Publications by authors named "David Mothersill"

21 Publications

  • Page 1 of 1

Knowledge, attitudes, and behaviours towards schizophrenia, bipolar disorder, and autism: a pilot study.

Ir J Psychol Med 2021 Dec 3:1-7. Epub 2021 Dec 3.

Psychology Department, School of Business, National College of Ireland, Dublin, Ireland.

Objectives: Lack of knowledge and discriminatory attitudes and behaviours towards individuals with mental disorders is a worldwide problem but may be particularly damaging for young people. This pilot study examined knowledge, attitudes and behaviours towards schizophrenia, bipolar disorder and autism within a large sample of adults in Ireland, a country with the youngest population in Europe, in order to better understand public views on these groups.

Methods: In a correlational, cross-sectional design, 307 adults in Ireland over the age of 18 completed a questionnaire over Google Forms examining knowledge, attitudes and behaviours towards schizophrenia, bipolar disorder and autism. Responses to questions specifically relating to each diagnosis were compared using trimmed mean ANOVA to examine whether responses to questions differed depending on diagnosis.

Results: Results indicate varied knowledge, attitudes and behaviours towards these groups, but a majority believe it should be a research priority. ANOVA and post hoc tests revealed significant differences in knowledge, attitudes and behaviours towards each of schizophrenia, bipolar disorder, and autism (p < 0.005), and reported attitudes and behaviours towards schizophrenia were more negative than either bipolar disorder or autism. A majority of participants (54.8%) felt not informed enough about mental health by the media.

Conclusions: In our Irish sample, type and level of stigma varies according to mental health diagnosis. Our sample also report feeling inadequately informed about mental health by the media. Thus future policy and campaigns could consider targeting individual mental health diagnoses, with a focus on increasing familiarity and knowledge.
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http://dx.doi.org/10.1017/ipm.2021.81DOI Listing
December 2021

Interleukin 6 predicts increased neural response during face processing in a sample of individuals with schizophrenia and healthy participants: A functional magnetic resonance imaging study.

Neuroimage Clin 2021 Oct 7;32:102851. Epub 2021 Oct 7.

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

Background: Deficits in facial emotion recognition are a core feature of schizophrenia and predictive of functional outcome. Higher plasma levels of the cytokine interleukin 6 (IL-6) have recently been associated with poorer facial emotion recognition in individuals with schizophrenia and healthy participants, but the neural mechanisms affected remain poorly understood.

Methods: Forty-nine individuals with schizophrenia or schizoaffective disorder and 158 healthy participants were imaged using functional magnetic resonance imaging during a dynamic facial emotion recognition task. Plasma IL-6 was measured from blood samples taken outside the scanner. Multiple regression was used in statistical parametric mapping software to test whether higher plasma IL-6 predicted increased neural response during task performance.

Results: Higher plasma IL-6 predicted increased bilateral medial prefrontal response during neutral face processing compared to angry face processing in the total sample (N = 207, t = 5.67) and increased left insula response during angry face processing compared to neutral face processing (N = 207, t = 4.40) (p < 0.05, family-wise error corrected across the whole brain at the cluster level).

Conclusions: These findings suggest that higher peripheral IL-6 levels predict altered neural response within brain regions involved in social cognition and emotion during facial emotion recognition. This is consistent with recent neuroimaging research on IL-6 and suggesting a possible neural mechanism by which this cytokine might affect facial emotion recognition accuracy.
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http://dx.doi.org/10.1016/j.nicl.2021.102851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8515297PMC
October 2021

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

Schizophr Res 2021 Nov 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
November 2021

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

Brain Behav Immun 2021 Nov 7;98:388-396. 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
November 2021

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

Schizophr Bull 2021 08;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

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

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

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

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

Detecting schizophrenia at the level of the individual: relative diagnostic value of whole-brain images, connectome-wide functional connectivity and graph-based metrics.

Psychol Med 2020 08 8;50(11):1852-1861. Epub 2019 Aug 8.

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

Background: Previous studies using resting-state functional neuroimaging have revealed alterations in whole-brain images, connectome-wide functional connectivity and graph-based metrics in groups of patients with schizophrenia relative to groups of healthy controls. However, it is unclear which of these measures best captures the neural correlates of this disorder at the level of the individual patient.

