Pilot study of using transcranial temporal interfering theta-burst stimulation for modulating motor excitability in rat.

Transcranial temporal interference stimulation (tTIS) is a promising brain stimulation method that can target deep brain regions by delivering an interfering current from surface electrodes. Most instances of tTIS stimulate the brain with a single-frequency sinusoidal waveform generated by wave interference. Theta burst stimulation is an effective stimulation scheme that can modulate neuroplasticity by generating long-term potentiation- or depression-like effects. To broaden tTIS application, we developed a theta burst protocol using tTIS technique to modulate neuroplasticity in rats. Two cannula electrodes were unilaterally implanted into the intact skull over the primary motor cortex. Electrical field of temporal interference envelopes generated by tTIS through cannula electrodes were recorded from primary motor cortex. Theta burst schemes were characterized, and motor activation induced by the stimulation was also evaluated simultaneously by observing electromyographic signals from the corresponding brachioradialis muscle. After validating the stimulation scheme, we further tested the modulatory effects of theta burst stimulation delivered by tTIS and by conventional transcranial electrical stimulation on primary motor cortex excitability. Changes in the amplitude of motor evoked potentials, elicited when the primary motor cortex was activated by electrical pulses, were measured before and after theta burst stimulation by both techniques. Significant potentiation and suppression were found at 15 to 30 min after the intermittent and continuous theta burst stimulation delivered using tTIS, respectively. However, comparing to theta burst stimulations delivered using conventional form of transcranial electrical stimulation, using tTIS expressed no significant difference in modulating motor evoked potential amplitudes. Sham treatment from both methods had no effect on changing the motor evoked potential amplitude. The present study demonstrated the feasibility of using tTIS to achieve a theta burst stimulation scheme for motor cortical neuromodulation. These findings also indicated the future potential of using tTIS to carry out theta burst stimulation protocols in deep-brain networks for modulating neuroplasticity.

The Influence of Dynamic Taping on Landing Biomechanics after Fatigue in Young Football Athletes: A Randomized, Sham-Controlled Crossover Trial.

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.

Neuromodulatory Responses Elicited by Intermittent versus Continuous Transcranial Focused Ultrasound Stimulation of the Motor Cortex in Rats.

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.

Effects of transcranial direct current stimulation alone and in combination with rehabilitation therapies on gait and balance among individuals with Parkinson's disease: a systematic review and meta-analysis.

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.

Transcranial burst electrical stimulation contributes to neuromodulatory effects in the rat motor cortex.

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.

Weak Ultrasound Contributes to Neuromodulatory Effects in the Rat Motor Cortex.

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, ISPTA < 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 (ISPTA 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.

A time-course study of urodynamic analyses in rat models with dopaminergic depletion induced through unilateral and bilateral 6-hydroxydopamine injections.

BACKGROUND: Bladder dysfunction is a common non-motor disorder in Parkinson's disease (PD). This study attempted to determine the bladder dysfunction with disease progression in the PD rat model produced from unilateral/bilateral injections of 6-hydroxydopamine (6-OHDA). METHODS: Cystometrographic (CMG) and external urethral sphincter electromyographic (EUS-EMG) measurements were scheduled in a time-course manner to determine the disease timing, onset, and severity. Animals were allotted into normal control, unilateral, bilateral 6-OHDA injected groups and subjected to scheduled CMG, EUS-EMG analyses at weeks 1, 2, and 4. RESULTS: The urodynamic results concluded that voiding efficiency (VE) was reduced in both unilateral and bilateral PD rats at all-time points. VE had decreased from 57 ± 11% to 31 ± 7% in unilateral PD rats and in bilateral PD rats, a decreased VE of 20 ± 6% was observed compared to control and unilateral PD rats. The EMG results in unilateral PD rats indicated declines in bursting period (BP) (3.78-2.94 s), active period (AP) (93.38-88.75 ms), and silent period (SP) (161.62-114.30 ms). A sudden reduction was noticed in BP (3.62-2.82 s), AP (92.21-86.01 ms), and SP (128.61-60.16 ms) of bilateral PD rats than in control and unilateral PD rats. Histological evidence exhibited a progressive dopaminergic neurons (DA) depletion in the substantia nigra (SN) region in 6-OHDA lesioned rats. CONCLUSION: The experimental outcomes strongly implied that significant variations in bladder function and VE decline were due to the depletion of DA neurons in the SN region of the brain.

