Selective cancellation of reactive or anticipated movements: Differences in speed of action reprogramming, but not stopping.

The ability to inhibit movements is an essential component of a healthy executive control system. Two distinct but commonly used tasks to assess motor inhibition are the stop signal task (SST) and the anticipated response inhibition (ARI) task. The SST and ARI tasks are similar in that they both require cancelation of a prepotent movement; however, the SST involves cancelation of a speeded reaction to a temporally unpredictable signal, while the ARI task involves cancelation of an anticipated response that the participant has prepared to enact at a wholly predictable time. 33 participants (mean age = 33.3 years, range = 18-55 years) completed variants of the SST and ARI task. In each task, the majority of trials required bimanual button presses, while on a subset of trials a stop signal indicated that one of the presses should be cancelled (i.e., motor selective inhibition). Additional variants of the tasks also included trials featuring signals which were to be ignored, allowing for insights into the attentional component of the inhibitory response. Electromyographic (EMG) recordings allowed detailed comparison of the characteristics of voluntary action and cancellation. The speed of the inhibitory process was not influenced by whether the enacted movement was reactive (SST) or anticipated (ARI task). However, the ongoing (non-cancelled) component of anticipated movements was more efficient than reactive movements, as a result of faster action reprogramming (i.e., faster ongoing actions following successful motor selective inhibition). Older age was associated with both slower inhibition and slower action reprogramming across all reactive and anticipated tasks.

Low-intensity repetitive transcranial magnetic stimulation is safe and well tolerated by people living with MS - outcomes of the phase I randomised controlled trial (TAURUS).

Background: Low-intensity repetitive transcranial magnetic stimulation (rTMS), delivered as a daily intermittent theta burst stimulation (iTBS) for four consecutive weeks, increased the number of new oligodendrocytes in the adult mouse brain. Therefore, rTMS holds potential as a remyelinating intervention for people with multiple sclerosis (MS). Objective: Primarily to determine the safety and tolerability of our rTMS protocol in people with MS. Secondary objectives include feasibility, blinding and an exploration of changes in magnetic resonance imaging (MRI) metrics, patient-reported outcome measures (PROMs) and cognitive or motor performance. Methods: A randomised (2:1), placebo controlled, single blind, parallel group, phase 1 trial of 20 rTMS sessions (600 iTBS pulses per hemisphere; 25% maximum stimulator output), delivered over 4-5 weeks. Twenty participants were randomly assigned to 'sham' (n = 7) or active rTMS (n = 13), with the coil positioned at 90° or 0°, respectively. Results: Five adverse events (AEs) including one serious AE reported. None were related to treatment. Protocol compliance was high (85%) and blinding successful. Within participant MRI metrics, PROMs and cognitive or motor performance were unchanged over time. Conclusion: Twenty sessions of rTMS is safe and well tolerated in a small group of people with MS. The study protocol and procedures are feasible. Improvement of sham is warranted before further investigating safety and efficacy.

Influence of age and cognitive demand on motor decision making under uncertainty: a study on goal directed reaching movements.

In everyday life, we constantly make decisions about actions to be performed subsequently. Research on motor decision making has provided empirical evidence for an influence of decision uncertainty on movement execution in young adults. Further, decision uncertainty was suggested to be increased in older adults due to limited cognitive resources for the integration of information and the prediction of the decision outcomes. However, the influence of cognitive aging on decision uncertainty during motor decision making and movement execution has not been investigated, yet. Thus, in the current study, we presented young and older adults with a motor decision making task, in which participants had to decide on pointing towards one out of five potential targets under varying cognitive demands. Statistical analyses revealed stronger decreases in correctly deciding upon the pointing target, i.e. task performance, from low to higher cognitive demand in older as compared to young adults. Decision confidence also decreased more strongly in older adults with increasing cognitive demand, however, only when collapsing across correct and incorrect decision trials, but not when considering correct decision trials, only. Further, older adults executed reaching movements with longer reaction times and increased path length, though the latter, again, not when considering correct decision trials, only. Last, reaction time and variability in movement execution were both affected by cognitive demand. The outcomes of this study provide a differentiated picture of the distinct and joint effects of aging and cognitive demand during motor decision making.

Stopping Speed in Response to Auditory and Visual Stop Signals Depends on Go Signal Modality.

