Effect of movement-evoked and tonic experimental pain on muscle force production.

INTRODUCTION: When performing an exercise or a functional test, pain that is evoked by movement or muscle contraction could be a stronger stimulus for changing how individuals move compared to tonic pain. We investigated whether the decrease in muscle force production is larger when experimentally-induced knee pain is directly associated to the torque produced (movement-evoked) compared to a constant painful stimulation (tonic). METHODS: Twenty-one participants performed three isometric knee extension maximal voluntary contractions without pain (baseline), during pain, and after pain. Knee pain was induced using sinusoidal electrical stimuli at 10 Hz over the infrapatellar fat pad, applied continuously or modulated proportionally to the knee extension torque. Peak torque and contraction duration were averaged across repetitions and normalized to baseline. RESULTS: During tonic pain, participants reported lower pain intensity during the contraction than at rest (p < 0.001), whereas pain intensity increased with contraction during movement-evoked pain (p < 0.001). Knee extension torque decreased during both pain conditions (p < 0.001), but a larger reduction was observed during movement-evoked compared to tonic pain (p < 0.001). Participants produced torque for longer during tonic compared to movement-evoked pain (p = 0.005). CONCLUSION: Our results indicate that movement-evoked pain was a more potent stimulus to reduce knee extension torque than tonic pain. The longer contraction time observed during tonic pain may be a result of a lower perceived pain intensity during muscle contraction. Overall, our results suggest different motor adaptation to tonic and movement-evoked pain and support the notion that motor adaptation to pain is a purposeful strategy to limit pain. This mechanistic evidence suggests that individuals experiencing prevalently tonic or movement-evoked pain may exhibit different motor adaptations, which may be important for exercise prescription.

Cerebellar GABA Change during Visuomotor Adaptation Relates to Adaptation Performance and Cerebellar Network Connectivity: A Magnetic Resonance Spectroscopic Imaging Study.

Motor adaptation is crucial for performing accurate movements in a changing environment and relies on the cerebellum. Although cerebellar involvement has been well characterized, the neurochemical changes in the cerebellum underpinning human motor adaptation remain unknown. We used a novel magnetic resonance spectroscopic imaging (MRSI) technique to measure changes in the inhibitory neurotransmitter GABA in the human cerebellum during visuomotor adaptation. Participants (n = 17, six female) used their right hand to adapt to a rotated cursor in the scanner, compared with a control task requiring no adaptation. We spatially resolved adaptation-driven GABA changes at the cerebellar nuclei and cerebellar cortex in the left and the right cerebellar hemisphere independently and found that simple right-hand movements increase GABA in the right cerebellar nuclei and decreases GABA in the left. When isolating adaptation-driven GABA changes, we found that GABA in the left cerebellar nuclei and the right cerebellar nuclei diverged, although GABA change from baseline at the right cerebellar nuclei was not different from zero at the group level. Early adaptation-driven GABA fluctuations in the right cerebellar nuclei correlated with adaptation performance. Participants showing greater GABA decrease adapted better, suggesting early GABA change is behaviorally relevant. Early GABA change also correlated with functional connectivity change in a cerebellar network. Participants showing greater decreases in GABA showed greater strength increases in cerebellar network connectivity. Results were specific to GABA, to adaptation, and to the cerebellar network. This study provides first evidence for plastic changes in cerebellar neurochemistry during motor adaptation. Characterizing these naturally occurring neurochemical changes may provide a basis for developing therapeutic interventions to facilitate human motor adaptation.SIGNIFICANCE STATEMENT Despite motor adaptation being fundamental to maintaining accurate movements, its neurochemical basis remains poorly understood, perhaps because measuring neurochemicals in the human cerebellum is technically challenging. Using a novel magnetic resonance spectroscopic imaging method, this study provides evidence for GABA changes in the left compared with the right cerebellar nuclei driven by both simple movement and motor adaptation. Although right cerebellar GABA changes were not significantly different from zero at the group level, the adaptation-driven GABA fluctuations in the right cerebellar nuclei correlated with adaptation performance and with functional connectivity change in a cerebellar network. These results show the first evidence for plastic changes in cerebellar neurochemistry during a cerebellar learning task. This provides the basis for developing therapeutic interventions that facilitate these naturally occurring changes to amplify cerebellar-dependent learning.

Performance on the balloon analogue risk task and anticipatory response inhibition task is associated with severity of impulse control behaviours in people with Parkinson's disease.

