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Electromagnetic stimulation probes and modulates the neural systems that control movement. Key to understanding their effects is the muscle recruitment curve, which maps evoked potential size against stimulation intensity. Current methods to estimate curve parameters require large samples; however, obtaining these is often impractical due to experimental constraints. Here, we present a hierarchical Bayesian framework that accounts for small samples, handles outliers, simulates high-fidelity data, and returns a posterior distribution over curve parameters that quantify estimation uncertainty. It uses a rectified-logistic function that estimates motor threshold and outperforms conventionally used sigmoidal alternatives in predictive performance, as demonstrated through cross-validation. In simulations, our method outperforms non-hierarchical models by reducing threshold estimation error on sparse data and requires fewer participants to detect shifts in threshold compared to frequentist testing. We present two common use cases involving electrical and electromagnetic stimulation data and provide an open-source library for Python, called hbMEP, for diverse applications.

Volitional movement requires descending input from the motor cortex and sensory feedback through the spinal cord. We previously developed a paired brain and spinal electrical stimulation approach in rats that relies on convergence of the descending motor and spinal sensory stimuli in the cervical cord. This approach strengthened sensorimotor circuits and improved volitional movement through associative plasticity. In humans, it is not known whether posterior epidural spinal cord stimulation targeted at the sensorimotor interface or anterior epidural spinal cord stimulation targeted within the motor system is effective at facilitating brain evoked responses. In 59 individuals undergoing elective cervical spine decompression surgery, the motor cortex was stimulated with scalp electrodes and the spinal cord was stimulated with epidural electrodes, with muscle responses being recorded in arm and leg muscles. Spinal electrodes were placed either posteriorly or anteriorly, and the interval between cortex and spinal cord stimulation was varied. Pairing stimulation between the motor cortex and spinal sensory (posterior) but not spinal motor (anterior) stimulation produced motor evoked potentials that were over five times larger than brain stimulation alone. This strong augmentation occurred only when descending motor and spinal afferent stimuli were timed to converge in the spinal cord. Paired stimulation also increased the selectivity of muscle responses relative to unpaired brain or spinal cord stimulation. Finally, clinical signs suggest that facilitation was observed in both injured and uninjured segments of the spinal cord. The large effect size of this paired stimulation makes it a promising candidate for therapeutic neuromodulation. KEY POINTS: Pairs of stimuli designed to alter nervous system function typically target the motor system, or one targets the sensory system and the other targets the motor system for convergence in cortex. In humans undergoing clinically indicated surgery, we tested paired brain and spinal cord stimulation that we developed in rats aiming to target sensorimotor convergence in the cervical cord. Arm and hand muscle responses to paired sensorimotor stimulation were more than five times larger than brain or spinal cord stimulation alone when applied to the posterior but not anterior spinal cord. Arm and hand muscle responses to paired stimulation were more selective for targeted muscles than the brain- or spinal-only conditions, especially at latencies that produced the strongest effects of paired stimulation. Measures of clinical evidence of compression were only weakly related to the paired stimulation effect, suggesting that it could be applied as therapy in people affected by disorders of the central nervous system., (© 2024 The Authors. The Journal of Physiology © 2024 The Physiological Society.)

Transcutaneous spinal cord stimulation (tSCS) is an emerging therapeutic strategy to target spinal autonomic circuitry to normalize and stabilize blood pressure (BP) in hypotensive persons living with chronic spinal cord injury (SCI). Our aim is to describe our current methodological approach to identify individual tSCS parameters that result in the maintenance of seated systolic blood pressure (SBP) within a pre-defined target range. The parent study is a prospective, randomized clinical trial in which eligible participants will undergo multiple mapping sessions to optimize tSCS parameter settings to promote stable SBP within a target range of 110-120 mm Hg for males and 100-120 mm Hg for females. Parameter mapping includes cathode electrode placement site (T7/8, T9/10, T11/12, and L1/2), stimulation frequency (30, 60 Hz), current amplitudes (0-120 mA), waveform (mono- and biphasic), pulse width (1000 μs), and use of carrier frequency (0, 10 kHz). Each participant will undergo up to 10 mapping sessions involving different electrode placement sites and parameter settings. BP will be continuously monitored throughout each mapping session. Stimulation amplitude (mA) will be increased at intervals of between 2 and 10 mA until one of the following occurs: 1) seated SBP reaches the target range; 2) tSCS intensity reaches 120 mA; or 3) the participant requests to stop. Secondary outcomes recorded include 1) symptoms related to autonomic dysreflexia and orthostatic hypotension, 2) Likert pain scale, and 3) skin appearance after removal of the tSCS electrode. Clinical Trials Registration: NCT05180227., Competing Interests: No competing financial interests exist., (© Caitlyn G. Peters et al., 2023; Published by Mary Ann Liebert, Inc.)

Purpose of Review: Remote ischemic conditioning (RIC) involves transient blood flow restriction to one limb leading to systemic tissue-protective effects. RIC shares some potential underlying mechanisms with intermittent hypoxia (IH), in which brief bouts of systemic hypoxia trigger increases in growth factor expression and neural plasticity. RIC has shown promise in acute myocardial infarction and stroke but may be applicable toward chronic neuropathology as well. Consequently, this review discusses similarities and differences between RIC and IH and presents preliminary and ongoing research findings regarding RIC., Recent Findings: Several publications demonstrated that combining RIC with motor training may enhance motor learning in adults with intact nervous systems, though the precise mechanisms were unclear. Our own preliminary data has found that RIC, in conjunction with task specific exercise, can increase corticospinal excitability in a subset of people without neurological injury and in those with chronic cervical spinal cord injury or amyotrophic lateral sclerosis., Summary: RIC is a low-cost intervention easy to deliver in a clinical or home setting. Its potential application to facilitate neural plasticity and motor learning during rehabilitation training for individuals with chronic neurological disorders is a novel concept requiring further investigation to characterize mechanisms, safety, and efficacy., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Multiple types and classes of medications are administered in the acute management of traumatic spinal cord injury. Prior clinical studies and evidence from animal models suggest that several of these medications could modify (i.e., enhance or impede) neurological recovery. We aimed to systematically determine the types of medications commonly administered, alone or in combination, in the transition from acute to subacute spinal cord injury. For that purpose, type, class, dosage, timing, and reason for administration were extracted from two large spinal cord injury datasets. Descriptive statistics were used to describe the medications administered within the first 60 days after spinal cord injury. Across 2040 individuals with spinal cord injury, 775 unique medications were administered within the two months after injury. On average, patients enrolled in a clinical trial were administered 9.9 ± 4.9 (range 0-34), 14.3 ± 6.3 (range 1-40), 18.6 ± 8.2 (range 0-58), and 21.5 ± 9.7 (range 0-59) medications within the first 7, 14, 30, and 60 days post-injury, respectively. Those enrolled in an observational study were administered on average 1.7 ± 1.7 (range 0-11), 3.7 ± 3.7 (range 0-24), 8.5 ± 6.3 (range 0-42), and 13.5 ± 8.3 (range 0-52) medications within the first 7, 14, 30, and 60 days post-injury, respectively. Polypharmacy was commonplace (up to 43 medications per day per patient). Approximately 10% of medications were administered acutely as prophylaxis (e.g., against the development of pain or infections). To our knowledge, this was the first time acute pharmacological practices have been comprehensively examined after spinal cord injury. Our study revealed a high degree of polypharmacy in the acute stages of spinal cord injury, raising the potential to impact neurological recovery. All results can be interactively explored on the R X SCI web site ( https://jutzelec.shinyapps.io/RxSCI/ ) and GitHub repository ( https://github.com/jutzca/Acute-Pharmacological-Treatment-in-SCI/ )., (© 2023. The Author(s).)

