Mechanisms and benefits of cardiac rehabilitation in individuals with stroke: emerging role of its impact on improving cardiovascular and neurovascular health.

Human and animal studies have demonstrated the mechanisms and benefits of aerobic exercise for both cardiovascular and neurovascular health. Aerobic exercise induces neuroplasticity and neurophysiologic reorganization of brain networks, improves cerebral blood flow, and increases whole-body VO2peak (peak oxygen consumption). The effectiveness of a structured cardiac rehabilitation (CR) program is well established and a vital part of the continuum of care for people with cardiovascular disease. Individuals post stroke exhibit decreased cardiovascular capacity which impacts their neurologic recovery and extends disability. Stroke survivors share the same risk factors as patients with cardiac disease and can therefore benefit significantly from a comprehensive CR program in addition to neurorehabilitation to address their cardiovascular health. The inclusion of individuals with stroke into a CR program, with appropriate adaptations, can significantly improve their cardiovascular health, promote functional recovery, and reduce future cardiovascular and cerebrovascular events thereby reducing the economic burden of stroke.

Integrating Cardiac Rehabilitation in Stroke Recovery.

Stroke remains a top contributor to long-term disability in the United States and substantially limits a person's physical activity. Decreased cardiovascular capacity is a major contributing factor to activity limitations and is a significant health concern. Addressing the cardiovascular capacity of stroke survivors as part of poststroke management results in significant improvements in their endurance, functional recovery, and medical outcomes such as all-cause rehospitalization and mortality. Incorporation of a structured approach similar to the cardiac rehabilitation program, including aerobic exercise and risk factor education, can lead to improved cardiovascular function, health benefits, and quality of life in stroke survivors.

Spinal magnetic stimulation to treat chronic back pain: a feasibility study in veterans.

Aim: Chronic low back pain represents a significant societal problem leading to increased healthcare costs and quality of life. This study was designed to evaluate the feasibility and effectiveness of non-invasive spinal electromagnetic simulation (SEMS) to treat nonspecific chronic low back pain (CLBP). Methods: A single-site prospective study was conducted to evaluate SEMS in reducing pain and improving disability. A total of 17 patients received SEMS two to three sessions a week. The Numeric Rating Scale and the Modified Oswestry Disability Questionnaire were used to assess pain and disability. Results: Participants receiving SEMS exhibited statistically significant reductions in pain and disability. Conclusion: Current results suggest that non-invasive SEMS can be an effective treatment in reducing pain and improving disability associated with CLBP.

Educating families of brain injury patients during acute rehabilitation: a quality improvement project.

ABSTRACT: Lack of information is cited as a source of distress for caregivers of patients with brain injury during the recovery process. This is a quality improvement project with the purpose of educating family members of brain injury patients about acute inpatient rehabilitation and providing a reliable source of information through the Model Systems Knowledge Translation Center (MSKTC) Traumatic Brain Injury Model Systems (TBIMS) Factsheets. The study was conducted in the brain injury unit of an acute inpatient rehabilitation facility and a total of n = 32 family members participated in the study. Educational sessions were provided verbally by phone based on the MSKTC-TBIMS "Traumatic Brain Injury and Acute Inpatient Rehabilitation" Factsheet. Surveys with five confidence statements and Likert scale graded responses were verbally administered by phone immediately before and after each educational session to evaluate for understanding. There was a statistically significant increase in confidence for all five confidence statements when comparing pre-and post-education responses (p < 0.05, Wilcoxon signed-rank test). This quality improvement project thereby presents an effective and feasible framework for teaching, improving communication, and providing valuable information to families early in the brain injury rehabilitation course.

Barriers and factors associated with adherence to a home exercise program of adults with musculoskeletal pain.

BACKGROUND: Home exercise programs (HEPs) are cost-effective and efficacious treatments for musculoskeletal pain conditions. Although HEPs are an important part of the continuum of care, non-adherence limits their effectiveness. OBJECTIVE: The objective of this study was to examine adherence and specific barriers to clinician-prescribed HEPs in adults with musculoskeletal pain. METHODS: A cross-sectional study was conducted with a total of 300 patients presenting to an outpatient pain clinic in an academic medical center. Participants' self-reported information, including HEP completion frequency and barriers, was collected through a survey. RESULTS: The participants' mean age was 54.1 ± 15.8 years (females = 133 (65.5%)). Of 203 participants, 99 (48.8%) adhered to HEP, 56 (27.6%) partially adhered, and 48 (23.6%) did not adhere. One hundred eighty-seven (92.1%) participants reported receiving adequate instructions, and 175 (86.2%) reported receiving instructional materials. Age and "sufficient instructions" were found to be significant determinants of adherence (p< 0.05), while gender and handouts were not (p> 0.05). Pain in more than one body part was significantly (p< 0.05) associated with motivational barriers for non-adherence. CONCLUSION: Age and participants' perception of sufficient instructions were significant factors for non-adherence. These results emphasize the importance of therapist-provided instructions to overcome barriers to adherence.