Effects of transcranial direct current stimulation on improving performance of delayed- reinforcement attentional set-shifting tasks in attention-deficit/hyperactivity disorder rat model.

Behavioral flexibility (or set-shifting), which is regulated by the prefrontal cortex (PFC), is often impaired in patients with attention-deficit/hyperactivity disorder (ADHD), which is characterized by poor inhibitory control and reinforcement learning. Transcranial direct current stimulation (tDCS) has been proposed as a means of noninvasive brain stimulation and a potential therapeutic tool for modulating behavioral flexibility. Animal studies can pave the way to know if tDCS application can potentially benefit rule- and goal-based activities in ADHD. Spontaneously hypertensive rats (SHRs) and inbred Wistar-Kyoto (WKY) rats were used as an animal model of ADHD and controls, respectively, and their strategy set-shifting abilities, including initial discrimination, set-shifting, and reversal learning tasks under 0-s or 15-s reinforcer delivery delay conditions, were evaluated. The tDCS treatment had a limited effect on the performance of the SHRs and WKY rats in initial discrimination task under 0-s delay condition. Under the 15-s delay condition, the SHRs had longer lever-press reaction times and/or more trial omissions than the WKY rats did when completing set-shifting and reversal-learning tasks. Among the SHRs, tDCS treatment improved the rats' reaction times and/or reduced their trial omissions in the set-shifting and reversal-learning tasks. Although tDCS may improve delayed reinforcement learning set-shifting performance in SHRs, further studies are required to clarify the responsible mechanism.

Dynamic Taping Improves Landing Biomechanics in Young Volleyball Athletes.

Poor landing biomechanics such as hip adduction, internal rotation, and knee valgus have been recognized as modifiable risk factors of anterior cruciate ligament (ACL) injury. Dynamic taping is a newly developed technique with better elasticity and extensibility, which could change the landing biomechanics. The purpose of this study was to identify whether dynamic taping could improve lower limb biomechanics in athletes. Forty-two high school volleyball athletes (21 males and 21 females) participated in the study. Biomechanical properties, including the landing error scoring system (LESS) and anterior-posterior knee laxity, were evaluated before and after the application of dynamic tape while athletes performed the jump-landing task. As a result, we found that dynamic tape significantly reduced the faulty landing strategy by an average of 0.64 errors in all volleyball athletes. The effect induced by dynamic tape was more prominent in female athletes and high-risk athletes (1.1 errors). Furthermore, the application of dynamic tape improved anterior-posterior knee laxity, especially in female athletes (p < 0.001). In conclusion, we found that dynamic tape provided a short-term, passive, and clinically significant means to normalize inadequate biomechanics during landing in athlete groups, which could have a protective effect and further alleviate the risk of ACL injury.

Hemodynamics and Tissue Optical Properties in Bimodal Infarctions Induced by Middle Cerebral Artery Occlusion.

Various infarct sizes induced by middle cerebral artery occlusion (MCAO) generate inconsistent outcomes for stroke preclinical study. Monitoring cerebral hemodynamics may help to verify the outcome of MCAO. The aim of this study was to investigate the changes in brain tissue optical properties by frequency-domain near-infrared spectroscopy (FD-NIRS), and establish the relationship between cerebral hemodynamics and infarct variation in MCAO model. The rats were undergone transient MCAO using intraluminal filament. The optical properties and hemodynamics were measured by placing the FD-NIRS probes on the scalp of the head before, during, and at various time-courses after MCAO. Bimodal infarction severities were observed after the same 90-min MCAO condition. Significant decreases in concentrations of oxygenated hemoglobin ([HbO]) and total hemoglobin ([HbT]), tissue oxygenation saturation (StO2), absorption coefficient (µa) at 830 nm, and reduced scattering coefficient (µs') at both 690 and 830 nm were detected during the occlusion in the severe infarction but not the mild one. Of note, the significant increases in [HbO], [HbT], StO2, and µa at both 690 and 830 nm were found on day 3; and increases in µs' at both 690 and 830 nm were found on day 2 and day 3 after MCAO, respectively. The interhemispheric correlation coefficient (IHCC) was computed from low-frequency hemodynamic oscillation of both hemispheres. Lower IHCCs standing for interhemispheric desynchronizations were found in both mild and severe infarction during occlusion, and only in severe infarction after reperfusion. Our finding supports that sequential FD-NIRS parameters may associated with the severity of the infarction in MCAO model, and the consequent pathologies such as vascular dysfunction and brain edema. Further study is required to validate the potential use of FD-NIRS as a monitor for MCAO verification.

