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In current functional neuromuscular stimulation systems (FNS), control and feedback signals are usually provided by external sensors and switches, which pose problems such as donning and calibration time, cosmesis, and mechanical vulnerability. Artificial sensors are difficult to build and are insufficiently biocompatible and reliable for implantation. With the advent of methods for electrical interfacing with nerves and muscles, natural sensors are being considered as an alternative source of feedback and command signals for FNS. Decision making methods for higher level control can perform equally well with natural or artificial sensors. Recording nerve cuff electrodes have been developed and tested in animals and demonstrated to be feasible in humans for control of dorsiflexion in foot-drop and grasp in quadriplegia. Electromyographic signals, being one thousand times larger than electroneurograms, are easier to measure but have not been able to provide reliable indicators (e.g., of muscle fatigue) that would be useful in FNS systems. Animal studies have shown that information about the shape and movement of arm trajectories can be extracted from brain cortical activity, suggesting that FNS may ultimately be directly controllable from the central nervous system. [ABSTRACT FROM AUTHOR]

Significance: This study reveals that Fc-enhanced anti-CTLA-4 harnesses novel mechanisms to overcome the limitations of conventional anti-CTLA-4, effectively treating poorly immunogenic and treatment-refractory cancers. Our findings support the development of a new class of immuno-oncology agents, capable of extending clinical benefit to patients with cancers resistant to current immunotherapies., (©2024 The Authors; Published by the American Association for Cancer Research.)

Hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis response can result in anxiety and other neuropsychiatric disorders and effective therapeutics are needed to mitigate this maladaptive response. Here we examined the effects of Teneurin C-terminal Associated Peptide (TCAP)-1, a peptide known to inhibit corticotropin releasing factor (CRF)-mediated stress, on the physiological expression of stress, and whether the effects of TCAP-1 were dependent on the route of administration. We first examined whether subcutaneous administration of TCAP-1 influenced tube restraint stress-induced corticosterone (CORT) increases in both male mice and rats. Using a similar model, we further examined the efficacy and time course of intranasal TCAP-1. Results showed that subcutaneous TCAP-1 administration attenuated the expression of the physiological manifestation of stress in male mice and rats, and that intranasal TCAP-1 delivered prophylactically is effective at attenuating stress-induced CORT increases in male rats. These data indicate that TCAP-1 delivered though non-invasive routes of administration could have potential as a clinically relevant anxiolytic., (© 2024 The Author(s). Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

Rationale: Corticotropin-releasing factor (CRF), the apical stress-inducing hormone, exacerbates stress and addictive behaviors. TCAP-1 is a peptide that directly inhibits both CRF-mediated stress and addiction-related behaviors; however, the direct action of TCAP-1 on morphine withdrawal-associated behaviors has not previously been examined., Objective: To determine whether TCAP-1 administration attenuates behavioral and physiological consequences of morphine withdrawal in mice., Methods: Mice were administered via subcutaneous route TCAP-1 either before or after initial morphine exposure, after which jumping behavior was quantified to assess the effects of TCAP-1 on naloxone-precipitated morphine withdrawal. As a comparison, mice were treated with nonpeptide CRF 1 receptor antagonist CP-154,526. In one experiment, plasma corticosterone (CORT) was also measured as a physiological stress indicator., Results: Pretreatment with TCAP-1 (10-250 nmol/kg) before morphine treatment significantly inhibited the development of naloxone-precipitated withdrawal. TCAP-1 (250-500 nmol/kg) treatment administered after morphine treatment attenuated the behavioral expression of naloxone-precipitated withdrawal. TCAP-1 (250 nmol/kg) treatment during morphine treatment was more effective than the optimal dosing of CP-154,526 (20 mg/kg) at suppressing the behavioral expression of naloxone-precipitated withdrawal, despite similar reduction of withdrawal-induced plasma CORT level increases., Conclusions: These findings establish TCAP-1 as a potential therapeutic candidate for the prevention and treatment of morphine withdrawal., (© 2024. The Author(s).)

Altered protein phosphorylation in cancer cells often leads to surface presentation of phosphopeptide neoantigens. However, their role in cancer immunogenicity remains unclear. Here we describe a mechanism by which an HLA-B*0702-specific acute myeloid leukemia phosphoneoantigen, pMLL 747-755 (EPR(pS)PSHSM), is recognized by a cognate T cell receptor named TCR27, a candidate for cancer immunotherapy. We show that the replacement of phosphoserine P 4 with serine or phosphomimetics does not affect pMHC conformation or peptide-MHC affinity but abrogates TCR27-dependent T cell activation and weakens binding between TCR27 and pMHC. Here we describe the crystal structures for TCR27 and cognate pMHC, map of the interface produced by nuclear magnetic resonance, and a ternary complex generated using information-driven protein docking. Our data show that non-covalent interactions between the epitope phosphate group and TCR27 are crucial for TCR specificity. This study supports development of new treatment options for cancer patients through target expansion and TCR optimization., (© 2023. The Author(s).)

Purpose: Postactivation depression of the Hoffmann reflex is reduced in Parkinson's disease (PD), but how the recovery is influenced by the state of the muscle is unknown. The present pilot study examined postactivation depression in PD at rest and during a voluntary contraction while patients were off treatment and while receiving medications and/or deep brain stimulation., Methods: The authors recruited nine patients with PD treated with implanted deep brain stimulation and examined postactivation depression under four treatment conditions. Paired pulses were delivered 25 to 300 ms apart, and soleus Hoffmann reflex recovery was tested at rest and during voluntary plantar flexion. Trials were matched for background muscle activity and compared with 10 age-matched controls., Results: Patients with Parkinson disease who were OFF medications (OFF meds) and OFF stimulation (OFF stim) at rest showed less postactivation depression at the 300 ms interpulse interval (86.1% ± 21.0%) relative to control subjects (36.4% ± 6.1%; P < 0.05). Postactivation depression was restored when dopaminergic medication and/or deep brain stimulation was applied. Comparisons between resting and active motor states revealed that the recovery curves were similar OFF meds/OFF stim owing to faster recovery in PD seen at rest. In contrast, the effect of the motor state was different ON meds/OFF stim and ON meds/ON stim (both P < 0.05), with a nonsignificant trend OFF meds/ON stim ( P > 0.08). During a contraction, recovery curves were similar between all treatment conditions in PD and control., Conclusions: Disrupted Hoffmann reflex recovery is restored to control levels in PD patients at rest when receiving medications and/or deep brain stimulation or when engaged in voluntary contraction., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2020 by the American Clinical Neurophysiology Society.)

