Dissociable Contributions of Precuneus and Cerebellum to Subjective and Objective Neuropathy in HIV.

Neuropathy, typically diagnosed by the presence of either symptoms or signs of peripheral nerve dysfunction, remains a frequently reported complication in the antiretroviral (ART)-treated HIV population. This study was conducted in 109 healthy controls and 57 HIV-infected individuals to investigate CNS regions associated with neuropathy. An index of objective neuropathy was computed based on 4 measures: deep tendon ankle reflex, vibration sense (great toes), position sense (great toes), and 2-point discrimination (feet). Subjective neuropathy (self-report of pain, aching, or burning; pins and needles; or numbness in legs or feet) was also evaluated. Structural MRI data were available for 126/166 cases. The HIV relative to the healthy control group was impaired on all 4 signs of neuropathy. Within the HIV group, an objective neuropathy index of 1 (bilateral impairment on 1 measure) or 2 (bilateral impairment on at least 2/4 measures) was associated with older age and a smaller volume of the cerebellar vermis. Moderate to severe symptoms of neuropathy were associated with more depressive symptoms, reduced quality of life, and a smaller volume of the parietal precuneus. This study is consistent with the recent contention that ART-treated HIV-related neuropathy has a CNS component. Distinguishing subjective symptoms from objective signs of neuropathy allowed for a dissociation between the precuneus, a brain region involved in conscious information processing and the vermis, involved in fine tuning of limb movements. Graphical Abstract In HIV patients, objective signs of neuropathy correlated with smaller cerebellar vermis (red) volumes whereas subjective symptoms of neuropathy were associated with smaller precuneus (blue) volumes.

Targeted neurotechnology restores walking in humans with spinal cord injury.

Spinal cord injury leads to severe locomotor deficits or even complete leg paralysis. Here we introduce targeted spinal cord stimulation neurotechnologies that enabled voluntary control of walking in individuals who had sustained a spinal cord injury more than four years ago and presented with permanent motor deficits or complete paralysis despite extensive rehabilitation. Using an implanted pulse generator with real-time triggering capabilities, we delivered trains of spatially selective stimulation to the lumbosacral spinal cord with timing that coincided with the intended movement. Within one week, this spatiotemporal stimulation had re-established adaptive control of paralysed muscles during overground walking. Locomotor performance improved during rehabilitation. After a few months, participants regained voluntary control over previously paralysed muscles without stimulation and could walk or cycle in ecological settings during spatiotemporal stimulation. These results establish a technological framework for improving neurological recovery and supporting the activities of daily living after spinal cord injury.

A finite element modeling study of peripheral nerve recruitment by percutaneous tibial nerve stimulation in the human lower leg.

Percutaneous tibial nerve stimulation (PTNS) is a clinical therapy for treating overactive bladder (OAB), where an un-insulated stainless steel needle electrode is used to target electrically the tibial nerve (TN) in the lower leg. Recent studies in anesthetized animals not only confirm that bladder-inhibitory reflexes can be evoked by stimulating the TN, but this reflex can also be evoked by stimulating the adjacent saphenous nerve (SAFN). Although cadaver studies indicate that the TN and major SAFN branch(es) overlap at the location of stimulation, the extent to which SAFN branches are co-activated is unknown. In this study, we constructed a finite element model of the human lower leg and applied a numeric axon model (MRG model) to simulate the electrical recruitment of TN and SAFN fibers during PTNS. The model showed that up to 80% of SAFN fibers (located at the level of the needle electrode) can be co-activated when electrical pulses are applied at the TN activation threshold, the standard therapeutic amplitude. Both the location of the inserted electrode and stimulation amplitude were important variables that affected the recruitment of SAFN branches. This study suggests further work is needed to investigate the potential therapeutic effects of SAFN stimulation in OAB patients.

Leg pain location and neurological signs relate to outcomes in primary care patients with low back pain.