Dopamine agonist medication is one of the largest risk factors for development of problematic impulse control behaviours (ICBs) in people with Parkinson's disease. The present study investigated the potential of dopamine gene profiling and individual performance on impulse control tasks to explain ICB severity. Clinical, genetic and task performance data were entered into a mixed-effects linear regression model for people with Parkinson's disease taking (n = 50) or not taking (n = 25) dopamine agonist medication. Severity of ICBs was captured via the Questionnaire for Impulsive-compulsive disorders in Parkinson's disease Rating Scale. A cumulative dopamine genetic risk score (DGRS) was calculated for each participant from variance in five dopamine-regulating genes. Objective measures of impulsive action and impulsive choice were measured on the Anticipatory Response Inhibition Task and Balloon Analogue Risk Task, respectively. For participants on dopamine agonist medication, task performance reflecting greater impulsive choice (p = 0.014), and to a trend level greater impulsive action (p = 0.056), as well as a longer history of DA medication (p < 0.001) all predicted increased ICB severity. DGRS however, did not predict ICB severity (p = 0.708). No variables could explain ICB severity in the non-agonist group. Our task-derived measures of impulse control have the potential to predict ICB severity in people with Parkinson's and warrant further investigation to determine whether they can be used to monitor ICB changes over time. The DGRS appears better suited to predicting the incidence, rather than severity, of ICBs on agonist medication.

Residual errors in visuomotor adaptation persist despite extended motor preparation periods.

A consistent finding in sensorimotor adaptation is a persistent undershoot of full compensation, such that performance asymptotes with residual errors greater than seen at baseline. This behavior has been attributed to limiting factors within the implicit adaptation system, which reaches a suboptimal equilibrium between trial-by-trial learning and forgetting. However, recent research has suggested that allowing longer motor planning periods prior to movement eliminates these residual errors. The additional planning time allows required cognitive processes to be completed before movement onset, thus increasing accuracy. Here, we looked to extend these findings by investigating the relationship between increased motor preparation time and the size of imposed visuomotor rotation (30°, 45°, or 60°), with regard to the final asymptotic level of adaptation. We found that restricting preparation time to 0.35 s impaired adaptation for moderate and larger rotations, resulting in larger residual errors compared to groups with additional preparation time. However, we found that even extended preparation time failed to eliminate persistent errors, regardless of magnitude of cursor rotation. Thus, the asymptote of adaptation was significantly less than the degree of imposed rotation, for all experimental groups. In addition, there was a positive relationship between asymptotic error and implicit retention. These data suggest that a prolonged motor preparation period is insufficient to reliably achieve complete adaptation, and therefore, our results suggest that factors beyond that of planning time contribute to asymptotic adaptation levels.NEW & NOTEWORTHY Residual errors in sensorimotor adaptation are commonly attributed to an equilibrium between trial-by-trial learning and forgetting. Recent research suggested that allowing sufficient time for mental rotation eliminates these errors. In a number of experimental conditions, we show that although restricted motor preparation time does limit adaptation-consistent with mental rotation-extending preparation time fails to eliminate the residual errors in motor adaptation.

Exploring stop signal reaction time over two sessions of the anticipatory response inhibition task.

Various behavioural tasks measure response inhibition encompassing the ability to cancel unwanted actions, evaluated via stop signal reaction time (SSRT). It is unclear whether SSRT is an unchangeable inherent measure of inhibitory network integrity or whether it can improve with repetition. The current study explored if and how SSRT changed over two sessions for the Anticipatory Response Inhibition Task (ARIT), and how this compared with the Stop Signal Task (SST). Forty-four participants repeated the ARIT and SST over two sessions. SSRT and its constituent measures (Go trial reaction time, stop signal delay) were calculated. SSRT reflecting non-selective response inhibition was consistent between sessions in the ARIT and SST (both p > 0.293). Reaction time and stop signal delay also remained stable across sessions in the ARIT (all p > 0.063), whereas in the SST, reaction time (p = 0.013) and stop signal delay (p = 0.009) increased. SSRT reflecting behaviourally selective stopping on the ARIT improved (p < 0.001) over two sessions, which was underpinned by changes to reaction time (p < 0.001) and stop signal delay (p < 0.001). Overall, the maximal efficiency of non-selective inhibition remained stable across two sessions in the ARIT. Results of the SST confirmed that non-selective inhibition can, however, be affected by more than inhibitory network integrity. Behaviourally selective stopping on the ARIT changed across sessions, suggesting the sequential neural process captured by the SSRT occurred more quickly in session two. These findings have implications for future studies that necessitate behavioural measures over multiple sessions.