Background: The seemingly simple tasks of standing and walking require continuous integration of complex spinal reflex circuits between descending motor commands and ascending sensory inputs. Spinal cord injury greatly impairs standing and walking ability, but both improve with locomotor training. However, even after multiple locomotor training sessions, abnormal muscle activity and coordination persist. Thus, locomotor training alone cannot fully optimize the neuronal plasticity required to strengthen the synapses connecting the brain, spinal cord, and local circuits and potentiate neuronal activity based on need. Transcutaneous spinal cord (transspinal) stimulation alters motoneuron excitability over multiple segments by bringing motoneurons closer to threshold, a prerequisite for effectively promoting spinal locomotor network neuromodulation and strengthening neural connectivity of the injured human spinal cord. Importantly, whether concurrent treatment with transspinal stimulation and locomotor training maximizes motor recovery after spinal cord injury is unknown., Methods: Forty-five individuals with chronic spinal cord injury are receiving 40 sessions of robotic gait training primed with 30 Hz transspinal stimulation at the Thoracic 10 vertebral level. Participants are randomized to receive 30 min of active or sham transspinal stimulation during standing or active transspinal stimulation while supine followed by 30 min of robotic gait training. Over the course of locomotor training, the body weight support, treadmill speed, and leg guidance force are adjusted as needed for each participant based on absence of knee buckling during the stance phase and toe dragging during the swing phase. At baseline and after completion of all therapeutic sessions, neurophysiological recordings registering corticospinal and spinal neural excitability changes along with clinical assessment measures of standing and walking, and autonomic function via questionnaires regarding bowel, bladder, and sexual function are taken., Discussion: The results of this mechanistic randomized clinical trial will demonstrate that tonic transspinal stimulation strengthens corticomotoneuronal connectivity and dynamic neuromodulation through posture-dependent corticospinal and spinal neuroplasticity. We anticipate that this mechanistic clinical trial will greatly impact clinical practice because, in real-world clinical settings, noninvasive transspinal stimulation can be more easily and widely implemented than invasive epidural stimulation. Additionally, by applying multiple interventions to accelerate motor recovery, we are employing a treatment regimen that reflects a true clinical approach., Trial Registration: ClinicalTrials.gov NCT04807764 . Registered on March 19, 2021., (© 2023. The Author(s).)

Although epidural stimulation of the lumbar spinal cord has emerged as a powerful modality for recovery of movement, how it should be targeted to the cervical spinal cord to activate arm and hand muscles is not well understood, particularly in humans. We sought to map muscle responses to posterior epidural cervical spinal cord stimulation in humans. We hypothesized that lateral stimulation over the dorsal root entry zone would be most effective and responses would be strongest in the muscles innervated by the stimulated segment. Twenty-six people undergoing clinically indicated cervical spine surgery consented to mapping of motor responses. During surgery, stimulation was performed in midline and lateral positions at multiple exposed segments; six arm and three leg muscles were recorded on each side of the body. Across all segments and muscles tested, lateral stimulation produced stronger muscle responses than midline despite similar latency and shape of responses. Muscles innervated at a cervical segment had the largest responses from stimulation at that segment, but responses were also observed in muscles innervated at other cervical segments and in leg muscles. The cervical responses were clustered in rostral (C4-C6) and caudal (C7-T1) cervical segments. Strong responses to lateral stimulation are likely due to the proximity of stimulation to afferent axons. Small changes in response sizes to stimulation of adjacent cervical segments argue for local circuit integration, and distant muscle responses suggest activation of long propriospinal connections. This map can help guide cervical stimulation to improve arm and hand function. NEW & NOTEWORTHY A map of muscle responses to cervical epidural stimulation during clinically indicated surgery revealed strongest activation when stimulating laterally compared to midline and revealed differences to be weaker than expected across different segments. In contrast, waveform shapes and latencies were most similar when stimulating midline and laterally, indicating activation of overlapping circuitry. Thus, a map of the cervical spinal cord reveals organization and may help guide stimulation to activate arm and hand muscles strongly and selectively.

The record-breaking pace of COVID-19 vaccine development and implementation depended heavily on collaboration among academic, government, and commercial stakeholders, especially through data-sharing and robust multicenter trials. Collaborative efforts have not been as fruitful in fields such as neurorehabilitation, where non-pharmacological interventions play a much larger role. Barriers to translating scientific advancements into clinical practice in neurorehabilitation include pervasively small study sizes, exacerbated by limited funding for non-pharmacological multicenter clinical trials; difficulty standardizing-and adequately describing-non-pharmacological interventions; and a lack of incentives for individual patient-level data-sharing. These barriers prevent reliable meta-analysis of non-pharmacological clinical studies in neurorehabilitation. This point-of-view will highlight these challenges as well as suggest practical steps that may be taken to improve the neurorehabilitation pipeline between evidence and implementation.

Brain-computer interfaces (BCIs) enabling the control of a personal computer could provide myriad benefits to individuals with disabilities including paralysis. However, to realize this potential, these BCIs must gain regulatory approval and be made clinically available beyond research participation. Therefore, a transition from engineering-oriented to clinically oriented outcome measures will be required in the evaluation of BCIs. This review examined how to assess the clinical benefit of BCIs for the control of a personal computer. We report that: (a) a variety of different patient-reported outcome measures can be used to evaluate improvements in how a patient feels , and we offer some considerations that should guide instrument selection. (b) Activities of daily living can be assessed to demonstrate improvements in how a patient functions , however, new instruments that are sensitive to increases in functional independence via the ability to perform digital tasks may be needed. (c) Benefits to how a patient survives has not previously been evaluated but establishing patient-initiated communication channels using BCIs might facilitate quantifiable improvements in health outcomes., (Creative Commons Attribution license.)