BACKGROUND: Low back pain (LBP) patients with related leg pain and signs of nerve root involvement are considered to have a worse prognosis than patients with LBP alone. However, it is unclear whether leg pain location above or below the knee and the presence of neurological signs are important in primary care patients. The objectives of this study were to explore whether the four Quebec Task Force categories (QTFC) based on the location of pain and on neurological signs have different characteristics at the time of care seeking, whether these QTFC are associated with outcome, and if so whether there is an obvious ranking of the four QTFC on the severity of outcomes. METHOD: Adult patients seeking care for LBP in chiropractic or general practice were classified into the four QTFC based on self-reported information and clinical findings. Analyses were performed to test the associations between the QTFC and baseline characteristics as well as the outcomes global perceived effect and activity limitation after 2 weeks, 3 months, and 1 year and also 1-year trajectories of LBP intensity. RESULTS: The study comprised 1271 patients; 947 from chiropractic practice and 324 from general practice. The QTFC at presentation were statistically significantly associated with most of the baseline characteristics, with activity limitation at all follow-up time points, with global perceived effect at 2 weeks but not 3 months and 1 year, and with trajectories of LBP. Severity of outcomes in the QTFC increased from LBP alone, across LBP with leg pain above the knee and below the knee to LBP with nerve root involvement. However, the variation within the categories was considerable. CONCLUSION: The QTFC identify different LBP subgroups at baseline and there is a consistent ranking of the four categories with respect to outcomes. The differences between outcomes appear to be large enough for the QTFC to be useful for clinicians in the communication with patients. However, due to variation of outcomes within each category individuals' outcome cannot be precisely predicted from the QTFC alone. It warrants further investigation to find out if the QTFC can improve existing prediction tools and guide treatment decisions.

Cortical and vestibular stimulation reveal preserved descending motor pathways in individuals with motor-complete spinal cord injury.

OBJECTIVE: To use a combination of electrophysiological techniques to determine the extent of preserved muscle activity below the clinically-defined level of motor-complete spinal cord injury. METHODS: Transcranial magnetic stimulation and vestibular-evoked myogenic potentials were used to investigate whether there was any preserved muscle activity in trunk, hip and leg muscles of 16 individuals with motor-complete spinal cord injury (C4-T12) and 16 able-bodied matched controls. RESULTS: Most individuals (14/16) with motor-complete spinal cord injury were found to have transcranial magnetic stimulation evoked, and/or voluntary evoked muscle activity in muscles innervated below the clinically classified lesion level. In most cases voluntary muscle activation was accompanied by a present transcranial magnetic stimulation response. Furthermore, motor-evoked potentials to transcranial magnetic stimulation could be observed in muscles that could not be voluntarily activated. Vestibular-evoked myogenic potentials responses were also observed in a small number of subjects, indicating the potential preservation of other descending pathways. CONCLUSION: These results highlight the importance of using multiple electrophysiological techniques to assist in determining the potential preservation of muscle activity below the clinically-defined level of injury in individuals with a motor-complete spinal cord injury. These techniques may provide clinicians with more accurate information about the state of various motor pathways, and could offer a method to more accurately target rehabilitation.

Maintenance of cutaneomuscular neuronal excitability after leg-cycling predicts lower limb muscle strength after incomplete spinal cord injury.

OBJECTIVE: Controlled leg-cycling modulates H-reflex activity after spinal cord injury (SCI). Preserved cutaneomuscular reflex activity is also essential for recovery of residual motor function after SCI. Here the effect of a single leg-cycling session was assessed on cutaneomuscular-conditioned H-reflex excitability in relation to residual lower limb muscle function after incomplete SCI (iSCI). METHODS: Modulation of Soleus H-reflex activity was evaluated following ipsilateral plantar electrical stimulation applied at 25-100ms inter-stimulus intervals (ISI's), before and after leg-cycling in ten healthy individuals and nine subjects with iSCI. RESULTS: Leg-cycling in healthy subjects increased cutaneomuscular-conditioned H-reflex excitability between 25 and 75ms ISI (p<0.001), compared to a small loss of excitability at 75ms ISI after iSCI (p<0.05). In addition, change in cutaneomuscular-conditioned H-reflex excitability at 50ms and 75ms ISI in subjects with iSCI after leg-cycling predicted lower ankle joint hypertonia and higher Triceps Surae muscle strength, respectively. CONCLUSION: Leg-cycling modulates cutaneomuscular-conditioned spinal neuronal excitability in healthy subjects and individuals with iSCI, and is related to residual lower limb muscle function. SIGNIFICANCE: Cutaneomuscular-conditioned H reflex modulation could be used as a surrogate biomarker of both central neuroplasticity and lower limb muscle function, and could benchmark lower-limb rehabilitation programs in subjects with iSCI.

