Publications by authors named "Gary Donohoe"

148 Publications

Current psychosocial stress, childhood trauma and cognition in patients with schizophrenia and healthy participants.

Schizophr Res 2021 Sep 11;237:115-121. Epub 2021 Sep 11.

School of Psychology, National University of Ireland Galway, Galway, Ireland; Centre for Neuroimaging, Cognition & Genomics, National University of Ireland Galway, Galway, Ireland. Electronic address:

Background: Cognitive difficulties are experienced frequently in schizophrenia (SZ) and are strongly predictive of functional outcome. Although severity of cognitive difficulties has been robustly associated with early life adversity, whether and how they are affected by current stress is unknown. The present study investigated whether acute stress reactivity as measured by heart rate and mood changes predict cognitive performance in patients with schizophrenia and healthy individuals, and whether this is moderated by diagnosis and previous childhood trauma exposure.

Methods: One hundred and four patients with schizophrenia and 207 healthy participants were administered a battery of tasks assessing cognitive performance after psychosocial stress induction (Trier Social Stress Test; TSST). Mood states (Profile of Mood States; POMS) and heart rate were assessed at baseline, immediately before, and after the TSST.

Results: Both healthy participants and patients showed increases in POMS Tension and Total Mood Disturbance scores between Time Point 2 (pre-TSST) and Time Point 3 (post-TSST). These changes were not associated with variation in cognition. Although childhood trauma exposure was associated with higher stress reactivity and poorer cognitive function in all participants, childhood trauma did not moderate the association between stress reactivity and cognition. Neither was diagnosis a moderator of this relationship.

Discussion: These findings suggest that while chronic stress exposure explains significant variation in cognition, acute stress reactivity (measured by changes in Tension and Total Mood Disturbance) did not. In the context of broader developmental processes, we conclude that stressful events that occur earlier in development, and with greater chronicity, are likely to be more strongly associated with cognitive variation than acute transient stressors experienced in adulthood.
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http://dx.doi.org/10.1016/j.schres.2021.08.030DOI Listing
September 2021

A meta-analysis of deep brain structural shape and asymmetry abnormalities in 2,833 individuals with schizophrenia compared with 3,929 healthy volunteers via the ENIGMA Consortium.

Hum Brain Mapp 2021 Sep 8. Epub 2021 Sep 8.

Tri-institutional Center for Translational Research in Neuroimaging and Data Science (TReNDS) [Georgia State University, Georgia Institute of Technology], Emory University, Atlanta, Georgia, USA.

Schizophrenia is associated with widespread alterations in subcortical brain structure. While analytic methods have enabled more detailed morphometric characterization, findings are often equivocal. In this meta-analysis, we employed the harmonized ENIGMA shape analysis protocols to collaboratively investigate subcortical brain structure shape differences between individuals with schizophrenia and healthy control participants. The study analyzed data from 2,833 individuals with schizophrenia and 3,929 healthy control participants contributed by 21 worldwide research groups participating in the ENIGMA Schizophrenia Working Group. Harmonized shape analysis protocols were applied to each site's data independently for bilateral hippocampus, amygdala, caudate, accumbens, putamen, pallidum, and thalamus obtained from T1-weighted structural MRI scans. Mass univariate meta-analyses revealed more-concave-than-convex shape differences in the hippocampus, amygdala, accumbens, and thalamus in individuals with schizophrenia compared with control participants, more-convex-than-concave shape differences in the putamen and pallidum, and both concave and convex shape differences in the caudate. Patterns of exaggerated asymmetry were observed across the hippocampus, amygdala, and thalamus in individuals with schizophrenia compared to control participants, while diminished asymmetry encompassed ventral striatum and ventral and dorsal thalamus. Our analyses also revealed that higher chlorpromazine dose equivalents and increased positive symptom levels were associated with patterns of contiguous convex shape differences across multiple subcortical structures. Findings from our shape meta-analysis suggest that common neurobiological mechanisms may contribute to gray matter reduction across multiple subcortical regions, thus enhancing our understanding of the nature of network disorganization in schizophrenia.
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http://dx.doi.org/10.1002/hbm.25625DOI Listing
September 2021

Early life Adversity, functional connectivity and cognitive performance in Schizophrenia: The mediating role of IL-6.

Brain Behav Immun 2021 Jul 7. Epub 2021 Jul 7.

Centre for Neuroimaging, Cognition and Genomics (NICOG), School of Psychology, National University of Ireland, Galway, Ireland. Electronic address:

Objective: Exposure to childhood trauma (CT) is associated with cognitive impairment in schizophrenia, and deficits in social cognition in particular. Here, we sought to test whether IL-6 mediated the association between CT and social cognition both directly, and sequentially via altered default mode network (DMN) connectivity.

Methods: Three-hundred-and-eleven participants (104 patients and 207 healthy participants) were included, with MRI data acquired in a subset of n = 147. CT was measured using the childhood trauma questionnaire (CTQ). IL-6 was measured in both plasma and in toll like receptor (TLR) stimulated whole blood. The CANTAB emotion recognition task (ERT) was administered to assess social cognition, and cortical connectivity was assessed based on resting DMN connectivity.

Results: Higher IL-6 levels, measured both in plasma and in toll-like receptor (TLR-2) stimulated blood, were significantly correlated with higher CTQ scores and lower cognitive and social cognitive function. Plasma IL-6 was further observed to partly mediate the association between higher CT scores and lower emotion recognition performance (CTQ total: β -0.0234, 95% CI: -0.0573 to -0.0074; CTQ physical neglect: β = -0.0316, 95% CI: -0.0741 to -0.0049). Finally, sequential mediation was observed between plasma IL-6 levels and DMN connectivity in mediating the effects of higher CTQ on lower social cognitive function (β = -0.0618, 95% CI: -0.1523 to -0.285).

Conclusion: This work suggests that previous associations between CT and social cognition may be partly mediated via an increased inflammatory response. IL-6's association with changes in DMN activity further suggest at least one cortical network via which CT related effects on cognition may be transmitted.
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http://dx.doi.org/10.1016/j.bbi.2021.06.016DOI Listing
July 2021

Identifying nootropic drug targets via large-scale cognitive GWAS and transcriptomics.

Neuropsychopharmacology 2021 09 25;46(10):1788-1801. Epub 2021 May 25.

Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Broad-based cognitive deficits are an enduring and disabling symptom for many patients with severe mental illness, and these impairments are inadequately addressed by current medications. While novel drug targets for schizophrenia and depression have emerged from recent large-scale genome-wide association studies (GWAS) of these psychiatric disorders, GWAS of general cognitive ability can suggest potential targets for nootropic drug repurposing. Here, we (1) meta-analyze results from two recent cognitive GWAS to further enhance power for locus discovery; (2) employ several complementary transcriptomic methods to identify genes in these loci that are credibly associated with cognition; and (3) further annotate the resulting genes using multiple chemoinformatic databases to identify "druggable" targets. Using our meta-analytic data set (N = 373,617), we identified 241 independent cognition-associated loci (29 novel), and 76 genes were identified by 2 or more methods of gene identification. Actin and chromatin binding gene sets were identified as novel pathways that could be targeted via drug repurposing. Leveraging our transcriptomic and chemoinformatic databases, we identified 16 putative genes targeted by existing drugs potentially available for cognitive repurposing.
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http://dx.doi.org/10.1038/s41386-021-01023-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8357785PMC
September 2021

Changes in Default-Mode Network Associated With Childhood Trauma in Schizophrenia.

Schizophr Bull 2021 Aug;47(5):1482-1494

School of Psychology, National University of Ireland Galway, Galway, Ireland.

Background: There is considerable evidence of dysconnectivity within the default-mode network (DMN) in schizophrenia, as measured during resting-state functional MRI (rs-fMRI). History of childhood trauma (CT) is observed at a higher frequency in schizophrenia than in the general population, but its relationship to DMN functional connectivity has yet to be investigated.

Methods: CT history and rs-fMRI data were collected in 65 individuals with schizophrenia and 132 healthy controls. Seed-based functional connectivity between each of 4 a priori defined seeds of the DMN (medial prefrontal cortex, right and left lateral parietal lobes, and the posterior cingulate cortex) and all other voxels of the brain were compared across groups. Effects of CT on functional connectivity were examined using multiple regression analyses. Where significant associations were observed, regression analyses were further used to determine whether variance in behavioral measures of Theory of Mind (ToM), previously associated with DMN recruitment, were explained by these associations.

Results: Seed-based analyses revealed evidence of widespread reductions in functional connectivity in patients vs controls, including between the left/right parietal lobe (LP) and multiple other regions, including the parietal operculum bilaterally. Across all subjects, increased CT scores were associated with reduced prefrontal-parietal connectivity and, in patients, with increased prefrontal-cerebellar connectivity also. These CT-associated differences in DMN connectivity also predicted variation in behavioral measures of ToM.

Conclusions: These findings suggest that CT history is associated with variation in DMN connectivity during rs-fMRI in patients with schizophrenia and healthy participants, which may partly mediate associations observed between early life adversity and cognitive performance.
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http://dx.doi.org/10.1093/schbul/sbab025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8379545PMC
August 2021

Cognitive Predictors of Social and Occupational Functioning in Early Psychosis: A Systematic Review and Meta-analysis of Cross-Sectional and Longitudinal Data.

Schizophr Bull 2021 Aug;47(5):1243-1253

Centre for Neuroimaging, Cognition & Genomics (NICOG), School of Psychology, National University of Ireland Galway, Galway, Ireland.

Many individuals with early psychosis experience impairments in social and occupational function. Identification of modifiable predictors of function such as cognitive performance has the potential to inform effective treatments. Our aim was to estimate the strength of the relationship between psychosocial function in early psychosis and different domains of cognitive and social cognitive performance. We conducted a systematic review and meta-analysis of peer-reviewed, cross-sectional, and longitudinal studies examining cognitive predictors of psychosocial function. Literature searches were conducted in PsycINFO, PubMed, and reference lists of relevant articles to identify studies for inclusion. Of the 2565 identified, 46 studies comprising 3767 participants met inclusion criteria. Separate meta-analyses were conducted for 9 cognitive domains. Pearson correlation values between cognitive variables and function were extracted. All cognitive domains were related to psychosocial function both cross-sectionally and longitudinally. Importantly, these associations remained significant even after the effects of symptom severity, duration of untreated psychosis, and length of illness were accounted for. Overall, general cognitive ability and social cognition were most strongly associated with both concurrent and long-term function. Associations demonstrated medium effect sizes. These findings suggest that treatments targeting cognitive deficits, in particular those focusing on social cognition, are likely to be important for improving functional outcomes in early psychosis.
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http://dx.doi.org/10.1093/schbul/sbab033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8379554PMC
August 2021

1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans.

Transl Psychiatry 2021 03 22;11(1):182. Epub 2021 Mar 22.

Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.

Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers-the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.
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http://dx.doi.org/10.1038/s41398-021-01213-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985307PMC
March 2021

Rare Copy Number Variants Are Associated With Poorer Cognition in Schizophrenia.

Biol Psychiatry 2021 07 19;90(1):28-34. Epub 2020 Dec 19.

MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom. Electronic address:

Background: Cognitive impairment in schizophrenia is a major contributor to poor outcomes, yet its causes are poorly understood. Some rare copy number variants (CNVs) are associated with schizophrenia risk and affect cognition in healthy populations, but their contribution to cognitive impairment in schizophrenia has not been investigated. We examined the effect of 12 schizophrenia CNVs on cognition in those with schizophrenia.

Methods: General cognitive ability was measured using the Measurement and Treatment Research to Improve Cognition in Schizophrenia composite z score in 875 patients with schizophrenia and in a replication sample of 519 patients with schizophrenia using Wechsler Adult Intelligence Scale Full Scale IQ. Using linear regression, we tested for association between cognition and schizophrenia CNV status, covarying for age and sex. In addition, we tested whether CNVs hitting genes in schizophrenia-enriched gene sets (loss-of-function intolerant and synaptic gene sets) were associated with cognitive impairment.

Results: A total of 23 schizophrenia CNV carriers were identified. Schizophrenia CNV carriers had lower general cognitive ability than nonschizophrenia CNV carriers in discovery (β = -0.66, 95% confidence interval [CI] = -1.31 to -0.01) and replication samples (β = -0.91, 95% CI = -1.71 to -0.11) and after meta-analysis (β = -0.76, 95% CI = -1.26 to -0.25, p = .003). CNVs hitting loss-of-function intolerant genes were associated with lower cognition (β = -0.15, 95% CI = -0.29 to -0.001, p = .048).