Purpose: Efforts to optimize human-computer interactions are becoming increasingly prevalent, especially with virtual reality (VR) rehabilitation paradigms that utilize engaging interfaces. We hypothesized that motor and perceptional behaviors within a virtual environment are modulated uniquely through different modes of control of a hand avatar depending on limb dominance. This study investigated the effects of limb dominance on performance and concurrent changes in perceptions, such as time-based measures for intentional binding, during virtual reach-to-grasp., Methods: Participants (n = 16, healthy) controlled a virtual hand through their own hand motions with control adaptations in speed, noise, and automation., Results: A significant (p < 0.01) positive relationship between performance (reaching pathlength) and binding (time-interval estimation of beep-sound after grasp contact) was observed for the dominant hand. Unique changes in performance (p < 0.0001) and binding (p < 0.0001) were observed depending on handedness and which control mode was applied., Conclusions: Developers of VR paradigms should consider limb dominance to optimize settings that facilitate better performance and perceptional engagement. Adapting VR rehabilitation for handedness may particularly benefit unilateral impairments, like hemiparesis or single-limb amputation., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Transcutaneous spinal cord stimulation (TSCS) has demonstrated potential to beneficially modulate spinal cord motor and autonomic circuitry. We are interested in pairing cervical TSCS with other forms of nervous system stimulation to enhance synaptic plasticity in circuits serving hand function. We use a novel configuration for cervical TSCS in which the anode is placed anteriorly over ~C4-C5 and the cathode posteriorly over ~T2-T4. We measured the effects of single pulses of TSCS paired with single pulses of motor cortex or median nerve stimulation timed to arrive at the cervical spinal cord at varying intervals. In 13 participants with and 15 participants without chronic cervical spinal cord injury, we observed that subthreshold TSCS facilitates hand muscle responses to motor cortex stimulation, with a tendency toward greater facilitation when TSCS is timed to arrive at cervical synapses simultaneously or up to 10 milliseconds after cortical stimulus arrival. Single pulses of subthreshold TSCS had no effect on the amplitudes of median H-reflex responses or F-wave responses. These findings support a model in which TSCS paired with appropriately timed cortical stimulation has the potential to facilitate convergent transmission between descending motor circuits, segmental afferents, and spinal motor neurons serving the hand. Studies with larger numbers of participants and repetitively paired cortical and spinal stimulation are needed.

Design: Prospective cohort study., Objectives: We aim to better understand the silent period (SP), an inhibitory counterpart to the well-known motor evoked potential (MEP) elicited by transcranial magnetic stimulation (TMS), in individuals with spinal cord injury (SCI)., Setting: Veterans Affairs Hospital in New York., Methods: EMG responses were measured in the target abductor pollicis brevis at rest (TMS at 120% of resting motor threshold (RMT)) and during maximal effort (TMS at 110% of RMT). Participants with chronic cervical SCI (n = 9) and AB participants (n = 12) underwent between 3 and 7 sessions of testing on separate days. The primary outcomes were the magnitude and reliability of SP duration, resting and active MEP amplitudes, and RMT., Results: SCI participants showed significantly lower MEP amplitudes compared to AB participants. SCI SP duration was not significantly different from AB SP duration. SP duration demonstrated reduced intra-participant variability within and across sessions compared with MEP amplitudes. SCI participants also demonstrated a higher prevalence of SP 'interruptions' compared to AB participants., Conclusions: In a small group of individuals with chronic cervical SCI, we confirmed the well-known findings that SCI individuals have lower TMS evoked potential amplitudes and a tendency toward higher TMS motor thresholds relative to able-bodied controls. We did not observe a significant difference in SP duration between individuals with versus without SCI. However, SP duration is a more reliable outcome within and across multiple sessions than MEP amplitude., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

​​​​​​ Background : Most spinal cord injuries (SCI) are not full transections, indicating that residual nerve circuits are retained. Rehabilitation interventions have been shown to beneficially reorganize motor pathways in the brain, corticospinal tract, and at the spinal level. However, rehabilitation training require a large number of repetitions, and intervention effects may be absent or show transient retention. Therefore, the need remains for an effective approach to synergistically improve the amount and duration of neuroplasticity in combination with other interventions. Remote ischemic conditioning (RIC) demonstrates several potential advantages as a candidate for such an approach. Therefore, we propose a protocol to investigate RIC coupled with physical training to promote neuroplasticity in hand muscles. Methods : This will be a prospective randomized-order crossover trial to be performed in eight able-bodied participants and eight participants with chronic cervical SCI. Patients will participate in two experimental sessions consisting of either active or sham RIC preceding a bout of pinch movement exercise. Serial evaluations will be conducted at baseline, after RIC, immediately after pinch exercise, and follow up 15-minutes later. The primary outcome is the change in corticospinal excitability (primarily measured by the motor evoked potential of abductor pollicis brevis muscle). Secondary outcomes will include maximal volitional pinch force, and inflammatory biomarkers. To ensure safety, we will monitor tolerability and hemodynamic responses during RIC. Discussion : This protocol will be the first to test RIC in people with cervical SCI and to investigate whether RIC alters corticospinal excitability. By sharing the details of our protocol, we hope other interested researchers will seek to investigate similar approaches - depending on overlap with the current study and mutual sharing of participant-level data, this could increase the sample size, power, and generalizability of the analysis and results. Trial registration : ClinicalTrial.gov, ID: NCT03851302; Date of registration: February 22, 2019., Competing Interests: No competing interests were disclosed., (Copyright: © 2022 Wu YK et al.)

Study Design: This is a narrative review focused on specific challenges related to adequate controls that arise in neuromodulation clinical trials involving perceptible stimulation and physiological effects of stimulation activation., Objectives: 1) To present the strengths and limitations of available clinical trial research designs for the testing of epidural stimulation to improve recovery after spinal cord injury. 2) To describe how studies can control for the placebo effects that arise due to surgical implantation, the physical presence of the battery, generator, control interfaces, and rehabilitative activity aimed to promote use-dependent plasticity. 3) To mitigate Hawthorne effects that may occur in clinical trials with intensive supervised participation, including rehabilitation., Materials and Methods: Focused literature review of neuromodulation clinical trials with integration to the specific context of epidural stimulation for persons with chronic spinal cord injury., Conclusions: Standard of care control groups fail to control for the multiple effects of knowledge of having undergone surgical procedures, having implanted stimulation systems, and being observed in a clinical trial. The irreducible effects that have been identified as "placebo" require sham controls or comparison groups in which both are implanted with potentially active devices and undergo similar rehabilitative training., (© 2021 International Neuromodulation Society.)

Study Design: Pre-post intervention., Objective: To explore the potential effect of exoskeletal-assisted walking (EAW) on seated balance for persons with chronic motor complete spinal cord injury (SCI)., Setting: A SCI research center., Methods: Eight participants who were over 18 years of age with chronic SCI and used a wheelchair for mobility were enrolled. Seven able-bodied participants were used for normal seated balance comparative values. Participants with chronic SCI received supervised EAW training using a powered exoskeleton (ReWalk TM ) for a median 30 sessions (range from 7 to 90 sessions). Before and after EAW training, seated balance testing outcomes were collected using computerized dynamic posturography, providing measurements of endpoint excursion (EPE), maximal excursion (MXE), and directional control (DCL). Modified functional reach test (MFRT) and the sub-scales of physical functioning and role limitations due to physical health from the Short Form (36) Health Survey (SF-36) were used to identify changes in functional activities., Results: After EAW training, seated balance significantly improved in total-direction EPE and MXE (P < 0.01 and P < 0.017 respectively). The results of MFRT and sub-scales of physical functioning and role limitations due to physical health improved after EAW training but were not statistically significant., Conclusions: EAW training may have the potential to improve seated balance for persons with chronic motor complete SCI. Due to the limitations of the study, such as small sample size and lack of a control group, further studies are needed to clarify the effect of improving seated balance through EAW training.