Purpose: Abnormal activity within the corticospinal system is believed to contribute to the motor dysfunction associated with Parkinson disease. However, the effect of treatment for parkinsonian motor symptoms on dysfunctional descending input to the motor neuron pool remains unclear., Methods: We recruited nine patients with PD treated with deep brain stimulation and examined the time course of interaction between a conditioning pulse from transcranial magnetic stimulation and the soleus H-reflex. Patients with Parkinson disease were examined under four treatment conditions and compared with 10 age-matched control subjects., Results: In healthy controls, transcranial magnetic stimulation conditioning led to early inhibition of the H-reflex (76.2% ± 6.3%) at a condition-test interval of -2 ms. This early inhibition was absent when patients were OFF medication/OFF stimulation (132.5% ± 20.4%; P > 0.05) but was maximally restored toward control levels ON medication/ON stimulation (80.3% ± 7.0%). Of note, early inhibition ON medication/ON stimulation tended to be stronger than when medication (85.4% ± 5.9%) or deep brain stimulation (95.7% ± 9.4%) were applied separately. Late facilitation was observed in controls at condition-test intervals ≥5 ms but was significantly reduced (by 50% to 80% of controls) in Parkinson disease OFF stimulation at condition-test intervals ≥15 ms. The late facilitation was akin to control subjects when patients were ON stimulation., Conclusions: The present pilot study demonstrates that the recruitment of early inhibition and late facilitation is disrupted in untreated Parkinson disease and that medication and deep brain stimulation may act together to normalize supraspinal drive to the motor neuron pool., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2020 by the American Clinical Neurophysiology Society.)

Modulation of a Hoffmann (H)-reflex following transcranial magnetic stimulation (TMS) has been used to assess the nature of signals transmitted from cortical centers to lower motor neurons. Further characterizing the recruitment and time-course of the TMS-induced effect onto the soleus H-reflex adds to the discussion of these pathways and may improve its utility in clinical studies. In 10 healthy controls, TMS was used to condition the soleus H-reflex using TMS intensities from 65 to 110% of the resting motor threshold (RMT). Early facilitation [- 5 to - 3 ms condition-test (C-T) interval] was evident when TMS was 110% of RMT (P < 0.05). By comparison, late facilitation (+ 10 to + 20 ms C-T interval) was several times larger and observed over a wider range of TMS intensities, including 65-110% of RMT. The early inhibition (- 3 to - 1 ms C-T interval) had a low TMS threshold and was elicited over a wide range of intensity from 65% to 95% of RMT (all P < 0.05). A second inhibitory phase was seen ~ 4 ms later (+ 1 to + 4 ms C-T intervals) and was only observed for a TMS intensity of 95% of RMT (P < 0.05). The present findings reaffirm that subthreshold TMS strongly modulates soleus motor neurons and demonstrates that distinct pathways can be selectively probed at discrete C-T intervals when using specific TMS intensities.

Adoptive T cell therapy using patient T cells redirected to recognize tumor-specific antigens by expressing genetically engineered high-affinity T-cell receptors (TCRs) has therapeutic potential for melanoma and other solid tumors. Clinical trials implementing genetically modified TCRs in melanoma patients have raised concerns regarding off-target toxicities resulting in lethal destruction of healthy tissue, highlighting the urgency of assessing which off-target peptides can be recognized by a TCR. As a model system we used the clinically efficacious NY-ESO-1-specific TCR C 259 , which recognizes the peptide epitope SLLMWITQC presented by HLA-A * 02:01. We investigated which amino acids at each position enable a TCR interaction by sequentially replacing every amino acid position outside of anchor positions 2 and 9 with all 19 possible alternative amino acids, resulting in 134 peptides (133 altered peptides plus epitope peptide). Each peptide was individually evaluated using three different in vitro assays: binding of the NY-ESO c259 TCR to the peptide, peptide-dependent activation of TCR-expressing cells, and killing of peptide-presenting target cells. To represent the TCR recognition kernel, we defined Position Weight Matrices (PWMs) for each assay by assigning normalized measurements to each of the 20 amino acids in each position. To predict potential off-target peptides, we applied a novel algorithm projecting the PWM-defined kernel into the human proteome, scoring NY-ESO c259 TCR recognition of 336,921 predicted human HLA-A * 02:01 binding 9-mer peptides. Of the 12 peptides with high predicted score, we confirmed 7 (including NY-ESO-1 antigen SLLMWITQC) strongly activate human primary NY-ESO c259 -expressing T cells. These off-target peptides include peptides with up to 7 amino acid changes (of 9 possible), which could not be predicted using the recognition motif as determined by alanine scans. Thus, this replacement scan assay determines the "TCR fingerprint" and, when coupled with the algorithm applied to the database of human 9-mer peptides binding to HLA-A * 02:01, enables the identification of potential off-target antigens and the tissues where they are expressed. This platform enables both screening of multiple TCRs to identify the best candidate for clinical development and identification of TCR-specific cross-reactive peptide recognition and constitutes an improved methodology for the identification of potential off-target peptides presented on MHC class I molecules., (Copyright © 2019 Karapetyan, Chaipan, Winkelbach, Wimberger, Jeong, Joshi, Stein, Underwood, Castle, van Dijk and Seibert.)

