Closed-loop Deep Brain Stimulation Systems Research Articles

Robust adaptive deep brain stimulation control of in-silico non-stationary Parkinsonian neural oscillatory dynamics

Objective. Closed-loop deep brain stimulation (DBS) is a promising therapy for Parkinson’s disease (PD) that works by adjusting DBS patterns in real time from the guidance of feedback neural activity. Current closed-loop DBS mainly uses threshold-crossing on-off controllers or linear time-invariant (LTI) controllers to regulate the basal ganglia (BG) Parkinsonian beta band oscillation power. However, the critical cortex-BG-thalamus network dynamics underlying PD are nonlinear, non-stationary, and noisy, hindering accurate and robust control of Parkinsonian neural oscillatory dynamics. Approach. Here, we develop a new robust adaptive closed-loop DBS method for regulating the Parkinsonian beta oscillatory dynamics of the cortex-BG-thalamus network. We first build an adaptive state-space model to quantify the dynamic, nonlinear, and non-stationary neural activity. We then construct an adaptive estimator to track the nonlinearity and non-stationarity in real time. We next design a robust controller to automatically determine the DBS frequency based on the estimated Parkinsonian neural state while reducing the system’s sensitivity to high-frequency noise. We adopt and tune a biophysical cortex-BG-thalamus network model as an in-silico simulation testbed to generate nonlinear and non-stationary Parkinsonian neural dynamics for evaluating DBS methods. Main results. We find that under different nonlinear and non-stationary neural dynamics, our robust adaptive DBS method achieved accurate regulation of the BG Parkinsonian beta band oscillation power with small control error, bias, and deviation. Moreover, the accurate regulation generalizes across different therapeutic targets and consistently outperforms current on-off and LTI DBS methods. Significance. These results have implications for future designs of closed-loop DBS systems to treat PD.

Model-based closed-loop control of thalamic deep brain stimulation.

Introduction: Closed-loop control of deep brain stimulation (DBS) is beneficial for effective and automatic treatment of various neurological disorders like Parkinson's disease (PD) and essential tremor (ET). Manual (open-loop) DBS programming solely based on clinical observations relies on neurologists' expertise and patients' experience. Continuous stimulation in open-loop DBS may decrease battery life and cause side effects. On the contrary, a closed-loop DBS system uses a feedback biomarker/signal to track worsening (or improving) of patients' symptoms and offers several advantages compared to the open-loop DBS system. Existing closed-loop DBS control systems do not incorporate physiological mechanisms underlying DBS or symptoms, e.g., how DBS modulates dynamics of synaptic plasticity. Methods: In this work, we propose a computational framework for development of a model-based DBS controller where a neural model can describe the relationship between DBS and neural activity and a polynomial-based approximation can estimate the relationship between neural and behavioral activities. A controller is used in our model in a quasi-real-time manner to find DBS patterns that significantly reduce the worsening of symptoms. By using the proposed computational framework, these DBS patterns can be tested clinically by predicting the effect of DBS before delivering it to the patient. We applied this framework to the problem of finding optimal DBS frequencies for essential tremor given electromyography (EMG) recordings solely. Building on our recent network model of ventral intermediate nuclei (Vim), the main surgical target of the tremor, in response to DBS, we developed neural model simulation in which physiological mechanisms underlying Vim-DBS are linked to symptomatic changes in EMG signals. By using a proportional-integral-derivative (PID) controller, we showed that a closed-loop system can track EMG signals and adjust the stimulation frequency of Vim-DBS so that the power of EMG reaches a desired control target. Results and discussion: We demonstrated that the model-based DBS frequency aligns well with that used in clinical studies. Our model-based closed-loop system is adaptable to different control targets and can potentially be used for different diseases and personalized systems.

Role of electrophysiological activity and interactions of lateral habenula in the development of depression-like behavior in a chronic restraint stress model

Closed-loop deep brain stimulation (DBS) system offers a promising approach for treatment-resistant depression, but identifying universally accepted electrophysiological biomarkers for closed-loop DBS systems targeting depression is challenging. There is growing evidence suggesting a strong association between the lateral habenula (LHb) and depression. Here, we took LHb as a key target, utilizing multi-site local field potentials (LFPs) to study the acute and chronic changes in electrophysiology, functional connectivity, and brain network characteristics during the formation of a chronic restraint stress (CRS) model. Furthermore, our model combining the electrophysiological changes of LHb and interactions between LHb and other potential targets of depression can effectively distinguish depressive states, offering a new way for developing effective closed-loop DBS strategies.