AAV Vector Mediated Delivery of NG2 Function Neutralizing Antibody and Neurotrophin NT-3 Improves Synaptic Transmission, Locomotion, and Urinary Tract Function after Spinal Cord Contusion Injury in Adult Rats.

NG2 is a structurally unique transmembrane chondroitin sulfate proteoglycan (CSPG). Its role in damaged spinal cord is dual. NG2 is considered one of key inhibitory factors restricting axonal growth following spinal injury. Additionally, we have recently detected its novel function as a blocker of axonal conduction. Some studies, however, indicate the importance of NG2 presence in the formation of synaptic contacts. We hypothesized that the optimal treatment would be neutralization of inhibitory functions of NG2 without its physical removal. Acute intraspinal injections of anti-NG2 monoclonal antibodies reportedly prevented an acute block of axonal conduction by exogenous NG2. For prolonged delivery of NG2 function neutralizing antibody, we have developed a novel gene therapy: adeno-associated vector (AAV) construct expressing recombinant single-chain variable fragment anti-NG2 antibody (AAV-NG2Ab). We examined effects of AAV-NG2Ab alone or in combination with neurotrophin NT-3 in adult female rats with thoracic T10 contusion injuries. A battery of behavioral tests was used to evaluate locomotor function. In vivo single-cell electrophysiology was used to evaluate synaptic transmission. Lower urinary tract function was assessed during the survival period using metabolic chambers. Terminal cystometry, with acquisition of external urethral sphincter activity and bladder pressure, was used to evaluate bladder function. Both the AAV-NG2Ab and AAV-NG2Ab combined with AAV-NT3 treatment groups demonstrated significant improvements in transmission, locomotion, and bladder function compared with the control (AAV-GFP) group. These functional improvements associated with improved remyelination and plasticity of 5-HT fibers. The best results were observed in the group that received combinational AAV-NG2Ab+AAV-NT3 treatment.SIGNIFICANCE STATEMENT We recently demonstrated beneficial, but transient, effects of neutralization of the NG2 proteoglycan using monoclonal antibodies delivered intrathecally via osmotic mini-pumps after spinal cord injury. Currently, we have developed a novel gene therapy tool for prolonged and clinically relevant delivery of a recombinant single-chain variable fragment anti-NG2 antibody: AAV-rh10 serotype expressing scFv-NG2 (AAV-NG2Ab). Here, we examined effects of AAV-NG2Ab combined with transgene delivery of Neurotrophin-3 (AAV-NT3) in adult rats with thoracic contusion injuries. The AAV-NG2Ab and AAV-NG2Ab+AAV-NT3 treatment groups demonstrated significant improvements of locomotor function and lower urinary tract function. Beneficial effects of this novel gene therapy on locomotion and bladder function associated with improved transmission to motoneurons and plasticity of axons in damaged spinal cord.

Buprenorphine, a partial opioid agonist, prevents modulation of H-reflex induced by pulsed electromagnetic stimulation in spinal cord injured rats.

