Generalized sleep decoding with basal ganglia signals in multiple movement disorders.

Sleep disturbances profoundly affect the quality of life in individuals with neurological disorders. Closed-loop deep brain stimulation (DBS) holds promise for alleviating sleep symptoms, however, this technique necessitates automated sleep stage decoding from intracranial signals. We leveraged overnight data from 121 patients with movement disorders (Parkinson's disease, Essential Tremor, Dystonia, Essential Tremor, Huntington's disease, and Tourette's syndrome) in whom synchronized polysomnograms and basal ganglia local field potentials were recorded, to develop a generalized, multi-class, sleep specific decoder - BGOOSE. This generalized model achieved 85% average accuracy across patients and across disease conditions, even in the presence of recordings from different basal ganglia targets. Furthermore, we also investigated the role of electrocorticography on decoding performances and proposed an optimal decoding map, which was shown to facilitate channel selection for optimal model performances. BGOOSE emerges as a powerful tool for generalized sleep decoding, offering exciting potentials for the precision stimulation delivery of DBS and better management of sleep disturbances in movement disorders.

Proceedings of the 11th Annual Deep Brain Stimulation Think Tank: pushing the forefront of neuromodulation with functional network mapping, biomarkers for adaptive DBS, bioethical dilemmas, AI-guided neuromodulation, and translational advancements.

The Deep Brain Stimulation (DBS) Think Tank XI was held on August 9-11, 2023 in Gainesville, Florida with the theme of "Pushing the Forefront of Neuromodulation". The keynote speaker was Dr. Nico Dosenbach from Washington University in St. Louis, Missouri. He presented his research recently published in Nature inn a collaboration with Dr. Evan Gordon to identify and characterize the somato-cognitive action network (SCAN), which has redefined the motor homunculus and has led to new hypotheses about the integrative networks underpinning therapeutic DBS. 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 DBS technologies, as well as logistical and ethical issues facing the field. The group estimated that globally more than 263,000 DBS devices have been implanted for neurological and neuropsychiatric disorders. This year's meeting was focused on advances in the following areas: cutting-edge translational neuromodulation, cutting-edge physiology, advances in neuromodulation from Europe and Asia, neuroethical dilemmas, artificial intelligence and computational modeling, time scales in DBS for mood disorders, and advances in future neuromodulation devices.

Multi-night cortico-basal recordings reveal mechanisms of NREM slow-wave suppression and spontaneous awakenings in Parkinson's disease.

Sleep disturbance is a prevalent and disabling comorbidity in Parkinson's disease (PD). We performed multi-night (n = 57) at-home intracranial recordings from electrocorticography and subcortical electrodes using sensing-enabled Deep Brain Stimulation (DBS), paired with portable polysomnography in four PD participants and one with cervical dystonia (clinical trial: NCT03582891). Cortico-basal activity in delta increased and in beta decreased during NREM (N2 + N3) versus wakefulness in PD. DBS caused further elevation in cortical delta and decrease in alpha and low-beta compared to DBS OFF state. Our primary outcome demonstrated an inverse interaction between subcortical beta and cortical slow-wave during NREM. Our secondary outcome revealed subcortical beta increases prior to spontaneous awakenings in PD. We classified NREM vs. wakefulness with high accuracy in both traditional (30 s: 92.6 ± 1.7%) and rapid (5 s: 88.3 ± 2.1%) data epochs of intracranial signals. Our findings elucidate sleep neurophysiology and impacts of DBS on sleep in PD informing adaptive DBS for sleep dysfunction.

Towards therapeutic electrophysiological neurofeedback in Parkinson's disease.

Neurofeedback (NF) techniques support individuals to self-regulate specific features of brain activity, which has been shown to impact behavior and potentially ameliorate clinical symptoms. Electrophysiological NF (epNF) may be particularly impactful for patients with Parkinson's disease (PD), as evidence mounts to suggest a central role of pathological neural oscillations underlying symptoms in PD. Exaggerated beta oscillations (12-30 Hz) in the basal ganglia-cortical network are linked to motor symptoms (e.g., bradykinesia, rigidity), and beta is reduced by successful therapy with dopaminergic medication and Deep Brain Stimulation (DBS). PD patients also experience non-motor symptoms related to sleep, mood, motivation, and cognitive control. Although less is known about the mechanisms of non-motor symptoms in PD and how to successfully treat them, low frequency neural oscillations (1-12 Hz) in the basal ganglia-cortical network are particularly implicated in non-motor symptoms. Here, we review how cortical and subcortical epNF could be used to target motor and non-motor specific oscillations, and potentially serve as an adjunct therapy that enables PD patients to endogenously control their own pathological neural activities. Recent studies have demonstrated that epNF protocols can successfully support volitional control of cortical and subcortical beta rhythms. Importantly, this endogenous control of beta has been linked to changes in motor behavior. epNF for PD, as a casual intervention on neural signals, has the potential to increase understanding of the neurophysiology of movement, mood, and cognition and to identify new therapeutic approaches for motor and non-motor symptoms.