Evaluation of the Efficacy and Robustness of a Second Generation Implantable Stimulator in a Patient With Hemiplegia During 20 Years of Functional Electrical Stimulation of the Common Peroneal Nerve.

We evaluated the efficacy and robustness of a second generation implantable stimulator for correcting drop foot (DF) in a patient with left-sided hemiplegia over 20 years of functional electrical stimulation (FES) of the common peroneal nerve (CPN). Dorsal flexion and eversion of the affected foot was partially restored by FES of the superficial region of the CPN innervating mostly the tibialis anterior (TA) and partly peroneus longus (PL) and peroneus brevis (PB) muscles. The reasons for implant failure during the long-term follow-up assessment were analyzed and resolving procedures were identified. The stimulator had an average failure rate of once every three years, due to repetitive mechanical load on the lead wires of its internal and/or external unit, and had to be serviced once per year to replace the heel switch integrated into the shoe sole. FES-associated mechanical trauma to the CPN elicited a thickening of the connective tissue around the CPN and a slightly compromised conduction velocity of the CPN. FES of the CPN, with the second generation implantable stimulator, improved gait parameters of the affected leg during the 20 years period. Long-term, daily FES enables a functional and reliable recruitment of nerve fibers, thus providing a sufficient dorsal flexion and optimal eversion of the affected foot to sustain unassisted, almost normal gait. Therefore, the presented implant is suitable for very long-term FES of the CPN.

Efficacy of QuadroPulse rTMS for improving motor function after spinal cord injury: Three case studies.

CONTEXT/OBJECTIVE: To examine the effects of repetitive QuadroPulse transcranial magnetic stimulation (rTMS(QP)) on hand/leg function after spinal cord injury (SCI). DESIGN: Interventional proof-of-concept study. SETTING: University laboratory. PARTICIPANTS: Three adult subjects with cervical SCI. Interventions Repeated trains of magnetic stimuli were applied to the motor cortical hand/leg area. Several exploratory single-day rTMS(QP) protocols were examined. Ultimately we settled on a protocol using three 5-day trials of (1) rTMS(QP) only; (2) exercise only (targeting hand or leg function); and (3) rTMS(QP) combined with exercise. OUTCOME MEASURES: Hand motor function was assessed by Purdue Pegboard and Complete Minnesota Dexterity tests. Walking function was based on treadmill walking and the Timed Up and Go test. Electromyographic recordings were used for neurophysiological testing of cortical (by single- and double-pulse TMS) and spinal (via tendon taps and electrical nerve stimulation) excitability. RESULTS: Single-day rTMS(QP) application had no clear effect in the 2 subjects whose hand function was targeted, but improved walking speed in the person targeted for walking, accompanied by increased cortical excitability and reduced spinal excitability. All 3 subjects showed functional improvement following the 5-day rTMS(QP) intervention, an effect being even more pronounced after the five-day combined rTMS(QP) + exercise sessions. There were no rTMS(QP)-associated adverse effects. CONCLUSION: Our findings suggest a functional benefit of motor cortical rTMS(QP) after SCI. The effect of rTMS(QP) appears to be augmented when stimulation is accompanied by targeted exercises, warranting expansion of this pilot study to a larger subject population.

Co-activation of saphenous nerve fibers: a potential therapeutic mechanism of percutaneous tibial nerve stimulation?