Conclusions: In those with schizophrenia, cognitive ability in schizophrenia CNV carriers is 0.5-1.0 standard deviations below non-CNV carriers, which may have implications for clinical assessment and management. We also demonstrate that rare CNVs hitting genes intolerant to loss-of-function variation lead to more severe cognitive impairment, above and beyond the effect of known schizophrenia CNVs.
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http://dx.doi.org/10.1016/j.biopsych.2020.11.025DOI Listing
July 2021

DNA methylation meta-analysis reveals cellular alterations in psychosis and markers of treatment-resistant schizophrenia.

Elife 2021 Feb 26;10. Epub 2021 Feb 26.

Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany.

We performed a systematic analysis of blood DNA methylation profiles from 4483 participants from seven independent cohorts identifying differentially methylated positions (DMPs) associated with psychosis, schizophrenia, and treatment-resistant schizophrenia. Psychosis cases were characterized by significant differences in measures of blood cell proportions and elevated smoking exposure derived from the DNA methylation data, with the largest differences seen in treatment-resistant schizophrenia patients. We implemented a stringent pipeline to meta-analyze epigenome-wide association study (EWAS) results across datasets, identifying 95 DMPs associated with psychosis and 1048 DMPs associated with schizophrenia, with evidence of colocalization to regions nominated by genetic association studies of disease. Many schizophrenia-associated DNA methylation differences were only present in patients with treatment-resistant schizophrenia, potentially reflecting exposure to the atypical antipsychotic clozapine. Our results highlight how DNA methylation data can be leveraged to identify physiological (e.g., differential cell counts) and environmental (e.g., smoking) factors associated with psychosis and molecular biomarkers of treatment-resistant schizophrenia.
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http://dx.doi.org/10.7554/eLife.58430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009672PMC
February 2021

Effects of copy number variations on brain structure and risk for psychiatric illness: Large-scale studies from the ENIGMA working groups on CNVs.

Hum Brain Mapp 2021 Feb 21. Epub 2021 Feb 21.

Center for Neuroimaging, Genetics and Genomics, School of Psychology, NUI Galway, Galway, Ireland.

The Enhancing NeuroImaging Genetics through Meta-Analysis copy number variant (ENIGMA-CNV) and 22q11.2 Deletion Syndrome Working Groups (22q-ENIGMA WGs) were created to gain insight into the involvement of genetic factors in human brain development and related cognitive, psychiatric and behavioral manifestations. To that end, the ENIGMA-CNV WG has collated CNV and magnetic resonance imaging (MRI) data from ~49,000 individuals across 38 global research sites, yielding one of the largest studies to date on the effects of CNVs on brain structures in the general population. The 22q-ENIGMA WG includes 12 international research centers that assessed over 533 individuals with a confirmed 22q11.2 deletion syndrome, 40 with 22q11.2 duplications, and 333 typically developing controls, creating the largest-ever 22q11.2 CNV neuroimaging data set. In this review, we outline the ENIGMA infrastructure and procedures for multi-site analysis of CNVs and MRI data. So far, ENIGMA has identified effects of the 22q11.2, 16p11.2 distal, 15q11.2, and 1q21.1 distal CNVs on subcortical and cortical brain structures. Each CNV is associated with differences in cognitive, neurodevelopmental and neuropsychiatric traits, with characteristic patterns of brain structural abnormalities. Evidence of gene-dosage effects on distinct brain regions also emerged, providing further insight into genotype-phenotype relationships. Taken together, these results offer a more comprehensive picture of molecular mechanisms involved in typical and atypical brain development. This "genotype-first" approach also contributes to our understanding of the etiopathogenesis of brain disorders. Finally, we outline future directions to better understand effects of CNVs on brain structure and behavior.
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http://dx.doi.org/10.1002/hbm.25354DOI Listing
February 2021

Personal practice in counselling and CBT trainees: the self-perceived impact of personal therapy and self-practice/self-reflection on personal and professional development.

Cogn Behav Ther 2021 09 16;50(5):422-438. Epub 2020 Dec 16.

School of Psychology, National University of Ireland, Galway, Ireland.

With growing evidence for the potential value of personal practices (PPs) in therapist training, it is important to determine which PPs may be most valuable for which therapists under what conditions. This is the first study to compare the impact of two different PPs selected by accredited therapy training programs as the most appropriate PP for their trainees. Using the same validated outcome measure, the Self-focused Practice Questionnaire, the impact of personal therapy for counselling psychology trainees was compared with the impact of self-practice/self-reflection (SP/SR) training for CBT trainees. The number of PP hours was similar across the two groups. The SP/SR group were older and may have been more experienced professionally. SP/SR was perceived by CBT trainees to be significantly more beneficial for personal and professional development than personal therapy by counselling trainees. Possible reasons are discussed. Although the study does not constitute a direct experimental comparison of personal therapy and SP/SR amongst matched trainees of the same theoretical orientation, it is notable in demonstrating that in training contexts where PP was mandatory, SP/SR was experienced more positively by the CBT trainees than personal therapy by the counselling trainees.
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http://dx.doi.org/10.1080/16506073.2020.1846608DOI Listing
September 2021

Childhood trauma, brain structure and emotion recognition in patients with schizophrenia and healthy participants.

Soc Cogn Affect Neurosci 2020 12;15(12):1336-1350

School of Psychology, National University of Ireland Galway, Galway, Ireland.

Childhood trauma, and in particular physical neglect, has been repeatedly associated with lower performance on measures of social cognition (e.g. emotion recognition tasks) in both psychiatric and non-clinical populations. The neural mechanisms underpinning this association have remained unclear. Here, we investigated whether volumetric changes in three stress-sensitive regions-the amygdala, hippocampus and anterior cingulate cortex (ACC)-mediate the association between childhood trauma and emotion recognition in a healthy participant sample (N = 112) and a clinical sample of patients with schizophrenia (N = 46). Direct effects of childhood trauma, specifically physical neglect, on Emotion Recognition Task were observed in the whole sample. In healthy participants, reduced total and left ACC volumes were observed to fully mediate the association between both physical neglect and total childhood trauma score, and emotion recognition. No mediating effects of the hippocampus and amygdala volumes were observed for either group. These results suggest that reduced ACC volume may represent part of the mechanism by which early life adversity results in poorer social cognitive function. Confirmation of the causal basis of this association would highlight the importance of resilience-building interventions to mitigate the detrimental effects of childhood trauma on brain structure and function.
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http://dx.doi.org/10.1093/scan/nsaa160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759212PMC
December 2020

Genes influenced by MEF2C contribute to neurodevelopmental disease via gene expression changes that affect multiple types of cortical excitatory neurons.