Dopamine-Dependent Loss Aversion during Effort-Based Decision-Making.

From psychology to economics, there has been substantial interest in how costs (e.g., delay, risk) are represented asymmetrically during decision-making when attempting to gain reward or avoid punishment. For example, in decision-making under risk, individuals show a tendency to prefer to avoid punishment rather than to acquire the equivalent reward (loss aversion). Although the cost of physical effort has recently received significant attention, it remains unclear whether loss aversion exists during effort-based decision-making. On the one hand, loss aversion may be hardwired due to asymmetric evolutionary pressure on losses and gains and therefore exists across decision-making contexts. On the other hand, distinct brain regions are involved with different decision costs, making it questionable whether similar asymmetries exist. Here, we demonstrate that young healthy human participants (females, 16; males, 6) exhibit loss aversion during effort-based decision-making by exerting more physical effort to avoid punishment than to gain a same-size reward. Next, we show that medicated Parkinson's disease (PD) patients (females, 9; males, 9) show a reduction in loss aversion compared with age-matched control subjects (females, 11; males, 9). Behavioral and computational analysis revealed that people with PD exerted similar physical effort in return for a reward but were less willing to produce effort to avoid punishment. Therefore, loss aversion is present during effort-based decision-making and can be modulated by altered dopaminergic state. This finding could have important implications for our understanding of clinical disorders that show a reduced willingness to exert effort in the pursuit of reward.SIGNIFICANCE STATEMENT Loss aversion-preferring to avoid punishment rather than to acquire equivalent reward-is an important concept in decision-making under risk. However, little is known about whether loss aversion also exists during decisions where the cost is physical effort. This is surprising given that motor cost shapes human behavior, and a reduced willingness to exert effort is a characteristic of many clinical disorders. Here, we show that healthy human individuals exert more effort to minimize punishment than to maximize reward (loss aversion). We also demonstrate that medicated Parkinson's disease patients exert similar effort to gain reward but less effort to avoid punishment when compared with healthy age-matched control subjects. This indicates that dopamine-dependent loss aversion is crucial for explaining effort-based decision-making.

The role of interhemispheric communication during complete and partial cancellation of bimanual responses.

Precise control of upper limb movements in response to external stimuli is vital to effectively interact with the environment. Accurate execution of bimanual movement is known to rely on finely orchestrated interhemispheric communication between the primary motor cortices (M1s). However, relatively little is known about the role of interhemispheric communication during sudden cancellation of prepared bimanual movement. The current study investigated the role of interhemispheric interactions during complete and partial cancellation of bimanual movement. In two experiments, healthy young human participants received transcranial magnetic stimulation to both M1s during a bimanual response inhibition task. The increased corticomotor excitability in anticipation of bimanual movement was accompanied by a release of inhibition from both M1s. After a stop cue, inhibition was reengaged onto both hemispheres to successfully cancel the complete bimanual response. However, when the stop cue signaled partial cancellation (stopping of one digit only), inhibition was reengaged with regard to the cancelled digit, but the responding digit representation was facilitated. This bifurcation in interhemispheric communication between M1s occurred 75 ms later in the more difficult condition when the nondominant, as opposed to dominant, hand was still responding. Our results demonstrate that interhemispheric communication is integral to response inhibition once a bimanual response has been prepared. Interestingly, M1-M1 interhemispheric circuitry does not appear to be responsible for the nonselective suppression of all movement components that has been observed during partial cancellation. Instead such interhemispheric communication enables uncoupling of bimanual response components and facilitates the selective initiation of just the required unimanual movement.NEW & NOTEWORTHY We provide the first evidence that interhemispheric communication plays an important role during sudden movement cancellation of two-handed responses. Simultaneously increased inhibition onto both hemispheres assists with two-handed movement cancellation. However, this network is not responsible for the widespread suppression of motor activity observed when only one of the two hands is cancelled. Instead, communication between hemispheres enables the separation of motor activity for the two hands and helps to execute the required one-handed response.

Pedunculopontine Nucleus Microstructure Predicts Postural and Gait Symptoms in Parkinson's Disease.