Percutaneous tibial nerve stimulation (PTNS) is a minimally invasive and effective treatment for overactive bladder (OAB). However, clinical trials show that positive therapeutic outcomes among patients are difficult to predict (failure rate = 35% to 50%). Inconsistencies in the stimulation amplitudes used clinically and those used in preclinical animal studies led us to hypothesize that OAB therapy involves a secondary bladder-inhibitory pathway. In this paper, we implemented and tested a computer model of the human lower leg that investigated the differential activation of the saphenous nerve (SAFN) and tibial nerve (TN) during percutaneous electrical stimulation. Our preliminary findings show that concomitant activation of SAFN branches occurs during PTNS, which suggests the possibility that the SAFN may influence the clinical outcome of treatment.

[Pseudo-radicular referred leg pain]. / Pseudoradikulärer/übertragener Beinschmerz.

Pseudo-radicular leg pain as initially described by Bruegger more than 55 years ago was at that time a genius explanation for so many non-radicular pain syndromes that needed not any kind of surgical intervention but in first line a manual treatment or a treatment by therapeutic local anesthetics. Today we describe this pain as a "referred pain" originating from other anatomic structures that may occur during the development of chronic pain. Nevertheless this pain is found in many patients and it still seems to be a big problem for many physicians and surgeons. Imaging does not help either. The history and the clinical symptoms, the examinations, the chain reactions in the motor system as well as the treatment options from the point of view of manual medicine are described.

Assessment of Neuromuscular Function Using Percutaneous Electrical Nerve Stimulation.

Percutaneous electrical nerve stimulation is a non-invasive method commonly used to evaluate neuromuscular function from brain to muscle (supra-spinal, spinal and peripheral levels). The present protocol describes how this method can be used to stimulate the posterior tibial nerve that activates plantar flexor muscles. Percutaneous electrical nerve stimulation consists of inducing an electrical stimulus to a motor nerve to evoke a muscular response. Direct (M-wave) and/or indirect (H-reflex) electrophysiological responses can be recorded at rest using surface electromyography. Mechanical (twitch torque) responses can be quantified with a force/torque ergometer. M-wave and twitch torque reflect neuromuscular transmission and excitation-contraction coupling, whereas H-reflex provides an index of spinal excitability. EMG activity and mechanical (superimposed twitch) responses can also be recorded during maximal voluntary contractions to evaluate voluntary activation level. Percutaneous nerve stimulation provides an assessment of neuromuscular function in humans, and is highly beneficial especially for studies evaluating neuromuscular plasticity following acute (fatigue) or chronic (training/detraining) exercise.

More gain less pain: balance control learning shifts the activation patterns of leg and neck muscles and increases muscular parsimony.

Athletes such as skaters or surfers maintain their balance on very unstable platforms. Remarkably, the most skilled athletes seem to execute these feats almost effortlessly. However, the dynamics that lead to the acquisition of a defined and efficient postural strategy are incompletely known. To understand the posture reorganization process due to learning and expertise, we trained twelve participants in a demanding balance/posture maintenance task for 4 months and measured their muscular activity before and after a (predictable) disturbance cued by an auditory signal. The balance training determined significant delays in the latency of participants' muscular activity: from largely anticipatory muscular activity (prior to training) to a mixed anticipatory-compensatory control strategy (after training). After training, the onset of activation was delayed for all muscles, and the sequence of activation systematically reflected the muscle position in the body from top to bottom: neck/upper body muscles were recruited first and in an anticipatory fashion, whereas leg muscles were recruited after the disturbance onset, producing compensatory adjustments. The resulting control strategy includes a mixture of anticipatory and compensatory postural adjustments, with a systematic sequence of muscular activation reflecting the different demands of neck and leg muscles. Our results suggest that subjects learned the precise timing of the disturbance onset and used this information to deploy postural adjustments just-in-time and to transfer at least part of the control of posture from anticipatory to less-demanding feedback-based strategies. In turn, this strategy shift increases the cost-efficiency of muscular activity, which is a key signature of skilled performance.

