Tsung-Hsun Hsieh

Background: Parkinson’s disease (PD) is the second most common neurodegenerative disorder among the elderly. Although pharmacological therapies can alleviate symptoms, they often fail to provide sustained or complete symptom control, underscoring the need for alternative therapeutic strategies. Neuromodulation techniques, particularly cortical electrical stimulation (CES), have shown promise in modulating cortical plasticity. However, the therapeutic efficacy of CES in PD remains to be fully elucidated. In this study we investigated the long-term therapeutic potential of a novel CES protocol in a transgenic MitoPark mouse model of PD. Methods: MitoPark mice received CES beginning at 8 weeks of age (one session per day, 2 days per week) for a total of 12 weeks. Motor function was assessed using a comprehensive behavioral battery, including beam walking, open-field, and gait performance tests. Neuroprotective effects were evaluated by quantifying dopaminergic neuronal survival and striatal fiber density using tyrosine hydroxylase (TH) immunohistochemistry. Results: Long-term CES treatment significantly ameliorated motor impairments in MitoPark mice, improving locomotor activity, gait coordination, and beam walking performance compared with sham controls. Immunohistochemical analyses further revealed enhanced survival of nigrostriatal dopaminergic neurons and fibers in the CES-treated group, indicating pronounced neuroprotective effects. Conclusions: These findings demonstrate that early and sustained CES intervention mitigates motor deficits and enhances dopaminergic neuron survival in the MitoPark PD model. The results provide compelling preclinical evidence supporting CES as a potential adjunctive neuromodulatory therapy for Parkinson’s disease.

Autophagy dysregulation plays a crucial role in the early pathological stage of Parkinson’s disease (PD), in which dopaminergic (DAergic) neurons und

Objectives: Limitation in physical functioning is common after spinal cord injury (SCI). Paired Associative stimulation (PAS) can impact brain and spinal cord networks to restore functionality. Therefore, this study aimed to predict the recovery models using motor evoked potential (MEP) and Basso, Beattie, and Bresnahan (BBB) scores in an animal SCI model after 4 weeks of PAS. Methods: A total of thirty-three adult Sprague-Dawley rats were recruited and divided into six groups including normal, sham, and four stimulation intervention groups. Four different combinations of PAS were employed for 4 weeks, including (1) 3 min rTMS-iTBS/ts-DCS (2), 3 min rTMS-iTBS/ts-iTBS (3), 20 min rTMS/ts-DCS, and (4) 20 min rTMS/ts-iTBS. The MEP was recorded two times before and six times after stimulation. The BBB score was measured after every week for 4 weeks. The MEP and BBB scores with different combinations were used to compute linear regression models for motor recovery in an SCI animal model. Results: Post-MEP amplitude was associated with locomotor (BBB) scores in different stimulation groups from week 2 to week 4 (adjusted R ² =0.77 to 0.99, p=0.001–0.046, with 95 % CIs reported for each model). Post-MEP recordings from all four weeks were closely correlated with BBB scores in all groups each week, often involving post-MEP amplitude at 5 and 10 min. However, timing, testing week, and stimulation group differed across models despite relying on a single marker. Conclusions: The 3 min rTMS-iTBS/ts-DCS, 3 min rTMS-iTBS/ts-iTBS, 20 min rTMS/ts-DCS, and 20 min rTMS/ts-iTBS models predicted significant outcomes during week 2, week 3, and week 4 for locomotor recovery (BBB scores) using post-MEP after paired stimulations in incomplete SCI rats. Because each stimulation group had a small sample size (n=3–5) and the study tested a variety of predictor variables, the findings are best regarded as preliminary and exploratory, generating hypotheses about associations rather than validating predictors of recovery.

Temporal Interference Stimulation (TIS) represents a novel non-invasive brain stimulation technique that deeply targets specific brain regions using the differential beat frequency of two high-frequency stimulation pairs. This study investigated the neuromodulatory effects of TIS at different beat frequencies on cortical excitability in the rat motor cortex. Rats were randomly assigned into four groups, receiving TIS at alpha (10 Hz), beta (20 Hz), gamma (70 Hz), or sham frequencies targeting the motor cortex for 20 min under anesthesia. Cortical excitability and inhibition were evaluated by measuring motor-evoked potentials (MEPs), input-output (I/O) curves, and long-interval intracortical inhibition (LICI) before and after TIS. Additionally, immunohistochemistry was performed for neural biomarkers c-Fos and glutamic acid decarboxylase (GAD-65) to confirm targeted neural activation following TIS. We also examined glial fibrillary acidic protein (GFAP)-positive cells in the stimulated region to assess astrocyte responses associated with TIS. Alpha and gamma TIS significantly increased MEP amplitudes compared to sham stimulation. The analysis of I/O curves revealed a significant enhancement in the area under the curve (AUC) post-stimulation in the alpha and gamma TIS groups. Notably, only gamma TIS significantly reduced intracortical inhibition, indicated by an increased LICI ratio post-stimulation. Immunohistochemical analysis demonstrated a significant 35% increase in c-Fos-positive cells in the stimulated motor cortex regions after TIS compared to sham, whereas no significant changes in GAD-65-positive cells or GFAP expression were observed. These findings indicate that a single session of alpha or gamma TIS effectively modulates cortical excitability, highlighting its potential for targeted neuromodulation applications.