Designing and Pilot Testing a Novel Transcranial Temporal Interference Stimulation Device for Neuromodulation.

Transcranial temporal interference stimulation (tTIS) has been proposed as a new neuromodulation technology for non-invasive deep-brain stimulation (DBS). However, few studies have detailed the design method of a tTIS device and provided system validation. Thus, a detailed design and validation scheme of a novel tTIS device for animal brain stimulation are presented in this study. In the proposed tTIS device, a direct digital synthesizer (DDS) was used to generate a sine wave potential of different frequencies, which was converted to an adjustable sine wave current. A current transformer was used to produce electrical isolation of different channels, which eliminated the current crosstalk between channels and greatly increased the load capacity by amplifying the output voltage. Several in vitro experiments were first conducted to validate the tTIS device. Our results indicated that the error percentages of the stimulation currents were within ±2%. Current crosstalk between channels was almost completely eliminated. Then, in vivo electric field measurement shows that the 2-pole arrangement may provide better cortical targeting than the 4-pole mode. A pilot animal experiment was conducted in which evoked motion and electromyographic activation of the contralateral forelimb were observed, which indicated that the 2-pole tTIS had successfully activated the primary motor cortex in a rat. Motor activation induced by the 2-pole tTIS demonstrated the feasibility and safety potential when applying our tTIS device for neuromodulation.

Long-Term Motor Cortical Electrical Stimulation Ameliorates 6-Hydroxydopamine-Induced Motor Dysfunctions and Exerts Neuroprotective Effects in a Rat Model of Parkinson's Disease.

OBJECTIVE: Cortical electrical stimulation (CES) can modulate cortical excitability through a plasticity-like mechanism and is considered to have therapeutic potentials in Parkinson's disease (PD). However, the precise therapeutic value of such approach for PD remains unclear. Accordingly, we adopted a PD rat model to determine the therapeutic effects of CES. The current study was thus designed to identify the therapeutic potential of CES in PD rats. METHODS: A hemiparkinsonian rat model, in which lesions were induced using unilateral injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle, was applied to identify the therapeutic effects of long-term (4-week) CES with intermittent theta-burst stimulation (iTBS) protocol (starting 24 h after PD lesion observation, 1 session/day, 5 days/week) on motor function and neuroprotection. After the CES intervention, detailed functional behavioral tests including gait analysis, akinesia, open-field locomotor activity, apomorphine-induced rotation as well as degeneration level of dopaminergic neurons were performed weekly up to postlesion week 4. RESULTS: After the CES treatment, we found that the 4-week CES intervention ameliorated the motor deficits in gait pattern, akinesia, locomotor activity, and apomorphine-induced rotation. Immunohistochemistry and tyrosine hydroxylase staining analysis demonstrated that the number of dopamine neurons was significantly greater in the CES intervention group than in the sham treatment group. CONCLUSION: This study suggests that early and long-term CES intervention could reduce the aggravation of motor dysfunction and exert neuroprotective effects in a rat model of PD. Further, this preclinical model of CES may increase the scope for the potential use of CES and serve as a link between animal and PD human studies to further identify the therapeutic mechanism of CES for PD or other neurological disorders.

Time-course gait pattern analysis in a rat model of foot drop induced by ventral root avulsion injury.