Closed-Loop Deep Brain Stimulation With Reinforcement Learning and Neural Simulation.

Deep Brain Stimulation (DBS) is effective for movement disorders, particularly Parkinson's disease (PD). However, a closed-loop DBS system using reinforcement learning (RL) for automatic parameter tuning, offering enhanced energy efficiency and the effect of thalamus restoration, is yet to be developed for clinical and commercial applications. In this research, we instantiate a basal ganglia-thalamic (BGT) model and design it as an interactive environment suitable for RL models. Four finely tuned RL agents based on different frameworks, namely Soft Actor-Critic (SAC), Twin Delayed Deep Deterministic Policy Gradient (TD3), Proximal Policy Optimization (PPO), and Advantage Actor-Critic (A2C), are established for further comparison. Within the implemented RL architectures, the optimized TD3 demonstrates a significant 67% reduction in average power dissipation when compared to the open-loop system while preserving the normal response of the simulated BGT circuitry. As a result, our method mitigates thalamic error responses under pathological conditions and prevents overstimulation. In summary, this study introduces a novel approach to implementing an adaptive parameter-tuning closed-loop DBS system. Leveraging the advantages of TD3, our proposed approach holds significant promise for advancing the integration of RL applications into DBS systems, ultimately optimizing therapeutic effects in future clinical trials.

Computational Neurosurgery in Deep Brain Stimulation.

Computational methods and technologies are critical for neurosurgery in general and in deep brain stimulation (DBS) in particular. They increasingly inform every aspect of clinical DBS therapy, from presurgical planning and hardware implantation to postoperative adjustment of stimulation parameters. Computational methods also occupy a prominent position within the DBS research sphere, where they facilitate efforts to better understand DBS' underlying mechanisms and optimize and individualize its delivery. This chapter provides a high-level overview of the various computational tools and methods that have been applied to DBS. First, we discuss the invaluable contribution of computational neuroimaging (primarily magnetic resonance imaging) to DBS, targeting and the role of postoperative methods of image analysis-specifically, electrode localization, volume of activated tissue modeling, and sweet-spot mapping-in precisely localizing DBS' targets in the brain and discerning optimal treatment loci. We then address the growing field of connectomics, which leverages specific magnetic resonance imaging (MRI) sequences and post-acquisition processing algorithms to explore how DBS operates at the level of brain-wide networks. Next, the search for electrophysiological and imaging-based biomarkers of optimal DBS therapy is explored. We lastly touch on the incipient field of spatial characterization analysis and discuss the ongoing development of adaptive, closed-loop DBS systems.

Quasi-LPV positive observer-based control of closed-loop deep brain stimulation systems

Parkinson’s disease is a neurodegenerative disorder in which dopamine (a specific type of neurotransmitter) production by neurons is destroyed in the brain. Therefore, there is less or no production of dopamine in the human brain and the patient has motor and non-motor complications. The main reason for Parkinson’s disease is the basal ganglia (BG) system imbalance. Therefore, it is imperative to find effective control methods to stabilize and regulate the BG system. To control the BG system within the normal oscillating performance, the opinion of closed-loop deep brain stimulation (DBS) system is used as the most innovative surgical treatment. In this paper, a quasi-linear parameter-varying (LPV) model is extracted from two known nonlinear models (the RT model and the modified RT model with 19 dynamics as the state variables of the BG system) as a comprehensive model to result in a more accurate control for the DBS system. The theoretical contributions in this paper are novel because this model is considered as a positive system and the related theories and properties are discussed. In view of this, quasi-LPV positive observer-based control method is designed for two situations; when all parameters are available for estimation (exact observer) and when all accurate parameters cannot be easily accessed (inexact observer). By designing such controllers, the provided algorithm does not need the availability of the scheduling parameters of the model, which is the novel challenge of this paper. The positivity and asymptotic stability of the proposed controllers have been studied based on linear matrix inequalities. The feasibility of the proposed closed-loop system and the effectiveness of the controllers are verified by numerical simulation. The designed controllers make the closed-loop DBS system stable and positive in both situations. It is while, without this controller, there is no such oscillating performance for Parkinsonian patients.

