Deep brain stimulation for Parkinson's disease modulates high-frequency evoked and spontaneous neural activity

Abstract

Deep brain stimulation is an established therapy for Parkinson's disease; however, its effectiveness is hindered by limited understanding of therapeutic mechanisms and the lack of a robust feedback signal for tailoring stimulation. We recently reported that subthalamic nucleus deep brain stimulation evokes a neural response resembling a decaying high-frequency (200-500 Hz) oscillation that typically has a duration of at least 10 ms and is localizable to the dorsal sub-region. As the morphology of this response suggests a propensity for the underlying neural circuitry to oscillate at a particular frequency, we have named it evoked resonant neural activity. Here, we determine whether this evoked activity is modulated by therapeutic stimulation – a critical attribute of a feedback signal. Furthermore, we investigated whether any related changes occurred in spontaneous local field potentials. Evoked and spontaneous neural activity was intraoperatively recorded from 19 subthalamic nuclei in patients with Parkinson's disease. Recordings were obtained before therapeutic stimulation and during 130 Hz stimulation at increasing amplitudes (0.67–3.38 mA), ‘washout’ of therapeutic effects, and non-therapeutic 20 Hz stimulation. Therapeutic efficacy was assessed using clinical bradykinesia and rigidity scores. The frequency and amplitude of evoked resonant neural activity varied with the level of 130 Hz stimulation (p < .001). This modulation coincided with improvement in bradykinesia and rigidity (p < .001), and correlated with spontaneous beta band suppression (p < .001). Evoked neural activity occupied a similar frequency band to spontaneous high-frequency oscillations (200-400 Hz), both of which decreased to around twice the 130 Hz stimulation rate. Non-therapeutic stimulation at 20 Hz evoked, but did not modulate, resonant activity. These results indicate that therapeutic deep brain stimulation alters the frequency of evoked and spontaneous oscillations recorded in the subthalamic nucleus that are likely generated by loops within the cortico-basal ganglia-thalamo-cortical network. Evoked resonant neural activity therefore has potential as a tool for providing insight into brain network function and has key attributes of a dynamic feedback signal for optimizing therapy.

Electroceutically induced subthalamic high frequency oscillations and evoked compound activity may explain the mechanism of therapeutic stimulation in Parkinson's Disease

“…It is important to note that a contradictory hypothesis was suggested by Sinclair et al 44 , since the authors report a decrease in HFO frequency after high-frequency DBS. The authors suggested that DBS and dopaminergic therapy have different mechanisms of action.…”

Proceedings of the Seventh Annual Deep Brain Stimulation Think Tank: Advances in Neurophysiology, Adaptive DBS, Virtual Reality, Neuroethics and Technology

“…These findings raise the possibility that the ERNA amplitude could help guide electrode contact selection. Moreover, the frequency of ERNA modulates during DBS (Supplementary Figure S4E), reducing on average from around 310 Hz pre-therapy to around 260 Hz when therapy reaches clinically effective levels (Sinclair et al, 2019). It is intriguing that the latter value is around twice the commonly employed applied STN DBS frequency of 130 Hz, though it is crucial to note that the plateau frequency that ERNA reaches with therapeutic DBS differs between individuals.…”

“…However, these oscillations are small (<15 µV), and can be difficult to detect in and across certain conditions. In this light, we propose a new biomarker, evoked resonant neural activity (ERNA), which is significantly larger than the beta band (>100 µV) and can be reliably recorded across all conditions (Sinclair et al, 2018(Sinclair et al, , 2019. ERNA is evoked and recorded from within the STN itself and is generated by a train of square biphasic pulses.…”

“…Future work will assess whether the plateau frequency that ERNA reaches with therapeutic DBS could inform on the ideal DBS frequency to apply in individuals. During DBS, modulation of ERNA frequency correlates with the amplitude of beta oscillations (a useful surrogate of the clinical state of the patient; Supplementary Figure S4F; Sinclair et al, 2019). During programming, the ERNA could facilitate optimization of more precise settings, especially given that there is a larger amplitude in the dorsal motor region of the STN (Sinclair et al, 2018).…”

Physiological Artefacts and the Implications for Brain-Machine-Interface Design

“…The advantage of these signals is that they use methods of synchronous detection to avoid artifacts. Similar to chopper methods to remove low-frequency offset and drift [25], if the stimulation frequency is above the cardiac energy, then the impact of the cardiac artifact is greatly attenuated. The major trade-off of this technique is the bandwidth required for sampling, typically ten times higher than for low frequency field potentials, and the need to manage stimulation artifacts to allow for resolution of physiological signals within milliseconds of stimulation termination [24], [26].…”