Stimulation Amplitude Research Articles

Evoking stable and precise tactile sensations via multi-electrode intracortical microstimulation of the somatosensory cortex.

Tactile feedback from brain-controlled bionic hands can be partially restored via intracortical microstimulation (ICMS) of the primary somatosensory cortex. In ICMS, the location of percepts depends on the electrode's location and the percept intensity depends on the stimulation frequency and amplitude. Sensors on a bionic hand can thus be linked to somatotopically appropriate electrodes, and the contact force of each sensor can be used to determine the amplitude of a stimulus. Here we report a systematic investigation of the localization and intensity of ICMS-evoked percepts in three participants with cervical spinal cord injury. A retrospective analysis of projected fields showed that they were typically composed of a focal hotspot with diffuse borders, arrayed somatotopically in keeping with their underlying receptive fields and stable throughout the duration of the study. When testing the participants' ability to rapidly localize a single ICMS presentation, individual electrodes typically evoked only weak sensations, making object localization and discrimination difficult. However, overlapping projected fields from multiple electrodes produced more localizable and intense sensations and allowed for a more precise use of a bionic hand.

Towards optimum amplitude and frequency of electrotactile stimulation in amputee for effective somatotopic sensory feedback

Towards optimum amplitude and frequency of electrotactile stimulation in amputee for effective somatotopic sensory feedback

The vestibular implant: effects of stimulation parameters on the electrically-evoked vestibulo-ocular reflex.

The vestibular implant is a neuroprosthesis which offers a potential treatment approach for patients suffering from vestibulopathy. Investigating the influence of electrical stimulation parameters is essential to improve the vestibular implant response. Optimization of the response focuses on the electrically evoked vestibulo-ocular reflex. It aims to facilitate high peak eye velocities and adequate alignment of the eye movement responses. In this study, the basic stimulation parameters of the vestibular implant were tested for their effect on the electrically evoked vestibulo-ocular reflex. Four stimulation parameters, including the stimulation amplitude, phase duration, stimulus rate and speed of change of stimulation, were systematically tested in a cohort of nine subjects with a vestibulo-cochlear implant. These parameters were tested to evaluate their effect on fitting settings (i.e., threshold of activation, upper comfortable limit and dynamic range) as well as on the electrically evoked vestibulo-ocular reflex (peak eye velocity and alignment). It was confirmed that, in addition to current amplitude, the peak eye velocity of the response can be increased by increasing the phase duration and pulse rate. Both parameters have little effect on the alignment of the eye response. However, a longer phase duration decreased the range between the threshold of activation and the upper comfortable limit of the electrical stimulation (i.e., dynamic range). Furthermore, these results show that next to the amplitude of the stimulation, the speed of change in stimulation has a determinative positive effect on the peak eye velocity. The observations in this study imply that the vestibular implant response, in terms of peak eye velocity, can be optimized with a higher pulse rate and longer phase duration. However, this comes at a trade-off between the dynamic range and power consumption. This study provides essential insights for fitting strategies in future vestibular implant care.

Characterization of Induced Current Density During Transcorneal Electrical Stimulation to Promote Neuroprotection in the Degenerating Retina.

Transcorneal electrical stimulation (TES) is a promising approach to delay retinal degeneration by inducing extracellular electric field-driven neuroprotective effects within photoreceptors. Although achieving precise electric field control is feasible in vitro, characterizing these fields becomes intricate and largely unexplored in vivo due to uneven distribution in the heterogeneous body. In this paper, we investigate and characterize electric fields within the retina during TES to assess the potential for therapeutic approaches Methods: We developed a computational model of a rat's head, enabling us to generate predictive simulations of the voltage and current density induced in the retina. Subsequently, an in vivo experimental setup involving Royal College of Surgeon (RCS) rats was implemented to measure the voltage across the retina using identical electrode configurations as employed in the simulations. A stimulation amplitude of 0.2-0.3 mA may be necessary during TES in rats to induce a current density of at least 20 A/[Formula: see text] in the retina, which is the lower limit for triggering neuroprotective effects according to culture studies on neural cells. Measurement taken from cadaveric pigs' eyes revealed that a stimulation amplitude of 1 mA is necessary for achieving the same current density. The computational modeling approach presented in this study was validated with experimental data and can be leveraged for predictive simulations to optimize the electrode design and stimulation parameters of TES. Once validated, the flexibility and low research cost of computational models are valuable in optimization studies where testing on live subjects is not feasible.

