Abstract
High-frequency electrical stimulation of specific brain structures, known as deep brain stimulation (DBS), is an effective treatment for movement disorders, but mechanisms of action remain unclear. We examined the time-dependent effects of DBS applied to the entopeduncular nucleus (EP), the rat homolog of the internal globus pallidus, a target used for treatment of both dystonia and Parkinson’s disease (PD). We performed simultaneous multi-site local field potential (LFP) recordings in urethane-anesthetized rats to assess the effects of high-frequency (HF, 130 Hz; clinically effective), low-frequency (LF, 15 Hz; ineffective) and sham DBS delivered to EP. LFP activity was recorded from dorsal striatum (STR), ventroanterior thalamus (VA), primary motor cortex (M1), and the stimulation site in EP. Spontaneous and acute stimulation-induced LFP oscillation power and functional connectivity were assessed at baseline, and after 30, 60, and 90 minutes of stimulation. HF EP DBS produced widespread alterations in spontaneous and stimulus-induced LFP oscillations, with some effects similar across regions and others occurring in a region- and frequency band-specific manner. Many of these changes evolved over time. HF EP DBS produced an initial transient reduction in power in the low beta band in M1 and STR; however, phase synchronization between these regions in the low beta band was markedly suppressed at all time points. DBS also enhanced low gamma synchronization throughout the circuit. With sustained stimulation, there were significant reductions in low beta synchronization between M1-VA and STR-VA, and increases in power within regions in the faster frequency bands. HF DBS also suppressed the ability of acute EP stimulation to induce beta oscillations in all regions along the circuit. This dynamic pattern of synchronizing and desynchronizing effects of EP DBS suggests a complex modulation of activity along cortico-BG-thalamic circuits underlying the therapeutic effects of GPi DBS for conditions such as PD and dystonia.
Highlights
High-frequency electrical stimulation of specific brain regions, known as deep brain stimulation (DBS), is an effective treatment strategy for a number of refractory neurological conditions
Given the evidence for circuit-wide effects of DBS, we examined how DBS delivered to the entopeduncular nucleus (EP; the rat homolog of the primate globus pallidus internus (GPi)) affected spontaneous and evoked synchronous local field potential (LFP) activity both within and between a number of regions comprising the primary motor circuit
The most prominent effect was a reduction in beta synchronization and enhancement of gamma synchronization; some effects appeared similar across regions, others occurred in a region- and frequency band-specific manner, and importantly, many evolved over time
Summary
High-frequency electrical stimulation of specific brain regions, known as deep brain stimulation (DBS), is an effective treatment strategy for a number of refractory neurological conditions. A variety of animal studies demonstrated that DBS inhibited activity in the stimulated region, through either depolarization blockade, neurotransmitter depletion, or enhanced local GABAergic transmission [5,6,7,8,9]. Electrical brain stimulation at clinically effective intensities preferentially excites axons as opposed to cell bodies [10], such that activation of afferent and efferent axons can modulate neuronal activity in sites distal to the stimulated nucleus [11,12,13,14,15]. GPi DBS can both inhibit local firing [5,16,17] as well as activate efferent GPi axons projecting to thalamus [18,19,20]
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