Past research has found that the speed of the action cancellation process is influenced by the sensory modality of the environmental change that triggers it. However, the effect on selective stopping processes (where participants must cancel only one component of a multicomponent movement) remains unknown, despite these complex movements often being required as we navigate our busy modern world. Thirty healthy adults (mean age = 31.1 years, SD = 10.5) completed five response-selective stop signal tasks featuring different combinations of "go signal" modality (the environmental change baring an imperative to initiate movement; auditory or visual) and "stop signal" modality (the environmental change indicating that action cancellation is required: auditory, visual, or audiovisual). EMG recordings of effector muscles allowed detailed comparison of the characteristics of voluntary action and cancellation between tasks. Behavioral and physiological measures of stopping speed demonstrated that the modality of the go signal influenced how quickly participants cancelled movement in response to the stop signal: Stopping was faster in two cross-modal experimental conditions (auditory go - visual stop; visual go - auditory stop), than in two conditions using the same modality for both signals. A separate condition testing for multisensory facilitation revealed that stopping was fastest when the stop signal consisted of a combined audiovisual stimulus, compared with all other go-stop stimulus combinations. These findings provide novel evidence regarding the role of attentional networks in action cancellation and suggest modality-specific cognitive resources influence the latency of the stopping process.

Impaired motor inhibition during perceptual inhibition in older, but not younger adults: a psychophysiological study.

The prefrontal cortex (PFC) governs the ability to rapidly cancel planned movements when no longer appropriate (motor inhibition) and ignore distracting stimuli (perceptual inhibition). It is unclear to what extent these processes interact, and how they are impacted by age. The interplay between perceptual and motor inhibition was investigated using a Flanker Task, a Stop Signal Task and a combined Stop Signal Flanker Task in healthy young (n = 33, Mean = 24 years) and older adults (n = 32, Mean = 71 years). PFC activity was measured with functional near-infrared spectroscopy (fNIRS), while electromyography (EMG) measured muscle activity in the fingers used to respond to the visual cues. Perceptual inhibition (the degree to which incongruent flankers slowed response time to a central cue) and motor inhibition (the speed of cancellation of EMG activation following stop cues) independently declined with age. When both processes were engaged together, PFC activity increased for both age groups, however only older adults exhibited slower motor inhibition. The results indicate that cortical upregulation was sufficient to compensate for the increased task demands in younger but not older adults, suggesting potential resource sharing and neural limitations particularly in older adults.

A unified account of simple and response-selective inhibition.

Response inhibition is a key attribute of human executive control. Standard stop-signal tasks require countermanding a single response; the speed at which that response can be inhibited indexes the efficacy of the inhibitory control networks. However, more complex stopping tasks, where one or more components of a multi-component action are cancelled (i.e., response-selective stopping) cannot be explained by the independent-race model appropriate for the simple task (Logan and Cowan 1984). Healthy human participants (n=28; 10 male; 19-40 years) completed a response-selective stopping task where a 'go' stimulus required simultaneous (bimanual) button presses in response to left and right pointing green arrows. On a subset of trials (30%) one, or both, arrows turned red (constituting the stop signal) requiring that only the button-press(es) associated with red arrows be cancelled. Electromyographic recordings from both index fingers (first dorsal interosseous) permitted the assessment of both voluntary motor responses that resulted in overt button presses, and activity that was cancelled prior to an overt response (i.e., partial, or covert, responses). We propose a simultaneously inhibit and start (SIS) model that extends the independent race model and provides a highly accurate account of response-selective stopping data. Together with fine-grained EMG analysis, our model-based analysis offers converging evidence that the selective-stop signal simultaneously triggers a process that stops the bimanual response and triggers a new unimanual response corresponding to the green arrow. Our results require a reconceptualisation of response-selective stopping and offer a tractable framework for assessing such tasks in healthy and patient populations. Significance Statement Response inhibition is a key attribute of human executive control, frequently investigated using the stop-signal task. After initiating a motor response to a go signal, a stop signal occasionally appears at a delay, requiring cancellation of the response. This has been conceptualised as a 'race' between the go and stop processes, with the successful (or failed) cancellation determined by which process wins the race. Here we provide a novel computational model for a complex variation of the stop-signal task, where only one component of a multicomponent action needs to be cancelled. We provide compelling muscle activation data that support our model, providing a robust and plausible framework for studying these complex inhibition tasks in both healthy and pathological cohorts.