Background: Stroke is the leading cause of serious long-term disability in the United States. Barriers to rehabilitation include cost, transportation, lack of trained personnel, and equipment. Telerehabilitation (TR) has emerged as a promising modality to reduce costs, improve accessibility, and retain patient independence. TR allows providers to remotely administer therapy, potentially increasing access to underserved regions. Objectives: To describe types of stroke rehabilitation therapy delivered through TR and to evaluate whether TR is as effective as traditional in-person outpatient therapy in improving satisfaction and poststroke residual deficits such as motor function, speech, and disability. Methods: A literature search of the term "telerehabilitation and stroke" was conducted across three databases. Full-text articles with results pertaining to TR interventions were reviewed. Articles were scored for methodological quality using the PEDro scale. Results: Thirty-four articles with 1,025 patients were included. Types of TR included speech therapy, virtual reality (VR), robotic, community-based, goal setting, and motor training exercises. Frequently measured outcomes included motor function, speech, disability, and satisfaction. All 34 studies reported improvement from baseline after TR therapy. PEDro scores ranged from 2 to 8 with a mean of 4.59 ± 1.94 (on a scale of 0-10). Studies with control interventions, randomized allocation, and blinded assessment had significantly higher PEDro scores. All 15 studies that compared TR with traditional therapy showed equivalent or better functional outcomes. Home-based robotic therapy and VR were less costly than in-person therapy. Patient satisfaction with TR and in-person clinical therapy was similar. Conclusions: TR is less costly and equally as effective as clinic-based rehabilitation at improving functional outcomes in stroke patients. TR produces similar patient satisfaction. TR can be combined with other therapies, including VR, speech, and robotic assistance, or used as an adjuvant to direct in-person care.

Sensory feedback from wearables can be effective to learn better movement through enhanced information and engagement. Facilitating greater user cognition during movement practice is critical to accelerate gains in motor function during rehabilitation following brain or spinal cord trauma. This preliminary study presents an approach using an instrumented glove to leverage sense of agency, or perception of control, to provide training feedback for functional grasp. Seventeen able-bodied subjects underwent training and testing with a custom-built sensor glove prototype from our laboratory. The glove utilizes onboard force and flex sensors to provide inputs to an artificial neural network that predicts achievement of "secure" grasp. Onboard visual and audio feedback was provided during training with progressively shorter time delay to induce greater agency by intentional binding, or perceived compression in time between an action (grasp) and sensory consequence (feedback). After training, subjects demonstrated a significant reduction ( p < 0.05) in movement pathlength and completion time for a functional task involving grasp-move-place of a small object. Future work will include a model-based algorithm to compute secure grasp, virtual reality immersion, and testing with clinical populations.

Spinal cord injury (SCI) disrupts autonomic circuits and impairs synchronistic functioning of the autonomic nervous system, leading to inadequate cardiovascular regulation. Individuals with SCI, particularly at or above the sixth thoracic vertebral level (T6), often have impaired regulation of sympathetic vasoconstriction of the peripheral vasculature and the splanchnic circulation, and diminished control of heart rate and cardiac output. In addition, impaired descending sympathetic control results in changes in circulating levels of plasma catecholamines, which can have a profound effect on cardiovascular function. Although individuals with lesions below T6 often have normal resting blood pressures, there is evidence of increases in resting heart rate and inadequate cardiovascular response to autonomic provocations such as the head-up tilt and cold face tests. This manuscript reviews the prevalence of cardiovascular disorders given the level, duration and severity of SCI, the clinical presentation, diagnostic workup, short- and long-term consequences, and empirical evidence supporting management strategies to treat cardiovascular dysfunction following a SCI., Competing Interests: None., (Thieme. All rights reserved.)

Study Design: Prospective, observational study., Objective: To explore the effects of exoskeletal-assisted walking (EAW) on bowel function in persons with spinal cord injury (SCI)., Setting: Ambulatory research facility located in a tertiary care hospital., Methods: Individuals 18-65 years of age, with thoracic vertebrae one (T1) to T11 motor-complete paraplegia of at least 12 months duration were enrolled. Pre- and post-EAW training, participants were asked to report on various aspects of their bowel function as well as on their overall quality of life (QOL) as related to their bowel function., Results: Ten participants completed 25-63 sessions of EAW over a period of 12-14 weeks, one participant was lost to follow up due to early withdrawal after ten sessions. Due to the small sample size, each participant's results were presented descriptively in a case series format. At least 5/10 participants reported improvements with frequency of bowel evacuations, less time spent on bowel management per bowel day, fewer bowel accidents per month, reduced laxative and/or stool softener use, and improved overall satisfaction with their bowel program post-EAW training. Furthermore, 8/10 reported improved stool consistency and 7/10 reported improved bowel function related QOL. One participant reported worsening of bowel function post-EAW., Conclusion: Between 50 and 80% of the participants studied reported improvements in bowel function and/or management post-EAW training. EAW training appeared to mitigate SCI-related bowel dysfunction and the potential benefits of EAW on bowel function after SCI is worthy or further study.

Objective: To test the hypothesis that higher-challenge gait and balance tasks are more sensitive than traditional metrics to subtle patient-reported gait dysfunction and future fall risk in early multiple sclerosis (MS)., Methods: Persons with early MS (n = 185; ≤5 years diagnosed) reported gait function (MS Walking Scale) and underwent traditional disability metrics (Expanded Disability Status Scale [EDSS], Timed 25 Foot Walk). Patients and healthy controls (n = 50) completed clinically feasible challenge tasks of gait endurance (2-Minute Walk Test), standing balance (NIH Toolbox), and dynamic balance (balance boards; tandem walk on 2 ten-foot boards of different widths, 4.5 and 1.5 in). MRI assessed global and regional brain volumes, total T2 lesion volume (T2LV), infratentorial T2LVs and counts, and cervical cord lesion counts. Falls, near falls, and fall-related injuries were assessed after 1 year. We examined links between all tasks and patient-reported gait, MRI markers, and fall data., Results: Patients performed worse on higher challenge balance, but not gait, tasks compared with healthy controls. Worse patient-reported gait disturbance was associated with worse performance on all tasks, but only dynamic balance was sensitive to mild patient-reported gait difficulty. Balance tasks were more correlated with MRI metrics than were walking tasks or EDSS score. Thirty percent of patients reported either a fall or near fall after 1 year, with poor dynamic balance as the only task independently predicting falls., Conclusions: Balance plays a leading role in gait dysfunction early in MS. Clinically feasible higher-challenge balance tasks were most sensitive to patient-reported gait, MRI disease markers, and risk of future falls, highlighting potential to advance functional outcomes in clinical practice and trials., (© 2020 American Academy of Neurology.)