Fatigue is believed to increase the risk of anterior cruciate ligament (ACL) injury by directly promoting high-risk biomechanics in the lower limbs. Studies have shown that dynamic taping can help normalize inadequate biomechanics during landings. This study aims to examine the effects of dynamic taping on landing biomechanics in fatigued football athletes. Twenty-seven high-school football athletes were recruited and randomly allocated to groups of either active taping or sham taping, with a crossover allocation two weeks later. In each group, the participants underwent a functional agility short-term fatigue protocol and were evaluated using the landing error scoring system before and after the fatigue protocol. The landing error scoring system (LESS) scores in the sham taping group increased from 4.24 ± 1.83 to 5.36 ± 2.00 (t = −2.07, p = 0.04, effect size = 0.61). In contrast, the pre–post difference did not reach statistical significance in the active taping group (from 4.24 ± 1.69 to 4.52 ± 1.69, t = −1.50, p = 0.15, effect size 0.46). Furthermore, the pre–post changes between the sham and active taping groups were statistically significant (sham taping: 1.12 ± 1.20; active taping: 0.28 ± 0.94, p = 0.007). Dynamic taping, particularly using the spiral technique, appeared to mitigate faulty landing biomechanics in the fatigued athletes by reducing hip and knee flexion and increasing hip internal rotation during landing. These results suggest that dynamic taping can potentially offer protective benefits in landing mechanics, which could further be applied to prevent ACL injuries in fatigued athletes.

Transcranial focused ultrasound stimulation (tFUS) has emerged as a promising neuromodulation technique that delivers acoustic energy with high spatial resolution for inducing long-term potentiation (LTP)- or depression (LTD)-like plasticity. The variability in the primary effects of tFUS-induced plasticity could be due to different stimulation patterns, such as intermittent versus continuous, and is an aspect that requires further detailed exploration. In this study, we developed a platform to evaluate the neuromodulatory effects of intermittent and continuous tFUS on motor cortical plasticity before and after tFUS application. Three groups of rats were exposed to either intermittent, continuous, or sham tFUS. We analyzed the neuromodulatory effects on motor cortical excitability by examining changes in motor-evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS). We also investigated the effects of different stimulation patterns on excitatory and inhibitory neural biomarkers, examining c-Fos and glutamic acid decarboxylase (GAD-65) expression using immunohistochemistry staining. Additionally, we evaluated the safety of tFUS by analyzing glial fibrillary acidic protein (GFAP) expression. The current results indicated that intermittent tFUS produced a facilitation effect on motor excitability, while continuous tFUS significantly inhibited motor excitability. Furthermore, neither tFUS approach caused injury to the stimulation sites in rats. Immunohistochemistry staining revealed increased c-Fos and decreased GAD-65 expression following intermittent tFUS. Conversely, continuous tFUS downregulated c-Fos and upregulated GAD-65 expression. In conclusion, our findings demonstrate that both intermittent and continuous tFUS effectively modulate cortical excitability. The neuromodulatory effects may result from the activation or deactivation of cortical neurons following tFUS intervention. These effects are considered safe and well-tolerated, highlighting the potential for using different patterns of tFUS in future clinical neuromodulatory applications.

Background: Parkinson’s disease (PD) is a neurogenerative disorder implicated in dysfunctions of motor functions, particularly gait and balance. Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation offered as a potential adjuvant therapy for PD. This systematic review and meta-analysis were conducted to identify whether tDCS alone and combined with additional rehabilitation therapies improve gait and balance among individuals with PD. Methods: We searched PubMed, Embase, Web of Science, and relevant databases for eligible studies from inception to December 2022. Studies with a comparative design investigating the effects of tDCS on motor functions, including gait and balance among individuals with PD, were included. A meta-analysis was performed for each outcome using a random effects model for subgroup analysis and pooling of overall effect sizes. Results: A total of 23 studies were included in the meta-analysis. The pooled results revealed that tDCS has moderate overall effects on gait, measured by gait speed (standardized mean deviation [SMD] = 0.238; 95% confidence interval [CI] − 0.026 to 0.502); stride length (SMD = 0.318; 95% CI − 0.015 to 0.652); cadence (SMD = − 0.632; 95% CI − 0.932 to − 0.333); freezing of gait questionnaire scores (SMD = − 0.360; 95% CI − 0.692 to − 0.027); step length (SMD = 0.459; 95% CI − 0.031 to 0.949); walking time (SMD = − 0.253; 95% CI − 0.758 to 0.252); stride time (SMD = − 0.785; 95% CI: − 1.680 to 0.111); double support time (SMD = 1.139; 95% CI − 0.244 to 0.523); and balance, measured by timed up and go (TUG) test (SMD = − 0.294; 95% CI − 0.516 to − 0.073), Berg balance scale (BBS) scores (SMD = 0.406; 95% CI − 0.059 to 0.87), and dynamic gait index (SMD = 0.275; 95% CI − 0.349 to 0.898). For the subgroup analysis, gait and balance demonstrated moderate effect sizes. However, only cadence, stride time, and TUG indicated a significant difference between real and sham tDCS (P = 0.027, P = 0.002, and P = 0.023, respectively), whereas cadence and BBS (P < 0.01 and P = 0.045, respectively) significantly differed after real tDCS plus other therapies rather than after sham tDCS plus other therapies. Conclusions: Our results indicated that tDCS is significantly associated with gait and balance improvements among individuals with PD. The findings of this study provide more proof supporting the effectiveness of tDCS, encouraging tDCS to be utilized alone or in combination with other therapies in clinical practice for PD rehabilitation.