Comparison of online and offline applications of dual-site transcranial alternating current stimulation (tACS) over the pre-supplementary motor area (preSMA) and right inferior frontal gyrus (rIFG) for improving response inhibition.

The efficacy of transcranial alternating current stimulation (tACS) is thought to be brain state-dependent, such that tACS during task performance would be hypothesised to offer greater potential for improving performance compared to tACS at rest. However, to date, no empirical study has tested this postulation. The current study compared the effects of dual-site beta tACS applied during a stop signal task (online) to the effects of the same tACS protocol applied prior to the task (offline) and a sham control stimulation in 53 young, healthy adults (32 female; 18-35 yrs). The right inferior frontal gyrus (rIFG) and centre (midline) of the pre-supplementary motor area (preSMA), which are thought to play critical roles in action cancellation, were simultaneously stimulated, sending phase-synchronised stimulation for 15 min with the aim of increasing functional connectivity. The offline group showed significant within-group improvement in response inhibition without showing overt task-related changes in functional connectivity measured with EEG connectivity analysis, suggesting offline tACS is efficacious in inducing behavioural changes potentially via a post-stimulation early plasticity mechanism. In contrast, neither the online nor sham group showed significant improvements in response inhibition. However, EEG connectivity analysis revealed significantly increased task-related functional connectivity following online stimulation and a medium effect size observed in correlation analyses suggested that an increase in functional connectivity in the beta band at rest was potentially associated with an improvement in response inhibition. Overall, the results indicate that both online and offline dual-site beta tACS can be beneficial in improving inhibitory control via distinct underlying mechanisms.

Proactive cues facilitate faster action reprogramming, but not stopping, in a response-selective stop signal task.

The ability to stop simple ongoing actions has been extensively studied using the stop signal task, but less is known about inhibition in more complex scenarios. Here we used a task requiring bimanual responses to go stimuli, but selective inhibition of only one of those responses following a stop signal. We assessed how proactive cues affect the nature of both the responding and stopping processes, and the well-documented stopping delay (interference effect) in the continuing action following successful stopping. In this task, estimates of the speed of inhibition based on a simple-stopping model are inappropriate, and have produced inconsistent findings about the effects of proactive control on motor inhibition. We instead used a multi-modal approach, based on improved methods of detecting and interpreting partial electromyographical responses and the recently proposed SIS (simultaneously inhibit and start) model of selective stopping behaviour. Our results provide clear and converging evidence that proactive cues reduce the stopping delay effect by slowing bimanual responses and speeding unimanual responses, with a negligible effect on the speed of the stopping process.

What mechanisms mediate prior probability effects on rapid-choice decision-making?

Rapid-choice decision-making is biased by prior probability of response alternatives. Conventionally, prior probability effects are assumed to selectively affect, response threshold, which determines the amount of evidence required to trigger a decision. However, there may also be effects on the rate at which evidence is accumulated and the time required for non-decision processes (e.g., response production). Healthy young (n = 21) and older (n = 20) adults completed a choice response-time task requiring left- or right-hand responses to imperative stimuli. Prior probability was manipulated using a warning stimulus that informed participants that a particular response was 70% likely (i.e., the imperative stimulus was either congruent or incongruent with the warning stimulus). In addition, prior probability was either fixed for blocks of trials (block-wise bias) or varied from trial-to-trial (trial-wise bias). Response time and accuracy data were analysed using the racing diffusion evidence-accumulation model to test the selective influence assumption. Response times for correct responses were slower on incongruent than congruent trials, and older adults' responses were slower, but more accurate, than young adults. Evidence-accumulation modelling favoured an effect of prior probability on both response thresholds and nondecision time. Overall, the current results cast doubt on the selective threshold influence assumption in the racing diffusion model.

Dissociating attentional capture from action cancellation during the inhibition of bimanual movement.