Foot drop is a common clinical gait impairment characterized by the inability to raise the foot or toes during walking due to the weakness of the dorsiflexors of the foot. Lumbar spine disorders are common neurogenic causes of foot drop. The accurate prognosis and treatment protocols of foot drop are not well delineated in the scientific literature due to the heterogeneity of the underlying lumbar spine disorders, different severities, and distinct definitions of the disease. For translational purposes, the use of animal disease models could be the best way to investigate the pathogenesis of foot drop and help develop effective therapeutic strategies for foot drops. However, no relevant and reproducible foot drop animal models with a suitable gait analysis method were developed for the observation of foot drop symptoms. Therefore, the present study aimed to develop a ventral root avulsion (VRA)-induced foot drop rat model and record detailed time-course changes of gait pattern following L5, L6, or L5 + L6 VRA surgery. Our results suggested that L5 + L6 VRA rats exhibited changes in gait patterns, as compared to sham lesion rats, including a significant reduction of walking speed, step length, toe spread, and swing phase time, as well as an increased duration of the stance phase time. The ankle kinematic data exhibited that the ankle joint angle increased during the mid-swing stage, indicating a significant foot drop pattern during locomotion. Time-course observations displayed that these gait impairments occurred as early as the first-day post-lesion and gradually recovered 7-14 days post-injury. We conclude that the proposed foot drop rat model with a video-based gait analysis approach can precisely detect the foot drop pattern induced by VRA in rats, which can provide insight into the compensatory changes and recovery in gait patterns and might be useful for serving as a translational platform bridging human and animal studies for developing novel therapeutic strategies for foot drop.

Cortical Electrical Stimulation Ameliorates Traumatic Brain Injury-Induced Sensorimotor and Cognitive Deficits in Rats.

Objective: Individuals with different severities of traumatic brain injury (TBI) often suffer long-lasting motor, sensory, neurological, or cognitive disturbances. To date, no neuromodulation-based therapies have been used to manage the functional deficits associated with TBI. Cortical electrical stimulation (CES) has been increasingly developed for modulating brain plasticity and is considered to have therapeutic potential in TBI. However, the therapeutic value of such a technique for TBI is still unclear. Accordingly, an animal model of this disease would be helpful for mechanistic insight into using CES as a novel treatment approach in TBI. The current study aims to apply a novel CES scheme with a theta-burst stimulation (TBS) protocol to identify the therapeutic potential of CES in a weight drop-induced rat model of TBI. Methods: TBI rats were divided into the sham CES treatment group and CES treatment group. Following early and long-term CES intervention (starting 24 h after TBI, 1 session/day, 5 days/week) in awake TBI animals for a total of 4 weeks, the effects of CES on the modified neurological severity score (mNSS), sensorimotor and cognitive behaviors and neuroinflammatory changes were identified. Results: We found that the 4-week CES intervention significantly alleviated the TBI-induced neurological, sensorimotor, and cognitive deficits in locomotor activity, sensory and recognition memory. Immunohistochemically, we found that CES mitigated the glial fibrillary acidic protein (GFAP) activation in the hippocampus. Conclusion: These findings suggest that CES has significant benefits in alleviating TBI-related symptoms and represents a promising treatment for TBI.

Sonogenetic-Based Neuromodulation for the Amelioration of Parkinson's Disease.

Sonogenetics is a promising strategy allowing the noninvasive and selective activation of targeted neurons in deep brain regions; nevertheless, its therapeutic outcome for neurodegeneration diseases that need long-term treatment remains to be verified. We previously enhanced the ultrasound (US) sensitivity of targeted cells by genetic modification with an engineered auditory-sensing protein, mPrestin (N7T, N308S). In this study, we expressed mPrestin in the dopaminergic neurons of the substantia nigra in Parkinson's disease (PD) mice and used 0.5 MHz US for repeated and localized brain stimulation. The mPrestin expression in dopaminergic neurons persisted for at least 56 days after a single shot of adeno-associated virus, suggesting that the period of expression was long enough for US treatment in mice. Compared to untreated mice, US stimulation ameliorated the dopaminergic neurodegeneration 10-fold and mitigated the PD symptoms of the mice 4-fold, suggesting that this sonogenetic strategy has the clinical potential to treat neurodegenerative diseases.

