Apoptosis of oligodendrocytes in the central nervous system results in rapid focal demyelination.

OBJECTIVE: Multiple sclerosis (MS) is a demyelinating disease of the central nervous system that presents with variable pathologies that may reflect different disease-causing mechanisms. Existing animal models of MS induce pathology using either local injection of gliotoxins or stimulation of the immune system with myelin-related peptides. In none of these models is the primary cellular target well characterized, and although demyelination is a hallmark pathological feature in MS, it is unclear to what extent this reflects local oligodendrocyte loss. To unambiguously identify the effects of oligodendrocyte death in the absence of inflammatory stimulation, we developed a method for experimentally inducing programmed cell death selectively in mature oligodendrocytes and assessed the effects on demyelination, immunological stimulation, and gliosis. The resulting pathology is discussed relative to observed MS pathologies. METHODS: Oligodendrocyte apoptosis was induced in the adult rat brain using a lentivirus to express experimentally inducible caspase 9 (iCP9) cDNA under transcriptional control of the promoter for myelin basic protein, which is oligodendrocyte-specific. Activation of iCP9 was achieved by distal injection of a small molecule dimerizer into the lateral ventricle resulting in localized, acute oligodendrocyte apoptosis. RESULTS: Induced oligodendrocyte apoptosis resulted in rapid demyelination and robust, localized microglial activation in the absence of peripheral immune cell infiltration. Lesion borders showed layers of preserved and degraded myelin, whereas lesion cores were demyelinated but only partially cleared of myelin debris. This resulted in local proliferation and mobilization of the oligodendrocyte progenitor pool. INTERPRETATION: This approach provides a novel model to understand the pathological changes that follow from localized apoptosis of myelinating oligodendrocytes. It provides the first direct proof that initiation of apoptosis in oligodendrocytes is sufficient to cause rapid demyelination, gliosis, and a microglial response that result in lesions sharing some pathological characteristics with a subset of MS lesions.

Development and deployment of cyclical focal muscle vibration system to improve walking performance in multiple sclerosis.

Vibration, a potent mechanical stimulus for activating muscle spindle primary afferents, may improve gait performance in persons with multiple sclerosis (MS), but has yet to be developed and deployed for multiple leg muscles with application during walking training. This study explored the development of a cyclic focal muscle vibration (FMV) system, and the deployment feasibility to correct MS walking swing phase deficits in order to determine whether this intervention warrants comprehensive study. The system was deployed during twelve, two-hour sessions of walking with cyclic FMV over six weeks. Participants served as their own control. Blood pressure, heart rate, walking speed, kinematics (peak hip, knee and ankle angles during swing), toe clearance, and step length were measured before and after deployment with blood pressure and heart rate monitored during deployment. During system deployment, there were no untoward sensations and physiological changes in blood pressure and heart rate, and volitional improvements were found in walking speed, improved swing phase kinematics, toe clearance and step length. This FMV training system was developed and deployed to improve joint flexion during walking in those with MS, and it demonstrated feasibility and benefits. Further study will determine the most effective vibration frequency and dose, carryover effects, and those most likely to benefit from this intervention.

Walking after incomplete spinal cord injury with an implanted neuromuscular electrical stimulation system and a hinged knee replacement: a single-subject study.

STUDY DESIGN: Single-subject repeated measures study. OBJECTIVES: Neuromuscular electrical stimulation (NMES) can enhance walking for people with partial paralysis from incomplete spinal cord injury (iSCI). This single-subject study documents an individual's experience who both received an experimental implanted NMES system and underwent clinical bilateral hinged total knee arthroplasty (TKA). She walked in the community with knee pain prior to either intervention. Walking performance improved with an implanted NMES system. Knee pain and instability continued to worsen over time and eventually required TKA. This study evaluates the effects of these interventions. SETTING: Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland OH, USA. METHODS: The differential and combined effects of NMES and hinged knee replacement were assessed in terms of walking speed, toe clearance, knee angle, and participant perceptions with and without stimulation assistance both before and after TKA. RESULTS: The combined approach both reduced pain and restored walking ability to levels achieved prior to developing significant knee pain that prevented walking without NMES. There was an interaction effect between NMES and TKA on walking speed. Toe clearance consistently improved with stimulation assistance and TKA prevented significant knee hyperextension. The greatest impact was on endurance. Knee replacement re-enabled long distance walking with the addition of stimulation again more than doubling her maximum walking distance from 214 to 513 m. CONCLUSIONS: These data support further research of combined implantable interventions that may benefit people with iSCI. Furthermore, joint laxity and pain may not necessarily be contraindications to NMES if addressed with conventional clinical treatments.