Our recent study revealed that spinal electromagnetic stimulation (sEMS) applied at low (0.2 Hz) frequencies may improve diminished transmission in damaged spinal cord in spinal cord injured (SCI) rats. We have recently begun a pilot study investigating the effects of sEMS in non-injured and SCI humans. One unexpected result was the reduction of chronic low back pain (CLBP), reported by some patients following sEMS treatment. Chronic low back pain is one of the main causes of disability affecting the general population. Opioids are the most common drugs prescribed to US adults with CLBP. To optimize parameters for sEMS for pain treatment, in this study we used the SCI animal model and examined effects of sEMS applied at lumbosacral level on parameters and frequency-dependent depression (FDD) of Hoffmann H-reflex responses, known as common neurophysiological measures for evaluation of sensorimotor condition and plasticity in humans. We have also examined the interactive effects of sEMS and the opiate partial agonist Buprenorphine on the parameters of H-reflex in naïve and SCI rats. Consistent with previous reports, chronic SCI resulted in a marked decrease of threshold intensity required to evoke H-reflex and a lesser rate of FDD of the H-response in adult rats. Our current study revealed the optimum parameters of spinal EMS for best recovery of the properties of the H-reflex in chronic SCI animals. Here we demonstrate that electro-magnetic stimulation applied at spinal L4-L5 level with a pulsed mode (pulse at 20 Hz frequency for 5 sec with 25 sec break between pulses, total 40 trains for 20 min; PSEMS) reversed effects of SCI on key parameters of H-reflex: i.e. (1) restored the threshold intensity of electric current applied at tibial nerve to evoke the H-reflex and (2) recovered FDD properties of the H-reflex in SCI rats. Importantly, subcutaneous injections of Buprenorphine, prior to PSEMS administration, abolished the ability of PSEMS to recover both threshold intensity and FDD of the H-reflex in chronic SCI animals. These results suggest that a semi-synthetic opioid Buprenorphine and PSEMS might share common sites of action. We thus conclude that PSEMS might carry potential as a non-invasive treatment approach for chronic low back pain.

Modulation of H-reflex responses and frequency-dependent depression by repetitive spinal electromagnetic stimulation: From rats to humans and back to chronic spinal cord injured rats.

The lack of propagation of signals through survived fibers is among the major reasons for functional loss after incomplete spinal cord injury (SCI). Our recent results of animal studies demonstrate that spinal electromagnetic stimulation (SEMS) can enhance transmission in damaged spinal cord, and this type of modulation depends on the function of NMDA receptors at the neuronal networks below the injury level. Here, our pilot human study revealed that administration of repetitive SEMS induced long-lasting modulation of H-responses in both healthy and participants with chronic SCI. In order to understand the mechanisms underlying these effects, we have used an animal model and examined effects of SEMS on H-responses. Effects of SEMS on H-responses, frequency-dependent depression (FDD) of H-reflex, and possible underlying mechanisms have been examined in both naïve and rats with SCI. Our results demonstrate that consistent with the effects of SEMS on H-reflex seen in humans, repetitive SEMS induced similar modulation in excitability of peripheral nerve responses in both non-injured and rats with SCI. Importantly, our results confirmed the reduced FDD of H-reflex in SCI animals and revealed that SEMS was able to recover FDD in rats with chronic SCI. Using intraspinal injections of the NMDA receptor blocker MK-801, we have identified NMDA receptors as an important contributor to these SEMS-induced effects in rats with SCI. These results identify SEMS as a novel non-invasive technique for modulation of neuro-muscular circuits and, importantly, modulation of spinal networks after chronic SCI.

Transcranial magnetic stimulation (TMS) responses elicited in hindlimb muscles as an assessment of synaptic plasticity in spino-muscular circuitry after chronic spinal cord injury.

Electromagnetic stimulation applied at the cranial level, i.e. transcranial magnetic stimulation (TMS), is a technique for stimulation and neuromodulation used for diagnostic and therapeutic applications in clinical and research settings. Although recordings of TMS elicited motor-evoked potentials (MEP) are an essential diagnostic tool for spinal cord injured (SCI) patients, they are reliably recorded from arm, and not leg muscles. Mid-thoracic contusion is a common SCI that results in locomotor impairments predominantly in legs. In this study, we used a chronic T10 contusion SCI rat model and examined whether (i) TMS-responses in hindlimb muscles can be used for evaluation of conduction deficits in cortico-spinal circuitry and (ii) if plastic changes at spinal levels will affect these responses. In this study, plastic changes of transmission in damaged spinal cord were achieved by repetitive electro-magnetic stimulation applied over the spinal level (rSEMS). Spinal electro-magnetic stimulation was previously shown to activate spinal nerves and is gaining large acceptance as a non-invasive alternative to direct current and/or epidural electric stimulation. Results demonstrate that TMS fails to induce measurable MEPs in hindlimbs of chronically SCI animals. After facilitation of synaptic transmission in damaged spinal cord was achieved with rSEMS, however, MEPs were recorded from hindlimb muscles in response to single pulse TMS stimulation. These results provide additional evidence demonstrating beneficial effects of TMS as a diagnostic technique for descending motor pathways in uninjured CNS and after SCI. This study confirms the ability of TMS to assess plastic changes of transmission occurring at the spinal level.