Hum Mol Genet 2021 May;30(11):961-970

Cognitive Genetics and Cognitive Therapy Group, Centre for Neuroimaging, Cognition and Genomics, School of Psychology and Discipline of Biochemistry, National University of Ireland Galway, Galway H91CF50, Ireland.

Myocyte enhancer factor 2 C (MEF2C) is an important transcription factor during neurodevelopment. Mutation or deletion of MEF2C causes intellectual disability (ID), and common variants within MEF2C are associated with cognitive function and schizophrenia risk. We investigated if genes influenced by MEF2C during neurodevelopment are enriched for genes associated with neurodevelopmental phenotypes and if this can be leveraged to identify biological mechanisms and individual brain cell types affected. We used a set of 1055 genes that were differentially expressed in the adult mouse brain following early embryonic deletion of Mef2c in excitatory cortical neurons. Using genome-wide association studies data, we found these differentially expressed genes (DEGs) to be enriched for genes associated with schizophrenia, intelligence and educational attainment but not autism spectrum disorder (ASD). For this gene set, genes that overlap with target genes of the Fragile X mental retardation protein (FMRP) are a major driver of these enrichments. Using trios data, we found these DEGs to be enriched for genes containing de novo mutations reported in ASD and ID, but not schizophrenia. Using single-cell RNA sequencing data, we identified that a number of different excitatory glutamatergic neurons in the cortex were enriched for these DEGs including deep layer pyramidal cells and cells in the retrosplenial cortex, entorhinal cortex and subiculum, and these cell types are also enriched for FMRP target genes. The involvement of MEF2C and FMRP in synapse elimination suggests that disruption of this process in these cell types during neurodevelopment contributes to cognitive function and risk of neurodevelopmental disorders.
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http://dx.doi.org/10.1093/hmg/ddaa213DOI Listing
May 2021

Effects of complement gene-set polygenic risk score on brain volume and cortical measures in patients with psychotic disorders and healthy controls.

Am J Med Genet B Neuropsychiatr Genet 2020 12 12;183(8):445-453. Epub 2020 Sep 12.

Cognitive Genetics & Cognitive Therapy Group, The Centre for Neuroimaging, Cognition and Genomics (NICOG), School of Psychology and Discipline of Biochemistry, National University of Ireland Galway, Galway, Ireland.

Multiple genome-wide association studies of schizophrenia have reported associations between genetic variants within the MHC region and disease risk, an association that has been partially accounted for by alleles of the complement component 4 (C4) gene. Following on previous findings of association between both C4 and other complement-related variants and memory function, we tested the hypothesis that polygenic scores calculated based on identified schizophrenia risk alleles within the "complement" system would be broadly associated with memory function and associated brain structure. We tested this using a polygenic risk score (PRS) calculated for complement genes, but excluding C4 variants. Higher complement-based PRS scores were observed to be associated with lower memory scores for the sample as a whole (N = 620, F change = 8.25; p = .004). A significant association between higher PRS and lower hippocampal volume was also observed (N = 216, R change = 0.016, p = .015). However, after correcting for further testing of association with the more general indices of cortical thickness, surface area or total brain volume, none of which were associated with complement, the association with hippocampal volume became non-significant. A post-hoc analysis of hippocampal subfields suggested an association between complement PRS and several hippocampal subfields, findings that appeared to be particularly driven by the patient sample. In conclusion, our study yielded suggestive evidence of association between complement-based schizophrenia PRS and variation in memory function and hippocampal volume.
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http://dx.doi.org/10.1002/ajmg.b.32820DOI Listing
December 2020

Functional Magnetic Resonance Imaging Connectivity Accurately Distinguishes Cases With Psychotic Disorders From Healthy Controls, Based on Cortical Features Associated With Brain Network Development.

Biol Psychiatry Cogn Neurosci Neuroimaging 2020 Jun 8. Epub 2020 Jun 8.

Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom; Cambridgeshire and Peterborough NHS Foundation Trust, Cambridge, United Kingdom.

Background: Machine learning (ML) can distinguish cases with psychotic disorder from healthy controls based on magnetic resonance imaging (MRI) data, but it is not yet clear which MRI metrics are the most informative for case-control ML, or how ML algorithms relate to the underlying biology.

Methods: We analyzed multimodal MRI data from 2 independent case-control studies of psychotic disorders (cases, n = 65, 28; controls, n = 59, 80) and compared ML accuracy across 5 selected MRI metrics from 3 modalities. Cortical thickness, mean diffusivity, and fractional anisotropy were estimated at each of 308 cortical regions, as well as functional and structural connectivity between each pair of regions. Functional connectivity data were also used to classify nonpsychotic siblings of cases (n = 64) and to distinguish cases from controls in a third independent study (cases, n = 67; controls, n = 81).

Results: In both principal studies, the most informative metric was functional MRI connectivity: The areas under the receiver operating characteristic curve were 88% and 76%, respectively. The cortical map of diagnostic connectivity features (ML weights) was replicable between studies (r = .27, p < .001); correlated with replicable case-control differences in functional MRI degree centrality and with a prior cortical map of adolescent development of functional connectivity; predicted intermediate probabilities of psychosis in siblings; and was replicated in the third case-control study.

Conclusions: ML most accurately distinguished cases from controls by a replicable pattern of functional MRI connectivity features, highlighting abnormal hubness of cortical nodes in an anatomical pattern consistent with the concept of psychosis as a disorder of network development.
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http://dx.doi.org/10.1016/j.bpsc.2020.05.013DOI Listing
June 2020

Childhood trauma, parental bonding, and social cognition in patients with schizophrenia and healthy adults.

J Clin Psychol 2021 01 12;77(1):241-253. Epub 2020 Aug 12.

School of Psychology, National University of Ireland Galway, Galway, Ireland.

Objective: This study investigated associations between childhood trauma, parental bonding, and social cognition (i.e., Theory of Mind and emotion recognition) in patients with schizophrenia and healthy adults.

