Psychiatry - Research Publications

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    Personalized and Circuit-Based Transcranial Magnetic Stimulation: Evidence, Controversies, and Opportunities.
    Cash, RFH ; Zalesky, A ; Zalesky, A (Elsevier, 2024-03-15)
    The development of neuroimaging methodologies to map brain connectivity has transformed our understanding of psychiatric disorders, the distributed effects of brain stimulation, and how transcranial magnetic stimulation can be best employed to target and ameliorate psychiatric symptoms. In parallel, neuroimaging research has revealed that higher-order brain regions such as the prefrontal cortex, which represent the most common therapeutic brain stimulation targets for psychiatric disorders, show some of the highest levels of interindividual variation in brain connectivity. These findings provide the rationale for personalized target site selection based on person-specific brain network architecture. Recent advances have made it possible to determine reproducible personalized targets with millimeter precision in clinically tractable acquisition times. These advances enable the potential advantages of spatially personalized transcranial magnetic stimulation targeting to be evaluated and translated to basic and clinical applications. In this review, we outline the motivation for target site personalization, preliminary support (mostly in depression), convergent evidence from other brain stimulation modalities, and generalizability beyond depression and the prefrontal cortex. We end by detailing methodological recommendations, controversies, and notable alternatives. Overall, while this research area appears highly promising, the value of personalized targeting remains unclear, and dedicated large prospective randomized clinical trials using validated methodology are critical.
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    Genetic and Epigenetic Regulation in Lingo-1: Effects on Cognitive Function and White Matter Microstructure in a Case-Control Study for Schizophrenia
    Andrews, JL ; Zalesky, A ; Nair, S ; Sullivan, RP ; Green, MJ ; Pantelis, C ; Newell, KA ; Fernandez, F (MDPI, 2023-11)
    Leucine-rich repeat and immunoglobulin domain-containing protein (Lingo-1) plays a vital role in a large number of neuronal processes underlying learning and memory, which are known to be disrupted in schizophrenia. However, Lingo-1 has never been examined in the context of schizophrenia. The genetic association of a single-nucleotide polymorphism (SNP, rs3144) and methylation (CpG sites) in the Lingo-1 3'-UTR region was examined, with the testing of cognitive dysfunction and white matter (WM) integrity in a schizophrenia case-control cohort (n = 268/group). A large subset of subjects (97 control and 161 schizophrenia subjects) underwent structural magnetic resonance imaging (MRI) brain scans to assess WM integrity. Frequency of the rs3144 minor allele was overrepresented in the schizophrenia population (p = 0.03), with an odds ratio of 1.39 (95% CI 1.016-1.901). CpG sites surrounding rs3144 were hypermethylated in the control population (p = 0.032) compared to the schizophrenia group. rs3144 genotype was predictive of membership to a subclass of schizophrenia subjects with generalized cognitive deficits (p < 0.05), in addition to having associations with WM integrity (p = 0.018). This is the first study reporting a potential implication of genetic and epigenetic risk factors in Lingo-1 in schizophrenia. Both of these genetic and epigenetic alterations may also have associations with cognitive dysfunction and WM integrity in the context of the schizophrenia pathophysiology.
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    Linking Polygenic Risk of Schizophrenia to Variation in Magnetic Resonance Imaging Brain Measures: A Comprehensive Systematic Review
    Jameei, H ; Rakesh, D ; Zalesky, A ; Cairns, MJ ; Reay, WR ; Wray, NR ; Di Biase, MA (OXFORD UNIV PRESS, 2024-01-01)
    BACKGROUND AND HYPOTHESIS: Schizophrenia is highly heritable, with a polygenic effect of many genes conferring risk. Evidence on whether cumulative risk also predicts alterations in brain morphology and function is inconsistent. This systematic review examined evidence for schizophrenia polygenic risk score (sczPRS) associations with commonly used magnetic resonance imaging (MRI) measures. We expected consistent evidence to emerge for significant sczPRS associations with variation in structure and function, specifically in frontal, temporal, and insula cortices that are commonly implicated in schizophrenia pathophysiology. STUDY DESIGN: In accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we searched MEDLINE, Embase, and PsycINFO for peer-reviewed studies published between January 2013 and March 2022. Studies were screened against predetermined criteria and National Institutes of Health (NIH) quality assessment tools. STUDY RESULTS: In total, 57 studies of T1-weighted structural, diffusion, and functional MRI were included (age range = 9-80 years, Nrange = 64-76 644). We observed moderate, albeit preliminary, evidence for higher sczPRS predicting global reductions in cortical thickness and widespread variation in functional connectivity, and to a lesser extent, region-specific reductions in frontal and temporal volume and thickness. Conversely, sczPRS does not predict whole-brain surface area or gray/white matter volume. Limited evidence emerged for sczPRS associations with diffusion tensor measures of white matter microstructure in a large community sample and smaller cohorts of children and young adults. These findings were broadly consistent across community and clinical populations. CONCLUSIONS: Our review supports the hypothesis that schizophrenia is a disorder of disrupted within and between-region brain connectivity, and points to specific whole-brain and regional MRI metrics that may provide useful intermediate phenotypes.