Objective: We aim to non-invasively facilitate activation of spared neural circuits after cervical spinal cord injury (SCI) and amyotrophic lateral sclerosis (ALS). We developed and tested a novel configuration for cervical transcutaneous spinal stimulation (cTSS)., Methods: cTSS was delivered via electrodes placed over the midline at ~T2-T4 levels posteriorly and ~C4-C5 levels anteriorly. Electromyographic responses were measured in arm and hand muscles across a range of stimulus intensities. Double-pulse experiments were performed to assess homosynaptic post-activation depression (PAD). Safety was closely monitored., Results: More than 170 cTSS sessions were conducted without major safety or tolerability issues. A cathode-posterior, 2 ms biphasic waveform provided optimal stimulation characteristics. Bilateral upper extremity muscle responses were easily obtained in subjects with SCI and ALS. Resting motor threshold at the abductor pollicis brevis muscle ranged from 5.5 to 51.0 mA. As stimulus intensity increased, response latencies to all muscles decreased. PAD was incomplete at lower stimulus intensities, and decreased at higher stimulus intensities., Conclusions: Posteroanterior cTSS has the capability to target motor neurons both trans-synaptically via large-diameter afferents and non-synaptically via efferent motor axons., Significance: Posteroanterior cTSS is well tolerated and easily activates upper extremity muscles in individuals with SCI and ALS., (Published by Elsevier B.V.)

Locomotion requires the continuous integration of descending motor commands and sensory inputs from the legs by spinal central pattern generator circuits. Modulation of spinal neural circuits by transspinal stimulation is well documented, but how transspinal stimulation affects corticospinal excitability during walking in humans remains elusive. We measured the motor evoked potentials (MEPs) at multiple phases of the step cycle conditioned with transspinal stimulation delivered at sub- and suprathreshold intensities of the spinally mediated transspinal evoked potential (TEP). Transspinal stimulation was delivered before or after transcranial magnetic stimulation during which summation between MEP and TEP responses in the surface EMG was absent or present. Relationships between MEP amplitude and background EMG activity, silent period duration, and phase-dependent EMG amplitude modulation during and after stimulation were also determined. Ankle flexor and extensor MEPs were depressed by suprathreshold transspinal stimulation when descending volleys were timed to interact with transspinal stimulation-induced motoneuron depolarization at the spinal cord. MEP depression coincided with decreased MEP gain, unaltered MEP threshold, and unaltered silent period duration. Locomotor EMG activity of bilateral knee and ankle muscles was significantly depressed during the step at which transspinal stimulation was delivered but fully recovered at the subsequent step. The results support a model in which MEP depression by transspinal stimulation occurs via subcortical or spinal mechanisms. Transspinal stimulation disrupts the locomotor output of flexor and extensor motoneurons initially, but the intact nervous system has the ability to rapidly overcome this pronounced locomotor adaptation. In conclusion, transspinal stimulation directly affects spinal locomotor centers in healthy humans. NEW & NOTEWORTHY Lumbar transspinal stimulation decreases ankle flexor and extensor motor evoked potentials (MEPs) during walking. The MEP depression coincides with decreased MEP gain, unaltered MEP threshold changes, and unaltered silent period duration. These findings indicate that MEP depression is subcortical or spinal in origin. Healthy subjects could rapidly overcome the pronounced depression of muscle activity during the step at which transspinal stimulation was delivered. Thus, transspinal stimulation directly affects the function of spinal locomotor networks in healthy humans.

Background and Purpose: Spared fibers after spinal cord injury (SCI) tend to consist predominantly of subcortical circuits that are not under volitional (cortical) control. We aim to improve function after SCI by using targeted physical exercises designed to simultaneously stimulate cortical and spared subcortical neural circuits., Methods: Participants with chronic motor-incomplete SCI enrolled in a single-center, prospective interventional crossover study. Participants underwent 48 sessions each of weight-supported robotic-assisted treadmill training and a novel combination of balance and fine hand exercises, in randomized order, with a 6-week washout period. Change post-intervention was measured for lower extremity motor score, soleus H-reflex facilitation; seated balance function; ambulation; spasticity; and pain., Results: Only 9 of 21 enrolled participants completed both interventions. Thirteen participants completed at least one intervention. Although there were no statistically significant differences, multimodal training tended to increase short-interval H-reflex facilitation, whereas treadmill training tended to improve dynamic seated balance., Discussion: The low number of participants who completed both phases of the crossover intervention limited the power of this study to detect significant effects. Other potential explanations for the lack of significant differences with multimodal training could include insufficient engagement of lower extremity motor cortex using skilled upper extremity exercises; and lack of skill transfer from upright postural stability during multimodal training to seated dynamic balance during testing. To our knowledge, this is the first published study to report seated posturography outcomes after rehabilitation interventions in individuals with SCI., Conclusion: In participants with chronic incomplete SCI, a novel mix of multimodal exercises incorporating balance exercises with skilled upper extremity exercises showed no benefit compared to an active control program of body weight-supported treadmill training. To improve participant retention in long-term rehabilitation studies, subsequent trials would benefit from a parallel group rather than crossover study design., Competing Interests: The authors have declared that no competing interests exist.

Objective: To determine whether antispasmodic medications are associated with neurological and functional outcomes during the first year after traumatic spinal cord injury (SCI)., Design/methods: Retrospective analysis of prospectively collected data from six inpatient SCI rehabilitation centers. Baseline-adjusted outcomes at discharge and one-year follow-up were compared using analysis of covariance between patients who received antispasmodic medication on at least 5 days during inpatient rehabilitation and patients who did not., Outcome Measures: Rasch-transformed motor subscore of the Functional Independence Measure (FIM); International Standards for Neurological Classification of Spinal Cord Injury motor scores, grade, and level., Results: Of 1,259 patients, 59.8%, 35.4%, and 4.8% were injured at the cervical, thoracic, and lumbosacral levels, respectively. 65.6% had motor complete injury. Rasch-transformed motor FIM score at admission averaged 23.3 (95% confidence interval (CI) 22.4-24.2). Total motor score averaged 39.2 (95% CI 37.8-40.6). 685 patients (54.4%) received one or more antispasmodic medications on at least 5 days. After controlling for demographic and injury variables at admission, Rasch-transformed motor FIM scores at discharge were significantly lower (P = 0.018) in patients receiving antispasmodic medications than in those who did not. This trend persisted in secondary analyses for cervical, thoracic, and lumbosacral subgroups. Multivariate regression showed that receiving antispasmodic medication significantly contributed to discharge motor FIM outcome. At one-year follow-up, no outcomes significantly differed between patients ON or OFF antispasmodics., Conclusions: Antispasmodic medications may be associated with decreased functional recovery at discharge from inpatient traumatic SCI rehabilitation. Randomized prospective studies are needed to directly evaluate the effects of antispasmodic medication on recovery.

