Ann-Maree Vallence

Background
Corticospinal excitability, measured by motor-evoked potentials (MEPs), is often impaired in neurological and musculoskeletal conditions. Transcranial direct current stimulation (tDCS) can modulate cortical excitability and improve clinical outcomes, yet inconsistencies in parameter settings complicate identification of optimal protocols.

Objective
Our primary objective was to examine the effects of: (i) stimulation polarity, (ii) duration, (iii) intensity, (iv) frequency, (v) electrode montage, and (vi) electrode design (size/shape) on MEP size.

Methods
Nine databases were searched from inception to 24th November 2023. We identified 84 individual cohorts (1,709 participants) and assessed time-dependent effects of each parameter on M1 MEP-to-baseline ratio in healthy and clinical populations using multi-level longitudinal meta-analysis.

Results
Anodal tDCS increased MEP size, with effects lasting up to 120 min post-stimulation. Consistent effects were observed with anodal tDCS durations ≥ 20 min and intensities ≥ 1.5 mA. Despite cohorts being matched, cathodal tDCS reduced MEP size for approximately 15 min post-stimulation, with significant effects at durations ≥ 9 min, intensity effects were inconclusive. Electrode montage and electrode size/shape influenced MEP, with greatest effect for electrodes over both the primary motor cortex and the dorsolateral pre-frontal cortex or over the cerebellar region, using 4 cm2 ring and 35 cm2 rectangular electrodes.

Conclusion
tDCS effects on corticospinal excitability are parameter dependent. Anodal tDCS tends to facilitate excitability, whereas cathodal tDCS tends to inhibit excitability (depending on stimulation parameters). Specific durations, intensities, electrode placements and designs will ensure effectiveness and optimise safety. Findings support a parameter-specific approach to guide tailored neuromodulation interventions to enhance motor cortex rehabilitation outcomes.

Purpose
Explore perspectives of people living with neurological conditions in Western Australia (WA) on robot-assisted lower limb neurorehabilitation (RALLR), and implementation requirements.

Materials and methods
This co-designed, qualitative descriptive study included people living with neurological conditions. In-person semi-structured focus groups (FGs) were facilitated by a person with lived experience of stroke. FGs were recorded, data were transcribed, and thematically analysed using a reflexive approach.

Results
Five FGs included 24 participants (54.2% women, median age 50 years). Of these, thirteen participants had RALLR experience. Primary neurological conditions represented among participants comprised spinal cord injury (n = 11), stroke (n = 3), multiple sclerosis (n = 2), and other conditions (n = 8). Three main themes were established: perceived benefits (physiological, psychosocial, therapy, ambulation, independence, and pain), barriers (awareness, access, cost, psychological challenges, and device limitations), and recommendations for future implementation in WA (access, design, and purpose of robotic devices).

Conclusions
This study highlights the desire for improved access to RALLR among people living with neurological conditions in WA. Participants acknowledged multiple benefits of RALLR; however, addressing financial, design, and availability barriers of RALLR are necessary for successful adoption. Future efforts should prioritise accessibility in both metropolitan and regional areas, optimise device usability, and foster interdisciplinary collaboration in RALLR integration.

Anterior cruciate ligament reconstruction (ACLR) can cause arthrogenic muscle inhibition (AMI) or persistent muscle weakness that impairs physical function and return to sport. Deficits in voluntary activation (one method to measure AMI) are thought to contribute to AMI, however, the specific neurophysiological underpinnings remain inconclusive. The primary objective of this study was to explore changes in intracortical excitability (inhibition and facilitation) of the quadriceps representation in the primary motor cortex pre- and post-ALCR. Our secondary objective was to explore changes in hamstrings intracortical excitability pre- and post-ALCR.
Prospective case-series pre-post-ACLR. Single- and paired-pulse transcranial magnetic stimulation (TMS) was delivered over the motor cortex with responses recorded via surface electromyography from the active vastus medialis (quadriceps) and semitendinosus (hamstrings). TMS outcomes were short- and long-interval-intracortical-inhibition (SICI, LICI) and short-interval-intracortical-facilitation (SICF). Data are reported as median (interquartile range [IQR]) and analysed using non-parametric analysis of variance, with significance accepted when p < 0.05.
Twenty-one participants (38% female) with a mean (standard deviation) age of 24.5 (4.7) years were included. Following ACLR participants had increased quadriceps inhibition (SICI, p = 0.005) and facilitation at all SICF peaks (Peak 1: p < 0.05 Peak 2: p = 0.016, Peak 3 < 0.05). There were no changes following ACLR in quadriceps LICI (p = 0.108). No differences were detected in hamstring excitability.
In the acute post-operative period following ACLR, there is increased activity within some intracortical pathways. The altered excitability of SICI and SICF circuits might contribute to long-term issues, such as impaired voluntary activation resulting in arthrogenic muscle inhibition, in post-ACLR patients.