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    Altered brain activity in unipolar depression unveiled using connectomics
    Cash, RFH ; Müller, VI ; Fitzgerald, PB ; Eickhoff, SB ; Zalesky, A (Springer Science and Business Media LLC, 2023-03-01)
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    Brain network communication: concepts, models and applications
    Seguin, C ; Sporns, O ; Zalesky, A (NATURE PORTFOLIO, 2023-09)
    Understanding communication and information processing in nervous systems is a central goal of neuroscience. Over the past two decades, advances in connectomics and network neuroscience have opened new avenues for investigating polysynaptic communication in complex brain networks. Recent work has brought into question the mainstay assumption that connectome signalling occurs exclusively via shortest paths, resulting in a sprawling constellation of alternative network communication models. This Review surveys the latest developments in models of brain network communication. We begin by drawing a conceptual link between the mathematics of graph theory and biological aspects of neural signalling such as transmission delays and metabolic cost. We organize key network communication models and measures into a taxonomy, aimed at helping researchers navigate the growing number of concepts and methods in the literature. The taxonomy highlights the pros, cons and interpretations of different conceptualizations of connectome signalling. We showcase the utility of network communication models as a flexible, interpretable and tractable framework to study brain function by reviewing prominent applications in basic, cognitive and clinical neurosciences. Finally, we provide recommendations to guide the future development, application and validation of network communication models.
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    Regional, circuit and network heterogeneity of brain abnormalities in psychiatric disorders
    Segal, A ; Parkes, L ; Aquino, K ; Kia, SM ; Wolfers, T ; Franke, B ; Hoogman, M ; Beckmann, CF ; Westlye, LT ; Andreassen, OA ; Zalesky, A ; Harrison, BJ ; Davey, CG ; Soriano-Mas, C ; Cardoner, N ; Tiego, J ; Yucel, M ; Braganza, L ; Suo, C ; Berk, M ; Cotton, S ; Bellgrove, MA ; Marquand, AF ; Fornito, A (Nature Research, 2023-09)
    The substantial individual heterogeneity that characterizes people with mental illness is often ignored by classical case-control research, which relies on group mean comparisons. Here we present a comprehensive, multiscale characterization of the heterogeneity of gray matter volume (GMV) differences in 1,294 cases diagnosed with one of six conditions (attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, depression, obsessive-compulsive disorder and schizophrenia) and 1,465 matched controls. Normative models indicated that person-specific deviations from population expectations for regional GMV were highly heterogeneous, affecting the same area in <7% of people with the same diagnosis. However, these deviations were embedded within common functional circuits and networks in up to 56% of cases. The salience-ventral attention system was implicated transdiagnostically, with other systems selectively involved in depression, bipolar disorder, schizophrenia and attention-deficit/hyperactivity disorder. Phenotypic differences between cases assigned the same diagnosis may thus arise from the heterogeneous localization of specific regional deviations, whereas phenotypic similarities may be attributable to the dysfunction of common functional circuits and networks.
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    Functional dysconnectivity in youth depression: Systematic review, meta-analysis, and network-based integration
    Tse, NY ; Ratheesh, A ; Ganesan, S ; Zalesky, A ; Cash, RFH (PERGAMON-ELSEVIER SCIENCE LTD, 2023-10)
    Youth depression has been associated with heterogenous patterns of aberrant brain connectivity. To make sense of these divergent findings, we conducted a systematic review encompassing 19 resting-state fMRI seed-to-whole-brain studies (1400 participants, comprising 795 youths with major depression and 605 matched healthy controls). We incorporated separate meta-analyses of connectivity abnormalities across the levels of the most commonly seeded brain networks (default-mode and limbic networks) and, based on recent additions to the literature, an updated meta-analysis of amygdala dysconnectivity in youth depression. Our findings indicated broad and distributed findings at an anatomical level, which could not be captured by conventional meta-analyses in terms of spatial convergence. However, we were able to parse the complexity of region-to-region dysconnectivity by considering constituent regions as components of distributed canonical brain networks. This integration revealed dysconnectivity centred on central executive, default mode, salience, and limbic networks, converging with findings from the adult depression literature and suggesting similar neurobiological underpinnings of youth and adult depression.
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    Revisiting deficits in threat and safety appraisal in obsessive-compulsive disorder
    Hearne, LJ ; Breakspear, M ; Harrison, BJ ; Hall, CV ; Savage, HS ; Robinson, C ; Sonkusare, S ; Savage, E ; Nott, Z ; Marcus, L ; Naze, S ; Burgher, B ; Zalesky, A ; Cocchi, L (Wiley, 2023-12-15)
    Current behavioural treatment of obsessive-compulsive disorder (OCD) is informed by fear conditioning and involves iteratively re-evaluating previously threatening stimuli as safe. However, there is limited research investigating the neurobiological response to conditioning and reversal of threatening stimuli in individuals with OCD. A clinical sample of individuals with OCD (N = 45) and matched healthy controls (N = 45) underwent functional magnetic resonance imaging. While in the scanner, participants completed a well-validated fear reversal task and a resting-state scan. We found no evidence for group differences in task-evoked brain activation or functional connectivity in OCD. Multivariate analyses encompassing all participants in the clinical and control groups suggested that subjective appraisal of threatening and safe stimuli were associated with a larger difference in brain activity than the contribution of OCD symptoms. In particular, we observed a brain-behaviour continuum whereby heightened affective appraisal was related to increased bilateral insula activation during the task (r = 0.39, pFWE = .001). These findings suggest that changes in conditioned threat-related processes may not be a core neurobiological feature of OCD and encourage further research on the role of subjective experience in fear conditioning.