BACKGROUND: There is an urgent need to identify individuals at risk of postural instability and gait difficulties, and the resulting propensity for falls, in Parkinson's disease. OBJECTIVES: Given known relationships between posture and gait and degeneration of the cholinergic pedunculopontine nucleus, we investigated whether metrics of pedunculopontine nucleus microstructural integrity hold independent utility for predicting future postural instability and gait difficulties and whether they could be combined with other candidate biomarkers to improve prognostication of these symptoms. METHODS: We used stereotactic mapping of the pedunculopontine nucleus and diffusion tensor imaging to extract baseline pedunculopontine nucleus diffusivity metrics in 147 participants with Parkinson's disease and 65 controls enrolled in the Parkinson's Progression Markers Initiative. We also recorded known candidate markers of posture and gait changes: loss of caudate dopamine and CSF ß-amyloid 1-42 levels at baseline; as well as longitudinal progression motor symptoms over 72-months. RESULTS: Survival analyses revealed that reduced dopamine in the caudate and increased axial diffusivity in the pedunculopontine nucleus incurred independent risk of postural instability and gait difficulties. Binary logistic regression and receiver operating characteristics analysis in 117 participants with complete follow-up data at 60 months revealed that only pedunculopontine nucleus microstructure provided more accurate discriminative ability for predicting future postural instability and gait difficulties than clinical and demographic variables alone. CONCLUSION: Dopaminergic and cholinergic loss incur independent risk for future postural instability and gait difficulties, and pedunculopontine nucleus microstructure can be used to prognosticate these symptoms from early Parkinson's disease stages. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

The role of the posterior cerebellum in saccadic adaptation: a transcranial direct current stimulation study.

The posterior vermis of the cerebellum is considered to be critically involved in saccadic adaptation. However, recent evidence suggests that the adaptive decrease (backward adaptation) and the adaptive increase (forward adaptation) of saccade amplitude rely on partially separate neural substrates. We investigated whether the posterior cerebellum could be differentially involved in backward and forward adaptation by using transcranial direct current stimulation (TDCS). To do so, participants' saccades were adapted backward or forward while they received anodal, cathodal, or sham TDCS. In two extra groups, subjects underwent a nonadaptation session while receiving anodal or cathodal TDCS to control for the direct effects of TDCS on saccadic execution. Surprisingly, cathodal stimulation tended to increase the extent of both forward and backward adaptations, while anodal TDCS strongly impaired forward adaptation and, to a smaller extent, backward adaptation. Forward adaptation was accompanied by a greater increase in velocity with cathodal stimulation, and reduced duration of change for anodal stimulation. In contrast, the expected velocity decrease in backward adaptation was noticeably weaker with anodal stimulation. Stimulation applied during nonadaptation sessions did not affect saccadic gain, velocity, or duration, demonstrating that the reported effects are not due to direct effects of the stimulation on the generation of eye movements. Our results demonstrate that cerebellar excitability is critical for saccadic adaptation. Based on our results and the growing evidence from studies of vestibulo-ocular reflex and saccadic adaptation, we conclude that the plasticity at the level of the oculomotor vermis is more fundamentally important for forward adaptation than for backward adaptation.

Paradoxical facilitation after depotentiation protocol can precede dyskinesia onset in early Parkinson's disease.

Loss of dopamine, a key modulator of synaptic signalling, and subsequent pulsatile non-physiological levodopa replacement is believed to underlie altered neuroplasticity in Parkinson's disease (PD). Animal models suggest that maladaptive plasticity (e.g. deficient depotentiation at corticostriatal synapses) is key in the development of levodopa-induced dyskinesia (LID), a common complication following levodopa replacement in PD. Human studies using transcranial magnetic stimulation protocols have shown similar depotentiation deficit in patients with LID. We hypothesized that subtle depotentiation deficits should precede LID if these deficits are mechanistically linked to LID onset. Moreover, patients on pulsatile levodopa-based therapy may show these changes earlier than those treated with levodopa-sparing strategies. We recruited 22 early non-dyskinetic PD patients (<5 years since diagnosis) and 12 age-matched healthy controls. We grouped patients into those on Levodopa-Based (n = 11) and Levodopa-Sparing therapies (n = 11). Patients were selected to obtain groups matched for age and disease severity. We used a theta-burst stimulation protocol to investigate potentiation and depotentiation in a single session. We report significant depotentiation deficits in the Levodopa-Based group, compared to both Levodopa-Sparing and Healthy Control groups. Potentiation and Depotentiation responses were similar between Levodopa-Sparing and Healthy Control groups. Although differences persist after accounting for potential confounds (e.g. levodopa-equivalent dose), these results may yet be caused by differences in disease severity and cumulative levodopa-equivalent dose as discussed in the text. In conclusion, we show for the first time that paradoxical facilitation in response to depotentiation protocols can occur in PD even prior to LID onset.

