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Abstract
Psychopathology is rooted in neurodevelopment. However, clinical and biological heterogeneity, together with a focus on case-control approaches, have made it difficult to link dimensions of psychopathology to abnormalities of neurodevelopment. Here, using the Philadelphia Neurodevelopmental Cohort, we built normative models of cortical volume and tested whether deviations from these models better predicted psychiatric symptoms compared to raw cortical volume. Specifically, drawing on the p-factor hypothesis, we distilled 117 clinical symptom measures into six orthogonal psychopathology dimensions: overall psychopathology, anxious-misery, externalizing disorders, fear, positive psychosis symptoms, and negative psychosis symptoms. We found that multivariate patterns of deviations yielded improved out-of-sample prediction of psychopathology dimensions compared to multivariate patterns of raw cortical volume. We also found that correlations between overall psychopathology and deviations in ventromedial prefrontal, inferior temporal, and dorsal anterior cingulate cortices were stronger than those observed for specific dimensions of psychopathology (e.g., anxious-misery). Notably, these same regions are consistently implicated in a range of putatively distinct disorders. Finally, we performed conventional case-control comparisons of deviations in a group of individuals with depression and a group with attention-deficit hyperactivity disorder (ADHD). We observed spatially overlapping effects between these groups that diminished when controlling for overall psychopathology. Together, our results suggest that modeling cortical brain features as deviations from normative neurodevelopment improves prediction of psychiatric symptoms in out-of-sample testing, and that p-factor models of psychopathology may assist in separating biomarkers that are disorder-general from those that are disorder-specific.
Highlights
Throughout childhood, adolescence, and young adulthood, the brain undergoes major structural changes that facilitate the emergence of complex behavior and cognition[1,2]
In partial support of hypothesis 1, our results demonstrate that modeling deviations from normative neurodevelopment provided better out-ofsample prediction of overall psychopathology, psychosispositive, and fear compared to using raw cortical volume
At the regional level, we demonstrated that overall psychopathology correlated with greater negative deviations in vmPFC/mOFC, inferior temporal, daCC, and insular cortices—all regions previously implicated in case-control literature across a broad spectrum of disorders35–40—and that these correlations were, in some cases, significantly larger than those observed for the psychosis-negative, anxious-misery, and externalizing dimensions
Summary
Throughout childhood, adolescence, and young adulthood, the brain undergoes major structural changes that facilitate the emergence of complex behavior and cognition[1,2]. Mental disorders often surface during this period[3] and are increasingly understood as resulting from. Linking abnormalities in neurodevelopment to psychopathology has been limited by several challenges. Diagnostic nosologies assign individuals with distinct symptom profiles to the same clinical diagnosis, yielding disorder groups with highly heterogenous clinical presentation[6]. Parkes et al Translational Psychiatry (2021)11:232 literature has adopted case-control designs that reveal only abnormalities associated with the ‘average’ patient, ignoring the dimensional nature of psychopathology[10]. Research linking individuals’ neurodevelopmental alterations with distinct dimensions of psychopathology relevant to multiple disorders is a critical step toward developing diagnostic biomarkers for mental health[11,12,13,14,15]
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