Effects of Anodal Transcranial Direct Current Stimulation With Overground Gait Training on Lower Limb Performance in Individuals With Incomplete Spinal Cord Injury.

OBJECTIVE: To determine the effects of anodal transcranial direct current stimulation (tDCS) combined with overground gait training on gait performance, dynamic balance, sit-to-stand performance, and quality of life in individuals with incomplete spinal cord injuries (iSCI). DESIGN: Double-blind sham-controlled trial with a matched-pair design. SETTING: Sirindhorn National Medical Rehabilitation Institute, Thailand. PARTICIPANTS: Individuals with iSCI (n=34) were allocated to the anodal or sham groups. INTERVENTION: Anodal tDCS was administered over the M1 lower-limb motor area at an intensity of 2 mA for 20 min in the anodal group, while the sham group received a 30-s stimulation. Both groups received 40 min of overground gait training after tDCS for 5 consecutive daily sessions. MAIN OUTCOME MEASURES: The 10-meter walk test (10MWT) was the primary outcome, while spatiotemporal gait parameters, the timed Up and Go test, Five-Time Sit-to-Stand Test, and World Health Organization Quality of Life-BREF were secondary outcomes. Outcomes were assessed at baseline, post-intervention, and at 1-month (1M) and 2-month (2M) follow-ups. RESULT: Improvements in walking speed measured using the 10MWT were observed in both groups. However, the anodal group showed a greater improvement than the sham group. For fast speed, the mean between-group differences were 0.10 m/s, 95% CI (0.02 to 0.17) (post-intervention), 0.11 m/s, (0.03 to 0.19) (1M), and 0.11 m/s, (0.03 to 0.20) (2M), while for self-selected speed, the median differences were 0.10 m/s, 95% CI (0.06 to 0.14) (post-intervention) and 0.09 m/s, (0.01 to 0.19) (2M). The anodal group also had a greater stride length difference post-intervention (median difference: 0.07 m, 95% CI (0.01 to 0.14)). No significant between-group differences were found for other outcomes. CONCLUSION: Five-session of anodal tDCS with gait training slightly improved walking speed, sustained for 2 months post-intervention. However, effect on spatiotemporal gait parameters was limited and dynamic balance, functional tasks (ie, sit-to-stand), and quality of life were unaffected compared with overground gait training.

Non-linear dose response effect of cathodal transcranial direct current stimulation on muscle strength in young healthy adults: a randomized controlled study.

BACKGROUND: Transcranial direct current stimulation (tDCS) is a technique that modulates brain excitability in humans. Increasing the stimulation intensity or duration within certain limits could enhance tDCS efficacy with a polarity-dependent effect; anodal stimulation increases cortical excitability, whereas cathodal stimulation decreases excitability. However, recent studies have reported a non-linear effect of cathodal tDCS on neuronal excitability in humans, and there is no conclusive result regarding the effect of cathodal tDCS on muscle performance. METHODS: Our study aimed to investigate the immediate effects of different intensities (i.e., 1, 1.5, and 2 mA and sham tDCS) of cathodal tDCS on muscle strength in healthy participants. All participants [mean age 23.17 (3.90) years] were recruited and randomly allocated into four groups (1, 1.5, and 2 mA cathodal tDCS and sham tDCS). Muscle strength in bilateral upper and lower extremities was measured before and immediately after tDCS using a handheld dynamometer. RESULTS: Our results showed that cathodal tDCS at 1 and 1.5 mA reduced muscle strength bilaterally in upper and lower extremity muscles, whereas stimulation at 2 mA tended to increase muscle strength on the dominant limb. CONCLUSION: These findings support the non-linear effects of cathodal tDCS on muscle strength, which should be considered for the clinical use of tDCS in motor rehabilitation. TRIAL REGISTRATION: NCT04672122, date of first registration 17/12/2020.

Effects of Different Montages of Transcranial Direct Current Stimulation on Haemodynamic Responses and Motor Performance in Acute Stroke: A Randomized Controlled Trial.