Methods: Using cross-sectional data, we examined the recollections of childhood trauma experiences and social cognitive abilities in 74 patients with schizophrenia and 116 healthy adults.

Results: Patients had significantly higher scores compared with healthy participants on childhood trauma, and lower scores on parental bonding and social cognitive measures. Physical neglect was found to be the strongest predictor of emotion recognition impairments in both groups. Optimal parental bonding attenuated the impact of childhood trauma on emotion recognition.

Conclusion: The present study provides evidence of an association between physical neglect and emotion recognition in patients with schizophrenia and healthy individuals and shows that both childhood trauma and parental bonding may influence social cognitive development. Psychosocial interventions should be developed to prevent and mitigate the long-term effects of childhood adversities.
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http://dx.doi.org/10.1002/jclp.23023DOI Listing
January 2021

Genes regulated by BCL11B during T-cell development are enriched for de novo mutations found in schizophrenia patients.

Am J Med Genet B Neuropsychiatr Genet 2020 09 29;183(6):370-379. Epub 2020 Jul 29.

Cognitive Genetics and Cognitive Therapy Group, Centre for Neuroimaging & Cognitive Genomics, School of Psychology and Discipline of Biochemistry, National University of Ireland Galway, Galway, Ireland.

While abnormal neurodevelopment contributes to schizophrenia (SCZ) risk, there is also evidence to support a role for immune dysfunction in SCZ. BCL11B, associated with SCZ in genome-wide association study (GWAS), is a transcription factor that regulates the differentiation and development of cells in the central nervous and immune systems. Here, we use functional genomics data from studies of BCL11B to investigate the contribution of neuronal and immune processes to SCZ pathophysiology. We identified the gene targets of BCL11B in brain striatal cells (n = 223 genes), double negative 4 (DN4) developing T cells (n = 114 genes) and double positive (DP) developing T cells (n = 518 genes) using an integrated analysis of RNA-seq and ChIP-seq data. No gene-set was enriched for genes containing common variants associated with SCZ but the DP gene-set was enriched for genes containing missense de novo mutations (DNMs; p = .001) using data from 3,447 SCZ trios. Post hoc analysis revealed the enrichment to be stronger for DP genes negatively regulated by BCL11B. Biological processes enriched for genes negatively regulated by BCL11B in DP gene-set included immune system development and cytokine signaling. These analyses, leveraging a GWAS-identified SCZ risk gene and data on gene expression and transcription factor binding, indicate that DNMs in immune pathways contribute to SCZ risk.
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http://dx.doi.org/10.1002/ajmg.b.32811DOI Listing
September 2020

ENIGMA-DTI: Translating reproducible white matter deficits into personalized vulnerability metrics in cross-diagnostic psychiatric research.

Hum Brain Mapp 2020 Apr 16. Epub 2020 Apr 16.

Department of Psychiatry, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

The ENIGMA-DTI (diffusion tensor imaging) workgroup supports analyses that examine the effects of psychiatric, neurological, and developmental disorders on the white matter pathways of the human brain, as well as the effects of normal variation and its genetic associations. The seven ENIGMA disorder-oriented working groups used the ENIGMA-DTI workflow to derive patterns of deficits using coherent and coordinated analyses that model the disease effects across cohorts worldwide. This yielded the largest studies detailing patterns of white matter deficits in schizophrenia spectrum disorder (SSD), bipolar disorder (BD), major depressive disorder (MDD), obsessive-compulsive disorder (OCD), posttraumatic stress disorder (PTSD), traumatic brain injury (TBI), and 22q11 deletion syndrome. These deficit patterns are informative of the underlying neurobiology and reproducible in independent cohorts. We reviewed these findings, demonstrated their reproducibility in independent cohorts, and compared the deficit patterns across illnesses. We discussed translating ENIGMA-defined deficit patterns on the level of individual subjects using a metric called the regional vulnerability index (RVI), a correlation of an individual's brain metrics with the expected pattern for a disorder. We discussed the similarity in white matter deficit patterns among SSD, BD, MDD, and OCD and provided a rationale for using this index in cross-diagnostic neuropsychiatric research. We also discussed the difference in deficit patterns between idiopathic schizophrenia and 22q11 deletion syndrome, which is used as a developmental and genetic model of schizophrenia. Together, these findings highlight the importance of collaborative large-scale research to provide robust and reproducible effects that offer insights into individual vulnerability and cross-diagnosis features.
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http://dx.doi.org/10.1002/hbm.24998DOI Listing
April 2020

The Relationship Between White Matter Microstructure and General Cognitive Ability in Patients With Schizophrenia and Healthy Participants in the ENIGMA Consortium.

Am J Psychiatry 2020 06 26;177(6):537-547. Epub 2020 Mar 26.

School of Psychology, Centre for Neuroimaging and Cognitive Genomics, National Centre for Biomedical Engineering Science and Galway Neuroscience Centre, National University of Ireland Galway, Galway (Holleran, Cannon, McDonald, Morris, Mothersill, Donohoe); Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Marina del Rey (Kelly, Thompson, Jahanshad); Department of Psychiatry, University of Edinburgh, Edinburgh (Alloza, Lawrie); Department of Child and Adolescent Psychiatry, Instituto de Investigación Sanitaria Gregorio Marañón, IiSGM, Hospital General Universitario Gregorio Marañón, School of Medicine, CIBERSAM, Universidad Complutense, Madrid (Alloza, Arango, Janssen, Martinez); NORMENT, K.G. Jebsen Center for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Oslo (Agartz); Department of Psychiatry, Ullevål University Hospital and Institute of Psychiatry, University of Oslo, Oslo (Andreassen); Laboratory of Neuropsychiatry, Department of Clinical and Behavioral Neurology, IRCCS Santa Lucia Foundation, Rome (Banaj, Piras, Spalletta); Mind Research Network and Department of Electrical and Computer Engineering, University of New Mexico, Albuquerque (Calhoun); Neuroscience Research Australia and School of Psychiatry, University of New South Wales, Sydney (Carr); Neuropsychiatric Genetics Research Group, Department of Psychiatry, Trinity College Dublin (Corvin); Olin Neuropsychiatric Research Center, Institute of Living, Hartford Hospital and Department of Psychiatry, Yale University School of Medicine, New Haven, Conn. (Glahn); Department of Psychiatry, University of Pennsylvania, Philadelphia (Gur, Roalf, Satterthwaite); Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore (Hong, Kochunov, Rowland); National Institute of Mental Health, Klecany, Czech Republic (Hoschl, Spaniel); Department of Psychiatry and Mental Health (Howells, Stein, Uhlmann) and Neuroscience Institute (Howells, Stein), University of Cape Town, Cape Town, South Africa; Highfield Unit, Warneford Hospital, Oxford, U.K. (James); Mind Research Network, Lovelace Biomedical and Environmental Research Institute, Albuquerque, N.Mex. (Liu); Melbourne Neuropsychiatry Centre, Department of Psychiatry, University of Melbourne and Melbourne Health, Carlton South, Australia (Pantelis, Zalesky); Department of Psychiatry and Human Behavior, School of Medicine, University of California, Irvine (Potkin); Priority Centre for Brain and Mental Health Research (Schall, Rasser) and Priority Research Centre for Stroke and Brain Injury, University of Newcastle, Newcastle, Australia (Rasser); Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston (Spalletta); Kimel Family Translational Imaging-Genetics Research Laboratory, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto, Toronto (Voineskos); Department of Biomedical Engineering and Melbourne Neuropsychiatry Centre, University of Melbourne, Melbourne, Australia (Zalesky); Clinical Translational Neuroscience Laboratory, Department of Psychiatry and Human Behavior, and Center for the Neurobiology of Learning and Memory, University of California Irvine, Irvine (van Erp); Department of Psychology, Georgia State University, Atlanta (Turner); and Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, University of Edinburgh, Edinburgh (Deary).

