Neurocircuitry of OCD: Effects of Modulation

Growing evidence indicates that psychiatric illnesses in general, and obsessive-compulsive disorder (OCD) in particular, are manifestations of circuit dysfunction across a network that mediates behavioral flexibility. These brain regions and their connections that show abnormalities in OCD, include the rostral anterior cingulate cortex (rACC), dorsal ACC (dACC), orbitofrontal cortex (OFC), and the striatum. These diverse regions are tightly connected to the ventrolateral prefrontal cortex (vlPFC) and the insula (I). Together these structures constitute the central nodes of a network that link motivation, salience, value-encoding, and stimulus-response processing. Collectively, we refer to these areas and their connections as the OCD network (OCDnet), which is central for behavioral flexibility that optimizes positive outcomes.

A key clinical feature of the disease is behavioral inflexibility, in which the individual compulsively and actively avoids situations despite a low probability of an aversive outcome. This persistent avoidance comes at the high cost of failing to achieve a positive goal. The overall goal of this Center is to further understand and probe OCDnet, and the abnormalities within it that result in the persistent avoidance associated with OCD.

Collectively the Center uses a multimodal, cross-species network approach to achieve 3 main aims:

1. Identify cortical hubs and their connectivity. Hubs are specific regions within each OCDnet node with unusually high and diverse connectivity and thus positioned to integrate and distribute information across nodes. Aim 1 uses a combination of animal studies (P1, 2), and human studies (P1, 3, CoresB, C) to characterize the OCDnet circuits anatomically and physiologically.
2. Understand how impairments in behavioral flexibility that results in persistent avoidance are associated with these connections in OCD patients compared to healthy control subjects. Using a newly developed probabilistic approach avoidance task (PAAT), aim 2 characterizes how impairments in the task are linked to the abnormalities in the OCDnet (P2-4, Core B-D)
3. Study the effects of neural modulation of these circuits on connectivity profiles and on behavioral inflexibility. Aim 3 will modulate the OCDnet in OCD patients using both conventional treatments (P4) and direct circuit manipulations (P2, 5) (Cores B-D) and study the effects on the OCDnet (with P1, Core B & C) and PAAT (with Cores D). Collectively, these studies further our understanding of circuit interactions of key brain regions implicated in OCD, their involvement in behavioral inflexibility that results in persistent avoidance associated with OCD, and the effects of neuromodulation of those circuits.