Are herbal medicines alone or in combination for diabetic peripheral neuropathy more effective than methylcobalamin alone? A systematic review and meta-analysis.

BACKGROUND AND PURPOSE: In Asian countries, herbal medicines have been used to treat diabetic peripheral neuropathy (DPN) as an adjunctive therapy. This review aims to assess the effectiveness and safety of herbal medicines for the treatment of DPN. METHODS: A literature search was conducted on PubMed, Embase, CENTRAL, Scopus, CINAHL, CNKI, DBPIA, and OASIS for randomized controlled trials that evaluated the effects of herbal medicines on DPN. The oral methylcobalamin administered group was selected as the control. The primary outcome measure was nerve conduction velocity (NCV), and the secondary outcome measure was the total efficacy rate (TER). The methodological quality of the included studies was assessed using the Cochrane risk of bias tool. A meta-analysis was conducted using Review Manager 5.4.1 software. RESULTS: Seventy-two RCTs with a total of 6260 patients were included. The meta-analysis showed that herbal medicine and co-administration of herbal medicine and methylcobalamin (CHM) treatment for DPN significantly increased the sensory nerve conduction velocity (SNCV) and motor nerve conduction velocity (MNCV) of the median and common peroneal nerves than methylcobalamin treatment alone. Herbal medicine and CHM treatment for DPN also significantly improved the TER compared to the control group. Herbal medicine and CHM treatment was found to be relatively safe. CONCLUSION: Our study suggests that herbal medicine and CHM might be more effective than methylcobalamin alone in the management of DPN. Further rigorous studies should be conducted to make more definite conclusions.

The effectiveness of manual therapy on pain, physical function, and nerve conduction studies in carpal tunnel syndrome patients: a systematic review and meta-analysis.

AIM OF THE STUDY: Systematic review and meta-analysis to assess the effectiveness of manual therapy in improving carpal tunnel syndrome (CTS) symptoms, physical function, and nerve conduction studies. METHOD: MEDLINE, Web of Science, SCOPUS, Cochrane Library, TRIP database, and PEDro databases were searched from the inception to September 2021. PICO search strategy was used to identify randomized controlled trials applying manual therapy on patients with CTS. Eligible studies and data extraction were conducted independently by two reviewers. Methodology quality and risk of bias were assessed by PEDro scale. Outcomes assessed were pain intensity, physical function, and nerve conduction studies. RESULTS: Eighty-one potential studies were identified and six studies involving 401 patients were finally included. Pain intensity immediately after treatment showed a pooled standard mean difference (SMD) of - 2.13 with 95% confidence interval (CI) (- 2.39, - 1.86). Physical function with Boston Carpal Tunnel Syndrome Questionnaire (BCTS-Q) showed a pooled SMD of - 1.67 with 95% CI (- 1.92, - 1.43) on symptoms severity, and a SMD of - 0.89 with 95% CI (- 1.08, - 0.70) on functional status. Nerve conduction studies showed a SMD of - 0.19 with 95% CI (- 0.40, - 0.02) on motor conduction and a SMD of - 1.15 with 95% CI (- 1.36, - 0.93) on sensory conduction. CONCLUSIONS: This study highlights the effectiveness of manual therapy techniques based on soft tissue and neurodynamic mobilizations, in isolation, on pain, physical function, and nerve conduction studies in patients with CTS.

Deciphering an AgRP-serotoninergic neural circuit in distinct control of energy metabolism from feeding.