Effects of aging on otolith morphology and functions in mice.

Increased fall risk caused by vestibular system impairment is a significant problem associated with aging. A vestibule is composed of linear acceleration-sensing otoliths and rotation-sensing semicircular canals. Otoliths, composed of utricle and saccule, detect linear accelerations. Otolithic organs partially play a role in falls due to aging. Aging possibly changes the morphology and functions of otoliths. However, the specific associations between aging and otolith changes remain unknown. Therefore, this study aimed to clarify these associations in mice. Young C56BL/6 N (8 week old) and old (108-117 weeks old) mice were used in a micro-computed tomography (μCT) experiment for morphological analysis and a linear acceleration experiment for functional analysis. Young C56BL/6 N (8 week old) and middle-aged (50 week old) mice were used in electron microscopy experiments for morphological analysis. μCT revealed no significant differences in the otolith volume (p = 0.11) but significant differences in the otolith density (p = 0.001) between young and old mice. μCT and electron microscopy revealed significant differences in the structure of striola at the center of the otolith (μCT; p = 0.029, electron microscopy; p = 0.017). Significant differences were also observed in the amplitude of the eye movement during the vestibulo-ocular reflex induced by linear acceleration (maximum amplitude of stimulation = 1.3G [p = 0.014]; maximum amplitude of stimulation = 0.7G [p = 0.015]), indicating that the otolith function was worse in old mice than in young mice. This study demonstrated the decline in otolith function with age caused by age-related morphological changes. Specifically, when otolith density decreased, inertial force acting on the hair cells decreased, and when the structure of striola collapsed, the function of cross-striolar inhibition decreased, thereby causing a decline in the overall otolith function.

Suppression of Visceral Nociception by Selective C-Fiber Transmission Block Using Temporal Interference Sinusoidal Stimulation.

Chronic visceral pain management remains challenging due to limitations in selective targeting of C-fiber nociceptors. This study investigates temporal interference stimulation (TIS) on dorsal root ganglia (DRG) as a novel approach for selective C-fiber transmission block. We employed (1) GCaMP6 recordings in mouse whole DRG using a flexible, transparent microelectrode array for visualizing L6 DRG neuron activation, (2) ex vivo single-fiber recordings to assess sinusoidal stimulation effects on peripheral nerve axons, (3) in vivo behavioral assessment measuring visceromotor responses (VMR) to colorectal distension in mice, including a TNBS-induced visceral hypersensitivity model, and (4) immunohistological analysis to evaluate immediate immune responses in DRG following TIS. We demonstrated that TIS (2000 Hz and 2020 Hz carrier frequencies) enabled tunable activation of L6 DRG neurons, with the focal region adjustable by altering stimulation amplitude ratios. Low-frequency (20-50 Hz) sinusoidal stimulation effectively blocked C-fiber and Aδ-fiber transmission while sparing fast-conducting A-fibers, with 20 Hz showing highest efficacy. TIS of L6 DRG reversibly suppressed VMR to colorectal distension in both control and TNBS-induced visceral hypersensitive mice. The blocking effect was fine-tunable by adjusting interfering stimulus signal amplitude ratios. No apparent immediate immune responses were observed in DRG following hours-long TIS. In conclusion, TIS on lumbosacral DRG demonstrates promise as a selective, tunable approach for managing chronic visceral pain by effectively blocking C-fiber transmission. This technique addresses limitations of current neuromodulation methods and offers potential for more targeted relief in chronic visceral pain conditions.

Nonlinear deterministic dynamic analysis of a GPL micropipe conveying pulsating laminar flow