After injury, electrical stimulation of the nervous system can augment plasticity of spared or latent circuits through focal modulation. Pairing stimulation of two parts of a spared circuit can target modulation more specifically to the intended circuit. We discuss 3 kinds of paired stimulation in the context of the corticospinal system, because of its importance in clinical neurorehabilitation. The first uses principles of Hebbian plasticity: by altering the stimulation timing of presynaptic neurons and their postsynaptic targets, synapse function can be modulated up or down. The second form uses synchronized presynaptic inputs onto a common synaptic target. We dub this a "convergent" mechanism, because stimuli have to converge on a common target with coordinated timing. The third form induces focal modulation by tonic excitation of one region (e.g., the spinal cord) during phasic stimulation of another (e.g., motor cortex). Additionally, endogenous neural activity may be paired with exogenous electrical stimulation. This review addresses what is known about paired stimulation of the corticospinal system of both humans and animal models, emphasizes how it qualitatively differs from single-site stimulation, and discusses the gaps in knowledge that must be addressed to maximize its use and efficacy in neurorehabilitation.

We tested the acute effect of exercises targeted simultaneously at cortical and brainstem circuits on neural transmission through corticobulbar connections. Corticobulbar pathways represent a potential target for rehabilitation after spinal cord injury (SCI), which tends to spare brainstem circuits to a greater degree than cortical circuits. To explore this concept, able-bodied volunteers (n=20) underwent one session each of three exercises targeted at different nervous system components: treadmill walking (spinal locomotor circuits), isolated balance exercise (brainstem and other pathways), and multimodal balance plus skilled hand exercise (hand motor cortex and corticospinal tract). We found that short-interval soleus H-reflex facilitation increased after one session of balance and multimodal exercise by 13.2±4.0% and 8.3±4.7%, and slightly decreased by 1.9±4.4% after treadmill exercise (p=0.042 on ANOVA across exercise type). Increases in long-interval H-reflex facilitation were not significantly different between exercises. Both balance and multimodal exercise increased central motor conduction velocity by 4.3±2.6% and 4.5±2.8%, whereas velocity decreased by 4.3±2.7% after treadmill exercise (p=0.045 on ANOVA across exercise type). In conclusion, electrophysiological transmission between the motor cortex and spinal motor neurons in able-bodied subjects increased more following one session of balance exercise than treadmill exercise., (Published by Elsevier Ltd.)

Traumatic spinal cord injury (SCI) causes long-term disability with limited functional recovery linked to the extent of axonal connectivity. Quantitative diffusion tensor imaging (DTI) of axonal integrity has been suggested as a potential biomarker for prognostic and therapeutic evaluation after trauma, but its correlation with functional outcomes has not been clearly defined. To examine this application, female Sprague-Dawley rats underwent midthoracic laminectomy followed by traumatic spinal cord contusion of differing severities or laminectomy without contusion. Locomotor scores and hindlimb kinematic data were collected for 4 weeks post-injury. Ex vivo DTI was then performed to assess axonal integrity using tractography and fractional anisotropy (FA), a numerical measure of relative white matter integrity, at the injury epicenter and at specific intervals rostral and caudal to the injury site. Immunohistochemistry for tissue sparing was also performed. Statistical correlation between imaging data and functional performance was assessed as the primary outcome. All injured animals showed some recovery of locomotor function, while hindlimb kinematics revealed graded deficits consistent with injury severity. Standard T2 magnetic resonance sequences illustrated conventional spinal cord morphology adjacent to contusions while corresponding FA maps indicated graded white matter pathology within these adjacent regions. Positive correlations between locomotor (Basso, Beattie, and Bresnahan score and gait kinematics) and imaging (FA values) parameters were also observed within these adjacent regions, most strongly within caudal segments beyond the lesion. Evaluation of axonal injury by DTI provides a mechanism for functional recovery assessment in a rodent SCI model. These findings suggest that focused DTI analysis of caudal spinal cord should be studied in human cases in relationship to motor outcome to augment outcome biomarkers for clinical cases.

In the context of injury to the corticospinal tract (CST), brainstem-origin circuits may provide an alternative system of descending motor influence. However, subcortical circuits are largely under subconscious control. To improve volitional control over spared fibers after CST injury, we hypothesized that a combination of physical exercises simultaneously stimulating cortical and brainstem pathways above the injury would strengthen corticobulbar connections through Hebbian-like mechanisms. We sought to test this hypothesis in mice with unilateral CST lesions. Ten days after pyramidotomy, mice were randomized to four training groups: (1) postural exercises designed to stimulate brainstem pathways (BS); (2) distal limb-grip exercises preferentially stimulating CST pathways (CST); (3) simultaneous multimodal exercises (BS+CST); or (4) no training (NT). Behavioral and anatomical outcomes were assessed after 20 training sessions over 4 weeks. Mice in the BS+CST training group showed a trend toward greater improvements in skilled limb performance than mice in the other groups. There were no consistent differences between training groups in gait kinematics. Anatomically, multimodal BS+CST training neither increased corticobulbar fiber density of the lesioned CST rostral to the lesion nor collateral sprouting of the unlesioned CST caudal to the lesion. Further studies should incorporate electrophysiological assessment to gauge changes in synaptic strength of direct and indirect pathways between the cortex and spinal cord in response to multimodal exercises., (Published by Elsevier B.V.)

Objective: To use vertical ground reaction force (vGRF) to show the magnitude and pattern of mechanical loading in persons with spinal cord injury (SCI) during powered exoskeleton-assisted walking., Research Design: A cross-sectional study was performed to analyze vGRF during powered exoskeleton-assisted walking (ReWalk™: Argo Medical Technologies, Inc, Marlborough, MA, USA) compared with vGRF of able-bodied gait., Setting: Veterans Affairs Medical Center., Participants: Six persons with thoracic motor-complete SCI (T1-T11 AIS A/B) and three age-, height-, weight- and gender-matched able-bodied volunteers participated., Interventions: SCI participants were trained to ambulate over ground using a ReWalk™. vGRF was recorded using the F-Scan™ system (TekScan, Boston, MA, USA)., Outcome Measures: Peak stance average (PSA) was computed from vGRF and normalized across all participants by percent body weight. Peak vGRF was determined for heel strike, mid-stance, and toe-off. Relative linear impulse and harmonic analysis provided quantitative support for analysis of powered exoskeletal gait., Results: Participants with motor-complete SCI, ambulating independently with a ReWalk™, demonstrated mechanical loading magnitudes and patterns similar to able-bodied gait. Harmonic analysis of PSA profile by Fourier transform contrasted frequency of stance phase gait components between able-bodied and powered exoskeleton-assisted walking., Conclusion: Powered exoskeleton-assisted walking in persons with motor-complete SCI generated vGRF similar in magnitude and pattern to that of able-bodied walking. This suggests the potential for powered exoskeleton-assisted walking to provide a mechanism for mechanical loading to the lower extremities. vGRF profile can be used to examine both magnitude of loading and gait mechanics of powered exoskeleton-assisted walking among participants of different weight, gait speed, and level of assist.

