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

Abstract

Despite having remarkable utility in treating movement disorders, the lack of understanding of the underlying mechanisms of high-frequency deep brain stimulation (DBS) is a main challenge in choosing personalized stimulation parameters. Here we investigate the modulations in local field potentials induced by therapeutic and non-therapeutic electrical stimulation of the subthalamic nucleus (STN) in Parkinson’s disease patients undergoing DBS surgery. We find that therapeutic high-frequency stimulation (130-180 Hz) induces high-frequency oscillations (~300 Hz, HFO) similar to those observed with pharmacological treatment. Along with HFOs, we also observed evoked compound activity (ECA) after each stimulation pulse. While ECA was observed in both therapeutic and non-therapeutic (20Hz) stimulation, the HFOs were induced only with therapeutic frequencies and the associated ECA were significantly more resonant. The relative degree of enhancement in the HFO power was related to the interaction of stimulation pulse with the phase of ECA.We propose that high-frequency STN-DBS tunes the neural oscillations to their healthy/treated state, similar to pharmacological treatment, and the stimulation frequency to maximize these oscillations can be inferred from the phase of ECA waveforms of individual subjects. The induced HFOs can, therefore, be utilized as a marker of successful re-calibration of the dysfunctional circuit generating PD symptoms.

Persistent synaptic inhibition of the subthalamic nucleus by high frequency stimulation

“…26 To this end, evoked resonant neural activity 27 has recently been hypothesized to be a substrate of STN efferent-driven recurrent inhibition from GPe. 28,29 This interpretation would also be consistent with persistent pallidal synaptic inhibition at high frequencies described in this study, given that evoked resonant neural activity is a resilient signal which occurs at frequencies above 250 Hz.…”

Evoked potentials generated by deep brain stimulation for Parkinson's disease

“…A recent report has shown that the frequency of the oscillation changes between periods and the signal lacks the attractor dynamics at DBS frequency harmonics [16]. However, Awad et al [61] found that paired pulse stimulation induced shortterm facilitation suggesting resonant activity, and Ozturk et al [67] observed evoked activity was greater at 160 Hz STN stimulation compared to 180 Hz stimulation. Only STN DBS demonstrates the later, oscillatory signal suggesting specific circuitry components are likely responsible [17,18,63,68].…”

“…Any correlation between DLEPs and HFO could also be explained as one being the epiphenomenon of the other. However, Ozturk et al [67] reports that the HFO persists after DBS pulse artifact and evoked waveforms were removed using a template extraction filter, although HFO did not occur when stimulating the STN at 20 Hz. These results suggest HFOs and evoked potentials may be independent of each other.…”

Theta-burst stimulation entrains frequency-specific oscillatory responses

“…There is mounting evidence that TBS renders change to the brain, but the way in which TBS directly influences neural signals is unknown. Human studies of invasive non-TBS stimulation paints a mixed picture: some evidence suggests neural responses will generally align with the stimulation frequency [ 18 , 19 ], while others have found that low-frequency responses can be readily observed even following high-frequency (>100 Hz) stimulation [ 20 , 21 ]. However, there is broader agreement that evoked responses to cortical stimulation are constrained by functional and structural architecture [ 20 , 22 – 25 ].…”