Methods: Here we investigated the relative diagnostic value of these measures. A total of 295 patients with schizophrenia and 452 healthy controls were investigated using resting-state functional Magnetic Resonance Imaging at five research centres. Connectome-wide functional networks were constructed by thresholding correlation matrices of 90 brain regions, and their topological properties were analyzed using graph theory-based methods. Single-subject classification was performed using three machine learning (ML) approaches associated with varying degrees of complexity and abstraction, namely logistic regression, support vector machine and deep learning technology.

Results: Connectome-wide functional connectivity allowed single-subject classification of patients and controls with higher accuracy (average: 81%) than both whole-brain images (average: 53%) and graph-based metrics (average: 69%). Classification based on connectome-wide functional connectivity was driven by a distributed bilateral network including the thalamus and temporal regions.

Conclusion: These results were replicated across the three employed ML approaches. Connectome-wide functional connectivity permits differentiation of patients with schizophrenia from healthy controls at single-subject level with greater accuracy; this pattern of results is consistent with the 'dysconnectivity hypothesis' of schizophrenia, which states that the neural basis of the disorder is best understood in terms of system-level functional connectivity alterations.
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http://dx.doi.org/10.1017/S0033291719001934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477363PMC
August 2020

Beyond C4: Analysis of the complement gene pathway shows enrichment for IQ in patients with psychotic disorders and healthy controls.

Genes Brain Behav 2019 11 30;18(8):e12602. Epub 2019 Aug 30.

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

Variation in cognitive performance, which strongly predicts functional outcome in schizophrenia (SZ), has been associated with multiple immune-relevant genetic loci. These loci include complement component 4 (C4A), structural variation at which was recently associated with SZ risk and synaptic pruning during neurodevelopment and cognitive function. Here, we test whether this genetic association with cognition and SZ risk is specific to C4A, or extends more broadly to genes related to the complement system. Using a gene-set with an identified role in "complement" function (excluding C4A), we used MAGMA to test if this gene-set was enriched for genes associated with human intelligence and SZ risk, using genome-wide association summary statistics (IQ; N = 269 867, SZ; N = 105 318). We followed up this gene-set analysis with a complement gene-set polygenic score (PGS) regression analysis in an independent data set of patients with psychotic disorders and healthy participants with cognitive and genomic data (N = 1000). Enrichment analysis suggested that genes within the complement pathway were significantly enriched for genes associated with IQ, but not SZ. In a gene-based analysis of 90 genes, SERPING1 was the most enriched gene for the phenotype of IQ. In a PGS regression analysis, we found that a complement pathway PGS associated with IQ genome-wide association studies statistics also predicted variation in IQ in our independent sample. This association (observed across both patients and controls) remained significant after controlling for the relationship between C4A and cognition. These results suggest a robust association between the complement system and cognitive function, extending beyond structural variation at C4A.
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http://dx.doi.org/10.1111/gbb.12602DOI Listing
November 2019

10Kin1day: A Bottom-Up Neuroimaging Initiative.

Front Neurol 2019 9;10:425. Epub 2019 May 9.

Department of Psychiatry, Stellenbosch University, Cape Town, South Africa.

We organized 10Kin1day, a pop-up scientific event with the goal to bring together neuroimaging groups from around the world to jointly analyze 10,000+ existing MRI connectivity datasets during a 3-day workshop. In this report, we describe the motivation and principles of 10Kin1day, together with a public release of 8,000+ MRI connectome maps of the human brain.
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http://dx.doi.org/10.3389/fneur.2019.00425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6524614PMC
May 2019

Neural Effects of Cognitive Training in Schizophrenia: A Systematic Review and Activation Likelihood Estimation Meta-analysis.

Biol Psychiatry Cogn Neurosci Neuroimaging 2019 08 27;4(8):688-696. Epub 2019 Mar 27.

School of Psychology and Centre for Neuroimaging and Cognitive Genomics, National University of Ireland Galway, Galway, Ireland.

