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Competing Interests: Declaration of competing interest H B–S: none. AM: none.

Objective . To provide a design analysis and guidance framework for the implementation of concurrent stimulation and sensing during adaptive deep brain stimulation (aDBS) with particular emphasis on artifact mitigations. Approach . We defined a general architecture of feedback-enabled devices, identified key components in the signal chain which might result in unwanted artifacts and proposed methods that might ultimately enable improved aDBS therapies. We gathered data from research subjects chronically-implanted with an investigational aDBS system, Summit RC + S, to characterize and explore artifact mitigations arising from concurrent stimulation and sensing. We then used a prototype investigational implantable device, DyNeuMo, and a bench-setup that accounts for tissue-electrode properties, to confirm our observations and verify mitigations. The strategies to reduce transient stimulation artifacts and improve performance during aDBS were confirmed in a chronic implant using updated configuration settings. Main results. We derived and validated a 'checklist' of configuration settings to improve system performance and areas for future device improvement. Key considerations for the configuration include (a) active instead of passive recharge, (b) sense-channel blanking in the amplifier, (c) high-pass filter settings, (d) tissue-electrode impedance mismatch management, (e) time-frequency trade-offs in the classifier, (f) algorithm blanking and transition rate limits. Without proper channel configuration, the aDBS algorithm was susceptible to limit-cycles of oscillating stimulation independent of physiological state. By applying the checklist, we could optimize each block's performance characteristics within the overall system. With system-level optimization, a 'fast' aDBS prototype algorithm was demonstrated to be feasible without reentrant loops, and with noise performance suitable for subcortical brain circuits. Significance . We present a framework to study sources and propose mitigations of artifacts in devices that provide chronic aDBS. This work highlights the trade-offs in performance as novel sensing devices translate to the clinic. Finding the appropriate balance of constraints is imperative for successful translation of aDBS therapies. Clinical trial: Institutional Review Board and Investigational Device Exemption numbers: NCT02649166/IRB201501021 (University of Florida), NCT04043403/IRB52548 (Stanford University), NCT03582891/IRB1824454 (University of California San Francisco). IDE #180 097., (Creative Commons Attribution license.)