Background: The ability to retain or improve seated balance function after spinal cord injury (SCI) may mean the difference between independence and requiring assistance for basic activities of daily living. Compared with assessments of standing and walking balance, seated balance assessments remain relatively underemphasized and under-utilized., Objective: To optimize tools for assessing seated balance deficits and recovery in SCI., Design: Cross-sectional observational study of different methods for assessing seated balance function., Setting: Veterans Affairs Center of Excellence for the Medical Consequences of Spinal Cord Injury., Participants: Seven able-bodied volunteers, seven participants with chronic motor-complete thoracic SCI., Interventions: A computerized pressure-plate apparatus designed for testing standing balance was adapted into a seated balance assessment system., Outcome Measures: Seated section of Berg Balance Scale; modified functional reach test; and two posturography tests: limits of stability and clinical test of sensory integration on balance., Results: Seated posturography demonstrated improved correlation with neurological level of lesion compared to that of routinely applied subjective clinical tests., Conclusion: Seated posturography represents an appealing outcome measure that may be applied toward the measurement of functional changes in response to various rehabilitation interventions in individuals with paralysis.

Objective: To compare the features of paraneoplastic syndrome of inappropriate antidiuretic hormone with those of limbic encephalitis., Design: Case study., Setting: Academic medical center., Patient: A 46-year-old woman with progressive memory impairment, hyponatremia, and seizures., Interventions: Magnetic resonance imaging of the brain, fluoro-2-deoxyglucose positron emission tomography of the body, and immunohistochemical analysis of a resected tumor., Results: Though the patient presented with clinical features of classic limbic encephalitis, magnetic resonance imaging, electroencephalogram, and cerebrospinal fluid analysis findings were unremarkable. Her chronic hyponatremia was ultimately found to be due to ectopic secretion of antidiuretic hormone by a neuroendocrine tumor with Merkel cell carcinoma phenotype., Conclusions: Patients presenting with memory impairment, seizures, and hyponatremia should undergo a thorough workup for occult malignancy. In addition to considering classic immune-mediated paraneoplastic limbic encephalitis, the ectopic secretion of antidiuretic hormone should be included in the differential diagnosis.

Objective: Several interventions promote axonal growth and functional recovery when initiated shortly after central nervous system injury, including blockade of myelin-derived inhibitors with soluble Nogo receptor (NgR1, RTN4R) decoy protein. We examined the efficacy of this intervention in the much more prevalent and refractory condition of chronic spinal cord injury., Methods: We eliminated the NgR1 pathway genetically in mice by conditional gene targeting starting 8 weeks after spinal hemisection injury and monitored locomotion in the open field and by video kinematics over the ensuing 4 months. In a separate pharmacological experiment, intrathecal NgR1 decoy protein administration was initiated 3 months after spinal cord contusion injury. Locomotion and raphespinal axon growth were assessed during 3 months of treatment between 4 and 6 months after contusion injury., Results: Conditional deletion of NgR1 in the chronic state results in gradual improvement of motor function accompanied by increased density of raphespinal axons in the caudal spinal cord. In chronic rat spinal contusion, NgR1 decoy treatment from 4 to 6 months after injury results in 29% (10 of 35) of rats recovering weight-bearing status compared to 0% (0 of 29) of control rats (p < 0.05). Open field Basso, Beattie, and Bresnahan locomotor scores showed a significant improvement in the NgR-treated group relative to the control group (p < 0.005, repeated measures analysis of variance). An increase in raphespinal axon density caudal to the injury is detected in NgR1 decoy-treated animals by immunohistology and by positron emission tomography using a serotonin reuptake ligand., Interpretation: Antagonizing myelin-derived inhibitors signaling with NgR1 decoy augments recovery from chronic spinal cord injury., (Copyright © 2011 American Neurological Association.)

We tested the ability of two plasticity-promoting approaches to enhance recovery in a mouse model of incomplete spinal cord injury (SCI). Genetically, we reduced myelin-mediated inhibition of neural plasticity through Nogo66-receptor (NgR) gene deletion. Behaviorally, we utilized a novel multimodal exercise training paradigm. Adult mice of wild-type or NgR-null genotype were subjected to partial lateral hemisection (LHx) at C3-C4 with the intent of producing anatomically and functionally mild deficits. Exercise training or control treatment proceeded for 14 weeks. Behavioral outcomes were assessed prior to tract tracing and histological analysis. Genotype and training exerted differing effects on performance; training improved performance on a test related to the training regimen (task-specific benefit), whereas genotype also improved performance on more generalized behaviors (task-non-specific benefit). There were no significant histological differences across genotype or training assignment with regard to lesion size or axonal tract staining. Thus either NgR gene deletion or exercise training benefits mice with mild cervical spinal injury. In this lesion model, the effects of NgR deletion and training were not synergistic for the tasks assessed. Further work is required to optimize the interaction between pharmacological and physical interventions for SCI.

Most epilepsy genes encode ion channels, but the LGI1 gene responsible for autosomal dominant partial epilepsy with auditory features produces a secreted protein. LGI1 is suggested to regulate PSD-95 via ADAM22. However, no unbiased screen of LGI1 action has been conducted. Here, we searched for brain genes supporting high affinity LGI-1 binding. ADAM23 was the only LGI1 interactor identified. The related proteins, ADAM22 and ADAM11, but not ADAM12, bind LGI1. Neither ADAM23 nor ADAM11, nor some forms of ADAM22, contain PDZ-interacting sequences, suggesting PSD-95-independent mechanisms in ADPEAF. Because ADAMs modulate integrins, we examined LGI1 effect on neurite outgrowth. LGI1 increases outgrowth from wild-type but not ADAM23-/- neurons. Furthermore, CA1 pyramidal neurons of ADAM23-/- hippocampi have reduced dendritic arborization. ADAM23-/- mice exhibit spontaneous seizures, while ADAM23+/- mice have decreased seizure thresholds. Thus, LGI1 binding to ADAM23 is necessary to correctly pattern neuronal morphology and altered anatomical patterning contributes to ADPEAF.

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease inherited in a small subset of patients. The SOD1(G93A) transgenic mouse models this subset of patients, and studies of this strain have suggested that endoplasmic reticulum (ER) stress and deficits in ER chaperone function are contributors to ALS pathophysiology. Here, we demonstrate that the reticulon family of proteins is a novel regulator of the ER chaperone protein disulfide isomerase (PDI), and that through PDI, reticulon-4A (Nogo-A) can protect mice against the neurodegeneration that characterizes ALS. We show that overexpressing reticulon protein induces a punctate redistribution of PDI intracellularly, both in vitro and in vivo. Conversely, reduction of endogenous NogoA expression causes a more homogeneous expression pattern in vivo. These effects occur without induction of the unfolded protein response. To examine the effect of PDI redistribution on ALS disease progression, we conducted survival and behavior studies of SOD1(G93A) mice. Deletion of a single copy of the NogoA,B gene accelerates disease onset and progression, while deletion of both copies further worsens disease. We conclude that NogoA contributes to the proper function of the ER resident chaperone PDI, and is protective against ALS-like neurodegeneration. Our results provide a novel intracellular role for reticulon proteins and support the hypothesis that modulation of PDI function is a potential therapeutic approach to ALS.

