Centre for Youth Mental Health - Research Publications

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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.
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    Relationships between global functioning and neuropsychological predictors in subjects at high risk of psychosis or with a recent onset of depression
    Squarcina, L ; Kambeitz-Ilankovic, L ; Bonivento, C ; Prunas, C ; Oldani, L ; Wenzel, J ; Ruef, A ; Dwyer, D ; Ferro, A ; Borgwardt, S ; Kambeitz, J ; Lichtenstein, TK ; Meisenzahl, E ; Pantelis, C ; Rosen, M ; Upthegrove, R ; Antonucci, LA ; Bertolino, A ; Lencer, R ; Ruhrmann, S ; Salokangas, RRK ; Schultze-Lutter, F ; Chisholm, K ; Stainton, A ; Wood, SJ ; Koutsouleris, N ; Brambilla, P (TAYLOR & FRANCIS LTD, 2022-09-14)
    OBJECTIVE: Psychotic disorders are frequently associated with decline in functioning and cognitive difficulties are observed in subjects at clinical high risk (CHR) for psychosis. In this work, we applied automatic approaches to neurocognitive and functioning measures, with the aim of investigating the link between global, social and occupational functioning, and cognition. METHODS: 102 CHR subjects and 110 patients with recent onset depression (ROD) were recruited. Global assessment of functioning (GAF) related to symptoms (GAF-S) and disability (GAF-D). and global functioning social (GF-S) and role (GF-R), at baseline and of the previous month and year, and a set of neurocognitive measures, were used for classification and regression. RESULTS: Neurocognitive measures related to GF-R at baseline (r = 0.20, p = 0.004), GF-S at present (r = 0.14, p = 0.042) and of the past year (r = 0.19, p = 0.005), for GAF-F of the past month (r = 0.24, p < 0.001) and GAF-D of the past year (r = 0.28, p = 0.002). Classification reached values of balanced accuracy of 61% for GF-R and GAF-D. CONCLUSION: We found that neurocognition was related to psychosocial functioning. More specifically, a deficit in executive functions was associated to poor social and occupational functioning.
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    Empathy and resting-state functional connectivity in children
    Bray, KO ; Pozzi, E ; Vijayakumar, N ; Richmond, S ; Seal, M ; Pantelis, C ; Anderson, V ; Whittle, S (Elsevier BV, 2022-12-01)
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    Intelligence trajectories in individuals at ultra-high risk for psychosis: An 8-year longitudinal analysis
    Cheng, N ; Lin, A ; Bowden, S ; Gao, C ; Yung, AR ; Nelson, B ; Thompson, A ; Yuen, HP ; Brewer, WJ ; Cagliarini, D ; Bruxner, A ; Simmons, M ; Broussard, C ; Pantelis, C ; McGorry, PD ; Allott, K ; Wood, SJ (ELSEVIER, 2022-10)
    Cognitive impairment is a well-documented predictor of transition to a full-threshold psychotic disorder amongst individuals at ultra-high risk (UHR) for psychosis. However, less is known about whether change in cognitive functioning differs between those who do and do not transition. Studies to date have not examined trajectories in intelligence constructs (e.g., acquired knowledge and fluid intelligence), which have demonstrated marked impairments in individuals with schizophrenia. This study aimed to examine intelligence trajectories using longitudinal data spanning an average of eight years, where some participants completed assessments over three time-points. Participants (N = 139) at UHR for psychosis completed the Wechsler Abbreviated Scale of Intelligence (WASI) at each follow-up. Linear mixed-effects models mapped changes in WASI Full-Scale IQ (FSIQ) and T-scores on Vocabulary, Similarities, Block Design, and Matrix Reasoning subtests. The sample showed stable and improving trajectories for FSIQ and all subtests. There were no significant differences in trajectories between those who did and did not transition to psychosis and between individuals with good and poor functional outcomes. However, although not significant, the trajectories of the acquired knowledge subtests diverged between transitioned and non-transitioned individuals (β = -0.12, 95 % CI [-0.29, 0.05] for Vocabulary and β = -0.14, 95 % CI [-0.33, 0.05] for Similarities). Overall, there was no evidence for long-term deterioration in intelligence trajectories in this UHR sample. Future studies with a larger sample of transitioned participants may be needed to explore potential differences in intelligence trajectories between UHR transition groups and other non-psychosis outcomes.