Objective: Schizophrenia has recently been associated with widespread white matter microstructural abnormalities, but the functional effects of these abnormalities remain unclear. Widespread heterogeneity of results from studies published to date preclude any definitive characterization of the relationship between white matter and cognitive performance in schizophrenia. Given the relevance of deficits in cognitive function to predicting social and functional outcomes in schizophrenia, the authors carried out a meta-analysis of available data through the ENIGMA Consortium, using a common analysis pipeline, to elucidate the relationship between white matter microstructure and a measure of general cognitive performance, IQ, in patients with schizophrenia and healthy participants.

Methods: The meta-analysis included 760 patients with schizophrenia and 957 healthy participants from 11 participating ENIGMA Consortium sites. For each site, principal component analysis was used to calculate both a global fractional anisotropy component (gFA) and a fractional anisotropy component for six long association tracts (LA-gFA) previously associated with cognition.

Results: Meta-analyses of regression results indicated that gFA accounted for a significant amount of variation in cognition in the full sample (effect size [Hedges' g]=0.27, CI=0.17-0.36), with similar effects sizes observed for both the patient (effect size=0.20, CI=0.05-0.35) and healthy participant groups (effect size=0.32, CI=0.18-0.45). Comparable patterns of association were also observed between LA-gFA and cognition for the full sample (effect size=0.28, CI=0.18-0.37), the patient group (effect size=0.23, CI=0.09-0.38), and the healthy participant group (effect size=0.31, CI=0.18-0.44).

Conclusions: This study provides robust evidence that cognitive ability is associated with global structural connectivity, with higher fractional anisotropy associated with higher IQ. This association was independent of diagnosis; while schizophrenia patients tended to have lower fractional anisotropy and lower IQ than healthy participants, the comparable size of effect in each group suggested a more general, rather than disease-specific, pattern of association.
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http://dx.doi.org/10.1176/appi.ajp.2019.19030225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938666PMC
June 2020

ENIGMA and global neuroscience: A decade of large-scale studies of the brain in health and disease across more than 40 countries.

Transl Psychiatry 2020 03 20;10(1):100. Epub 2020 Mar 20.

Department of Psychiatry & Behavioral Sciences, Stanford University, Stanford, CA, USA.

This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of "big data" (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA's activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors.
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http://dx.doi.org/10.1038/s41398-020-0705-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7083923PMC
March 2020

The genetic architecture of the human cerebral cortex.

Science 2020 03;367(6484)

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder.
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http://dx.doi.org/10.1126/science.aay6690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295264PMC
March 2020

Identifying schizophrenia patients who carry pathogenic genetic copy number variants using standard clinical assessment: retrospective cohort study.

Br J Psychiatry 2020 05;216(5):275-279

Professor, Head of Discipline, Neuropsychiatric Genetics Research Group, Department of Psychiatry, School of Medicine, Trinity College Dublin, Ireland.

Background: Copy number variants (CNVs) play a significant role in disease pathogenesis in a small subset of individuals with schizophrenia (~2.5%). Chromosomal microarray testing is a first-tier genetic test for many neurodevelopmental disorders. Similar testing could be useful in schizophrenia.

Aims: To determine whether clinically identifiable phenotypic features could be used to successfully model schizophrenia-associated (SCZ-associated) CNV carrier status in a large schizophrenia cohort.

Method: Logistic regression and receiver operating characteristic (ROC) curves tested the accuracy of readily identifiable phenotypic features in modelling SCZ-associated CNV status in a discovery data-set of 1215 individuals with psychosis. A replication analysis was undertaken in a second psychosis data-set (n = 479).

Results: In the discovery cohort, specific learning disorder (OR = 8.12; 95% CI 1.16-34.88, P = 0.012), developmental delay (OR = 5.19; 95% CI 1.58-14.76, P = 0.003) and comorbid neurodevelopmental disorder (OR = 5.87; 95% CI 1.28-19.69, P = 0.009) were significant independent variables in modelling positive carrier status for a SCZ-associated CNV, with an area under the ROC (AUROC) of 74.2% (95% CI 61.9-86.4%). A model constructed from the discovery cohort including developmental delay and comorbid neurodevelopmental disorder variables resulted in an AUROC of 83% (95% CI 52.0-100.0%) for the replication cohort.

Conclusions: These findings suggest that careful clinical history taking to document specific neurodevelopmental features may be informative in screening for individuals with schizophrenia who are at higher risk of carrying known SCZ-associated CNVs. Identification of genomic disorders in these individuals is likely to have clinical benefits similar to those demonstrated for other neurodevelopmental disorders.
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http://dx.doi.org/10.1192/bjp.2019.262DOI Listing
May 2020

Cognitive Genomics: Recent Advances and Current Challenges.

Curr Psychiatry Rep 2020 01 10;22(1). Epub 2020 Jan 10.

