Psychiatry - Research Publications

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    Impaired olfactory ability associated with larger left hippocampus and rectus volumes at earliest stages of schizophrenia: A sign of neuroinflammation?
    Masaoka, Y ; Velakoulis, D ; Brewer, WJ ; Cropley, VL ; Bartholomeusz, CF ; Yung, AR ; Nelson, B ; Dwyer, D ; Wannan, CMJ ; Izumizaki, M ; McGorry, PD ; Wood, SJ ; Pantelis, C (ELSEVIER IRELAND LTD, 2020-07-01)
    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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    Multimodal Machine Learning Workflows for Prediction of Psychosis in Patients With Clinical High-Risk Syndromes and Recent-Onset Depression
    Koutsouleris, N ; Dwyer, DB ; Degenhardt, F ; Maj, C ; Urquijo-Castro, MF ; Sanfelici, R ; Popovic, D ; Oeztuerk, O ; Haas, SS ; Weiske, J ; Ruef, A ; Kambeitz-Ilankovic, L ; Antonucci, LA ; Neufang, S ; Schmidt-Kraepelin, C ; Ruhrmann, S ; Penzel, N ; Kambeitz, J ; Haidl, TK ; Rosen, M ; Chisholm, K ; Riecher-Rossler, A ; Egloff, L ; Schmidt, A ; Andreou, C ; Hietala, J ; Schirmer, T ; Romer, G ; Walger, P ; Franscini, M ; Traber-Walker, N ; Schimmelmann, BG ; Fluckiger, R ; Michel, C ; Rossler, W ; Borisov, O ; Krawitz, PM ; Heekeren, K ; Buechler, R ; Pantelis, C ; Falkai, P ; Salokangas, RKR ; Lencer, R ; Bertolino, A ; Borgwardt, S ; Noethen, M ; Brambilla, P ; Wood, SJ ; Upthegrove, R ; Schultze-Lutter, F ; Theodoridou, A ; Meisenzahl, E (AMER MEDICAL ASSOC, 2020-12-02)
    Importance: Diverse models have been developed to predict psychosis in patients with clinical high-risk (CHR) states. Whether prediction can be improved by efficiently combining clinical and biological models and by broadening the risk spectrum to young patients with depressive syndromes remains unclear. Objectives: To evaluate whether psychosis transition can be predicted in patients with CHR or recent-onset depression (ROD) using multimodal machine learning that optimally integrates clinical and neurocognitive data, structural magnetic resonance imaging (sMRI), and polygenic risk scores (PRS) for schizophrenia; to assess models' geographic generalizability; to test and integrate clinicians' predictions; and to maximize clinical utility by building a sequential prognostic system. Design, Setting, and Participants: This multisite, longitudinal prognostic study performed in 7 academic early recognition services in 5 European countries followed up patients with CHR syndromes or ROD and healthy volunteers. The referred sample of 167 patients with CHR syndromes and 167 with ROD was recruited from February 1, 2014, to May 31, 2017, of whom 26 (23 with CHR syndromes and 3 with ROD) developed psychosis. Patients with 18-month follow-up (n = 246) were used for model training and leave-one-site-out cross-validation. The remaining 88 patients with nontransition served as the validation of model specificity. Three hundred thirty-four healthy volunteers provided a normative sample for prognostic signature evaluation. Three independent Swiss projects contributed a further 45 cases with psychosis transition and 600 with nontransition for the external validation of clinical-neurocognitive, sMRI-based, and combined models. Data were analyzed from January 1, 2019, to March 31, 2020. Main Outcomes and Measures: Accuracy and generalizability of prognostic systems. Results: A total of 668 individuals (334 patients and 334 controls) were included in the analysis (mean [SD] age, 25.1 [5.8] years; 354 [53.0%] female and 314 [47.0%] male). Clinicians attained a balanced accuracy of 73.2% by effectively ruling out (specificity, 84.9%) but ineffectively ruling in (sensitivity, 61.5%) psychosis transition. In contrast, algorithms showed high sensitivity (76.0%-88.0%) but low specificity (53.5%-66.8%). A cybernetic risk calculator combining all algorithmic and human components predicted psychosis with a balanced accuracy of 85.5% (sensitivity, 84.6%; specificity, 86.4%). In comparison, an optimal prognostic workflow produced a balanced accuracy of 85.9% (sensitivity, 84.6%; specificity, 87.3%) at a much lower diagnostic burden by sequentially integrating clinical-neurocognitive, expert-based, PRS-based, and sMRI-based risk estimates as needed for the given patient. Findings were supported by good external validation results. Conclusions and Relevance: These findings suggest that psychosis transition can be predicted in a broader risk spectrum by sequentially integrating algorithms' and clinicians' risk estimates. For clinical translation, the proposed workflow should undergo large-scale international validation.
