Neurocircuitry Underlying Deep Brain Stimulation for OCD: A Window into Mechanisms of Action

Overview:

Obsessive Compulsive Disorder (OCD) is a chronic psychiatric illness that affects 2-3% of the worldwide population. OCD is characterized by persistent, intrusive thoughts and impulses (obsessions), and repetitive intentional behaviors (compulsions). These behaviors, often driven by fear and unrealistic beliefs about potential danger, lead to excessive avoidance. In normal behavior, there is a balance between avoidance and approach behaviors. Indeed, avoiding an aversive outcome can be considered rewarding. A driving hypothesis of this Center is that OCD symptoms are, in part, due to impairment with the normal balance between avoidance and reward-seeking. The neural network that underlies avoidance behaviors, including specific regions of the prefrontal cortex (PFC), ventral striatum and amygdala, is the same general circuit that underlies reward-seeking behaviors and its dysfunction is strongly implicated in OCD. The overall aim of this Center is to delineate the neural circuitry and mechanisms that underlie behaviors that are associated with OCD. Importantly, these behaviors are not limited to OCD, but are associated with a range of affective and addictive disorders.

Deep brain stimulation (DBS), a therapy now being actively investigated for OCD, targets this circuit by placing the electrodes in the ventral anterior internal capsule and adjacent ventral striatum. (Deep Brain Stimulation Video) Several ascending and descending fiber bundles pass through this site, each of which may differentially modulate these behaviors and, thus, the impact on OCD symptoms. A central hypothesis of this application is that DBS at this site, changes activity in fronto-basal ganglia circuits and therefore affects the balance between avoidance and reward-seeking behaviors; this balance underlies the therapeutic effects of DBS in OCD.

Our goal is to improve our understanding of the neural network that underlies OCD-related behaviors through a series of integrated translational experiments that involve DBS: effects of DBS on extinction recall and avoidance-reward conflict, and functional neuroimaging in OCD patients, (Project 1); circuit modeling of prefrontal, and subcortical pathways associated with stimulation sites, (Project 2); recording prefrontal cortical and VS activity associated with an avoidance-reward conflict task and the effects of DBS on these behaviors and on cellular activity, (Project 3); using DBS to map prefrontal areas involved in fear expression, extinction, and transfer of extinction to instrumental avoidance in an animal model of OCD-like behavior, (Project 4); studying systems and cellular electrophysiological responses to DBS to investigate cortical rhythm generation and cortico-cortical interactions at a systems and cellular level, and how such activation leads to functional changes, synaptic plasticity, neuronal synchrony, and changes in axonal and synaptic dynamics (Projects 5 & 6).

 

 

 

 

 

 

 

 

 

 

 

 

 

Investigators

Suzanne N. Haber, Ph.D. Suzanne N. Haber
Center PI, Project 2
University of Rochester
Benjamin D. Greenberg, M.D., Ph.D. Benjamin D. Greenberg
Center Co-Pi, Project 1
Brown University
Darin Dougherty, M.D. Darin Dougherty
Project 1
Harvard University
Mohammed Milad, Ph.D. Mohammed Milad
Project 1
Harvard University
Emad N. Eskandar, M.D. Emad N. Eskandar
Project 3
Harvard University
Gregory J. Quirk, Ph.D. Gregory J. Quirk
Project 4
University of Puerto Rico
Anthony A. Grace, Ph.D. Anthony A. Grace
Project 5
University of Pittsburgh
Barry W. Connors, Ph.D. Barry W. Connors
Project 6
Brown University
Steven A. Rasmussen, M.D. Steven A. Rasmussen
Informatics
Brown University