ID: 209013 Combining Remote Programming and Remote Monitoring Towards a Closed-Loop DBS System

Deep Brain Stimulation (DBS) is an effective therapy for Parkinson’s Disease (PD). However, it is currently applied in an open-loop fashion and symptom management relies on iterative programming. The field is trending towards closed-loop solutions that enable stimulation parameters to be adjusted in real-time in response to patient-specific feedback signals. Identifying reliable and robust feedback signals is a challenge in developing closed-loop DBS solutions. As such, in this study, we aim to combine remote monitoring and remote programming to identify specific sensor signals that correlate with DBS programming and symptom profile changes.

Real-Time Adjustment of Impulse Stimulation Parameters Using a Closed-Loop Deep Brain Stimulation System

The closed-loop deep brain stimulation system is a new research that provides real-time adjustment of impulse stimulation parameters. This system belongs to the implantation medical equipment technical field, which is designed for gathering physiological signals of patients. It includes a host computer that displays data in real-time, data storage, design optimization algorithms, and renewal embedded programs. The system has two modes of operation: one is where the embedded nerve stimulator carries out the formation closed-loop control of Embedded algorithm processing data, and the other is where the data collection reaches the host computer by wireless communication module. The stimulation parameter is controlled by the wireless communication module after host computer algorithm process, forming a closed loop. This research aimed to investigate the feasibility of using the closed-loop deep brain stimulation system for electronic stimulation of the nervous system disease and its potential for clinical research or zooscopy for closed-loop stimulation methods. The study provides a good platform for the research of closed-loop stimulation methods.

Subthalamic Beta Oscillations Are Transient and Encoded by Periodic Bursting of Individual Neurons

Increased beta (13-30Hz) in the subthalamic nucleus (STN) is a hallmark of Parkinson’s disease (PD) and a prime candidate for closed-loop deep brain stimulation (DBS) systems such as the Medtronic Percept PC. Investigating the dynamics of beta oscillations across spatiotemporal domains revealed insights into the nature of this activity, which can moreover be leveraged by closed-loop DBS systems.

Deep Brain Stimulation for Addictive Disorders—Where Are We Now?

In the face of a global epidemic of drug addiction, neglecting to develop new effective therapies will perpetuate the staggering human and economic costs of substance use. This review aims to summarize and evaluate the preclinical and clinical studies of deep brain stimulation (DBS) as a novel therapy for refractory addiction, in hopes to engage and inform future research in this promising novel treatment avenue. An electronic database search (MEDLINE, EMBASE, Cochrane library) was performed using keywords and predefined inclusion criteria between 1974 and 6/18/2021 (registered on Open Science Registry). Selected articles were reviewed in full text and key details were summarized and analyzed to understand DBS’ therapeutic potential and possible mechanisms of action. The search yielded 25 animal and 22 human studies. Animal studies showed that DBS of targets such as nucleus accumbens (NAc), insula, and subthalamic nucleus reduces drug use and seeking. All human studies were case series/reports (level 4/5 evidence), mostly targeting the NAc with generally positive outcomes. From the limited evidence in the literature, DBS, particularly of the NAc, appears to be a reasonable last resort option for refractory addictive disorders. We propose that future research in objective electrophysiological (e.g., local field potentials) and neurochemical (e.g., extracellular dopamine levels) biomarkers would assist monitoring the progress of treatment and developing a closed-loop DBS system. Preclinical literature also highlighted the prefrontal cortex as a promising DBS target, which should be explored in human research.

Practical Closed-Loop Strategies for Deep Brain Stimulation: Lessons From Chronic Pain.

Deep brain stimulation (DBS) is a plausible therapy for various neuropsychiatric disorders, though continuous tonic stimulation without regard to underlying physiology (open-loop) has had variable success. Recently available DBS devices can sense neural signals which, in turn, can be used to control stimulation in a closed-loop mode. Closed-loop DBS strategies may mitigate many drawbacks of open-loop stimulation and provide more personalized therapy. These devices contain many adjustable parameters that control how the closed-loop system operates, which need to be optimized using a combination of empirically and clinically informed decision making. We offer a practical guide for the implementation of a closed-loop DBS system, using examples from patients with chronic pain. Focusing on two research devices from Medtronic, the Activa PC+S and Summit RC+S, we provide pragmatic details on implementing closed- loop programming from a clinician’s perspective. Specifically, by combining our understanding of chronic pain with data-driven heuristics, we describe how to tune key parameters to handle feature selection, state thresholding, and stimulation artifacts. Finally, we discuss logistical and practical considerations that clinicians must be aware of when programming closed-loop devices.