In several industries, the handling of fluid-filled micropipes is common. New-brand structures are increasingly being manufactured using advanced materials. This article tackles one of the crucial dynamic analyses that an advanced fluid-filled micropipe encounters. The dynamics of a graphene nanoplatelets-reinforced micropipe (GPL micropipe) under pulsating laminar flow for the first time is examined. The Euler-Bernoulli beam model follows the modified couple stress theory (MCST) and von-Karman’s nonlinear strain to formulate the problem. The impression of the flow profile exerted by a real flow as a consequence of fluid viscosity, is taken into account. The plug flow model results are compared to those regarding real flow consideration. Using the method of multiple scales (MMS), we determine the instability area and the steady state response of the GPL micropipe subjected to the principal parametric resonance of one of its modes due to pulsating laminar flow by applying this method to the discretized couple nonlinear gyroscopic governing equations. The Floquet theory treats the linear equations and fourth-order Runge–Kutta (RK4) method attacks nonlinear ones to validate MMS findings. It is confirmed that the 0.3 % addition of the GPL to matrix phase significantly enhances its advanced attributes, making it a highly effective material. The GPL reinforcement phase in the FGO pattern increases the critical flow velocity that exhibits the micropipe to static instability by 37.98 % , and critical flow stimulation amplitude fraction by 152.19 % , while declines instability area bandwidth by 36.95 % , and steady state response by 67.17 % relative to a non-reinforced micropipe. A denser flow degrades the corresponding values by 18.40 % , 42.59 % , 41.67 % , and 227.28 % in comparison to a lighter fluid. The declared findings provide crucial insights into the key design elements affecting significantly the functioning of fluid-filled GPL micropipes system, and regulate future research and expand openings for industry applications.

TDCS Cranial Nerve Co-Stimulation: Unveiling Brainstem Pathways Involved in Trigeminal Nerve Direct Current Stimulation in Rats.

The effects of transcranial direct current stimulation (tDCS) are typically attributed to the polarization of cortical neurons by the weak electric fields it generates in the cortex. However, emerging evidence indicates that certain tDCS effects may be mediated through the co-stimulation of peripheral or cranial nerves, particularly the trigeminal nerve (TN), which projects to critical brainstem nuclei that regulate the release of various neurotransmitters throughout the central nervous system. Despite this, the specific pathways involved remain inadequately characterized. In this study, we examined the effects of acute transcutaneous TN direct current stimulation (TN-DCS) on tonic (i.e. mean spike rate and spike rate over time) and phasic (number of bursts, spike rate per burst, burst duration, and inter-burst interval) activities while simultaneously recording single-neuron activity across three brainstem nuclei in rats: the locus coeruleus (LC), dorsal raphe nucleus (DRN), and median raphe nucleus (MnRN). We found that TN-DCS significantly modulated tonic activity in the LC, with notable interactions between stimulation amplitude, polarity, and time epoch affecting mean spike rates. Similar effects were observed in the DRN regarding tonic activity. Further, phasic activity in the LC was influenced by TN-DCS, with changes in burst number, duration, and inter-burst intervals linked to stimulation parameters. Conversely, MnRN tonic activity following TN-DCS remained unchanged. Importantly, xylocaine administration to block TN abolished the effects on tonic activities in both the LC and DRN. These results suggest that tDCS effects may partially arise from indirect modulation of the TN, leading to altered neuronal activity in DRN and LC. Besides, the differential changes in tonic and phasic LC activities underscore their complementary roles in mediating TN-DCS effects on higher cortical regions. This research bears significant translational implications, providing mechanistic insights that could enhance the efficacy of tDCS applications and deepen our understanding of its neurophysiological effects.

We Will, We Will Shock You: Adaptive Versus Conventional Functional Electrical Stimulation in Individuals Post-Stroke.

Functional electrical stimulation (FES) is often used in poststroke gait rehabilitation to address decreased walking speed, foot drop, and decreased forward propulsion. However, not all individuals experience clinically meaningful improvements in gait function with stimulation. Previous research has developed adaptive functional electrical stimulation (AFES) systems that adjust stimulation timing and amplitude at every stride to deliver optimal stimulation. The purpose of this work was to determine the effects of a novel AFES system on functional gait outcomes and compare them to the effects of the existing FES system. Twenty-four individuals with chronic poststroke hemiparesis completed 64-min walking trials on an adaptive and fixed-speed treadmill with no stimulation, stimulation from the existing FES system, and stimulation from the AFES system. There was no significant effect of stimulation condition on walking speed, peak dorsiflexion angle, or peak propulsive force. Walking speed was significantly faster and peak propulsive force was significantly larger on the adaptive treadmill (ATM) than the fixed-speed treadmill (both p < 0.0001). Dorsiflexor stimulation timing was similar between stimulation conditions, but plantarflexor stimulation timing was significantly improved with the AFES system compared to the FES system (p = 0.0059). Variability between and within subjects was substantial, and some subjects experienced clinically meaningful improvements in walking speed, peak dorsiflexion angle, and peak propulsive force. However, not all subjects experienced benefits, suggesting that further research to characterize which subjects exhibit the best instantaneous response to FES is needed to optimize poststroke gait rehabilitation using FES.

