Timing-dependent synergies between motor cortex and posterior spinal stimulation in humans.

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.

Implications of Delayed Testosterone Recovery in Patients with Prostate Cancer.

To assess the clinical impact of delayed testosterone recovery (TR) following the discontinuation of medical androgen deprivation therapy (ADT), a retrospective, longitudinal analysis was conducted in adult males with prostate cancer using the Optum® de-identified Electronic Health Record data set and Optum® Enriched Oncology Data (2010-2021). Of 3875 patients who initiated and discontinued ADT, 1553 received one or more testosterone-level tests within the 12 mo following discontinuation and were included in this study. These 1553 patients were categorized into two cohorts: 25% as TR (testosterone levels >280 ng/dl at any test within 12 mo following ADT discontinuation) and 75% as non-TR. At baseline, non-TR patients were older, had lower testosterone levels, and were more likely to have diabetes, hyperlipidemia, and hypertension, but less likely to have sexual dysfunction. After adjustment for baseline characteristics, the TR cohort had a lower risk of new-onset diabetes (hazard ratio [HR] 0.47; 95% confidence interval [CI] 0.27-0.79), trended toward a lower risk of new-onset depression (HR 0.58; 95% CI 0.33-1.02), and had a higher likelihood of seeking treatment for sexual dysfunction (HR 1.33; 95% CI 0.99-1.78) versus the non-TR cohort. These findings support monitoring testosterone levels after ADT discontinuation to manage potential long-term comorbidities in patients with prostate cancer. Patient summary: This real-world analysis of males with prostate cancer who were treated with medical androgen deprivation therapy (ADT) found that most patients did not have their testosterone level checked in the 12 mo after stopping ADT. Of those who did, 75% did not achieve normal testosterone levels (>280 ng/dl), and these patients were more likely to experience new-onset diabetes than those who achieved normal testosterone levels. These results suggest that to ensure effective clinical decision-making, physicians should check patients' testosterone levels after stopping ADT.

Cost-Effectiveness Modeling of Prostate-Specific Membrane Antigen Positron Emission Tomography with Piflufolastat F 18 for the Initial Diagnosis of Patients with Prostate Cancer in the United States.

BACKGROUND AND OBJECTIVES: Piflufolastat F 18 is a novel prostate-specific membrane antigen (PSMA)-targeted positron emission tomography (PET) radiotracer that is superior to standard of care (SOC) imaging for the initial staging of prostate cancer and the detection of biochemical recurrence. As piflufolastat F 18 has been approved in the United States (US) for this indication, this modeling study assessed the cost effectiveness of piflufolastat F 18 versus fluciclovine F-18, gallium68-PSMA-11 (PSMA 11), and SOC imaging (a mix of bone scans, computed tomography, and magnetic resonance imaging) for the diagnosis and staging of prostate cancer from a US healthcare system perspective. PERSPECTIVE: A US third-party payer perspective was used, which for this population reflects a mix of commercial and Medicare, considering only direct healthcare costs. SETTING: This study utilized a tertiary healthcare setting. METHODS: A decision tree was used to map the diagnostic/treatment pathway, consisting of the proportion of patients with local, regional, distant, or no disease; prostate-specific antigen (PSA) ≤ 1.0 or > 1.0; and accuracy of imaging modalities. A Markov model predicted the long-term outcomes of disease progression according to treatment decisions. Inputs to the model were informed by data from the OSPREY and CONDOR clinical trials, public data, and the literature. Treatment mix included active surveillance, radiation therapy, prostatectomy, androgen deprivation therapy (ADT), and radiation therapy + ADT, informed by expert opinion. Outcomes included life-years (LY), quality-adjusted life-years (QALY), and the incremental cost-effectiveness ratio (ICER). All costs were reported in 2021 US dollars, using the US Bureau of Labor Statistics Consumer Price Index. A willingness-to-pay (WTP) threshold of $150,000 was considered cost effective, consistent with the upper range used as the standard for price benchmarks by the Institute for Clinical and Economic Review. The robustness of the base-case results was assessed in deterministic and probabilistic sensitivity analyses. RESULTS: Over a lifetime horizon, piflufolastat F 18 had the greatest effectiveness in terms of LYs (6.80) and QALYs (5.33); for the comparators, LYs ranged from 6.58 (SOC) to 6.76 (PSMA 11) and QALYs ranged from 5.12 (SOC) and 5.30 (PSMA 11). Piflufolastat F 18 was more cost effective compared with fluciclovine F 18, PSMA 11, and SOC, with ICERs of $21,122, $55,836, and $124,330 per QALY gained, respectively. Piflufolastat F 18 was associated with the greatest net monetary benefit ($627,918) compared with the other options at a WTP threshold of $150,000. The results of the deterministic and probabilistic sensitivity analyses supported the robustness of the base-case results. CONCLUSIONS: This study suggests that piflufolastat F 18 is a cost-effective diagnostic option for men with prostate cancer in the US, with higher associated LY, QALY, and greater net monetary benefit than fluciclovine F 18, PSMA 11, and SOC imaging.