Mutation-derived neoantigens distinguish tumor from normal cells. T cells can sense the HLA-presented mutations, recognize tumor cells as non-self and destroy them. Therapeutically, immunotherapy antibodies can increase the virulence of the immune system by increasing T-cell cytotoxicity targeted toward neoantigens. Neoantigen vaccines act through antigen-presenting cells, such as dendritic cells, to activate patient-endogenous T cells that recognize vaccine-encoded mutations. Infusion of mutation-targeting T cells by adoptive cell therapy (ACT) directly increases the number and frequency of cytotoxic T cells recognizing and killing tumor cells. At the same time, publicly-funded consortia have profiled tumor genomes across many indications, identifying mutations in each tumor. For example, we find basal and HER2 positive tumors contain more mutated proteins and more TP53 mutations than luminal A/B breast tumors. HPV negative tumors have more mutated proteins than HPV positive head and neck tumors and in agreement with the hypothesis that HPV activity interferes with p53 activity, only 14% of the HPV positive mutations have TP53 mutations vs. 86% of the HPV negative tumors. Lung adenocarcinomas in smokers have over four times more mutated proteins relative to those in never smokers (median 248 vs. 61, respectively). With an eye toward immunotherapy applications, we review the spectrum of mutations in multiple indications, show variations in indication sub-types, and examine intra- and inter-indication prevalence of re-occurring mutation neoantigens that could be used for warehouse vaccines and ACT.

Objective: To investigate whether low intensity transcranial electrical stimulation (TES) can be used to condition post-activation depression of the H-reflex and simultaneously monitor the integrity of spinal motor pathways during spinal deformity correction surgery., Methods: In 20 pediatric patients undergoing corrective surgery for spinal deformity, post-activation depression of the medial gastrocnemius H-reflex was initiated by delivering two pulses 50-125ms apart, and the second H-reflex was conditioned by TES., Results: Low intensity TES caused no visible shoulder or trunk movements during 19/20 procedures and the stimulation reduced post-activation depression of the H-reflex. The interaction was present in 20/20 patients and did not diminish throughout the surgical period. In one case, the conditioning effect was lost within minutes of the disappearance of the lower extremity motor evoked potentials., Conclusion: Post-activation depression was used to detect the arrival of a subthreshold motor evoked potential at the lower motor neuron. The interaction produced minimal movement within the surgical field and remained stable throughout the surgical period., Significance: This is the first use of post-activation depression during intraoperative neurophysiological monitoring to directly assess the integrity of descending spinal motor pathways., (Copyright © 2016 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Objective: Spinal cord injury causes a drastic loss of motor, sensory and autonomic function. The goal of this project was to investigate the use of intraspinal microstimulation (ISMS) for producing long distances of walking over ground. ISMS is an electrical stimulation method developed for restoring motor function by activating spinal networks below the level of an injury. It produces movements of the legs by stimulating the ventral horn of the lumbar enlargement using fine penetrating electrodes (≤50 μm diameter)., Approach: In each of five adult cats (4.2-5.5 kg), ISMS was applied through 16 electrodes implanted with tips targeting lamina IX in the ventral horn bilaterally. A desktop system implemented a physiologically-based control strategy that delivered different stimulation patterns through groups of electrodes to evoke walking movements with appropriate limb kinematics and forces corresponding to swing and stance. Each cat walked over an instrumented 2.9 m walkway and limb kinematics and forces were recorded., Main Results: Both propulsive and supportive forces were required for over-ground walking. Cumulative walking distances ranging from 609 to 835 m (longest tested) were achieved in three animals. In these three cats, the mean peak supportive force was 3.5 ± 0.6 N corresponding to full-weight-support of the hind legs, while the angular range of the hip, knee, and ankle joints were 23.1 ± 2.0°, 29.1 ± 0.2°, and 60.3 ± 5.2°, respectively. To further demonstrate the viability of ISMS for future clinical use, a prototype implantable module was successfully implemented in a subset of trials and produced comparable walking performance., Significance: By activating inherent locomotor networks within the lumbosacral spinal cord, ISMS was capable of producing bilaterally coordinated and functional over-ground walking with current amplitudes <100 μA. These exciting results suggest that ISMS may be an effective intervention for restoring functional walking after spinal cord injury.

Postactivation depression of the Hoffmann (H) reflex is associated with a transient period of suppression following activation of the reflex pathway. In soleus, the depression lasts for 100-200 ms during voluntary contraction and up to 10 s at rest. A reflex root evoked potential (REP), elicited after a single pulse of transcutaneous stimulation to the thoracolumbar spine, has been shown to exhibit similar suppression. The present study systematically characterized the effect of transcranial magnetic stimulation (TMS) on postactivation depression using double-pulse H reflexes and REPs. A TMS pulse reduced the period of depression to 10-15 ms for both reflexes. TMS could even produce postactivation facilitation of the H reflex, as the second reflex response was increased to 243 ± 51% of control values at the 75-ms interval. The time course was qualitatively similar for the REP, yet the overall increase was less. While recovery of the H reflex was slower in the relaxed muscle, the profile exhibited a distinct bimodal shape characterized by an early peak at the 25-ms interval, reaching 72 ± 23% of control values, followed by a trough at 50 ms, and then a gradual recovery at intervals > 50 ms. The rapid recovery of two successively depressed H reflexes, ∼ 25 ms apart, was also possible with double-pulse TMS. The effect of the TMS-induced corticospinal excitation on postactivation depression may be explained by a combination of pre- and postsynaptic mechanisms, although further investigation is required to distinguish between them., (Copyright © 2015 the American Physiological Society.)