Individuals who face difficulties with voluntary movement experience considerable challenges in performing everyday tasks, significantly compromising their sense of autonomy. Transcranial alternating current stimulation (tACS) holds promise in modulating sensorimotor beta oscillations, which underscore voluntary movement. However, the exact effect of beta tACS on oscillatory power is still largely elusive. This study aimed to examine the effect of different intensities of beta tACS (20 Hz) on both resting-state and event-related sensorimotor oscillations. Twenty-one healthy young adults (13 female; mean age 24.30 ± 4.84 years) received four separate 20 min sessions of tACS at different intensities (sham, 0.5 mA, 1.0 mA, or 1.5 mA, peak-to-peak), targeting the left primary motor cortex during rest. Electroencephalography (EEG) was recorded before and after stimulation, during both resting state and a self-paced right index finger button press task. Changes in sensorimotor beta power (13–30 Hz) were analyzed. For the resting-state, none of the real stimulation intensities induced significant changes in beta power relative to sham. For event-related activity, we observed intensity-dependent changes in bilateral broadband power (4–90 Hz): during movement preparation, 1.0 mA stimulation increased power; during movement termination, 0.5 mA stimulation decreased power while 1.0 mA and 1.5 mA stimulation induced comparable increases in power. While none of the stimulation intensities induced changes in broadband power during movement execution, 1.0 mA stimulation shifted participants’ peak beta frequency toward the tACS frequency. Interestingly, changes in power during movement preparation and execution following 1.0 mA stimulation were negatively associated with participants’ pre-tACS peak beta frequency. Together, these findings contribute to our understanding of the sensorimotor response to beta tACS, as well as the effect of stimulation intensity on tACS-induced neuromodulation, which has important implications for research and clinical settings.

Purpose
This study aimed to investigate bilateral motor control and connectivity between supplementary motor area (SMA) and primary motor cortex (M1) in younger, middle-aged, and older healthy adults.

Methods
32 younger (mean age 22.8 ± 5.3 years), 18 middle-aged (47.6 ± 6.5 years), and 23 older (75.8 ± 6.7 years) adults were tested. Bilateral motor control was assessed using the Purdue pegboard. Dual-site transcranial magnetic stimulation (TMS) was used to measure SMA–M1 connectivity at different conditioning stimulation intensities.

Results
Older adults had significantly poorer motor performance than younger and middle-aged in all pegboard subtests. Notably, there were no conclusive differences in motor performance between younger and middle-aged adults. There was no conclusive evidence supporting age-related and intensity-related differences in SMA–M1 connectivity between younger, middle-aged, and older adults. There was also no conclusive evidence to support clear associations between SMA–M1 connectivity and bilateral motor control.

Conclusion
Age-related declines in bilateral motor functioning was found in older, but not middle-aged adults. The bilateral motor functioning of middle-aged adults is more young-like than old-like. The lack of conclusive age- and intensity-related differences in SMA–M1 connectivity, and lack of conclusive association with bilateral motor performance, might be due to high inter-individual variability in SMA–M1 connectivity. Potential factors contributing to this variability include SMA and M1 morphometry, the structural connectivity between these regions, and the localisation of SMA.

Objective
Tremor is one of the most common motor symptoms of Parkinson’s disease (PD), with adverse effects on daily functioning and quality of life. This study investigated the effects of concurrent intermittent theta-burst stimulation and gamma frequency transcranial alternating current stimulation (iTBS-γ-tACS) on neuroplasticity in the motor cortex and resting tremor severity in individuals with tremor-dominant PD.