Inhibiting ongoing responses when environmental demands change is a critical component of motor control. Experimentally, the stop signal task (SST) represents the gold standard response inhibition paradigm. However, an emerging body of evidence suggests that the SST conflates two dissociable sources of inhibition, namely an involuntarily pause associated with attentional capture and the (subsequent) voluntary cancellation of action. The extent to which these processes also occur in other response tasks is unknown. Younger n = 24 (20-35 years) and older n = 23 (60-85 years) adults completed tasks involving rapid unimanual or bimanual responses to visual stimuli. A subset of trials required cancellation of one component of an initial bimanual response (i.e., selective stop task; stop left response, continue right response) or enacting an additional response (e.g., press left button as well as right button). Critically, both tasks involved some infrequent stimuli baring no behavioral imperative (i.e., they had to be ignored). EMG recordings of voluntary responses during stopping tasks revealed bimanual covert responses (muscle activation, which was suppressed before a button press ensued), consistent with a pause process, following both stop and ignore stimuli, before the required response was subsequently enacted. Critically, we also observed the behavioral consequences of a similar involuntary pause in trials where action cancellation was not part of the response set. Notably, the period over which movements were susceptible to response delays from additional stimuli was longer for older adults than younger adults. The findings demonstrate that an involuntary attentional component of inhibition significantly contributes to action cancellation processes.

A single bout of moderate-intensity aerobic exercise improves motor learning in premanifest and early Huntington's disease.

Introduction: Cardiorespiratory exercise has emerged as a promising candidate to modify disease progression in Huntington's disease (HD). In animal models, exercise has been found to alter biomarkers of neuroplasticity and delay evidence of disease, and some interventions-including exercise-have shown benefits in human HD patients. In healthy human populations, increasing evidence suggests that even a single bout of exercise can improve motor learning. In this pilot study, we investigated the effect of a single bout of moderate intensity aerobic exercise on motor skill learning in presymptomatic and early manifest HD patients. Methods: Participants were allocated to either an exercise (n = 10) or control (n = 10) group. They performed either 20 min of moderate intensity cycling or rest before practicing a novel motor task, the sequential visual isometric pinch force task (SVIPT). After 1 week, the retention of the SVIPT was measured in both groups. Results: We found that the exercise group performed significantly better during initial task acquisition. There were no significant differences in offline memory consolidation between groups, but total skill gain across both acquisition and retention sessions was greater in the group who exercised. The better performance of the exercise group was driven by improvements in accuracy, rather than speed. Discussion: We have shown that a single bout of moderate intensity aerobic exercise can facilitate motor skill learning in people with HD gene-expansion. More research is needed to investigate the underlying neural mechanisms and to further explore the potential for neurocognitive and functional benefits of exercise for people with HD.

Investigating the role of contextual cues and interhemispheric inhibitory mechanisms in response-selective stopping: a TMS study.

Response-selective stopping requires cancellation of only one component of a multicomponent action. While research has investigated how delays to the continuing action components ("stopping interference") can be attenuated by way of contextual cues of the specific stopping demands ("foreknowledge"), little is known of the underlying neural mechanisms. Twenty-seven, healthy, young adults undertook a multicomponent stop-signal task. For two thirds of trials, participants responded to an imperative (go) stimulus (IS) with simultaneous button presses using their left and right index fingers. For the remaining one third of trials, the IS was followed by a stop-signal requiring cancellation of only the left, or right, response. To manipulate foreknowledge of stopping demands, a cue preceded the IS that informed participants which hand might be required to stop (proactive) or provided no such information (reactive). Transcranial magnetic stimulation (TMS) assessed corticospinal excitability (CSE) as well as short- and long-interval interhemispheric inhibition (SIHI, LIHI) between the primary motor cortices. Proactive cues reduced, but did not eliminate, stopping interference relative to the reactive condition. Relative to TMS measures at cue onset, decreases in CSE (both hands and both cue conditions) and LIHI (both hands, proactive condition only) were observed during movement preparation. During movement cancellation, LIHI reduction in the continuing hand was greater than that in the stopping hand and greater than LIHI reductions in both hands during execution of multicomponent responses. Our results indicate that foreknowledge attenuates stopping interference and provide evidence for a novel role of LIHI, mediated via prefrontal regions, in facilitating continuing action components.

Safety of low-intensity repetitive transcranial magneTic brAin stimUlation foR people living with mUltiple Sclerosis (TAURUS): study protocol for a randomised controlled trial.

