Dopamine and deep brain stimulation accelerate the neural dynamics of volitional action in Parkinson's disease.

The ability to initiate volitional action is fundamental to human behaviour. Loss of dopaminergic neurons in Parkinson's disease is associated with impaired action initiation, also termed akinesia. Both dopamine and subthalamic deep brain stimulation (DBS) can alleviate akinesia, but the underlying mechanisms are unknown. An important question is whether dopamine and DBS facilitate de novo build-up of neural dynamics for motor execution or accelerate existing cortical movement initiation signals through shared modulatory circuit effects. Answering these questions can provide the foundation for new closed-loop neurotherapies with adaptive DBS, but the objectification of neural processing delays prior to performance of volitional action remains a significant challenge. To overcome this challenge, we studied readiness potentials and trained brain signal decoders on invasive neurophysiology signals in 25 DBS patients (12 female) with Parkinson's disease during performance of self-initiated movements. Combined sensorimotor cortex electrocorticography (ECoG) and subthalamic local field potential (LFP) recordings were performed OFF therapy (N = 22), ON dopaminergic medication (N = 18) and ON subthalamic deep brain stimulation (N = 8). This allowed us to compare their therapeutic effects on neural latencies between the earliest cortical representation of movement intention as decoded by linear discriminant analysis classifiers and onset of muscle activation recorded with electromyography (EMG). In the hypodopaminergic OFF state, we observed long latencies between motor intention and motor execution for readiness potentials and machine learning classifications. Both, dopamine and DBS significantly shortened these latencies, hinting towards a shared therapeutic mechanism for alleviation of akinesia. To investigate this further, we analysed directional cortico-subthalamic oscillatory communication with multivariate granger causality. Strikingly, we found that both therapies independently shifted cortico-subthalamic oscillatory information flow from antikinetic beta (13-35 Hz) to prokinetic theta (4-10 Hz) rhythms, which was correlated with latencies in motor execution. Our study reveals a shared brain network modulation pattern of dopamine and DBS that may underlie the acceleration of neural dynamics for augmentation of movement initiation in Parkinson's disease. Instead of producing or increasing preparatory brain signals, both therapies modulate oscillatory communication. These insights provide a link between the pathophysiology of akinesia and its' therapeutic alleviation with oscillatory network changes in other non-motor and motor domains, e.g. related to hyperkinesia or effort and reward perception. In the future, our study may inspire the development of clinical brain computer interfaces based on brain signal decoders to provide temporally precise support for action initiation in patients with brain disorders.

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.

Single threshold adaptive deep brain stimulation in Parkinson's disease depends on parameter selection, movement state and controllability of subthalamic beta activity.

BACKGROUND: Deep brain stimulation (DBS) is an invasive treatment option for patients with Parkinson's disease. Recently, adaptive DBS (aDBS) systems have been developed, which adjust stimulation timing and amplitude in real-time. However, it is unknown how changes in parameters, movement states and the controllability of subthalamic beta activity affect aDBS performance. OBJECTIVE: To characterize how parameter choice, movement state and controllability interactively affect the electrophysiological and behavioral response to single threshold aDBS. METHODS: We recorded subthalamic local field potentials in 12 patients with Parkinson's disease receiving single threshold aDBS in the acute post-operative state. We investigated changes in two aDBS parameters: the onset time and the smoothing of real-time beta power. Electrophysiological patterns and motor performance were assessed while patients were at rest and during a simple motor task. We further studied the impact of controllability on aDBS performance by comparing patients with and without beta power modulation during continuous stimulation. RESULTS: Our findings reveal that changes in the onset time control the extent of beta power suppression achievable with single threshold adaptive stimulation during rest. Behavioral data indicate that only specific parameter combinations yield a beneficial effect of single threshold aDBS. During movement, action induced beta power suppression reduces the responsivity of the closed loop algorithm. We further demonstrate that controllability of beta power is a prerequisite for effective parameter dependent modulation of subthalamic beta activity. CONCLUSION: Our results highlight the interaction between single threshold aDBS parameter selection, movement state and controllability in driving subthalamic beta activity and motor performance. By this means, we identify directions for the further development of closed-loop DBS algorithms.

Invasive neurophysiology and whole brain connectomics for neural decoding in patients with brain implants.

