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)
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
Wilson, Charles J; Barraza, David; Troyer, Todd et al. (2014) Predicting the responses of repetitively firing neurons to current noise. PLoS Comput Biol 10:e1003612
Surmeier, D James; Graves, Steven M; Shen, Weixing (2014) Dopaminergic modulation of striatal networks in health and Parkinson's disease. Curr Opin Neurobiol 29:109-17
Sanchez-Padilla, Javier; Guzman, Jaime N; Ilijic, Ema et al. (2014) Mitochondrial oxidant stress in locus coeruleus is regulated by activity and nitric oxide synthase. Nat Neurosci 17:832-40
Gittis, Aryn H; Berke, Joshua D; Bevan, Mark D et al. (2014) New roles for the external globus pallidus in basal ganglia circuits and behavior. J Neurosci 34:15178-83
Deister, Christopher A; Dodla, Ramana; Barraza, David et al. (2013) Firing rate and pattern heterogeneity in the globus pallidus arise from a single neuronal population. J Neurophysiol 109:497-506
Atherton, Jeremy F; Menard, Ariane; Urbain, Nadia et al. (2013) Short-term depression of external globus pallidus-subthalamic nucleus synaptic transmission and implications for patterning subthalamic activity. J Neurosci 33:7130-44
Dodla, Ramana; Wilson, Charles J (2013) Effect of phase response curve skewness on synchronization of electrically coupled neuronal oscillators. Neural Comput 25:2545-610
Wilson, C J (2013) Active decorrelation in the basal ganglia. Neuroscience 250:467-82
Sulzer, David; Surmeier, D James (2013) Neuronal vulnerability, pathogenesis, and Parkinson's disease. Mov Disord 28:715-24
Dryanovski, Dilyan I; Guzman, Jaime N; Xie, Zhong et al. (2013) Calcium entry and *-synuclein inclusions elevate dendritic mitochondrial oxidant stress in dopaminergic neurons. J Neurosci 33:10154-64

Showing the most recent 10 out of 76 publications