BACKGROUND: Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease, characterised by oligodendrocyte death and demyelination. Oligodendrocyte progenitor cells can differentiate into new replacement oligodendrocytes; however, remyelination is insufficient to protect neurons from degeneration in people with MS. We previously reported that 4 weeks of daily low-intensity repetitive transcranial magnetic stimulation (rTMS) in an intermittent theta-burst stimulation (iTBS) pattern increased the number of new myelinating oligodendrocytes in healthy adult mice. This study translates this rTMS protocol and aims to determine its safety and tolerability for people living with MS. We will also perform magnetic resonance imaging (MRI) and symptom assessments as preliminary indicators of myelin addition following rTMS. METHODS: Participants (N = 30, aged 18-65 years) will have a diagnosis of relapsing-remitting or secondary progressive MS. ≤2 weeks before the intervention, eligible, consenting participants will complete a physical exam, baseline brain MRI scan and participant-reported MS symptom assessments [questionnaires: Fatigue Severity Scale, Quality of Life (AQoL-8D), Hospital Anxiety and Depression Scale; and smartphone-based measures of cognition (electronic symbol digit modalities test), manual dexterity (pinching test, draw a shape test) and gait (U-Turn test)]. Participants will be pseudo-randomly allocated to rTMS (n=20) or sham (placebo; n=10), stratified by sex. rTMS or sham will be delivered 5 days per week for 4 consecutive weeks (20 sessions, 6 min per day). rTMS will be applied using a 90-mm circular coil at low-intensity (25% maximum stimulator output) in an iTBS pattern. For sham, the coil will be oriented 90° to the scalp, preventing the magnetic field from stimulating the brain. Adverse events will be recorded daily. We will evaluate participant blinding after the first, 10th and final session. After the final session, participants will repeat symptom assessments and brain MRI, for comparison with baseline. Participant-reported assessments will be repeated at 4-month post-allocation follow-up. DISCUSSION: This study will determine whether this rTMS protocol is safe and tolerable for people with MS. MRI and participant-reported symptom assessments will serve as preliminary indications of rTMS efficacy for myelin addition to inform further studies. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12619001196134 . Registered on 27 August 2019.

The TAS Test project: a prospective longitudinal validation of new online motor-cognitive tests to detect preclinical Alzheimer's disease and estimate 5-year risks of cognitive decline and dementia.

BACKGROUND: The worldwide prevalence of dementia is rapidly rising. Alzheimer's disease (AD), accounts for 70% of cases and has a 10-20-year preclinical period, when brain pathology covertly progresses before cognitive symptoms appear. The 2020 Lancet Commission estimates that 40% of dementia cases could be prevented by modifying lifestyle/medical risk factors. To optimise dementia prevention effectiveness, there is urgent need to identify individuals with preclinical AD for targeted risk reduction. Current preclinical AD tests are too invasive, specialist or costly for population-level assessments. We have developed a new online test, TAS Test, that assesses a range of motor-cognitive functions and has capacity to be delivered at significant scale. TAS Test combines two innovations: using hand movement analysis to detect preclinical AD, and computer-human interface technologies to enable robust 'self-testing' data collection. The aims are to validate TAS Test to [1] identify preclinical AD, and [2] predict risk of cognitive decline and AD dementia. METHODS: Aim 1 will be addressed through a cross-sectional study of 500 cognitively healthy older adults, who will complete TAS Test items comprising measures of motor control, processing speed, attention, visuospatial ability, memory and language. TAS Test measures will be compared to a blood-based AD biomarker, phosphorylated tau 181 (p-tau181). Aim 2 will be addressed through a 5-year prospective cohort study of 10,000 older adults. Participants will complete TAS Test annually and subtests of the Cambridge Neuropsychological Test Battery (CANTAB) biennially. 300 participants will undergo in-person clinical assessments. We will use machine learning of motor-cognitive performance on TAS Test to develop an algorithm that classifies preclinical AD risk (p-tau181-defined) and determine the precision to prospectively estimate 5-year risks of cognitive decline and AD. DISCUSSION: This study will establish the precision of TAS Test to identify preclinical AD and estimate risk of cognitive decline and AD. If accurate, TAS Test will provide a low-cost, accessible enrichment strategy to pre-screen individuals for their likelihood of AD pathology prior to more expensive tests such as blood or imaging biomarkers. This would have wide applications in public health initiatives and clinical trials. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05194787 , 18 January 2022. Retrospectively registered.