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    S166. EFFECTIVE CONNECTIVITY OF FRONTOSTRIATAL SYSTEMS IN FIRST-EPISODE PSYCHOSIS
    Sabaroedin, K ; Razi, A ; Aquino, K ; Chopra, S ; Finlay, A ; Nelson, B ; Allott, K ; Alvarez-Jimenez, M ; Graham, J ; Baldwin, L ; Tahtalian, S ; Yuen, HP ; Harrigan, S ; Cropley, V ; Pantelis, C ; Wood, S ; O’Donoghue, B ; Francey, S ; McGorry, P ; Fornito, A (Oxford University Press (OUP), 2020-05-18)
    Abstract Background Neuroimaging studies have found dysconnectivity of frontostriatal circuits across a broad spectrum of psychotic symptoms. However, it is unknown whether dysconnectivity within frontostriatal circuits originates from disrupted bottom-up or top-down control signaling within these systems. Here, we used dynamic causal modelling (DCM) to examine the effective connectivity of frontostriatal systems in first-episode psychosis (FEP). Methods A total of 55 FEP patients (26 males; mean [SD] age = 19.24 [2.89]) and 24 healthy controls (15 males; mean [SD] age = 21.83 [1.93]) underwent a resting-state functional magnetic resonance imaging protocol. Biologically plausible connections between eight left hemisphere regions encompassing the dorsal and ventral frontostriatal systems were modelled using spectral DCM. The regions comprise dorsolateral prefrontal cortex, ventromedial prefrontal cortex, anterior hippocampus, amygdala, dorsal caudate, nucleus accumbens, thalamus, and the midbrain. Effective connectivity between groups were assessed using a parametric Bayesian model. Associations between effective connectivity parameters and positive symptoms, measured by the Brief Psychiatric Rating Scale positive subscale, was assessed in the patient group in a separate Bayesian general linear model. Results DCM shows evidence for differences in effective connectivity between patients and healthy controls, namely in the bottom-down connections distributed in the frontostriatal system encompassing the hippocampus, amygdala, striatum, and midbrain. Compared to healthy controls, patients also demonstrated increased disinhibition of the midbrain. In patients, positive symptoms are associated with increased top-down connections to the midbrain. Outgoing connection from the midbrain to the nucleus accumbens is also increased in association with positive symptoms. Discussion Aberrant top-down connectivity in the frontostriatal system in patients is consistent with top-down dysregulation of dopamine function in FEP, as dopaminergic activity in the midbrain is proposed to be under the control of higher brain areas. In patients, increased self-inhibition of the midbrain, as well as symptom associations in both ingoing and outgoing connections of this region, are congruous with hyperactivity of the midbrain as proposed by the dopamine dysregulation hypothesis. Here, we demonstrate that mathematical models of brain imaging signals can be used to identify the key disruptions driving brain circuit dysfunction, identifying new targets for treatment.
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    S94. PREDICTION OF CANNABIS RELAPSE IN CLINICAL HIGH-RISK INDIVIDUALS AND RECENT ONSET PSYCHOSIS - PRELIMINARY RESULTS FROM THE PRONIA STUDY
    Penzel, N ; Sanfelici, R ; Betz, L ; Antonucci, L ; Falkai, P ; Upthegrove, R ; Bertolino, A ; Borgwardt, S ; Brambilla, P ; Lencer, R ; Meisenzahl, E ; Ruhrmann, S ; Salokangas, RKR ; Pantelis, C ; Schultze-Lutter, F ; Wood, S ; Koutsouleris, N ; Kambeitz, J (Oxford University Press (OUP), 2020-05-18)
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    O2.3. ABNORMAL BRAIN AGING IN YOUTH WITH SUBCLINICAL PSYCHOSIS AND OBSESSIVE-COMPULSIVE SYMPTOMS
    Cropley, V ; Tian, Y ; Fernando, K ; Mansour, S ; Pantelis, C ; Cocchi, L ; Zalesky, A (Oxford University Press (OUP), 2020-05-18)
    Abstract Background Psychiatric symptoms in childhood and adolescence have been associated with both delayed and accelerated patterns of grey matter development. This suggests that deviation in brain structure from a normative range of variation for a given age might be important in the emergence of psychopathology. Distinct from chronological age, brain age refers to the age of an individual that is inferred from a normative model of brain structure for individuals of the same age and sex. We predicted brain age from a common set of grey matter features and examined whether the difference between an individual’s chronological and brain age was associated with the severity of psychopathology in children and adolescents. Methods Participants included 1313 youths (49.8% male) aged 