DISSECTING OCD CIRCUITS: FROM ANIMAL MODELS TO TARGETED TREATMENTS

Abstract

Obsessive-compulsive disorder (OCD) is a chronic, severe mental illness with up to 2-3% prevalence worldwide. In fact, OCD has been classified as one of the world's 10 leading causes of illness-related disability according to the World Health Organization, largely because of the chronic nature of disabling symptoms.([1]) Despite the severity and high prevalence of this chronic and disabling disorder, there is still relatively limited understanding of its pathophysiology. However, this is now rapidly changing due to development of powerful technologies that can be used to dissect the neural circuits underlying pathologic behaviors. In this article, we describe recent technical advances that have allowed neuroscientists to start identifying the circuits underlying complex repetitive behaviors using animal model systems. In addition, we review current surgical and stimulation-based treatments for OCD that target circuit dysfunction. Finally, we discuss how findings from animal models may be applied in the clinical arena to help inform and refine targeted brain stimulation-based treatment approaches.

Keywords: anxiety; basal ganglia; cortico-striato-thalamo-cortical circuits; deep brain stimulation (DBS); obsessive-compulsive disorder (OCD); optogenetics; orbitofrontal cortex (OFC); prefrontal cortex; transcranial magnetic stimulation (TMS); ventral striatum.

Figure 1. Schematic diagram of direct vs. indirect pathway

A simplified diagram of the direct and indirect pathways through the cortex and basal ganglia are shown; thalamo-striatal projections and reciprocal connections between striatum and cortex are not shown for simplicity. Direct pathway is represented by green; indirect pathway is represented by pink. Direct pathway exerts a net excitatory effect on thalamic output to the cortex, while indirect pathway exerts a net inhibitory effect. GPi: globus pallidus interna; GPe: globus pallidus externa; STN: subthalamic nucleus; SNr: substantia nigra pars reticulata

Figure 2. Cortical-basal ganglia circuits implicated in OCD pathophysiology

Both structural and functional imaging studies provide evidence that orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), caudate, and anterior thalamus are involved in OCD pathophysiology. A) A circuit linking medial OFC (mOFC), ventral striatum (vStr), ventral pallidum (VP), and thalamus is thought to be involved in OCD pathology. This circuit has classically been associated with attribution of value to the outcome of particular actions to facilitate reward learning. Evidence from both stereotactic ablation and deep brain stimulation (DBS) studies indicates that interrupting this dysfunctional circuit can decrease symptoms in OCD patients. Links between this circuit and amygdala provide opportunities for regulation of activity by affect. Dopaminergic projections from substantia nigra/ ventral tegmental area (SN/VTA) provide critical modulatory input. B) Though the role of ACC in OCD symptomatology is unclear, a circuit linking dorsal ACC (dACC), dorsal striatum (dStr), VP (ventral pallidum), and thalamus is critical for action selection. Abnormalities in this loop could therefore contribute to perseverative behaviors in OCD.