Cognitive inhibition tasks interfere with dual-task walking and increase prefrontal cortical activity more than working memory tasks in young and older adults

BACKGROUND: Prior work suggests there may be greater reliance on executive function for walking in older people. The pre-frontal cortex (PFC), which controls aspects of executive function, is known to be active during dual-task walking (DTW). However, there is debate on how PFC activity during DTW is impacted by ageing and the requirements of the cognitive task. RESEARCH QUESTION: Functional near infrared spectroscopy, was used to investigate how PFC activity during walking was affected by (i) healthy ageing; and (ii) dual-tasks that utilise inhibition or working memory aspects of executive function. METHODS: Young (n = 26, 16 females, mean 20.9 years) and older (n = 26, 16 females, mean 70.3 years) adults performed five conditions: normal walking; Reciting Alternate Letters of the alphabet (RAL, requiring cognitive inhibition and working memory) during standing and walking; and serial subtraction by threes (SS3, requiring working memory alone) during standing and walking. Walking speed, cognitive performance, the PFC haemodynamic response, and fear of falling ratings were analysed using linear mixed-effects modelling. RESULTS: Compared to quiet standing, PFC activity increased during normal walking for older adults but decreased for young adults (p < 0.01). Across both groups, fear of falling contributed to higher PFC activity levels when walking (p < 0.01). PFC activity increased during DTW, and this increase was greater when performing RAL compared to the SS3 task (p < 0.01). Although the rate of correct responses was higher for RAL, walking speed reduced more with RAL than SS3 in the young group (p = 0.01), and the rate of correct responses reduced more when walking with RAL than SS3 in the older group (p < 0.01). SIGNIFICANCE: Older adults have increased levels of PFC activation during walking compared to younger adults and fear of falling is a cofounding factor. The interference between gait and a concurrent cognitive task is higher when the cognitive task requires inhibition.

Influence of tDCS over right inferior frontal gyrus and pre-supplementary motor area on perceptual decision-making and response inhibition: A healthy ageing perspective.

A wide body of literature suggests that transcranial direct current stimulation (tDCS) administered over the prefrontal cortex can improve executive function - including decision-making and inhibitory control - in healthy young adults. However, the effects of tDCS in older adults are largely unknown. Here, using a double-blind, sham-controlled approach, changes in a combined perceptual decision-making and inhibitory control task were assessed before and after the application of tDCS (1 mA, 20 minute) targeting the right inferior frontal gyrus (rIFG) or pre-supplementary motor area (preSMA) in 42 young (18-34 years) and 41 older (60-80 years) healthy adults. Compared to sham stimulation, anodal tDCS over the preSMA improved decision-making speed for both age groups. Furthermore, the inhibitory control performance of older and younger adults was improved by preSMA and rIFG stimulation, respectively. This study provides evidence that tDCS can improve both perceptual decision-making and inhibitory control in healthy older adults, with the causal role of the preSMA and rIFG regions in cognitive control appearing to vary as a function of healthy ageing.

OSARI, an Open-Source Anticipated Response Inhibition Task.

The stop-signal paradigm has become ubiquitous in investigations of inhibitory control. Tasks inspired by the paradigm, referred to as stop-signal tasks, require participants to make responses on go trials and to inhibit those responses when presented with a stop-signal on stop trials. Currently, the most popular version of the stop-signal task is the 'choice-reaction' variant, where participants make choice responses, but must inhibit those responses when presented with a stop-signal. An alternative to the choice-reaction variant of the stop-signal task is the 'anticipated response inhibition' task. In anticipated response inhibition tasks, participants are required to make a planned response that coincides with a predictably timed event (such as lifting a finger from a computer key to stop a filling bar at a predefined target). Anticipated response inhibition tasks have some advantages over the more traditional choice-reaction stop-signal tasks and are becoming increasingly popular. However, currently, there are no openly available versions of the anticipated response inhibition task, limiting potential uptake. Here, we present an open-source, free, and ready-to-use version of the anticipated response inhibition task, which we refer to as the OSARI (the Open-Source Anticipated Response Inhibition) task.

Response bias reveals the role of interhemispheric inhibitory networks in movement preparation and execution.

