Toward a Neurobiology of Obsessive-Compulsive Disorder

Even if imaging studies identify the cascades of activity in cortico-basal ganglia circuits occurring during expression of OCD symptoms, it still will be unclear what form of neural encoding is responsible for the symptoms or for their resolution. One interesting possibility is that the neural circuits that normally mediate habits and automated behaviors become hyperactive or inaccessible to a stop signal in OCD and related disorders. Three recent models for studying what goes on in cortico-basal ganglia circuits when habits are formed are pertinent here. In the first, monkeys were taught a sensorimotor conditioning task in which light or sound cues were associated with reward, and recordings were made from the tonically active neurons of the striatum thought to be the cholinergic interneurons. As the monkeys learned the task, the neurons acquired responses to the conditioning stimuli, and they maintained those responses as long as dopamine was present in the striatum. Removal of dopamine reduced the acquired responses (2xEffects of the nigrostriatal dopamine system on acquired neural responses in the striatum of behaving monkeys. Aosaki, T, Graybiel, A.M, and Kimura, M. Science. 1994; 265: 412–415Crossref | PubMedSee all References, 3xResponses of tonically active neurons in the primate's striatum undergo systematic changes during behavioral sensorimotor conditioning. Aosaki, T, Tsubokawa, H, Ishida, A, Watanabe, K, Graybiel, A.M, and Kimura, M. J. Neurosci. 1994; 14: 3969–3984PubMedSee all References), and so did inactivation of the intralaminar thalamus (Matsumoto et al. 2000xNeurons in the thalamic CM-Pf complex supply neurons in the striatum with polysensory information with orienting value. Matsumoto, N, Minamimoto, T, Graybiel, A.M, and Kimura, M. J. Neurophysiol. 2000; in pressSee all ReferencesMatsumoto et al. 2000). In related work, removal of dopamine in the striatum before learning of a simple sequential push-button task prevented the task from being executed without cues as a unified behavioral sequence (Matsumoto et al. 1999xRole of nigrostriatal dopamine system in learning to perform sequential motor tasks in a predictive manner. Matsumoto, N, Hanakawa, T, Maki, S, Graybiel, A.M, and Kimura, M. J. Neurophysiol. 1999; 82: 978–998PubMedSee all ReferencesMatsumoto et al. 1999). In the second set of experiments, the activity of projection neurons in the sensorimotor striatum of rats was monitored with chronically implanted tetrodes. The ensemble activity of these neurons was found to undergo large-scale and long-lasting changes as the rats learned the procedure and then performed it after learning (Jog et al. 1999xBuilding neural representations of habits. Jog, M, Kubota, Y, Connolly, C.I, Hillegaart, V, and Graybiel, A.M. Science. 1999; 286: 1745–1749Crossref | PubMed | Scopus (489)See all ReferencesJog et al. 1999; see also Carelli et al. 1997xLoss of lever press-related firing of rat striatal forelimb neurons after repeated sessions in a lever pressing task. Carelli, R.M, Wolske, M, and West, M.O. J. Neurosci. 1997; 17: 1804–1814PubMedSee all ReferencesCarelli et al. 1997). These studies suggest that, with experience, striatal neurons can develop new responses to environmental stimuli. Given the activity changes in striatal projection neurons, this plasticity is likely to affect basal ganglia outputs and thus cortico-basal ganglia loop function. In the third set of experiments, the expression of stereotypies induced in rats by repeated doses of psychomotor stimulant drugs was found to be closely correlated with heightened activation of the striosomal compartment of the striatum—the compartment preferentially interconnected with the anterior cingulate and orbitofrontal cortex (Canales and Graybiel 2000xA measure of striatal function predicts motor stereotypy. Canales, J.J and Graybiel, A.M. Nat. Neurosci. 2000; 3: 377–383Crossref | PubMed | Scopus (249)See all ReferencesCanales and Graybiel 2000). Such experiments highlight the potential for identifying the changes in neuronal activity that occur in cortico-basal ganglia circuits as repetitive action repertoires come to dominate behavior. A first step toward testing whether such striatal function could be affected in OCD has been carried out by testing people with OCD on implicit learning tasks that normally activate the striatum. Striatal activation was found to be deficient in the OCD subjects, but activation of the hippocampal system (normally recruited during explicit learning tasks) was abnormally high (Rauch et al. 1997xProbing striatal function in obsessive compulsive disorder (a PET study of implicit sequence learning) . Rauch, S, Savage, C, Alpert, N, Dougherty, D, Kendrick, A, Curran, T, Brown, H, Manzo, P, Fischman, A, and Jenike, M. J Neuropsych. Clin. Neurosci. 1997; 9: 568–573PubMedSee all ReferencesRauch et al. 1997). Coordination of human brain imaging of this sort with laboratory-based experiments holds great promise for uncovering the neurobiology of OCD.‡To whom correspondence should be addressed (e-mail: graybiel@mit.edu).