Subthalamic Nucleus Neurons Are Synchronized to Primary Motor Cortex Local Field Potentials in Parkinson's Disease

Abstract

In Parkinson’s disease (PD), striatal dopamine denervation results in a cascade of abnormalities in the single unit activity of downstream basal ganglia nuclei that include increased firing rate, altered firing patterns, and increased oscillatory activity. However, the effects of these abnormalities on cortical function are poorly understood. Here, in humans undergoing deep brain stimulator implantation surgery, we utilize the novel technique of subdural electrocorticography in combination with subthalamic nucleus (STN) single unit recording to study basal ganglia-cortex interactions at the millisecond time scale. We show that in patients with PD, STN spiking is synchronized with primary motor cortex (M1) local field potentials in two distinct patterns: First, STN spikes are phase-synchronized with M1 rhythms in the theta, alpha, or beta (4-30 Hz) bands. Second, STN spikes are synchronized with M1 gamma activity over a broad spectral range (50-200 Hz). The amplitude of STN spike-synchronized gamma activity in M1 is itself rhythmically modulated by the phase of a lower frequency rhythm (phase-amplitude coupling), such that “waves” of phase-synchronized gamma activity precede the occurrence of STN spikes. We show the disease specificity of these phenomena in PD, by comparison with STN-M1 paired recordings performed in a group of patients with a different disorder, primary cranio-cervical dystonia. Our findings support a model of the basal ganglia-thalamocortical loop in PD in which gamma activity in primary motor cortex, modulated by the phase of low frequency rhythms, drives STN unit discharge.

New Roles for the External Globus Pallidus in Basal Ganglia Circuits and Behavior

“…Furthermore, GPe-STN and STN neurons exhibit anticorrelated firing both during cortical slow-wave activity and activated cortical states in which abnormally persistent and widespread beta band activity is manifest (Hammond et al, 2007;Mallet et al, 2008b;Shimamoto et al, 2013). The altered firing rates of GPe and STN neurons are likely due to hyperactivity of D2 SPNs, which leads to excessive inhibition of GPe-STN neurons and disinhibition of the STN (Gerfen and Surmeier, 2011).…”

Deep brain stimulation: a mechanistic and clinical update

“…Another publication by the same group showed that epochs of M1 phase-amplitude coupling predicted STN spikes. 177 This theory contrasts with older literature emphasizing the importance of intrastriatal b-synchrony as the driver of pathological oscillations. 19 Oscillatory activity in the motor cortex is now also being studied with magnetoencephalography as a possible biomarker for PD.…”

“…78 Taken together, these data fit into the model proposed by Shimamoto and colleagues in which excess motor cortical b synchrony, manifesting clinically as hypokinesia, is a result of strong pathological b oscillations passed from the basal ganglia. 177 This increased cortical b synchronization, in turn, leads to reinforcement of the basal ganglia b oscillations through pathological M1 b-phase g-amplitude coupling (Fig. 1).…”

“…In PD, subthalamic nucleus (STN) field potentials have been found to exhibit abnormal phase-amplitude coupling and spike-local field potential (LFP) coupling to primary motor cortex. 45,177 Furthermore, globus pallidus internus (GPi) neurons were found to entrain high-frequency stimulation at therapeutic parameters. 42 The "modulation of brain rhythms" hypothesis will likely provide a useful framework from which to make predictions about possible therapeutic targets for DBS.…”

Intracranial neuronal ensemble recordings and analysis in epilepsy

“…During the clinical procedure of therapeutic lead implantation for patients with Parkinson's disease (PD) and other movement disorders, microelectrode recording is routinely performed intraoperatively (Starr, 2002). Analysis of unit activity coregistered with cortical EEG markers could be identified underlying the effect of DBS on PD symptoms (de Hemptinne et al, 2015;Shimamoto et al, 2013). Since DBS therapy is available for epilepsy patients (Fisher et al, 2010), the widespread use of DBS in the clinical setting will provide detailed information about subcortical control of epileptic cortex.…”