Freezing of gait (FOG) is a devastating motor symptom of Parkinson's disease that leads to falls, reduced mobility, and decreased quality of life. Reliably eliciting FOG has been difficult in the clinical setting, which has limited discovery of pathophysiology and/or documentation of the efficacy of treatments, such as different frequencies of subthalamic deep brain stimulation (STN DBS). In this study we validated an instrumented gait task, the turning and barrier course (TBC), with the international standard FOG questionnaire question 3 (FOG-Q3, r = 0.74, p < 0.001). The TBC is easily assembled and mimics real-life environments that elicit FOG. People with Parkinson's disease who experience FOG (freezers) spent more time freezing during the TBC compared to during forward walking (p = 0.007). Freezers also exhibited greater arrhythmicity during non-freezing gait when performing the TBC compared to forward walking (p = 0.006); this difference in gait arrhythmicity between tasks was not detected in non-freezers or controls. Freezers' non-freezing gait was more arrhythmic than that of non-freezers or controls during all walking tasks (p < 0.05). A logistic regression model determined that a combination of gait arrhythmicity, stride time, shank angular range, and asymmetry had the greatest probability of classifying a step as FOG (area under receiver operating characteristic curve = 0.754). Freezers' percent time freezing and non-freezing gait arrhythmicity decreased, and their shank angular velocity increased in the TBC during both 60 Hz and 140 Hz STN DBS (p < 0.05) to non-freezer values. The TBC is a standardized tool for eliciting FOG and demonstrating the efficacy of 60 Hz and 140 Hz STN DBS for gait impairment and FOG. The TBC revealed gait parameters that differentiated freezers from non-freezers and best predicted FOG; these may serve as relevant control variables for closed loop neurostimulation for FOG in Parkinson's disease., Competing Interests: Dr. Helen Bronte-Stewart is a member of a clinical advisory board for Medtronic Inc. and Scott Delp is a scientific advisor and board member of Cala Health, Circuit Therapeutics, and Zebra Medical Technologies, and receives compensation for this service. Dr.Helen Bronte-Stewart and Johanna O’Day have submitted a provisional patent as co-inventors of systems and methods for deep brain stimulation kinematic controllers (patent #S19-551). This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Closed loop deep brain stimulation (clDBS) in Parkinson's disease (PD) using subthalamic (STN) neural feedback has been shown to be efficacious only in the acute post-operative setting, using externalized leads and stimulators., Objective: To determine feasibility of neural (N)clDBS using the clinical implanted neurostimulator (Activa™ PC + S, FDA IDE approved) and a novel beta dual threshold algorithm in tremor and bradykinesia dominant PD patients on chronic DBS., Methods: 13 PD subjects (20 STNs), on open loop (ol)DBS for 22 ± 7.8 months, consented to NclDBS driven by beta (13-30 Hz) power using a dual threshold algorithm, based on patient specific therapeutic voltage windows. Tremor was assessed continuously, and bradykinesia was evaluated after 20 min of NclDBS using a repetitive wrist flexion-extension task (rWFE). Total electrical energy delivered (TEED) on NclDBS was compared to olDBS using the same active electrode., Results: NclDBS was tolerated for 21.67 [21.10-26.15] minutes; no subject stopped early. Resting beta band power was measurable and similar between tremor and bradykinesia dominant patients. NclDBS improved bradykinesia and tremor while delivering only 56.86% of the TEED of olDBS; rWFE velocity (p = 0.003) and frequency (p < 0.001) increased; tremor was below 0.15 rad/sec for 95.4% of the trial and averaged 0.26 rad/sec when present., Conclusion: This is the first study to demonstrate that STN NclDBS is feasible, efficacious and more efficient than olDBS in tremor and bradykinesia dominant PD patients, on long-term DBS, using an implanted clinical neurostimulator and driven by beta power with a novel dual threshold algorithm, based on customized therapeutic voltage windows., (Copyright © 2019. Published by Elsevier Inc.)

Clinical deep brain stimulation (DBS) technology is evolving to enable chronic recording of local field potentials (LFPs) that represent electrophysiological biomarkers of the underlying disease state. However, little is known about the biophysical basis of LFPs, or how the patient's unique brain anatomy and electrode placement impact the recordings. Therefore, we developed a patient-specific computational framework to analyze LFP recordings within a clinical DBS context. We selected a subject with Parkinson's disease implanted with a Medtronic Activa PC+S DBS system and reconstructed their subthalamic nucleus (STN) and DBS electrode location using medical imaging data. The patient-specific STN volume was populated with 235,280 multicompartment STN neuron models, providing a neuron density consistent with histological measurements. Each neuron received time-varying synaptic inputs and generated transmembrane currents that gave rise to the LFP signal recorded at DBS electrode contacts residing in a finite element volume conductor model. We then used the model to study the role of synchronous beta-band inputs to the STN neurons on the recorded power spectrum. Three bipolar pairs of simultaneous clinical LFP recordings were used in combination with an optimization algorithm to customize the neural activity parameters in the model to the patient. The optimized model predicted a 2.4-mm radius of beta-synchronous neurons located in the dorsolateral STN. These theoretical results enable biophysical dissection of the LFP signal at the cellular level with direct comparison to the clinical recordings, and the model system provides a scientific platform to help guide the design of DBS technology focused on the use of subthalamic beta activity in closed-loop algorithms. NEW & NOTEWORTHY The analysis of deep brain stimulation of local field potential (LFP) data is rapidly expanding from scientific curiosity to the basis for clinical biomarkers capable of improving the therapeutic efficacy of stimulation. With this growing clinical importance comes a growing need to understand the underlying electrophysiological fundamentals of the signals and the factors contributing to their modulation. Our model reconstructs the clinical LFP from first principles and highlights the importance of patient-specific factors in dictating the signals recorded.