Motor network gamma oscillations in chronic home recordings predict dyskinesia in Parkinson's disease.

In Parkinson's disease, imbalances between "antikinetic" and "prokinetic" patterns of neuronal oscillatory activity are related to motor dysfunction. Invasive brain recordings from the motor network have suggested that medical or surgical therapy can promote a prokinetic state by inducing narrowband gamma rhythms (65-90 Hz). Excessive narrowband gamma in the motor cortex promotes dyskinesia in rodent models, but the relationship between narrowband gamma and dyskinesia in humans has not been well established. To assess this relationship, we used a sensing-enabled deep brain stimulator system, attached to both motor cortex and basal ganglia (subthalamic or pallidal) leads, paired with wearable devices that continuously tracked motor signs in the contralateral upper limbs. We recorded 984 hours of multisite field potentials in 30 hemispheres of 16 subjects with Parkinson's disease (2/16 female, mean age 57 ± 12 years) while at home on usual antiparkinsonian medications. Recordings were done two to four weeks after implantation, prior to starting therapeutic stimulation. Narrowband gamma was detected in the precentral gyrus, subthalamic nucleus, or both structures on at least one side of 92% of subjects with a clinical history of dyskinesia. Narrowband gamma was not detected in the globus pallidus. Narrowband gamma spectral power in both structures co-fluctuated similarly with contralateral wearable dyskinesia scores (mean correlation coefficient of ρ=0.48 with a range of 0.12-0.82 for cortex, ρ=0.53 with a range of 0.5-0.77 for subthalamic nucleus). Stratification analysis showed the correlations were not driven by outlier values, and narrowband gamma could distinguish "on" periods with dyskinesia from "on" periods without dyskinesia. Time lag comparisons confirmed that gamma oscillations herald dyskinesia onset without a time lag in either structure when using 2-minute epochs. A linear model incorporating the three oscillatory bands (beta, theta/alpha, and narrowband gamma) increased the predictive power of dyskinesia for several subject hemispheres. We further identified spectrally distinct oscillations in the low gamma range (40-60 Hz) in three subjects, but the relationship of low gamma oscillations to dyskinesia was variable. Our findings support the hypothesis that excessive oscillatory activity at 65-90 Hz in the motor network tracks with dyskinesia similarly across both structures, without a detectable time lag. This rhythm may serve as a promising control signal for closed-loop deep brain stimulation using either cortical or subthalamic detection.

Beta and theta oscillations track effort and previous reward in human basal ganglia and prefrontal cortex during decision making.

Choosing whether to exert effort to obtain rewards is fundamental to human motivated behavior. However, the neural dynamics underlying the evaluation of reward and effort in humans is poorly understood. Here, we investigate this with chronic intracranial recordings from prefrontal cortex (PFC) and basal ganglia (BG; subthalamic nuclei and globus pallidus) in people with Parkinson's disease performing a decision-making task with offers that varied in levels of reward and physical effort required. This revealed dissociable neural signatures of reward and effort, with BG beta (12-20 Hz) oscillations tracking subjective effort on a single trial basis and PFC theta (4-7 Hz) signaling previous trial reward. Stimulation of PFC increased overall acceptance of offers in addition to increasing the impact of reward on choices. This work uncovers oscillatory mechanisms that guide fundamental decisions to exert effort for reward across BG and PFC, as well as supporting a causal role of PFC for such choices.

Multi-night cortico-basal recordings reveal mechanisms of NREM slow wave suppression and spontaneous awakenings at high-temporal resolution in Parkinson's disease.

