Self-initiated behavior is accompanied by the experience of intending our actions. Here, we leverage the unique opportunity to examine the full intentional chain-from intention to action to environmental effects-in a tetraplegic person outfitted with a primary motor cortex (M1) brain-machine interface (BMI) generating real hand movements via neuromuscular electrical stimulation (NMES). This combined BMI-NMES approach allowed us to selectively manipulate each element of the intentional chain (intention, action, effect) while probing subjective experience and performing extra-cellular recordings in human M1. Behaviorally, we reveal a novel form of intentional binding: motor intentions are reflected in a perceived temporal attraction between the onset of intentions and that of actions. Neurally, we demonstrate that evoked spiking activity in M1 largely coincides in time with the onset of the experience of intention and that M1 spike counts and the onset of subjective intention may co-vary on a trial-by-trial basis. Further, population-level dynamics, as indexed by a decoder instantiating movement, reflect intention-action temporal binding. The results fill a significant knowledge gap by relating human spiking activity in M1 with the onset of subjective intention and complement prior human intracranial work examining pre-motor and parietal areas.

The sensorimotor dysfunction caused by cervical and thoracic spinal cord injury (SCI) is concomitant with sympathetic nervous system dysfunction, evidenced by the high prevalence of orthostatic hypotension and autonomic dysreflexia. Although the International Standards for Neurological Classification of SCI evaluate sensorimotor function both above and below the injury level, there are limited quantitative measures for gauging sympathetic outflow and the extent of dysautonomia resulting from neurological damage. Despite studies on the effects of SCI on electrodermal activity (EDA) and blood pressure (BP), there is a lack of detailed feature comparisons involving EDA, skin vasomotor activity, and BP. Therefore, we investigated the relationship between EDA, skin vasomotor, and BP responses to sympathetic activation via median nerve stimulation in persons with and without SCI. Adults with and without SCI (cohort demographics presented in poster) participated in this study. Lead II electrocardiogram (ECG), pneumogram (P), photoplethysmogram (PPG), and EDA were recorded from either the trunk (ECG, P) or both limbs (PPG, EDA). Beat-by-beat BP was recorded from the middle finger of the left hand (VitalStream, CareTaker Medical). Evoked responses in the above signals were measured surrounding a cathodal electrical pulse (30 mA, 200 μs) delivered to the distal right median nerve 1-2 cm proximal and medial to the radial styloid process either during systole or diastole of the cardiac cycle. There were notable differences between baseline signals before and after the experimental session, along with a consistent reduction of limb temperature (> 2° Celsius). Increases in EDA (greater than two standard deviations from baseline) were found across non-SCI participants following stimulation both during systole and diastole, along with skin vasoconstriction following the onset of EDA modulation (> 50% of trials). Individual differences were noted in evoked responses to stimulation at systole vs. diastole. Furthermore, attenuated responses were observed in individuals with SCI. Stimulation caused no evoked signal response habituation across trials within participants. Additionally, evoked BP changes were not consistent across all individuals with respect to stimulation. Our results show a fixed relationship between evoked skin vasomotor and sudomotor responses to single pulse stimuli across participants and had consistent waveform features. Potential individual effects of stimulation delivered at systole vs. diastole warrant an in-depth analysis of reflex gating of sudomotor and skin vasomotor responses. This would present insight into the population with SCI, where dysfunction could greatly exaggerate reflex gating. 1R01NS131493-01. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Targeted plasticity therapy (TPT) utilizes vagus nerve stimulation (VNS) to promote improvements in function following neurological injury and disease. During TPT, a brief burst of VNS induces neuromodulator release, which when paired with relevant behavioral events can influence functionally relevant neuroplasticity. Functional improvements following TPT are therefore in part mediated by neuromodulator signaling. Unfortunately, comorbidities associated with neurological disease often result in altered cognitive states that can influence neuromodulator signaling, potentially impeding neuroplasticity induced by TPT. Aside from altered cognitive states, cardiorespiratory rhythms also affect neuromodulator signaling, due to the vagus nerve’s role in relaying visceral sensory information from the cardiovascular and respiratory systems. Moreover, precise VNS delivery during specific periods of the cardiorespiratory rhythms may further improve TPT. Ultimately, understanding the impact of patient-specific states on neuromodulator signaling may likely facilitate optimized VNS delivery, paving the way for personalized neuromodulation during TPT. Overall, this review explores challenges and considerations for developing advanced TPT paradigms, focusing on altered cognitive states and cardiorespiratory rhythms. We specifically discuss the possible impact of these cognitive states and autonomic rhythms on neuromodulator signaling and subsequent neuroplasticity. Altered cognitive states (arousal deficits or pain) could affect VNS intensity, while cardiorespiratory rhythms may further inform optimized timing of VNS. We propose that understanding these interactions will lead to the development of personalized state dependent VNS paradigms for TPT.

