Neurosurgical interventions, such as deep brain stimulation (DBS) of the internal pallidal segment (GPi) or the subthalamic nucleus (STN), or GPi lesions (pallidotomy), are commonly used to help patients with advanced Parkinson's disease. DBS and lesioning procedures produce contrasting effects on their immediate brain targets: Lesions reduce the output of the lesioned nucleus, while electrical stimulation of STN or GPi is thought to lead to complex activity changes in the stimulated tissue, including local neuron inhibition, and stimulation of efferent or afferent fibers. Despite these differences, lesions and stimulation have remarkably similar clinical and behavioral effects. We hypothesize that one of the reasons for this paradox is that, although the surgical interventions produce different local effects, they lead to similar effects in nuclei further downstream, particularly in the anterior ventrolateral thalamus (VLa), the recipient of a dense GABAergic projection from the motor portion of the basal ganglia output nuclei. Previous studies have suggested that VLa neurons show an increased tendency to fire in bursts and to generate oscillatory patterns of activity in parkinsonism, which may act to disrupt thalamocortical interactions, and may be involved in the generation of parkinsonian signs. We hypothesize that lesions and DBS aimed at GPi or STN have different effects on VLa firing rates, but that both regularize the firing patterns of VLa neurons, thus allowing cortico-thalamo-cortical interactions to proceed more normally. To test these hypotheses, we will examine the effects of GPi inactivation on neuronal activities, GABA levels, and morphological aspects of the synaptic pallldothalamic interactions in MPTP-treated (parkinsonian) monkeys (aim 1). Results from these studies will then be compared with the effects of electrical stimulation of STN or GPi on thalamic neuronal activity in MPTP-treated monkeys (aim 2). A better understanding of the common downstream effects of lesions and stimulation may help us to define more specific neurosurgical or pharmacological therapies, or therapies that combine pharmacologic treatments with the neurosurgical interventions, in order to eliminate parkinsonisian motor signs.
These studies will identify firing abnormalities in the thalamus that contribute to the development of parkinsonism. This knowledge may define the thalamus as a target for new pharmacological or surgical therapies, and may identify specific drug or surgical therapies to target thalamic firing abnormalities, with the goal of helping patients with Parkinson's disease more effectively and with fewer side effects.
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