Case report: An N-of-1 study using amplitude modulated transcranial alternating current stimulation between Broca's area and the right homotopic area to improve post-stroke aphasia with increased inter-regional synchrony.

Over one-third of stroke survivors develop aphasia, and language dysfunction persists for the remainder of their lives. Brain language network changes in patients with aphasia. Recently, it has been reported that phase synchrony within a low beta-band (14-19 Hz) frequency between Broca's area and the homotopic region of the right hemisphere is positively correlated with language function in patients with subacute post-stroke aphasia, suggesting that synchrony is important for language recovery. Here, we employed amplitude-modulated transcranial alternating current stimulation (AM-tACS) to enhance synchrony within the low beta band frequency between Broca's area and the right homotopic area, and to improve language function in a case of chronic post-stroke aphasia. According to an N-of-1 study design, the patient underwent short-term intervention with a one-time intervention of 15 Hz-AM-tACS with Broca's and the right homotopic areas (real condition), sham stimulation (sham condition), and 15 Hz-AM-tACS with Broca's and the left parietal areas (control condition) and long-term intervention with sham and real conditions (10 sessions in total, each). In the short-term intervention, the reaction time and accuracy rate of the naming task improved after real condition, not after sham and control conditions. The synchrony between the stimulated areas evaluated by coherence largely increased after the real condition. In the long-term intervention, naming ability, verbal fluency and overall language function improved, with the increase in the synchrony, and those improvements were sustained for more than a month after real condition. This suggests that AM-tACS on Broca's area and the right homotopic areas may be a promising therapeutic approach for patients with poststroke aphasia.

Swallow-related Brain Activity in Post-total Laryngectomy Patients: A Case Series Study.

Background: Total laryngectomy is a surgical procedure to completely remove the hyoid bone, larynx, and associated muscles as a curative treatment for laryngeal cancer. This leads to insufficient swallowing function with compensative movements of the residual tongue to propel the food bolus to the pharynx and esophagus. However, the neurophysiological mechanisms of compensative swallowing after total laryngectomy remain unclear. Recently, swallowing-related cortical activation such as event-related desynchronization (ERD) during swallowing has been reported in healthy participants and neurological patients with dysphagia. Abnormal ERD elucidates the pathophysiological cortical activities that are related to swallowing. No report has investigated ERD in post-total laryngectomy patients. Case: We investigated ERD during volitional swallowing using electroencephalography in three male patients after total laryngectomy for laryngeal cancer (age and time after surgery: Case 1, 75 years, 10 years; Case 2, 85 years, 19 years; Case 3, 73 years, 19 years). In video fluorographic swallowing studies, we observed compensatory tongue movements such as posterior-inferior retraction of the tongue and contact on the posterior pharyngeal wall in all three cases. Significant ERD was localized in the bilateral medial sensorimotor areas and the left lateral parietal area in Case 1, in the bilateral frontal and left temporal areas in Case 2, and in the left prefrontal and premotor areas in Case 3. Discussion: These results suggest that cortical activities related to swallowing might reflect cortical reorganization for modified swallowing movements of residual tongue muscles to compensate for reduced swallowing pressure in patients after total laryngectomy.

Gait-combined closed-loop brain stimulation can improve walking dynamics in Parkinsonian gait disturbances: a randomised-control trial.

OBJECTIVE: Gait disturbance lowers activities of daily living in patients with Parkinson's disease (PD) and related disorders. However, the effectiveness of pharmacological, surgical and rehabilitative treatments is limited. We recently developed a novel neuromodulation approach using gait-combined closed-loop transcranial electrical stimulation (tES) for healthy volunteers and patients who are post-stroke, and achieved significant entrainment of gait rhythm and an increase in gait speed. Here, we tested the efficacy of this intervention in patients with Parkinsonian gait disturbances. METHODS: Twenty-three patients were randomly assigned to a real intervention group using gait-combined closed-loop oscillatory tES over the cerebellum at the frequency of individualised comfortable gait rhythm, and to a sham control group. RESULTS: Ten intervention sessions were completed for all patients and showed that the gait speed (F (1, 21)=13.0, p=0.002) and stride length (F (1, 21)=8.9, p=0.007) were significantly increased after tES, but not after sham stimulation. Moreover, gait symmetry measured by swing phase time (F (1, 21)=11.9, p=0.002) and subjective feelings about freezing (F (1, 21)=14.9, p=0.001) were significantly improved during gait. CONCLUSIONS: These findings showed that gait-combined closed-loop tES over the cerebellum improved Parkinsonian gait disturbances, possibly through the modulation of brain networks generating gait rhythms. This new non-pharmacological and non-invasive intervention could be a breakthrough in restoring gait function in patients with PD and related disorders.