In recent decades, vagus nerve stimulation (VNS) therapy has become widely used for clinical applications including epilepsy, depression, and enhancing the effects of rehabilitation. However, several questions remain regarding optimization of this therapy to maximize clinical outcomes. Although stimulation parameters such as pulse width, amplitude, and frequency are well studied, the timing of stimulation delivery both acutely (with respect to disease events) and chronically (over the timeline of a disease’s progression) has generally received less attention. Leveraging such information would provide a framework for the implementation of next generation closed-loop VNS therapies. In this mini-review, we summarize a number of VNS therapies and discuss (1) general timing considerations for these applications and (2) open questions that could lead to further therapy optimization.

Self-initiated behavior is accompanied by the experience of willing our actions. Here, we leverage the unique opportunity to examine the full intentional chain – from will (W) to action (A) to environmental effects (E) - in a tetraplegic person fitted with a primary motor cortex (M1) brain machine interface (BMI) generating hand movements via neuromuscular electrical stimulation (NMES). This combined BMI-NMES approach allowed us to selectively manipulate each element of the intentional chain (W, A, and E) while performing extra-cellular recordings and probing subjective experience. Our results reveal single-cell, multi-unit, and population-level dynamics in human M1 that encode W and may predict its subjective onset. Further, we show that the proficiency of a neural decoder in M1 reflects the degree of W-A binding, tracking the participant’s subjective experience of intention in (near) real time. These results point to M1 as a critical node in forming the subjective experience of intention and demonstrate the relevance of intention-related signals for translational neuroprosthetics.

Over 100,000 people in the USA alone are currently living with a cervical spinal cord injury (SCI), unable to use their hands to perform even the basic activities of daily living (ADL). This patient population identifies restoration of hand function as a critical, unmet need to regain independence and improve quality of life. In recent years, individuals with tetraplegia have been able to regain motor function of their upper limbs with brain computer interface–controlled functional electrical stimulation (BCI-FES) neuroprosthetics. However, this medical and technological breakthrough has only been demonstrated in controlled clinical research environments. For this technology to be integrated into the daily lives of SCI patients and provide assistive functional benefits, significant improvements need to be made. In this chapter, we will detail our approach to developing a home-use neuroprosthetic for individuals with tetraplegia, discuss challenges and opportunities for translational research, and provide insight into the future direction for assistive neuroprosthetics.

The in vitro study demonstrates wirelessly controlled activation of action potentials using magnetoelectric nanoparticles (MENPs), synchronized to magnetic field application with a sub-25-msec temporal response. Herein, MENPs are sub-30-nm CoFe 2 O 4 @BaTiO 3 core-shell nanostructures. MENPs were added to E18 rat hippocampal cell cultures (0.5 µg of MENPs per 100,000 neurons) tagged with fluorescent Ca 2+ sensitive indicator cal520. MENPs were shown to wirelessly induce calcium transients which were synchronized with application of 1,200-Oe bipolar 25-msec magnetic pulses at a rate of 20 pulses/sec. The observed calcium transients were similar, in shape and magnitude, to those generated through the control electric field stimulation with a 50-µA current, and they were inhibited by the sodium channel blocker tetrodotoxin. The observed MENP-based magnetic excitation of neural activity is in agreement with the non-linear M-H hysteresis loop of the MENPs, wherein the MENPs’ coercivity value sets the threshold for the externally applied magnetic field.

Intracortical brain-machine interfaces decode motor commands from neural signals and translate them into actions, enabling movement for paralysed individuals. The subjective sense of agency associated with actions generated via intracortical brain-machine interfaces, the neural mechanisms involved and its clinical relevance are currently unknown. By experimentally manipulating the coherence between decoded motor commands and sensory feedback in a tetraplegic individual using a brain-machine interface, we provide evidence that primary motor cortex processes sensory feedback, sensorimotor conflicts and subjective states of actions generated via the brain-machine interface. Neural signals processing the sense of agency affected the proficiency of the brain-machine interface, underlining the clinical potential of the present approach. These findings show that primary motor cortex encodes information related to action and sensing, but also sensorimotor and subjective agency signals, which in turn are relevant for clinical applications of brain-machine interfaces.