Brain computer interfaces (BCI) provide unprecedented spatiotemporal precision that will enable significant expansion in how numerous brain disorders are treated. Decoding dynamic patient states from brain signals with machine learning is required to leverage this precision, but a standardized framework for identifying and advancing novel clinical BCI approaches does not exist. Here, we developed a platform that integrates brain signal decoding with connectomics and demonstrate its utility across 123 hours of invasively recorded brain data from 73 neurosurgical patients treated for movement disorders, depression and epilepsy. First, we introduce connectomics-informed movement decoders that generalize across cohorts with Parkinson's disease and epilepsy from the US, Europe and China. Next, we reveal network targets for emotion decoding in left prefrontal and cingulate circuits in DBS patients with major depression. Finally, we showcase opportunities to improve seizure detection in responsive neurostimulation for epilepsy. Our platform provides rapid, high-accuracy decoding for precision medicine approaches that can dynamically adapt neuromodulation therapies in response to the individual needs of patients.

Deep net detection and onset prediction of electrographic seizure patterns in responsive neurostimulation.

OBJECTIVE: Managing the progress of drug-resistant epilepsy patients implanted with the Responsive Neurostimulation (RNS) System requires the manual evaluation of hundreds of hours of intracranial recordings. The generation of these large amounts of data and the scarcity of experts' time for evaluation necessitate the development of automatic tools to detect intracranial electroencephalographic (iEEG) seizure patterns (iESPs) with expert-level accuracy. We developed an intelligent system for identifying the presence and onset time of iESPs in iEEG recordings from the RNS device. METHODS: An iEEG dataset from 24 patients (36 293 recordings) recorded by the RNS System was used for training and evaluating a neural network model (iESPnet). The model was trained to identify the probability of seizure onset at each sample point of the iEEG. The reliability of the net was assessed and compared to baseline methods, including detections made by the device. iESPnet performance was measured using balanced accuracy and the F1 score for iESP detection. The prediction time was assessed via both the error and the mean absolute error. The model was evaluated following a hold-one-out strategy, and then validated in a separate cohort of 26 patients from a different medical center. RESULTS: iESPnet detected the presence of an iESP with a mean accuracy value of 90% and an onset time prediction error of approximately 3.4 s. There was no relationship between electrode location and prediction outcome. Model outputs were well calibrated and unbiased by the RNS detections. Validation on a separate cohort further supported iESPnet applicability in real clinical scenarios. Importantly, RNS device detections were found to be less accurate and delayed in nonresponders; therefore, tools to improve the accuracy of seizure detection are critical for increasing therapeutic efficacy. SIGNIFICANCE: iESPnet is a reliable and accurate tool with the potential to alleviate the time-consuming manual inspection of iESPs and facilitate the evaluation of therapeutic response in RNS-implanted patients.

Pallidal activities during sleep and sleep decoding in dystonia, Huntington's, and Parkinson's disease.

BACKGROUND: Sleep disturbances are highly prevalent in movement disorders, potentially due to the malfunctioning of basal ganglia structures. Pallidal deep brain stimulation (DBS) has been widely used for multiple movement disorders and been reported to improve sleep. We aimed to investigate the oscillatory pattern of pallidum during sleep and explore whether pallidal activities can be utilized to differentiate sleep stages, which could pave the way for sleep-aware adaptive DBS. METHODS: We directly recorded over 500 h of pallidal local field potentials during sleep from 39 subjects with movement disorders (20 dystonia, 8 Huntington's disease, and 11 Parkinson's disease). Pallidal spectrum and cortical-pallidal coherence were computed and compared across sleep stages. Machine learning approaches were utilized to build sleep decoders for different diseases to classify sleep stages through pallidal oscillatory features. Decoding accuracy was further associated with the spatial localization of the pallidum. RESULTS: Pallidal power spectra and cortical-pallidal coherence were significantly modulated by sleep-stage transitions in three movement disorders. Differences in sleep-related activities between diseases were identified in non-rapid eye movement (NREM) and REM sleep. Machine learning models using pallidal oscillatory features can decode sleep-wake states with over 90% accuracy. Decoding accuracies were higher in recording sites within the internus-pallidum than the external-pallidum, and can be precited using structural (P < 0.0001) and functional (P < 0.0001) whole-brain neuroimaging connectomics. CONCLUSION: Our findings revealed strong sleep-stage dependent distinctions in pallidal oscillations in multiple movement disorders. Pallidal oscillatory features were sufficient for sleep stage decoding. These data may facilitate the development of adaptive DBS systems targeting sleep problems that have broad translational prospects.

Movement decoding using spatio-spectral features of cortical and subcortical local field potentials.

