Psychiatry - Research Publications
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ItemNo Preview AvailablePlasma neurofilament light chain protein is not increased in treatment-resistant schizophrenia and first-degree relatives(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.
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ItemNo Preview AvailableDisruptions in white matter microstructure associated with impaired visual associative memory in schizophrenia-spectrum illness(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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ItemAffinity scores: An individual-centric fingerprinting framework for neuropsychiatric disorders(SPRINGERNATURE, 2022-08-09)Population-centric frameworks of biomarker identification for psychiatric disorders focus primarily on comparing averages between groups and assume that diagnostic groups are (1) mutually-exclusive, and (2) homogeneous. There is a paucity of individual-centric approaches capable of identifying individual-specific 'fingerprints' across multiple domains. To address this, we propose a novel framework, combining a range of biopsychosocial markers, including brain structure, cognition, and clinical markers, into higher-level 'fingerprints', capable of capturing intra-illness heterogeneity and inter-illness overlap. A multivariate framework was implemented to identify individualised patterns of brain structure, cognition and clinical markers based on affinity to other participants in the database. First, individual-level affinity scores defined each participant's "neighbourhood" across each measure based on variable-specific hop sizes. Next, diagnostic verification and classification algorithms were implemented based on multivariate affinity score profiles. To perform affinity-based classification, data were divided into training and test samples, and 5-fold nested cross-validation was performed on the training data. Affinity-based classification was compared to weighted K-nearest neighbours (KNN) classification. The framework was applied to the Australian Schizophrenia Research Bank (ASRB) dataset, which included data from individuals with chronic and treatment resistant schizophrenia and healthy controls. Individualised affinity scores provided a 'fingerprint' of brain structure, cognition, and clinical markers, which described the affinity of an individual to the representative groups in the dataset. Diagnostic verification capability was moderate to high depending on the choice of multivariate affinity metric. Affinity score-based classification achieved a high degree of accuracy in the training, nested cross-validation and prediction steps, and outperformed KNN classification in the training and test datasets. Affinity scores demonstrate utility in two keys ways: (1) Early and accurate diagnosis of neuropsychiatric disorders, whereby an individual can be grouped within a diagnostic category/ies that best matches their fingerprint, and (2) identification of biopsychosocial factors that most strongly characterise individuals/disorders, and which may be most amenable to intervention.
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ItemCortico-cognition coupling in treatment resistant schizophrenia(ELSEVIER SCI LTD, 2022)BACKGROUND: Brain structural alterations and cognitive dysfunction are independent predictors for poor clinical outcome in schizophrenia, and the associations between these domains remains unclear. We employed a novel, multiblock partial least squares correlation (MB-PLS-C) technique and investigated multivariate cortico-cognitive patterns in patients with treatment-resistant schizophrenia (TRS) and matched healthy controls (HC). METHOD: Forty-one TRS patients (age 38.5 ± 9.1, 30 males (M)), and 45 HC (age 40.2 ± 10.6, 29 M) underwent 3T structural MRI. Volumes of 68 brain regions and seven variables from CANTAB covering memory and executive domains were included. Univariate group differences were assessed, followed by the MB-PLS-C analyses to identify group-specific multivariate patterns of cortico-cognitive coupling. Supplementary three-group analyses, which included 23 non-affected first-degree relatives (NAR), were also conducted. RESULTS: Univariate tests demonstrated that TRS patients showed impairments in all seven cognitive tasks and volume reductions in 12 cortical regions following Bonferroni correction. The MB-PLS-C analyses revealed two significant latent variables (LVs) explaining > 90% of the sum-of-squares variance. LV1 explained 78.86% of the sum-of-squares variance, describing a shared, widespread structure-cognitive pattern relevant to both TRS patients and HCs. In contrast, LV2 (13.47% of sum-of-squares variance explained) appeared specific to TRS and comprised a differential cortico-cognitive pattern including frontal and temporal lobes as well as paired associates learning (PAL) and intra-extra dimensional set shifting (IED). Three-group analyses also identified two significant LVs, with NARs more closely resembling healthy controls than TRS patients. CONCLUSIONS: MB-PLS-C analyses identified multivariate brain structural-cognitive patterns in the latent space that may provide a TRS signature.