Interaction of transcutaneous spinal stimulation and transcranial magnetic stimulation in human leg muscles.

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

Ultrasound-guided placement of a paddle lead onto peripheral nerves: surgical anatomy and methodology.

OBJECTIVES: Implanted peripheral nerve stimulation is one of the earliest developed methods of neuromodulation for the treatment of chronic neuropathic pain. It is traditionally performed by surgical exposure and implantation of a paddle lead. Ultrasound-guided percutaneous placement of cylindrical leads has been proposed as an alternative. However, those leads are fragile and prone to migration. Minimally invasive paddle lead implantation may improve long-term results while minimizing surgical insult. A feasibility laboratory study was performed. MATERIALS AND METHODS: Ultrasound-guided placements of a narrow paddle lead were performed in the upper and lower extremities of a human cadaver. Ultrasonography was used to record the lead position relative to the target nerves. Dissections were performed, and digital photography was completed. Anatomic images were analyzed. RESULTS: All experiments were successfully accomplished. Although ultrasound localization of the upper extremity nerves was straightforward and clear, all procedural steps were technically easier at the lower extremity. For the latter, fewer attempts were required to maintain the lead in the desired tissue plane. Ultrasound revealed an acoustic shadowing of the underlying nerves in both the short- and long-axis views by the inserted lead. All dissections revealed a parallel to the nerve lead placement with at least four contacts facing the nerve. The lead appeared to be more mechanically stable at the lower extremity. CONCLUSIONS: This anatomic study confirmed technical feasibility of percutaneous placement of a narrow paddle-type lead for the peripheral nerve stimulation that may potentially improve stimulation and reduce migrations.

Nonoperative treatment for lumbar spinal stenosis with neurogenic claudication.

BACKGROUND: Lumbar spinal stenosis with neurogenic claudication is one of the most commonly diagnosed and treated pathological spinal conditions. It frequently afflicts the elderly population. OBJECTIVES: To systematically review the evidence for the effectiveness of nonoperative treatment of lumbar spinal stenosis with neurogenic claudication. SEARCH METHODS: CENTRAL, MEDLINE, CINAHL, and Index to Chiropractic Literature (ICL) databases were searched up to June 2012. SELECTION CRITERIA: Randomized controlled trials published in English, in which at least one arm provided data on nonoperative treatments DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by The Cochrane Collaboration. Risk of bias in each study was independently assessed by two review authors using the 12 criteria recommended by the Cochrane Back Review Group (Furlan 2009). Dichotomous outcomes were expressed as relative risk, continuous outcomes as mean difference or standardized mean difference; uncertainty was expressed with 95% confidence intervals. If possible a meta-analysis was performed, otherwise results were described qualitatively. GRADE was used to assess the quality of the evidence. MAIN RESULTS: From the 8635 citations screened, 56 full-text articles were assessed and 21 trials (1851 participants) were included. There was very low-quality evidence from six trials that calcitonin is no better than placebo or paracetamol, regardless of mode of administration or outcome assessed. From single small trials, there was low-quality evidence for prostaglandins, and very low-quality evidence for gabapentin or methylcobalamin that they improved walking distance. There was very low-quality evidence from a single trial that epidural steroid injections improved pain, function, and quality of life, up to two weeks, compared with home exercise or inpatient physical therapy. There was low-quality evidence from a single trial that exercise is of short-term benefit for leg pain and function compared with no treatment. There was low and very low-quality evidence from six trials that multimodal nonoperative treatment is less effective than indirect or direct surgical decompression with or without fusion. A meta-analysis of two trials comparing direct decompression with or without fusion to multimodal nonoperative care found no significant difference in function at six months (mean difference (MD) -3.66, 95% CI -10.12 to 2.80) and one year (MD -6.18, 95% CI -15.03 to 2.66), but at 24 months a significant difference was found favouring decompression (MD -4.43, 95% CI -7.91 to -0.96). AUTHORS' CONCLUSIONS: Moderate and high-quality evidence for nonoperative treatment is lacking and thus prohibits recommendations for guiding clinical practice. Given the expected exponential rise in the prevalence of lumbar spinal stenosis with neurogenic claudication, large high-quality trials are urgently needed.