Contrasting to the established role of the hypothalamic agouti-related protein (AgRP) neurons in feeding regulation, the neural circuit and signaling mechanisms by which they control energy expenditure remains unclear. Here, we report that energy expenditure is regulated by a subgroup of AgRP neurons that send non-collateral projections to neurons within the dorsal lateral part of dorsal raphe nucleus (dlDRN) expressing the melanocortin 4 receptor (MC4R), which in turn innervate nearby serotonergic (5-HT) neurons. Genetic manipulations reveal a bi-directional control of energy expenditure by this circuit without affecting food intake. Fiber photometry and electrophysiological results indicate that the thermo-sensing MC4RdlDRN neurons integrate pre-synaptic AgRP signaling, thereby modulating the post-synaptic serotonergic pathway. Specifically, the MC4RdlDRN signaling elicits profound, bi-directional, regulation of body weight mainly through sympathetic outflow that reprograms mitochondrial bioenergetics within brown and beige fat while feeding remains intact. Together, we suggest that this AgRP neural circuit plays a unique role in persistent control of energy expenditure and body weight, hinting next-generation therapeutic approaches for obesity and metabolic disorders.

Experiment for teaching virtual cathode in nerve conduction studies.

INTRODUCTION/AIMS: The virtual cathode (VC) is a site near the anode where the nerve can be stimulated. Costimulation of neighboring nerves via the VC can affect recording and interpretation of responses. Hence, it is important to teach trainees the concept of the VC. The VC has been demonstrated previously with subtle changes in response latency, amplitude, and shape. Herein we describe an experiment that simply demonstrates a VC with its effects recognizable by gross changes in waveforms. METHODS: Compound muscle action potentials of the abductor pollicis brevis were recorded using various placements of the cathode and anode at different stimulus intensity levels. Studies were performed in nine healthy subjects. RESULTS: Three patterns were observed that demonstrated no stimulation, partial stimulation, and complete nerve stimulation by the VC. Partial stimulation yielded responses with long duration and low amplitude. Response patterns also depended on stimulus strength and proximity of the nerve from the skin surface. DISCUSSION: This experiment demonstrates that nerve stimulation can occur near the anode when high-intensity stimulus is used. It also illustrates collision of action potentials. This exercise can help trainees understand potential pitfalls in nerve conduction studies, especially at very proximal stimulation sites or when high stimulus intensity is used.

Diabetic Neuropathy: a Critical, Narrative Review of Published Data from 2019.

PURPOSE OF REVIEW: This manuscript is a systematic, narrative review that compiles and describes all data available from 2019 related to epidemiologic, diagnostic, and therapeutic advances in diabetic neuropathy (DN). RECENT FINDINGS: Epidemiology of DN is discussed. Diagnostic modalities include predictive models, electrodiagnostics, imaging, and biomarkers. A majority of studies on the treatment of diabetic peripheral neuropathy (DPN) involve pharmacotherapy, but complementary and alternative medicine, exercise, modalities, psychological, interventional, and surgical options are also explored. DN is a highly prevalent and debilitating consequence of diabetes that can present challenges to the clinician as the assessment is largely subjective with different phenotypic presentations among patients. Treatment of DN is largely symptomatic as the pathogenesis of DN is not fully understood and is likely multifactorial. It is evident from the broad range of treatments that too often provide unsatisfactory relief that there is no consensus about a single most effective treatment for DN, and monotherapy rarely proves to be successful.

Electrophysiological and Clinical Improvement in Non-Invasive Treatment of Carpal Tunnel Syndrome.

BACKGROUND AND OBJECTIVE: Carpal tunnel syndrome (CTS) is the most common form of nerve entrapment. Clinically, various signs and symptoms compare due to overexposure to mechanical vibrations transmitted to the wrist bones and cartilage, resulting in compression of the sensory and motor nerve fibers of the median nerve. Early symptoms include nocturnal paresthesia and electromyography reveals reduced sensory nerve conduction velocity. Aim of this study was to evaluate the efficacy of a dietary integrator composed of acetyl-L-carnitine, α-lipoic acid, quercetin, bromelain, pantothenic acid, C and B1 and B2 and B6 and B12 vitamins in patients with early (minimal) carpal tunnel syndrome. METHODS: 36 patients (28 female and 8 male) with early CTS characterized by sensory nerve demyelination and inflammation of the transverse carpal ligament. Patients were divided into two groups, group A (18 patients received physical therapy) and group B (18 patients received physical therapy and an oral integrator). Clinical (sleep quality questionnaire to measure severity of paresthesia) and neurophysiological assessment (Sensory Nerve Conduction Velocity) performed at baseline, and then at 30 and 60 days after treatment. RESULTS: Sleep quality and Sensory Nerve Conduction Velocity data analysis show improvement in both groups at 30 and 60 days, with statistical difference between them in both time of analysis. CONCLUSION: In the early CTS, with sensory fibers damage, use of dietary integrator, such as Micronil Dol®, composed of acetyl-L-carnitine, α-lipoic acid, quercetin, bromelain, pantothenic acid, C and B1 and B2 and B6 and B12 vitamins can be effective in quick recovery of median nerve sensory.