Transcutaneous Spinal Cord Stimulation to Stabilize Seated Systolic Blood Pressure in Persons With Chronic Spinal Cord Injury: Protocol Development.

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.

Remote Ischemic conditioning as an emerging tool to improve corticospinal transmission in individuals with chronic spinal cord injury.

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.

Timing dependent synergies between motor cortex and posterior spinal stimulation in humans.

Volitional movement requires descending input from 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 dorsal epidural SCS targeted at the sensorimotor interface or anterior epidural SCS 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 with epidural electrodes while muscle responses were 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, paired stimulation effects were present regardless of the severity of myelopathy as measured by clinical signs or spinal cord imaging. The large effect size of this paired stimulation makes it a promising candidate for therapeutic neuromodulation.

Pharmacological management of acute spinal cord injury: a longitudinal multi-cohort observational study.

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 RXSCI web site ( https://jutzelec.shinyapps.io/RxSCI/ ) and GitHub repository ( https://github.com/jutzca/Acute-Pharmacological-Treatment-in-SCI/ ).

Priming locomotor training with transspinal stimulation in people with spinal cord injury: study protocol of a randomized clinical trial.

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-minutes of active or sham transspinal stimulation during standing or active transspinal stimulation while supine followed by 30-minutes 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.

Priming locomotor training with transspinal stimulation in people with spinal cord injury: study protocol of a randomized clinical trial.

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.

Intraoperative electrical stimulation of the human dorsal spinal cord reveals a map of arm and hand muscle responses.

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 impact of transitive annotation on the training of taxonomic classifiers.

Introduction: A common task in the analysis of microbial communities involves assigning taxonomic labels to the sequences derived from organisms found in the communities. Frequently, such labels are assigned using machine learning algorithms that are trained to recognize individual taxonomic groups based on training data sets that comprise sequences with known taxonomic labels. Ideally, the training data should rely on labels that are experimentally verified-formal taxonomic labels require knowledge of physical and biochemical properties of organisms that cannot be directly inferred from sequence alone. However, the labels associated with sequences in biological databases are most commonly computational predictions which themselves may rely on computationally-generated data-a process commonly referred to as "transitive annotation." Methods: In this manuscript we explore the implications of training a machine learning classifier (the Ribosomal Database Project's Bayesian classifier in our case) on data that itself has been computationally generated. We generate new training examples based on 16S rRNA data from a metagenomic experiment, and evaluate the extent to which the taxonomic labels predicted by the classifier change after re-training. Results: We demonstrate that even a few computationally-generated training data points can significantly skew the output of the classifier to the point where entire regions of the taxonomic space can be disturbed. Discussion and conclusions: We conclude with a discussion of key factors that affect the resilience of classifiers to transitively-annotated training data, and propose best practices to avoid the artifacts described in our paper.

Reaching a Tipping Point for Neurorehabilitation Research: Obstacles and Opportunities in Trial Design, Description, and Pooled Analysis.

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.

Evaluating the clinical benefit of brain-computer interfaces for control of a personal computer.

