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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZNS1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Emory University
United States
Zip Code
Sanders, Teresa H (2017) Stimulation of Cortico-Subthalamic Projections Amplifies Resting Motor Circuit Activity and Leads to Increased Locomotion in Dopamine-Depleted Mice. Front Integr Neurosci 11:24
Chen, Erdong; Paré, Jean-Francois; Wichmann, Thomas et al. (2017) Sub-synaptic localization of Cav3.1 T-type calcium channels in the thalamus of normal and parkinsonian monkeys. Brain Struct Funct 222:735-748
Masilamoni, Gunasingh Jeyaraj; Groover, Olivia; Smith, Yoland (2017) Reduced noradrenergic innervation of ventral midbrain dopaminergic cell groups and the subthalamic nucleus in MPTP-treated parkinsonian monkeys. Neurobiol Dis 100:9-18
Dunn, Amy R; Stout, Kristen A; Ozawa, Minagi et al. (2017) Synaptic vesicle glycoprotein 2C (SV2C) modulates dopamine release and is disrupted in Parkinson disease. Proc Natl Acad Sci U S A 114:E2253-E2262
Huddleston, Daniel E; Langley, Jason; Sedlacik, Jan et al. (2017) In vivo detection of lateral-ventral tier nigral degeneration in Parkinson's disease. Hum Brain Mapp 38:2627-2634
Langley, Jason; Huddleston, Daniel E; Merritt, Michael et al. (2016) Diffusion tensor imaging of the substantia nigra in Parkinson's disease revisited. Hum Brain Mapp 37:2547-56
Devergnas, Annaelle; Chen, Erdong; Ma, Yuxian et al. (2016) Anatomical localization of Cav3.1 calcium channels and electrophysiological effects of T-type calcium channel blockade in the motor thalamus of MPTP-treated monkeys. J Neurophysiol 115:470-85
Wichmann, Thomas; DeLong, Mahlon R (2016) Deep Brain Stimulation for Movement Disorders of Basal Ganglia Origin: Restoring Function or Functionality? Neurotherapeutics 13:264-83
Iskhakova, Liliya; Smith, Yoland (2016) mGluR4-containing corticostriatal terminals: synaptic interactions with direct and indirect pathway neurons in mice. Brain Struct Funct 221:4589-4599
Galvan, Adriana; Devergnas, Annaelle; Pittard, Damien et al. (2016) Lack of Antiparkinsonian Effects of Systemic Injections of the Specific T-Type Calcium Channel Blocker ML218 in MPTP-Treated Monkeys. ACS Chem Neurosci 7:1543-1551

Showing the most recent 10 out of 92 publications