Psychiatry - Research Publications

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    Investigation of Brain Iron in Niemann-Pick Type C: A 7T Quantitative Susceptibility Mapping Study
    Ravanfar, P ; Syeda, WT ; Rushmore, RJ ; Moffat, B ; Lyall, AE ; Merritt, AH ; Devenyi, GA ; Chakravarty, MM ; Desmond, P ; Cropley, VL ; Makris, N ; Shenton, ME ; Bush, AI ; Velakoulis, D ; Pantelis, C ; Walterfang, M (AMER SOC NEURORADIOLOGY, 2023-06-22)
    BACKGROUND AND PURPOSE: While brain iron dysregulation has been observed in several neurodegenerative disorders, its association with the progressive neurodegeneration in Niemann-Pick type C is unknown. Systemic iron abnormalities have been reported in patients with Niemann-Pick type C and in animal models of Niemann-Pick type C. In this study, we examined brain iron using quantitative susceptibility mapping MR imaging in individuals with Niemann-Pick type C compared with healthy controls. MATERIALS AND METHODS: A cohort of 10 patients with adolescent- and adult-onset Niemann-Pick type C and 14 age- and sex-matched healthy controls underwent 7T brain MR imaging with T1 and quantitative susceptibility mapping acquisitions. A probing whole-brain voxelwise comparison of quantitative susceptibility mapping between groups was conducted. Mean quantitative susceptibility mapping in the ROIs (thalamus, hippocampus, putamen, caudate nucleus, and globus pallidus) was further compared. The correlations between regional volume, quantitative susceptibility mapping values, and clinical features, which included disease severity on the Iturriaga scale, cognitive function, and the Social and Occupational Functioning Assessment Scale, were explored as secondary analyses. RESULTS: We observed lower volume in the thalamus and voxel clusters of higher quantitative susceptibility mapping in the pulvinar nuclei bilaterally in patients with Niemann-Pick type C compared with the control group. In patients with Niemann-Pick type C, higher quantitative susceptibility mapping in the pulvinar nucleus clusters correlated with lower volume of the thalamus on both sides. Moreover, higher quantitative susceptibility mapping in the right pulvinar cluster was associated with greater disease severity. CONCLUSIONS: Our findings suggest iron deposition in the pulvinar nucleus in Niemann-Pick type C disease, which is associated with thalamic atrophy and disease severity. This preliminary evidence supports the link between iron and neurodegeneration in Niemann-Pick type C, in line with existing literature on other neurodegenerative disorders.
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    Investigation of brain iron in anorexia nervosa, a quantitative susceptibility mapping study
    Ravanfar, P ; Rushmore, RJ ; Lyall, AEE ; Cropley, V ; Makris, N ; Desmond, P ; Velakoulis, D ; Shenton, MEE ; Bush, AII ; Rossell, SLL ; Pantelis, C ; Syeda, WTT ; Phillipou, A (BMC, 2023-08-21)
    BACKGROUND: Anorexia nervosa (AN) is a potentially fatal psychiatric condition, associated with structural brain changes such as gray matter volume loss. The pathophysiological mechanisms for these changes are not yet fully understood. Iron is a crucial element in the development and function of the brain. Considering the systemic alterations in iron homeostasis in AN, we hypothesized that brain iron would be altered as a possible factor associated with structural brain changes in AN. METHODS: In this study, we used quantitative susceptibility mapping (QSM) magnetic resonance imaging to investigate brain iron in current AN (c-AN) and weight-restored AN compared with healthy individuals. Whole-brain voxel wise comparison was used to probe areas with possible group differences. Further, the thalamus, caudate nucleus, putamen, nucleus accumbens, hippocampus, and amygdala were selected as the regions of interest (ROIs) for ROI-based comparison of mean QSM values. RESULTS: Whole-brain voxel-wise and ROI-based comparison of QSM did not reveal any differences between groups. Exploratory analyses revealed a correlation between higher regional QSM (higher iron) and lower body mass index, higher illness severity, longer illness duration, and younger age at onset in the c-AN group. CONCLUSIONS: This study did not find evidence of altered brain iron in AN compared to healthy individuals. However, the correlations between clinical variables and QSM suggest a link between brain iron and weight status or biological processes in AN, which warrants further investigation.
