A systematic review of local field potential physiomarkers in Parkinson’s disease: from clinical correlations to adaptive deep brain stimulation algorithms

Abstract

Deep brain stimulation (DBS) treatment has proven effective in suppressing symptoms of rigidity, bradykinesia, and tremor in Parkinson’s disease. Still, patients may suffer from disabling fluctuations in motor and non-motor symptom severity during the day. Conventional DBS treatment consists of continuous stimulation but can potentially be further optimised by adapting stimulation settings to the presence or absence of symptoms through closed-loop control. This critically relies on the use of ‘physiomarkers’ extracted from (neuro)physiological signals. Ideal physiomarkers for adaptive DBS (aDBS) are indicative of symptom severity, detectable in every patient, and technically suitable for implementation. In the last decades, much effort has been put into the detection of local field potential (LFP) physiomarkers and in their use in clinical practice. We conducted a research synthesis of the correlations that have been reported between LFP signal features and one or more specific PD motor symptoms. Features based on the spectral beta band (~ 13 to 30 Hz) explained ~ 17% of individual variability in bradykinesia and rigidity symptom severity. Limitations of beta band oscillations as physiomarker are discussed, and strategies for further improvement of aDBS are explored.

Adaptive Stimulations in a Biophysical Network Model of Parkinson’s Disease

“…At the present moment, there is one commercially available brain stimulation system that provides closed-loop DBS [ 11 ]. While research on aDBS is still in its early stages, the preliminary findings suggest that aDBS is superior to the current standard open-loop HF stimulation being used [ 51 , 52 , 53 ]. Meta-analysis of the existing studies has proven to be challenging due to the heterogeneity of research methodologies and the small number of studies that have been conducted [ 52 ].…”

In Search of a Feedback Signal for Closed-Loop Deep Brain Stimulation: Stimulation of the Subthalamic Nucleus Reveals Altered Glutamate Dynamics in the Globus Pallidus in Anesthetized, 6-Hydroxydopamine-Treated Rats

“…The main focus of developing adaptive or feedback-controlled DBS has been on finding an appropriate biomarker that reflects the entire spectrum of parkinsonian symptoms [ 8 , 37 ]. Finding an ideal biomarker has not, thus far, been possible [ 9 , 10 ]. A variety of biomarkers, usually unprocessed or processed, restricted frequency domains of the LFPs measured in the STN at the site of DBS, have been used for feedback-controlled DBS, but none of them has been shown to be superior to the tried and true open loop tuning of DBS over time based on physician-observed symptom control and minimization of side effects [ 10 ].…”

“…A variety of biomarkers, usually unprocessed or processed, restricted frequency domains of the LFPs measured in the STN at the site of DBS, have been used for feedback-controlled DBS, but none of them has been shown to be superior to the tried and true open loop tuning of DBS over time based on physician-observed symptom control and minimization of side effects [ 10 ]. Individual components of the spectral characteristics of LFPs in the STN turn out to be poorly correlated with the full spectrum of parkinsonian symptoms, and even the correlations between the specific symptoms (e.g., rigidity) and restricted spectral domains of LFPs are weak and variable among patients with PD [ 9 ]. The transfer functions that we identified in the 6-OHDA-treated rats tell a similar story: much as LFP activity in the STN is poorly or weakly correlated with parkinsonian symptoms, glutamate levels in the STN are poorly correlated with loss of dopaminergic neurons in the SNc.…”

“…A similar strategy based on glutamate levels in the STN seems unlikely to work for systems designed to use glutamate levels as the feedback signal because glutamate levels are not changed appreciably at the site of stimulation in the STN by the co-existing loss of dopaminergic neurons in the SNc. That a strategy in which stimulation and feedback signal detection occur in the same anatomical location is less than ideal, is reflected in the lack of significantly improved control of the spectrum of parkinsonian symptoms achieved to date by adaptive DBS compared to the usual, tried and true, open-loop tuning of DBS [ 9 , 10 ].…”

“…Once the optimal stimulation waveform has been chosen, it is programmed into the stimulator, and the device operates in an open-loop mode with no feedback from the brain—the stimulation is dissociated from any of its immediate effects within the central nervous system. Numerous surrogate indices to try to improve the optimization process have been suggested, usually based on electrophysiological signatures of the circuit pathology of PD in the STN or GPi (e.g., the burstiness of neuronal activity in the STN or the spectral characteristics of local field potentials (LFPs) in the STN or other emergent electrophysiological patterns in the LFPs), but no single surrogate measure is clearly better than the tried and true method across the spectrum of parkinsonian symptoms [ 8 , 9 , 10 ].…”