Mechanism of Deep Brain Stimulation: Inhibition, Excitation, or Disruption?

Abstract

Deep brain stimulation (DBS), applying high-frequency electrical stimulation to deep brain structures, has now provided an effective therapeutic option for treatment of various neurological and psychiatric disorders. DBS targeting the internal segment of the globus pallidus, subthalamic nucleus, and thalamus is used to treat symptoms of movement disorders, such as Parkinson's disease, dystonia, and tremor. However, the mechanism underlying the beneficial effects of DBS remains poorly understood and is still under debate: Does DBS inhibit or excite local neuronal elements? In this short review, we would like to introduce our recent work on the physiological mechanism of DBS and propose an alternative explanation: DBS dissociates input and output signals, resulting in the disruption of abnormal information flow through the stimulation site.

Keywords: Parkinson’s disease; deep brain stimulation; dystonia; globus pallidus; stereotactic surgery; subthalamic nucleus.

Figure 1.

Deep brain stimulation (DBS) inhibits local neuronal firings. (A) Responses of an internal pallidal (GPi) neuron to local repetitive high-frequency stimulation (GPi-DBS; 30 µA, 100 Hz, 10 pulses; arrows) in a normal monkey. Raw traces of spike discharges after removing the stimulus artifacts (1) and raster and peristimulus time histograms (PSTHs; 100 trials; binwidth, 1 ms) (2) are shown. Spontaneous discharge of the GPi neuron was completely inhibited by GPi-DBS. (B) Effect of local injection of gabazine (GABA_A receptor antagonist) in the vicinity of the recorded GPi neuron. The inhibition induced by GPi-DBS (1) was abolished after gabazine injection (2). Modified from Chiken and Nambu (2013).

Figure 2.

Directly evoked spikes of internal pallidal (GPi) neurons are inhibited during GPi–deep brain stimulation (DBS). (A) Raw traces showing directly evoked spikes (arrowheads) of a GPi neuron by GPi-DBS (40 µA, 100 Hz, 10 pulses; arrows with dotted lines) in a normal monkey. Traces with long (top) and short (bottom) time scales are shown. GPi-DBS failed to evoke spikes (from 6th to 10th stimuli). (B) Effects of local gabazine injection on the inhibition of directly evoked GPi responses. Gabazine injection decreased the failure rate, and each stimulus successfully evoked spikes (5th, 9th, and 10th stimuli). Modified from Chiken and Nambu (2013).

Figure 3.

Deep brain stimulation (DBS) of the internal segment of the globus pallidus (GPi) disrupts information flow through the GPi. (A, B) Effects of local GPi-DBS on cortically evoked responses of a GPi neuron in a normal monkey. PSTHs in response to a single-pulse stimulation of the primary motor cortex (Cx) (arrowhead with dotted line) without (A) and with GPi-DBS (arrows) (B) are shown. In (B), cortical stimulation was applied 50 ms after the initiation of GPi-DBS. The cortically evoked responses were entirely inhibited during GPi-DBS. (C) Schematic diagram showing the cortico-basal ganglia pathways and stimulating (Stim and DBS) and recording (Rec) sites. Cortically evoked early excitation, inhibition and late excitation in (A) are mediated by the hyperdirect, direct, and indirect pathways, respectively. Cx, cerebral cortex; GPe, external segment of the globus pallidus; STN, subthalamic nucleus. Red and blue triangles represent glutamatergic excitatory and GABAergic inhibitory terminals, respectively. Modified from Chiken and Nambu (2013).

Figure 4.

“Disruption hypothesis” explaining the mechanism underlying the effectiveness of deep brain stimulation (DBS). DBS activates axon terminals in the stimulated nucleus, induces extensive release of neurotransmitters, such as GABA and glutamate (Glu), and dissociates inputs and outputs in the stimulated nucleus. Thus, DBS results in disruption of the abnormal information flow through the cortico-basal ganglia loop in the pathological conditions. GABA_A, GABA_A receptors.