Individualized closed-loop TMS synchronized with exoskeleton for modulation of cortical-excitability in patients with stroke: a proof-of-concept study.

Background: Repetitive TMS is used in stroke rehabilitation with predefined passive low and high-frequency stimulation. Brain State-Dependent Stimulation (BSDS)/Activity-Dependent Stimulation (ADS) using bio-signal has been observed to strengthen synaptic connections. Without the personalization of brain-stimulation protocols, we risk a one-size-fits-all approach. Methods: We attempted to close the ADS loop via intrinsic-proprioceptive (via exoskeleton-movement) and extrinsic-visual-feedback to the brain. We developed a patient-specific brain stimulation platform with a two-way feedback system, to synchronize single-pulse TMS with exoskeleton along with adaptive performance visual feedback, in real-time, for a focused neurorehabilitation strategy to voluntarily engage the patient in the brain stimulation process. Results: The novel TMS Synchronized Exoskeleton Feedback (TSEF) platform, controlled by the patient's residual Electromyogram, simultaneously triggered exoskeleton movement and single-pulse TMS, once in 10 s, implying 0.1 Hz frequency. The TSEF platform was tested for a demonstration on three patients (n = 3) with different spasticity on the Modified Ashworth Scale (MAS = 1, 1+, 2) for one session each. Three patients completed their session in their own timing; patients with (more) spasticity tend to take (more) inter-trial intervals. A proof-of-concept study on two groups-TSEF-group and a physiotherapy control-group was performed for 45 min/day for 20-sessions. Dose-matched Physiotherapy was given to control-group. Post 20 sessions, an increase in ipsilesional cortical-excitability was observed; Motor Evoked Potential increased by ~48.5 µV at a decreased Resting Motor Threshold by ~15.6%, with improvement in clinical scales relevant to the Fugl-Mayer Wrist/Hand joint (involved in training) by 2.6 units, an effect not found in control-group. This strategy could voluntarily engage the patient. Conclusion: A brain stimulation platform with a real-time two-way feedback system was developed to voluntarily engage the patients during the brain stimulation process and a proof-of-concept study on three patients indicates clinical gains with increased cortical excitability, an effect not observed in the control-group; and the encouraging results nudge for further investigations on a larger cohort.

Designing and validating a robust adaptive neuromodulation algorithm for closed-loop control of brain states.

Objective. Neuromodulation systems that use closed-loop brain stimulation to control brain states can provide new therapies for brain disorders. To date, closed-loop brain stimulation has largely used linear time-invariant controllers. However, nonlinear time-varying brain network dynamics and external disturbances can appear during real-time stimulation, collectively leading to real-time model uncertainty. Real-time model uncertainty can degrade the performance or even cause instability of time-invariant controllers. Three problems need to be resolved to enable accurate and stable control under model uncertainty. First, an adaptive controller is needed to track the model uncertainty. Second, the adaptive controller additionally needs to be robust to noise and disturbances. Third, theoretical analyses of stability and robustness are needed as prerequisites for stable operation of the controller in practical applications.Approach. We develop a robust adaptive neuromodulation algorithm that solves the above three problems. First, we develop a state-space brain network model that explicitly includes nonlinear terms of real-time model uncertainty and design an adaptive controller to track and cancel the model uncertainty. Second, to improve the robustness of the adaptive controller, we design two linear filters to increase steady-state control accuracy and reduce sensitivity to high-frequency noise and disturbances. Third, we conduct theoretical analyses to prove the stability of the neuromodulation algorithm and establish a trade-off between stability and robustness, which we further use to optimize the algorithm design. Finally, we validate the algorithm using comprehensive Monte Carlo simulations that span a broad range of model nonlinearity, uncertainty, and complexity.Main results. The robust adaptive neuromodulation algorithm accurately tracks various types of target brain state trajectories, enables stable and robust control, and significantly outperforms state-of-the-art neuromodulation algorithms.Significance. Our algorithm has implications for future designs of precise, stable, and robust closed-loop brain stimulation systems to treat brain disorders and facilitate brain functions.