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    Genetic variation in glutamatergic genes moderates the effects of childhood adversity on brain volume and IQ in treatment-resistant schizophrenia
    Saini, SM ; Bousman, CA ; Mancuso, SG ; Cropley, V ; Van Rheenen, TE ; Lenroot, RK ; Bruggemann, J ; Weickert, CS ; Weickert, TW ; Sundram, S ; Everall, IP ; Pantelis, C (Nature Portfolio, 2023-09-14)
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    The neural, stress hormone and inflammatory correlates of childhood deprivation and threat in psychosis: A systematic review
    Thomas, M ; Rakesh, D ; Whittle, S ; Sheridan, M ; Upthegrove, R ; Cropley, V (PERGAMON-ELSEVIER SCIENCE LTD, 2023-11)
    Childhood adversity increases the risk of developing psychosis, but the biological mechanisms involved are unknown. Disaggregating early adverse experiences into core dimensions of deprivation and threat may help to elucidate these mechanisms. We therefore systematically searched the literature investigating associations between deprivation and threat, and neural, immune and stress hormone systems in individuals on the psychosis spectrum. Our search yielded 74 articles, from which we extracted and synthesized relevant findings. While study designs were heterogeneous and findings inconsistent, some trends emerged. In psychosis, deprivation tended to correlate with lower global cortical volume, and some evidence supported threat-related variation in prefrontal cortex morphology. Greater threat exposure was also associated with higher C-reactive protein, and higher and lower cortisol measures. When examined, associations in controls were less evident. Overall, findings indicate that deprivation and threat may associate with partially distinct biological mechanisms in the psychosis spectrum, and that associations may be stronger than in controls. Dimensional approaches may help disentangle the biological correlates of childhood adversity in psychosis, but more studies are needed.
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    Complement proteins are elevated in blood serum but not CSF in clinical high-risk and antipsychotic-naive first-episode psychosis
    Cropley, VL ; Kittel, M ; Heurich, M ; Focking, M ; Leweke, FM ; Pantelis, C (ACADEMIC PRESS INC ELSEVIER SCIENCE, 2023-10)
    Alterations in the complement system have been reported in some people with psychotic disorder, including in pre-psychotic individuals, suggesting that complement pathway dysregulation may be a feature of the early psychosis phenotype. Measurement of complement protein expression in psychosis has been largely restricted to the blood from patients with established illness who were taking antipsychotic medication. The present study examined a range of complement proteins in blood and cerebrospinal fluid (CSF) derived from individuals at clinical high-risk for psychosis (CHR), antipsychotic-naïve first-episode psychosis (FEP) and healthy controls. A panel of complement proteins (C1q, C3, C3b/iC3b, C4, factor B and factor H) were quantified in serum and matched CSF in 72 participants [n = 23 individuals at CHR, n = 24 antipsychotic-naïve FEP, n = 25 healthy controls] using a multiplex immunoassay. Analysis of covariance was used to assess between-group differences in complement protein levels in serum and CSF. Pearson's correlation was used to assess the relationship between serum and CSF proteins, and between complement proteins and symptom severity. In serum, all proteins, except for C3, were significantly higher in FEP and CHR. While a trend was observed, protein levels in CSF did not statistically differ between groups and appeared to be impacted by BMI and sample storage time. Across the whole sample, serum and CSF protein levels were not correlated. In FEP, higher levels of serum classical and alternative grouped pathway components were correlated with symptom severity. Our exploratory study provides evidence for increased activity of the peripheral complement system in the psychosis spectrum, with such elevations varying with clinical severity. Further study of complement in CSF is warranted. Longitudinal investigations are required to elucidate whether complement proteins change peripherally and/or centrally with progression of psychotic illness.
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    Inflammatory subgroups of schizophrenia and their association with brain structure: A semi-supervised machine learning examination of heterogeneity
    Lalousis, PA ; Schmaal, L ; Wood, SJ ; Reniers, RLEP ; Cropley, VL ; Watson, A ; Pantelis, C ; Suckling, J ; Barnes, NM ; Pariante, C ; Jones, PB ; Joyce, E ; Barnes, TRE ; Lawrie, SM ; Husain, N ; Dazzan, P ; Deakin, B ; Weickert, CS ; Upthegrove, R (ACADEMIC PRESS INC ELSEVIER SCIENCE, 2023-10)
    OBJECTIVE: Immune system dysfunction is hypothesised to contribute to structural brain changes through aberrant synaptic pruning in schizophrenia. However, evidence is mixed and there is a lack of evidence of inflammation and its effect on grey matter volume (GMV) in patients. We hypothesised that inflammatory subgroups can be identified and that the subgroups will show distinct neuroanatomical and neurocognitive profiles. METHODS: The total sample consisted of 1067 participants (chronic patients with schizophrenia n = 467 and healthy controls (HCs) n = 600) from the Australia Schizophrenia Research Bank (ASRB) dataset, together with 218 recent-onset patients with schizophrenia from the external Benefit of Minocycline on Negative Symptoms of Psychosis: Extent and Mechanism (BeneMin) dataset. HYDRA (HeterogeneitY through DiscRiminant Analysis) was used to separate schizophrenia from HC and define disease-related subgroups based on inflammatory markers. Voxel-based morphometry and inferential statistics were used to explore GMV alterations and neurocognitive deficits in these subgroups. RESULTS: An optimal clustering solution revealed five main schizophrenia groups separable from HC: Low Inflammation, Elevated CRP, Elevated IL-6/IL-8, Elevated IFN-γ, and Elevated IL-10 with an adjusted Rand index of 0.573. When compared with the healthy controls, the IL-6/IL-8 cluster showed the most widespread, including the anterior cingulate, GMV reduction. The IFN-γ inflammation cluster showed the least GMV reduction and impairment of cognitive performance. The CRP and the Low Inflammation clusters dominated in the younger external dataset. CONCLUSIONS: Inflammation in schizophrenia may not be merely a case of low vs high, but rather there are pluripotent, heterogeneous mechanisms at play which could be reliably identified based on accessible, peripheral measures. This could inform the successful development of targeted interventions.