N-of-1 Trial of Electrical Sensory Stimulation Therapy on the Tibial Innervated Area during Gait in a Case of Post-stroke Sensory Disturbance.

Background: Transcutaneous electrical sensory nerve stimulation (TESS) is used to enhance the recovery of sensorimotor function in post-stroke hemiparesis. However, TESS efficacy for post-stroke gait disturbance remains unknown. We hypothesized that TESS on the area innervated by the tibial nerve, targeting the superficial plantar sensation, combined with gait training would improve gait function in patients with gait disturbance caused by severe superficial sensory disturbance after stroke. Case: A 42-year-old man was referred to the convalescent rehabilitation hospital 4 months after a left pontine hemorrhage. He showed severe superficial sensory disturbance without motor paresis in the right lower leg and planta pedis. Gait training with TESS on the tibial nerve innervated area was performed, targeting plantar sensation according to an N-of-1 study design of a single-case ABCAB that included two 10-min sessions of gait training without TESS (phase A), two gait training sessions with TESS targeting the right plantar sensation (phase B), and one session with TESS targeting the upper leg sensation as control (phase C). The patient showed increased gait distance and stride length, improved superficial sensation on the right planta pedis, and improved balance after phase B, but not after phases A and C. Discussion: Gait training with TESS on the tibial nerve innervated area improved gait ability, superficial plantar sensation on the targeted side, and balance function in a post-stroke patient with sensory disturbance. Gait training with TESS may be effective for gait dysfunction caused by sensory disturbance in patients with central nervous system disorders.

Low-frequency repetitive transcranial magnetic stimulation can alleviate spasticity and induce functional recovery in patients with severe chronic stroke: A prospective, non-controlled, pilot study.

Objective: Developing new therapies to improve motor function in patients with severe chronic stroke remains a major focus of neurorehabilitation. In this prospective, non-controlled, pilot study, we aimed to investigate the effects of low-frequency repetitive transcranial magnetic stimulation (rTMS) combined with occupational therapy (OT) on the motor function recovery of the affected upper limb in chronic stroke patients with severe upper limb hemiparesis. Methods: Consecutive patients (n = 40) diagnosed with chronic stroke (time since stroke, ≥1 year) and upper limb hemiparesis were enrolled in this study. Patients were classified according to the Brunnstrom recovery stage (BRS) for fingers. The severity of upper limb hemiparesis was categorized as mild (BRS IV-VI) or severe (BRS I-III). Patients received low-frequency rTMS to the contralesional primary motor area (M1) followed by OT for 12 consecutive days. The primary outcome was upper limb motor recovery, as measured with the Fugl-Meyer assessment (FMA). Secondary outcomes included manual dexterity, upper limb use, spasticity of the fingers and wrist, and motor evoked potential (MEP). Results: Patients with severe hemiparesis showed a significant increase in upper limb use, significantly improved quality of movement, and significantly reduced spasticity. Those with mild hemiparesis showed significant improvements in the FMA scores and manual dexterity, a significant increase in upper limb use and MEP, and significantly reduced spasticity. Conclusions: Low-frequency rTMS applied to the contralesional M1 combined with OT was effective in the rehabilitation of chronic stroke patients with severe upper limb hemiparesis by reducing the spasticity of the fingers.

Non-invasive Brain Stimulation in Post-stroke Dysphagia Rehabilitation: A Narrative Review of Meta-analyses in 2022.