Improved biomarkers would facilitate the diagnosis and treatment of amyotrophic lateral sclerosis (ALS). Muscle content of the neuritic outgrowth inhibitor Nogo-A is increased in patients with ALS and other denervating conditions. Seeking a less invasive diagnostic method, we sought to determine whether or not Nogo increases in the serum of ALS patients. We developed a dissociation-enhanced lanthanide fluorescent immunoassay (DELFIA) protocol to screen serum samples from 172 ALS patients and 172 healthy controls for Nogo-A immunoreactivity. Unexpectedly, there was a trend toward decreased levels of serum Nogo-A in ALS. Mean serum Nogo-A level in ALS patients was 0.71 nM (95% confidence interval (CI) 0.42-1.00), as opposed to 1.15 nM (95% CI 0.72-1.59) in healthy controls. A significantly larger percentage of healthy control sera (11.0% vs 4.7%) displayed markedly elevated levels of Nogo-A. Additional study is required to determine the factors that lead to elevated Nogo-A levels in a subset of both ALS patients and healthy controls.

Substantial progress has been made towards understanding the molecular basis for limited endogenous central nervous system (CNS) axonal growth after injuries such as spinal cord trauma. Realization of the potential benefit of therapeutic interventions requires methods to assess axonal growth and functional reorganization over time after neurological damage. Here, we discuss the technical challenges of analyzing and interpreting the effects of various interventions on CNS repair, specifically in the context of spinal cord injury. Evolving technologies such as functional magnetic resonance imaging and other non-invasive imaging techniques will be reviewed. These technologies should revolutionize our ability to track changes in both CNS structure and function.

The production and aggregation of cerebral amyloid-beta (Abeta) peptide are thought to play a causal role in Alzheimer's disease (AD). Previously, we found that the Nogo-66 receptor (NgR) interacts physically with both Abeta and the amyloid precursor protein (APP). The inverse correlation of Abeta levels with NgR levels within the brain may reflect regulation of Abeta production and/or Abeta clearance. Here, we assess the potential therapeutic benefit of peripheral NgR-mediated Abeta clearance in APPswe/PSEN-1deltaE9 transgenic mice. Through site-directed mutagenesis, we demonstrate that the central 15-28 aa of Abeta associate with specific surface-accessible patches on the leucine-rich repeat concave side of the solenoid structure of NgR. In transgenic mice, subcutaneous NgR(310)ecto-Fc treatment reduces brain Abeta plaque load while increasing the relative levels of serum Abeta. These changes in Abeta are correlated with improved spatial memory in the radial arm water maze. The benefits of peripheral NgR administration are evident when therapy is initiated after disease onset. Thus, the peripheral association of NgR(310)ecto-Fc with central Abeta residues provides an effective therapeutic approach for AD.

The precise wiring of the adult mammalian CNS originates during a period of stunning growth, guidance and plasticity that occurs during and shortly after development. When injured in adults, this intricate system fails to regenerate. Even when the obstacles to regeneration are cleared, growing adult CNS fibres usually remain misdirected and fail to reform functional connections. Here, we attempt to fill an important niche related to the topics of nervous system development and regeneration. We specifically contrast the difficulties faced by growing fibres within the adult context to the precise circuit-forming capabilities of developing fibres. In addition to focusing on methods to stimulate growth in the adult, we also expand on approaches to recapitulate development itself.

The 86-kDa major immediate-early protein (IE2/IEP86) of human cytomegalovirus (HCMV) contains a serine-rich region (amino acids 258 to 275) with several consensus casein kinase II (CKII) sites. We performed extensive mutational analysis of this region, changing serines to alternating alanines and glycines. Mutation of the serines between amino acids 266 and 275 eliminated in vitro phosphorylation by CKII. In vitro CKII phosphorylation of the serines between amino acids 266 and 269 or between amino acids 271 and 275 inhibited the ability of IE2/IEP86 to bind to TATA-binding protein. Correspondingly, nonphosphorylatable mutants in these regions showed increased activation of specific HCMV gene promoters in transfection studies. Viruses containing mutations of the serines throughout the entire region (amino acids 258 to 275) or the second half (amino acids 266 to 275) of the region showed delayed expression of all viral proteins tested and, correspondingly, delayed growth compared to wild-type HCMV. Mutation of the serines in the first half of the serine-rich region (amino acids 258 to 264) or between amino acids 266 and 269 propagated very slowly and has not been further studied. In contrast, mutation of the serines between amino acids 271 and 275 resulted in accelerated virus growth and accelerated temporal expression of viral proteins. These results suggest that the serine-rich region is structurally complex, possibly affecting multiple functions of IE2/IEP86. The data show that the phosphorylation state of the serine-rich region, particularly between amino acids 271 and 275, modulates the temporal expression of viral genes.

Cardiac embolism accounts for a large proportion of ischemic stroke. Revascularization using systemic or intra-arterial thrombolysis is associated with increasing risks of cerebral hemorrhage as time passes from stroke onset. We report successful mechanical thrombectomy from a distal branch of the middle cerebral artery (MCA) using a novel technique. A 72-year old man suffered an acute ischemic stroke from an echocardiographically proven ventricular thrombus due to a recent myocardial infarction. Intraarterial administration of 4 mg rt-PA initiated at 5.7 hours post-ictus failed to recanalize an occluded superior division branch of the left MCA. At 6 hours, symptomatic embolic occlusion persisted. Mechanical extraction of the clot using an Attracter-18 device (Target Therapeutics, Freemont, CA) resulted in immediate recanalization of the MCA branch. Attracter-18 for acute occlusion of MCA branches may be considered in selected patients who fail conventional thrombolysis or are nearing closure of the therapeutic window for use of thrombolytic agents.

We have investigated the phosphorylation state of the human cytomegalovirus 86-kDa immediate-early (IE) protein IEP86 from transfected and infected cells. We show that multiple domains of IEP86 are phosphorylated by cellular kinases, both in vitro and in vivo. Our data suggest that serum-inducible kinases play a significant role in cell-mediated IE protein phosphorylation and that a member of the mitogen-activated protein (MAP) kinase (MAPK) family, extracellular regulated kinase 2 (ERK2), phosphorylates several domains of IEP86 in vitro. Alanine substitution mutagenesis was performed on specific serines or threonines (T27, S144, T233/S234, and T555) found in consensus MAP kinase motifs. Analysis of these mutations showed that T27 and T233/S234 are the major sites for serum-inducible kinases and are the major ERK2 sites in vitro. S144 appeared to be phosphorylated in a serum-independent manner in vitro. All of the mutations except T555 eliminated specific phosphorylation in vivo. In transient transfection analyses, IEP86 isoforms containing mutations in S144 and, especially, T233/S234 displayed increased transcriptional activation relative to the wild type, suggesting that phosphorylation at these sites in wild-type IEP86 may result in reduction of its transcriptional activation ability.