Effects of Diacutaneous Fibrolysis on Mechanosensitivity, Disability, and Nerve Conduction Studies in Mild to Moderate Carpal Tunnel Syndrome: Secondary Analysis of a Randomized Controlled Trial.

OBJECTIVE: People diagnosed with carpal tunnel syndrome (CTS) have fibrosis between the soft, connective, and neural tissues that could worsen the compression of the median nerve. The diacutaneous fibrolysis (DF) technique may release tissue adhesions and increase the mobility of connective tissues. The purpose of this study was to compare the outcomes of DF in people with mild to moderate CTS on mechanosensitivity, disability, and nerve conduction studies. METHODS: This was a secondary analysis of a double-blinded, randomized, placebo-controlled trial. Patients were recruited between April and September 2016 from the Department of Neurophysiology at the Hospital Miguel Servet, Zaragoza, Spain. Thirty-nine people (52 wrists) diagnosed with mild to moderate CTS were included. Participants were randomly assigned to either the DF group (n = 26) or the sham group (n = 26). Both groups received 5 therapy sessions, 2 sessions per week. Mechanosensitivity with the Upper Limb Neurodynamic Test 1, symptom severity and functional status with the Boston Carpal Tunnel Questionnaire, and median nerve sensory conduction velocity with nerve conduction studies were the outcomes measured. Assessments were recorded at baseline and after the intervention. RESULTS: The DF group showed significant improvements in the following: mechanosensitivity, with 28.46 degrees of elbow extension range of motion (95% CI = 19.2-37.7); an increase of 1.0 point (95% CI = 0.7-1.4) for the Boston Carpal Tunnel Questionnaire symptom severity and functional status score; and sensory conduction velocity of median nerve, which improved to 5.8 m/s (95% CI = 2.5-9.2). CONCLUSION: Participants with mild to moderate CTS experienced improvements in symptom severity, functional status, mechanosensitivity, and nerve conduction studies after 5 sessions of DF. IMPACT: This study provides evidence of an approach based on soft and connective tissues around the median nerve in patients with CTS.

Moxibustion for the treatment of diabetic peripheral neuropathy: A systematic review and meta-analysis following PRISMA guidelines.

BACKGROUND: At present, the effect of western-medicine (WM) therapy to treat diabetic peripheral neuropathy (DPN) is limited. Moxibustion is a representative external treatment in traditional Chinese medicine that has been beneficial to DPN. We aim to systematically assess the efficacy and safety of moxibustion in treating DPN, following PRISMA guidelines. METHODS: Eight electronic databases were searched to acquire information on eligible trials published from inception to June 1, 2019. We included randomized controlled trials (RCTs) applying moxibustion therapy with a minimum of 14-days treatment duration for DPN patients compared with placebo, no intervention, or conventional WM interventions. The primary outcomes in our study include the sensory-nerve conduction velocity (SNCV) and motor-nerve conduction velocity (MNCV). We used the Cochrane Collaboration Risk of Bias tool to assess the methodological quality of eligible RCTs. Statistical analyses were conducted using Review Manager 5.3. Risk ratios (RR) and mean differences (MD) were calculated with a 95% confidence interval (CI). The χ test was applied to assess the heterogeneity. RESULTS: In total, 11 RCTs were included that involved 927 DPN patients. Compared with the control group, there was an increase in median MNCV (MD = 6.26, 95% CI 2.64-9.89, Z = 3.39, P = .0007) and peroneal MNCV (MD = 6.45, 95% CI 5.30-7.61, P < .00001). There was also an increase in median SNCV (MD = 6.64, 95% CI 3.25-10.03, P = .0001) and peroneal SNCV (MD = 3. 57, 95% CI 2.06-5.09, Z = 4.63, P < .00001) in the treatment groups. The treatment groups receiving moxibustion therapy indicated a more significant improvement in total effectiveness rate (RR = 0.25, 95% CI 0.18-0.37, Z = 7.16, P < .00001). Toronto Clinical Scoring System indicated a significant decrease in the treatment groups (MD = -2.12, 95% CI -2.82 to 1.43, P < .00001). Only 1 study reported that treatment groups experienced no adverse reactions. The other 10 studies did not mention adverse events. CONCLUSIONS: Moxibustion therapy may be an effective and safe option for DPN patients but needs to be verified in further rigorous studies.