Background: Sleep disturbance is a prevalent and highly disabling comorbidity in individuals with Parkinson's disease (PD) that leads to worsening of daytime symptoms, reduced quality of life and accelerated disease progression. Objectives: We aimed to record naturalistic overnight cortico-basal neural activity in people with PD, in order to determine the neurophysiology of spontaneous awakenings and slow wave suppression in non-rapid eye movement (NREM) sleep, towards the development of novel sleep-targeted neurostimulation therapies. Methods: Multi-night (n=58) intracranial recordings were performed at-home, from chronic electrocorticography and subcortical electrodes, with sensing-enabled Deep Brain Stimulation (DBS), paired with portable polysomnography. Four participants with PD and one participant with cervical dystonia were evaluated to determine the neural structures, signals and functional connectivity modulated during NREM sleep and prior to spontaneous awakenings. Intracranial recordings were performed both ON and OFF DBS to evaluate the impact of stimulation. Sleep staging was then classified with machine-learning models using intracranial cortico-basal signals on classical (30 s) and rapid (5 s) timescales. Results: We demonstrate an increase in cortico-basal slow wave delta (1-4 Hz) activity and a decrease in beta (13-31 Hz) activity during NREM (N2 and N3) versus wakefulness in PD. Cortical-basal ganglia coherence was also found to be higher in the delta range and lower in the beta range during NREM. DBS stimulation resulted in a further elevation in cortical delta and a decrease in alpha (8-13 Hz) and low beta (13-15 Hz) power compared to the OFF stimulation state. Within NREM sleep, we observed a strong inverse interaction between subcortical beta and cortical slow wave activity and found that subcortical beta increases prior to spontaneous awakenings at high-temporal resolution (5s). Our machine-learning models trained on intracranial cortical or subcortical power features achieved high accuracy in both traditional (30s) and rapid (5s) time windows for NREM vs. wakefulness classification (30s: 92.6±1.7%; 5s: 88.3±2.1%). Conclusions: Chronic, multi-night recordings in PD reveal increased cortico-basal slow wave, decreased beta activity, and changes in functional connectivity in NREM vs wakefulness, effects that are enhanced in the presence of DBS. Within NREM, subcortical beta and cortical delta are strongly inversely correlated and subcortical beta power increases prior to spontaneous awakenings. Our findings elucidate the network-level neurophysiology of sleep dysfunction in PD and the mechanistic impact of conventional DBS. Additionally, through accurate machine-learning classification of spontaneous awakenings, this study also provides a foundation for future personalized adaptive DBS therapies for sleep dysfunction in PD.

Uncovering the neurophysiology of mood, motivation and behavioral symptoms in Parkinson's disease through intracranial recordings.

Neuropsychiatric mood and motivation symptoms (depression, anxiety, apathy, impulse control disorders) in Parkinson's disease (PD) are highly disabling, difficult to treat and exacerbated by current medications and deep brain stimulation therapies. High-resolution intracranial recording techniques have the potential to undercover the network dysfunction and cognitive processes that drive these symptoms, towards a principled re-tuning of circuits. We highlight intracranial recording as a valuable tool for mapping and desegregating neural networks and their contribution to mood, motivation and behavioral symptoms, via the ability to dissect multiplexed overlapping spatial and temporal neural components. This technique can be powerfully combined with behavioral paradigms and emerging computational techniques to model underlying latent behavioral states. We review the literature of intracranial recording studies investigating mood, motivation and behavioral symptomatology with reference to 1) emotional processing, 2) executive control 3) subjective valuation (reward & cost evaluation) 4) motor control and 5) learning and updating. This reveals associations between different frequency specific network activities and underlying cognitive processes of reward decision making and action control. If validated, these signals represent potential computational biomarkers of motivational and behavioural states and could lead to principled therapy development for mood, motivation and behavioral symptoms in PD.

Sub-harmonic entrainment of cortical gamma oscillations to deep brain stimulation in Parkinson's disease: Model based predictions and validation in three human subjects.

