Psychiatry - Research Publications

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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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    Heterogeneous aging across multiple organ systems and prediction of chronic disease and mortality
    Tian, YE ; Cropley, V ; Maier, AB ; Lautenschlager, NT ; Breakspear, M ; Zalesky, A (NATURE PORTFOLIO, 2023-05)
    Biological aging of human organ systems reflects the interplay of age, chronic disease, lifestyle and genetic risk. Using longitudinal brain imaging and physiological phenotypes from the UK Biobank, we establish normative models of biological age for three brain and seven body systems. Here we find that an organ's biological age selectively influences the aging of other organ systems, revealing a multiorgan aging network. We report organ age profiles for 16 chronic diseases, where advanced biological aging extends from the organ of primary disease to multiple systems. Advanced body age associates with several lifestyle and environmental factors, leukocyte telomere lengths and mortality risk, and predicts survival time (area under the curve of 0.77) and premature death (area under the curve of 0.86). Our work reveals the multisystem nature of human aging in health and chronic disease. It may enable early identification of individuals at increased risk of aging-related morbidity and inform new strategies to potentially limit organ-specific aging in such individuals.
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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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    Evaluation of Brain-Body Health in Individuals With Common Neuropsychiatric Disorders
    Tian, YE ; Di Biase, MA ; Mosley, PE ; Lupton, MK ; Xia, Y ; Fripp, J ; Breakspear, M ; Cropley, V ; Zalesky, A (AMER MEDICAL ASSOC, 2023-06)
    IMPORTANCE: Physical health and chronic medical comorbidities are underestimated, inadequately treated, and often overlooked in psychiatry. A multiorgan, systemwide characterization of brain and body health in neuropsychiatric disorders may enable systematic evaluation of brain-body health status in patients and potentially identify new therapeutic targets. OBJECTIVE: To evaluate the health status of the brain and 7 body systems across common neuropsychiatric disorders. DESIGN, SETTING, AND PARTICIPANTS: Brain imaging phenotypes, physiological measures, and blood- and urine-based markers were harmonized across multiple population-based neuroimaging biobanks in the US, UK, and Australia, including UK Biobank; Australian Schizophrenia Research Bank; Australian Imaging, Biomarkers, and Lifestyle Flagship Study of Ageing; Alzheimer's Disease Neuroimaging Initiative; Prospective Imaging Study of Ageing; Human Connectome Project-Young Adult; and Human Connectome Project-Aging. Cross-sectional data acquired between March 2006 and December 2020 were used to study organ health. Data were analyzed from October 18, 2021, to July 21, 2022. Adults aged 18 to 95 years with a lifetime diagnosis of 1 or more common neuropsychiatric disorders, including schizophrenia, bipolar disorder, depression, generalized anxiety disorder, and a healthy comparison group were included. MAIN OUTCOMES AND MEASURES: Deviations from normative reference ranges for composite health scores indexing the health and function of the brain and 7 body systems. Secondary outcomes included accuracy of classifying diagnoses (disease vs control) and differentiating between diagnoses (disease vs disease), measured using the area under the receiver operating characteristic curve (AUC). RESULTS: There were 85 748 participants with preselected neuropsychiatric disorders (36 324 male) and 87 420 healthy control individuals (40 560 male) included in this study. Body health, especially scores indexing metabolic, hepatic, and immune health, deviated from normative reference ranges for all 4 neuropsychiatric disorders studied. Poor body health was a more pronounced illness manifestation compared to brain changes in schizophrenia (AUC for body = 0.81 [95% CI, 0.79-0.82]; AUC for brain = 0.79 [95% CI, 0.79-0.79]), bipolar disorder (AUC for body = 0.67 [95% CI, 0.67-0.68]; AUC for brain = 0.58 [95% CI, 0.57-0.58]), depression (AUC for body = 0.67 [95% CI, 0.67-0.68]; AUC for brain = 0.58 [95% CI, 0.58-0.58]), and anxiety (AUC for body = 0.63 [95% CI, 0.63-0.63]; AUC for brain = 0.57 [95% CI, 0.57-0.58]). However, brain health enabled more accurate differentiation between distinct neuropsychiatric diagnoses than body health (schizophrenia-other: mean AUC for body = 0.70 [95% CI, 0.70-0.71] and mean AUC for brain = 0.79 [95% CI, 0.79-0.80]; bipolar disorder-other: mean AUC for body = 0.60 [95% CI, 0.59-0.60] and mean AUC for brain = 0.65 [95% CI, 0.65-0.65]; depression-other: mean AUC for body = 0.61 [95% CI, 0.60-0.63] and mean AUC for brain = 0.65 [95% CI, 0.65-0.66]; anxiety-other: mean AUC for body = 0.63 [95% CI, 0.62-0.63] and mean AUC for brain = 0.66 [95% CI, 0.65-0.66). CONCLUSIONS AND RELEVANCE: In this cross-sectional study, neuropsychiatric disorders shared a substantial and largely overlapping imprint of poor body health. Routinely monitoring body health and integrated physical and mental health care may help reduce the adverse effect of physical comorbidity in people with mental illness.