Transcutaneous stimulation of the human lumbar spine can be used to elicit root-evoked potentials (REPs). These sensory-motor responses display notable similarities to the monosynaptic H-reflex. The purpose of this study was to compare post-activation depression of the soleus REP to that of the H-reflex, when conditioned by either an H-reflex or an REP. Paired pulses were delivered 25-200ms apart and the recovery was characterized using three levels of stimulation. In all conditions, post-activation depression was reduced during contraction as compared to rest (P<0.001). REP doublets, delivered using an inter-pulse interval of 150ms, recovered to 68±8% of control during plantarflexion and 20±6% of control at rest. During contraction, recovery of a second REP was 65% of the corresponding recovery for a second H-reflex. The recovery of an H-reflex was equivalent, when conditioned by either an H-reflex or an REP, even though the spinal stimulus activated and/or engaged more afferent and efferent fibers. Our results suggest that the additional elements activated by the spinal stimulus did not affect the recovery of the H-reflex. However, the transcutaneous spinal stimulus produced more inhibition when it was assessed using two low-intensity REPs (P<0.05) suggesting that the pathway mediating the spinally-evoked response was more susceptible to being inhibited., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objective: To investigate the safety, feasibility, and acceptability of a novel treatment, intermittent electrical stimulation (IES), for preventing deep tissue injury (DTI) in different healthcare settings. Approach: Testing was conducted in an acute rehabilitation unit of a general hospital, a tertiary rehabilitation hospital, a long-term care facility, and homecare (HC). IES was delivered through surface electrodes placed either directly on the gluteal muscles or through mesh panels inside a specialized garment. Study participants at risk for DTI used the system for an average of 4 weeks. Outcome measures included skin reaction to long-term stimulation, demands on the caregiver, stability of induced muscle contraction, and acceptability as part of the users' daily routine. Results: A total of 48 study participants used the IES system. The system proved to be safe and feasible in all four clinical settings. No pressure ulcers were observed in any of the participants. There was no difference between the clinical settings in patient positioning, ease of finding optimal stimulation site, and patient acceptance. Although donning and doffing time was longer in the long-term care and HC settings than the acute rehabilitation unit and tertiary rehabilitation facility, time required to apply the IES system was <18 min (including data collection). The patients and caregivers did not find the application disruptive and indicated that the stimulation was acceptable as part of their daily routine in over 97% of the time. Innovation and Conclusion: We demonstrated the safety, feasibility, and acceptability of a novel method of IES to prevent DTI in a continuum of healthcare settings.

Transcutaneous spinal stimulation is a noninvasive method that can activate dorsal and/or ventral roots depending on the location and intensity of stimulation. Reflex root-evoked potentials (REPs) were studied in muscles that traditionally evoke large (soleus) and small H-reflexes (tibialis anterior), as well as muscles where H-reflexes are difficult to study (hamstrings). This study characterizes the interaction of the REP and the motor-evoked potential (MEP). Transcranial magnetic stimulation (TMS) delivered 11-25 ms before spinal stimulation resulted in more than linear summation of the two responses. Because of overlap, the modulation was quantified after subtracting the contribution of the conditioning MEP or REP. At rest, the mean-rectified soleus response was facilitated by up to ~250 μV (21-times the MEP or 161% of the REP). The increases were more reliable during a voluntary contraction (up to ~300 μV, 517% of the MEP or 181% of the REP). At the 13-ms interval, the mean-rectified response in the pre-contracted hamstrings was increased by 227% of the MEP or 300% of the REP. In some subjects, TMS could also eliminate the post-activation depression produced using two spinal stimuli, confirming that the interaction can extend to presynaptic spinal neurons. The spatiotemporal facilitation in tibialis anterior was not significant. However, the large MEP was facilitated when the spinal stimulus preceded TMS by 100-150 ms, presumably because of rebound excitation. These strong interactions may be important for inducing motor plasticity and improved training procedures for recovery after neurological damage.

Objective: The goal of this study was to decode sensory information from the dorsal root ganglia (DRG) in real time, and to use this information to adapt the control of unilateral stepping with a state-based control algorithm consisting of both feed-forward and feedback components., Approach: In five anesthetized cats, hind limb stepping on a walkway or treadmill was produced by patterned electrical stimulation of the spinal cord through implanted microwire arrays, while neuronal activity was recorded from the DRG. Different parameters, including distance and tilt of the vector between hip and limb endpoint, integrated gyroscope and ground reaction force were modelled from recorded neural firing rates. These models were then used for closed-loop feedback., Main Results: Overall, firing-rate-based predictions of kinematic sensors (limb endpoint, integrated gyroscope) were the most accurate with variance accounted for >60% on average. Force prediction had the lowest prediction accuracy (48 ± 13%) but produced the greatest percentage of successful rule activations (96.3%) for stepping under closed-loop feedback control. The prediction of all sensor modalities degraded over time, with the exception of tilt., Significance: Sensory feedback from moving limbs would be a desirable component of any neuroprosthetic device designed to restore walking in people after a spinal cord injury. This study provides a proof-of-principle that real-time feedback from the DRG is possible and could form part of a fully implantable neuroprosthetic device with further development.

Background: Studies have demonstrated the efficacy of functional electrical stimulation in the management of foot drop after stroke., Objective: To compare changes in walking performance with the WalkAide (WA) foot-drop stimulator and a conventional ankle-foot orthosis (AFO)., Methods: Individuals with stroke within the previous 12 months and residual foot drop were enrolled in a multicenter, randomized controlled, crossover trial. Subjects were assigned to 1 of 3 parallel arms for 12 weeks (6 weeks/device): arm 1 (WA-AFO), n = 38; arm 2 (AFO-WA), n = 31; arm 3 (AFO-AFO), n = 24. Primary outcomes were walking speed and Physiological Cost Index for the Figure-of-8 walking test. Secondary measures included 10-m walking speed and perceived safety during this test, general mobility, and device preference for arms 1 and 2 for continued use. Walking tests were performed with (On) and without a device (Off) at 0, 3, 6, 9, and 12 weeks., Results: Both WA and AFO had significant orthotic (On-Off difference), therapeutic (change over time when Off), and combined (change over time On vs baseline Off) effects on walking speed. An AFO also had a significant orthotic effect on Physiological Cost Index. The WA had a higher, but not significantly different therapeutic effect on speed than an AFO, whereas an AFO had a greater orthotic effect than the WA (significant at 12 weeks). Combined effects on speed after 6 weeks did not differ between devices. Users felt as safe with the WA as with an AFO, but significantly more users preferred the WA., Conclusions: Both devices produce equivalent functional gains.

