Psychiatry - Research Publications

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    Disruptions in white matter microstructure associated with impaired visual associative memory in schizophrenia-spectrum illness
    Wannan, CMJ ; Bartholomeusz, CF ; Pantelis, C ; Di Biase, MA ; Syeda, WT ; Chakravarty, MM ; Bousman, CA ; Everall, IP ; McGorry, PD ; Zalesky, A ; Cropley, VL (SPRINGER HEIDELBERG, 2022-09-01)
    Episodic memory ability relies on hippocampal-prefrontal connectivity. However, few studies have examined relationships between memory performance and white matter (WM) microstructure in hippocampal-prefrontal pathways in schizophrenia-spectrum disorder (SSDs). Here, we investigated these relationships in individuals with first-episode psychosis (FEP) and chronic schizophrenia-spectrum disorders (SSDs) using tractography analysis designed to interrogate the microstructure of WM tracts in the hippocampal-prefrontal pathway. Measures of WM microstructure (fractional anisotropy [FA], radial diffusivity [RD], and axial diffusivity [AD]) were obtained for 47 individuals with chronic SSDs, 28 FEP individuals, 52 older healthy controls, and 27 younger healthy controls. Tractography analysis was performed between the hippocampus and three targets involved in hippocampal-prefrontal connectivity (thalamus, amygdala, nucleus accumbens). Measures of WM microstructure were then examined in relation to episodic memory performance separately across each group. Both those with FEP and chronic SSDs demonstrated impaired episodic memory performance. However, abnormal WM microstructure was only observed in individuals with chronic SSDs. Abnormal WM microstructure in the hippocampal-thalamic pathway in the right hemisphere was associated with poorer memory performance in individuals with chronic SSDs. These findings suggest that disruptions in WM microstructure in the hippocampal-prefrontal pathway may contribute to memory impairments in individuals with chronic SSDs but not FEP.
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    S187. EXPLORING NEURODEVELOPMENTAL AND FAMILIAL ORIGINS OF NEUROLOGICAL SOFT SIGNS IN SCHIZOPHRENIA
    Cooper, R ; Van Rheenen, T ; Zalesky, A ; Wannan, C ; Wang, Y ; Bousman, C ; Everall, I ; Pantelis, C ; Cropley, V (Oxford University Press (OUP), 2020-05-18)
    Abstract Background The neurodevelopmental hypothesis is the most widely regarded framework for understanding the development of schizophrenia. One of the most commonly cited pieces of evidence for this theory is the presence of neurological soft signs (NSS) in individuals prior to the onset of psychosis. Increased NSS is also reported in unaffected individuals with a family history of schizophrenia, suggesting that NSS may also have a familial component. Although much research has implicated reduced grey matter volume (GMV) in association with these signs, a subcomponent of volume, known as gyrification, has been poorly researched. Given that gyrification develops predominantly in prenatal life it may be particularly susceptible to a neurodevelopmental abnormality. The aims of this study were to investigate the neurodevelopmental and familial underpinnings of NSS in schizophrenia. Specifically, we examined the brain structural correlates, at both the level of GMV and gyrification, of NSS in individuals with schizophrenia, their unaffected relatives and healthy controls. We aimed to determine whether gyrification better predicted NSS severity than GMV, and whether the relationship between brain structure and NSS were present in a step-wise manner across the diagnostic groups. Methods The sample consisted of individuals with schizophrenia (N=66), their unaffected relatives (N=27) and healthy controls (N=53). NSS was assessed with the Neurological Evaluation Scale (NES), and GMV and gyrification were extracted from MRI using the FreeSurfer imaging suite. A series of analysis of covariance were used to compare NES scores and brain measures between the groups. Separate linear regression analyses were used to assess whether whole-brain GMV and gyrification predicted NES above a covariate-only model. Moderation analyses were used to assess whether the relationship between NES and brain structure were different between the diagnostic groups. Error control was achieved with a false discovery rate of 5%. Results NES was significantly higher in schizophrenia patients than relatives (p<.0001), who were in turn significantly higher than controls (p=.034). With the groups combined, lower GMV (p<.0001), as well as lower gyrification (p=.004), predicted higher NES above a covariate-only model. GMV predicted greater variance in NSS in comparison to gyrification, explaining an additional 20.3% of the variance in NES, in comparison to the additional 5.5% of variance in NES explained by gyrification. Diagnostic group moderated the association between GMV and NES (p=.019), but not between gyrification and NES (p=.245). Follow-up tests revealed that lower GMV was associated with higher NES in schizophrenia (t=-4.5, p<.0001) and relatives (t=-2.5, p=.015) but not controls (t=-1.9, p=.055). Discussion Our findings indicate that NSS is heritable, being present in patients with established schizophrenia, and to a lesser extent, in unaffected relatives. Consistent with previous research, we revealed that GMV predicted NSS severity, suggesting that abnormalities in volume may underlie these signs. We additionally found that gyrification predicted, although to a lesser extent than volume, NSS severity, providing some support for schizophrenia being of possible neurodevelopmental origin. Evidence for an association between volume and NSS in relatives, whom are not confounded by illness-related factors such as medication and symptom severity, indicates a familial contribution to the neural underpinnings of NSS. Together, our study suggests that there may be various aetiological pathways underlying soft signs across the schizophrenia diathesis, some that may be of familial or neurodevelopmental origin.