Objectives: This study aimed to update the current knowledge on non-invasive brain stimulation (NIBS) effects, such as repetitive transcranial brain stimulation and transcranial direct current stimulation, in patients with post-stroke dysphagia (PSD). Methods: We summarized the basic principles and therapeutic strategies of NIBS. We then reviewed nine meta-analyses from 2022 that investigated the efficacy of NIBS in PSD rehabilitation. Results: Although dysphagia is a common and devastating sequela of stroke, the efficacy of conventional swallowing therapies remains controversial. NIBS techniques have been proposed as promising approaches for managing PSD via neuromodulation. Recent meta-analyses have shown that NIBS techniques are beneficial for the recovery of patients with PSD. Conclusions: NIBS has the potential to become a novel alternative treatment for PSD rehabilitation.

Case report: Backward gait training combined with gait-synchronized cerebellar transcranial alternating current stimulation in progressive supranuclear palsy.

Progressive supranuclear palsy (PSP) is characterized by recurrent falls caused by postural instability, and a backward gait is considered beneficial for postural instability. Furthermore, a recent approach for rehabilitation combined with gait-oriented synchronized stimulation using non-invasive transcranial patterned stimulation could be promising for balance function. Here, we present a case of PSP with backward gait training combined with gait-synchronized transcranial alternating current stimulation (tACS). A 70-year-old woman with PSP-Richardson's syndrome underwent backward gait training combined with synchronized cerebellar tACS. Initially, she underwent short-term intervention with combined training of backward gait with synchronized cerebellar tACS, asynchronized, or sham stimulation according to the N-of-1 study design. Synchronized tACS training demonstrated a decrease in postural instability, whereas asynchronized or sham stimulation did not. The additional long-term interventions of combined backward gait training with synchronized cerebellar tACS demonstrated further decrease in postural instability with improvements in gait speed, balance function, and fall-related self-efficacy in daily life. The present case describes a novel approach for motor symptoms in a patient with PSP. Backward gait training with synchronized cerebellar tACS may be a promising therapeutic approach.

Case report: A novel approach of closed-loop brain stimulation combined with robot gait training in post-stroke gait disturbance.

Most post-stroke patients have long-lasting gait disturbances that reduce their daily activities. They often show impaired hip and knee joint flexion and ankle dorsiflexion of the lower limbs during the swing phase of gait, which is controlled by the corticospinal tract from the primary motor cortex (M1). Recently, we reported that gait-synchronized closed-loop brain stimulation targeting swing phase-related activity in the affected M1 can improve gait function in post-stroke patients. Subsequently, a gait-training robot (Orthobot®) was developed that could assist lower-limb joint movements during the swing phase of gait. Therefore, we investigated whether gait-synchronized closed-loop brain stimulation combined with robot-assisted training targeting the swing phase could enhance the recovery of post-stroke gait disturbance. A 57-year-old female patient with chronic post-stroke hemiparesis underwent closed-loop brain stimulation combined with robot-assisted training for 10 min 2 years after left pons infarction. For closed-loop brain stimulation, we used transcranial oscillatory electrical current stimulation over the lesioned M1 foot area with 1.5 mA of DC offset and 0-3 mA of sine-wave formed currents triggered by the paretic heel contact to set the maximum current just before the swing phase (intervention A; two times repeated, A1 and A2). According to the N-of-1 study design, we also performed sham stimulation (intervention B) and control stimulation not targeting the swing phase (intervention C) combined with robot-assisted training in the order of A1-B-A2-C interventions. As a result, we found larger improvements in gait speed, the Timed Up and Go test result, and muscle strength after the A1 and A2 interventions than after the B and C interventions. After confirming the short-term effects, we performed an additional long-term intervention twice a week for 5 weeks, for a total of 10 sessions. Gait parameters also largely improved after long-term intervention. Gait-synchronized closed-loop brain stimulation combined with robot-assisted training targeting the swing phase of gait may promote the recovery of gait function in post-stroke patients. Further studies with a larger number of patients are necessary.