Balance between competing spectral states in subthalamic nucleus is linked to motor impairment in Parkinson's disease.

Exaggerated local field potential bursts of activity at frequencies in the low beta band are a well-established phenomenon in the subthalamic nucleus of patients with Parkinson’s disease. However, such activity is only moderately correlated with motor impairment. Here we test the hypothesis that beta bursts are just one of several dynamic states in the subthalamic nucleus local field potential in Parkinson’s disease, and that together these different states predict motor impairment with high fidelity.Local field potentials were recorded in 32 patients (64 hemispheres) undergoing deep brain stimulation surgery targeting the subthalamic nucleus. Recordings were performed following overnight withdrawal of anti-parkinsonian medication, and after administration of levodopa. Local field potentials were analysed using hidden Markov modelling to identify transient spectral states with frequencies under 40 Hz.Findings in the low beta frequency band were similar to those previously reported; levodopa reduced occurrence rate and duration of low beta states, and the greater the reductions, the greater the improvement in motor impairment. However, additional local field potential states were distinguished in the theta, alpha and high beta bands, and these behaved in an opposite manner. They were increased in occurrence rate and duration by levodopa, and the greater the increases, the greater the improvement in motor impairment. In addition, levodopa favoured the transition of low beta states to other spectral states. When all local field potential states and corresponding features were considered in a multivariate model it was possible to predict 50% of the variance in patients’ hemibody impairment OFF medication, and in the change in hemibody impairment following levodopa. This only improved slightly if signal amplitude or gamma band features were also included in the multivariate model. In addition, it compares with a prediction of only 16% of the variance when using beta bursts alone.We conclude that multiple spectral states in the subthalamic nucleus local field potential have a bearing on motor impairment, and that levodopa-induced shifts in the balance between these states can predict clinical change with high fidelity. This is important in suggesting that some states might be upregulated to improve parkinsonism and in suggesting how local field potential feedback can be made more informative in closed-loop deep brain stimulation systems.

Advances in neurochemical measurements: A review of biomarkers and devices for the development of closed-loop deep brain stimulation systems.

Neurochemical recording techniques have expanded our understanding of the pathophysiology of neurological disorders, as well as the mechanisms of action of treatment modalities like deep brain stimulation (DBS). DBS is used to treat diseases such as Parkinson’s disease, Tourette syndrome, and obsessive-compulsive disorder, among others. Although DBS is effective at alleviating symptoms related to these diseases and improving the quality of life of these patients, the mechanism of action of DBS is currently not fully understood. A leading hypothesis is that DBS modulates the electrical field potential by modifying neuronal firing frequencies to non-pathological rates thus providing therapeutic relief. To address this gap in knowledge, recent advances in electrochemical sensing techniques have given insight into the importance of neurotransmitters, such as dopamine, serotonin, glutamate, and adenosine, in disease pathophysiology. These studies have also highlighted their potential use in tandem with electrophysiology to serve as biomarkers in disease diagnosis and progression monitoring, as well as characterize response to treatment. Here, we provide an overview of disease-relevant neurotransmitters and their roles and implications as biomarkers, as well as innovations to the biosensors used to record these biomarkers. Furthermore, we discuss currently available neurochemical and electrophysiological recording devices, and discuss their viability to be implemented into the development of a closed-loop DBS system.

Prediction of mild parkinsonism revealed by neural oscillatory changes and machine learning.