The first commercially sensing enabled deep brain stimulation (DBS) devices for the treatment of movement disorders have recently become available. In the future, such devices could leverage machine learning based brain signal decoding strategies to individualize and adapt therapy in real-time. As multi-channel recordings become available, spatial information may provide an additional advantage for informing machine learning models. To investigate this concept, we compared decoding performances from single channels vs. spatial filtering techniques using intracerebral multitarget electrophysiology in Parkinson's disease patients undergoing DBS implantation. We investigated the feasibility of spatial filtering in invasive neurophysiology and the putative utility of combined cortical ECoG and subthalamic local field potential signals for decoding grip-force, a well-defined and continuous motor readout. We found that adding spatial information to the model can improve decoding (6% gain in decoding), but the spatial patterns and additional benefit was highly individual. Beyond decoding performance results, spatial filters and patterns can be used to obtain meaningful neurophysiological information about the brain networks involved in target behavior. Our results highlight the importance of individualized approaches for brain signal decoding, for which multielectrode recordings and spatial filtering can improve precision medicine approaches for clinical brain computer interfaces.

Electrocorticography is superior to subthalamic local field potentials for movement decoding in Parkinson's disease.

Brain signal decoding promises significant advances in the development of clinical brain computer interfaces (BCI). In Parkinson's disease (PD), first bidirectional BCI implants for adaptive deep brain stimulation (DBS) are now available. Brain signal decoding can extend the clinical utility of adaptive DBS but the impact of neural source, computational methods and PD pathophysiology on decoding performance are unknown. This represents an unmet need for the development of future neurotechnology. To address this, we developed an invasive brain-signal decoding approach based on intraoperative sensorimotor electrocorticography (ECoG) and subthalamic LFP to predict grip-force, a representative movement decoding application, in 11 PD patients undergoing DBS. We demonstrate that ECoG is superior to subthalamic LFP for accurate grip-force decoding. Gradient boosted decision trees (XGBOOST) outperformed other model architectures. ECoG based decoding performance negatively correlated with motor impairment, which could be attributed to subthalamic beta bursts in the motor preparation and movement period. This highlights the impact of PD pathophysiology on the neural capacity to encode movement vigor. Finally, we developed a connectomic analysis that could predict grip-force decoding performance of individual ECoG channels across patients by using their connectomic fingerprints. Our study provides a neurophysiological and computational framework for invasive brain signal decoding to aid the development of an individualized precision-medicine approach to intelligent adaptive DBS.

Deep Learning-Based Indoor Localization Using Multi-View BLE Signal.

In this paper, we present a novel Deep Neural Network-based indoor localization method that estimates the position of a Bluetooth Low Energy (BLE) transmitter (tag) by using the received signals' characteristics at multiple Anchor Points (APs). We use the received signal strength indicator (RSSI) value and the in-phase and quadrature-phase (IQ) components of the received BLE signals at a single time instance to simultaneously estimate the angle of arrival (AoA) at all APs. Through supervised learning on simulated data, various machine learning (ML) architectures are trained to perform AoA estimation using varying subsets of anchor points. In the final stage of the system, the estimated AoA values are fed to a positioning engine which uses the least squares (LS) algorithm to estimate the position of the tag. The proposed architectures are trained and rigorously tested on several simulated room scenarios and are shown to achieve a localization accuracy of 70 cm. Moreover, the proposed systems possess generalization capabilities by being robust to modifications in the room's content or anchors' configuration. Additionally, some of the proposed architectures have the ability to distribute the computational load over the APs.

Machine learning based brain signal decoding for intelligent adaptive deep brain stimulation.

Sensing enabled implantable devices and next-generation neurotechnology allow real-time adjustments of invasive neuromodulation. The identification of symptom and disease-specific biomarkers in invasive brain signal recordings has inspired the idea of demand dependent adaptive deep brain stimulation (aDBS). Expanding the clinical utility of aDBS with machine learning may hold the potential for the next breakthrough in the therapeutic success of clinical brain computer interfaces. To this end, sophisticated machine learning algorithms optimized for decoding of brain states from neural time-series must be developed. To support this venture, this review summarizes the current state of machine learning studies for invasive neurophysiology. After a brief introduction to the machine learning terminology, the transformation of brain recordings into meaningful features for decoding of symptoms and behavior is described. Commonly used machine learning models are explained and analyzed from the perspective of utility for aDBS. This is followed by a critical review on good practices for training and testing to ensure conceptual and practical generalizability for real-time adaptation in clinical settings. Finally, first studies combining machine learning with aDBS are highlighted. This review takes a glimpse into the promising future of intelligent adaptive DBS (iDBS) and concludes by identifying four key ingredients on the road for successful clinical adoption: i) multidisciplinary research teams, ii) publicly available datasets, iii) open-source algorithmic solutions and iv) strong world-wide research collaborations.