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    Pathways from threat exposure to psychotic symptoms in youth: The role of emotion recognition bias and brain structure
    Thomas, M ; Whittle, S ; Tian, YE ; van Rheenen, TE ; Zalesky, A ; Cropley, VL (ELSEVIER, 2023-11)
    BACKGROUND: Research supports an association between threatening experiences in childhood and psychosis. It is possible that early threat exposure disrupts the development of emotion recognition (specifically, producing a bias for facial expressions relating to threat) and the brain structures subserving it, contributing to psychosis development. METHODS: Using data from the Philadelphia Neurodevelopmental Cohort, we examined associations between threat exposure and both the misattribution of facial expressions to fear/anger in an emotion recognition task, and gray matter volumes in key emotion processing regions. Our sample comprised youth with psychosis spectrum symptoms (N = 304), control youth (N = 787), and to evaluate specificity, youth with internalizing symptoms (N = 92). The moderating effects of group and sex were examined. RESULTS: Both the psychosis spectrum and internalizing groups had higher levels of threat exposure than controls. In the total sample, threat exposure was associated with lower left medial prefrontal cortex (mPFC) volume but not misattributions to fear/anger. The effects of threat exposure did not significantly differ by group or sex. CONCLUSIONS: The findings of this study provide evidence for an effect of threat exposure on mPFC morphology, but do not support an association between threat exposure and a recognition bias for threat-related expressions, that is particularly pronounced in psychosis. Future research should investigate factors linking transdiagnostic alterations related to threat exposure with psychotic symptoms, and attempt to clarify the mechanisms underpinning emotion recognition misattributions in threat-exposed youth.
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    Plasma neurofilament light chain protein is not increased in treatment-resistant schizophrenia and first-degree relatives
    Eratne, D ; Janelidze, S ; Malpas, CB ; Loi, S ; Walterfane, M ; Merritt, A ; Diouf, I ; Blennow, K ; Zetterberg, H ; Cilia, B ; Warman, C ; Bousman, C ; Everall, I ; Zalesky, A ; Jayaram, M ; Thomas, N ; Berkovic, SF ; Hansson, O ; Velakoulis, D ; Pantelis, C ; Santillo, A (SAGE PUBLICATIONS LTD, 2022-10)
    OBJECTIVE: Schizophrenia, a complex psychiatric disorder, is often associated with cognitive, neurological and neuroimaging abnormalities. The processes underlying these abnormalities, and whether a subset of people with schizophrenia have a neuroprogressive or neurodegenerative component to schizophrenia, remain largely unknown. Examining fluid biomarkers of diverse types of neuronal damage could increase our understanding of these processes, as well as potentially provide clinically useful biomarkers, for example with assisting with differentiation from progressive neurodegenerative disorders such as Alzheimer and frontotemporal dementias. METHODS: This study measured plasma neurofilament light chain protein (NfL) using ultrasensitive Simoa technology, to investigate the degree of neuronal injury in a well-characterised cohort of people with treatment-resistant schizophrenia on clozapine (n = 82), compared to first-degree relatives (an at-risk group, n = 37), people with schizophrenia not treated with clozapine (n = 13), and age- and sex-matched controls (n = 59). RESULTS: We found no differences in NfL levels between treatment-resistant schizophrenia (mean NfL, M = 6.3 pg/mL, 95% confidence interval: [5.5, 7.2]), first-degree relatives (siblings, M = 6.7 pg/mL, 95% confidence interval: [5.2, 8.2]; parents, M after adjusting for age = 6.7 pg/mL, 95% confidence interval: [4.7, 8.8]), controls (M = 5.8 pg/mL, 95% confidence interval: [5.3, 6.3]) and not treated with clozapine (M = 4.9 pg/mL, 95% confidence interval: [4.0, 5.8]). Exploratory, hypothesis-generating analyses found weak correlations in treatment-resistant schizophrenia, between NfL and clozapine levels (Spearman's r = 0.258, 95% confidence interval: [0.034, 0.457]), dyslipidaemia (r = 0.280, 95% confidence interval: [0.064, 0.470]) and a negative correlation with weight (r = -0.305, 95% confidence interval: [-0.504, -0.076]). CONCLUSION: Treatment-resistant schizophrenia does not appear to be associated with neuronal, particularly axonal degeneration. Further studies are warranted to investigate the utility of NfL to differentiate treatment-resistant schizophrenia from neurodegenerative disorders such as behavioural variant frontotemporal dementia, and to explore NfL in other stages of schizophrenia such as the prodome and first episode.