Potentially damaging “heart stress” is reversed using reactive nerve stimulation controlled by artificial intelligence.

Rationale Paralyzed muscles can be reanimated following spinal cord injury (SCI) using a brain-computer interface (BCI) to enhance motor function alone. Importantly, the sense of touch is a key component of motor function. Simultaneously restoring the sense of touch and movement would meet functional needs for BCI users that seek to enhance upper limb function following SCI. Methods The study met institutional requirements for the conduct of human subjects and is registered on the http://www.ClinicalTrials.gov website (identifier: NCT01997125). The participant was a 27-year-old male with stable, non-spastic C5 quadriplegia resulting from a cervical SCI. The participant underwent implantation of a 96 channel Utah microelectrode recording array (Blackrock Microsystems, Inc.; Salt Lake, Utah) in his left primary motor cortex. The hand area of motor cortex was identified preoperatively by fusing functional magnetic resonance imaging (fMRI) activation maps obtained while the participant attempted movements co-registered to the preoperative planning MRI. During experiments, the participant was either completely blinded to the experimental conditions or given brief instructions to complete the necessary actions. Cue and trial parameters were randomized as needed. Results Results are adapted from (Ganzer PD, Colachis 4th SC, Schwemmer MA, Friedenberg DA, Dunlap CF, Swiftney CE, Sharma G in Restoring the sense of touch using a sensorimotor demultiplexing neural interface. Cell 2020). We demonstrate that a human participant with a clinically complete SCI can use a BCI to simultaneously reanimate both motor function and the sense of touch, leveraging residual touch signaling from their own hand. In primary motor cortex (M1), residual subperceptual hand touch signals are simultaneously demultiplexed from ongoing efferent motor intention, enabling intracortically controlled closed-loop sensory feedback. Using the closed-loop demultiplexing BCI almost fully restored the ability to detect object touch, and significantly improved several sensorimotor functions. Conclusion These results demonstrate that subperceptual neural signals can be decoded from human cortex and transformed into conscious perception, significantly augmenting function.

Paralyzed muscles can be reanimated following spinal cord injury (SCI) using a brain-computer interface (BCI) to enhance motor function alone. Importantly, the sense of touch is a key component of motor function. Here, we demonstrate that a human participant with a clinically complete SCI can use a BCI to simultaneously reanimate both motor function and the sense of touch, leveraging residual touch signaling from his own hand. In the primary motor cortex (M1), residual subperceptual hand touch signals are simultaneously demultiplexed from ongoing efferent motor intention, enabling intracortically controlled closed-loop sensory feedback. Using the closed-loop demultiplexing BCI almost fully restored the ability to detect object touch and significantly improved several sensorimotor functions. Afferent grip-intensity levels are also decoded from M1, enabling grip reanimation regulated by touch signaling. These results demonstrate that subperceptual neural signals can be decoded from the cortex and transformed into conscious perception, significantly augmenting function.

Background The sense of touch is a key component of motor function. Severe spinal cord injury (SCI) should essentially eliminate sensory information transmission to the brain, that originates from skin innervated from below the lesion. We assessed the hypothesis that, following SCI, residual hand sensory information is transmitted to the brain, can be decoded amongst competing sensorimotor signals, and used to enhance the sense of touch via an intracortically controlled closed-loop brain-computer interface (BCI) system. Methods Experiments were performed with a participant who has an AIS-A C5 SCI and an intracortical recording array implanted in left primary motor cortex (M1). Sensory stimulation and standard clinical sensorimotor functional assessments were used throughout a series of several mechanistic experiments. Findings Our results demonstrate that residual afferent hand sensory signals surprisingly reach human primary motor cortex and can be simultaneously demultiplexed from ongoing efferent motor intention, enabling closed-loop sensory feedback during brain-computer interface (BCI) operation. The closed-loop sensory feedback system was able to detect residual sensory signals from up to the C8 spinal level. Using the closed-loop sensory feedback system enabled significantly enhanced object touch detection, sense of agency, movement speed, and other sensorimotor functions. Interpretation To our knowledge, this is the first demonstration of simultaneously decoding multiplexed afferent and efferent activity from human cortex to control multiple assistive devices, constituting a ‘sensorimotor demultiplexing’ BCI. Overall, our results support the hypothesis that sub-perceptual neural signals can be decoded reliably and transformed to conscious perception, significantly augmenting function. Funding Internal funding was provided for this study from Battelle Memorial Institute and The Ohio State University Center for Neuromodulation.

