The organization of prefrontal-subthalamic inputs in primates provides an anatomical substrate for both functional specificity and integration: implications for Basal Ganglia models and deep brain stimulation.

The identification of a hyperdirect cortico-subthalamic nucleus connection highlighted the important role of the subthalamic nucleus (STN) in regulating behavior. However, this pathway was shown primarily from motor areas. Hyperdirect pathways associated with cognitive and motivational cortical regions are particularly relevant given recent data from deep brain stimulation, both for neurologic and psychiatric disorders. Our experiments were designed to demonstrate the existence and organization of prefrontal-STN projections, help delineate the "limbic" STN, and determine whether convergence between cortico-STN fibers from functionally diverse cortical areas exists in the STN. We injected anterograde tracers in the ventromedial prefrontal, orbitofrontal, anterior cingulate, and dorsal prefrontal cortices of Macaca nemestrina and Macaca fascicularis to analyze the organization of terminals and passing fibers in the STN. Results show a topographically organized prefrontal hyperdirect pathway in primates. Limbic areas project to the medial tip of the nucleus, straddling its border and extending into the lateral hypothalamus. Associative areas project to the medial half, motor areas to the lateral half. Limbic projections terminated primarily rostrally and motor projections more caudally. The extension of limbic projections into the lateral hypothalamus, suggests that this region be included in the STN. A high degree of convergence exists between projections from functionally diverse cortical areas, creating potentially important interfaces between terminal fields. Taken together, the results provide an anatomical substrate to extend the role of the hyperdirect pathway in models of basal ganglia function, and new keys for understanding deep brain stimulation effects on cognitive and motivational aspects of behavior.

High-frequency stimulation of deep brain structures in obsessive-compulsive disorder: the search for a valid circuit.

Obsessive-compulsive disorder (OCD) is a common, disabling, psychiatric disease combining intrusive thoughts (obsessions) and repetitive behaviours (compulsions). Although most patients respond well to conventional pharmacological and/or psychological therapy, 25-30%, often with extremely severe symptoms, fail to improve after treatment. High-frequency stimulation of deep brain structures (basal ganglia included), a surgical technique developed for movement disorders and otherwise known as deep brain stimulation (DBS), has been proposed as an alternative to ablative surgery for these intractable cases. Here, we review the scientific data that explain why the use of this technique is currently being investigated in OCD, from the first hypotheses based on neuroimaging studies (anatomical and functional) to more recent animal models and clinical observations. The general outcome of each clinical trial is outlined in order to discuss its relation to pathophysiology; however, more specific clinical information (side-effects, latencies, and other behavioural modifications) is not given. Finally, a description of the models of OCD that stem from these data and how they might be affected by DBS is provided.

Altered anatomical connections of associative and limbic cortico-basal-ganglia circuits in obsessive-compulsive disorder.

BACKGROUND: Current neurocognitive models suppose dysfunctions of associative and limbic cortico-basal ganglia circuits to be at the core of obsessive-compulsive disorder (OCD). As little is known about the state of underlying anatomical connections, we investigated whether these connections were reduced and/or not properly organised in OCD patients compared to control. METHODS: Diffusion magnetic resonance images were obtained in 37 OCD patients with predominant checking symptoms and 37 matched healthy controls. We developed indices to characterise the quantity (spatial extent and density) and the organisation (topography and segregation) of 24 anatomical connections between associative and limbic cortical (anterior cingulate, dorsolateral prefrontal, orbitofrontal cortices and the frontal pole), and subcortical (caudate nucleus, putamen and thalamus) areas in each hemisphere. RESULTS: Associative and limbic cortico-basal-ganglia connections were reduced in OCD patients compared to controls: 19/24 connections had a reduced subcortical spatial extent, 9/24 had a reduced density. Moreover, while the general topography was conserved, the different cortical projection fields in the striatum and thalamus were hyper-segregated in OCD patients compared to controls. CONCLUSION: These quantitative and qualitative differences of anatomical connections go beyond the current model of a reduced cortical control of automatic behaviour stored in the basal ganglia. The hyper-segregation in OCD could also impair the integration of cortical information in the thalamus and striatum and distort the subsequent behavioural selection process. This provides new working hypotheses for functional and behavioural studies on OCD.