Oxygen Consumption While Walking With Multijoint Neuromuscular Electrical Stimulation After Stroke.

This case study evaluated the effect of implanted multijoint neuromuscular electrical stimulation gait assistance on oxygen consumption relative to walking without neuromuscular electrical stimulation after stroke. The participant walked slowly with an asymmetric gait pattern after stroke. He completed repeated 6-min walk tests at a self-selected walking speed with and without hip, knee, and ankle stimulation assistance. His walking speed with neuromuscular electrical stimulation more than doubled from 0.28 ± 0.01 m/sec to 0.58 ± 0.04 m/sec, whereas average step length and cadence increased by 0.12 m and 24 steps/min, respectively. As a result, energy cost of walking with neuromuscular electrical stimulation decreased by 0.19 ml O2/kg per meter as compared with walking without stimulation while oxygen consumption increased by 1.1 metabolic equivalent of tasks (3.9 ml O2/kg per minute). These metabolic demands are similar to those reported for stroke survivors capable of walking at equivalent speeds without stimulation, suggesting the increase in oxygen consumption and decreased energy cost result from improved efficiency of faster walking facilitated by neuromuscular electrical stimulation. Although the effect of neuromuscular electrical stimulation on gait economy has implications for community walking within the user's metabolic reserves, this case study's results should be interpreted with caution and the hypothesis that multijoint neuromuscular electrical stimulation improves metabolic efficiency should be tested in a wide population of stroke survivors with varied deficits.

Nutrition management methods effective in increasing weight, survival time and functional status in ALS patients: a systematic review.

Poor prognosis and decreased survival time correlate with the nutritional status of patients with amyotrophic lateral sclerosis (ALS). Various studies were reviewed which assessed weight, body mass index (BMI), survival time and ALS functional rating scale revised (ALSFRS-R) in order to determine the best nutrition management methods for this patient population. A systematic review was conducted using CINAHL, Medline, and PubMed, and various search terms in order to determine the most recent clinical trials and observational studies that have been conducted concerning nutrition and ALS. Four articles met criteria to be included in the review. Data were extracted from these articles and were inputted into the Data Extraction Tool (DET) provided by the Academy of Nutrition and Dietetics (AND). Results showed that nutrition supplementation does promote weight stabilisation or weight gain in individuals with ALS. Given the low risk and low cost associated with intervention, early and aggressive nutrition intervention is recommended. This systematic review shows that there is a lack of high quality evidence regarding the efficacy of any dietary interventions for promoting survival in ALS or slowing disease progression; therefore more research is necessary related to effects of nutrition interventions.

The Role of Toll-Like Receptor 2 and 4 Innate Immunity Pathways in Intracortical Microelectrode-Induced Neuroinflammation.

We have recently demonstrated that partial inhibition of the cluster of differentiation 14 (CD14) innate immunity co-receptor pathway improves the long-term performance of intracortical microelectrodes better than complete inhibition. We hypothesized that partial activation of the CD14 pathway was critical to a neuroprotective response to the injury associated with initial and sustained device implantation. Therefore, here we investigated the role of two innate immunity receptors that closely interact with CD14 in inflammatory activation. We implanted silicon planar non-recording neural probes into knockout mice lacking Toll-like receptor 2 (Tlr2-/-), knockout mice lacking Toll-like receptor 4 (Tlr4-/-), and wildtype (WT) control mice, and evaluated endpoint histology at 2 and 16 weeks after implantation. Tlr4-/- mice exhibited significantly lower BBB permeability at acute and chronic time points, but also demonstrated significantly lower neuronal survival at the chronic time point. Inhibition of the Toll-like receptor 2 (TLR2) pathway had no significant effect compared to control animals. Additionally, when investigating the maturation of the neuroinflammatory response from 2 to 16 weeks, transgenic knockout mice exhibited similar histological trends to WT controls, except that knockout mice did not exhibit changes in microglia and macrophage activation over time. Together, our results indicate that complete genetic removal of Toll-like receptor 4 (TLR4) was detrimental to the integration of intracortical neural probes, while inhibition of TLR2 had no impact within the tests performed in this study. Therefore, approaches focusing on incomplete or acute inhibition of TLR4 may still improve intracortical microelectrode integration and long term recording performance.