Effects of a Single Myofascial Induction Session on Neural Mechanosensitivity in Breast Cancer Survivors: A Secondary Analysis of a Crossover Study.

OBJECTIVES: The purpose of this study was to investigate the short-term effects of myofascial induction on mechanosensitivity of upper limb nerves. METHODS: In this secondary analysis of a randomized, single-blind, placebo-controlled crossover study, 21 breast cancer survivors with stage I-IIIA cancer were randomly allocated to an experimental group (30 minutes of myofascial induction session) or placebo control group (unplugged pulsed 30 minutes of shortwave therapy), with a 4-week washout period between sessions that occurred in a physical therapy laboratory in the Health Science Faculty (University of Granada, Spain). Range of motion (universal goniometry), structural differentiation, symptoms (yes/no), and pressure pain thresholds (electronic algometry) were assessed during neurodynamic tests and attitude toward massage scale as covariate. RESULTS: An analysis of covariance revealed significant time × group interactions for range of motion in affected upper limb nerves (median, P < .001; radial, P = .036; ulnar, P = .002), but not for nonaffected upper limb nerves (median, P = .083; radial, P = .072; ulnar, P = .796). A χ2 or Fisher exact test, as appropriate, also revealed a significant difference (P = .044) in sensitivity for the affected upper limb ulnar nerve in the experimental group, whereas the rest of the assessed nerves (affected and nonaffected upper limb nerves) showed no significant changes in either the experimental or control groups (P > .05). An analysis of covariance revealed no significant interactions on pressure pain thresholds over the nerves for affected (all P > .05) and nonaffected (all P > .05) upper limb nerves. CONCLUSION: A single myofascial induction session may partially improve mechanosensitivity of median, radial, and ulnar nerves and yield positive effects on symptom mechanosensitivity, especially regarding the ulnar nerve in breast cancer survivors.

Effective self-stretching of carpal ligament for the treatment of carpal tunnel syndrome: A double-blinded randomized controlled study.

INTRODUCTION: Carpal tunnel syndrome (CTS) is the most common nerve entrapment syndrome worldwide. There are limited studies on the effectiveness of carpal ligament stretching on symptomatic and electrophysiologic outcomes. PURPOSE OF THE STUDY: The purpose of this study was to evaluate the effect of self-myofascial stretching of the carpal ligament on symptom outcomes and nerve conduction findings in persons with CTS. STUDY DESIGN: This is a prospective, double-blinded, randomized, placebo-controlled trial. METHODS: Eighty-three participants diagnosed with median mononeuropathy across the wrist by nerve conduction study were randomized 1:1 to sham treatment or self-carpal ligament stretching. Participants were instructed to perform the self-treatment four times a day for six weeks. Seventeen participants in the sham treatment group and 19 participants in the carpal ligament stretching group completed the study. Pre- and post-treatment outcome measures included subjective complaints, strength, nerve conduction findings, and functional scores. RESULTS: Groups were balanced on age, sex, hand dominance, symptom duration, length of treatment, presence of nocturnal symptoms, and compliance with treatment. Even though the ANOVA analyses were inconclusive about group differences, explorative post hoc analyses revealed significant improvements in numbness (P = .011, Cohen's d = .53), tingling (P = .007, Cohen's d = .60), pinch strength (P = .007, Cohen's d = -.58), and symptom severity scale (P = .007, Cohen's d = .69) for the treatment group only. CONCLUSIONS: The myofascial stretching of the carpal ligament showed statistically significant symptom improvement in persons with CTS. Larger comparative studies that include other modalities such as splinting should be performed to confirm the effectiveness of this treatment option.