Predictive modeling of evoked intracranial EEG response to medial temporal lobe stimulation in patients with epilepsy

Despite promising advancements, closed-loop neurostimulation for drug-resistant epilepsy (DRE) still relies on manual tuning and produces variable outcomes, while automated predictable algorithms remain an aspiration. As a fundamental step towards addressing this gap, here we study predictive dynamical models of human intracranial EEG (iEEG) response under parametrically rich neurostimulation. Using data from n = 13 DRE patients, we find that stimulation-triggered switched-linear models with ~300 ms of causal historical dependence best explain evoked iEEG dynamics. These models are highly consistent across different stimulation amplitudes and frequencies, allowing for learning a generalizable model from abundant STIM OFF and limited STIM ON data. Further, evoked iEEG in nearly all subjects exhibited a distance-dependent pattern, whereby stimulation directly impacts the actuation site and nearby regions (≲ 20 mm), affects medium-distance regions (20 ~ 100 mm) through network interactions, and hardly reaches more distal areas (≳ 100 mm). Peak network interaction occurs at 60 ~ 80 mm from the stimulation site. Due to their predictive accuracy and mechanistic interpretability, these models hold significant potential for model-based seizure forecasting and closed-loop neurostimulation design.

Prevalence of autonomic dysreflexia during spinal cord stimulation after spinal cord injury.

Over the past decade, clinical trials have shown that spinal cord stimulation can restore motor functions that were thought to be permanently impaired in persons with spinal cord injury. However, the off-target effects of delivering electrical impulses to intertwined spinal networks remain largely unknown. This generates safety concerns for this otherwise fast-progressing technology. Herein, we present the prevalence of autonomic dysreflexia (AD) that occurred during implanted spinal cord stimulation testing for motor activation of the lower extremities. Eleven participants with spinal cord injury underwent implantation of temporary percutaneous epidural and dorsal root ganglia stimulation leads. Participants completed two days of parameter testing at baseline, then six days of motor rehabilitation sessions, and two days of parameter testing at end of study. The goal of parameter testing was to determine electrode configuration(s), pulse amplitudes, and frequencies that activated lumbosacral spinal sensorimotor networks that generate lower extremity functions. During all parameter testing sessions, continuous blood pressure and heart rate monitoring recordings were collected. Evidence of autonomic dysreflexia was found in 22% of all parameter tests with participants at rest. Most of these episodes (97%) were asymptomatic. These episodes occurred more frequently when using epidural stimulation, at or near amplitudes that elicited whole leg muscle activation and using a wide-field electrode configuration. Although monitoring occurred during passive testing, motor rehabilitation sessions use stimulation for longer periods, at higher frequencies and amplitudes. These sessions may carry additional risks of autonomic dysreflexia. Investigation of these concerns should continue as spinal cord stimulation progresses toward clinical translation.NEW & NOTEWORTHY Spinal cord stimulation for motor recovery after spinal cord injury is a popular research intervention, though off-target effects are a concern. Using continual blood pressure and heart rate recordings during passive spinal cord stimulation parameter testing, we identified frequent episodes of autonomic dysreflexia that were rarely associated with symptoms. This presents a previously unrecognized risk of spinal cord stimulation and appropriate vigilance in targeted monitoring is urged to maintain participant safety.

Label-free functional imaging of vagus nerve stimulation-evoked potentials at the cortical surface

Vagus nerve stimulation (VNS) is an FDA-approved stimulation therapy to treat patients with refractory epilepsy. In this work, we use a coherent holographic imaging system to characterize vagus nerve-evoked potentials (VEPs) in the cortex in response to VNS stimulation paradigms without electrode placement or any genetic, structural, or functional labels. We analyze stimulation amplitude up to saturation, pulse width up to 800 μs, and frequency from 10 Hz to 30 Hz, finding that stimulation amplitude strongly modulates VEPs response magnitude (effect size 0.401), while pulse width has a moderate modulatory effect (effect size 0.127) and frequency has almost no modulatory effect (effect size 0.009) on the evoked potential magnitude. We find mild interactions between pulse width and frequency. This non-contact label-free functional imaging technique may serve as a non-invasive rapid-feedback tool to characterize VEPs and may increase the efficacy of VNS in patients with refractory epilepsy.