Targeting CD14 on blood derived cells improves intracortical microelectrode performance.

Intracortical microelectrodes afford researchers an effective tool to precisely monitor neural spiking activity. Additionally, intracortical microelectrodes have the ability to return function to individuals with paralysis as part of a brain computer interface. Unfortunately, the neural signals recorded by these electrodes degrade over time. Many strategies which target the biological and/or materials mediating failure modes of this decline of function are currently under investigation. The goal of this study is to identify a precise cellular target for future intervention to sustain chronic intracortical microelectrode performance. Previous work from our lab has indicated that the Cluster of Differentiation 14/Toll-like receptor pathway (CD14/TLR) is a viable target to improve chronic laminar, silicon intracortical microelectrode recordings. Here, we use a mouse bone marrow chimera model to selectively knockout CD14, an innate immune receptor, from either brain resident microglia or blood-derived macrophages, in order to understand the most effective targets for future therapeutic options. Using single-unit recordings we demonstrate that inhibiting CD14 from the blood-derived macrophages improves recording quality over the 16 week long study. We conclude that targeting CD14 in blood-derived cells should be part of the strategy to improve the performance of intracortical microelectrodes, and that the daunting task of delivering therapeutics across the blood-brain barrier may not be needed to increase intracortical microelectrode performance.

Inhibition of the cluster of differentiation 14 innate immunity pathway with IAXO-101 improves chronic microelectrode performance.

OBJECTIVE: Neuroinflammatory mechanisms are hypothesized to contribute to intracortical microelectrode failures. The cluster of differentiation 14 (CD14) molecule is an innate immunity receptor involved in the recognition of pathogens and tissue damage to promote inflammation. The goal of the study was to investigate the effect of CD14 inhibition on intracortical microelectrode recording performance and tissue integration. APPROACH: Mice implanted with intracortical microelectrodes in the motor cortex underwent electrophysiological characterization for 16 weeks, followed by endpoint histology. Three conditions were examined: (1) wildtype control mice, (2) knockout mice lacking CD14, and (3) wildtype control mice administered a small molecule inhibitor to CD14 called IAXO-101. MAIN RESULTS: The CD14 knockout mice exhibited acute but not chronic improvements in intracortical microelectrode performance without significant differences in endpoint histology. Mice receiving IAXO-101 exhibited significant improvements in recording performance over the entire 16 week duration without significant differences in endpoint histology. SIGNIFICANCE: Full removal of CD14 is beneficial at acute time ranges, but limited CD14 signaling is beneficial at chronic time ranges. Innate immunity receptor inhibition strategies have the potential to improve long-term intracortical microelectrode performance.

Feasibility of Restoring Walking in Multiple Sclerosis with Multichannel Implanted Electrical Stimulation.

A patient with multiple sclerosis-related gait dysfunction was followed over the course of his disease. Despite aggressive treatment, he developed significant weakness in ankle dorsiflexors and hip and knee flexors and was no longer capable of consistently taking a step on his own. With electrical stimulation of hip and knee flexors and ankle dorsiflexors using implanted electrodes, he was able to consistently walk short distances as far as 30 m, thus significantly improving his Expanded Disability Status Scale score. This case study supports further exploration into the potential benefits of an implanted pulse generator to ameliorate gait dysfunction and improve quality of life for people with multiple sclerosis.

Delivering tertiary centre specialty care to ALS patients via telemedicine: a retrospective cohort analysis.