Comparisons of electrophysiological and clinical findings between young and elderly patients with Carpal Tunnel Syndrome.

BACKGROUND: Few studies have been published on differences between young and old patients with Carpal Tunnel Syndrome regarding clinical and electrophysiological findings. We compared the findings in participants of two age ranges. METHODS: For one year from August 2016, we performed a two-group cross-sectional study in an outpatient clinic of physical medicine and rehabilitation at a University Hospital. Two samples of young and old women with a diagnosis of the syndrome without known risk factors affecting electrophysiological findings were selected. We measured sensory and motor amplitudes and latencies, the conduction velocity of the median nerve, severity, and recurrence of the manifestations, weakness, atrophy, and severity of the syndrome. RESULTS: We had two groups of 24 young (<35 years) and 24 old (>65 years) patients with CTS. Severity of symptoms was higher in young participants [Mean (SD) 3.0(0.6) vs. 2.0(0.8), P<0.001]. Muscular weakness was not different [young 2.6(0.88) vs. old 1.9(1.6), P=0.541]. Five young and nine old participants showed thenar wasting (P=0.104). The severity of CTS was similar (P=0.129). For the group young patients, mean sensory amplitude was higher [14.07(10.98) vs. 7.58(5.08), P=0.012], while mean latency was lower [3.86(0.57) vs. 5.15(1.17), P<0.001]. In motor studies, mean latency was more prolonged in the group old patients [3.86(0.57) vs. 5.15(1.17), P<0.001]. CONCLUSION: Clinical symptoms are more severe among young people, while the pathophysiological process is more intense in the elderly. Patients should not be clinically judged merely by subjective manifestations. Both diagnostic workup and treatment should be designed holistically with all the evidence taken into consideration.

Impact of electrodiagnostic (EMG/NCS) tests on clinical decision-making and patient perceived benefit in the outpatient physical therapy practice.

BACKGROUND: Utilizing Electromyography and Nerve Conduction Study (EMG/NCS) tests, when indicated, may have implications for efficient patient management and assist in more efficient referral to appropriate providers or specialists. OBJECTIVE: To investigate the impact of Electromyography and Nerve Conduction Studies (EMG/NCS) on clinical decision-making and patient perspectives within PT practice settings. METHODS: 462 patients, who were candidates for diagnostic testing (EMG/NCS) were included in this outcome study and questionnaire-based survey design. Pre-test diagnosis was compared to post-test diagnosis. Post-test, patients were asked to rate their perceived benefit of the testing. RESULTS: Management was changed in 60.61% of patients post EMG/NCS testing (p < 0.0001). The diagnosis was changed post-EMG/NCS test in 39% of the patients with a change in management, which is greater than expected (p < 0.0004). There was no effect of gender or age (p > 0.05) on change in treatment (tx) or diagnosis (dx). 89.8% of patients agreed, or strongly agreed, that they were better able to understand their condition; 92.4% strongly agreed, or agreed, that they were reassured about their condition; 89.1% strongly agreed, or agreed, that they were better able to manage their condition and 92% reported very high, or high, value perceived from the EMG/NCS test administered. CONCLUSION: This study demonstrates that EMG/NCS testing appears to have a significant impact on clinical decision-making, and higher scores on the patient perceived benefit.

Postsurgical Electrical Stimulation Enhances Recovery Following Surgery for Severe Cubital Tunnel Syndrome: A Double-Blind Randomized Controlled Trial.

