Beta-driven closed-loop deep brain stimulation can compromise human motor behavior in Parkinson’s Disease

Abstract

Closed-loop or adaptive deep brain stimulation (DBS) for Parkinson's Disease (PD) has shown comparable clinical improvements to continuous stimulation, yet with less stimulation times and side effects. In this form of control, stimulation is driven by pathological beta oscillations recorded from the subthalamic nucleus, which have been shown to correlate with PD motor symptoms. An important consideration is that beta activity is itself modulated during volitional movements, yet it is unknown the impact that these volitional modulations may have on the efficacy of closed-loop systems. Here, three PD patients performed a functional reaching task during closed-loop stimulation while we measured their motor behavior. Our results show that closed-loop stimulation can alter motor performance at distinct movement intervals. Of particular relevance, closed-loop DBS compromised behavior during the returning period by increasing the amount of submovements executed, and in turn delayed movement termination. Following these findings, we hypothesize that the use of machine learning decoding different movement intervals to fully switch off the stimulator may be beneficial, and present here an exemplary approach decoding the initiation of the movement returning interval above chance level. These findings highlight the importance of evaluating these systems during functional tasks, and the need of extracting more robust biomarkers encoding ongoing symptoms or tasks execution intervals. Abbreviations: DBS: deep brain stimulation LFP: local field potentials PD: Parkinson's disease STN: subthalamic nucleus LMM: linear mixed model UPDRS: Unified Parkinson's Disease rating scale CLDBS: closed-loop deep brain stimulation AUC: area under the receiver-operating characteristic curve

Gait-related frequency modulation of beta oscillatory activity in the subthalamic nucleus of parkinsonian patients

“…3). Of relevance, the use of a suboptimal biomarker could be detrimental, possibly interfering with the FM needed for the transition from upright quiet standing to steady state walking [15].…”

“…However, caution is warranted in using beta oscillations for aDBS, as they are relevant for many perceptual, cognitive, and motor physiological processes [14]. Indeed, while ameliorating certain symptoms, power beta modulation might impair the residual task-related physiological coding capacity of the stimulated area [15]. Furthermore, amplitude modulation might not capture circuit dynamics, such as frequency-and phase-specific synchronization [16,17], which would be fundamental in routing the information flow across distant brain areas [18,19].…”

Acute effects of adaptive Deep Brain Stimulation in Parkinson’s disease

“…However, this might reflect the reduction in the response of bradykinesia items to stimulation reported in some of the studies following DBS patients for more than 5 years [ 3 , 4 ]. This may also explain why the level of improvement in subUPDRS scores with both aDBS and cDBS (~20%) was at the lower limit of the range of improvements seen under similar blinded conditions when these interventions are contrasted acutely following electrode implantation [ 9 , 10 , 12 , 14 , 32 ]. Note too that scores from blinded video assessments are lower than those made during direct, unblinded clinical examination [ 9 ].…”

Acute effects of Adaptive Deep Brain Stimulation in Parkinson’s disease

“…However, this might reflect the reduction in the response of bradykinesia items to stimulation reported in some of the studies following DBS patients for more than 5 years [3,4]. This may also explain why the level of improvement in subUPDRS scores with both aDBS and cDBS (~20%) was at the lower limit of the range of improvements seen under similar blinded conditions when these interventions are contrasted acutely following electrode implantation [9,10,12,14,33]. Note too that scores from blinded video assessments are lower than those made during direct, unblinded clinical examination [9].…”

“…Although studies have confirmed the efficacy of 'beta-based' aDBS [9][10][11][12][13], and suggested a superior side effect profile compared to continuous, conventional, DBS (cDBS) [14,15], these have been mostly performed in newly implanted patients. Such studies are potentially compromised by the microlesion effect [16], as this confounding factor provides temporary symptom relief, which can mask the true effects of stimulation.…”