Neuroimaging, Cognition & Genomics (NICOG) Centre, School of Psychology and Discipline of Biochemistry, National University of Ireland Galway, Rm 1040 School of Psychology, University Road, Galway, Ireland.

Purpose Of Review: We review recent progress in uncovering the complex genetic architecture of cognition, arising primarily from genome-wide association studies (GWAS). We explore the genetic correlations between cognitive performance and neuropsychiatric disorders, the genetic and environmental factors associated with age-related cognitive decline, and speculate about the future role of genomics in the understanding of cognitive processes.

Recent Findings: Improvements in genomic methods, and the increasing availability of large datasets via consortia cooperation, have led to a greater understanding of the role played by common and rare variants in the genomics of cognition, the highly polygenic basis of cognitive function and dysfunction, and the multiple biological processes involved. Recent research has aided in our understanding of the complex biological nature of genomics of cognition. Further development of data banks and techniques to analyze this data hold significant promise for understanding cognitive ability, and for treating cognitively related disability.
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http://dx.doi.org/10.1007/s11920-019-1125-xDOI Listing
January 2020

Effects of early life adversity on immune function and cognitive performance: results from the ALSPAC cohort.

Soc Psychiatry Psychiatr Epidemiol 2020 Jun 2;55(6):723-733. Epub 2020 Jan 2.

Cognitive Genetics and Cognitive Therapy Group, The Centre for Neuroimaging, Cognition and Genomics (NICOG), School of Psychology and Discipline of Biochemistry, National University of Ireland Galway, Galway, Ireland.

Background: Early life adversity (ELA) is a significant risk factor for mental health disorders. One hypothesised mechanism by which this occurs is via an effect on immune response. In this analysis of epidemiological data, we tested whether ELA was associated with cognitive performance, and if so, whether these effects were influenced by immune function.

Methods: We investigated the longitudinal relationship between ELA, inflammatory markers, and cognition in data from Avon Longitudinal Study of Parents And Children (ALSPAC; n ~ 5000). ELA was defined in terms of physical/emotional abuse, harsh parenting, or domestic violence before 5 years. Social cognition was measured in terms of theory of mind, and general cognitive ability was measured using IQ. Inflammatory markers included serum C-reactive protein and interleukin-6 levels.

Results: A significant association was observed between IQ and harsh parenting, whereby children who were physically disciplined had lower IQ scores (accounting for relevant social factors). Both immune markers were associated with variation in cognition, however, neither accounted for the effects of ELA on cognition.

Discussion: This study highlights the impact of ELA on cognition. In the absence of evidence that these effects are explained by inflammation, other mechanisms by which the effects of ELA are mediated are discussed.
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http://dx.doi.org/10.1007/s00127-019-01813-8DOI Listing
June 2020

Altered gene regulation as a candidate mechanism by which ciliopathy gene SDCCAG8 contributes to schizophrenia and cognitive function.

Hum Mol Genet 2020 02;29(3):407-417

Cognitive Genetics and Cognitive Therapy Group, Neuroimaging and Cognitive Genomics (NICOG) Centre, School of Psychology and Discipline of Biochemistry, National University of Ireland Galway, Ireland.

Mutations in genes that encode centrosomal/ciliary proteins cause severe cognitive deficits, while common single-nucleotide polymorphisms in these genes are associated with schizophrenia (SZ) and cognition in genome-wide association studies. The role of these genes in neuropsychiatric disorders is unknown. The ciliopathy gene SDCCAG8 is associated with SZ and educational attainment (EA). Genome editing of SDCCAG8 caused defects in primary ciliogenesis and cilium-dependent cell signalling. Transcriptomic analysis of SDCCAG8-deficient cells identified differentially expressed genes that are enriched in neurodevelopmental processes such as generation of neurons and synapse organization. These processes are enriched for genes associated with SZ, human intelligence (IQ) and EA. Phenotypic analysis of SDCCAG8-deficent neuronal cells revealed impaired migration and neuronal differentiation. These data implicate ciliary signalling in the aetiology of SZ and cognitive dysfunction. We found that centrosomal/ciliary genes are enriched for association with IQ, suggesting altered gene regulation as a general model for neurodevelopmental impacts of centrosomal/ciliary genes.
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http://dx.doi.org/10.1093/hmg/ddz292DOI Listing
February 2020

Moral cognition, the missing link between psychotic symptoms and acts of violence: a cross-sectional national forensic cohort study.

BMC Psychiatry 2019 12 19;19(1):408. Epub 2019 Dec 19.

National Forensic Mental Health Service, Central Mental Hospital, Dundrum, Dublin, Ireland.

Background: People with schizophrenia are ten times more likely to commit homicide than a member of the general population. The relationship between symptoms of schizophrenia and acts of violence is unclear. There has also been limited research on what determines the seriousness and form of violence, such as reactive or instrumental violence. Moral cognition may play a paradoxical role in acts of violence for people with schizophrenia. Thoughts which have moral content arising from psychotic symptoms may be a cause of serious violence.

Method: We investigated if psychotic symptoms and moral cognitions at the time of a violent act were associated with acts of violence using a cross-sectional national forensic cohort (n = 55). We examined whether moral cognitions were associated with violence when controlling for neurocognition and violence proneness. We explored the association between all psychotic symptoms present at the time of the violent act, psychotic symptoms judged relevant to the violent act and moral cognitions present at that time. Using mediation analysis, we examined whether moral cognitions were the missing link between symptoms and the relevance of symptoms for violence. We also investigated if specific moral cognitions mediated the relationship between specific psychotic symptoms, the seriousness of violence (including homicide), and the form of violence.

Results: Psychotic symptoms generally were not associated with the seriousness or form of violence. However, specific moral cognitions were associated with the seriousness and form of violence even when controlling for neurocognition and violence proneness. Specific moral cognitions were associated with specific psychotic symptoms present and relevant to violence. Moral cognitions mediated the relationship between the presence of specific psychotic symptoms and their relevance for violence, homicide, seriousness of violence, and the form of violence.

Conclusions: Moral cognitions including the need to reduce suffering, responding to an act of injustice or betrayal, the desire to comply with authority, or the wish to punish impure or disgusting behaviour, may be a key mediator explaining the relationship between psychotic symptoms and acts of violence. Our findings may have important implications for risk assessment, treatment and violence prevention.
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http://dx.doi.org/10.1186/s12888-019-2372-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6921589PMC
December 2019

White matter microstructural alterations across four major psychiatric disorders: mega-analysis study in 2937 individuals.