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    Associations of Changes in Sleep and Emotional and Behavioral Problems From Late Childhood to Early Adolescence
    Cooper, R ; Di Biase, MA ; Bei, B ; Quach, J ; Cropley, V (AMER MEDICAL ASSOC, 2023-06)
    IMPORTANCE: Sleep problems and psychopathology symptoms are highly comorbid and bidirectionally correlated across childhood and adolescence. Whether these associations are specific to discrete profiles of sleep problems and specific internalizing and externalizing phenomena is currently unclear. OBJECTIVE: To characterize individual changes in profiles of sleep problems and their prospective associations with psychopathology symptoms across the transition from childhood to adolescence. DESIGN, SETTING, AND PARTICIPANTS: This observational cohort study used baseline data (participant age of 9 to 11 years) and 2-year follow-up data (participant age of 11 to 13 years) from the community-setting, multicenter Adolescent Brain Cognitive Development (ABCD) study. Individuals were assessed for a range of sleep problems at both waves and categorized into profiles via latent profile analysis. The stability and change in these profiles over time was assessed via latent transition analysis. Logistic regression models examined whether psychopathology symptoms were cross-sectionally associated with profile membership and whether transitions between profiles were associated with changes psychopathology symptoms over time. Data were collected from September 2016 to January 2020, and data were analyzed from August 2021 to July 2022. EXPOSURES: Sleep problems were assessed at both baseline and follow-up via the parent-reported Sleep Disturbance Scale for Children (SDSC). MAIN OUTCOMES AND MEASURES: Psychopathology symptoms at both baseline and follow-up were assessed using the internalizing and externalizing dimension scores derived from the parent-reported Child Behavior Checklist. RESULTS: A total of 10 313 individuals (4913 [47.6%] were female) were categorized into 4 latent profiles of sleep problems at both baseline and follow-up: a low disturbance profile, a sleep onset/maintenance problems profile, a moderate and nonspecific disturbance profile (termed mixed disturbance), and a high disturbance profile. Individuals in the 3 more severe problem profiles displayed greater risk of concurrent internalizing symptoms (sleep onset/maintenance problems: odds ratio [OR], 1.30; 95% CI, 1.25-1.35; P < .001; mixed disturbance: OR, 1.29; 95% CI, 1.25-1.33; P < .001; high disturbance: OR, 1.44; 95% CI, 1.40-1.49; P < .001) and externalizing symptoms (sleep onset/maintenance problems: OR, 1.20; 95% CI, 1.16-1.23; P < .001; mixed disturbance: OR, 1.17; 95% CI, 1.14-1.20; P < .001; high disturbance: OR, 1.24; 95% CI, 1.21-1.28; P < .001). Transitions between sleep profiles over time were associated with prospective internalizing and externalizing symptoms, but not vice versa. CONCLUSIONS AND RELEVANCE: There are substantial changes in sleep problems across the transition to adolescence that are associated with later internalizing and externalizing symptoms. Sleep profiles could be targeted in future intervention and treatment programs to improve sleep-related and mental health-related outcomes across development.
