Axonal and synaptic failure suppress the transfer of firing rate oscillations, synchrony and information during high frequency deep brain stimulation.
High frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a widely used treatment for Parkinson's disease, but its effects on neural activity in basal ganglia circuits are not fully understood. DBS increases the excitation of STN efferents yet decouples STN spiking patterns from the spiking patterns of STN synaptic targets. We propose that this apparent paradox is resolved by recent studies showing an increased rate of axonal and synaptic failures in STN projections during DBS. To investigate this hypothesis, we combine in vitro and in vivo recordings to derive a computational model of axonal and synaptic failure during DBS. Our model shows that these failures induce a short term depression that suppresses the synaptic transfer of firing rate oscillations, synchrony and rate-coded information from STN to its synaptic targets. In particular, our computational model reproduces the widely reported suppression of parkinsonian β oscillations and synchrony during DBS. Our results support the idea that short term depression is a therapeutic mechanism of STN DBS that works as a functional lesion by decoupling the somatic spiking patterns of STN neurons from spiking activity in basal ganglia output nuclei.
Department of Mathematics, University of Pittsburgh, Pittsburgh, PA, USA; Center for the Neural Basis of Cognition, Pittsburgh, PA, USA. Electronic address: robertr@pitt.edu.
Robert
R
Rosenbaum
Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA, USA.
Andrew
A
Zimnik
Institute of Physiology and Pathophysiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany.
Fang
F
Zheng
Center for the Neural Basis of Cognition, Pittsburgh, PA, USA; Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA, USA.
Robert S
RS
Turner
Institute of Physiology and Pathophysiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany.
Christian
C
Alzheimer
Department of Mathematics, University of Pittsburgh, Pittsburgh, PA, USA; Center for the Neural Basis of Cognition, Pittsburgh, PA, USA.
Brent
B
Doiron
Department of Mathematics, University of Pittsburgh, Pittsburgh, PA, USA; Center for the Neural Basis of Cognition, Pittsburgh, PA, USA.
Jonathan E
JE
Rubin
D000200:Action Potentials / Q000502:physiology*; D000818:Animals; D001369:Axons / Q000502:physiology*; D003198:Computer Simulation; D046690:Deep Brain Stimulation; D059290:Dopaminergic Neurons / Q000502:physiology; D005917:Globus Pallidus / Q000502:physiology*; D008253:Macaca mulatta; D008297:Male; D008959:Models, Neurological; D009434:Neural Pathways; D051381:Rats; D017208:Rats, Wistar; D013378:Substantia Nigra / Q000502:physiology; D020531:Subthalamic Nucleus / Q000502:physiology*; D013569:Synapses / Q000502:physiology*
Axonal failure; Beta oscillations; Deep brain stimulation; Parkinson's disease; Short term depression; Synaptic failure