OBJECTIVES: The exact mechanisms of deep brain stimulation (DBS) are still an active area of investigation, in spite of its clinical successes. This is due in part to the lack of understanding of the effects of stimulation on neuronal rhythms. Entrainment of brain oscillations has been hypothesised as a potential mechanism of neuromodulation. A better understanding of entrainment might further inform existing methods of continuous DBS, and help refine algorithms for adaptive methods. The purpose of this study is to develop and test a theoretical framework to predict entrainment of cortical rhythms to DBS across a wide range of stimulation parameters. MATERIALS AND METHODS: We fit a model of interacting neural populations to selected features characterising PD patients' off-stimulation finely-tuned gamma rhythm recorded through electrocorticography. Using the fitted models, we predict basal ganglia DBS parameters that would result in 1:2 entrainment, a special case of sub-harmonic entrainment observed in patients and predicted by theory. RESULTS: We show that the neural circuit models fitted to patient data exhibit 1:2 entrainment when stimulation is provided across a range of stimulation parameters. Furthermore, we verify key features of the region of 1:2 entrainment in the stimulation frequency/amplitude space with follow-up recordings from the same patients, such as the loss of 1:2 entrainment above certain stimulation amplitudes. CONCLUSION: Our results reveal that continuous, constant frequency DBS in patients may lead to nonlinear patterns of neuronal entrainment across stimulation parameters, and that these responses can be predicted by modelling. Should entrainment prove to be an important mechanism of therapeutic stimulation, our modelling framework may reduce the parameter space that clinicians must consider when programming devices for optimal benefit.

Adaptive Deep Brain Stimulation for sleep stage targeting in Parkinson's disease.

BACKGROUND: Sleep dysfunction is disabling in people with Parkinson's disease and is linked to worse motor and non-motor outcomes. Sleep-specific adaptive Deep Brain Stimulation has the potential to target pathophysiologies of sleep. OBJECTIVE: Develop an adaptive Deep Brain Stimulation algorithm that modulates stimulation parameters in response to intracranially classified sleep stages. METHODS: We performed at-home, multi-night intracranial electrocorticography and polysomnogram recordings to train personalized linear classifiers for discriminating the N3 NREM sleep stage. Classifiers were embedded into investigational Deep Brain Stimulators for N3 specific adaptive DBS. RESULTS: We report high specificity of embedded, autonomous, intracranial electrocorticography N3 sleep stage classification across two participants and provide proof-of-principle of successful sleep stage specific adaptive Deep Brain Stimulation. CONCLUSION: Multi-night cortico-basal recordings and sleep specific adaptive Deep Brain Stimulation provide an experimental framework to investigate sleep pathophysiology and mechanistic interactions with stimulation, towards the development of therapeutic neurostimulation paradigms directly targeting sleep dysfunction.

Personalized chronic adaptive deep brain stimulation outperforms conventional stimulation in Parkinson's disease.

Deep brain stimulation is a widely used therapy for Parkinson's disease (PD) but currently lacks dynamic responsiveness to changing clinical and neural states. Feedback control has the potential to improve therapeutic effectiveness, but optimal control strategy and additional benefits of "adaptive" neurostimulation are unclear. We implemented adaptive subthalamic nucleus stimulation, controlled by subthalamic or cortical signals, in three PD patients (five hemispheres) during normal daily life. We identified neurophysiological biomarkers of residual motor fluctuations using data-driven analyses of field potentials over a wide frequency range and varying stimulation amplitudes. Narrowband gamma oscillations (65-70 Hz) at either site emerged as the best control signal for sensing during stimulation. A blinded, randomized trial demonstrated improved motor symptoms and quality of life compared to clinically optimized standard stimulation. Our approach highlights the promise of personalized adaptive neurostimulation based on data-driven selection of control signals and may be applied to other neurological disorders.

Bringing the Clinic Home: An At-Home Multi-Modal Data Collection Ecosystem to Support Adaptive Deep Brain Stimulation.

Adaptive deep brain stimulation (aDBS) shows promise for improving treatment for neurological disorders such as Parkinson's disease (PD). aDBS uses symptom-related biomarkers to adjust stimulation parameters in real-time to target symptoms more precisely. To enable these dynamic adjustments, parameters for an aDBS algorithm must be determined for each individual patient. This requires time-consuming manual tuning by clinical researchers, making it difficult to find an optimal configuration for a single patient or to scale to many patients. Furthermore, the long-term effectiveness of aDBS algorithms configured in-clinic while the patient is at home remains an open question. To implement this therapy at large scale, a methodology to automatically configure aDBS algorithm parameters while remotely monitoring therapy outcomes is needed. In this paper, we share a design for an at-home data collection platform to help the field address both issues. The platform is composed of an integrated hardware and software ecosystem that is open-source and allows for at-home collection of neural, inertial, and multi-camera video data. To ensure privacy for patient-identifiable data, the platform encrypts and transfers data through a virtual private network. The methods include time-aligning data streams and extracting pose estimates from video recordings. To demonstrate the use of this system, we deployed this platform to the home of an individual with PD and collected data during self-guided clinical tasks and periods of free behavior over the course of 1.5 years. Data were recorded at sub-therapeutic, therapeutic, and supra-therapeutic stimulation amplitudes to evaluate motor symptom severity under different therapeutic conditions. These time-aligned data show the platform is capable of synchronized at-home multi-modal data collection for therapeutic evaluation. This system architecture may be used to support automated aDBS research, to collect new datasets and to study the long-term effects of DBS therapy outside the clinic for those suffering from neurological disorders.