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    Network-Based Spreading of Gray Matter Changes Across Different Stages of Psychosis
    Chopra, S ; Segal, A ; Oldham, S ; Holmes, A ; Sabaroedin, K ; Orchard, ER ; Francey, SM ; O'Donoghue, B ; Cropley, V ; Nelson, B ; Graham, J ; Baldwin, L ; Tiego, J ; Yuen, HP ; Allott, K ; Alvarez-Jimenez, M ; Harrigan, S ; Fulcher, BD ; Aquino, K ; Pantelis, C ; Wood, SJ ; Bellgrove, M ; McGorry, PD ; Fornito, A (American Medical Association, 2023-12)
    IMPORTANCE: Psychotic illness is associated with anatomically distributed gray matter reductions that can worsen with illness progression, but the mechanisms underlying the specific spatial patterning of these changes is unknown. OBJECTIVE: To test the hypothesis that brain network architecture constrains cross-sectional and longitudinal gray matter alterations across different stages of psychotic illness and to identify whether certain brain regions act as putative epicenters from which volume loss spreads. DESIGN, SETTINGS, AND PARTICIPANTS: This case-control study included 534 individuals from 4 cohorts, spanning early and late stages of psychotic illness. Early-stage cohorts included patients with antipsychotic-naive first-episode psychosis (n = 59) and a group of patients receiving medications within 3 years of psychosis onset (n = 121). Late-stage cohorts comprised 2 independent samples of people with established schizophrenia (n = 136). Each patient group had a corresponding matched control group (n = 218). A sample of healthy adults (n = 356) was used to derive representative structural and functional brain networks for modeling of network-based spreading processes. Longitudinal illness-related and antipsychotic-related gray matter changes over 3 and 12 months were examined using a triple-blind randomized placebo-control magnetic resonance imaging study of the antipsychotic-naive patients. All data were collected between April 29, 2008, and January 15, 2020, and analyses were performed between March 1, 2021, and January 14, 2023. MAIN OUTCOMES AND MEASURES: Coordinated deformation models were used to estimate the extent of gray matter volume (GMV) change in each of 332 parcellated areas by the volume changes observed in areas to which they were structurally or functionally coupled. To identify putative epicenters of volume loss, a network diffusion model was used to simulate the spread of pathology from different seed regions. Correlations between estimated and empirical spatial patterns of GMV alterations were used to quantify model performance. RESULTS: Of 534 included individuals, 354 (66.3%) were men, and the mean (SD) age was 28.4 (7.4) years. In both early and late stages of illness, spatial patterns of cross-sectional volume differences between patients and controls were more accurately estimated by coordinated deformation models constrained by structural, rather than functional, network architecture (r range, >0.46 to <0.57; P < .01). The same model also robustly estimated longitudinal volume changes related to illness (r ≥ 0.52; P < .001) and antipsychotic exposure (r ≥ 0.50; P < .004). Network diffusion modeling consistently identified, across all 4 data sets, the anterior hippocampus as a putative epicenter of pathological spread in psychosis. Epicenters of longitudinal GMV loss were apparent in posterior cortex early in the illness and shifted to the prefrontal cortex with illness progression. CONCLUSION AND RELEVANCE: These findings highlight a central role for white matter fibers as conduits for the spread of pathology across different stages of psychotic illness, mirroring findings reported in neurodegenerative conditions. The structural connectome thus represents a fundamental constraint on brain changes in psychosis, regardless of whether these changes are caused by illness or medication. Moreover, the anterior hippocampus represents a putative epicenter of early brain pathology from which dysfunction may spread to affect connected areas.
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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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    Development of morning-eveningness in adolescence: implications for brain development and psychopathology
    Cooper, R ; Di Biase, MA ; Bei, B ; Allen, NB ; Schwartz, O ; Whittle, S ; Cropley, V (WILEY, 2023-03)
    BACKGROUND: Morning-evening preference is defined as an individual's preference for a morning- or evening-oriented rhythm. Across adolescence, a preference for eveningness becomes more predominant. Although eveningness is cross-sectionally associated with internalizing and externalizing psychopathology, few studies have examined developmental changes in eveningness and its potential biological substrates. Here, we investigated the longitudinal relationships among the trajectory of eveningness preference, internalizing and externalizing psychopathology and white matter development, across adolescence. METHODS: Two-hundred and nine adolescents (49% male) were assessed longitudinally at four separate time points between 12 and 19 years of age. Morning-evening preference and internalizing and externalizing symptoms were assessed at each time point. Diffusion-weighted images were acquired on a subset of participants at the final two time points to estimate changes in global mean fractional anisotropy (FA). Linear mixed models were performed to estimate the change in eveningness over time. A series of linear regression models assessed the influence of change in eveningness on psychopathology and white matter development at age 19. RESULTS: Across the sample, a preference for eveningness became more predominant by 19 years of age. Greater individual-level change towards eveningness significantly predicted greater severity in externalizing, but not internalizing, symptoms at 19 years of age. In contrast, change in psychopathology from 12 to 19 years of age was not associated with morning-eveningness at age 19. A change towards eveningness predicted an attenuated increase in FA between 17 and 19 years of age. CONCLUSIONS: This study suggests that developmental changes in morning-evening preference may predict both neurodevelopmental and psychological outcomes in adolescents.