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    Pineal morphology of the clinical high-risk state for psychosis and different psychotic disorders
    Takahashi, T ; Wood, SJ ; Yung, AR ; Nelson, B ; Lin, A ; Yuen, HP ; Phillips, LJ ; Suzuki, M ; McGorry, PD ; Velakoulis, D ; Pantelis, C (ELSEVIER, 2022-06)
    BACKGROUND: Pineal volume reductions have been reported in schizophrenia and clinical high-risk states for the development of psychosis, supporting the role of melatonin dysregulation in the pathophysiology of psychosis. However, it remains unclear whether pineal volume is associated with the later onset of psychosis in individuals at clinical high-risk (CHR) of psychosis or if pineal atrophy is specific to schizophrenia among different psychotic disorders. METHODS: This magnetic resonance imaging study examined the volume of and cyst prevalence in the pineal gland in 135 individuals at CHR of psychosis [52 (38.5%) subsequently developed psychosis], 162 with first-episode psychosis (FEP), 89 with chronic schizophrenia, and 87 healthy controls. The potential contribution of the pineal morphology to clinical characteristics was also examined in the CHR and FEP groups. RESULTS: Pineal volumes did not differ significantly between the CHR, FEP, and chronic schizophrenia groups, but were significantly smaller than that in healthy controls. However, pineal volumes were not associated with the later onset of psychosis in the CHR group or FEP sub-diagnosis (i.e., schizophrenia, schizophreniform disorder, affective psychosis, and other psychoses). No significant differences were observed in the prevalence of pineal cysts between the groups, and it also did not correlate with clinical characteristics in the CHR and FEP groups. CONCLUSION: These results suggest that pineal atrophy is a general vulnerability marker of psychosis, while pineal cysts do not appear to contribute to the pathophysiology of psychosis.
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    Virtual Ontogeny of Cortical Growth Preceding Mental Illness
    Patel, Y ; Shin, J ; Abe, C ; Agartz, I ; Alloza, C ; Alnaes, D ; Ambrogi, S ; Antonucci, LA ; Arango, C ; Arolt, V ; Auzias, G ; Ayesa-Arriola, R ; Banaj, N ; Banaschewski, T ; Bandeira, C ; Basgoze, Z ; Cupertino, RB ; Bau, CHD ; Bauer, J ; Baumeister, S ; Bernardoni, F ; Bertolino, A ; del Mar Bonnin, C ; Brandeis, D ; Brem, S ; Bruggemann, J ; Bulow, R ; Bustillo, JR ; Calderoni, S ; Calvo, R ; Canales-Rodriguez, EJ ; Cannon, DM ; Carmona, S ; Carr, VJ ; Catts, SV ; Chenji, S ; Chew, QH ; Coghill, D ; Connolly, CG ; Conzelmann, A ; Craven, AR ; Crespo-Facorro, B ; Cullen, K ; Dahl, A ; Dannlowski, U ; Davey, CG ; Deruelle, C ; Diaz-Caneja, CM ; Dohm, K ; Ehrlich, S ; Epstein, J ; Erwin-Grabner, T ; Eyler, LT ; Fedor, J ; Fitzgerald, J ; Foran, W ; Ford, JM ; Fortea, L ; Fuentes-Claramonte, P ; Fullerton, J ; Furlong, L ; Gallagher, L ; Gao, B ; Gao, S ; Goikolea, JM ; Gotlib, I ; Goya-Maldonado, R ; Grabe, HJ ; Green, M ; Grevet, EH ; Groenewold, NA ; Grotegerd, D ; Gruber, O ; Haavik, J ; Hahn, T ; Harrison, BJ ; Heindel, W ; Henskens, F ; Heslenfeld, DJ ; Hilland, E ; Hoekstra, PJ ; Hohmann, S ; Holz, N ; Howells, FM ; Ipser, JC ; Jahanshad, N ; Jakobi, B ; Jansen, A ; Janssen, J ; Jonassen, R ; Kaiser, A ; Kaleda, V ; Karantonis, J ; King, JA ; Kircher, T ; Kochunov, P ; Koopowitz, S-M ; Landen, M ; Landro, NI ; Lawrie, S ; Lebedeva, I ; Luna, B ; Lundervold, AJ ; MacMaster, FP ; Maglanoc, LA ; Mathalon, DH ; McDonald, C ; McIntosh, A ; Meinert, S ; Michie, PT ; Mitchell, P ; Moreno-Alcazar, A ; Mowry, B ; Muratori, F ; Nabulsi, L ; Nenadic, I ; Tuura, RO ; Oosterlaan, J ; Overs, B ; Pantelis, C ; Parellada, M ; Pariente, JC ; Pauli, P ; Pergola, G ; Piarulli, FM ; Picon, F ; Piras, F ; Pomarol-Clotet, E ; Pretus, C ; Quide, Y ; Radua, J ; Ramos-Quiroga, JA ; Rasser, PE ; Reif, A ; Retico, A ; Roberts, G ; Rossell, S ; Rovaris, DL ; Rubia, K ; Sacchet, M ; Salavert, J ; Salvador, R ; Sarro, S ; Sawa, A ; Schall, U ; Scott, R ; Selvaggi, P ; Silk, T ; Sim, K ; Skoch, A ; Spalletta, G ; Spaniel, F ; Stein, DJ ; Steinstrater, O ; Stolicyn, A ; Takayanagi, Y ; Tamm, L ; Tavares, M ; Teumer, A ; Thiel, K ; Thomopoulos, SI ; Tomecek, D ; Tomyshev, AS ; Tordesillas-Gutierrez, D ; Tosetti, M ; Uhlmann, A ; Van Rheenen, T ; Vazquez-Bourgon, J ; Vernooij, MW ; Vieta, E ; Vilarroya, O ; Weickert, C ; Weickert, T ; Westlye, LT ; Whalley, H ; Willinger, D ; Winter, A ; Wittfeld, K ; Yang, TT ; Yoncheva, Y ; Zijlmans, JL ; Hoogman, M ; Franke, B ; van Rooij, D ; Buitelaar, J ; Ching, CRK ; Andreassen, OA ; Pozzi, E ; Veltman, D ; Schmaal, L ; van Erp, TGM ; Turner, J ; Castellanos, FX ; Pausova, Z ; Thompson, P ; Paus, T (ELSEVIER SCIENCE INC, 2022-08-15)
    BACKGROUND: Morphology of the human cerebral cortex differs across psychiatric disorders, with neurobiology and developmental origins mostly undetermined. Deviations in the tangential growth of the cerebral cortex during pre/perinatal periods may be reflected in individual variations in cortical surface area later in life. METHODS: Interregional profiles of group differences in surface area between cases and controls were generated using T1-weighted magnetic resonance imaging from 27,359 individuals including those with attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depressive disorder, schizophrenia, and high general psychopathology (through the Child Behavior Checklist). Similarity of interregional profiles of group differences in surface area and prenatal cell-specific gene expression was assessed. RESULTS: Across the 11 cortical regions, group differences in cortical area for attention-deficit/hyperactivity disorder, schizophrenia, and Child Behavior Checklist were dominant in multimodal association cortices. The same interregional profiles were also associated with interregional profiles of (prenatal) gene expression specific to proliferative cells, namely radial glia and intermediate progenitor cells (greater expression, larger difference), as well as differentiated cells, namely excitatory neurons and endothelial and mural cells (greater expression, smaller difference). Finally, these cell types were implicated in known pre/perinatal risk factors for psychosis. Genes coexpressed with radial glia were enriched with genes implicated in congenital abnormalities, birth weight, hypoxia, and starvation. Genes coexpressed with endothelial and mural genes were enriched with genes associated with maternal hypertension and preterm birth. CONCLUSIONS: Our findings support a neurodevelopmental model of vulnerability to mental illness whereby prenatal risk factors acting through cell-specific processes lead to deviations from typical brain development during pregnancy.