Loading enhances the occurrence of startle responses in leg muscles.

INTRODUCTION: The startle reflex is an involuntary reaction to sudden sensory input and consists of a generalized flexion response. Startle responses in distal leg muscles occur more frequently during standing compared to sitting. We hypothesized that sensory input from load receptors modulates the occurrence of startle responses in leg muscles. METHODS: We administered sudden startling auditory stimuli (SAS) to 11 healthy subjects while (1) sitting relaxed, (2) standing relaxed, (3) standing while bearing 60% of their weight on the right leg, (4) standing while bearing 60% of their weight on the left leg, and (5) standing with 30% body weight support ('bilateral unloaded'). The requested weight distribution for each condition was verified using force plates. Electromyography data were collected from both tibialis anterior (TA) and the left sternocleidomastoid muscles. RESULTS: In the TA, startle responses occurred much more frequently during normal standing (26% of trials) compared to both sitting (6% of trials, p<0.01) and bilateral unloading (3% of trials, p<0.01). In the asymmetrical stance conditions, startle responses in the TA were more common in the loaded leg (21% of trials) compared to the unloaded leg (10% of trials, p<0.05). DISCUSSION: The occurrence of startle responses in the leg muscles was strongly influenced by load. Hence, it is likely that information from load receptors influences startle response activity. We suggest that, in a stationary position, startling stimuli result in a descending volley from brainstem circuits, which is gated at the spinal level by afferent input from load receptors.

[Transcutaneous electrical stimulation of the spinal cord: non-invasive tool for activation of locomotor circuitry in human].

A new tool for locomotor circuitry activation in the non-injured human by transcutaneous electrical spinal cord stimulation (tSCS) has been described. We show that continuous tSCS over T11-T12 vertebrae at 5-40 Hz induced involuntary locomotor-like stepping movements in subjects with their legs in a gravity-independent position. The increase of frequency of tSCS from 5 to 30 Hz augmented the amplitude of evoked stepping movements. The duration of cycle period did not depend on frequency of tSCS. During tSCS the hip, knee and ankle joints were involved in the stepping performance. It has been suggested that tSCS activates the locomotor circuitry through the dorsal roots. It appears that tSCS can be used as a non-invasive method in rehabilitation of spinal pathology.

Investigation of the effects of a centrally applied lumbar sustained natural apophyseal glide mobilization on lower limb sympathetic nervous system activity in asymptomatic subjects.

OBJECTIVE: The purpose of this study was to investigate the effects of a manual mobilization technique on indirect measures of sympathetic nervous system activity. METHODS: Forty-five healthy volunteers participated in this randomized, single-blinded, parallel-group 3-arm design (experimental, sham [placebo], and control group), comprising 15 subjects each. For the experimental group, lumbar mobilization involving an active movement, the Mulligan sustained natural apophyseal glide (SNAG), was applied on L4 spinous process by an experienced manual therapist. Sustained natural apophyseal glides were performed in sitting with active flexion (6 times × 3 sets). The sham technique simulated the SNAG without applying any force. In the control group, participants were placed in a static sitting position throughout the experiment. Measures of skin conductance in the lower limbs (L4 dermatome) were recorded to reflect sympathetic nervous system activity in the preintervention, periintervention, and postintervention periods. Differences in percentage change of skin conductance were analyzed with analysis of variance and post hoc tests. RESULTS: Lumbar SNAG produced sympathoexcitation compared with the control group in the intervention period (P = .04). No significant difference was found between SNAG and sham groups, and no statistically significant difference was found between groups in the final rest period. CONCLUSION: The results of this study showed that, in asymptomatic participants, both lumbar SNAG and sham techniques performed on L4/5 intervertebral joint with active flexion induced a sympathoexcitatory response in lower limbs compared with the control group.