Neural oscillatory changes within and across different frequency bands are thought to underlie motor dysfunction in Parkinson's disease (PD) and may serve as biomarkers for closed-loop deep brain stimulation (DBS) approaches. Here, we used neural oscillatory signals derived from chronically implanted cortical and subcortical electrode arrays as features to train machine learning algorithms to discriminate between naive and mild PD states in a nonhuman primate model. Local field potential (LFP) data were collected over several months from a 12-channel subdural electrocorticography (ECoG) grid and a 6-channel custom array implanted in the subthalamic nucleus (STN). Relative to the naive state, the PD state showed elevated primary motor cortex (M1) and STN power in the beta, high gamma, and high-frequency oscillation (HFO) bands and decreased power in the delta band. Theta power was found to be decreased in STN but not M1. In the PD state there was elevated beta-HFO phase-amplitude coupling (PAC) in the STN. We applied machine learning with support vector machines with radial basis function (SVM-RBF) kernel and k-nearest neighbors (KNN) classifiers trained by features related to power and PAC changes to discriminate between the naive and mild states. Our results show that the most predictive feature of parkinsonism in the STN was high beta (∼86% accuracy), whereas it was HFO in M1 (∼98% accuracy). A feature fusion approach outperformed every individual feature, particularly in the M1, where ∼98% accuracy was achieved with both classifiers. Overall, our data demonstrate the ability to use various frequency band power to classify the clinical state and are also beneficial in developing closed-loop DBS therapeutic approaches.NEW & NOTEWORTHY Neurophysiological biomarkers that correlate with motor symptoms or disease severity are vital to improve our understanding of the pathophysiology in Parkinson's disease (PD) and for the development of more effective treatments, including deep brain stimulation (DBS). This work provides direct insight into the application of these biomarkers in training classifiers to discriminate between brain states, which is a first step toward developing closed-loop DBS systems.

Fractional order controllers increase the robustness of closed-loop deep brain stimulation systems.

We studied the effects of using fractional order proportional, integral, and derivative (PID) controllers in a closed-loop mathematical model of deep brain stimulation. The objective of the controller was to dampen oscillations from a neural network model of Parkinson's disease. We varied intrinsic parameters, such as the gain of the controller, and extrinsic variables, such as the excitability of the network. We found that in most cases, fractional order components increased the robustness of the model multi-fold to changes in the gains of the controller. Similarly, the controller could be set to a fixed set of gains and remain stable to a much larger range, than for the classical PID case, of changes in synaptic weights that otherwise would cause oscillatory activity. The increase in robustness is a consequence of the properties of fractional order derivatives that provide an intrinsic memory trace of past activity, which works as a negative feedback system. Fractional order PID controllers could provide a platform to develop stand-alone closed-loop deep brain stimulation systems.

Demonstration of Kinematic-Based Closed-loop Deep Brain Stimulation for Mitigating Freezing of Gait in People with Parkinson's Disease.

Impaired gait in Parkinson's disease is marked by slow, arrhythmic stepping, and often includes freezing of gait episodes where alternating stepping halts completely. Wearable inertial sensors offer a way to detect these gait changes and novel deep brain stimulation (DBS) systems can respond with clinical therapy in a real-time, closed-loop fashion. In this paper, we present two novel closed-loop DBS algorithms, one using gait arrhythmicity and one using a logistic-regression model of freezing of gait detection as control signals. Benchtop validation results demonstrate the feasibility of running these algorithms in conjunction with a closed-loop DBS system by responding to real-time human subject kinematic data and pre-recorded data from leg-worn inertial sensors from a participant with Parkinson's disease. We also present a novel control policy algorithm that changes neurostimulator frequency in response to the kinematic inputs. These results provide a foundation for further development, iteration, and testing in a clinical trial for the first closed-loop DBS algorithms using kinematic signals to therapeutically improve and understand the pathophysiological mechanisms of gait impairment in Parkinson's disease.

Deep Brain Stimulation for Obesity: A Review and Future Directions.