CCL5 via GPX1 activation protects hippocampal memory function after mild traumatic brain injury.

Traumatic brain injury (TBI) is a prevalent head injury worldwide which increases the risk of neurodegenerative diseases. Increased reactive oxygen species (ROS) and inflammatory chemokines after TBI induces secondary effects which damage neurons. Targeting NADPH oxidase or increasing redox systems are ways to reduce ROS and damage. Earlier studies show that C-C motif chemokine ligand 5 (CCL5) has neurotrophic functions such as promoting neurite outgrowth as well as reducing apoptosis. Although CCL5 levels in blood are associated with severity in TBI patients, the function of CCL5 after brain injury is unclear. In the current study, we induced mild brain injury in C57BL/6 (wildtype, WT) mice and CCL5 knockout (CCL5-KO) mice using a weight-drop model. Cognitive and memory functions in mice were analyzed by Novel-object-recognition and Barnes Maze tests. The memory performance of both WT and KO mice were impaired after mild injury. Cognition and memory function in WT mice quickly recovered after 7 days but recovery took more than 14 days in CCL5-KO mice. FJC, NeuN and Hypoxyprobe staining revealed large numbers of neurons damaged by oxidative stress in CCL5-KO mice after mTBI. NADPH oxidase activity show increased ROS generation together with reduced glutathione peroxidase-1 (GPX1) and glutathione (GSH) activity in CCL5-KO mice; this was opposite to that seen in WT mice. CCL5 increased GPX1 expression and reduced intracellular ROS levels which subsequently increased cell survival both in primary neuron cultures and in an overexpression model using SHSY5Y cell. Memory impairment in CCL5-KO mice induced by TBI could be rescued by i.p. injection of the GSH precursor - N-acetylcysteine (NAC) or intranasal delivery of recombinant CCL5 into mice after injury. We conclude that CCL5 is an important molecule for GPX1 antioxidant activation during post-injury day 1-3, and protects hippocampal neurons from ROS as well as improves memory function after trauma.

Neuromodulatory effects of repetitive transcranial magnetic stimulation on neural plasticity and motor functions in rats with an incomplete spinal cord injury: A preliminary study.

We investigated the effects of intermittent theta-burst stimulation (iTBS) on locomotor function, motor plasticity, and axonal regeneration in an animal model of incomplete spinal cord injury (SCI). Aneurysm clips with different compression forces were applied extradurally around the spinal cord at T10. Motor plasticity was evaluated by examining the motor evoked potentials (MEPs). Long-term iTBS treatment was given at the post-SCI 5th week and continued for 2 weeks (5 consecutive days/week). Time-course changes in locomotor function and the axonal regeneration level were measured by the Basso Beattie Bresnahan (BBB) scale, and growth-associated protein (GAP)-43 expression was detected in brain and spinal cord tissues. iTBS-induced potentiation was reduced at post-1-week SCI lesion and had recovered by 4 weeks post-SCI lesion, except in the severe group. Multiple sessions of iTBS treatment enhanced the motor plasticity in all SCI rats. The locomotor function revealed no significant changes between pre- and post-iTBS treatment in SCI rats. The GAP-43 expression level in the spinal cord increased following 2 weeks of iTBS treatment compared to the sham-treatment group. This preclinical model may provide a translational platform to further investigate therapeutic mechanisms of transcranial magnetic stimulation and enhance the possibility of the potential use of TMS with the iTBS scheme for treating SCIs.

Subsequent Acupuncture Reverses the Aftereffects of Intermittent Theta-Burst Stimulation.