Percutaneous spinal stimulation is a promising new technique for understanding human spinal reflexes and for evaluating the pathophysiology of motor roots. Previous studies have generally stimulated the T11/T12 or T12/L1 vertebral junctions, sites that overlie the lumbosacral enlargement. The present study sought to determine the best location for targeting sensory and motor roots during sitting. We used paired stimuli, 50 ms apart, to distinguish the contribution of the reflex and motor components which make up the root evoked potential. This assumed that post-stimulation attenuation, primarily through homosynaptic depression, would abolish the second potential if it was trans-synaptic in origin. Conversely, successive responses would be unchanged if motor roots were being stimulated. Here, we show that sensory root reflexes were optimally elicited with percutaneous stimulation over the L1-L3 vertebrae. However, the optimal position varied between subjects and depended on the target muscle being studied. A collision test showed that the reflex recorded in pre-tibial flexors was low in amplitude and was prone to crosstalk from neighbouring muscles. In contrast to the reflex response, direct motor root activation was optimal with stimulation over the more caudal L5-S1 vertebrae. The present results support the utility of paired stimulation for evaluating the topographical recruitment of sensory and motor roots to human leg muscles.

Functional electrical stimulation (FES) can improve walking in individuals with mobility impairments. We evaluated accelerometers, force sensitive resistors, segment angles, and segment angular velocities to identify which sensor best determines the activation and deactivation times of the main muscles used during walking. This sensor(s) can be used in the future in conjunction with FES systems to improve walking. Able-bodied subjects walked at various speeds. Threshold levels were set for each sensor that minimized the difference between the times of activating and deactivating the electromyogram (EMG) of six muscles and the times of sensor threshold crossings as a percent of the step cycle. Mobility-impaired subjects walked at their preferred speed with and without FES to correct foot drop. Thresholds were set for these subjects so that sensor signals would cross at times that matched those of able-bodied subjects. Segment angles were generally the most effective sensor signals. Using segment angles of the thigh, shank, and foot, activation and deactivation times of the six muscles could be determined to within 6% of the step cycle. The shank segment angle produced the lowest overall error and was among the top three sensors for 10 of the 12 events (activation and deactivation of six muscle groups). A segment angle sensor was implemented using a complementary filter (accelerometer/gyroscope combination). Using this sensor improved rule-based timing of FES in subjects with foot drop as compared to accelerometers alone.

The biological central pattern generator (CPG) integrates open and closed loop control to produce over-ground walking. The goal of this study was to develop a physiologically based algorithm capable of mimicking the biological system to control multiple joints in the lower extremities for producing over-ground walking. The algorithm used state-based models of the step cycle each of which produced different stimulation patterns. Two configurations were implemented to restore over-ground walking in five adult anaesthetized cats using intramuscular stimulation (IMS) of the main hip, knee and ankle flexor and extensor muscles in the hind limbs. An open loop controller relied only on intrinsic timing while a hybrid-CPG controller added sensory feedback from force plates (representing limb loading), and accelerometers and gyroscopes (representing limb position). Stimulation applied to hind limb muscles caused extension or flexion in the hips, knees and ankles. A total of 113 walking trials were obtained across all experiments. Of these, 74 were successful in which the cats traversed 75% of the 3.5 m over-ground walkway. In these trials, the average peak step length decreased from 24.9 ± 8.4 to 21.8 ± 7.5 (normalized units) and the median number of steps per trial increased from 7 (Q1 = 6, Q3 = 9) to 9 (8, 11) with the hybrid-CPG controller. Moreover, within these trials, the hybrid-CPG controller produced more successful steps (step length ≤ 20 cm; ground reaction force ≥ 12.5% body weight) than the open loop controller: 372 of 544 steps (68%) versus 65 of 134 steps (49%), respectively. This supports our previous preliminary findings, and affirms that physiologically based hybrid-CPG approaches produce more successful stepping than open loop controllers. The algorithm provides the foundation for a neural prosthetic controller and a framework to implement more detailed control of locomotion in the future.

This paper reports on a wireless stimulator device for use in animal experiments as part of an ongoing investigation into intraspinal stimulation (ISMS) for restoration of walking in humans with spinal cord injury. The principle behind using ISMS is the activation of residual motor-control neural networks within the spinal cord ventral horn below the level of lesion following a spinal cord injury. The attractiveness to this technique is that a small number of electrodes can be used to induce bilateral walking patterns in the lower limbs. In combination with advanced feedback algorithms, ISMS has the potential to restore walking for distances that exceed that produced by other types of functional electrical stimulation. Recent acute animal experiments have demonstrated the feasibility of using ISMS to produce the coordinated walking patterns. Here we described a wireless implantable stimulation system to be used in chronic animal experiments and for providing the basis for a system suitable for use in humans. Electrical operation of the wireless system is described, including a demonstration of reverse telemetry for monitoring the stimulating electrode voltages.

Functional electrical stimulation (FES) is used to improve motor function after injury to the central nervous system. Some FES systems use artificial sensors to switch between finite control states. To optimize FES control of the complex behavior of the musculo-skeletal system in activities of daily life, it is highly desirable to implement feedback control. In theory, sensory neural signals could provide the required control signals. Recent studies have demonstrated the feasibility of deriving limb-state estimates from the firing rates of primary afferent neurons recorded in dorsal root ganglia (DRG). These studies used multiple linear regression (MLR) methods to generate estimates of limb position and velocity based on a weighted sum of firing rates in an ensemble of simultaneously recorded DRG neurons. The aim of this study was to test whether the use of a neuro-fuzzy (NF) algorithm (the generalized dynamic fuzzy neural networks (GD-FNN)) could improve the performance, robustness and ability to generalize from training to test sets compared to the MLR technique. NF and MLR decoding methods were applied to ensemble DRG recordings obtained during passive and active limb movements in anesthetized and freely moving cats. The GD-FNN model provided more accurate estimates of limb state and generalized better to novel movement patterns. Future efforts will focus on implementing these neural recording and decoding methods in real time to provide closed-loop control of FES using the information extracted from sensory neurons.