Utilising activity patterns of a complex biophysical network model to optimise intra-striatal deep brain stimulation

A large-scale biophysical network model for the isolated striatal body is developed to optimise potential intrastriatal deep brain stimulation applied to, e.g. obsessive-compulsive disorder. The model is based on modified Hodgkin–Huxley equations with small-world connectivity, while the spatial information about the positions of the neurons is taken from a detailed human atlas. The model produces neuronal spatiotemporal activity patterns segregating healthy from pathological conditions. Three biomarkers were used for the optimisation of stimulation protocols regarding stimulation frequency, amplitude and localisation: the mean activity of the entire network, the frequency spectrum of the entire network (rhythmicity) and a combination of the above two. By minimising the deviation of the aforementioned biomarkers from the normal state, we compute the optimal deep brain stimulation parameters, regarding position, amplitude and frequency. Our results suggest that in the DBS optimisation process, there is a clear trade-off between frequency synchronisation and overall network activity, which has also been observed during in vivo studies.

Probing hippocampal stimulation in experimental temporal lobe epilepsy with functional MRI.

Electrical neurostimulation is currently used to manage epilepsy, but the most effective approach for minimizing seizure occurrence is uncertain. While functional MRI (fMRI) can reveal which brain areas are affected by stimulation, simultaneous deep brain stimulation (DBS)-fMRI examinations in patients are rare and the possibility to investigate multiple stimulation protocols is limited. In this study, we utilized the intrahippocampal kainate mouse model of mesial temporal lobe epilepsy (mTLE) to systematically examine the brain-wide responses to electrical stimulation using fMRI. We compared fMRI responses of saline-injected controls and epileptic mice during stimulation in the septal hippocampus (HC) at 10 Hz and demonstrated the effects of different stimulation amplitudes (80-230 μA) and frequencies (1-100 Hz) in epileptic mice. Motivated by recent studies exploring 1 Hz stimulation to prevent epileptic seizures, we furthermore investigated the effect of prolonged 1 Hz stimulation with fMRI. Compared to sham controls, epileptic mice showed less propagation to the contralateral HC, but significantly stronger responses in the ipsilateral HC and a wider spread to the entorhinal cortex and septal region. Varying the stimulation amplitude had little effect on the resulting activation patterns, whereas the stimulation frequency represented the key parameter and determined whether the induced activation remained local or spread from the hippocampal formation into cortical areas. Prolonged stimulation of epileptic mice at 1 Hz caused a slight reduction in local excitability. In this way, our study contributes to a better understanding of these stimulation paradigms.

Lateralized Subthalamic Stimulation for Axial Dysfunction in Parkinson's Disease: Exploratory Outcomes and Open-Label Extension.

A randomized trial suggested that reducing left-sided subthalamic stimulation amplitude could improve axial dysfunction. To explore open-label tolerability and associations between trial outcomes and asymmetry data. We collected adverse events in trial participants treated with open-label lateralized settings for ≥3 months. We explored associations between trial outcomes, location of stimulation and motor asymmetry. 14/17 participants tolerated unilateral amplitude reduction (left-sided = 10, right-sided = 4). Two hundred eighty-four left-sided and 1113 right-sided stimulated voxels were associated with faster gait velocity, 81 left-sided and 22 right-sided stimulated voxels were associated with slower gait velocity. Amplitude reduction contralateral to shorter step length was associated with 2.4-point reduction in axial MDS-UPDRS. Reduction contralateral to longer step length was associated with 10-point increase in MDS-UPDRS. Left-sided amplitude reduction is potentially more tolerable than right-sided amplitude reduction. Right-sided more than left-sided stimulation could be associated with faster gait velocity. Shortened step length might reflect contralateral overstimulation.