Views on minimum unit pricing for alcohol before its introduction among people with alcohol dependence in Scotland: A qualitative interview study.

INTRODUCTION: Scotland implemented a minimum price per unit of alcohol (MUP) of £0.50 in May 2018 (1 UK unit = 10 mL/8 g ethanol). Some stakeholders expressed concerns about the policy having potential negative consequences for people with alcohol dependence. This study aimed to investigate anticipated impacts of MUP on people presenting to alcohol treatment services in Scotland before policy implementation. METHODS: Qualitative interviews were conducted with 21 people with alcohol dependence accessing alcohol treatment services in Scotland between November 2017 and April 2018. Interviews examined respondents' current and anticipated patterns of drinking and spending, effects on their personal life, and their views on potential policy impact. Interview data were thematically analysed using a constant comparison method. RESULTS: Three key themes were identified: (i) strategies used to manage the cost of alcohol and anticipated responses to MUP; (ii) broader effects of MUP; and (iii) awareness and preparedness for MUP. Respondents expected to be impacted by MUP, particularly those on low incomes and those with more severe dependence symptoms. They anticipated using familiar strategies including borrowing and reprioritising spending to keep alcohol affordable. Some respondents anticipated negative consequences. Respondents were sceptical about the short-term benefits of MUP for current drinkers but felt it might prevent harm for future generations. Respondents had concerns about the capacity of treatment services to meet support needs. DISCUSSION AND CONCLUSIONS: People with alcohol dependence identified immediate concerns alongside potential long-term benefits of MUP before its introduction. They also had concerns over the preparedness of service providers.

Adaptive Deep Brain Stimulation: From Experimental Evidence Toward Practical Implementation.

Closed-loop adaptive deep brain stimulation (aDBS) can deliver individualized therapy at an unprecedented temporal precision for neurological disorders. This has the potential to lead to a breakthrough in neurotechnology, but the translation to clinical practice remains a significant challenge. Via bidirectional implantable brain-computer-interfaces that have become commercially available, aDBS can now sense and selectively modulate pathophysiological brain circuit activity. Pilot studies investigating different aDBS control strategies showed promising results, but the short experimental study designs have not yet supported individualized analyses of patient-specific factors in biomarker and therapeutic response dynamics. Notwithstanding the clear theoretical advantages of a patient-tailored approach, these new stimulation possibilities open a vast and mostly unexplored parameter space, leading to practical hurdles in the implementation and development of clinical trials. Therefore, a thorough understanding of the neurophysiological and neurotechnological aspects related to aDBS is crucial to develop evidence-based treatment regimens for clinical practice. Therapeutic success of aDBS will depend on the integrated development of strategies for feedback signal identification, artifact mitigation, signal processing, and control policy adjustment, for precise stimulation delivery tailored to individual patients. The present review introduces the reader to the neurophysiological foundation of aDBS for Parkinson's disease (PD) and other network disorders, explains currently available aDBS control policies, and highlights practical pitfalls and difficulties to be addressed in the upcoming years. Finally, it highlights the importance of interdisciplinary clinical neurotechnological research within and across DBS centers, toward an individualized patient-centered approach to invasive brain stimulation. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

High precision magnetoencephalography reveals increased right-inferior frontal gyrus beta power during response conflict.

Flexibility of behavior and the ability to rapidly switch actions is critical for adaptive living in humans. It is well established that the right-inferior frontal gyrus (R-IFG) is recruited during outright action-stopping, relating to increased beta (12-30 Hz) power. It has also been posited that inhibiting incorrect response tendencies and switching is central to motor flexibility. However, it is not known if the commonly reported R-IFG beta signature of response inhibition in action-stopping is also recruited during response conflict, which would suggest overlapping networks for stopping and switching. In the current study, we analyzed high precision magnetoencephalography (hpMEG) data recorded with multiple within subject recording sessions (trials n > 10,000) from 8 subjects during different levels of response conflict. We hypothesized that a R-IFG-triggered network for response inhibition is domain general and therefore also involved in mediating response conflict. We tested whether R-IFG showed increased beta power dependent on the level of response conflict. Using event-related spectral perturbations and linear mixed modeling, we found that R-IFG beta power increased for response conflict trials. The R-IFG beta increase was specific to trials with strong response conflict, and increased R-IFG beta power related to less error. This supports a more generalized role for R-IFG beta, beyond simple stopping behavior towards response switching.