Background: Cognitive dysfunction is a core feature of schizophrenia and a strong predictor of functional outcome. There is growing evidence for the effectiveness of behaviorally based cognitive training programs, although the neural basis of these benefits is unclear. To address this, we reviewed all published studies that have used neuroimaging to measure neural changes following cognitive training in schizophrenia to identify brain regions most consistently affected.

Methods: We searched PubMed for all neuroimaging studies examining cognitive training in schizophrenia published until December 2018. An activation likelihood estimation meta-analysis was conducted on a subset of functional magnetic resonance imaging studies to examine whether any brain regions showed consistent effects across studies.

Results: In total, 31 original neuroimaging studies of cognitive training were retrieved. Of these studies, 16 were functional neuroimaging studies, and 15 of these studies reported increased neural activation following cognitive training, with increased left prefrontal activation being the most frequently observed finding. However, activation likelihood estimation meta-analysis did not reveal any specific brain regions showing consistent effects across studies but rather suggested a broader, more distributed pattern of effects resulting from the interventions tested.

Conclusions: Although several studies reported increased left prefrontal cortical activation after cognitive training, the lack of statistically significant overlap of brain regions affected by training across studies suggests broad effects of training on brain activation, possibly due to the variety of training programs used.
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http://dx.doi.org/10.1016/j.bpsc.2019.03.005DOI Listing
August 2019

Cortical patterning of abnormal morphometric similarity in psychosis is associated with brain expression of schizophrenia-related genes.

Proc Natl Acad Sci U S A 2019 05 19;116(19):9604-9609. Epub 2019 Apr 19.

Department of Psychiatry, University of Cambridge, Cambridge CB2 0SZ, United Kingdom.

Schizophrenia has been conceived as a disorder of brain connectivity, but it is unclear how this network phenotype is related to the underlying genetics. We used morphometric similarity analysis of MRI data as a marker of interareal cortical connectivity in three prior case-control studies of psychosis: in total, = 185 cases and = 227 controls. Psychosis was associated with globally reduced morphometric similarity in all three studies. There was also a replicable pattern of case-control differences in regional morphometric similarity, which was significantly reduced in patients in frontal and temporal cortical areas but increased in parietal cortex. Using prior brain-wide gene expression data, we found that the cortical map of case-control differences in morphometric similarity was spatially correlated with cortical expression of a weighted combination of genes enriched for neurobiologically relevant ontology terms and pathways. In addition, genes that were normally overexpressed in cortical areas with reduced morphometric similarity were significantly up-regulated in three prior post mortem studies of schizophrenia. We propose that this combined analysis of neuroimaging and transcriptional data provides insight into how previously implicated genes and proteins as well as a number of unreported genes in their topological vicinity on the protein interaction network may drive structural brain network changes mediating the genetic risk of schizophrenia.
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http://dx.doi.org/10.1073/pnas.1820754116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6511038PMC
May 2019

Correction: Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia.

Mol Psychiatry 2020 Mar;25(3):692-695

Department of Psychiatry and Mental Health, Anzio Road, 7925, Cape Town, South Africa.

Prior to and following the publication of this article the authors noted that the complete list of authors was not included in the main article and was only present in Supplementary Table 1. The author list in the original article has now been updated to include all authors, and Supplementary Table 1 has been removed. All other supplementary files have now been updated accordingly. Furthermore, in Table 1 of this Article, the replication cohort for the row Close relative in data set, n (%) was incorrect. All values have now been corrected to 0(0%). The publishers would like to apologise for this error and the inconvenience it may have caused.
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http://dx.doi.org/10.1038/s41380-019-0358-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608381PMC
March 2020

Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia.

Mol Psychiatry 2020 03 3;25(3):584-602. Epub 2018 Oct 3.

Department of Psychiatry and Mental Health, Anzio Road, 7925, Cape Town, South Africa.

Carriers of large recurrent copy number variants (CNVs) have a higher risk of developing neurodevelopmental disorders. The 16p11.2 distal CNV predisposes carriers to e.g., autism spectrum disorder and schizophrenia. We compared subcortical brain volumes of 12 16p11.2 distal deletion and 12 duplication carriers to 6882 non-carriers from the large-scale brain Magnetic Resonance Imaging collaboration, ENIGMA-CNV. After stringent CNV calling procedures, and standardized FreeSurfer image analysis, we found negative dose-response associations with copy number on intracranial volume and on regional caudate, pallidum and putamen volumes (β = -0.71 to -1.37; P < 0.0005). In an independent sample, consistent results were obtained, with significant effects in the pallidum (β = -0.95, P = 0.0042). The two data sets combined showed significant negative dose-response for the accumbens, caudate, pallidum, putamen and ICV (P = 0.0032, 8.9 × 10, 1.7 × 10, 3.5 × 10 and 1.0 × 10, respectively). Full scale IQ was lower in both deletion and duplication carriers compared to non-carriers. This is the first brain MRI study of the impact of the 16p11.2 distal CNV, and we demonstrate a specific effect on subcortical brain structures, suggesting a neuropathological pattern underlying the neurodevelopmental syndromes.
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http://dx.doi.org/10.1038/s41380-018-0118-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042770PMC
March 2020

Computerised working memory-based cognitive remediation therapy does not affect Reading the Mind in The Eyes test performance or neural activity during a Facial Emotion Recognition test in psychosis.

Eur J Neurosci 2018 May 27. Epub 2018 May 27.

School of Psychology & Center for Neuroimaging and Cognitive Genomics, National University of Ireland Galway, Galway, Ireland.

Working memory-based cognitive remediation therapy (CT) for psychosis has recently been associated with broad improvements in performance on untrained tasks measuring working memory, episodic memory and IQ, and changes in associated brain regions. However, it is unclear whether these improvements transfer to the domain of social cognition and neural activity related to performance on social cognitive tasks. We examined performance on the Reading the Mind in the Eyes test (Eyes test) in a large sample of participants with psychosis who underwent working memory-based CT (N = 43) compared to a control group of participants with psychosis (N = 35). In a subset of this sample, we used functional magnetic resonance imaging (fMRI) to examine changes in neural activity during a facial emotion recognition task in participants who underwent CT (N = 15) compared to a control group (N = 15). No significant effects of CT were observed on Eyes test performance or on neural activity during facial emotion recognition, either at p < 0.05 family-wise error or at a p < 0.001 uncorrected threshold, within a priori social cognitive regions of interest. This study suggests that working memory-based CT does not significantly impact an aspect of social cognition which was measured behaviourally and neurally. It provides further evidence that deficits in the ability to decode mental state from facial expressions are dissociable from working memory deficits, and suggests that future CT programmes should target social cognition in addition to working memory for the purposes of further enhancing social function.
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http://dx.doi.org/10.1111/ejn.13976DOI Listing
May 2018

Effects of MiR-137 genetic risk score on brain volume and cortical measures in patients with schizophrenia and controls.

Am J Med Genet B Neuropsychiatr Genet 2018 04 8;177(3):369-376. Epub 2018 Feb 8.

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

Multiple genome-wide association studies of schizophrenia have implicated genetic variants within the gene encoding microRNA-137. As risk variants within or regulated by MIR137 have been implicated in memory performance, we investigated the additive effects of schizophrenia-associated risk variants in genes empirically regulated by MIR137 on brain regions associated with memory function. A polygenic risk score (PRS) was calculated (at a p = 0.05 threshold), using this empirically regulated MIR137 gene set, to investigate associations between this PRS and structural brain measures. These measures included total brain volume, cortical thickness, cortical surface area, and hippocampal volume, in a sample of 216 individuals consisting of healthy participants (n = 171) and patients with psychosis (n = 45). We did not observe a significant association between MIR137 PRS and these cortical thickness, surface area or hippocampal volume measures linked to memory function; a significant association between increasing PRS and decreasing total brain volume, independent of diagnosis status (R  = 0.008, Beta = -0.09, p = 0.029), was observed. This did not survive correction for multiple testing. In conclusion, our study yielded only suggestive evidence that risk variants interacting with MIR137 impacts on cortical structure.
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http://dx.doi.org/10.1002/ajmg.b.32620DOI Listing
April 2018
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