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    Brain morphology is differentially impacted by peripheral cytokines in schizophrenia-spectrum disorder
    Laskaris, L ; Mancuso, S ; Shannon Weickert, C ; Zalesky, A ; Chana, G ; Wannan, C ; Bousman, C ; Baune, BT ; McGorry, P ; Pantelis, C ; Cropley, VL (Elsevier, 2021)
    Deficits in brain morphology are one of the most widely replicated neuropathological features in schizophrenia-spectrum disorder (SSD), although their biological underpinnings remain unclear. Despite the existence of hypotheses by which peripheral inflammation may impact brain structure, few studies have examined this relationship in SSD. This study aimed to establish the relationship between peripheral markers of inflammation and brain morphology and determine whether such relationships differed across healthy controls and individuals with first episode psychosis (FEP) and chronic schizophrenia. A panel of 13 pro- and anti-inflammatory cytokines were quantified from serum in 175 participants [n = 84 Healthy Controls (HC), n = 40 FEP, n = 51 Chronic SCZ]. We first performed a series of permutation tests to identify the cytokines most consistently associated with brain structural regions. Using moderation analysis, we then determined the extent to which individual variation in select cytokines, and their interaction with diagnostic status, predicted variation in brain structure. We found significant interactions between cytokine level and diagnosis on brain structure. Diagnostic status significantly moderated the relationship of IFNγ, IL4, IL5 and IL13 with frontal thickness, and of IFNγ and IL5 and total cortical volume. Specifically, frontal thickness was positively associated with IFNγ, IL4, IL5 and IL13 cytokine levels in the healthy control group, whereas pro-inflammatory cytokines IFNγ and IL5 were associated with lower total cortical volume in the FEP group. Our findings suggest that while there were no relationships detected in chronic schizophrenia, the relationship between peripheral inflammatory markers and select brain regions are differentially impacted in FEP and healthy controls. Longitudinal investigations are required to determine whether the relationship between brain structure and peripheral inflammation changes over time.
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    Individual deviations from normative models of brain structure in a large cross-sectional schizophrenia cohort
    Lv, J ; Di Biase, M ; Cash, RFH ; Cocchi, L ; Cropley, VL ; Klauser, P ; Tian, Y ; Bayer, J ; Schmaal, L ; Cetin-Karayumak, S ; Rathi, Y ; Pasternak, O ; Bousman, C ; Pantelis, C ; Calamante, F ; Zalesky, A (SPRINGERNATURE, 2021-07)
    The heterogeneity of schizophrenia has defied efforts to derive reproducible and definitive anatomical maps of structural brain changes associated with the disorder. We aimed to map deviations from normative ranges of brain structure for individual patients and evaluate whether the loci of individual deviations recapitulated group-average brain maps of schizophrenia pathology. For each of 48 white matter tracts and 68 cortical regions, normative percentiles of variation in fractional anisotropy (FA) and cortical thickness (CT) were established using diffusion-weighted and structural MRI from healthy adults (n = 195). Individuals with schizophrenia (n = 322) were classified as either within the normative range for healthy individuals of the same age and sex (5-95% percentiles), infra-normal (<5% percentile) or supra-normal (>95% percentile). Repeating this classification for each tract and region yielded a deviation map for each individual. Compared to the healthy comparison group, the schizophrenia group showed widespread reductions in FA and CT, involving virtually all white matter tracts and cortical regions. Paradoxically, however, no more than 15-20% of patients deviated from the normative range for any single tract or region. Furthermore, 79% of patients showed infra-normal deviations for at least one locus (healthy individuals: 59 ± 2%, p < 0.001). Thus, while infra-normal deviations were common among patients, their anatomical loci were highly inconsistent between individuals. Higher polygenic risk for schizophrenia associated with a greater number of regions with infra-normal deviations in CT (r = -0.17, p = 0.006). We conclude that anatomical loci of schizophrenia-related changes are highly heterogeneous across individuals to the extent that group-consensus pathological maps are not representative of most individual patients. Normative modeling can aid in parsing schizophrenia heterogeneity and guiding personalized interventions.