Case Report: Event-Related Desynchronization Observed During Volitional Swallow by Electroencephalography Recordings in ALS Patients With Dysphagia.

Dysphagia is a severe disability affecting daily life in patients with amyotrophic lateral sclerosis (ALS). It is caused by degeneration of both the bulbar motor neurons and cortical motoneurons projecting to the oropharyngeal areas. A previous report showed decreased event-related desynchronization (ERD) in the medial sensorimotor areas in ALS dysphagic patients. In the process of degeneration, brain reorganization may also be induced in other areas than the sensorimotor cortices. Furthermore, ALS patients with dysphagia often show a longer duration of swallowing. However, there have been no reports on brain activity in other cortical areas and the time course of brain activity during prolonged swallowing in these patients. In this case report, we investigated the distribution and the time course of ERD and corticomuscular coherence (CMC) in the beta (15-25 Hz) frequency band during volitional swallow using electroencephalography (EEG) in two patients with ALS. Case 1 (a 71-year-old man) was diagnosed 2 years before the evaluation. His first symptom was muscle weakness in the right hand; 5 months later, dysphagia developed and exacerbated. Since his dietary intake decreased, he was given an implantable venous access port. Case 2 (a 64-year-old woman) was diagnosed 1 year before the evaluation. Her first symptom was open-nasal voice and dysarthria; 3 months later, dysphagia developed and exacerbated. She was given a percutaneous endoscopic gastrostomy. EEG recordings were performed during volitional swallowing, and the ERD was calculated. The average swallow durations were 7.6 ± 3.0 s in Case 1 and 8.3 ± 2.9 s in Case 2. The significant ERD was localized in the prefrontal and premotor areas and lasted from a few seconds after the initiation of swallowing to the end in Case 1. The ERD was localized in the lateral sensorimotor areas only at the initiation of swallowing in Case 2. CMC was not observed in either case. These results suggest that compensatory processes for cortical motor outputs might depend on individual patients and that a new therapeutic approach using ERD should be developed according to the individuality of ALS patients with dysphagia.

Strengthening the GABAergic System Through Neurofeedback Training Suppresses Implicit Motor Learning.

Gamma-aminobutyric acid (GABA) activity within the primary motor cortex (M1) is essential for motor learning in cortical plasticity, and a recent study has suggested that real-time neurofeedback training (NFT) can self-regulate GABA activity. Therefore, this study aimed to investigate the effect of GABA activity strengthening via NFT on subsequent motor learning. Thirty-six healthy participants were randomly assigned to either an NFT group or control group, which received sham feedback. GABA activity was assessed for short intracortical inhibition (SICI) within the right M1 using paired-pulse transcranial magnetic stimulation. During the NFT intervention period, the participants tried to modulate the size of a circle, which was altered according to the degree of SICI in the NFT group. However, the size was altered independently of the degree of SICI in the control group. We measured the reaction time before, after (online learning), and 24 h after (offline learning) the finger-tapping task. Results showed the strengthening of GABA activity induced by the NFT intervention, and the suppression of the online but not the offline learning. These findings suggest that prior GABA activity modulation may affect online motor learning.

Event-Related Desynchronization and Corticomuscular Coherence Observed During Volitional Swallow by Electroencephalography Recordings in Humans.

Swallowing in humans involves many cortical areas although it is partly mediated by a series of brainstem reflexes. Cortical motor commands are sent to muscles during swallow. Previous works using magnetoencephalography showed event-related desynchronization (ERD) during swallow and corticomuscular coherence (CMC) during tongue movements in the bilateral sensorimotor and motor-related areas. However, there have been few analogous works that use electroencephalography (EEG). We investigated the ERD and CMC in the bilateral sensorimotor, premotor, and inferior prefrontal areas during volitional swallow by EEG recordings in 18 healthy human subjects. As a result, we found a significant ERD in the beta frequency band and CMC in the theta, alpha, and beta frequency bands during swallow in those cortical areas. These results suggest that EEG can detect the desynchronized activity and oscillatory interaction between the cortex and pharyngeal muscles in the bilateral sensorimotor, premotor, and inferior prefrontal areas during volitional swallow in humans.

