No biomarker of Parkinson’s disease exists that allows clinicians to adjust chronic therapy, either medication or deep brain stimulation, with real-time feedback. Consequently, clinicians rely on time-intensive, empirical, and subjective clinical assessments of motor behaviour and adverse events to adjust therapies. Accumulating evidence suggests that hypokinetic aspects of Parkinson’s disease and their improvement with therapy are related to pathological neural activity in the beta band (beta oscillopathy) in the subthalamic nucleus. Additionally, effectiveness of deep brain stimulation may depend on modulation of the dorsolateral sensorimotor region of the subthalamic nucleus, which is the primary site of this beta oscillopathy. Despite the feasibility of utilizing this information to provide integrated, biomarker-driven precise deep brain stimulation, these measures have not been brought together in awake freely moving individuals. We sought to directly test whether stimulation-related improvements in bradykinesia were contingent on reduction of beta power and burst durations, and/or the volume of the sensorimotor subthalamic nucleus that was modulated. We recorded synchronized local field potentials and kinematic data in 16 subthalamic nuclei of individuals with Parkinson’s disease chronically implanted with neurostimulators during a repetitive wrist-flexion extension task, while administering randomized different intensities of high frequency stimulation. Increased intensities of deep brain stimulation improved movement velocity and were associated with an intensity-dependent reduction in beta power and mean burst duration, measured during movement. The degree of reduction in this beta oscillopathy was associated with the improvement in movement velocity. Moreover, the reduction in beta power and beta burst durations was dependent on the theoretical degree of tissue modulated in the sensorimotor region of the subthalamic nucleus. Finally, the degree of attenuation of both beta power and beta burst durations, together with the degree of overlap of stimulation with the sensorimotor subthalamic nucleus significantly explained the stimulation-related improvement in movement velocity. The above results provide direct evidence that subthalamic nucleus deep brain stimulation-related improvements in bradykinesia are related to the reduction in beta oscillopathy within the sensorimotor region. With the advent of sensing neurostimulators, this beta oscillopathy combined with lead location could be used as a marker for real-time feedback to adjust clinical settings or to drive closed-loop deep brain stimulation in freely moving individuals with Parkinson’s disease.

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Objective: To investigate the progression of neural and motor features of Parkinson's disease in a longitudinal study, after washout of medication and bilateral subthalamic nucleus deep brain stimulation (STN DBS). Methods: Participants with clinically established Parkinson's disease underwent bilateral implantation of DBS leads (18 participants, 13 male) within the STN using standard functional frameless stereotactic technique and multi-pass microelectrode recording. Both DBS leads were connected to an implanted investigative sensing neurostimulator (Activa TM PC + S, Medtronic, PLC). Resting state STN local field potentials (LFPs) were recorded and motor disability, (the Movement Disorder Society-Unified Parkinson's Disease Rating Scalemotor subscale, MDS-UPDRS III) was assessed off therapy at initial programming, and after 6 months, 1 year, and yearly out to 5 years of treatment. The primary endpoint was measured at 3 years. At each visit, medication had been held for over 12/ 24 h and DBS was turned off for at least 60 min, by which time LFP spectra reached a steady state. Results: After 3 years of chronic DBS, there were no increases in STN beta band dynamics (p = 0.98) but there were increases in alpha band dynamics (p = 0.0027, 25 STNs). Similar results were observed in a smaller cohort out to 5 years. There was no increase in the MDS-UPDRS III score. Interpretation: These findings provide evidence that the beta oscillopathy does not substantially progress following combined STN DBS plus medication in moderate to advanced Parkinson's disease.

Parkinson's disease, Deep Brain Stimulation HighlightsA novel method for measuring variability in subthalamic local field potential oscillations in Parkinson's disease using a physiological baseline of power.Modeling normal brain activity using a physiological 1/f spectrum.Burst durations depend on choice of bandwidth and center frequency.Defining an inert frequency band whose mean burst duration overlap the physiological 1/f spectrum, from which the baseline was determined.Burst durations progressively shortened during increasing intensities of deep brain stimulation. ABSTRACT BackgroundPathological bursts of neural activity in Parkinson's disease present as exaggerated subthalamic neuronal oscillations in the 8-30 Hz frequency range and are related to motor impairment. New MethodThis study introduces a novel method for determining burst dynamics using a baseline that matches physiological 1/f spectrum activity. We used resting state local field potentials from people with Parkinson's disease and a simulated 1/f signal to measure beta burst durations, to demonstrate how tuning parameters (i.e., bandwidth and center frequency) affect burst durations, to compare this with high power threshold methods, and to study the effect of increasing neurostimulation intensities on burst duration. ResultsBurst durations calculated using the Anderson method captured the longest and broadest distribution of burst durations in a pathological beta band compared to previous methods. Mean beta band burst durations were significantly shorter on compared to off neurostimulation (p = 0.011), and their distribution was shifted towards that of the physiological 1/f spectrum during increasing intensities of stimulation. Comparison with Existing MethodExisting methods of measuring local field potential power either lack temporal specificity to detect bursts (power spectral density diagrams and spectrograms) or include only higher power bursts and portions of the neural signal. ConclusionsWe suggest that this novel method is well suited to quantify the full range of fluctuations in beta band neural activity in the Parkinsonian brain. This method may reveal more relevant feedback biomarkers than averaged beta band power for future closed loop algorithms.

DBS Think Tank IX was held on August 25–27, 2021 in Orlando FL with US based participants largely in person and overseas participants joining by video conferencing technology. The DBS Think Tank was founded in 2012 and provides an open platform where clinicians, engineers and researchers (from industry and academia) can freely discuss current and emerging deep brain stimulation (DBS) technologies as well as the logistical and ethical issues facing the field. The consensus among the DBS Think Tank IX speakers was that DBS expanded in its scope and has been applied to multiple brain disorders in an effort to modulate neural circuitry. After collectively sharing our experiences, it was estimated that globally more than 230,000 DBS devices have been implanted for neurological and neuropsychiatric disorders. As such, this year’s meeting was focused on advances in the following areas: neuromodulation in Europe, Asia and Australia; cutting-edge technologies, neuroethics, interventional psychiatry, adaptive DBS, neuromodulation for pain, network neuromodulation for epilepsy and neuromodulation for traumatic brain injury.