Spinal electro-magnetic stimulation combined with transgene delivery of neurotrophin NT-3 and exercise: novel combination therapy for spinal contusion injury.

Our recent terminal experiments revealed that administration of a single train of repetitive spinal electromagnetic stimulation (sEMS; 35 min) enhanced synaptic plasticity in spinal circuitry following lateral hemisection spinal cord injury. In the current study, we have examined effects of repetitive sEMS applied as a single train and chronically (5 wk, every other day) following thoracic T10 contusion. Chronic studies involved examination of systematic sEMS administration alone and combined with exercise training and transgene delivery of neurotrophin [adeno-associated virus 10-neurotrophin 3 (AAV10-NT3)]. Electrophysiological intracellular/extracellular recordings, immunohistochemistry, behavioral testing, and anatomical tracing were performed to assess effects of treatments. We found that administration of a single sEMS train induced transient facilitation of transmission through preserved lateral white matter to motoneurons and hindlimb muscles in chronically contused rats with effects lasting for at least 2 h. These physiological changes associated with increased immunoreactivity of GluR1 and GluR2/3 glutamate receptors in lumbar neurons. Systematic administration of sEMS alone for 5 wk, however, was unable to induce cumulative improvements of transmission in spinomuscular circuitry or improve impaired motor function following thoracic contusion. Encouragingly, chronic administration of sEMS, followed by exercise training (running in an exercise ball and swimming), induced the following: 1) sustained strengthening of transmission to lumbar motoneurons and hindlimb muscles, 2) better retrograde transport of anatomical tracer, and 3) improved locomotor function. Greatest improvements were seen in the group that received exercise combined with sEMS and AAV-NT3.

Combination of chondroitinase ABC and AAV-NT3 promotes neural plasticity at descending spinal pathways after thoracic contusion in rats.

Transmission through descending pathways to lumbar motoneurons, although important for voluntary walking in humans and rats, has not been fully understood at the cellular level in contusion models. Major descending pathways innervating lumbar motoneurons include those at corticospinal tract (CST) and ventrolateral funiculus (VLF). We examined transmission and plasticity at synaptic pathways from dorsal (d)CST and VLF to individual motoneurons located in ventral horn and interneurons located in dorsomedial gray matter at lumbar segments after thoracic chronic contusion in adult anesthetized rats. To accomplish this, we used intracellular electrophysiological recordings and performed acute focal spinal lesions during the recordings. We directly demonstrate that after thoracic T10 chronic contusion the disrupted dCST axons spontaneously form new synaptic contacts with individual motoneurons, extending around the contusion cavity, through spared ventrolateral white matter. These detour synaptic connections are very weak, and strengthening these connections in order to improve function may be a target for therapeutic interventions after spinal cord injury (SCI). We found that degradation of scar-related chondroitin sulfate proteoglycans with the enzyme chondroitinase ABC (ChABC) combined with adeno-associated viral (AAV) vector-mediated prolonged delivery of neurotrophin NT-3 (AAV-NT3) strengthened these spontaneously formed connections in contused spinal cord. Moreover, ChABC/AAV-NT3 treatment induced the appearance of additional detour synaptic pathways innervating dorsomedial interneurons. Improved transmission in ChABC/AAV-NT3-treated animals was associated with increased immunoreactivity of 5-HT-positive fibers in lumbar dorsal and ventral horns. Improved locomotor function assessed with automated CatWalk highlights the physiological significance of these novel connections.

Neutralization of inhibitory molecule NG2 improves synaptic transmission, retrograde transport, and locomotor function after spinal cord injury in adult rats.

