Linking the Development of Association Cortex Plasticity to Trans-Diagnostic Psychopathology in Youth

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PROJECT SUMMARY Association cortex undergoes protracted development throughout childhood and adolescence. This extended window of association cortex plasticity is understood to enhance executive and socioemotional functioning, whereas experiences that diminish plasticity—such as environmental adversity—confer risk for psychopathology. At present, the biological origins of prolonged association cortex plasticity in humans remain under characterized, precluding a mechanistic understanding of how neurodevelopmental malleability interacts with the environment to foster either resilience or psychiatric vulnerability. Animal studies of cortical plasticity have identified maturational increases in inhibitory neurotransmission and cortical myelination as two key biological regulators of plasticity. As inhibition and myelination increase and the murine cortex transitions from plastic to mature, intrinsic cortical activity transitions from widespread and synchronized (producing high amplitude neural recordings) to suppressed and sparse — producing low amplitude recordings. This development-linked shift in intrinsic activity amplitude thus provides an animal model-informed, functional readout of local circuit plasticity. We recently leveraged this functional marker in humans and found that declines in the amplitude of intrinsic fMRI fluctuations (termed fluctuation amplitude) were coupled to the maturation of cortical myelin and temporally unfolded along a hierarchical, sensorimotor-association cortical axis (Sydnor et al., Nature Neuroscience 2023). Here we will map the normative progression of developmental plasticity from sensory to association cortex and link precocious reductions in association cortex plasticity to transdiagnostic overall psychopathology. Building upon our initial work examining plasticity measures in one cross-sectional dataset, we propose to generalize our findings to two additional cross-sectional datasets (the HCP-Development and the Healthy Brain Network; total n=6,530) and map within-participant change using the ABCD study (n=11,563). These datasets will allow us to comprehensively map the development of our functional measure of plasticity (Aim 1) and link it to both the development of a major plasticity restricting factor (intracortical myelin; Aim 2). Next, we will determine whether lower socioeconomic status (SES) is associated with accelerated closure of plasticity in association cortex (Aim 3), and finally delineate links to trans-diagnostic overall psychopathology (Aim 4). This research program capitalizes upon a highly successful first project period (>60 publications) and robust preliminary data and a highly cohesive team of UPenn investigators with expertise in neurodevelopmental psychopathology and neuroinformatics (Satterthwaite), network science and machine learning (Bassett), imaging statistics (Shinohara), psychometrics (Moore), and developmental psychology (Mackey). Together, this innovative proposal will provide compelling evidence that development of association cortex plasticity is critical for transdiagnostic psychopathology.