Mol Psychiatry 2020 04 29;25(4):883-895. Epub 2019 Nov 29.

Department of Psychiatry, Tokushima University Hospital, Tokushima, Japan.

Identifying both the commonalities and differences in brain structures among psychiatric disorders is important for understanding the pathophysiology. Recently, the ENIGMA-Schizophrenia DTI Working Group performed a large-scale meta-analysis and reported widespread white matter microstructural alterations in schizophrenia; however, no similar cross-disorder study has been carried out to date. Here, we conducted mega-analyses comparing white matter microstructural differences between healthy comparison subjects (HCS; N = 1506) and patients with schizophrenia (N = 696), bipolar disorder (N = 211), autism spectrum disorder (N = 126), or major depressive disorder (N = 398; total N = 2937 from 12 sites). In comparison with HCS, we found that schizophrenia, bipolar disorder, and autism spectrum disorder share similar white matter microstructural differences in the body of the corpus callosum; schizophrenia and bipolar disorder featured comparable changes in the limbic system, such as the fornix and cingulum. By comparison, alterations in tracts connecting neocortical areas, such as the uncinate fasciculus, were observed only in schizophrenia. No significant difference was found in major depressive disorder. In a direct comparison between schizophrenia and bipolar disorder, there were no significant differences. Significant differences between schizophrenia/bipolar disorder and major depressive disorder were found in the limbic system, which were similar to the differences in schizophrenia and bipolar disorder relative to HCS. While schizophrenia and bipolar disorder may have similar pathological characteristics, the biological characteristics of major depressive disorder may be close to those of HCS. Our findings provide insights into nosology and encourage further investigations of shared and unique pathophysiology of psychiatric disorders.
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http://dx.doi.org/10.1038/s41380-019-0553-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156346PMC
April 2020

Integrating machining learning and multimodal neuroimaging to detect schizophrenia at the level of the individual.

Hum Brain Mapp 2020 04 18;41(5):1119-1135. Epub 2019 Nov 18.

Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, De Crespigny Park, London, UK.

Schizophrenia is a severe psychiatric disorder associated with both structural and functional brain abnormalities. In the past few years, there has been growing interest in the application of machine learning techniques to neuroimaging data for the diagnostic and prognostic assessment of this disorder. However, the vast majority of studies published so far have used either structural or functional neuroimaging data, without accounting for the multimodal nature of the disorder. Structural MRI and resting-state functional MRI data were acquired from a total of 295 patients with schizophrenia and 452 healthy controls at five research centers. We extracted features from the data including gray matter volume, white matter volume, amplitude of low-frequency fluctuation, regional homogeneity and two connectome-wide based metrics: structural covariance matrices and functional connectivity matrices. A support vector machine classifier was trained on each dataset separately to distinguish the subjects at individual level using each of the single feature as well as their combination, and 10-fold cross-validation was used to assess the performance of the model. Functional data allow higher accuracy of classification than structural data (mean 82.75% vs. 75.84%). Within each modality, the combination of images and matrices improves performance, resulting in mean accuracies of 81.63% for structural data and 87.59% for functional data. The use of all combined structural and functional measures allows the highest accuracy of classification (90.83%). We conclude that combining multimodal measures within a single model is a promising direction for developing biologically informed diagnostic tools in schizophrenia.
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http://dx.doi.org/10.1002/hbm.24863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268084PMC
April 2020

Association of Copy Number Variation of the 15q11.2 BP1-BP2 Region With Cortical and Subcortical Morphology and Cognition.

JAMA Psychiatry 2020 04;77(4):420-430

Department of Biological Psychology and Netherlands Twin Register, VU University Amsterdam, Amsterdam, the Netherlands.

Importance: Recurrent microdeletions and duplications in the genomic region 15q11.2 between breakpoints 1 (BP1) and 2 (BP2) are associated with neurodevelopmental disorders. These structural variants are present in 0.5% to 1.0% of the population, making 15q11.2 BP1-BP2 the site of the most prevalent known pathogenic copy number variation (CNV). It is unknown to what extent this CNV influences brain structure and affects cognitive abilities.

Objective: To determine the association of the 15q11.2 BP1-BP2 deletion and duplication CNVs with cortical and subcortical brain morphology and cognitive task performance.

Design, Setting, And Participants: In this genetic association study, T1-weighted brain magnetic resonance imaging were combined with genetic data from the ENIGMA-CNV consortium and the UK Biobank, with a replication cohort from Iceland. In total, 203 deletion carriers, 45 247 noncarriers, and 306 duplication carriers were included. Data were collected from August 2015 to April 2019, and data were analyzed from September 2018 to September 2019.

Main Outcomes And Measures: The associations of the CNV with global and regional measures of surface area and cortical thickness as well as subcortical volumes were investigated, correcting for age, age2, sex, scanner, and intracranial volume. Additionally, measures of cognitive ability were analyzed in the full UK Biobank cohort.

Results: Of 45 756 included individuals, the mean (SD) age was 55.8 (18.3) years, and 23 754 (51.9%) were female. Compared with noncarriers, deletion carriers had a lower surface area (Cohen d = -0.41; SE, 0.08; P = 4.9 × 10-8), thicker cortex (Cohen d = 0.36; SE, 0.07; P = 1.3 × 10-7), and a smaller nucleus accumbens (Cohen d = -0.27; SE, 0.07; P = 7.3 × 10-5). There was also a significant negative dose response on cortical thickness (β = -0.24; SE, 0.05; P = 6.8 × 10-7). Regional cortical analyses showed a localization of the effects to the frontal, cingulate, and parietal lobes. Further, cognitive ability was lower for deletion carriers compared with noncarriers on 5 of 7 tasks.

Conclusions And Relevance: These findings, from the largest CNV neuroimaging study to date, provide evidence that 15q11.2 BP1-BP2 structural variation is associated with brain morphology and cognition, with deletion carriers being particularly affected. The pattern of results fits with known molecular functions of genes in the 15q11.2 BP1-BP2 region and suggests involvement of these genes in neuronal plasticity. These neurobiological effects likely contribute to the association of this CNV with neurodevelopmental disorders.
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http://dx.doi.org/10.1001/jamapsychiatry.2019.3779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6822096PMC
April 2020
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