7. PROJECT SUMMARY:
Cannabis use (CU) initiated in adolescence is associated with substantial consequences, from cognitive
decline to addiction. While CU may disrupt normal processes of adolescent brain development, relatively little
is known about how adolescent CU disrupts circuits mediating cognitive flexibility (adaptation to changing
rewards and punishments) and intrinsic resting state functional connectivity (RSFC), and impacts reward
motivation (the amount of goal-directed behavior to earn reinforcement). These domains are all understudied
areas relative to adult CU yet advancing knowledge of these processes may explain why adolescent-onset CU
is linked to functional impairments and higher rates of problematic substance use. Dr. Thomas’s long-term
career goal is to become an independent researcher identifying bio-behavioral mechanisms of risks and effects
of adolescent drug use in order to improve identification methods for targeted prevention and treatment. The
central hypothesis to be tested in this 4-year patient-oriented mentored career award is that CU in the context
of adolescent brain development is linked to frontostriatal alterations and impaired cognitive flexibility, reward
motivation, and intrinsic RSFC that will vary as a function of CU exposure. The central methodology is to use
symptom, circuit, and behavioral data in 14-17 year old adolescents who are engaged in CU and also typically-
developing control adolescents (n=40 of each). The career development objectives of this NIDA K23
application are to gain hands-on mentorship in (a) phenomenology and assessment of adolescent CU, (b) the
use of fMRI to measure brain/behavior alterations underlying adolescent CU, and (c) advanced statistical
methods for greater level of inference from these data, by learning a computational psychiatry model. The
research objectives of this K23 are to: (1) to identify the brain/behavior mechanisms of cognitive flexibility and
RSFC associated with CU using fMRI; (2) to define behavioral alterations in reward motivation; (3) to use
advanced statistical methods, including a specific computational model, to integrate the neural and behavioral
contributions to decision-making during a cognitive flexibility task and determine how decision-making
components vary for CU adolescents and control adolescents. Brown University is a rich scientific environment
to conduct this research due to the expertise of mentors in adolescent substance use, neuroscience, and
advanced statistical methods with ample resources to carry out Dr. Thomas’s training plan consisting of hands-
on mentorship, workshops, coursework (e.g., neuroanatomy), and professional development (conference
presentations, publications). This project is significant because addressing the dearth of knowledge about
cognitive flexibility, reward motivation, and RSFC is the first step towards facilitating mechanism-based (a)
predictors of progression from regular CU to addiction, and (b) treatments for CU among adolescents. This
project is innovative in its use of fMRI to probe the relatively understudied domains of cognitive flexibility and
reward motivation among adolescents with and without CU using computational psychiatry analyses.