Subthalamic nucleus (STN) local field potential (LFP) recordings demonstrate beta (13-30Hz) band oscillations in Parkinson's disease (PD) defined as elevations of spectral power. The amount of attenuation of beta band power on therapeutic levels of high frequency (HF) deep brain stimulation (DBS) and/or dopaminergic medication has been correlated with the degree of improvement in bradykinesia and rigidity from the therapy, which has led to the suggestion that elevated beta band power is a marker of PD motor disability. A fundamental question has not been answered: whether there is a prolonged attenuation of beta band power after withdrawal of chronic HF DBS and whether this is related to a lack of progression or even improvement in the underlying motor disability. Until now, in human PD subjects, STN LFP recordings were only attainable in the peri-operative period and after short periods of stimulation. For the first time, using an investigational, implanted sensing neurostimulator (Activa® PC+S, Medtronic, Inc.), STN LFPs and motor disability were recorded/assessed after withdrawal of chronic (6 and 12month) HF DBS in freely moving PD subjects. Beta band power was similar within 14s and 60min after stimulation was withdrawn, suggesting that "off therapy" experiments can be conducted almost immediately after stimulation is turned off. After withdrawal of 6 and 12months of STN DBS, beta band power was significantly lower (P<0.05 at 6 and 12months) and off therapy UPDRS scores were better (P<0.05 at 12months) compared to before DBS was started. The attenuation in beta band power was correlated with improvement in motor disability scores (P<0.05). These findings were supported by evidence of a gradual increase in beta band power in two unstimulated STNs after 24months and could not be explained by changes in lead impedance. This suggests that chronic HF DBS exerts long-term plasticity in the sensorimotor network, which may contribute to a lack of progression in underlying motor disability in PD., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Current deep brain stimulation paradigms deliver continuous stimulation to deep brain structures to ameliorate the symptoms of Parkinson's disease. This continuous stimulation has undesirable side effects and decreases the lifespan of the unit's battery, necessitating earlier replacement. A closed-loop deep brain stimulator that uses brain signals to determine when to deliver stimulation based on the occurrence of symptoms could potentially address these drawbacks of current technology. Attempts to detect Parkinsonian tremor using brain signals recorded during the implantation procedure have been successful. However, the ability of these methods to accurately detect tremor over extended periods of time is unknown. Here we use local field potentials recorded during a deep brain stimulation clinical follow-up visit 1 month after initial programming to build a tremor detection algorithm and use this algorithm to detect tremor in subsequent visits up to 8 months later. Using this method, we detected the occurrence of tremor with accuracies between 68-93%. These results demonstrate the potential of tremor detection methods for efficacious closed-loop deep brain stimulation over extended periods of time.

The proceedings of the 2nd Annual Deep Brain Stimulation Think Tank summarize the most contemporary clinical, electrophysiological, and computational work on DBS for the treatment of neurological and neuropsychiatric disease and represent the insights of a unique multidisciplinary ensemble of expert neurologists, neurosurgeons, neuropsychologists, psychiatrists, scientists, engineers and members of industry. Presentations and discussions covered a broad range of topics, including advocacy for DBS, improving clinical outcomes, innovations in computational models of DBS, understanding of the neurophysiology of Parkinson's disease (PD) and Tourette syndrome (TS) and evolving sensor and device technologies.

Objectives: 1) To characterize patterns of globus pallidus interna neural synchrony in patients with secondary dystonia; 2) to determine whether neural hypersynchrony in the globus pallidus externa (GPe) and interna (GPi) is attenuated during high frequency deep brain stimulation (HF DBS) in a patient with DYT3+ dystonia and in a patient with secondary dystonia due to childhood encephalitis., Materials and Methods: We recorded local field potentials from the DBS lead in the GPi of four patients (seven hemispheres) with secondary dystonia and from one patient (two hemispheres) with primary DYT3+ dystonia. In two patients, we also recorded pallidal local field potentials during the administration of 10 sec epochs of HF DBS., Results: Power spectral densities during rest demonstrated visible peaks in the beta band in seven out of nine cases. In DYT3+ dystonia, power in the alpha and beta bands, but not theta band, was attenuated during HF DBS in the GPe and in GPi, and attenuation was most prominent in the high beta band. This patient demonstrated an early and maintained improvement in dystonia. There was no beta peak and the power spectrum was not attenuated during HF DBS in a patient with secondary dystonia due to childhood encephalitis., Conclusions: These results suggest that beta hypersynchrony, demonstrated now in both primary and secondary dystonia, may play a pathophysiological role in pathological hyperkinesis. Further investigation is needed in a larger cohort of well-characterized primary and secondary dystonia patients., (© 2012 International Neuromodulation Society.)

