Project 2

Mapping Cortical Circuit Maturation in High Risk Adolescents

Description

Principal Investigators: Aysenil Belger, PhD and Diana O. Perkins, MD

Executive function and social-affective processing deficits represent cognitive endophenotypes of schizophrenia, as they occur in both individuals with schizophrenia and in those at genetic-high-risk (GHR). The timing of the emergence of neurocognitive deficits, and whether they are anchored to specific mechanisms of cortical development in younger GHR individuals remains to be clarified.  The highest risk period for onset of psychosis is post-puberty, a critical time for the final shaping of neural infrastructure supporting mature executive control and social-affective cognition.  Studies conducted under the initial funding period of the UNC Conte Center found functional and structural abnormalities in fronto-striate-limbic regions, particularly in prefrontal regions were already present in sub-syndromal symptomatic high-risk subjects.  The proposed study will shift its focus to adolescent brain development that occurs prior to the prodrome, and investigate executive control, social-affective processes, and structural changes that accompany peripubertal cortical maturation in GHR individuals.

Our overarching hypothesis is that children and adolescents with genetic risk for schizophrenia show altered cortical activation, organization, and connectivity as compared to age-matched non-genetic risk individuals, reflecting alterations in cortical and synaptic development.  We further hypothesize that neurocognitive deficits will worsen in early adolescence in parallel with post-pubertal cortical development.  We will probe attention and executive and affective processing in fronto-striate-limbic regions in GHR individuals using a multimodal protocol that includes (a) neurocognitive testing (b) functional magnetic resonance imaging (fMRI), (c) electrophysiological recordings (ERPs), and (d) structural and diffusion imaging (sMRI and DTI).  These complementary measures should provide converging evidence of aberrant cortical circuitry and connectivity that develops during early adolescence.  We will cross-sectionally compare 60 GHR and 60 healthy subjects aged 9-18, and then longitudinally evaluate the developmental trajectory of the higher-order neurocognitive functions at 1 year follow-up. The specific aims are as follows:

Specifc Aim 1.  To characterize neurocognitive functioning in GHR children and adolescents.

Hypothesis 1: Measures of executive control, attention, distractibility and affective processing will be significantly more impaired in GHR subjects than in controls, with greatest severity in post-pubertal subjects.

Hypothesis 2: Compared to healthy subjects, GHR individuals will show altered maturational trajectory of attention/executive functions and social-affective processing during puberty.

Specific Aim 2.  To study fronto-striate-limbic circuit function in GHR children and adolescents.

Hypothesis 1: GHR individuals will show significantly altered FMRI activation relative to controls in prefrontal, basal ganglia, and amygdala/hippocampal regions.

Hypothesis 2: GHR individuals will show significantly smaller N2 and P3 ERP amplitudes, indicative of abnormal novelty orientation, attention and affective processes.

Specific Aim 3.  To characterize the structural profile of fronto-striate-limbic regions in GHR

Hypothesis 1: Key fronto-limbic and fronto-striate structures, in particular the medial prefrontal, hippocampal and basal ganglia regions, will show significant structural alterations in GHR individuals.