The global prevalence of obesity has been steadily increasing. Although pharmacotherapy and bariatric surgeries can be useful adjuvants in the treatment of morbid obesity, they may lose long-term effectiveness. Obesity result largely from unbalanced energy homeostasis. Palatable and densely caloric foods may affect the brain overlapped circuits involved with homeostatic hypothalamus and hedonic feeding. Deep brain stimulation (DBS) consists of delivering electrical impulses to specific brain targets to modulate a disturbed neuronal network. In selected patients, DBS has been shown to be safe and effective for movement disorders. We review all the cases reports and series of patients treated with DBS for obesity using a PubMed search and will address the following obesity-related issues: (i) the hypothalamic regulation of homeostatic feeding; (ii) the reward mesolimbic circuit and hedonic feeding; (iii) basic concepts of DBS as well as the rationale for obesity treatment; (iv) perspectives and challenges in obesity DBS. The small number of cases provides preliminary evidence for the safety and the tolerability of a potential DBS approach. The ventromedial (n = 2) and lateral (n = 8) hypothalamic nuclei targets have shown mixed and disappointing outcomes. Although nucleus accumbens (n = 7) targets were more encouraging for the outcomes of body weight reduction and behavioral control for eating, there was one suicide reported after 27 months of follow-up. The authors did not attribute the suicide to DBS therapy. The identification of optimal brain targets, appropriate programming strategies and the development of novel technologies will be important as next steps to move DBS closer to a clinical application. The identification of electrical control signals may provide an opportunity for closed-loop adaptive DBS systems to address obesity. Metabolic and hormonal sensors such as glycemic levels, leptin, and ghrelin levels are candidate control signals for DBS. Focused excitation or alternatively inhibition of regions of the hypothalamus may provide better outcomes compared to non-selective DBS. Utilization of the NA delta oscillation or other physiological markers from one or multiple regions in obesity-related brain network is a promising approach. Experienced multidisciplinary team will be critical to improve the risk-benefit ratio for this approach.

Biomarkers for closed-loop deep brain stimulation in Parkinson disease and beyond.

Subthalamic deep brain stimulation (DBS) for Parkinson disease (PD) currently requires laborious open-loop programming, which can mitigate the benefits of this treatment. Experimental closed-loop DBS systems are emerging that can sense the electrophysiological surrogates of PD motor signs and respond with delivery of an automatically adapted stimulation. Such biomarker-based neural interfaces constitute a major advance towards improving the outcomes of patients treated with DBS and enhancing our understanding of the pathophysiological mechanisms underlying PD. In this Perspectives article, we argue that closed-loop DBS, in addition to offering advantages in patients with PD, might extend the current indications for DBS to include selected psychiatric disorders in which the symptoms are similarly driven by pathological brain circuit activity. The success of closed-loop DBS in such settings will depend on the identification of symptom-specific biomarkers, which ideally should reflect causal mechanisms of the underlying pathology.

Closed-loop deep brain stimulation based on a stream-clustering system

Idiopathic Parkinsons disease (PD) is currently the second most important neurodegenerative disease in incidence. Deep brain stimulation (DBS) constitutes a successful and necessary therapy; however, the continuous stimulation it provides can be associated with multiple side effects. DBS uses an implanted pulse generator that delivers, through a set of electrodes, electrical stimulation to the target area, normally the Sub Thalamic Nucleus. Recently, Closed-loop DBS has emerged as a promising new strategy, where the device stimulates only when necessary, thereby reducing any adverse effects. Here, we present a Closed-loop DBS system for PD, which is able to recognize, with 100% accuracy, when the patient is going to enter into the tremor phase, thus allowing the device to stimulate only in such cases. The expert system has been designed and implemented within the data stream mining paradigm, suitable for our scenario since it can cope with continuous data of a theoretical infinite length and with a certain variability, which uses the synchronization among the neural population within the Sub Thalamic Nucleus as the continuous data stream input to the system.

A Miniature Dual-Biomarker-Based Sensing and Conditioning Device for Closed-Loop DBS.

In this paper, a dual-biomarker-based neural sensing and conditioning device is proposed for closing the feedback loop in deep brain stimulation devices. The device explores both local field potentials (LFPs) and action potentials (APs) as measured biomarkers. It includes two channels, each having four main parts: (1) a pre-amplifier with built-in low-pass filter, (2) a ground shifting circuit, (3) an amplifier with low-pass function, and (4) a high-pass filter. The design specifications include miniature-size, light-weight, and 100 dB gain in the LFP and AP channels. This device has been validated through bench and in-vitro tests. The bench tests have been performed using different sinusoidal signals and pre-recorded neural signals. The in-vitro tests have been conducted in the saline solution that mimics the brain environment. The total weight of the device including a 3 V coin battery, and battery holder is 1.2 g. The diameter of the device is 11.2 mm. The device can be used to concurrently sense LFPs and APs for closing the feedback loop in closed-loop deep brain stimulation systems. It provides a tetherless head-mountable platform suitable for pre-clinical trials.