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    Brain charts for the human lifespan (vol 604, pg 525, 2022)
    Bethlehem, RAI ; Seidlitz, J ; White, SR ; Vogel, JW ; Anderson, KM ; Adamson, C ; Adler, S ; Alexopoulos, GS ; Anagnostou, E ; Areces-Gonzalez, A ; Astle, DE ; Auyeung, B ; Ayub, M ; Bae, J ; Ball, G ; Baron-Cohen, S ; Beare, R ; Bedford, SA ; Benegal, V ; Beyer, F ; Blangero, J ; Blesa Cabez, M ; Boardman, JP ; Borzage, M ; Bosch-Bayard, JF ; Bourke, N ; Calhoun, VD ; Chakravarty, MM ; Chen, C ; Chertavian, C ; Chetelat, G ; Chong, YS ; Cole, JH ; Corvin, A ; Costantino, M ; Courchesne, E ; Crivello, F ; Cropley, VL ; Crosbie, J ; Crossley, N ; Delarue, M ; Delorme, R ; Desrivieres, S ; Devenyi, GA ; Di Biase, MA ; Dolan, R ; Donald, KA ; Donohoe, G ; Dunlop, K ; Edwards, AD ; Elison, JT ; Ellis, CT ; Elman, JA ; Eyler, L ; Fair, DA ; Feczko, E ; Fletcher, PC ; Fonagy, P ; Franz, CE ; Galan-Garcia, L ; Gholipour, A ; Giedd, J ; Gilmore, JH ; Glahn, DC ; Goodyer, IM ; Grant, PE ; Groenewold, NA ; Gunning, FM ; Gur, RE ; Gur, RC ; Hammill, CF ; Hansson, O ; Hedden, T ; Heinz, A ; Henson, RN ; Heuer, K ; Hoare, J ; Holla, B ; Holmes, AJ ; Holt, R ; Huang, H ; Im, K ; Ipser, J ; Jack, CR ; Jackowski, AP ; Jia, T ; Johnson, KA ; Jones, PB ; Jones, DT ; Kahn, RS ; Karlsson, H ; Karlsson, L ; Kawashima, R ; Kelley, EA ; Kern, S ; Kim, KW ; Kitzbichler, MG ; Kremen, WS ; Lalonde, F ; Landeau, B ; Lee, S ; Lerch, J ; Lewis, JD ; Li, J ; Liao, W ; Liston, C ; Lombardo, MV ; Lv, J ; Lynch, C ; Mallard, TT ; Marcelis, M ; Markello, RD ; Mathias, SR ; Mazoyer, B ; McGuire, P ; Meaney, MJ ; Mechelli, A ; Medic, N ; Misic, B ; Morgan, SE ; Mothersill, D ; Nigg, J ; Ong, MQW ; Ortinau, C ; Ossenkoppele, R ; Ouyang, M ; Palaniyappan, L ; Paly, L ; Pan, PM ; Pantelis, C ; Park, MM ; Paus, T ; Pausova, Z ; Paz-Linares, D ; Pichet Binette, A ; Pierce, K ; Qian, X ; Qiu, J ; Qiu, A ; Raznahan, A ; Rittman, T ; Rodrigue, A ; Rollins, CK ; Romero-Garcia, R ; Ronan, L ; Rosenberg, MD ; Rowitch, DH ; Salum, GA ; Satterthwaite, TD ; Schaare, HL ; Schachar, RJ ; Schultz, AP ; Schumann, G ; Scholl, M ; Sharp, D ; Shinohara, RT ; Skoog, I ; Smyser, CD ; Sperling, RA ; Stein, DJ ; Stolicyn, A ; Suckling, J ; Sullivan, G ; Taki, Y ; Thyreau, B ; Toro, R ; Traut, N ; Tsvetanov, KA ; Turk-Browne, NB ; Tuulari, JJ ; Tzourio, C ; Vachon-Presseau, E ; Valdes-Sosa, MJ ; Valdes-Sosa, PA ; Valk, SL ; van Amelsvoort, T ; Vandekar, SN ; Vasung, L ; Victoria, LW ; Villeneuve, S ; Villringer, A ; Vertes, PE ; Wagstyl, K ; Wang, YS ; Warfield, SK ; Warrier, V ; Westman, E ; Westwater, ML ; Whalley, HC ; Witte, AV ; Yang, N ; Yeo, B ; Yun, H ; Zalesky, A ; Zar, HJ ; Zettergren, A ; Zhou, JH ; Ziauddeen, H ; Zugman, A ; Zuo, XN ; Bullmore, ET ; Alexander-Bloch, AF (NATURE PORTFOLIO, 2022-10-13)
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    Brain charts for the human lifespan
    Bethlehem, RAI ; Seidlitz, J ; White, SR ; Vogel, JW ; Anderson, KM ; Adamson, C ; Adler, S ; Alexopoulos, GS ; Anagnostou, E ; Areces-Gonzalez, A ; Astle, DE ; Auyeung, B ; Ayub, M ; Bae, J ; Ball, G ; Baron-Cohen, S ; Beare, R ; Bedford, SA ; Benegal, V ; Beyer, F ; Blangero, J ; Blesa Cabez, M ; Boardman, JP ; Borzage, M ; Bosch-Bayard, JF ; Bourke, N ; Calhoun, VD ; Chakravarty, MM ; Chen, C ; Chertavian, C ; Chetelat, G ; Chong, YS ; Cole, JH ; Corvin, A ; Costantino, M ; Courchesne, E ; Crivello, F ; Cropley, VL ; Crosbie, J ; Crossley, N ; Delarue, M ; Delorme, R ; Desrivieres, S ; Devenyi, GA ; Di Biase, MA ; Dolan, R ; Donald, KA ; Donohoe, G ; Dunlop, K ; Edwards, AD ; Elison, JT ; Ellis, CT ; Elman, JA ; Eyler, L ; Fair, DA ; Feczko, E ; Fletcher, PC ; Fonagy, P ; Franz, CE ; Galan-Garcia, L ; Gholipour, A ; Giedd, J ; Gilmore, JH ; Glahn, DC ; Goodyer, IM ; Grant, PE ; Groenewold, NA ; Gunning, FM ; Gur, RE ; Gur, RC ; Hammill, CF ; Hansson, O ; Hedden, T ; Heinz, A ; Henson, RN ; Heuer, K ; Hoare, J ; Holla, B ; Holmes, AJ ; Holt, R ; Huang, H ; Im, K ; Ipser, J ; Jack, CR ; Jackowski, AP ; Jia, T ; Johnson, KA ; Jones, PB ; Jones, DT ; Kahn, RS ; Karlsson, H ; Karlsson, L ; Kawashima, R ; Kelley, EA ; Kern, S ; Kim, KW ; Kitzbichler, MG ; Kremen, WS ; Lalonde, F ; Landeau, B ; Lee, S ; Lerch, J ; Lewis, JD ; Li, J ; Liao, W ; Liston, C ; Lombardo, MV ; Lv, J ; Lynch, C ; Mallard, TT ; Marcelis, M ; Markello, RD ; Mathias, SR ; Mazoyer, B ; McGuire, P ; Meaney, MJ ; Mechelli, A ; Medic, N ; Misic, B ; Morgan, SE ; Mothersill, D ; Nigg, J ; Ong, MQW ; Ortinau, C ; Ossenkoppele, R ; Ouyang, M ; Palaniyappan, L ; Paly, L ; Pan, PM ; Pantelis, C ; Park, MM ; Paus, T ; Pausova, Z ; Paz-Linares, D ; Pichet Binette, A ; Pierce, K ; Qian, X ; Qiu, J ; Qiu, A ; Raznahan, A ; Rittman, T ; Rodrigue, A ; Rollins, CK ; Romero-Garcia, R ; Ronan, L ; Rosenberg, MD ; Rowitch, DH ; Salum, GA ; Satterthwaite, TD ; Schaare, HL ; Schachar, RJ ; Schultz, AP ; Schumann, G ; Scholl, M ; Sharp, D ; Shinohara, RT ; Skoog, I ; Smyser, CD ; Sperling, RA ; Stein, DJ ; Stolicyn, A ; Suckling, J ; Sullivan, G ; Taki, Y ; Thyreau, B ; Toro, R ; Traut, N ; Tsvetanov, KA ; Turk-Browne, NB ; Tuulari, JJ ; Tzourio, C ; Vachon-Presseau, E ; Valdes-Sosa, MJ ; Valdes-Sosa, PA ; Valk, SL ; van Amelsvoort, T ; Vandekar, SN ; Vasung, L ; Victoria, LW ; Villeneuve, S ; Villringer, A ; Vertes, PE ; Wagstyl, K ; Wang, YS ; Warfield, SK ; Warrier, V ; Westman, E ; Westwater, ML ; Whalley, HC ; Witte, AV ; Yang, N ; Yeo, B ; Yun, H ; Zalesky, A ; Zar, HJ ; Zettergren, A ; Zhou, JH ; Ziauddeen, H ; Zugman, A ; Zuo, XN ; Bullmore, ET ; Alexander-Bloch, AF (NATURE PORTFOLIO, 2022-04-21)
    Over the past few decades, neuroimaging has become a ubiquitous tool in basic research and clinical studies of the human brain. However, no reference standards currently exist to quantify individual differences in neuroimaging metrics over time, in contrast to growth charts for anthropometric traits such as height and weight1. Here we assemble an interactive open resource to benchmark brain morphology derived from any current or future sample of MRI data ( http://www.brainchart.io/ ). With the goal of basing these reference charts on the largest and most inclusive dataset available, acknowledging limitations due to known biases of MRI studies relative to the diversity of the global population, we aggregated 123,984 MRI scans, across more than 100 primary studies, from 101,457 human participants between 115 days post-conception to 100 years of age. MRI metrics were quantified by centile scores, relative to non-linear trajectories2 of brain structural changes, and rates of change, over the lifespan. Brain charts identified previously unreported neurodevelopmental milestones3, showed high stability of individuals across longitudinal assessments, and demonstrated robustness to technical and methodological differences between primary studies. Centile scores showed increased heritability compared with non-centiled MRI phenotypes, and provided a standardized measure of atypical brain structure that revealed patterns of neuroanatomical variation across neurological and psychiatric disorders. In summary, brain charts are an essential step towards robust quantification of individual variation benchmarked to normative trajectories in multiple, commonly used neuroimaging phenotypes.