Dynamic neural correlates of motor error monitoring and adaptation during trial-to-trial learning.

A basic EEG feature upon voluntary movements in healthy human subjects is a ß (13-30 Hz) band desynchronization followed by a postmovement event-related synchronization (ERS) over contralateral sensorimotor cortex. The functional implications of these changes remain unclear. We hypothesized that, because ß ERS follows movement, it may reflect the degree of error in that movement, and the salience of that error to the task at hand. As such, the signal might underpin trial-to-trial modifications of the internal model that informs future movements. To test this hypothesis, EEG was recorded in healthy subjects while they moved a joystick-controlled cursor to visual targets on a computer screen, with different rotational perturbations applied between the joystick and cursor. We observed consistently lower ß ERS in trials with large error, even when other possible motor confounds, such as reaction time, movement duration, and path length, were controlled, regardless of whether the perturbation was random or constant. There was a negative trial-to-trial correlation between the size of the absolute initial angular error and the amplitude of the ß ERS, and this negative correlation was enhanced when other contextual information about the behavioral salience of the angular error, namely, the bias and variance of errors in previous trials, was additionally considered. These same features also had an impact on the behavioral performance. The findings suggest that the ß ERS reflects neural processes that evaluate motor error and do so in the context of the prior history of errors.

Reversing motor adaptation deficits in the ageing brain using non-invasive stimulation.

KEY POINTS: Healthy ageing in man is associated with a decline in motor adaptation. Transcranial direct current stimulation (TDCS) over the primary motor cortex (M1) or the lateral cerebellum can improve motor adaptation in young and older adults, but as yet no direct comparisons of TDCS effects exist between the two age groups and the two stimulation sites. TDCS over M1 enhanced the motor adaptation in both age groups by ∼30% relative to their respective non-stimulated groups and improved the performance of older adults to the extent that it compared with that of young adults without stimulation. The study suggests that the plastic mechanisms activated by TDCS that underpin improvements in motor behaviour in young adults remain available in older adults. The results indicate that TDCS may be a useful tool to help combat the normal decline in motor performance seen in normal healthy ageing. ABSTRACT: Healthy ageing is characterised by deterioration of motor performance. In normal circumstances motor adaptation corrects for movements' inaccuracies and as such, it is critical in maintaining optimal motor control. However, motor adaptation performance is also known to decline with age. Anodal transcranial direct current stimulation (TDCS) of the cerebellum and the primary motor cortex (M1) have been found to improve visuomotor adaptation in healthy young and older adults. However, no study has directly compared the effect of TDCS on motor adaptation between the two age populations. The aim of our study was to investigate whether the application of anodal TDCS over the lateral cerebellum and M1 affected motor adaptation in young and older adults similarly. Young and older participants performed a visuomotor rotation task and concurrently received TDCS over the left M1, the right cerebellum or received sham stimulation. Our results replicated the finding that older adults are impaired compared to the young adults in visuomotor adaptation. At the end of the adaptation session, older adults displayed a larger error (-17 deg) than the young adults (-10 deg). The stimulation of the lateral cerebellum did not change the adaptation in both age groups. In contrast, anodal TDCS over M1 improved initial adaptation in both age groups by around 30% compared to sham and this improvement lasted up to 40 min after the end of the stimulation. These results demonstrate that TDCS of M1 can enhance visuomotor adaptation, via mechanisms that remain available in the ageing population.

Subthalamic nucleus local field potential activity during the Eriksen flanker task reveals a novel role for theta phase during conflict monitoring.

The subthalamic nucleus (STN) is thought to play a central role in modulating responses during conflict. Computational models have suggested that the location of the STN in the basal ganglia, as well as its numerous connections to conflict-related cortical structures, allows it to be ideally situated to act as a global inhibitor during conflict. Additionally, recent behavioral experiments have shown that deep brain stimulation to the STN results in impulsivity during high-conflict situations. However, the precise mechanisms that mediate the "hold-your-horses" function of the STN remain unclear. We recorded from deep brain stimulation electrodes implanted bilaterally in the STN of 13 human subjects with Parkinson's disease while they performed a flanker task. The incongruent trials with the shortest reaction times showed no behavioral or electrophysiological differences from congruent trials, suggesting that the distracter stimuli were successfully ignored. In these trials, cue-locked STN theta band activity demonstrated phase alignment across trials and was followed by a periresponse increase in theta power. In contrast, incongruent trials with longer reaction times demonstrated a relative reduction in theta phase alignment followed by higher theta power. Theta phase alignment negatively correlated with subject reaction time, and theta power positively correlated with trial reaction time. Thus, when conflicting stimuli are not properly ignored, disruption of STN theta phase alignment may help operationalize the hold-your-horses role of the nucleus, whereas later increases in the amplitude of theta oscillations may help overcome this function.