NG2 belongs to the family of chondroitin sulfate proteoglycans that are upregulated after spinal cord injury (SCI) and are major inhibitory factors restricting the growth of fibers after SCI. Neutralization of NG2's inhibitory effect on axon growth by anti-NG2 monoclonal antibodies (NG2-Ab) has been reported. In addition, recent studies show that exogenous NG2 induces a block of axonal conduction. In this study, we demonstrate that acute intraspinal injections of NG2-Ab prevented an acute block of conduction by NG2. Chronic intrathecal infusion of NG2-Ab improved the following deficits induced by chronic midthoracic lateral hemisection (HX) injury: (1) synaptic transmission to lumbar motoneurons, (2) retrograde transport of fluororuby anatomical tracer from L5 to L1, and (3) locomotor function assessed by automated CatWalk gait analysis. We collected data in an attempt to understand the cellular and molecular mechanisms underlying the NG2-Ab-induced improvement of synaptic transmission in HX-injured spinal cord. These data showed the following: (1) that chronic NG2-Ab infusion improved conduction and axonal excitability in chronically HX-injured rats, (2) that antibody treatment increased the density of serotonergic axons with ventral regions of spinal segments L1-L5, (3) and that NG2-positive processes contact nodes of Ranvier within the nodal gap at the location of nodal Na(+) channels, which are known to be critical for propagation of action potentials along axons. Together, these results demonstrate that treatment with NG2-Ab partially improves both synaptic and anatomical plasticity in damaged spinal cord and promotes functional recovery after HX SCI. Neutralizing antibodies against NG2 may be an excellent way to promote axonal conduction after SCI.

Repetitive spinal electromagnetic stimulation opens a window of synaptic plasticity in damaged spinal cord: role of NMDA receptors.

As we reported previously, propagation of action potentials through surviving axons is impaired dramatically, resulting in reduced transmission to lumbar motoneurons after midthoracic lateral hemisection (HX) in rats. The aim of the present study was to evoke action potentials through the spared fibers using noninvasive electromagnetic stimulation (EMS) over intact T2 vertebrae in an attempt to activate synaptic inputs to lumbar motoneurons and thus to enhance plasticity of spinal neural circuits after HX. We found that EMS was able to activate synaptic inputs to lumbar motoneurons and motor-evoked potentials (MEP) in hindlimb muscles in adult anesthetized rats. Amplitude of MEP was attenuated in parallel with the decline of responses recorded from the motoneuron pool after HX. Repetitive EMS (50 min, 0.2 Hz) facilitated the amplitudes of responses elicited by electric stimulation of lateral white matter or dorsal corticospinal tracts in HX rats. Facilitation sustained for at least 1.5 h after termination of EMS. The N-methyl-d-aspartate (NMDA) receptor blocker MK-801, injected intraspinally close to the recording electrode prior to EMS, did not alter these responses but blocked the EMS-induced facilitation, suggesting that activation of NMDA receptors is required to initiate an EMS-evoked increase. When MK-801 was administered after EMS-induced facilitation was established, it induced depression of these elevated responses. Results suggest that repetitive EMS over intact vertebrae could be used as a therapeutic approach to open a window of synaptic plasticity after incomplete midthoracic injuries, i.e., to activate NMDA receptors in the lumbar motoneuron pool at synaptic inputs and to strengthen transmission in damaged spinal cord.

Chondroitinase ABC combined with neurotrophin NT-3 secretion and NR2D expression promotes axonal plasticity and functional recovery in rats with lateral hemisection of the spinal cord.

Elevating spinal levels of neurotrophin NT-3 (NT3) while increasing expression of the NR2D subunit of the NMDA receptor using a HSV viral construct promotes formation of novel multisynaptic projections from lateral white matter (LWM) axons to motoneurons in neonates. However, this treatment is ineffective after postnatal day 10. Because chondroitinase ABC (ChABC) treatment restores plasticity in the adult CNS, we have added ChABC to this treatment and applied the combination to adult rats receiving a left lateral hemisection (Hx) at T8. All hemisected animals initially dragged the ipsilateral hindpaw and displayed abnormal gait. Rats treated with ChABC or NT3/HSV-NR2D recovered partial hindlimb locomotor function, but animals receiving combined therapy displayed the most improved body stability and interlimb coordination [Basso-Beattie-Bresnahan (BBB) locomotor scale and gait analysis]. Electrical stimulation of the left LWM at T6 did not evoke any synaptic response in ipsilateral L5 motoneurons of control hemisected animals, indicating interruption of the white matter. Only animals with the full combination treatment recovered consistent multisynaptic responses in these motoneurons indicating formation of a detour pathway around the Hx. These physiological findings were supported by the observation of increased branching of both cut and intact LWM axons into the gray matter near the injury. ChABC-treated animals displayed more sprouting than control animals and those receiving NT3/HSV-NR2D; animals receiving the combination of all three treatments showed the most sprouting. Our results indicate that therapies aimed at increasing plasticity, promoting axon growth and modulating synaptic function have synergistic effects and promote better functional recovery than if applied individually.