Deep brain stimulation (DBS) of the subthalamic nucleus is a useful treatment for Parkinson's disease (PD), but its therapeutic mechanism is unknown. Effective DBS requires high frequency stimulation, well above the average firing rate of basal ganglia output neurons. Periodicity of DBS is also essential;random stimulation patterns at the same mean frequency are ineffective. Three mechanisms for its effect on basal ganglia output neurons have been proposed. DBS may correct a pathological change in: (1) firing rate of basal ganglia output cells and their targets in the thalamus, (2) bursting or oscillations of those cells, or (3) the degree to which the firing of the cells are correlated. Neither the rate nor the bursting model for the action of DBS adequately explains either the frequency or periodicity requirements. We have shown that a periodically-driven oscillator model of basal ganglia output cells exhibits a sequence of synchronizing entrainment and then failure of entrainment and desynchrony as the frequency of an excitatory stimulus is increased. In this model, the range of stimulus frequency, intensity and periodicity required for chaotic desynchronization matches that of the therapeutic effectiveness of DBS. This application will test our desynchronization hypothesis by measuring the degree of correlation among pairs of simultaneously recorded neurons in slices of the substantia nigra pars reticulata (SNR) during application of DBS-like natural and artificial synaptic conductances.
Aim 1 will test the fundamental mechanisms at work in the model using purely excitatory input.
Aim 2 will add an inhibitory component to the synaptic input, and test our method for designing the optimal stimulus.
Aim 3 will determine the influence of inhibitory coupling between output neurons on normal firing patterns and during DBS.
Aim 4 will determine whether the cellular dynamics or synaptic connections underlying DBS are altered after chronic dopamine depletion. Our model offers a mechanistic explanation of DBS and its properties, and a mathematical model that can be used to predict the effects of future DBS-like stimulation therapies. At this point, the model has not been validated, and this proposal will provide a test of the proposed mechanism. If it survives experimental test, our idea may be useful for explaining DBS and for designing future stimulation therapies.

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
Northwestern University at Chicago
United States
Zip Code
Hunt Jr, Albert J; Dasgupta, Rajan; Rajamanickam, Shivakumar et al. (2018) Paraventricular hypothalamic and amygdalar CRF neurons synapse in the external globus pallidus. Brain Struct Funct 223:2685-2698
Guzman, Jaime N; Ilijic, Ema; Yang, Ben et al. (2018) Systemic isradipine treatment diminishes calcium-dependent mitochondrial oxidant stress. J Clin Invest 128:2266-2280
Higgs, Matthew H; Wilson, Charles J (2017) Measurement of phase resetting curves using optogenetic barrage stimuli. J Neurosci Methods 289:23-30
Surmeier, D James; Obeso, José A; Halliday, Glenda M (2017) Selective neuronal vulnerability in Parkinson disease. Nat Rev Neurosci 18:101-113
Chu, Hong-Yuan; McIver, Eileen L; Kovaleski, Ryan F et al. (2017) Loss of Hyperdirect Pathway Cortico-Subthalamic Inputs Following Degeneration of Midbrain Dopamine Neurons. Neuron 95:1306-1318.e5
Shi, Han; Deng, Han-Xiang; Gius, David et al. (2017) Sirt3 protects dopaminergic neurons from mitochondrial oxidative stress. Hum Mol Genet 26:1915-1926
Surmeier, D James; Halliday, Glenda M; Simuni, Tanya (2017) Calcium, mitochondrial dysfunction and slowing the progression of Parkinson's disease. Exp Neurol 298:202-209
Galtieri, Daniel J; Estep, Chad M; Wokosin, David L et al. (2017) Pedunculopontine glutamatergic neurons control spike patterning in substantia nigra dopaminergic neurons. Elife 6:
Surmeier, D James; Schumacker, Paul T; Guzman, Jaime D et al. (2017) Calcium and Parkinson's disease. Biochem Biophys Res Commun 483:1013-1019
Burbulla, Lena F; Song, Pingping; Mazzulli, Joseph R et al. (2017) Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson's disease. Science 357:1255-1261

Showing the most recent 10 out of 119 publications