8–21 who underwent structural imaging as part of the Philadelphia Neurodevelopmental Cohort. Independent Component Analysis was used to obtain 7 psychopathology dimensions representing Conduct, Anxiety, Obsessive-Compulsive, Attention, Depression, Bipolar, and Psychosis symptoms and an overall measure of severity (General Psychopathology). Using 10-fold cross-validation, support vector machine regression was trained in 402 typically developing youth to predict individual age based on a feature space comprising 111 grey matter regions. This yielded a brain age prediction for each individual. Brain age gap was calculated for each individual by subtracting chronological age from predicted brain age. The general linear model was used to test for an association between brain age gap and each of the 8 dimensions of psychopathology in a test sample of 911 youth. The regional specificity and spatial pattern of brain age gap was also investigated. Error control across the 8 models was achieved with a false discovery rate of 5%. Results Brain age gap was significantly associated with dimensions characterizing obsessive-compulsive (t=2.5, p=0.01), psychosis (t=3.16, p=0.0016) and general psychopathology (t=4.08, p<0.0001). For all three dimensions, brain age gap was positively associated with symptom severity, indicating that individuals with a brain that was predicted to be ‘older’ than expectations set by youth of the same chronological age and sex tended to have higher symptom scores. Findings were confirmed with a categorical approach, whereby higher brain age gap was observed in youth with a lifetime endorsement of psychosis (t=2.35, p=0.02) and obsessive-compulsive (t=2.35, p=0.021) symptoms, in comparison to typically developing individuals. Supplementary analyses revealed that frontal grey matter was the most important feature mediating the association between brain age gap and psychosis symptoms, whereas subcortical volumes were most important for the association between brain age gap and obsessive-compulsive and general symptoms. Discussion We found that the brain was ‘older’ in youth experiencing higher subclinical symptoms of psychosis, obsession-compulsion, and general psychopathology, compared to normally developing youth of the same chronological age. Our results suggest that deviations in normative brain age patterns in youth may contribute to the manifestation of specific psychiatric symptoms of subclinical severity that cut across psychopathology dimensions.
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    S12. A MACHINE LEARNING FRAMEWORK FOR ROBUST AND RELIABLE PREDICTION OF SHORT- AND LONG-TERM CLINICAL RESPONSE IN INITIALLY ANTIPSYCHOTIC-NAïVE SCHIZOPHRENIA PATIENTS BASED ON MULTIMODAL NEUROPSYCHIATRIC DATA
    Ambrosen, KS ; Skjerbæk, MW ; Foldager, J ; Axelsen, MC ; Bak, N ; Arvastson, L ; Christensen, SR ; Johansen, LB ; Raghava, JM ; Oranje, B ; Rostrup, E ; Nielsen, MØ ; Osler, M ; Fagerlund, B ; Pantelis, C ; Kinon, BJ ; Glenthøj, BY ; Hansen, LK ; Ebdrup, BH (Oxford University Press (OUP), 2020-05-18)
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    T223. MULTIVARIATE PREDICTION OF FOLLOW UP SOCIAL AND OCCUPATIONAL OUTCOME IN CLINICAL HIGH-RISK INDIVIDUALS BASED ON GRAY MATTER VOLUMES AND HISTORY OF ENVIRONMENTAL ADVERSE EVENTS
    Antonucci, L ; Pigoni, A ; Sanfelici, R ; Kambeitz-Ilankovic, L ; Dwyer, D ; Ruef, A ; Chisholm, K ; Haidl, T ; Rosen, M ; Kambeitz, J ; Ruhrmann, S ; Schultze-Lutter, F ; Falkai, P ; Lencer, R ; Dannlowski, U ; Upthegrove, R ; Salokangas, R ; Pantelis, C ; Meisenzahl, E ; Wood, S ; Brambilla, P ; Borgwardt, S ; Bertolino, A ; Koutsouleris, N (Oxford University Press (OUP), 2020-05-18)
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    T162. THICKER PREFRONTAL CORTEX IS ASSOCIATED WITH SUBCLINICAL NEGATIVE SYMPTOMS IN SCHIZOTYPY - AN ENIGMA CONSORTIUM META-ANALYSIS
    Kirschner, M ; Hodzic-Santor, B ; Kircher, T ; Nenadic, I ; Fornito, A ; Green, M ; Quide, Y ; Pantelis, C ; Dannlowski, U ; DeRosse, P ; Chan, R ; Debbané, M ; Rössler, W ; Lebedeva, I ; Park, H ; Marsman, J-B ; Gilleen, J ; Fett, A-K ; van Erp, T ; Turner, J ; Thompson, P ; Aleman, A ; Modinos, G ; Kaiser, S (Oxford University Press (OUP), 2020-05-18)
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    T60. GENETIC INFLUENCES ON MEMORY FUNCTIONS AND RELATED BRAIN STRUCTURES AND ASSOCIATIONS WITH SCHIZOPHRENIA SPECTRUM DISORDERS: A NATION-WIDE TWIN STUDY
    Lemvigh, C ; Brouwer, R ; Baruel Johansen, L ; Hilker, R ; Pantelis, C ; Glenthoj, B ; Fagerlund, B (Oxford University Press (OUP), 2020-05-18)