SAFE-OPT: a Bayesian optimization algorithm for learning optimal deep brain stimulation parameters with safety constraints

Objective.To treat neurological and psychiatric diseases with deep brain stimulation (DBS), a trained clinician must select parameters for each patient by monitoring their symptoms and side-effects in a months-long trial-and-error process, delaying optimal clinical outcomes. Bayesian optimization has been proposed as an efficient method to quickly and automatically search for optimal parameters. However, conventional Bayesian optimization does not account for patient safety and could trigger unwanted or dangerous side-effects.Approach.In this study we develop SAFE-OPT, a Bayesian optimization algorithm designed to learn subject-specific safety constraints to avoid potentially harmful stimulation settings during optimization. We prototype and validate SAFE-OPT using a rodent multielectrode stimulation paradigm which causes subject-specific performance deficits in a spatial memory task. We first use data from an initial cohort of subjects to build a simulation where we design the best SAFE-OPT configuration for safe and accurate searchingin silico. Main results.We then deploy both SAFE-OPT and conventional Bayesian optimization without safety constraints in new subjectsin vivo, showing that SAFE-OPT can find an optimally high stimulation amplitude that does not harm task performance with comparable sample efficiency to Bayesian optimization and without selecting amplitude values that exceed the subject's safety threshold.Significance.The incorporation of safety constraints will provide a key step for adopting Bayesian optimization in real-world applications of DBS.

Non-invasive Transcutaneous Spinal Cord Stimulation Programming Recommendations for the Treatment of Upper Extremity Impairment in Tetraplegia

ObjectivesThis study analyzes the stimulation parameters implemented during two successful trials that used non-invasive transcutaneous spinal cord stimulation (tSCS) to effectively improve upper extremity function after chronic spinal cord injury (SCI). It proposes a framework to guide stimulation programming decisions for the successful translation of these techniques into the clinic. Materials and MethodsProgramming data from 60 participants who completed the Up-LIFT trial and from 17 participants who subsequently completed the LIFT Home trial were analyzed. All observations of stimulation amplitudes, frequencies, waveforms, and electrode configurations were examined. The incidence of adverse events and relatedness to stimulation parameters is reported. A comparison of parameter usage across the American Spinal Injury Association Impairment Scale (AIS) subgroups was conducted to evaluate stimulation strategies across participants with varying degrees of sensorimotor preservation. ResultsActive (cathodal) electrodes were typically placed between the C3/C4 and C6/C7 spinous processes. Most sessions featured return (anodal) electrodes positioned bilaterally over the anterior superior iliac spine, although clavicular placement was frequently used by 12 participants. Stimulation was delivered with a 10-kHz carrier frequency and typically a 30-Hz burst frequency. Biphasic waveforms were used in 83% of sessions. Average stimulation amplitudes were higher for biphasic waveforms. The AIS B subgroup required significantly higher amplitudes than did the AIS C and D subgroups. Device-related adverse events were infrequent, and not correlated with specific waveforms or amplitudes. Within the home setting, participants maintained their current amplitudes within 1% of the preset values. The suggested stimulation programming framework dictates the following hierarchical order of parameter adjustments: current amplitude, waveform type, active/return electrode positioning, and burst frequency, guided by clinical observations as required. ConclusionsThis analysis summarizes effective stimulation parameters from the trials and provides a decision-making framework for clinical implementation of tSCS for upper extremity functional restoration after SCI. The parameters are aligned with existing literature and proved safe and well tolerated by participants.

Tonic Stimulation of Dorsal Root Ganglion Results in Progressive Decline in Recruitment of Aα/β-Fibers in Rats

ObjectivesIn this study, we aimed to characterize the recruitment and maintenance of action potential firing in Aα/β-fibers generated during tonic dorsal root ganglion stimulation (DRGS) applied over a range of clinically relevant stimulation parameters. Materials and MethodsWe delivered electrical stimulation to the L5 dorsal root ganglion and recorded antidromic evoked compound action potentials (ECAPs) in the sciatic nerve during DRGS in Sprague Dawley rats. We measured charge thresholds to elicit ECAPs in Aα/β-fibers during DRGS applied at multiple pulse widths (50, 150, 300, 500 μs) and frequencies (5, 20, 50, 100 Hz). We measured the peak-to-peak amplitudes, latencies, and widths of ECAPs generated during 180 seconds of DRGS, and excitation threshold changes to investigate potential mechanisms of ECAP suppression. ResultsTonic DRGS produced ECAPs in Aα/β-fibers at charge thresholds below the motor threshold. Increasing the pulse width of DRGS led to a significant increase in the charge required to elicit ECAPs in Aα/β-fibers, while varying DRGS frequency did not influence ECAP thresholds. Over the course of 180 seconds, ECAP peak-to-peak amplitude decreased progressively in a frequency-dependent manner, where 5- and 100-Hz DRGS resulted in 22% and 87% amplitude reductions, respectively, and ECAP latencies increased from baseline measurements during DRGS at 10, 20, 50, and 100 Hz. Regardless of DRGS frequency, ECAP amplitudes recovered within 120 seconds after turning DRGS off. We determined that ECAP suppression may be attributed to increasing excitation thresholds for individual fibers during DRGS. Following 180 seconds of DRGS, an average of 7.33% increase in stimulation amplitude was required to restore the ECAP to baseline amplitude. ConclusionsDRGS produces a progressive and frequency-dependent reduction in ECAP amplitude that occurs within and above the frequency range used clinically to relieve pain. If DRGS-mediated analgesia relies on Aβ-fiber activation, then the frequency or duty cycle of stimulation should be set to the lowest effective level to maintain sufficient activation of Aβ-fibers.