OBJECTIVE: This study was undertaken to determine if ALS patients evaluated via telemedicine received the same quality of care as patients evaluated by traditional face-to-face encounters. METHODS: A retrospective cohort study design was used. Participants were patients diagnosed with ALS that received multidisciplinary care at the tertiary Cleveland VA ALS Centre between 1 March 2008- and 31 anuary 2015. Participants were not randomised, but chose telemedicine based on preference, disability level or distance from the clinic. Telemedicine in this study consisted of a video conferencing platform enabling remote rather than face-to-face encounters with participants. RESULTS: There was no significant association between receiving quality ALS care and the mode of care. There was a trend for telemedicine patients to utilise home health care less often than those that received clinic care (AOR 0.50; 95% CI 0.16-1.59). There was no significant difference in survival time between the two groups (log-rank test χ2 = 3.62, df = 1, p = 0.05). Patients receiving telemedicine had a higher probability of remaining stable or having <30% decrease in ALSFRS-R over time (log-rank test χ2 = 4.46, df = 1, p = 0.03). There was a significantly lower risk of disease progression for patients receiving telemedicine (HR = 0.39, 95% CI = 0.16-0.93). CONCLUSIONS: Patients managed by telemedicine received the same quality of care and had similar outcomes to those patients seen via traditional face-to-face encounters. Telemedicine is an effective platform for delivering high quality tertiary ALS care.

Low back pain, radiculopathy.

Low back pain is a pervasive problem in the adult population. Most patients with low back pain will not require imaging as spontaneous recovery within 12 weeks is the rule. However, a small percentage of patients with low back pain will have serious underlying pathology requiring more intensive investigation. This chapter delineates the signs and symptoms related to potential serious underlying causes and discusses appropriate imaging modalities that should be utilized in patients with low back pain.

Improving Walking with an Implanted Neuroprosthesis for Hip, Knee, and Ankle Control After Stroke.

OBJECTIVE: The objective of this work was to quantify the effects of a fully implanted pulse generator to activate or augment actions of hip, knee, and ankle muscles after stroke. DESIGN: The subject was a 64-year-old man with left hemiparesis resulting from hemorrhagic stroke 21 months before participation. He received an 8-channel implanted pulse generator and intramuscular stimulating electrodes targeting unilateral hip, knee, and ankle muscles on the paretic side. After implantation, a stimulation pattern was customized to assist with hip, knee, and ankle movement during gait.The subject served as his own concurrent and longitudinal control with and without stimulation. Outcome measures included 10-m walk and 6-minute timed walk to assess gait speed, maximum walk time, and distance to measure endurance, and quantitative motion analysis to evaluate spatial-temporal characteristics. Assessments were repeated under 3 conditions: (1) volitional walking at baseline, (2) volitional walking after training, and (3) walking with stimulation after training. RESULTS: Volitional gait speed improved with training from 0.29 m/s to 0.35 m/s and further increased to 0.72 m/s with stimulation. Most spatial-temporal characteristics improved and represented more symmetrical and dynamic gait. CONCLUSIONS: These data suggest that a multijoint approach to implanted neuroprostheses can provide clinically relevant improvements in gait after stroke. TO CLAIM CME CREDITS: Complete the self-assessment activity and evaluation online at http://www.physiatry.org/JournalCME CME OBJECTIVES:: Upon completion of this article, the reader should be able to do the following: (1) Describe the rationale for evaluating a multijoint implanted neuroprosthesis to improvewalkingafter stroke; (2)Understand the study design and conclusions that can be inferred as a result of the design; and (3) Discuss the statistical significance and clinical relevance of changes between (a) volitional walking at baseline, (b) volitional walking after training, and (c) walking with stimulation after training. LEVEL: Advanced ACCREDITATION:: The Association of Academic Physiatrists is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The Association of Academic Physiatrists designates this activity for a maximum of 1.5 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

The roles of blood-derived macrophages and resident microglia in the neuroinflammatory response to implanted intracortical microelectrodes.