Human movement is influenced by various cognitive processes, such as bias, that dynamically shape competing movement representations. However, the neurophysiological mechanisms underlying the effects of bias on movement selection across the lifespan remains poorly understood. Healthy young (n = 21) and older (n = 20) adults completed a choice reaction-time task necessitating left- or right-hand responses to imperative stimuli (IS). Response bias was manipulated via a cue that informed participants a particular response was 70% likely (i.e., the IS was either congruent, or incongruent, with the cue); biasing was either fixed for blocks of trials (block-wise bias) or varied from trial-to-trial (trial-wise bias). As well as assessing the behavioural manifestations of bias, we used transcranial magnetic stimulation to determine changes in corticospinal excitability (CSE) and short- and long-interval interhemispheric inhibition (SIHI, LIHI) during movement preparation and execution. Participants responded more quickly, and accurately, in congruent compared to incongruent trials. CSE decreases occurred in both hands following the cue, consistent with the 'inhibition for impulse control' hypothesis of preparatory inhibition. In contrast, IHI modulations occurred in a hand-specific manner. Greater SIHI was observed during movement preparation in the hand biased away from, compared to the hand biased towards, the cue; furthermore, greater SIHI was observed during movement execution in the hand biased towards the cue when it was not required to respond (i.e., incongruent trial) compared to when it was required to respond (congruent trial). Additionally, during the movement preparation period, the LIHI ratio of the hand biased towards, compared to the hand biased away from, the cue was greatest when the cue varied trial-by-trial. Overall, the IHI results provide support for the 'inhibition for competition resolution' hypothesis, with hand specific modulation of inhibition during movement preparation and execution.

Subthreshold repetitive transcranial magnetic stimulation drives structural synaptic plasticity in the young and aged motor cortex.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive tool commonly used to drive neural plasticity in the young adult and aged brain. Recent data from mouse models have shown that even at subthreshold intensities (0.12 T), rTMS can drive neuronal and glial plasticity in the motor cortex. However, the physiological mechanisms underlying subthreshold rTMS induced plasticity and whether these are altered with normal ageing are unclear. OBJECTIVE: To assess the effect of subthreshold rTMS, using the intermittent theta burst stimulation (iTBS) protocol on structural synaptic plasticity in the mouse motor cortex of young and aged mice. METHODS: Longitudinal in vivo 2-photon microscopy was used to measure changes to the structural plasticity of pyramidal neuron dendritic spines in the motor cortex following a single train of subthreshold rTMS (in young adult and aged animals) or the same rTMS train administered on 4 consecutive days (in young adult animals only). Data were analysed with Bayesian hierarchical generalized linear regression models and interpreted with the aid of Bayes Factors (BF). RESULTS: We found strong evidence (BF > 10) that subthreshold rTMS altered the rate of dendritic spine losses and gains, dependent on the number of stimulation sessions and that a single session of subthreshold rTMS was effective in driving structural synaptic plasticity in both young adult and aged mice. CONCLUSION: These findings provide further evidence that rTMS drives synaptic plasticity in the brain and uncovers structural synaptic plasticity as a key mechanism of subthreshold rTMS induced plasticity.

Significant cognitive decline in Parkinson's disease exacerbates the reliance on visual feedback during upper limb reaches.

While upper limb reaches are often made in a feed-forward manner, visual feedback during the movement can be used to guide the reaching hand towards a target. In Parkinson's disease (PD), there is evidence that the utilisation of this visual feedback is increased. However, it is unclear if this is due solely to the characteristic slowness of movements in PD providing more opportunity for incorporating visual feedback to modify reach trajectories, or whether it is due to cognitive decline impacting (feed-forward) movement planning ability. To investigate this, we compared reaction times and movement times of reaches to a target in groups of PD patients with normal cognition (PD-NC), mild cognitive impairment (PD-MCI) or dementia (PD-D), to that of controls with normal cognition (CON-NC) or mild cognitive impairment (CON-MCI). Reaches were undertaken with full visual feedback (at a 'natural' and 'fast-as-possible' pace); with reduced visual feedback of the reaching limb to an illuminated target; and without any visual feedback to a remembered target with eyes closed. The PD-D group exhibited slower reaction times than all other groups across conditions, indicative of less efficient movement planning. When reaching to a remembered target with eyes closed, all PD groups exhibited slower movement times relative to their natural pace with full visual feedback. Crucially, this relative slowing was most pronounced for the PD-D group, compared to the PD-MCI and PD-NC groups, suggesting that substantial cognitive decline in PD exacerbates dependence on visual feedback during upper limb reaches.