Real-time suppression and amplification of frequency-specific neural activity using stimulation evoked oscillations.

BACKGROUND: Approaches to predictably control neural oscillations are needed to understand their causal role in brain function in healthy or diseased states and to advance the development of neuromodulation therapies. OBJECTIVE: We present a closed-loop neural control and optimization framework to actively suppress or amplify low-frequency neural oscillations observed in local field potentials in real-time by using electrical stimulation. The rationale behind this control approach and our working hypothesis is that neural oscillatory activity evoked by electrical pulses can suppress or amplify spontaneous oscillations via destructive or constructive interference when the pulses are continuously delivered with appropriate amplitudes and at precise phases of the modulated oscillations in a closed-loop scheme. METHODS: We tested our hypothesis in two nonhuman primates that exhibited a robust increase in low-frequency (8-30 Hz) oscillatory power in the subthalamic nucleus (STN) following administration of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). To test our neural control approach, we targeted 8-17 Hz oscillations and used electrode arrays and electrical stimulation waveforms similar to those used in humans chronically implanted with brain stimulation systems. Stimulation parameters that maximize the suppression or amplification of neural oscillations were predicted using mathematical models of the stimulation evoked oscillations. RESULTS: Our neural control and optimization approach was capable of actively and robustly suppressing or amplifying oscillations in the targeted frequency band (8-17 Hz) in real-time in the studied subjects. CONCLUSIONS: The results from this study support our hypothesis and suggest that the proposed neural control framework allows one to characterize in controlled experiments the functional role of frequency-specific neural oscillations by using electrodes and stimulation waveforms currently being employed in humans.

Effect of Theta Transcranial Alternating Current Stimulation and Phase-Locked Transcranial Pulsed Current Stimulation on Learning and Cognitive Control.

Non-invasive brain stimulation (NIBS) is emerging as a robust treatment alternative for major depressive disorder, with a potential for achieving higher remission rates by providing targeted stimulation to underlying brain networks, such as the salience network (SN). Growing evidence suggests that these therapeutic effects are dependent on the frequency and phase synchrony between SN oscillations and stimulation as well as the task-specific state of the SN during stimulation. However, the development of phase-synchronized non-invasive stimulation has proved challenging until recently. Here, we use a phase-locked pulsed brain stimulation approach to study the effects of two NIBS methods: transcranial alternating current stimulation (tACS) versus phase-locked transcranial pulsed current stimulation (tPCS), on the SN during an SN activating task. 20 healthy volunteers participated in the study. Each volunteer partook in four sessions, receiving one stimulation type at random (theta-tACS, peak tPCS, trough tPCS or sham) while undergoing a learning game, followed by an unstimulated test based on learned material. Each session lasted approximately 1.5 h, with an interval of at least 2 days to allow for washout and to avoid cross-over effects. Our results showed no statistically significant effect of stimulation on the event related potential (ERP) recordings, resting electroencephalogram (EEG), and the performance of the volunteers. While stimulation effects were not apparent in this study, the nominal performance of the phase-locking algorithm offers a technical foundation for further research in determining effective stimulation paradigms and conditions. Specifically, future work should investigate stronger stimulation and true task-specific stimulation of SN nodes responsible for the task as well as their recording. If refined, NIBS could offer an effective, homebased treatment option.

A Real-Time Phase-Locking System for Non-invasive Brain Stimulation.