Knee Valgus during Jump Landing Is Related to the Inaccuracy of Knee Position Recognition in Healthy Young Women.

OBJECTIVE: Knee valgus during jump landing is a cause of knee injuries during sports activities. Body recognition is important for maintaining the knees and other body parts in their proper positions. The aim of this study was to investigate whether knee valgus during jump landing in healthy young women is related to the inaccuracy of recognition of bilateral knee positions in the squatting position. METHODS: In 39 healthy young women, the degree of knee valgus was evaluated during the drop vertical jump test using the ratio of the knee separation distance to the ankle separation distance. The accuracy of recognition of bilateral knee positions in the squatting position was evaluated by having the blindfolded subjects indicate with their index fingers the subjective positions of their bilateral patellae by placing their fingers on a horizontal bar positioned in front of them 3 cm below the navel. The difference ratio of the recognized distance to the actual distance between the bilateral patellae was measured as an inaccuracy index. RESULTS: The degree of knee valgus during the drop vertical jump test was positively correlated with the degree of inaccuracy of the recognized knee position with the knees in the neutral position (r=0.358, P=0.025). CONCLUSIONS: In healthy young women, knee valgus during jump landing was significantly correlated with the inaccuracy in knee position recognition in the squatting posture. This finding suggests that the assessment of knee position recognition in the squatting position could be useful as a screening tool for preventing knee injuries on jump landing during sports activities.

Transcranial static magnetic stimulation over the motor cortex can facilitate the contralateral cortical excitability in human.

Transcranial static magnetic stimulation (tSMS) has been focused as a new non-invasive brain stimulation, which can suppress the human cortical excitability just below the magnet. However, the non-regional effects of tSMS via brain network have been rarely studied so far. We investigated whether tSMS over the left primary motor cortex (M1) can facilitate the right M1 in healthy subjects, based on the hypothesis that the functional suppression of M1 can cause the paradoxical functional facilitation of the contralateral M1 via the reduction of interhemispheric inhibition (IHI) between the bilateral M1. This study was double-blind crossover trial. We measured the corticospinal excitability in both M1 and IHI from the left to right M1 by recording motor evoked potentials from first dorsal interosseous muscles using single-pulse and paired-pulse transcranial magnetic stimulation before and after the tSMS intervention for 30 min. We found that the corticospinal excitability of the left M1 decreased, while that of the right M1 increased after tSMS. Moreover, the evaluation of IHI revealed the reduced inhibition from the left to the right M1. Our findings provide new insights on the mechanistic understanding of neuromodulatory effects of tSMS in human.

[Manipulation of Human Brain Oscillation to Control Neuron Network Dynamics and its Clinical Application].

Electroencephalographic recordings of human brain oscillations have been performed over approximately a century. Noninvasive methods for manipulation of brain oscillations are currently available. Reportedly, the manipulation of brain oscillations alters human behavior and cognition and is also used for "oscillotherapy" to treat many neurological diseases. In this review, we summarize the physiological mechanisms of brain oscillations, human behavioral and cognitive changes, and oscillotherapy; we have focused on our recent findings of the manipulation of human brain oscillations during bipedal walking and gait disorder recovery.

Gait-combined transcranial alternating current stimulation modulates cortical control of muscle activities during gait.

Non-invasive brain stimulation has been of interest as a therapeutic tool to modulate cortical excitability. However, there is little evidence that oscillatory brain stimulation can modulate the cortical control of muscle activities during gait, which can be assessed using coherence analysis of paired surface electromyographic (EMG) recordings. This study aimed to investigate the effects of gait-combined transcranial alternating current stimulation (tACS) at the gait cycle frequency on the cortical control of muscle activities during gait using EMG-EMG coherence analysis. Fourteen healthy young adults participated in this study. All participants underwent 2 test conditions (real tACS and sham stimulation over the leg area of the primary motor cortex during 10-min treadmill walking). The average peak-to-peak amplitudes of the motor evoked potentials (MEPs) from the tibialis anterior (TA) and lateral gastrocnemius muscles in the sitting position and EMG-EMG coherences in the TA muscle, triceps surae muscles, quadriceps muscles, and hamstring muscles during gait were measured before and after stimulation. Entrainment effect was significantly higher during real tACS than during sham stimulation. After real tACS, the MEP amplitude and beta band (13-33 Hz) coherence area increased in the TA muscle. The change in MEP amplitude from the TA muscle was positively correlated with the change in beta band coherence area in the TA muscle. Gait-combined tACS can modulate the strength of descending neural drive to TA motoneurons during gait. This suggests that oscillatory brain stimulation is a useful therapeutic tool to modulate the cortical control of muscle activities during gait.