BACKGROUND: Patients with severe cubital tunnel syndrome often have poor functional recovery with conventional surgical treatment. Postsurgical electrical stimulation (PES) has been shown to enhance axonal regeneration in animal and human studies. OBJECTIVE: To determine if PES following surgery for severe cubital tunnel syndrome would result in better outcomes compared to surgery alone. METHODS: Patients with severe cubital tunnel syndrome in this randomized, double-blind, placebo-controlled trial were randomized in a 1:2 ratio to the control or stimulation groups. Control patients received cubital tunnel surgery and sham stimulation, whereas patients in the stimulation group received 1-h of 20 Hz PES following surgery. Patients were assessed by a blinded evaluator annually for 3 yr. The primary outcome was motor unit number estimation (MUNE) and secondary outcomes were grip and key pinch strength and McGowan grade and compound muscle action potential. RESULTS: A total of 31 patients were enrolled: 11 received surgery alone and 20 received surgery and PES. Three years following surgery, MUNE was significantly higher in the PES group (176 ± 23, mean + SE) compared to controls (88 ± 11, P < .05). The mean gain in key pinch strength in the PES group was almost 3 times greater than in the controls (P < .05). Similarly, other functional and physiological outcomes showed significantly greater improvements in the PES group. CONCLUSION: PES enhanced muscle reinnervation and functional recovery following surgery for severe cubital tunnel syndrome. It may be a clinically useful adjunct to surgery for severe ulnar neuropathy, in which functional recovery with conventional treatment is often suboptimal.

Resting-state functional connectivity modulates the BOLD activation induced by nucleus accumbens stimulation in the swine brain.

INTRODUCTION: While the clinical efficacy of deep brain stimulation (DBS) the treatment of motor-related symptoms is well established, the mechanism of action of the resulting cognitive and behavioral effects has been elusive. METHODS: By combining functional magnetic resonance imaging (fMRI) and DBS, we investigated the pattern of blood-oxygenation-level-dependent (BOLD) signal changes induced by stimulating the nucleus accumbens in a large animal model. RESULTS: We found that diffused BOLD activation across multiple functional networks, including the prefrontal, limbic, and thalamic regions during the stimulation, resulted in a significant change in inter-regional functional connectivity. More importantly, the magnitude of the modulation was closely related to the strength of the inter-regional resting-state functional connectivity. CONCLUSIONS: Nucleus accumbens stimulation affects the functional activity in networks that underlie cognition and behavior. Our study provides an insight into the nature of the functional connectivity, which mediates activation effect via brain networks.

Volume conduction, waveform analysis, and near- and far-field potentials.

Waveform analysis plays an important role in the assessment of nerve and muscle action potentials. A sequence of potential changes arises as two sufficiently close wave fronts, leading and trailing dipoles, travel in the volume conductor from left to right. This results in a positive-negative-positive triphasic wave as depolarization and repolarization approach, reach, and finally pass beyond the point of the recording electrode. Physiologic temporal dispersion can reduce the area of a short-duration sensory potential by phase cancellation. Pathologic temporal dispersion, which can reduce the size of muscle action potential, may conversely increase the size of a sensory response by countering the physiologic phase cancellation. The near-field potential relates to the propagating signal recorded when the impulse passes under the pickup electrodes, whereas the far-field potential implies either a distant nonpropagating signal or a stationary peak generated by a propagating signal when it crosses a volume conductor junction located far from the recording site. The second type of far-field signal, or junctional potential, helps detect a voltage source generated at a distance before the signal reaches the pickup electrodes. A consensus has emerged that the volume entered becomes initially positive compared with the volume departed when the generator approaches the boundary of a volume conductor followed by a negative rebound.

Electrical safety.