A Realist Review of How Community-Based Drug Checking Services Could Be Designed and Implemented to Promote Engagement of People Who Use Drugs.

With rising numbers of drug-related deaths in the UK and globally, exploration of interventions that seek to reduce drug-related harm is essential. Drug checking services (DCS) allow people to submit drug samples for chemical analysis and receive feedback about the sample, as well as harm reduction advice. The use of DCS is often linked to festival and/or nightlife settings and to so-called 'recreational' drug use, but research has also shown the potential of community-based DCS as an intervention serving more varied demographics of people who use drugs, including more marginalised individuals and those experiencing drug dependence. Whilst there is a growing evidence base on the effectiveness of drug checking as a harm reduction intervention, there is still limited evidence of the underlying mechanisms and processes within DCS which may aid implementation and subsequent engagement of people who use drugs. This presents a challenge to understanding why engagement differs across types of DCS, and how best to develop and deliver services across different contexts and for different populations. To explore the contexts and mechanisms which impact engagement in community-based DCS, a realist review was undertaken to synthesise the international evidence for the delivery and implementation of DCS. There were 133 sources included in the review. From these sources the underlying contexts, mechanisms, and outcomes relating to DCS implementation and engagement were developed and refined into seven programme theories. The findings of this review are theoretically novel and hold practical relevance for the design of DCS, with implications for optimisation, tailoring, and implementing services to reach individuals in different settings.

Cortico-Subthalamic Field Potentials Support Classification of the Natural Gait Cycle in Parkinson's Disease and Reveal Individualized Spectral Signatures.

The ability of humans to coordinate stereotyped, alternating movements between the two legs during bipedal walking is a complex motor behavior that requires precisely timed activities across multiple nodes of the supraspinal network. Understanding of the neural network dynamics that underlie natural walking in humans is limited. We investigated cortical and subthalamic neural activities during overground walking and evaluated spectral biomarkers to decode the gait cycle in three patients with Parkinson's disease without gait disturbances. Patients were implanted with chronic bilateral deep brain stimulation (DBS) leads in the subthalamic nucleus (STN) and electrocorticography paddles overlaying the primary motor and somatosensory cortices. Local field potentials were recorded from these areas while the participants performed overground walking and synchronized to external gait kinematic sensors. We found that the STN displays increased low-frequency (4-12 Hz) spectral power during the period before contralateral leg swing. Furthermore, STN shows increased theta frequency (4-8 Hz) coherence with the primary motor through the initiation and early phase of contralateral leg swing. Additional analysis revealed that each patient had specific frequency bands that could detect a significant difference between left and right initial leg swing. Our findings indicate that there are alternating spectral changes between the two hemispheres in accordance with the gait cycle. In addition, we identified patient-specific, gait-related biomarkers in both the STN and cortical areas at discrete frequency bands that may be used to drive adaptive DBS to improve gait dysfunction in patients with Parkinson's disease.

Proceedings of the Ninth Annual Deep Brain Stimulation Think Tank: Advances in Cutting Edge Technologies, Artificial Intelligence, Neuromodulation, Neuroethics, Pain, Interventional Psychiatry, Epilepsy, and Traumatic Brain Injury.

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.

Embedding digital chronotherapy into bioelectronic medicines.

Biological rhythms pervade physiology and pathophysiology across multiple timescales. Because of the limited sensing and algorithm capabilities of neuromodulation device technology to-date, insight into the influence of these rhythms on the efficacy of bioelectronic medicine has been infeasible. As the development of new devices begins to mitigate previous technology limitations, we propose that future devices should integrate chronobiological considerations in their control structures to maximize the benefits of neuromodulation therapy. We motivate this proposition with preliminary longitudinal data recorded from patients with Parkinson's disease and epilepsy during deep brain stimulation therapy, where periodic symptom biomarkers are synchronized to sub-daily, daily, and longer timescale rhythms. We suggest a physiological control structure for future bioelectronic devices that incorporates time-based adaptation of stimulation control, locked to patient-specific biological rhythms, as an adjunct to classical control methods and illustrate the concept with initial results from three of our recent case studies using chronotherapy-enabled prototypes.