Entrainment of chewing rhythm by gait speed during treadmill walking in humans.

It remains unclear whether the rhythmic processes of chewing and gait synchronize during concurrent execution in humans. To evaluate the entrainment of chewing rhythm by gait speed, we measured electromyography from the masseter and tibialis anterior muscles during chewing at a habitual rhythm while walking on a linear treadmill in 12 healthy volunteers. Vertical movement of the head was also measured using an accelerometer. Each 5-min session included gait tasks using a treadmill at three speeds: Auto: the participant's self-selected gait speed, High: Auto × 1.3, and Low: Auto ÷ 1.3. Electromyography from the masseter muscles were also measured during chewing while stationary (Chew-Only). Chewing rhythm during walking was the same as that for head movement, occurring at twice the speed of the walking rhythm, in nine participants (Low), eight participants (Auto), and eight participants (High). For these participants, chewing rhythm in the Auto and High conditions differed significantly from that in the Chew-Only condition. Significant differences in chewing rhythm were also observed among gait speeds　(Low vs. Auto vs. High). Our findings demonstrate that entrainment of habitual chewing rhythm to gait speed is a significant phenomenon, and that the dominant ratio of chewing-walking-head movement rhythms is 2:1:2.

Cerebellar transcranial alternating current stimulation modulates human gait rhythm.

Although specific brain regions are important for regularly patterned limb movements, the rhythm generation system that governs bipedal locomotion in humans is not thoroughly understood. We investigated whether rhythmic transcranial brain stimulation over the cerebellum could alter walking rhythm. Fourteen healthy subjects performed over-ground walking for 10 min during which they were given, in a random order, transcranial alternating current stimulation (tACS) over the left cerebellum at the approximated frequency of their gait cycle, tACS over the skin of the scalp, and during sham stimulation. Cerebellar tACS showed a significant entrainment of gait rhythm compared with the control conditions. When the direction of the tACS currents was symmetrically inverted, some subjects showed entrainment at an approximately 180° inverted phase, suggesting that gait modulation is dependent on current orientation. These findings indicate that tACS over cerebellum can modulate gait generation system in cerebellum and become an innovative approach for the recovery of locomotion in patients with gait disturbances caused by CNS disorders.

Gait-synchronized oscillatory brain stimulation modulates common neural drives to ankle muscles in patients after stroke: A pilot study.

The present study aimed to investigate the long-term effects of gait intervention with transcranial alternating current stimulation (tACS) synchronized with gait cycle frequency on the cortical control of muscle activity during gait, using coherence analyses, in patients after stroke. Eight chronic post-stroke patients participated in a single-blinded crossover study, and 7 patients completed the long-term intervention. Each patient received tACS over the primary motor cortex foot area on the affected side, which was synchronized with individual gait cycle frequency, and sham stimulation during treadmill gait in a random order. Electrical neuromuscular stimulation was used to assist the paretic ankle movement in both conditions. After gait intervention with tACS, beta band (15-35 Hz) coherence, which is considered to have a cortical origin, significantly increased in the paretic tibialis anterior (TA) muscle during 6-min of over-ground gait. The change in beta band coherence in the paretic TA muscle was positively correlated with the change in gait distance. These results indicate that gait intervention with tACS synchronized with gait cycle frequency may induce gait-specific plasticity that modulates the common neural drive to the TA motoneurons on the paretic side during gait and leads to changes in gait function in patients after stroke.