Non-invasive brain stimulation techniques are entering widespread use for the investigation and treatment of a range of neurological and neuropsychiatric disorders. However, most current techniques are 'open-loop', without feedback from target brain region activity; this limitation could contribute to heterogeneous effects seen for nominally 'inhibitory' and 'excitatory' protocols across individuals. More potent and consistent effects may ensue from closed-loop and, in particular, phase-locked brain stimulation. In this work, a closed-loop brain stimulation system is introduced that can analyze EEG data in real-time, provide a forecast of the phase of an underlying brain rhythm of interest, and control pulsed transcranial electromagnetic stimulation to deliver pulses at a specific phase of the target frequency band. The technique was implemented using readily available equipment such as a basic EEG system, a low-cost Arduino board and MATLAB scripts. The phase-locked brain stimulation method was tested in 5 healthy volunteers and its phase-locking performance evaluated at 0, 90, 180, and 270 degree phases in theta and alpha frequency bands. On average phase locking values of 0.55° ± 0.11° and 0.52° ± 0.14° and error angles of 11° ± 11° and 3.3° ± 18° were achieved for theta and alpha stimulation, respectively. Despite the low-cost hardware implementation, signal processing time generated a phase delay of only 3.8° for theta and 57° for alpha stimulation, both readily accommodated in the pulse trigger algorithm. This work lays the methodological steps for achieving phase-locked brain stimulation for brief-pulse transcranial electrical stimulation (tES) and repetitive transcranial magnetic stimulation (rTMS), facilitating further research on the effect of stimulation phase for these techniques.

Chasing tics in the human brain: development of open, scheduled and closed loop responsive approaches to deep brain stimulation for tourette syndrome.

Tourette syndrome is a childhood-onset disorder characterized by a combination of motor and vocal tics, often associated with psychiatric comorbidities including attention deficit and hyperactivity disorder and obsessive-compulsive disorder. Despite an onset early in life, half of patients may present symptoms in adulthood, with variable degrees of severity. In select cases, the syndrome may lead to significant physical and social impairment, and a worrisome risk for self injury. Evolving research has provided evidence supporting the idea that the pathophysiology of Tourette syndrome is directly related to a disrupted circuit involving the cortex and subcortical structures, including the basal ganglia, nucleus accumbens, and the amygdala. There has also been a notion that a dysfunctional group of neurons in the putamen contributes to an abnormal facilitation of competing motor responses in basal ganglia structures ultimately underpinning the generation of tics. Surgical therapies for Tourette syndrome have been reserved for a small group of patients not responding to behavioral and pharmacological therapies, and these therapies have been directed at modulating the underlying pathophysiology. Lesion therapy as well as deep brain stimulation has been observed to suppress tics in at least some of these cases. In this article, we will review the clinical aspects of Tourette syndrome, as well as the evolution of surgical approaches and we will discuss the evidence and clinical responses to deep brain stimulation in various brain targets. We will also discuss ongoing research and future directions as well as approaches for open, scheduled and closed loop feedback-driven electrical stimulation for the treatment of Tourette syndrome.

Chasing Tics in the Human Brain: Development of Open, Scheduled and Closed Loop Responsive Approaches to Deep Brain Stimulation for Tourette Syndrome

Tourette syndrome is a childhood-onset disorder characterized by a combination of motor and vocal tics, often associated with psychiatric comorbidities including attention deficit and hyperactivity disorder and obsessive-compulsive disorder. Despite an onset early in life, half of patients may present symptoms in adulthood, with variable degrees of severity. In select cases, the syndrome may lead to significant physical and social impairment, and a worrisome risk for self injury. Evolving research has provided evidence supporting the idea that the pathophysiology of Tourette syndrome is directly related to a disrupted circuit involving the cortex and subcortical structures, including the basal ganglia, nucleus accumbens, and the amygdala. There has also been a notion that a dysfunctional group of neurons in the putamen contributes to an abnormal facilitation of competing motor responses in basal ganglia structures ultimately underpinning the generation of tics. Surgical therapies for Tourette syndrome have been reserved for a small group of patients not responding to behavioral and pharmacological therapies, and these therapies have been directed at modulating the underlying pathophysiology. Lesion therapy as well as deep brain stimulation has been observed to suppress tics in at least some of these cases. In this article, we will review the clinical aspects of Tourette syndrome, as well as the evolution of surgical approaches and we will discuss the evidence and clinical responses to deep brain stimulation in various brain targets. We will also discuss ongoing research and future directions as well as approaches for open, scheduled and closed loop feedback-driven electrical stimulation for the treatment of Tourette syndrome.