P3-related brain components and the externalizing spectrum disorders.

Abstract

Objective: This dissertation explored the neurophysiological correlates of lifetime externalizing (EXT) spectrum disorders in two studies using a community-based sample of 29-year-old adult men assessed longitudinally. The first study used high-density EEG brain data to test the hypothesis that reductions in time-domain and time-frequency component measures previously identified in 17-year-old youth with EXT continue to be present in adults at age 29 when participants have largely passed through the age of heaviest substance misuse, and when brain development is further complete. The second study tested the notion that reductions on these brain measures could serve as endophenotypes (or inherited biomarkers) for EXT risk by investigating the developmental stability of these associations across a 12-year span. We further uniquely tested whether significant reduction in time-domain P3 amplitude could be used to predict the eventual diagnosis of an externalizing disorder over a decade later. Method: In both studies, EEG data were obtained using a visual oddball task. Participants were assessed from age-17 through age-29 for the lifetime presence of EXT disorders. The first study used data from 378 male twin participants from the original 17-year-old cohort of the Minnesota Twin Family Study (MTFS) who had high-density EEG data that allowed for regional scalp analyses, including data from the frontal region that was not available before. The second study included the same 29-year-old males who had EEG data collected from a midline parietal site (site-Pz) at both their age-17 and age-29 assessments (n = 325). All comparisons were made against controls free of any EXT diagnosis by age 29. Results: The hypothesis tested in the first study was supported with both time-domain and time-frequency components coinciding with P3 activity significantly reduced across all EXT groups, particularly at the posterior regions. Furthermore, a theta time-frequency component yielded frontal discriminations that were not apparent in the time-domain. Hypotheses from the second study were also confirmed with group results demonstrating reductions in these brain measures across all EXT groups with comparable effects observed at both age-17 and age-29. Finally, P3 amplitude at age-17 was predictive of EXT status by age-29 with every one-microvolt decrease in P3 amplitude associated with an approximately 5% increase in risk for an age-29 EXT diagnosis. In both studies, the effects of acute and cumulative substance exposure on the various brain measures were insignificant. Conclusions: Despite brain changes associated with normative development and potential substance exposure related to EXT symptomatology, both time-domain and time-frequency measures associated with P3 activity continue to provide effective, stable and predictive brain markers related to a wide spectrum of EXT psychopathology. These findings offer further support for the notion that P3-related measures constitute endophenotypes that tap into a neural substrate underlying behavioral disinhibition.