OBJECTIVE: Transcranial direct current stimulation (tDCS) has shown positive results in neurorehabilitation. However, there is limited evidence on its use in acute stroke, and unclear evidence regarding the best tDCS montage (anodal-, cathodal-, or dualtDCS) for stroke recovery. This study investigated the effects of these montages combined with physical therapy on haemodynamic response and motor performance. METHODS: Eighty-two eligible acute stroke participants were allocated randomly into anodal, cathodal, dual, and sham groups. They received 5 consecutive sessions of tDCS combined with physical therapy for 5 days. Cerebral mean blood flow velocity (MFV) and motor outcomes were assessed pre and post-intervention and at a 1-month follow-up. RESULTS: None of the groups showed significant changes in the MFV in the lesioned or non-lesioned hemispheres immediately post-intervention or at a 1-month follow-up. For motor performance, all outcomes improved over time for all groups; between-group comparisons showed that the dual-tDCS group had significantly greater improvement than the other groups for most of the lower-limb performance measures. All 5-day tDCS montages were safe. CONCLUSION: MFV was not modulated following active or sham groups. However, dual-tDCS was more efficient in improving motor performance than other groups, especially for lower-limb performance, with after-effects lasting at least 1 month.

Five-Session Dual-Transcranial Direct Current Stimulation With Task-Specific Training Does Not Improve Gait and Lower Limb Performance Over Training Alone in Subacute Stroke: A Pilot Randomized Controlled Trial.

OBJECTIVE: To determine the effect of five-session dual-transcranial direct current stimulation (dual-tDCS) combined with task-specific training on gait and lower limb motor performance in individuals with subacute stroke. MATERIALS AND METHODS: Twenty-five participants who had a stroke in the subacute phase with mild motor impairment were recruited, randomized, and allocated into two groups. The active group (n = 13) received dual-tDCS with anodal over the lesioned hemisphere M1 and cathodal over the nonlesioned hemisphere, at 2 mA for 20 min before training for five consecutive days, while the sham group (n = 12) received sham mode before training. Gait speed as a primary outcome, temporospatial gait variables, lower-limb functional tasks (sit-to-stand and walking mobility), and muscle strength as secondary outcomes were collected at preintervention and postintervention (day 5), one-week follow-up, and one-month follow-up. RESULTS: The primary outcome and most of the secondary outcomes were improved in both groups, with no significant difference between the two groups, and most of the results indicated small to moderate effect sizes of active tDCS compared to sham tDCS. CONCLUSION: The combined intervention showed no benefit over training alone in improving gait variables and lower-limb performance. However, some performances were saturated at some point, as moderate to high function participants were recruited in the present study. Future studies should consider recruiting participants with more varied motor impairment levels and may need to determine the optimal stimulation protocols and parameters to improve gait and lower-limb performance.

Effects of cathodal transcranial direct current stimulation on inhibitory and attention control in children and adolescents with attention-deficit hyperactivity disorder: A pilot randomized sham-controlled crossover study.

The pathophysiological of attention-deficit hyperactivity disorder (ADHD) includes hypoactivation of the dorso-lateral prefrontal cortex (DLPFC). Most studies have used anodal (excitatory) transcranial direct current stimulation (tDCS) to improve ADHD symptoms, however, a meta-analysis showed limited effect on improving inhibition, and no evidence of attention improvement. We thus present a pilot protocol for investigating the effect of other montage i.e. cathodal (inhibitory) tDCS on neurophysiological and behavioral measures in ADHD. Eleven participants underwent active (1.5 mA, 20 min) and sham cathodal tDCS over the left DLPFC for 5 consecutive days at a 1-month interval. Quantitative electroencephalography was recorded in a resting state with the eyes opened and closed during visual go/no-go and auditory continuous performance tasks at baseline, after five sessions, and at 1-week and 1-month follow-ups. Correct responses and omission errors were recorded. After five active sessions, alpha power increased in the right frontal area when the eyes were opened, and delta power in the left frontal area and omission errors decreased during go/no-go tasks, with no differences at follow-ups. The results revealed improvements in inhibitory control, but not for attention. No aftereffects were observed in either outcomes. However, the changes found in both hemispheres would probably support the hypothesis that cathodal stimulation over the left DLPFC may increase the activity of the right DLPFC via transcallosal inhibition. Results of this pilot trial would help to design and implement a full-scale randomized control trials for further ADHD research. This study was registered on ClinicalTrials.gov (NCT03955692).

