophrenia. Positive correlations between changes in IQ and cortical volume and thickness were found globally and in widespread regions across frontal, temporal, and parietal cortices (P values were between <.001 and .03 after clusterwise correction). These findings were independent of symptom severity at follow-up, cannabis use, and the use of cumulative antipsychotic medications during the 3 years of follow-up.CONCLUSIONS AND RELEVANCE:Progressive brain tissue loss in schizophrenia is related to relative cognitive decline during the early course of illness

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Association of IQ Changes and Progressive Brain Changes in Patients With Schizophrenia

IMPORTANCE Although schizophrenia is characterized by impairments in intelligence and the loss of brain volume, the relationship between changes in IQ and brain measures is not clear. OBJECTIVE To investigate the association between IQ and brain measures in patients with schizophrenia across time. DESIGN, SETTING, AND PARTICIPANTS Case-control longitudinal study at the Department of Psychiatry at the University Medical Center Utrecht, Utrecht, the Netherlands, comparing patients with schizophrenia and healthy control participants between September 22, 2004, and April 17, 2008. Magnetic resonance imaging of the brain and IQ scores were obtained at baseline and the 3-year follow-up. Participants included 84 patients with schizophrenia (mean illness duration, 4.35 years) and 116 age-matched healthy control participants. MAIN OUTCOMES AND MEASURES Associations between changes in IQ and the total brain, cerebral gray matter, cerebral white matter, lateral ventricular, third ventricles, cortical, and subcortical volumes; cortical thickness; and cortical surface area. RESULTS Cerebral gray matter volume (P = .006) and cortical volume (P = .03) and thickness (P = .02) decreased more in patients with schizophrenia across time compared with control participants. Patients showed additional loss in cortical volume and thickness of the right supramarginal, posterior superior temporal, left supramarginal, left postcentral, and occipital regions (P values were between CONCLUSIONS AND RELEVANCE Progressive brain tissue loss in schizophrenia is related to relative cognitive decline during the early course of illness