Beta Burst-Driven Adaptive Deep Brain Stimulation Improves Gait Impairment and Freezing of Gait in Parkinson's Disease.

Freezing of gait (FOG) is a debilitating symptom of Parkinson's disease (PD) that is often refractory to medication. Pathological prolonged beta bursts within the subthalamic nucleus (STN) are associated with both worse impairment and freezing behavior in PD, which are improved with deep brain stimulation (DBS). The goal of the current study was to investigate the feasibility, safety, and tolerability of beta burst-driven adaptive DBS (aDBS) for FOG in PD. Seven individuals with PD were implanted with the investigational Summit™ RC+S DBS system (Medtronic, PLC) with leads placed bilaterally in the STN. A PC-in-the-loop architecture was used to adjust stimulation amplitude in real-time based on the observed beta burst durations in the STN. Participants performed either a harnessed stepping-in-place task or a free walking turning and barrier course, as well as clinical motor assessments and instrumented measures of bradykinesia, OFF stimulation, on aDBS, continuous DBS (cDBS), or random intermittent DBS (iDBS). Beta burst driven aDBS was successfully implemented and deemed safe and tolerable in all seven participants. Gait metrics such as overall percent time freezing and mean peak shank angular velocity improved from OFF to aDBS and showed similar efficacy as cDBS. Similar improvements were also seen for overall clinical motor impairment, including tremor, as well as quantitative metrics of bradykinesia. Beta burst driven adaptive DBS was feasible, safe, and tolerable in individuals with PD with gait impairment and FOG.

A NEW POSTURAL MOTOR RESPONSE TO SPINAL CORD STIMULATION: POST-STIMULATION REBOUND EXTENSION.

Spinal cord stimulation (SCS) has emerged as a therapeutic tool for improving motor function following spinal cord injury. While many studies focus on restoring locomotion, little attention is paid to enabling standing which is a prerequisite of walking. In this study, we fully characterize a new type of response to SCS, a long extension activated post-stimulation (LEAP). LEAP is primarily directed to ankle extensors and hence has great clinical potential to assist postural movements. To characterize this new response, we used the decerebrate cat model to avoid the suppressive effects of anesthesia, and combined EMG and force measurement in the hindlimb with intracellular recordings in the lumbar spinal cord. Stimulation was delivered as five-second trains via bipolar electrodes placed on the cord surface, and multiple combinations of stimulation locations (L4 to S2), amplitudes (50-600 uA), and frequencies (10-40 Hz) were tested. While the optimum stimulation location and frequency differed slightly among animals, the stimulation amplitude was key for controlling LEAP duration and amplitude. To study the mechanism of LEAP, we performed in vivo intracellular recordings of motoneurons. In 70% of motoneurons, LEAP increased at hyperpolarized membrane potentials indicating a synaptic origin. Furthermore, spinal interneurons exhibited changes in firing during LEAP, confirming the circuit origin of this behavior. Finally, to identify the type of afferents involved in generating LEAP, we used shorter stimulation pulses (more selective for proprioceptive afferents), as well as peripheral stimulation of the sural nerve (cutaneous afferents). The data indicates that LEAP primarily relies on proprioceptive afferents and has major differences from pain or withdrawal reflexes mediated by cutaneous afferents. Our study has thus identified and characterized a novel postural motor response to SCS which has the potential to expand the applications of SCS for patients with motor disorders.