Objective: This study explored whether acupuncture affects the maintenance of long-term potentiation (LTP)-like plasticity induced by transcranial magnetic stimulation (TMS) and the acquisition of motor skills following repetitive sequential visual isometric pinch task (SVIPT) training. Methods: Thirty-six participants were recruited. The changes in the aftereffects induced by intermittent theta-burst stimulation (iTBS) and followed acupuncture were tested by the amplitude motor evoked potential (MEP) at pre-and-post-iTBS for 30 min and at acupuncture-in and -off for 30 min. Secondly, the effects of acupuncture on SVIPT movement in inducing error rate and learning skill index were tested. Results: Following one session of iTBS, the MEP amplitude was increased and maintained at a high level for 30 min. The facilitation of MEP was gradually decreased to the baseline level during acupuncture-in and did not return to a high level after needle extraction. The SVIPT-acupuncture group had a lower learning skill index than those in the SVIPT group, indicating that acupuncture intervention after SVIPT training may restrain the acquisition ability of one's learning skills. Conclusion: Acupuncture could reverse the LTP-like plasticity of the contralateral motor cortex induced by iTBS. Subsequent acupuncture may negatively affect the efficacy of the acquisition of learned skills in repetitive exercise training.

Early Repetitive Transcranial Magnetic Stimulation Exerts Neuroprotective Effects and Improves Motor Functions in Hemiparkinsonian Rats.

Repetitive transcranial magnetic stimulation (rTMS) is a popular noninvasive technique for modulating motor cortical plasticity and has therapeutic potential for the treatment of Parkinson's disease (PD). However, the therapeutic benefits and related mechanisms of rTMS in PD are still uncertain. Accordingly, preclinical animal research is helpful for enabling translational research to explore an effective therapeutic strategy and for better understanding the underlying mechanisms. Therefore, the current study was designed to identify the therapeutic effects of rTMS on hemiparkinsonian rats. A hemiparkinsonian rat model, induced by unilateral injection of 6-hydroxydopamine (6-OHDA), was applied to evaluate the therapeutic potential of rTMS in motor functions and neuroprotective effect of dopaminergic neurons. Following early and long-term rTMS intervention with an intermittent theta burst stimulation (iTBS) paradigm (starting 24 h post-6-OHDA lesion, 1 session/day, 7 days/week, for a total of 4 weeks) in awake hemiparkinsonian rats, the effects of rTMS on the performance in detailed functional behavioral tests, including video-based gait analysis, the bar test for akinesia, apomorphine-induced rotational analysis, and tests of the degeneration level of dopaminergic neurons, were identified. We found that four weeks of rTMS intervention significantly reduced the aggravation of PD-related symptoms post-6-OHDA lesion. Immunohistochemically, the results showed that tyrosine hydroxylase- (TH-) positive neurons in the substantia nigra pars compacta (SNpc) and fibers in the striatum were significantly preserved in the rTMS treatment group. These findings suggest that early and long-term rTMS with the iTBS paradigm exerts neuroprotective effects and mitigates motor impairments in a hemiparkinsonian rat model. These results further highlight the potential therapeutic effects of rTMS and confirm that long-term rTMS treatment might have clinical relevance and usefulness as an additional treatment approach in individuals with PD.

The voiding efficiency in rat models with dopaminergic brain lesions induced through unilateral and bilateral intrastriatal injections.

Bladder dysfunction is a common phenomenon in Parkinson's disease (PD) patients. A research attempt was made to analyze the voiding efficiency (VE) and bladder functions in rats with PD induced by unilateral or bilateral injections of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle. PD rats were divided into unilateral- and bilateral-injected groups and subjected to rotation and beam walking tests. Further, the experimental rats underwent cystometric measurements for analyses of bladder dysfunction and VE. Immunohistochemical analysis was performed to analyze the dopaminergic neuron depletion on the target area. Outcomes of the rotation and beam walking tests revealed the extent of parkinsonism in the experimental rats. Urodynamic observations denoted that rats with unilateral PD exhibited a significantly decreased VE (from 68.3±3.5% to 32.7±5.8%), while rats with bilateral PD displayed a much-reduced and substantially lower level of VE of 18.3±5.1% compared to the control value and to that of rats with unilateral PD. Rats with bilateral PD showed more-extensive behavioral deficits and urodynamic changes than did rats with unilateral PD. These significant changes in motor, behavioral, bladder function and VE were due to an extensive degeneration of dopaminergic neurons in the substantia nigra region on both sides of the brain. The obtained results were substantiated with appropriate immunohistochemical results.