Methods
Eighteen individuals (mean age 66.8 ± 10.0 years, 6 females) with tremor-dominant PD attended two sessions, one involving iTBS-γ-tACSreal (real iTBS and real tACS), and the other involving iTBS-γ-tACSsham (real iTBS and sham tACS). Measures of neuroplasticity (corticospinal excitability and intracortical inhibition) and tremor severity were measured before and after iTBS-γ-tACS.

Results
Corticospinal excitability in the target muscle increased significantly after iTBS-γ-tACSreal, but not iTBS-γ-tACSsham. Intracortical inhibition and tremor severity were not significantly modulated by either stimulation condition.

Conclusions
iTBS-γ-tACSreal, but not iTBS-γ-tACSsham, elicited long-term potentiation-like neuroplastic changes in the target muscle.

Significance
This is the first study to show iTBS-γ-tACS can induce neuroplasticity in individuals with tremor-dominant PD. Despite no significant changes in tremor severity, future research should explore if targeting neuroplasticity in the cortical representation of the tremor-dominant muscle and/or multi-session administrations of iTBS-γ-tACS can reduce tremor.

Background
Mobility impairments are common in persons with multiple sclerosis (MS), reducing independence and quality of life. Walking interventions can enhance mobility skills, with auditory-motor coupling (synchronising steps with auditory beats) serving as a promising method. Design and participants’ characteristics may impact intervention effectiveness, but have not yet been compared across studies in persons with MS.

Aims
This scoping review aims to determine what design and implementation features are present in studies involving auditory-motor coupling for mobility in persons with MS. Features being assessed include auditory stimuli, mobility variables, participants’ characteristics, and the acceptability and appropriateness of the interventions.

Methods
We searched eight scientific databases and three clinical trial registries for literature on auditory-motor coupling in studies of persons with MS. We extracted features related to study design, participants, and intervention acceptability.

Results
Fifteen original research articles were identified, including seven randomised controlled intervention studies. Most articles involved persons with mild to moderate disability. Auditory stimulation was provided via music or metronome. Few studies reported involving people with MS in the design (n=2) or allowed autonomy in music choice (n=2). Common outcomes were walking quality and speed. All studies reported that acceptability was high.

Conclusion
Review findings on existing evidence of auditory-motor coupling in persons with MS indicate good user acceptability. However consideration of participants’ characteristics, such as musical experience and MS symptoms, and auditory stimuli consideration, alongside inclusion of persons with MS in intervention development is needed to strength the evidence of auditory coupling as an intervention in MS.

Blood flow restriction (BFR) combined with low work rate exercise can enhance muscular and cardiovascular fitness. However, whether neural mechanisms mediate these enhancements remains unknown. This study examined changes in corticospinal excitability and motor cortical inhibition following arm cycle ergometry with and without BFR. Twelve healthy males (24 ± 4 years) completed four, randomized 15‐min arm cycling conditions: high work rate (HW: 60% maximal power output), low work rate (LW: 30% maximal power output), low work rate with BFR (LW‐BFR) and BFR without exercise (BFR‐only). For BFR conditions, cuffs were applied around the upper arm and inflated to 70% of arterial occlusion pressure continuously during exercise. Single‐pulse transcranial magnetic stimulation was delivered to left primary motor cortex (M1) to elicit motor‐evoked potentials (MEP) in the right biceps brachii during a low‐level isometric contraction. MEP amplitude and cortical silent period (cSP) duration were measured before and 1, 10 and 15 min post‐exercise. MEP amplitude increased significantly from baseline to Post‐10 and Post‐15 for both the HW (both z  < −7.07, both P  < 0.001) and LW‐BFR conditions (both z  < −5.56, both P  < 0.001). For the LW condition without BFR, MEP amplitude increased significantly from baseline to Post‐10 ( z  = −3.53, P  = 0.003) but not Post‐15 ( z =  −1.85, P  = 0.388). The current findings show that HW arm cycling and LW‐BFR led to longer‐lasting increases in corticospinal excitability than LW arm cycling alone. Future research should examine whether the increased corticospinal excitability is associated with the improvements in muscle strength observed with BFR exercise. A mechanistic understanding of BFR exercise improvement could guide BFR interventions in clinical populations.
What is the central question of this study? Does low work rate arm cycling with blood flow restriction (BFR) lead to an increase in corticospinal excitability and decrease in cortical inhibition that is comparable to high work rate arm cycling and greater than low work rate arm cycling and BFR without exercise? What is the main finding and its importance? Unrestricted high work rate arm cycling and low work rate arm cycling combined with BFR led to longer lasting increases in corticospinal excitability than low work rate arm cycling alone. Future research is needed to examine whether the increased corticospinal excitability is associated with the improvements in muscle strength observed with BFR exercise.