A randomized sham-controlled trial on the effects of dual-tDCS "during" physical therapy on lower limb performance in sub-acute stroke and a comparison to the previous study using a "before" stimulation protocol.

BACKGROUND: Dual-transcranial direct current stimulation (tDCS) has been used to rebalance the cortical excitability of both hemispheres following unilateral-stroke. Our previous study showed a positive effect from a single-session of dual-tDCS applied before physical therapy (PT) on lower limb performance. However, it is still undetermined if other timings of brain stimulation (i.e., during motor practice) induce better effects. The objective of this study was to examine the effect of a single-session of dual-tDCS "during" PT on lower limb performance in sub-acute stroke and then compare the results with our previous data using a "before" stimulation paradigm. METHOD: For the current "during" protocol, 19 participants were participated in a randomized sham-controlled crossover trial. Dual-tDCS over the M1 of both cortices (2 mA) was applied during the first 20 min of PT. The Timed Up and Go and Five-Times-Sit-To-Stand tests were assessed at pre- and post-intervention and 1-week follow-up. Then, data from the current study were compared with those of the previous "before" study performed in a different group of 19 subjects. Both studies were compared by the difference of mean changes from the baseline. RESULTS: Dual-tDCS "during" PT and the sham group did not significantly improve lower limb performance. By comparing with the previous data, performance in the "before" group was significantly greater than in the "during" and sham groups at post-intervention, while at follow-up the "before" group had better improvement than sham, but not greater than the "during" group. CONCLUSION: A single-session of dual-tDCS during PT induced no additional advantage on lower limb performance. The "before" group seemed to induce better acute effects; however, the benefits of the after-effects on motor learning for both stimulation protocols were probably not different. Trial registration Current randomized controlled trials was prospectively registered at the clinicaltrials.gov, registration number: NCT04051671. The date of registration was 09/08/2019.

Anodal tDCS of contralesional hemisphere modulates ipsilateral control of spinal motor networks targeting the paretic arm post-stroke.

OBJECTIVE: The role of ipsilateral motor cortex efferent pathways in the transmission of voluntary command to spinal motor nuclei remains controversial in humans. In healthy subjects, their implication in cortical control is hidden by predominant role of crossed corticospinal tract. However, evidence from electrophysiological and imaging studies suggest that ipsilateral tracts may contribute to functional recovery after unilateral brain damage. This randomized-sham control study aims to explore to what extent ipsilateral tracts from the undamaged hemisphere may strengthen corticospinal control onto spinal motor networks following stroke. METHODS: Anodal transcranial direct current stimulation (tDCS) was combined with monosynaptic H-reflex method to evaluate the variations of reciprocal inhibition (RI) in wrist flexors in 21 stroke participants. RESULTS: Anodal tDCS decreased RI in wrist flexors in stroke participants in both arms. tDCS unmasks an ipsilateral control from the undamaged hemisphere onto spinal motor networks controlling affected arm muscles in stroke participants. In the unaffected (contralateral) arm, effects in stroke participants were opposite to those induced in healthy subjects. CONCLUSIONS: Stimulation of the undamaged cortex in stroke participants induces modulation of ipsilateral motor networks controlling the hemiparetic side. SIGNIFICANCE: Rehabilitation could leverage stimulation of the undamaged hemisphere to enhance motor recovery post stroke.

Effects of home-based dual-hemispheric transcranial direct current stimulation combined with exercise on upper and lower limb motor performance in patients with chronic stroke.