Since the purpose of clinical neurophysiology testing is to record the electrical activity of the nervous system, and often to electrically stimulate the peripheral or central nervous system (for evoked potentials, nerve conduction studies, etc.), these tests by their very nature demand an excellent electrical connection to the patient. This direct electrical connection by definition puts the patient at increased risk of electrical shock. When patients suffer from other nonneurological disorders that also require equipment to be attached to or inserted into their body, the additional and more direct electrical pathways to the heart make them even more vulnerable, especially when undergoing monitoring in the operating room or intensive care unit. Although we depend on the hospital's construction and utilities to follow appropriate regulations (the National Electrical Code in the United States) and on the vendors to sell only safe equipment (approved by the Food and Drug Administration in the United States), there may exist combinations of equipment and connections that put the patient at risk of injurious or fatal electrical shock. Regular testing and safe practices, informed by a scientific understanding of the risks, are the responsibilities of the healthcare providers in order to protect the patient from harm from electricity.

Transcutaneous high-frequency alternating current for rapid reversible muscle force reduction below pain threshold.

OBJECTIVE: The development of non-invasive, quickly reversible techniques for controlling undesired muscle force production (e.g. spasticity) could expand rehabilitation approaches in those with pathology by increasing the type and intensity of exercises that can be performed. High-frequency alternating current (HFAC) has been previously established as a viable method for blocking neural conduction in peripheral nerves. However, clinical application of HFAC for nerve conduction block is limited due to the invasiveness of surgical procedures and the painful onset response. This study aimed to examine the use of transcutaneous HFAC (tHFAC) at various stimulation frequencies to address these shortfalls. APPROACH: Ten individuals participated in the study. Surface electrodes were utilized to apply tHFAC (0.5-12 kHz) to the median and ulnar nerves. Individual pain threshold was determined by gradual increase of stimulation amplitude. Subjects then performed a force-matching task by producing grip forces up to the maximal voluntary contraction level with and without application of tHFAC below the pain threshold. MAIN RESULTS: Pain threshold current amplitude increased linearly with stimulation frequency. Statistical analysis showed that both stimulation frequency and charge injected per phase had significant effects (p  < 0.05) on grip force reduction. At the group level, application of tHFAC below pain threshold reduced grip force by a maximum of 40.7% ± 8.1%. Baseline grip force trials interspersed between tHFAC trials showed consistent grip force, indicating that fatigue was not a factor in force reduction. SIGNIFICANCE: Our results demonstrate the effectiveness of tHFAC at reducing muscle force when applied below the pain threshold, suggesting its potential clinical viability. Future studies are necessary to further elucidate the mechanism of force reduction before clinical application.

Biomarker Identification, Safety, and Efficacy of High-Dose Antioxidants for Adrenomyeloneuropathy: a Phase II Pilot Study.

X-Adrenoleukodystrophy (X-ALD) and its adult-onset, most prevalent variant adrenomyeloneuropathy (AMN) are caused by mutations in the peroxisomal transporter of the very long-chain fatty acid ABCD1. AMN patients classically present spastic paraparesis that can progress over decades, and a satisfactory treatment is currently lacking. Oxidative stress is an early culprit in X-ALD pathogenesis. A combination of antioxidants halts the clinical progression and axonal damage in a murine model of AMN, providing a strong rationale for clinical translation. In this phase II pilot, open-label study, 13 subjects with AMN were administered a high dose of α-tocopherol, N-acetylcysteine, and α-lipoic acid in combination. The primary outcome was the validation of a set of biomarkers for monitoring the biological effects of this and future treatments. Functional clinical scales, the 6-minute walk test (6MWT), electrophysiological studies, and cerebral MRI served as secondary outcomes. Most biomarkers of oxidative damage and inflammation were normalized upon treatment, indicating an interlinked redox and inflammatory homeostasis. Two of the inflammatory markers, MCP1 and 15-HETE, were predictive of the response to treatment. We also observed a significant decrease in central motor conduction time, together with an improvement or stabilization of the 6MWT in 8/10 subjects. This study provides a series of biomarkers that are useful to monitor redox and pro-inflammatory target engagement in future trials, together with candidate biomarkers that may serve for patient stratification and disease progression, which merit replication in future clinical trials. Moreover, the clinical results suggest a positive signal for extending these studies to phase III randomized, placebo-controlled, longer-term trials with the actual identified dose. ClinicalTrials.gov Identifier: NCT01495260.