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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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    Heschl's gyrus duplication pattern and clinical characteristics in borderline personality disorder: A preliminary study
    Takahashi, T ; Sasabayashi, D ; Velakoulis, D ; Suzuki, M ; McGorry, PD ; Pantelis, C ; Chanen, AM (FRONTIERS MEDIA SA, 2022-11-03)
    Inter-individual variations in the sulco-gyral pattern of Heschl's gyrus (HG) might contribute to emotional processing. However, it remains largely unknown whether borderline personality disorder (BPD) patients exhibit an altered HG gyrification pattern, compared with healthy individuals, and whether such a brain morphological feature, if present, might contribute to their clinical characteristics. The present study used magnetic resonance imaging to investigate the distribution of HG gyrification patterns (single or duplicated) and their relationship to clinical characteristics in teenage BPD patients with minimal treatment exposure. No significant difference was noted for the prevalence of HG patterns between 20 BPD and 20 healthy participants. However, the BPD participants with left duplicated HG were characterized by higher prevalence of comorbid disruptive behavior disorders, with higher externalizing score compared with those with left single HG. Our preliminary results suggest that neurodevelopmental pathology associated with gyral formation might be implicated in the neurobiology of early BPD, especially for emotional and behavioral control.
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    The impact of visual dysfunctions in recent-onset psychosis and clinical high-risk state for psychosis
    Schwarzer, JM ; Meyhoefer, I ; Antonucci, LA ; Kambeitz-Ilankovic, L ; Surmann, M ; Bienek, O ; Romer, G ; Dannlowski, U ; Hahn, T ; Korda, A ; Dwyer, DB ; Ruef, A ; Haas, SS ; Rosen, M ; Lichtenstein, T ; Ruhrmann, S ; Kambeitz, J ; Salokangas, RKR ; Pantelis, C ; Schultze-Lutter, F ; Meisenzahl, E ; Brambilla, P ; Bertolino, A ; Borgwardt, S ; Upthegrove, R ; Koutsouleris, N ; Lencer, R (SPRINGERNATURE, 2022-11)
    Subtle subjective visual dysfunctions (VisDys) are reported by about 50% of patients with schizophrenia and are suggested to predict psychosis states. Deeper insight into VisDys, particularly in early psychosis states, could foster the understanding of basic disease mechanisms mediating susceptibility to psychosis, and thereby inform preventive interventions. We systematically investigated the relationship between VisDys and core clinical measures across three early phase psychiatric conditions. Second, we used a novel multivariate pattern analysis approach to predict VisDys by resting-state functional connectivity within relevant brain systems. VisDys assessed with the Schizophrenia Proneness Instrument (SPI-A), clinical measures, and resting-state fMRI data were examined in recent-onset psychosis (ROP, n = 147), clinical high-risk states of psychosis (CHR, n = 143), recent-onset depression (ROD, n = 151), and healthy controls (HC, n = 280). Our multivariate pattern analysis approach used pairwise functional connectivity within occipital (ON) and frontoparietal (FPN) networks implicated in visual information processing to predict VisDys. VisDys were reported more often in ROP (50.34%), and CHR (55.94%) than in ROD (16.56%), and HC (4.28%). Higher severity of VisDys was associated with less functional remission in both CHR and ROP, and, in CHR specifically, lower quality of life (Qol), higher depressiveness, and more severe impairment of visuospatial constructability. ON functional connectivity predicted presence of VisDys in ROP (balanced accuracy 60.17%, p = 0.0001) and CHR (67.38%, p = 0.029), while in the combined ROP + CHR sample VisDys were predicted by FPN (61.11%, p = 0.006). These large-sample study findings suggest that VisDys are clinically highly relevant not only in ROP but especially in CHR, being closely related to aspects of functional outcome, depressiveness, and Qol. Findings from multivariate pattern analysis support a model of functional integrity within ON and FPN driving the VisDys phenomenon and being implicated in core disease mechanisms of early psychosis states.