High frequency deep brain stimulation is an effective therapy for motor symptoms in Parkinson's disease. However, the relative clinical efficacy of regular versus non-regular temporal patterns of stimulation in Parkinson's disease remains unclear. To determine the temporal characteristics of non-regular temporal patterns of stimulation important for the treatment of Parkinson's disease, we compared the efficacy of temporally regular stimulation with four non-regular patterns of stimulation in subjects with Parkinson's disease using an alternating finger tapping task. The patterns of stimulation were also evaluated in a biophysical model of the parkinsonian basal ganglia that exhibited prominent oscillatory activity in the beta frequency range. The temporal patterns of stimulation differentially improved motor task performance. Three of the non-regular patterns of stimulation improved performance of the finger tapping task more than temporally regular stimulation. In the computational model all patterns of deep brain stimulation suppressed beta band oscillatory activity, and the degree of suppression was strongly correlated with the clinical efficacy across stimulation patterns. The three non-regular patterns of stimulation that improved motor performance over regular stimulation also suppressed beta band oscillatory activity in the computational model more effectively than regular stimulation. These data demonstrate that the temporal pattern of stimulation is an important consideration for the clinical efficacy of deep brain stimulation in Parkinson's disease. Furthermore, non-regular patterns of stimulation may ameliorate motor symptoms and suppress pathological rhythmic activity in the basal ganglia more effectively than regular stimulation. Therefore, non-regular patterns of deep brain stimulation may have useful clinical and experimental applications., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Aims and Objectives: To assess the effect of disease severity, dopaminergic medication (med) and STN-DBS on postural stability in Parkinson's disease (PD)., Methods: Postural sway in quiet stance, and the Unified Parkinson's Disease Rating Scale (motor) (UPDRS III) were evaluated in 129 subjects in the off-med state. A subgroup of 28 subjects was studied on-med and after STN-DBS. Postural sway was measured using center of pressure (CoP) root mean square displacement (RMS(CoP)) and mean velocity (V(CoP)) in the anterior-posterior (AP) and medial-lateral (ML) directions., Results: All CoP parameters were larger in moderate/advanced subjects vs controls (P < 0.001) and early subjects. Only RMS(CoP)ML was larger in early subjects vs controls (P < 0.05). Med, DBS and DBS + med decreased UPDRS III compared to off-med (P < 0.001). RMS(CoP)ML and V(CoP)ML were larger on-med vs off-med and vs DBS (P < 0.001). Compared to controls and PD subjects with normal CoP sway off-med, med increased all CoP parameters (P < 0.01) but DBS returned V(CoP)ML to normal values. For 'abnormal' PD subjects, STN-DBS improved the excessive V(CoP) in ML compared to off and on-med pre-DBS (P < 0.05)., Conclusions: Postural sway in quiet stance increased with disease severity. Only ML CoP displacement was abnormal in early stage PD, and this may be a compensatory mechanism. Medication increased ML postural sway. In 'normal' PD subjects, STN-DBS reversed medication induced postural instability. Subjects with abnormal balance in quiet stance did not benefit from medication or DBS, except for improvement in ML CoP velocity from DBS. This may serve to reduce postural instability and falling., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