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ItemCognitive behavioral markers of neurodevelopmental trajectories in rodents(SPRINGERNATURE, 2021-10-30)Between adolescence and adulthood, the brain critically undergoes maturation and refinement of synaptic and neural circuits that shape cognitive processing. Adolescence also represents a vulnerable period for the onset of symptoms in neurodevelopmental psychiatric disorders. Despite the wide use of rodent models to unravel neurobiological mechanisms underlying neurodevelopmental disorders, there is a surprising paucity of rigorous studies focusing on normal cognitive-developmental trajectories in such models. Here, we sought to behaviorally capture maturational changes in cognitive trajectories during adolescence and into adulthood in male and female mice using distinct behavioral paradigms. C57 BL/6J mice (4.5, 6, and 12 weeks of age) were assessed on three behavioral paradigms: drug-induced locomotor hyperactivity, prepulse inhibition, and a novel validated version of a visuospatial paired-associate learning touchscreen task. We show that the normal maturational trajectories of behavioral performance on these paradigms are dissociable. Responses in drug-induced locomotor hyperactivity and prepulse inhibition both displayed a 'U-shaped' developmental trajectory; lower during mid-adolescence relative to early adolescence and adulthood. In contrast, visuospatial learning and memory, memory retention, and response times indicative of motivational processing progressively improved with age. Our study offers a framework to investigate how insults at different developmental stages might perturb normal trajectories in cognitive development. We provide a brain maturational approach to understand resilience factors of brain plasticity in the face of adversity and to examine pharmacological and non-pharmacological interventions directed at ameliorating or rescuing perturbed trajectories in neurodevelopmental and neuropsychiatric disorders.
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ItemNo Preview AvailableImpaired olfactory ability associated with larger left hippocampus and rectus volumes at earliest stages of schizophrenia: A sign of neuroinflammation?(ELSEVIER IRELAND LTD, 2020-07)Impaired olfactory identification has been reported as a first sign of schizophrenia during the earliest stages of illness, including before illness onset. The aim of this study was to examine the relationship between volumes of these regions (amygdala, hippocampus, gyrus rectus and orbitofrontal cortex) and olfactory ability in three groups of participants: healthy control participants (Ctls), patients with first-episode schizophrenia (FE-Scz) and chronic schizophrenia patients (Scz). Exploratory analyses were performed in a sample of individuals at ultra-high risk (UHR) for psychosis in a co-submission paper (Masaoka et al., 2020). The relationship to brain structural measures was not apparent prior to psychosis onset, but was only evident following illness onset, with a different pattern of relationships apparent across illness stages (FE-Scz vs Scz). Path analysis found that lower olfactory ability was related to larger volumes of the left hippocampus and gyrus rectus in the FE-Scz group. We speculate that larger hippocampus and rectus in early schizophrenia are indicative of swelling, potentially caused by an active neurochemical or immunological process, such as inflammation or neurotoxicity, which is associated with impaired olfactory ability. The volumetric decreases in the chronic stage of Scz may be due to degeneration resulting from an active immune process and its resolution.
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ItemS187. EXPLORING NEURODEVELOPMENTAL AND FAMILIAL ORIGINS OF NEUROLOGICAL SOFT SIGNS IN SCHIZOPHRENIA(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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ItemNo Preview AvailableBrain morphology is differentially impacted by peripheral cytokines in schizophrenia-spectrum disorder(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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ItemNeurological, neuropsychiatric and neurodevelopmental complications of COVID-19(SAGE PUBLICATIONS LTD, 2021-08)Although COVID-19 is predominantly a respiratory disease, it is known to affect multiple organ systems. In this article, we highlight the impact of SARS-CoV-2 (the coronavirus causing COVID-19) on the central nervous system as there is an urgent need to understand the longitudinal impacts of COVID-19 on brain function, behaviour and cognition. Furthermore, we address the possibility of intergenerational impacts of COVID-19 on the brain, potentially via both maternal and paternal routes. Evidence from preclinical models of earlier coronaviruses has shown direct viral infiltration across the blood-brain barrier and indirect secondary effects due to other organ pathology and inflammation. In the most severely ill patients with pneumonia requiring intensive care, there appears to be additional severe inflammatory response and associated thrombophilia with widespread organ damage, including the brain. Maternal viral (and other) infections during pregnancy can affect the offspring, with greater incidence of neurodevelopmental disorders, such as autism, schizophrenia and epilepsy. Available reports suggest possible vertical transmission of SARS-CoV-2, although longitudinal cohort studies of such offspring are needed. The impact of paternal infection on the offspring and intergenerational effects should also be considered. Research targeted at mechanistic insights into all aspects of pathogenesis, including neurological, neuropsychiatric and haematological systems alongside pulmonary pathology, will be critical in informing future therapeutic approaches. With these future challenges in mind, we highlight the importance of national and international collaborative efforts to gather the required clinical and preclinical data to effectively address the possible long-term sequelae of this global pandemic, particularly with respect to the brain and mental health.