Single-neuron bursts encode pathological oscillations in subcortical nuclei of patients with Parkinson’s disease and essential tremor

Abstract

Deep brain stimulation procedures offer an invaluable opportunity to study disease through intracranial recordings from awake patients. Here, we address the relationship between single-neuron and aggregate-level (local field potential; LFP) activities in the subthalamic nucleus (STN) and thalamic ventral intermediate nucleus (Vim) of patients with Parkinson’s disease ( n = 19) and essential tremor ( n = 16), respectively. Both disorders have been characterized by pathologically elevated LFP oscillations, as well as an increased tendency for neuronal bursting. Our findings suggest that periodic single-neuron bursts encode both pathophysiological beta (13 to 33 Hz; STN) and tremor (4 to 10 Hz; Vim) LFP oscillations, evidenced by strong time-frequency and phase-coupling relationships between the bursting and LFP signals. Spiking activity occurring outside of bursts had no relationship to the LFP. In STN, bursting activity most commonly preceded the LFP oscillation, suggesting that neuronal bursting generated within STN may give rise to an aggregate-level LFP oscillation. In Vim, LFP oscillations most commonly preceded bursting activity, suggesting that neuronal firing may be entrained by periodic afferent inputs. In both STN and Vim, the phase-coupling relationship between LFP and high-frequency oscillation (HFO) signals closely resembled the relationships between the LFP and single-neuron bursting. This suggests that periodic single-neuron bursting is likely representative of a higher spatial and temporal resolution readout of periodic increases in the amplitude of HFOs, which themselves may be a higher resolution readout of aggregate-level LFP oscillations. Overall, our results may reconcile “rate” and “oscillation” models of Parkinson’s disease and shed light on the single-neuron basis and origin of pathophysiological oscillations in movement disorders.

Spatially specific, closed-loop infrared thalamocortical deep brain stimulation

“…After observation of spatial selectivity in thalamocortical INS, we sought to control small neural populations through closed-loop feedback. Current adaptive DBS systems used in Parkinson’s disease use relatively simple control algorithms centered around reducing β band biomarker correlates of symptomology using single or dual threshold “thermostatic” control(42, 75, 76) which may interfere with activities such as volitional movement(42) and may potentially occlude oscillatory neural dynamics unrelated to disease(39). Control of smaller populations of neurons relevant to disease with control algorithms that encode subject specific firing dynamics may provide targeted treatment and a reduction in off-target side effects.…”

The Genetic Etiology of Parkinson's Disease Does Not Robustly Affect Subthalamic Physiology

“…It is still debated whether intrinsic pacemaker activity of single focus generates the abnormal β synchronous oscillations, or it is generated by more complex network activity 23‐25 . Because certain evidences indicate that the cortex is critically involved in the generation of this pathological activity, 26,27 we initially hypothesized that β oscillatory activity would not be identical between groups.…”

“…22 It is still debated whether intrinsic pacemaker activity of single focus generates the abnormal β synchronous oscillations, or it is generated by more complex network activity. [23][24][25] Because certain evidences indicate that the cortex is critically involved in the generation of this pathological activity, 26,27 we initially hypothesized that β oscillatory activity would not be identical between groups. This assumption was based on knowledge regarding the cortical sparing in PRKN-PD that contrasts the extensive cortical involvement in GBA-PD (demonstrated also in this study by more severe cognitive impairments).…”

“…A distinctive electrophysiological activity is usually demonstrated in the subthalamic nuclei (STNs) of patients with PD. 3,4 This electrophysiological signature includes oscillatory activity in the β range (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) localized to the dorsolateral STN (dorsolateral oscillatory region [DLOR], probably the STN motor domain). Increased β oscillatory activity reflects clinical OFF, and the DLOR, where such an activity is recorded, is the optimal target for deep brain stimulation (DBS).…”

Non-linear input-output relationships in the subthalamic nucleus of Parkinson’s patients

“…Beta oscillations in LFP recordings play a role in the temporal dynamics of high frequency oscillations (HFOs) 16, 17 . A recent study reported that periodic single-neuron bursts in the STN commonly preceded the LFP oscillation (13∼33 Hz), but that other neuronal firing activity had no relationship to the LFP 18 .…”