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    Exploring Links Between Psychosis and Frontotemporal Dementia Using Multimodal Machine Learning Dementia Praecox Revisited
    Koutsouleris, N ; Pantelis, C ; Velakoulis, D ; McGuire, P ; Dwyer, DB ; Urquijo-Castro, M-F ; Paul, R ; Sen, D ; Popovic, D ; Oeztuerk, O ; Kambeitz, J ; Salokangas, RKR ; Hietala, J ; Bertolino, A ; Brambilla, P ; Upthegrove, R ; Wood, SJ ; Lencer, R ; Borgwardt, S ; Maj, C ; Nothen, M ; Degenhardt, F ; Polyakova, M ; Mueller, K ; Villringer, A ; Danek, A ; Fassbender, K ; Fliessbach, K ; Jahn, H ; Kornhuber, J ; Landwehrmeyer, B ; Anderl-Straub, S ; Prudlo, J ; Synofzik, M ; Wiltfang, J ; Riedl, L ; Diehl-Schmid, J ; Otto, M ; Meisenzahl, E ; Falkai, P ; Schroeter, ML (AMER MEDICAL ASSOC, 2022-09)
    IMPORTANCE: The behavioral and cognitive symptoms of severe psychotic disorders overlap with those seen in dementia. However, shared brain alterations remain disputed, and their relevance for patients in at-risk disease stages has not been explored so far. OBJECTIVE: To use machine learning to compare the expression of structural magnetic resonance imaging (MRI) patterns of behavioral-variant frontotemporal dementia (bvFTD), Alzheimer disease (AD), and schizophrenia; estimate predictability in patients with bvFTD and schizophrenia based on sociodemographic, clinical, and biological data; and examine prognostic value, genetic underpinnings, and progression in patients with clinical high-risk (CHR) states for psychosis or recent-onset depression (ROD). DESIGN, SETTING, AND PARTICIPANTS: This study included 1870 individuals from 5 cohorts, including (1) patients with bvFTD (n = 108), established AD (n = 44), mild cognitive impairment or early-stage AD (n = 96), schizophrenia (n = 157), or major depression (n = 102) to derive and compare diagnostic patterns and (2) patients with CHR (n = 160) or ROD (n = 161) to test patterns' prognostic relevance and progression. Healthy individuals (n = 1042) were used for age-related and cohort-related data calibration. Data were collected from January 1996 to July 2019 and analyzed between April 2020 and April 2022. MAIN OUTCOMES AND MEASURES: Case assignments based on diagnostic patterns; sociodemographic, clinical, and biological data; 2-year functional outcomes and genetic separability of patients with CHR and ROD with high vs low pattern expression; and pattern progression from baseline to follow-up MRI scans in patients with nonrecovery vs preserved recovery. RESULTS: Of 1870 included patients, 902 (48.2%) were female, and the mean (SD) age was 38.0 (19.3) years. The bvFTD pattern comprising prefrontal, insular, and limbic volume reductions was more expressed in patients with schizophrenia (65 of 157 [41.2%]) and major depression (22 of 102 [21.6%]) than the temporo-limbic AD patterns (28 of 157 [17.8%] and 3 of 102 [2.9%], respectively). bvFTD expression was predicted by high body mass index, psychomotor slowing, affective disinhibition, and paranoid ideation (R2 = 0.11). The schizophrenia pattern was expressed in 92 of 108 patients (85.5%) with bvFTD and was linked to the C9orf72 variant, oligoclonal banding in the cerebrospinal fluid, cognitive impairment, and younger age (R2 = 0.29). bvFTD and schizophrenia pattern expressions forecasted 2-year psychosocial impairments in patients with CHR and were predicted by polygenic risk scores for frontotemporal dementia, AD, and schizophrenia. Findings were not associated with AD or accelerated brain aging. Finally, 1-year bvFTD/schizophrenia pattern progression distinguished patients with nonrecovery from those with preserved recovery. CONCLUSIONS AND RELEVANCE: Neurobiological links may exist between bvFTD and psychosis focusing on prefrontal and salience system alterations. Further transdiagnostic investigations are needed to identify shared pathophysiological processes underlying the neuroanatomical interface between the 2 disease spectra.