The overall objective of this project is to develop a feedback-driven intraspinal microstimulation (ISMS) system. We hypothesize that ISMS will enhance the functionality of stepping by reducing muscle fatigue and producing synergistic movements by activating neural networks in the spinal cord. In the present pilot study, the controller was tested with ISMS and external sensors (force plates, gyroscopes, and accelerometers). Cats were partially supported in a sling and bi-laterally stepped overground on a 4-m instrumented walkway. The walkway had variable friction. Limb angle was controlled to within 10° even in the presence of variable friction. Peak ground reaction forces in each limb were approximately 12% of body weight (12.5% was full load bearing in this experimental setup); rarely, the total supportive force briefly decreased to as low as 4.1%. Magnetic resonance images were acquired of the excised spinal cord and the implanted array. The majority of electrodes (75%) were implanted successfully into their target regions. This represents the first successful application of ISMS for overground walking.

Background: Long-term use of a foot-drop stimulator applying functional electrical stimulation (FES) to the common peroneal nerve improves walking performance even when the stimulator is off. This "therapeutic" effect might result from neuroplastic changes., Objective: To determine the effect of long-term use of a foot-drop stimulator on residual corticospinal connections in people with central nervous system disorders., Methods: Ten people with nonprogressive disorders (eg, stroke) and 26 with progressive disorders (eg, multiple sclerosis) used a foot-drop stimulator for 3 to 12 months while walking in the community. Walking performance and electrophysiological variables were measured before and after FES use. From the surface electromyogram of the tibialis anterior muscle, we measured the following: (1) motor-evoked potential (MEP) from transcranial magnetic stimulation over the motor cortex, (2) maximum voluntary contraction (MVC), and (3) maximum motor wave (M(max)) from stimulating the common peroneal nerve., Results: After using FES, MEP and MVC increased significantly by comparable amounts, 50% and 48%, respectively, in the nonprogressive group and 27% and 17% in the progressive group; the changes were positively correlated (R(2) = .35; P < .001). Walking speed increased with the stimulator off (therapeutic effect) by 24% (P = .008) and 7% (P = .014) in the nonprogressive and progressive groups, respectively. The changes in M(max) were small and not correlated with changes in MEP., Conclusions: The large increases in MVC and MEP suggest that regular use of a foot-drop stimulator strengthens activation of motor cortical areas and their residual descending connections, which may explain the therapeutic effect on walking speed.

Background: Stimulators applying functional electrical stimulation (FES) to the common peroneal nerve improve walking with a foot drop, which occurs in several disorders., Objective: To compare the orthotic and therapeutic effects of a foot drop stimulator on walking performance of subjects with chronic nonprogressive (eg, stroke) and progressive (eg, multiple sclerosis) disorders., Methods: Subjects with nonprogressive (41) and progressive (32) conditions used a foot drop stimulator for 3 to 12 months while walking in the community. Walking speed was measured with a 10-m test and a 4-minute figure-8 test; physiological cost index (PCI) and device usage were also measured. The subjects were tested with FES on and off (orthotic effect) before and after (therapeutic effect) stimulator use., Results: After 3 months of FES use, the nonprogressive and progressive groups had a similar, significant orthotic effect (5.0% and 5.7%, respectively, P < .003; percentage change in mean values) and therapeutic effect with FES off (17.8% and 9.1%, respectively, P < .005) on figure-8 walking speed. Overall, PCI showed a decreasing trend (P = .031). The therapeutic effect on figure-8 speed diverged later between both groups to 28.0% (P < .001) and 7.9% at 11 months. The combined therapeutic plus orthotic effect on figure-8 speed at 11 months was, respectively, 37.8% (P < .001) and 13.1% (P = .012); PCI decreased 18.2% (P = .038) and 6.5%, respectively., Conclusions: Subjects with progressive and nonprogressive disorders had an orthotic benefit from FES up to 11 months. The therapeutic effect increased for 11 months in nonprogressive disorders but only for 3 months in progressive disorders. The combined effect remained significant and clinically relevant.

Objective: Spinal reciprocal inhibitory and excitatory reflexes of ankle extensor and flexor muscles were investigated in ambulatory participants with chronic central nervous system (CNS) lesions causing foot drop as a function of time after lesion and stimulator use., Methods: Thirty-nine participants with progressive (eg, secondary progressive MS) and 36 with generally nonprogressive (eg, stroke) conditions were studied. The tibialis anterior (TA) and soleus maximum H-reflex/M-wave (Hmax/Mmax) ratios and maximum voluntary contractions (MVC) were measured and compared with those in age-matched control participants. Reciprocal inhibition was measured as a depression of the ongoing electromyographic (EMG) activity produced by antagonist muscle-nerve stimulation., Results: Participants with CNS lesions had significantly higher soleus Hmax/Mmax ratios than control participants, and reduced voluntary modulation of the reflexes occurred in both muscles. Reciprocal inhibition of soleus from common peroneal (CP) nerve stimulation was not significantly different from controls in either group. Inhibition of the TA by tibial nerve stimulation decreased and was eventually replaced by excitation in participants with nonprogressive disorders. No significant change occurred in progressive disorders. Use of a foot drop stimulator increased the TA, but not the soleus MVC overall. H-reflexes only showed small changes. Reciprocal inhibition of the TA increased considerably, while that of the soleus muscle decreased toward control values., Conclusions: Disorders that produce foot drop also produce reflex changes, some of which only develop over a period of years or even decades. Regular use of a foot drop stimulator strengthens voluntary pathways and changes some reflexes toward control values. Thus, stimulators may provide multiple benefits to people with foot drop.