Abstract
Resting tremor—involuntary and rhythmic shaking that usually occurs in the limbs—is the most common presenting motor symptom in Parkinson’s disease (PD). Tremor is not associated with the severity of dopamine depletion in the basal ganglia, and dopaminergic medication, which is used primarily to target dopamine depletion in the basal ganglia, has limited efficacy in reducing tremor. This suggests that other brain regions might underpin tremor in PD. Intracortical inhibition within the primary motor cortex (M1) has been implicated in tremor: intracortical inhibition in M1 is lower in PD than controls, higher motor cortex GABA is associated with lower tremor severity in PD, and pharmacological increases in GABA activity reduce tremor severity in PD. A combined intermittent theta-burst stimulation (iTBS)—gamma transcranial alternating current stimulation (tACS) protocol has been shown to increase short-interval intracortical inhibition (SICI) in PD. Therefore, in the current study, we examined M1 excitability, SICI, and resting tremor before and after real and sham iTBS-tACS. In a within-subjects design, we tested 19 participants (13 male; mean age 66 years) with idiopathic, tremor-dominant PD OFF medication. M1 excitability increased after real but not sham iTBS-tACS. There was no change in SICI after either real or sham iTBS-tACS. Resting tremor in the extensor carpi radialis showed a trend to increase after sham but not real iTBS, indicating that real iTBS-tACS might have prevented resumption of tremor activity in PD participants OFF medication. These findings provide preliminary evidence that iTBS-tACS induced long-term potentiation-like plasticity in M1 in tremor-dominant PD, which could influence tremor severity. However, further research is needed to examine the time-course of iTBS-tACS-induced changes in M1 excitability and tremor severity. If iTBS-tACS can reduce tremor, it could offer an alternative, or supplementary, treatment to levodopa medication for people with tremor-dominant PD.

Research Category and Technology and Methods
Clinical Research: 10. Transcranial Magnetic Stimulation (TMS)

Aim
Non-invasive brain stimulation (NIBS) is increasingly being trialled in people with neurodevelopmental disorders, including autism spectrum disorder (ASD), but limited literature exists examining safety and tolerability. We explored safety and tolerability data from an ongoing clinical trial of intermittent theta burst stimulation (iTBS) in young people with ASD.

Methods
Interim analyses of safety and tolerability included data from 73 young people (14-40 years) participating in an Australian clinical trial of iTBS in ASD. Intervention involved twenty sessions of active [mage=22.0 (7.50), 56.8% male] or sham [mage=21.9 (6.70); 63.2% male] stimulation to the right temporoparietal junction. Baseline measures were collected prior to intervention and safety was evaluated four times throughout the course of iTBS using a structured questionnaire.

Results
Preliminary data show that 73.2% of participants report experiencing at least one side effect at any stage of intervention [(active=75%, sham=71%), χ2(1, N=82)=6.45, p>.05]. Commonly reported symptoms at any stage across the twenty sessions were headaches (active = 59%, sham=50%), anxiety (active=41%, sham=53%), fatigue (active=39%, sham=42%) and neck pain (active=27%, sham=21%). Mean symptom severity ranged from 1 (mild) to 3 (moderate) out of 5 (severe). Chi-squared testing indicated that anxiety was more commonly reported in the sham condition compared to active [χ2(1, N=82)=6.16, p=.01], however this effect was small (φ=0.15). No serious adverse events have been reported.

Conclusions
These interim findings suggest that side effects from iTBS in autism are relatively common but are typically of mild severity and not specific to active stimulation. The incidence of reported symptoms across treatment conditions could at least partially be explained by factors other than iTBS (e.g., travel) and methodology (e.g., obtaining weekly reports). While the trial is continuing, these findings add to a growing body of literature supporting the safety and tolerability of NIBS in neurodevelopmental disorders.
Research Category and Technology and Methods

Research Category and Technology and Methods
Clinical Research: 10. Transcranial Magnetic Stimulation (TMS)