PURPOSE: This study aimed to determine the effects of home-based dual-hemispheric transcranial direct current stimulation (dual-tDCS) combined with exercise on motor performance in patients with chronic stroke. MATERIALS AND METHODS: We allocated 24 participants to the active or sham group. They completed 1-h home-based exercise after 20-min dual-tDCS at 2-mA, thrice a week for 4 weeks. The patients were assessed using the Fugl-Meyer Assessment (FMA), Wolf Motor Function Test, Timed Up and Go test, Five Times Sit-to-Stand Test, Six-meter Walk Test, and muscle strength assessment. RESULTS: Compared with the sham group, the active group showed improved FMA scores, which were sustained for at least 1 month. There was no between-group difference in the outcomes of the functional tasks. CONCLUSION: Home-based dual-tDCS could facilitate motor recovery in patients with chronic stroke with its effect lasting for at least 1 month. However, its effects on functional tasks remain unclear. tDCS is safe and easy for home-based self-administration for patients who can use their paretic arms. This could benefit patients without access to health care centres or in situations requiring physical distancing. This home-based tDCS combined with exercise has the potential to be incorporated into telemedicine in stroke rehabilitation.IMPLICATIONS FOR REHABILITATIONTwelve sessions of home-based dual-tDCS combined with exercises (3 days/week for 4 weeks) facilitated upper and lower limb motor recovery in patients with chronic stroke compared with exercise alone, with a post-effect for at least 1 month.Home-based tDCS could be safe and easily self-administrable by patients who can use their paretic arms.This intervention could be beneficial for patients living in the community without easy access to a health care centre or in situations where physical distancing is required.

Brain Metabolite Changes After Anodal Transcranial Direct Current Stimulation in Autism Spectrum Disorder.

OBJECTIVES: Previous research has provided evidence that transcranial direct current stimulation (tDCS) can reduce severity of autism spectrum disorder (ASD); however, the exact mechanism of this effect is still unknown. Magnetic resonance spectroscopy has demonstrated low levels of brain metabolites in the anterior cingulate cortex (ACC), amygdala, and left dorsolateral prefrontal cortex (DLPFC) in individuals with ASD. The aim of this study was to investigate the effects of anodal tDCS on social functioning of individuals with ASD, as measured by the social subscale of the Autism Treatment Evaluation Checklist (ATEC), through correlations between pretreatment and posttreatment concentrations of brain metabolites in the areas of interest (DLPFC, ACC, amygdala, and locus coeruleus) and scores on the ATEC social subscale. METHODS: Ten participants with ASD were administered 1 mA anodal tDCS to the left DLPFC for 20 min over five consecutive days. Measures of the ATEC social subscale and the concentrations of brain metabolites were performed before and immediately after the treatment. RESULTS: The results showed a significant decrease between pretreatment and immediately posttreatment in the ATEC social subscale scores, significant increases in N-acetylaspartate (NAA)/creatine (Cr) and myoinositol (mI)/Cr concentrations, and a decrease in choline (Cho)/Cr concentrations in the left DLPFC and locus coeruleus after tDCS treatment. Significant associations between decreased ATEC social subscale scores and changed concentrations in NAA/Cr, Cho/Cr, and mI/Cr in the locus coeruleus were positive. CONCLUSION: Findings suggest that beneficial effects of tDCS in ASD may be due to changes in neuronal and glia cell activity and synaptogenesis in the brain network of individuals with ASD. Further studies with larger sample sizes and control groups are warranted.

One session of motor control exercise improves joint position sense assessed by an iPhone application: a randomized controlled trial.

[Purpose] To establish the test-retest reliability of an iPhone application and determine the immediate effect of motor control exercise (MCE) on lumbar position sense. [Participants and Methods] This study used a two-arm, randomized controlled trial design with a blinded assessor. Sixty healthy participants were randomized into the exercise or control group. The exercise group underwent 30-min MCE, whereas the control group rested for 15 min. Lumbar motion measured by two iPhones with goniometer application was used to determine the test-retest reliability. Absolute repositioning errors (pre- and post-test) from the control and exercise groups were used to determine the immediate effect of MCE on lumbar position sense. [Results] The test-retest reliability was 0.67-0.95. A significant interaction effect was found for Angle*Time, main effect of Angle, and main effect of Time. Post-hoc comparison showed a significant improvement in position sense at 45° and 60° in the exercise group. [Conclusion] The findings suggest that a mobile phone application has the ability to detect changes in lumbar position sense between sessions that exceed measurement error following MCE. One session of specific MCE can improve lumbar position sense at high lumbar flexion.