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 inhow a patient feels, and we offer some considerations that should guide instrument selection. (b) Activities of daily living can be assessed to demonstrate improvements inhow 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 tohow a patient surviveshas not previously been evaluated but establishing patient-initiated communication channels using BCIs might facilitate quantifiable improvements in health outcomes.

Hand dominance in the performance and perceptions of virtual reach control.

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.

The experience of a severe hypoglycaemic event from the perspective of people with diabetes and their caregivers: "What am I going to do?"

AIMS: Among people with diabetes using insulin, severe hypoglycaemia (SH) can be a life-threatening complication, if untreated. The personal experiences during an SH event from the perspectives of people with diabetes and their caregivers are not well-characterized. This study assessed the perceptions of the event and the decision making processes of people with diabetes (T1D n = 36; T2D n = 24) and their caregivers during SH events. METHODS: In-depth one-on-one telephone interviews were conducted with dyads of people with diabetes and caregivers in the United States (n = 120). An initial synopsis and inductive codebook schema were used to analyse the data with two independent coders (kappa = 0.87-0.89). Themes were developed from the codes, and codes were re-mapped to the themes. RESULTS: Four themes were formed: (1) Caregivers scramble to do the right thing and support people with diabetes in treating SH; (2) Decision making capacity is impaired during an SH event, often a panicked time; (3) People learn to manage SH events through their own experiences and frequently make lifestyle changes to prevent and treat future events; and (4) Discussion with healthcare providers about SH, and particularly SH treatment, is limited. CONCLUSIONS: SH events are stressful and often evoke emotional reactions that can impair decision making. Thus, advance treatment planning of SH events needs to occur. Much of the knowledge about SH treatment derives from prior experience rather than healthcare provider guidance, suggesting a need for healthcare providers to initiate proactive discussions about SH treatment.

Posteroanterior Cervical Transcutaneous Spinal Cord Stimulation: Interactions with Cortical and Peripheral Nerve Stimulation.

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.

Instantaneous Degelling Thermoresponsive Hydrogel.

Responsive polymeric hydrogels have found wide application in the clinic as injectable, biocompatible, and biodegradable materials capable of controlled release of therapeutics. In this article, we introduce a thermoresponsive polymer hydrogel bearing covalent disulfide bonds. The cold aqueous polymer solution forms a hydrogel upon heating to physiological temperatures and undergoes slow degradation by hydrolytic cleavage of ester bonds. The disulfide functionality allows for immediate reductive cleavage of the redox-sensitive bond embedded within the polymer structure, affording the option of instantaneous hydrogel collapse. Poly(ethylene glycol)-b-poly(lactic acid)-S-S-poly(lactic acid)-b-poly(ethylene glycol) (PEG-PLA-SS-PLA-PEG) copolymer was synthesized by grafting PEG to PLA-SS-PLA via urethane linkages. The aqueous solution of the resultant copolymer was a free-flowing solution at ambient temperatures and formed a hydrogel above 32 °C. The immediate collapsibility of the hydrogel was displayed via reaction with NaBH4 as a relatively strong reducing agent, yet stability was displayed even in glutathione solution, in which the polymer degraded slowly by hydrolytic degradation. The polymeric hydrogel is capable of either long-term or immediate degradation and thus represents an attractive candidate as a biocompatible material for the controlled release of drugs.

Antiviral Polymers Based on N-Halamine Polyurea.

N-halamines are a commonly applied class of antimicrobial agents used for a variety of applications relating to human health. Here, we present the modulation of the common polymers polyurea and polyguanidine with the N-halamine technology. The N-H bonds in either polymer were converted to N-Cl or N-Br bonds capable of releasing Cl+ or Br+ cations to aqueous media as antiviral agents. Controlled release of the oxidizing agents was monitored for a period of 4 weeks. Antiviral activity was evaluated against the T4 bacteriophage as well as against the highly stable plant virus belonging to the Tobamovirus genus, tomato brown rugose fruit virus. The incorporation of the N-halamine technology on commonly used polymers has effectively introduced antiviral functionality for a wide variety of potential applications.

Duration and reliability of the silent period in individuals with spinal cord injury.

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.