Background and objective: Transcranial Burst Electrical Stimulation (tBES) is an innovative non-invasive brain stimulation technique that combines direct current (DC) and theta burst stimulation (TBS) for brain neuromodulation. It has been suggested that the tBES protocol may efficiently induce neuroplasticity. However, few studies have systematically tested neuromodulatory effects and underlying neurophysiological mechanisms by manipulating the polarity of DC and TBS patterns. This study aimed to develop the platform and assess neuromodulatory effects and neuronal activity changes following tBES.Methods: Five groups of rats were exposed to anodal DC combined with intermittent TBS (tBES+), cathodal DC combined with continuous TBS (tBES−), anodal and cathodal transcranial direct current stimulation (tDCS+ and tDCS−), and sham groups. The neuromodulatory effects of each stimulation on motor cortical excitability were analyzed by motor-evoked potentials (MEPs) changes. We also investigated the effects of tBES on both excitatory and inhibitory neural biomarkers. We specifically examined c-Fos and glutamic acid decarboxylase (GAD-65) using immunohistochemistry staining techniques. Additionally, we evaluated the safety of tBES by analyzing glial fibrillary acidic protein (GFAP) expression.Results: Our findings demonstrated significant impacts of tBES on motor cortical excitability up to 30 min post-stimulation. Specifically, MEPs significantly increased after tBES (+) compared to pre-stimulation (p = 0.026) and sham condition (p = 0.025). Conversely, tBES (−) led to a notable decrease in MEPs relative to baseline (p = 0.04) and sham condition (p = 0.048). Although tBES showed a more favorable neuromodulatory effect than tDCS, statistical analysis revealed no significant differences between these two groups (p > 0.05). Additionally, tBES (+) exhibited a significant activation of excitatory neurons, indicated by increased c-Fos expression (p < 0.05), and a reduction in GAD-65 density (p < 0.05). tBES (−) promoted GAD-65 expression (p < 0.05) while inhibiting c-Fos activation (p < 0.05), suggesting the involvement of cortical inhibition with tBES (−). The expression of GFAP showed no significant difference between tBES and sham conditions (p > 0.05), indicating that tBES did not induce neural injury in the stimulated regions.Conclusion: Our study indicates that tBES effectively modulates motor cortical excitability. This research significantly contributes to a better understanding of the neuromodulatory effects of tBES, and could provide valuable evidence for its potential clinical applications in treating neurological disorders.

Transcranial focused ultrasound (tFUS) is a novel neuromodulating technique. It has been demonstrated that the neuromodulatory effects can be induced by weak ultrasound exposure levels (spatial-peak temporal average intensity, I_SPTA < 10 mW/cm²) in vitro. However, fewer studies have examined the use of weak tFUS to potentially induce long-lasting neuromodulatory responses in vivo. The purpose of this study was to determine the lower-bound threshold of tFUS stimulation for inducing neuromodulation in the motor cortex of rats. A total of 94 Sprague–Dawley rats were used. The sonication region aimed at the motor cortex under weak tFUS exposure (I_SPTA of 0.338–12.15 mW/cm²). The neuromodulatory effects of tFUS on the motor cortex were evaluated by the changes in motor-evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS). In addition to histology analysis, the in vitro cell culture was used to confirm the neuromodulatory mechanisms following tFUS stimulation. In the results, the dose-dependent inhibitory effects of tFUS were found, showing increased intensities of tFUS suppressed MEPs and lasted for 30 min. Weak tFUS significantly decreased the expression of excitatory neurons and increased the expression of inhibitory GABAergic neurons. The PIEZO-1 proteins of GABAergic neurons were found to involve in the inhibitory neuromodulation. In conclusion, we show the use of weak ultrasound to induce long-lasting neuromodulatory effects and explore the potential use of weak ultrasound for future clinical neuromodulatory applications.