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    High-resolution connectomic fingerprints: Mapping neural identity and behavior
    Mansour, SL ; Tian, Y ; Yeo, BTT ; Cropley, V ; Zalesky, A (ACADEMIC PRESS INC ELSEVIER SCIENCE, 2021-04-01)
    Connectomes are typically mapped at low resolution based on a specific brain parcellation atlas. Here, we investigate high-resolution connectomes independent of any atlas, propose new methodologies to facilitate their mapping and demonstrate their utility in predicting behavior and identifying individuals. Using structural, functional and diffusion-weighted MRI acquired in 1000 healthy adults, we aimed to map the cortical correlates of identity and behavior at ultra-high spatial resolution. Using methods based on sparse matrix representations, we propose a computationally feasible high-resolution connectomic approach that improves neural fingerprinting and behavior prediction. Using this high-resolution approach, we find that the multimodal cortical gradients of individual uniqueness reside in the association cortices. Furthermore, our analyses identified a striking dichotomy between the facets of a person's neural identity that best predict their behavior and cognition, compared to those that best differentiate them from other individuals. Functional connectivity was one of the most accurate predictors of behavior, yet resided among the weakest differentiators of identity; whereas the converse was found for morphological properties, such as cortical curvature. This study provides new insights into the neural basis of personal identity and new tools to facilitate ultra-high-resolution connectomics.
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    White Matter Alterations Between Brain Network Hubs Underlie Processing Speed Impairment in Patients With Schizophrenia.
    Klauser, P ; Cropley, VL ; Baumann, PS ; Lv, J ; Steullet, P ; Dwir, D ; Alemán-Gómez, Y ; Bach Cuadra, M ; Cuenod, M ; Do, KQ ; Conus, P ; Pantelis, C ; Fornito, A ; Van Rheenen, TE ; Zalesky, A (Oxford University Press (OUP), 2021-01)
    Processing speed (PS) impairment is one of the most severe and common cognitive deficits in schizophrenia. Previous studies have reported correlations between PS and white matter diffusion properties, including fractional anisotropy (FA), in several fiber bundles in schizophrenia, suggesting that white matter alterations could underpin decreased PS. In schizophrenia, white matter alterations are most prevalent within inter-hub connections of the rich club. However, the spatial and topological characteristics of this association between PS and FA have not been investigated in patients. In this context, we tested whether structural connections comprising the rich club network would underlie PS impairment in 298 patients with schizophrenia or schizoaffective disorder and 190 healthy controls from the Australian Schizophrenia Research Bank. PS, measured using the digit symbol coding task, was largely (Cohen's d = 1.33) and significantly (P < .001) reduced in the patient group when compared with healthy controls. Significant associations between PS and FA were widespread in the patient group, involving all cerebral lobes. FA was not associated with other cognitive measures of phonological fluency and verbal working memory in patients, suggesting specificity to PS. A topological analysis revealed that despite being spatially widespread, associations between PS and FA were over-represented among connections forming the rich club network. These findings highlight the need to consider brain network topology when investigating high-order cognitive functions that may be spatially distributed among several brain regions. They also reinforce the evidence that brain hubs and their interconnections may be particularly vulnerable parts of the brain in schizophrenia.
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    Neighborhood disadvantage and longitudinal brain-predicted-age trajectory during adolescence
    Rakesh, D ; Cropley, V ; Zalesky, A ; Vijayakumar, N ; Allen, NB ; Whittle, S (ELSEVIER SCI LTD, 2021-10)
    Neighborhood disadvantage has consistently been linked to alterations in brain structure; however, positive environmental (e.g., positive parenting) and psychological factors (e.g., temperament) may buffer these effects. We aimed to investigate associations between neighborhood disadvantage and deviations from typical neurodevelopmental trajectories during adolescence, and examine the moderating role of positive parenting and temperamental effortful control (EC). Using a large dataset (n = 1313), a normative model of brain morphology was established, which was then used to predict the age of youth from a longitudinal dataset (n = 166, three time-points at age 12, 16, and 19). Using linear mixed models, we investigated whether trajectories of the difference between brain-predicted-age and chronological age (brainAGE) were associated with neighborhood disadvantage, and whether positive parenting (positive behavior during a problem-solving task) and EC moderated these associations. We found that neighborhood disadvantage was associated with positive brainAGE during early adolescence and a deceleration (decreasing brainAGE) thereafter. EC moderated this association such that in disadvantaged adolescents, low EC was associated with delayed development (negative brainAGE) during late adolescence. Findings provide evidence for complex associations between environmental and psychological factors, and brain maturation. They suggest that neighborhood disadvantage may have long-term effects on neurodevelopment during adolescence, but high EC could buffer these effects.
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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&lt;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.