The peripheral nervous system plays a major role in the maintenance of our physiology. Several peripheral nerves intimately regulate the state of the brain, spinal cord, and visceral systems. A new class of therapeutics, called bioelectronic medicines, are being developed to precisely regulate physiology and treat dysfunction using peripheral nerve stimulation. In this review, we first discuss new work using closed-loop bioelectronic medicine to treat upper limb paralysis. In contrast to open-loop bioelectronic medicines, closed-loop approaches trigger ‘on demand’ peripheral nerve stimulation due to a change in function (e.g., during an upper limb movement or a change in cardiopulmonary state). We also outline our perspective on timing rules for closed-loop bioelectronic stimulation, interface features for non-invasively stimulating peripheral nerves, and machine learning algorithms to recognize disease events for closed-loop stimulation control. Although there will be several challenges for this emerging field, we look forward to future bioelectronic medicines that can autonomously sense changes in the body, to provide closed-loop peripheral nerve stimulation and treat disease.

Objective: Individuals with paralysis often have mobility and dexterity impairments that limit their ability to operate motor vehicle controls. Integrating brain-machine interface (BMI) neurotechnology with vehicle control systems (VCS) provides a novel solution to this problem. In this proof-of-concept study, we show that an intracortical BMI developed to restore voluntary grasp can be repurposed to decode motor intention for vehicle velocity and steering control. Methods: The BMI-VCS consists of four components: 1) implanted motor cortex microelectrode array and NeuroPort data acquisition system, 2) machine learning workstation, 3) Python interface to generate control signals, and 4) vehicle control system. Results: Direct cortical steering and velocity control were achieved through accurate decoding of movement intention (supination, pronation, hand open, hand close) from the participant's motor cortex, translating intention into vehicle commands (turn right, turn left, accelerate, decelerate, respectively), and dynamically switching between commands to turn corners, start and stop, shift from forward to reverse, and parallel park. Conclusion: By translating BMI decoder outputs into high-level vehicle commands, a participant with tetraparesis from C5 ASIA A spinal cord injury successfully navigated CARLA driving simulator courses in real time. These decoder outputs could also be used offline for shared control of a scale model car. Significance: High-level, shared vehicle control with BMI-VCS offers an innovative way to return independent driving abilities to those with disability. BMI systems that can control multiple end-effectors may be particularly useful to those with paralysis.

Nerve damage can cause chronic, debilitating problems including loss of motor control and paresthesia, and generates maladaptive neuroplasticity as central networks attempt to compensate for the loss of peripheral connectivity. However, it remains unclear if this is a critical feature responsible for the expression of symptoms. Here, we use brief bursts of closed-loop vagus nerve stimulation (CL-VNS) delivered during rehabilitation to reverse the aberrant central plasticity resulting from forelimb nerve transection. CL-VNS therapy drives extensive synaptic reorganization in central networks paralleled by improved sensorimotor recovery without any observable changes in the nerve or muscle. Depleting cortical acetylcholine blocks the plasticity-enhancing effects of CL-VNS and consequently eliminates recovery, indicating a critical role for brain circuits in recovery. These findings demonstrate that manipulations to enhance central plasticity can improve sensorimotor recovery and define CL-VNS as a readily translatable therapy to restore function after nerve damage.

Background and Purpose— Chronic impairment of the arm and hand is a common consequence of stroke. Animal and human studies indicate that brief bursts of vagus nerve stimulation (VNS) in conjunction with rehabilitative training improve recovery of motor function after stroke. In this study, we tested whether VNS could promote generalization, long-lasting recovery, and structural plasticity in motor networks. Methods— Rats were trained on a fully automated, quantitative task that measures forelimb supination. On task proficiency, unilateral cortical and subcortical ischemic lesions were administered. One week after ischemic lesion, rats were randomly assigned to receive 6 weeks of rehabilitative training on the supination task with or without VNS. Rats then underwent 4 weeks of testing on a task assessing forelimb strength to test generalization of recovery. Finally, the durability of VNS benefits was tested on the supination task 2 months after the cessation of VNS. After the conclusion of behavioral testing, viral tracing was performed to assess synaptic connectivity in motor networks. Results— VNS enhances plasticity in corticospinal motor networks to increase synaptic connectivity to musculature of the rehabilitated forelimb. Adding VNS more than doubled the benefit of rehabilitative training, and the improvements lasted months after the end of VNS. Pairing VNS with supination training also significantly improved performance on a similar, but untrained task that emphasized volitional forelimb strength, suggesting generalization of forelimb recovery. Conclusions— This study provides the first evidence that VNS paired with rehabilitative training after stroke (1) doubles long-lasting recovery on a complex task involving forelimb supination, (2) doubles recovery on a simple motor task that was not paired with VNS, and (3) enhances structural plasticity in motor networks.