This paper contrasts responses in the soleus muscle of normal human subjects to two major inputs: the tibial nerve (TN) and the corticospinal tract. Paired transcranial magnetic stimulation (TMS) of the motor cortex at intervals of 10-25 ms strongly facilitated the motor evoked potential (MEP) produced by the second stimulus. In contrast, paired TN stimulation produced a depression of the reflex response to the second stimulus. Direct activation of the pyramidal tract did not facilitate a second response, suggesting that the MEP facilitation observed using paired TMS occurred in the cortex. A TN stimulus also depressed a subsequent MEP. Since the TN stimulus depressed both inputs, the mechanism is probably post-synaptic, such as afterhyperpolarization of motor neurons. Presynaptic mechanisms, such as homosynaptic depression, would only affect the pathway used as a conditioning stimulus. When TN and TMS pulses were paired, the largest facilitation occurred when TMS preceded TN by about 5 ms, which is optimal for summation of the two pathways at the level of the spinal motor neurons. A later, smaller facilitation occurred when a single TN stimulus preceded TMS by 50-60 ms, an interval that allows enough time for the sensory afferent input to reach the sensory cortex and be relayed to the motor cortex. Other work indicates that repetitively pairing nerve stimuli and TMS at these intervals, known as paired associative stimulation, produces long-term increases in the MEP and may be useful in strengthening residual pathways after damage to the central nervous system.

Objective: To determine the mechanisms underlying the mirroring of distal movements in both upper and lower limbs present in one individual from birth., Methods: Transcranial magnetic stimulation (TMS), magnetic resonance imaging (MRI), functional magnetic resonance imaging (fMRI), voluntary and reflexly evoked electromyograms (EMG) and force measurements were used to obtain information about the motor pathways responsible for the mirror movements., Results: MRI showed a significant loss of brain tissue from one hemisphere and fMRI indicated a significant functional reorganization had taken place. An obligatory mirroring of voluntary movement on the sound side occurs on the affected side, but some independent movement can be produced on the affected side, if enabled by weak contractions on the sound side. TMS mapping revealed bilateral projections from one hemisphere and virtually absent projections from the primary motor cortex of the other hemisphere. Spinal reflexes were restricted to the stimulated side. Transcortical reflexes were evoked bilaterally from the sound side, but not from the affected side., Conclusions: The physiological and imaging data are consistent with a mirroring from the intact motor cortex via the supplementary motor area., Significance: Mirror movements in this individual represent a major cortical reorganization and a partial solution to the neonatal loss of substantial amounts of brain tissue.

The human soleus H-reflex is commonly tested as an indicator of the reflex excitability of the calf muscles with infrequent stimuli to a subject seated and at rest. However, the reflex varies widely with the level of voluntary contraction and with the time history of stimulation. We studied two aspects of this variation. Antagonist (tibialis anterior) activation decreases the response, while increasing agonist (soleus) activation increases the H-reflex to a peak after which it declines. In subjects with large H-reflexes at rest, the reflex peaked at low levels of contraction. In contrast, in subjects with small H-reflexes at rest, the reflex peaked at higher levels of contraction for reasons that were elucidated using a realistic computer model. A parabolic curve fitted the maximum amplitude of the H-reflex in the model and over the entire range of contractile levels studied. The second aspect studied was post-activation depression or homosynaptic depression (HD), which has been described previously as a reduction of a second H-reflex elicited shortly after an initial reflex. We confirmed the presence of HD in resting, seated subjects for intervals up to 4 s. However, by voluntarily activating the soleus muscle, HD was drastically reduced when seated and abolished when standing. This suggests that HD may be absent in normal, functional movements and perhaps in clinical conditions that alter H-reflexes. Meaningful, quantitative measurements of reflex excitability can only be made under voluntary activity that mimics the condition of interest.

Functional electrical stimulation (FES) holds great potential for restoring motor functions after brain and spinal cord injury. Currently, most FES systems are under simple finite state control, using external sensors which tend to be bulky, uncomfortable and prone to failure. Sensory nerve signals offer an interesting alternative, with the possibility of continuous feedback control. To test feasibility, we recorded from ensembles of sensory neurons with microelectrode arrays implanted in the dorsal root ganglion (DRG) of walking cats. Limb position and velocity variables were estimated accurately (average R2 values >0.5) over a range of walking speeds (0.1-0.5 m s(-1)) using a linear combination of firing rates from 10 or more neurons. We tested the feasibility of sensory control of intraspinal FES by recording from DRG neurons during hindlimb movements evoked by intraspinal microstimulation of the lumbar spinal cord in an anesthetized cat. Although electrical stimulation generated artifacts, this problem was overcome by detecting and eliminating events that occurred synchronously across the array of microelectrodes. The sensory responses to limb movement could then be measured and decoded to generate an accurate estimate of the limb state. Multichannel afferent recordings may thus provide FES systems with the feedback needed for adaptive control and perturbation compensation, though long-term stability remains a challenge.

Methods have been developed to study excitatory and inhibitory reflexes during human movements because dramatic task-dependent changes occur between different voluntary activities, and phase-dependent changes occur within cyclic movements. Interestingly, segmental reflexes are relatively unimportant for standing balance, although reflex responses are strong, yet they contribute substantially to force in several muscles during walking, when some reflex responses are weaker.

Objectives: To test the efficacy and acceptance of a footdrop stimulator controlled by a tilt sensor., Methods: A nonrandomized, test-retest study of 26 subjects with footdrop of more than 1 year's duration, resulting from various central nervous system disorders, was performed in 4 centers for at least 3 months. Speed of walking in a straight line, speed around a figure of 8, and physiological cost index (PCI) were measured with and without the device. Hours/day and steps/day using the device were recorded., Results: All but 2 subjects used the tilt sensor at home, rather than a foot switch. Walking speed increased by 15% after 3 months (n = 26; P < 0.01), 32% after 6 months (n = 16; P < 0.01), and 47% after 12 months (n = 8; P < 0.05), while PCI decreased. The number of steps taken per day of use increased significantly over time, and increased speed was directly correlated with usage. Walking speed also increased with the stimulator off, but to a lesser extent, indicating a training effect. Subject feedback from a questionnaire indicated satisfaction with the stimulator., Conclusions: Both efficacy and acceptance of the stimulator were good in a population of subjects with chronic footdrop.