Furosemide Unmasks Inhibitory Dysfunction after Spinal Cord Injury in Humans: Implications for Spasticity.

Spasticity after spinal cord injury has considerable quality of life implications, impacts on rehabilitation efforts and necessitates long-term multi-disciplinary pharmacological and non-pharmacological management. The potassium chloride co-transporter (KCC2) plays a central role in intracellular chloride homeostasis and the inhibitory function of mature neurons. Animal studies consistently have demonstrated a downregulation of KCC2 activity after spinal cord transection, causing a shift from the inhibitory action of gamma-aminobutyric acid and glycine to an excitatory effect. Furosemide, a recognized KCC2 antagonist in animals, blocks the formation of inhibitory post-synaptic potentials in spinal motoneurons without affecting excitatory post-synaptic potentials. Based on observations in animals studies, we hypothesized that furosemide may be used to unmask KCC2 downregulation after spinal cord injury in humans, which contributes to reflex hyperexcitability. We have shown previously that furosemide reduces both pre-synaptic and post-synaptic inhibition in healthy subjects without altering monosynaptic excitatory transmission. These findings provide evidence that furosemide may be used in humans to evaluate inhibitory synapses in the spinal cord. In this present study, we show that furosemide fails to modulate both pre- and post-synaptic inhibitions relayed to soleus spinal motor neurons in persons with spinal cord injury. The lack of furosemide effect after spinal cord injury suggests KCC2 dysfunction in humans, resulting in reduced inhibitory synaptic transmission in spinal neurons. Our findings suggest that KCC2 dysfunction may be an important etiological factor in hyperreflexia after spinal cord injury. These observations may pave the way to novel therapeutic strategies against spasticity centered on chloride homeostasis.

Effect of single-session dual-tDCS before physical therapy on lower-limb performance in sub-acute stroke patients: A randomized sham-controlled crossover study.

Anodal stimulation increases cortical excitably, whereas cathodal stimulation decreases cortical excitability. Dual transcranial direct current stimulation (tDCS; anodal over the lesioned hemisphere, cathodal over the non-lesioned hemisphere) was found to enhance motor learning. The corresponding tDCS-induced changes were reported to reduce the inhibition exerted by the unaffected hemisphere on the affected hemisphere and restore the normal balance of the interhemispheric inhibition. Most studies were devoted to the possible modification of upper-limb motor function after tDCS; however, almost no study has demonstrated its effects on lower-limb function and gait, which are also commonly disordered in stroke patients with motor deficits. In this randomized sham-controlled crossover study, we included 19 patients with sub-acute stroke. Participants were randomly allocated to receive real or sham dual-tDCS followed by conventional physical therapy with an intervention interval of at least 1 week. Dual-tDCS was applied over the lower-limb M1 at 2-mA intensity for 20min. Lower-limb performance was assessed by the Timed Up and Go (TUG) and Five-Times-Sit-To-Stand (FTSTS) tests and muscle strength was assessed by peak knee torque of extension. We found a significant increase in time to perform the FTSST for the real group, with improvements significantly greater than for the sham group; the TUG score was significantly increased but not higher than for the sham group. An after-effect on FTSTS was found at approximately 1 week after the real intervention. Muscle strength was unchanged in both limbs for both real and sham groups. Our results suggest that a single session of dual-tDCS before conventional physical therapy could improve sit-to-stand performance, which appeared to be improved over conventional physical therapy alone. However, strength performance was not increased after the combination treatment.

Basic principles of transcranial magnetic stimulation (TMS) and repetitive TMS (rTMS).