Objective: Paralysis resulting from spinal cord injury (SCI) can have a devastating effect on multiple arm and hand motor functions. Rotary hand movements, such as supination and pronation, are commonly impaired by upper extremity paralysis, and are essential for many activities of daily living. In this proof-of-concept study, we utilize a neural bypass system (NBS) to decode motor intention from motor cortex to control combinatorial rotary hand movements elicited through stimulation of the arm muscles, effectively bypassing the SCI of the study participant. We describe the NBS system architecture and design that enabled this functionality. Methods: The NBS consists of three main functional components: 1) implanted intracortical microelectrode array, 2) neural data processing using a computer, and, 3) a noninvasive neuromuscular electrical stimulation (NMES) system. Results: We address previous limitations of the NBS, and confirm the enhanced capability of the NBS to enable, in real-time, combinatorial hand rotary motor functions during a functionally relevant object manipulation task. Conclusion: This enhanced capability was enabled by accurate decoding of multiple movement intentions from the participant's motor cortex, interleaving NMES patterns to combine hand movements, and dynamically switching between NMES patterns to adjust for hand position changes during movement. Significance: These results have implications for enabling complex rotary hand functions in sequence with other functionally relevant movements for patients suffering from SCI, stroke, and other sensorimotor dysfunctions.

Severe spinal cord injury (SCI) damages descending motor and serotonin (5-HT) fiber projections leading to paralysis and serotonin depletion. 5-HT receptors (5-HTRs) subsequently upregulate following 5-HT fiber degeneration, and dendritic density decreases indicative of atrophy. 5-HT pharmacotherapy or exercise can improve locomotor behavior after SCI. One might expect that 5-HT pharmacotherapy acts on upregulated spinal 5-HTRs to enhance function, and that exercise alone can influence dendritic atrophy. In the current study, we assessed locomotor recovery and spinal proteins influenced by SCI and therapy. 5-HT, 5-HT2AR, 5-HT1AR, and dendritic densities were quantified both early (1 week) and late (9 weeks) after SCI, and also following therapeutic interventions (5-HT pharmacotherapy, bike therapy, or a combination). Interestingly, chronic 5-HT pharmacotherapy largely normalized spinal 5-HTR upregulation following injury. Improvement in locomotor behavior was not correlated to 5-HTR density. These results support the hypothesis that chronic 5-HT pharmacotherapy can mediate recovery following SCI, despite acting on largely normal spinal 5-HTR levels. We next assessed spinal dendritic plasticity and its potential role in locomotor recovery. Single therapies did not normalize the loss of dendritic density after SCI. Groups displaying significantly atrophied dendritic processes were rarely able to achieve weight supported open-field locomotion. Only a combination of 5-HT pharmacotherapy and bike therapy enabled significant open-field weigh-supported stepping, mediated in part by restoring spinal dendritic density. These results support the use of combined therapies to synergistically impact multiple markers of spinal plasticity and improve motor recovery.

Recovery from serious neurological injury requires substantial rewiring of neural circuits. Precisely-timed electrical stimulation could be used to restore corrective feedback mechanisms and promote adaptive plasticity after neurological insult, such as spinal cord injury (SCI) or stroke. This study provides the first evidence that closed-loop vagus nerve stimulation (CLV) based on the synaptic eligibility trace leads to dramatic recovery from the most common forms of SCI. The addition of CLV to rehabilitation promoted substantially more recovery of forelimb function compared to rehabilitation alone following chronic unilateral or bilateral cervical SCI in a rat model. Triggering stimulation on the most successful movements is critical to maximize recovery. CLV enhances recovery by strengthening synaptic connectivity from remaining motor networks to the grasping muscles in the forelimb. The benefits of CLV persist long after the end of stimulation because connectivity in critical neural circuits has been restored.