High‐Frequency Oscillations in the Pallidum: A Pathophysiological Biomarker in Parkinson's Disease?

Abstract

A BS TRACT: Background: Abnormal oscillatory neural activity in the beta-frequency band (13-35 Hz) is thought to play a role in Parkinson's disease (PD); however, increasing evidence points to alterations in high-frequency ranges (>100 Hz) also having pathophysiological relevance. Objectives: Studies have found that power in subthalamic nucleus (STN) high-frequency oscillations is increased with dopaminergic medication and during voluntary movements, implicating these brain rhythms in normal basal ganglia function. The objective of this study was to investigate whether similar signaling occurs in the internal globus pallidus (GPi), a nucleus increasingly used as a target for deep brain stimulation (DBS) for PD. Methods: Spontaneous and movement-related GPi field potentials were recorded from DBS leads in 5 externalized PD patients on and off dopaminergic medication, as well as from 3 rhesus monkeys before and after the induction of parkinsonism with the neurotoxin 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine. Results: In the parkinsonian condition, we identified a prominent oscillatory peak centered at 200-300 Hz that increased during movement. In patients the magnitude of highfrequency oscillation modulation was negatively correlated with bradykinesia. In monkeys, high-frequency oscillations were mostly absent in the naive condition but emerged after the neurotoxin 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine. In patients, spontaneous high-frequency oscillations were significantly attenuated on-medication. Conclusions: Our findings provide evidence in support of the hypothesis that exaggerated, movementmodulated high-frequency oscillations in the GPi are pathophysiological features of PD. These findings suggest that the functional role(s) of high-frequency oscillations may differ between the STN and GPi and motivate additional investigations into their relationship to motor control in normal and diseased states.

Controlling pallidal oscillations in real-time in Parkinson’s disease using evoked interference deep brain stimulation (eiDBS): proof of concept in the human

“…We tested eiDBS in-vivo with the study participant using the stimulation parameters found to be optimal (stimulation at 2 mA and phase angles equal to -85 and 95 deg for suppression and amplification). eiDBS was capable of suppressing or amplifying pallidal activity in the targeted frequency interval (16)(17)(18)(19)(20)(21)(22). See Figs.…”

“…Using the patient-specific ER mathematical models and recorded LFP data, we constructed a computer simulation (Fig. 2A,B) to characterize the neural modulation attained with eiDBS and search for the stimulation parameters (amplitude and phase angle) that maximized suppression and amplification of neural activity in the targeted band (16)(17)(18)(19)(20)(21)(22). See optimization curve in Fig.…”

“…The location of the DBS lead contacts in the GPi was confirmed based on information obtained during intraoperative electrophysiological mapping as well as co-registered preoperative 3T MRI and postoperative CT scans [21]. Electrode localization and orientation for this patient was previously described in [22]. Briefly, the lead orientation relative to the brain was derived using a modified version of the DiODe algorithm [23] and based on unique artifacts of the lead contacts and fiducial marker superior to the most distal contact from the lead tip.…”

“…For sensing, we selected contacts 2c and 4, whose differential LFP had the largest signal-to-noise ratio in the frequency band targeted for modulation (16)(17)(18)(19)(20)(21)(22). This frequency band was centered on the peak of the LFP power spectral density.…”

“…We tested eiDBS in a PD patient implanted with a directional DBS lead in the GPi and evaluated the suppression and amplification capabilities of this neuromodulation approach. eiDBS was capable of suppressing or amplifying GPi oscillations in the targeted frequency band (16)(17)(18)(19)(20)(21)(22) in real-time. Stimulation-evoked responses (ERs) that mediated this modulation resonated in the beta band, within the same frequency range where the peak power of the spontaneous LFPs was located.…”