Resident microglia and blood-borne macrophages have both been implicated to play a dominant role in mediating the neuroinflammatory response affecting implanted intracortical microelectrodes. However, the distinction between each cell type has not been demonstrated due to a lack of discriminating cellular markers. Understanding the subtle differences of each cell population in mediating neuroinflammation can aid in determining the appropriate therapeutic approaches to improve microelectrode performance. Therefore, the goal of this study is to characterize the role of infiltrating blood-derived cells, specifically macrophages, in mediating neuroinflammation following intracortical microelectrode implantation. Interestingly, we found no correlation between microglia and neuron populations at the microelectrode-tissue interface. On the other hand, blood-borne macrophages consistently dominated the infiltrating cell population following microelectrode implantation. Most importantly, we found a correlation between increased populations of blood-derived cells (including the total macrophage population) and neuron loss at the microelectrode-tissue interface. Specifically, the total macrophage population was greatest at two and sixteen weeks post implantation, at the same time points when we observed the lowest densities of neuronal survival in closest proximity to the implant. Together, our results suggest a dominant role of infiltrating macrophages, and not resident microglia, in mediating neurodegeneration following microelectrode implantation.

An organotypic spinal cord slice culture model to quantify neurodegeneration.

Activated microglia cells have been implicated in the neurodegenerative process of Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis; however, the precise roles of microglia in disease progression are unclear. Despite these diseases having been described for more than a century, current FDA approved therapeutics are symptomatic in nature with little evidence to supporting a neuroprotective effect. Furthermore, identifying novel therapeutics remains challenging due to undetermined etiology, a variable disease course, and the paucity of validated targets. Here, we describe the use of a novel ex vivo spinal cord culture system that offers the ability to screen potential neuroprotective agents, while maintaining the complexity of the in vivo environment. To this end, we treated spinal cord slice cultures with lipopolysaccharide and quantified neuron viability in culture using measurements of axon length and FluoroJadeC intensity. To simulate a microglia-mediated response to cellular debris, antigens, or implanted materials/devices, we supplemented the culture media with increasing densities of microspheres, facilitating microglia-mediated phagocytosis of the particles, which demonstrated a direct correlation between the phagocytic activities of microglia and neuronal health. To validate our model's capacity to accurately depict neuroprotection, cultures were treated with resveratrol, which demonstrated enhanced neuronal health. Our results successfully demonstrate the use of this model to reproducibly quantify the extent of neurodegeneration through the measurement of axon length and FluoroJadeC intensity, and we suggest this model will allow for accurate, high-throughput screening, which could result in expedited success in translational efficacy of therapeutic agents to clinical trials.

Elevation of osteopontin levels in brain tumor cells reduces burden and promotes survival through the inhibition of cell dispersal.

Osteopontin (OPN) is a pleotrophic molecule that has been associated with multiple disorders of the central nervous system (CNS). Its roles in CNS malignancy are unclear but suggest that higher levels of OPN expression correlate with increased tumor grade and increased migratory capacity of tumor cells. In this study OPN cDNA was cloned into a retroviral vector and used to infect F98 Fischer rat-derived glioma cells and U87 human-derived glioblastoma multiforme (GBM) cells in vitro. Cells expressing high levels of OPN migrated less distance than control cells in vitro. This effect was not RGD mediated, but was reversed in the presence of c-Jun N-terminal kinase (JNK) inhibitor suggesting that JNK1 is an essential component of a negative feedback loop affecting OPN activated signaling cascades. Implantation of tumor cells expressing high levels of OPN into adult Fischer rats and nude rats resulted in morphologically distinct tumors and prolonged host survival relative to controls. We propose that local produced, high level OPN expression limits the malignant character of glioma cells and that the downstream mechanisms involved represent pathways that may have therapeutic value in the treatment of human CNS malignancy.

Relapsing-remitting tumefactive multiple sclerosis.

Tumefactive multiple sclerosis (MS) is a rare form of demyelinating disease. The natural course of the disease has been characterized as presenting with a mass-like demyelinating lesion converting to typical relapsing-remitting disease with future exacerbations. Herein we describe a case of a patient whom over a six-year period developed relapsing-remitting tumefactive MS. The natural course, pathophysiology, prognosis and diagnosis are briefly discussed.