The Indirect Pathway has long been a key part of classical models of the basal ganglia. The Indirect Pathway refers to projections from the striatum to the external globus pallidus (GPe), which continue to the internal globus pallidus (GPi). This pathway is posited to exert an inhibitory influence on thalami-cortical drive and to thus subserve the control of specifi movements, motivations, and cognitions. Pathology of this pathway may underlie several neuropsychiatric disorders, the textbook example being Huntington's disease (HD). Yet this model is almost entirely based on histopathology in humans and neurophysiologic recording in non-human primates and rodents. There has been very little characterization of the Indirect Pathway using in vivo methods in humans. This presumably relates to uncertainty as to which behavioral paradigms recruit the indirect pathway, as well as to limitations in the spatial resolution of functional and structural MRI. Our proposal is to overcome these limitations with an integrated study of the behavioral, physiological, and structural properties of the Indirect Pathway using the human disease model of early manifest and premanifest HD. Our preliminary data with structural MRI show that this population has specific atrophy of subcortical regions such as the striatum and the GP (globus pallidus). We have also developed behavioral and physiological methods to index the functional role of the Indirect Pathway. We will study 25 HD and 25 matched controls using a selective stopping behavioral paradigm, Transcranial Magnetic Stimulation (TMS), and functional and structural MRI. We predict that, relative to controls, HD participants will show behavioral impairments in the selective stopping task (which putatively engages the Indirect Pathway), but not on stopping tasks that bypass that pathway. We predict that, relative to controls, HD participants will also show physiological differences in corticomoto excitability during the selective stopping paradigm, assessed with TMS. Using imaging methods that achieve high fidelity subcortical alignment, we will examine functional MRI activation of the GPe. We predict that the HD group will have less GPe activation during the selective stopping task than controls. Finally, using newly developed structural MRI methods at our center, we will perform volumetric segmentation of the internal and external GP at the single participant level. We predict that GP atrophy in HD primarily affects the external sector corresponding to the Indirect Pathway. Taken together, these four experiments, within a single overall study of the same participants, could provide key in vivo evidence for the functional and structural properties of the Indirect Pathway.
Being able to successfully stop one's actions is an essential aspect of everyday behavior. Failures in stopping are also important in many disorders such as Obsessive Compulsive Disorder (OCD), Tourrette Syndrome, and Attention Deficit Hyperactivity Disorder (ADHD). However, what brain pathways are necessary to bring about controlled stopping? Classical neurology models suggest that the Indirect Pathway through the basal ganglia may be very important, but studying this pathway in humans in vivo has never been accomplished. Huntington's disease, where the deep structures of the brain degenerate, may give us an important model to study this pathway in vivo using novel behavioral, physiological, and neuroimaging measures - providing us valuable insights into how we control our actions.
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