When considering a patient with dystonia for deep brain stimulation (DBS) surgery several factors need to be considered. Level B evidence has shown that all motor features and associated pain in primary generalized and segmental dystonia are potentially responsive to globus pallidus internus (GPi) DBS. However, improvements in clinical series of ≥ 90% may reflect methods that need improvement, and larger prospective studies are needed to address these factors. Nevertheless, to date the selection criteria for DBS-specifically in terms of patient features (severity and nature of symptoms, age, time of evolution, or any other demographic or disease aspects)--have not been assessed in a systematic fashion. In general, dystonia patients are not considered for DBS unless medical therapies have been previously and extensively tested. The vast majority of reported patients have had DBS surgery when the disease was provoking important disability, with loss of independence and impaired quality of life. There does not appear to be an upper age limit or a minimum age limit, although there are no published data regarding the outcome of GPi DBS for dystonia in children younger than 7 years of age. There is currently no enough evidence to prove that subjects with primary--generalized dystonia who undergo DBS at an early age and sooner rather than later after disease onset may gain more benefit from DBS than those undergoing DBS after the development of fixed skeletal deformities. There is no enough evidence to refuse or support consideration of DBS in patients with previous ablative procedures., (Copyright © 2011 Movement Disorder Society.)

Producing accurate movements may rely on the functional independence of sensorimotor circuits within basal ganglia nuclei. In parkinsonism there is abnormal synchrony of electrical activity within these circuits that results in a loss of independence across motor channels. Local field potential (LFP) recordings reflect the summation of local electrical fields and an increase in LFP power reflects increased synchrony in local neuronal networks. We recorded LFPs from the subthalamic nucleus (STN) deep brain stimulation (DBS) lead in the operating room in 22 cases from 16 subjects with Parkinson's disease (PD) who were off medication. There was elevated LFP power at beta frequencies (13-35 Hz) at rest. The LFP spectral profile was consistent across several periods of rest that were separated by movement and/or DBS, and appeared to be a relatively stationary phenomenon. The spectral profile and frequencies of the beta-band peak(s) varied among subjects but were similar between the right and left STNs within certain individuals. These results suggest that the LFP spectrum at rest may characterize a "signature" rhythm for an individual with PD. Beta-band power was attenuated after intra-operative STN DBS (p<0.05). The attenuation lasted for 10 s after short periods (30 s) and for up to 50 s after longer periods (5 min) of DBS. The finding that longer periods of DBS attenuated beta power for a longer time suggests that there may be long-acting functional changes to networks in the STN in PD after chronic DBS.

Background: Deep brain stimulation (DBS) is gaining wide acceptance as treatment for Parkinson's disease (PD), essential tremor, and dystonia., Methods: A 40-item questionnaire commissioned by the DBS Study Group was sent to 46 centers that had performed at least 25 DBS implantations. These centers were identified through the DBS Study Group, other professional societies, and with the assistance of the Medtronic Corporation. The results were then tabulated and descriptive analyses were performed., Results: Thirty-six of 47 centers (77%) responded, they had implanted 4,553 patients. The timing for bilaterally implanted patients varied, as 13 sites almost always implanted simultaneously whereas 14 sites almost never implanted simultaneously. Stereotactic frames included Leksell (n = 19), CRW (n = 15) and Compass (n = 2). Post-placement imaging was routinely performed by almost all centers and included MRI (n = 23), CT (n = 4), CT/MRI variably (n = 5), and ventriculography (n = 1). Two centers used more than one electrode per side. The 34 centers that used a single electrode averaged 2.3 +/- 1.4 passes per electrode (range: 1-18 passes). Most centers used macro-stimulation to confirm placement by assessing the intra-operative clinical response (n = 34), and to assess for adverse events (n = 26) at high voltages, averaging 6.7 +/- 2.3 V (range: 4-10). The initial activation averaged 18 +/- 12 days after electrode placement (average range: 11 +/- 10 to 28 +/- 18 days, absolute range: 1-90 days). Most sites had several programmers; however, the primary programmers were neurology staff (n = 15), the neurologist (n = 13), neurosurgery staff (n = 6), the neurosurgeon (n = 2), or a physiatrist (n = 1). Twelve centers automatically reduced PD medications on the day of initial activation, 9 centers reduced them variably, and 16 centers initially did not reduce them. Eventually, 80.4% of patients were reported to have some dose reduction, and 47.1% had a greater than 50% reduction of PD medications., Conclusions: Strategies regarding DBS placement and adjustment vary in North America., (Copyright 2005 S. Karger AG, Basel.)