Transcranial magnetic stimulation (TMS) and repetitive TMS (rTMS) are indirect and non-invasive methods used to induce excitability changes in the motor cortex via a wire coil generating a magnetic field that passes through the scalp. Today, TMS has become a key method to investigate brain functioning in humans. Moreover, because rTMS can lead to long-lasting after-effects in the brain, it is thought to be able to induce plasticity. This tool appears to be a potential therapy for neurological and psychiatric diseases. However, the physiological mechanisms underlying the effects induced by TMS and rTMS have not yet been clearly identified. The purpose of the present review is to summarize the main knowledge available for TMS and rTMS to allow for understanding their mode of action and to specify the different parameters that influence their effects. This review takes an inventory of the most-used rTMS paradigms in clinical research and exhibits the hypotheses commonly assumed to explain rTMS after-effects.

Anodal transcranial direct current stimulation of the motor cortex induces opposite modulation of reciprocal inhibition in wrist extensor and flexor.

Transcranial direct current stimulation (tDCS) is used as a noninvasive tool to modulate brain excitability in humans. Recently, several studies have demonstrated that tDCS applied over the motor cortex also modulates spinal neural network excitability and therefore can be used to explore the corticospinal control acting on spinal neurons. Previously, we showed that reciprocal inhibition directed to wrist flexor motoneurons is enhanced during contralateral anodal tDCS, but it is likely that the corticospinal control acting on spinal networks controlling wrist flexors and extensors is not similar. The primary aim of the study was to explore the effects of anodal tDCS on reciprocal inhibition directed to wrist extensor motoneurons. To further examine the supraspinal control acting on the reciprocal inhibition between wrist flexors and extensors, we also explored the effects of the tDCS applied to the ipsilateral hand motor area. In healthy volunteers, we tested the effects induced by sham and anodal tDCS on reciprocal inhibition pathways innervating wrist muscles. Reciprocal inhibition directed from flexor to extensor muscles and the reverse situation, i.e., reciprocal inhibition, directed from extensors to flexors were studied in parallel with the H reflex technique. Our main finding was that contralateral anodal tDCS induces opposing effects on reciprocal inhibition: it decreases reciprocal inhibition directed from flexors to extensors, but it increases reciprocal inhibition directed from extensors to flexors. The functional result of these opposite effects on reciprocal inhibition seems to favor wrist extension excitability, suggesting an asymmetric descending control onto the interneurons that mediate reciprocal inhibition.

Changes in spinal inhibitory networks induced by furosemide in humans.

During neural development in animals, GABAergic and glycinergic neurons are first excitatory, and then become inhibitory in the mature state. This developmental shift is due mainly to strong expression of the cation-chloride K-Cl cotransporter 2 (KCC2) and down-regulation of Na-K-Cl cotransporter 1 (NKCC1) during maturation. The down-regulation of co-transporter KCC2 after spinal cord transection in animals leads to the depolarising (excitatory) action of GABA and glycine and thus results in a reduction of inhibitory synaptic efficiency. Furosemide, a loop diuretic, has been shown to selectively and reversibly block inhibitory postsynaptic potentials without affecting excitatory postsynaptic potentials in animal spinal neurons. Moreover, this diuretic has been also demonstrated to block the cation-chloride co-transporters. Here, we used furosemide to demonstrate changes in spinal inhibitory networks in healthy human subjects. Non-invasive electrophysiological techniques were used to assess presynaptic inhibition, postsynaptic inhibition and the efficacy of synaptic transmission between muscle afferent terminals and soleus motoneurons in the spinal cord. Orally administered furosemide, at doses commonly used in the clinic (40 mg), significantly reduced spinal inhibitory interneuronal activity for at least 70 min from intake compared to control experiments in the same subjects while no changes were observed in the efficacy of synaptic transmission between muscle afferent terminals and soleus motoneurons. The reduction of inhibition was dose-dependent. Our results provide indirect evidence that reversible changes in the cation-chloride transport system induce modulations of inhibitory neuronal activity at spinal cord level in humans.