Sensory feedback is required by biological motor control systems to maintain stability, respond to perturbations, and adapt. Similarly, motor neuroprostheses require feedback to provide natural and complete restoration of motor functions. In this paper, we show that ensemble firing rates from the body's mechanoreceptors can provide a natural source of kinematic state feedback and could be useful for prosthetic control. Single unit recordings from multiple primary afferent neurons were obtained during walking using multichannel electrode arrays implanted chronically in the L7 dorsal root ganglia of three cats. We typically recorded simultaneously from over 20-30 neurons during the first 7-14 days after surgery, but recordings gradually worsened thereafter. Histology indicates that a ring of inflammatory and connective tissues (100 microm thick) develops around each microelectrode and likely contributes to the degradation in recording quality. Accurate estimates of the hindlimb trajectory were made using a linear filter with inputs from only a few neurons highly correlated with limb kinematics. The coefficients for the linear filter were identified in a least-squares fit with 5-10 s of walking data (model training stage). The estimated and actual trajectories of separate walking data generally match well for walking at a range of speeds accounting for 63 +/- 22% (mean +/- S.D. for hip, knee, and ankle) of the variance in joint angle and 72 +/- 4% of the variance in joint angular velocities. These results indicate that a neural interface with primary sensory neurons in the dorsal root ganglion can provide accurate kinematic state information that may be useful for closed loop control of a neuroprosthesis.

The purpose of this study was to investigate short-term effects of walking with functional electrical stimulation (FES) on inhibitory and excitatory spinal reflexes in healthy subjects. The FES was applied to the common peroneal (CP) nerve during the swing phase of the step cycle when the ankle flexors are active. We have previously shown that corticospinal excitability for the tibialis anterior (TA) muscle increased after 30 min of FES-assisted walking. An increase of corticospinal excitability could be due to the changes in spinal and/or cortical excitability. Thus, we wished to examine whether a short-term application of FES would increase spinal motoneuronal excitability. Changes could also result from effects on inhibitory as well as excitatory pathways, but to our knowledge no studies have investigated short-term effects of FES on spinal inhibitory pathways. Therefore, we measured reciprocal and presynaptic inhibition, as well as reflex excitability, before and after FES-assisted walking. As controls, effects of FES-like stimulation at rest and walking without stimulation were tested in separate sessions. The TA H-reflex amplitude did not increase after FES in any of the conditions tested, so we have no evidence that FES increases spinal excitability for the TA. The soleus H-reflex decreased slightly (10%) after FES-assisted walking, and remained decreased for at least 30 min. However, the control experiment indicated that this decrease was associated with walking and not with stimulation. Thirty minutes of FES did not produce any significant effects on spinal inhibitory pathways examined in the present study. In conclusion, the soleus H-reflex showed a small but consistent decrease and no spinal circuits examined showed an increase, as was observed in the corticospinal excitability. Thus, we suggest that a short-term application of FES increases the excitability of the cortex or its connections to the spinal cord more effectively than that of spinal pathways.

Neural plasticity occurs throughout adult life. In healthy individuals, different spinal pathways are differently modulated during different daily activities. Drastic changes to nervous system activity and connections caused by injuries or diseases alter spinal reflexes, and this is often related to disturbed motor functions. In both health and disease, spinal reflexes are subject to substantial modifications. Plasticity in supraspinal descending connections is even more remarkable; corticospinal connectivity has been shown to be extremely plastic. In this session, we describe two approaches for possibly improving recovery after central nervous system (CNS) lesions. They are very different, but both involve repetitive nerve stimulation and CNS plasticity. The first approach is functional electrical stimulation (FES) of the common peroneal nerve, which has been used to treat foot drop in patients with CNS lesions. The second approach is operant conditioning of a spinal reflex. Spinal reflex operant conditioning studies in animal models have shown plastic changes in spinal cord neurons associated with this form of learning and improved locomotor function in incomplete spinal cord injured rats. Thus, reflex conditioning might be a robust approach to inducing plasticity at spinal and supraspinal levels. As a first step in establishing this approach and characterizing its effects in the human adult CNS, we are currently investigating the extent and time course of operant conditioning of the soleus H-reflex in healthy subjects. In results to date, all subjects (n=5) have changed reflex size in the correct direction to various degree (16-36%) over 2-3 months of conditioning, indicating possibility that H-reflex conditioning can occur in humans. At the same time, the substantial inter-subject variation in the time course and extent of conditioning suggest that additional data are needed to establish its principal features. We hope that studying modulation and modification o- f the CNS by different approaches will help us further understand the plasticity of the human adult nervous system.

In this paper, we compare seven models on their ability to fit isometric muscle force. We stimulated the ankle dorsiflexors of eight subjects at seven ankle angles (85 degrees-120 degrees). Three different stimulation patterns (twitch, triangular, and random) were applied at all ankle angles. Four additional patterns (doublets, steady rates, "catch property," and walking-like) were applied at 95 degrees. Parameter values were optimized for each model at each angle. Parameters for the general linear model were calculated using a novel least-squares algorithm. A linear, second-order critically damped model gave the poorest fits (average root mean square (rms) error: 15 N). The models of Ding et al. (2002) and Bobet and Stein (1998) gave the best fits (average rms errors: 9.2 and 9.4 N). The other models (general linear second-order model, Wiener model, Zhou et al. (1995) model, general linear model) gave intermediate results. Results were similar at all ankle angles. We conclude that the Ding and Bobet-Stein models are the best overall for isometric contractions, that no linear model of any kind will give an error less than 9% of maximum force, and that the models tested are consistent across lengths.

Many diseases and injuries lead to loss of motor function. Can we reanimate paralyzed limbs to produce effective, graceful movements? Recent insights into the function of the motor system and greatly improved computing capabilities have made this a realistic goal, even in the absence of regeneration of motor pathways. Some approaches involve stimulating muscles, nerves or the spinal cord below the level of a lesion. Others involve recording a subject's intention from the cortex, and using this intention to control computers, robots or systems for stimulating the limbs. Here, we critically analyze the possibilities and limitations of various approaches for restoring motor function based on recent human trials and underlying neuroscience research.