Dietary Cocoa Flavanols Do Not Alter Brain Excitability in Young Healthy Adults.

The ingestion of dietary cocoa flavanols acutely alters functions of the cerebral endothelium, but whether the effects of flavanols permeate beyond this to alter other brain functions remains unclear. Based on converging evidence, this work tested the hypothesis that cocoa flavanols would alter brain excitability in young healthy adults. In a randomised, cross-over, double-blinded, placebo-controlled design, transcranial magnetic stimulation was used to assess corticospinal and intracortical excitability before as well as 1 and 2 h post-ingestion of a beverage containing either high (695 mg flavanols, 150 mg (-)-epicatechin) or low levels (5 mg flavanols, 0 mg (-)-epicatechin) of cocoa flavanols. In addition to this acute intervention, the effects of a short-term chronic intervention where the same cocoa flavanol doses were ingested once a day for 5 consecutive days were also investigated. For both the acute and chronic interventions, the results revealed no robust alteration in corticospinal or intracortical excitability. One possibility is that cocoa flavanols yield no net effect on brain excitability, but predominantly alter functions of the cerebral endothelium in young healthy adults. Future studies should increase intervention durations to maximize the acute and chronic accumulation of flavanols in the brain, and further investigate if cocoa flavanols would be more effective at altering brain excitability in older adults and clinical populations than in younger adults.

A role for the subthalamic nucleus in response inhibition during conflict.

The subthalamic nucleus (STN) is a key node in the network that supports response inhibition. It is suggested that the STN rapidly inhibits basal ganglia activity, to pause motor output during conflict until an appropriate motor plan is ready. Here, we recorded neural activity during a Stroop task from deep brain stimulation electrodes implanted in the human STN. We intended to determine whether cognitive psychological phenomena such as the Stroop effect can be explained via mechanisms of response inhibition involving the STN, or whether higher cognitive centers are alone responsible. We show stimulus-driven desychronization in the beta band (15-35 Hz) that lasts throughout the verbal response, in keeping with the idea that beta-band synchrony decreases to allow motor output to occur. During incongruent trials--in which response times were elongated due to the Stroop effect--a resynchronization was seen in the beta band before response. Crucially, in the incongruent trials during which the participant was unable to withhold the prepotent response, this resynchronization occurred after response onset. We suggest that this beta-band resynchronization pauses the motor system until conflict can be resolved.

A spatiotemporal analysis of gait freezing and the impact of pedunculopontine nucleus stimulation.

Gait freezing is an episodic arrest of locomotion due to an inability to take normal steps. Pedunculopontine nucleus stimulation is an emerging therapy proposed to improve gait freezing, even where refractory to medication. However, the efficacy and precise effects of pedunculopontine nucleus stimulation on Parkinsonian gait disturbance are not established. The clinical application of this new therapy is controversial and it is unknown if bilateral stimulation is more effective than unilateral. Here, in a double-blinded study using objective spatiotemporal gait analysis, we assessed the impact of unilateral and bilateral pedunculopontine nucleus stimulation on triggered episodes of gait freezing and on background deficits of unconstrained gait in Parkinson's disease. Under experimental conditions, while OFF medication, Parkinsonian patients with severe gait freezing implanted with pedunculopontine nucleus stimulators below the pontomesencephalic junction were assessed during three conditions; off stimulation, unilateral stimulation and bilateral stimulation. Results were compared to Parkinsonian patients without gait freezing matched for disease severity and healthy controls. Pedunculopontine nucleus stimulation improved objective measures of gait freezing, with bilateral stimulation more effective than unilateral. During unconstrained walking, Parkinsonian patients who experience gait freezing had reduced step length and increased step length variability compared to patients without gait freezing; however, these deficits were unchanged by pedunculopontine nucleus stimulation. Chronic pedunculopontine nucleus stimulation improved Freezing of Gait Questionnaire scores, reflecting a reduction of the freezing encountered in patients' usual environments and medication states. This study provides objective, double-blinded evidence that in a specific subgroup of Parkinsonian patients, stimulation of a caudal pedunculopontine nucleus region selectively improves gait freezing but not background deficits in step length. Bilateral stimulation was more effective than unilateral.

Alpha oscillations in the pedunculopontine nucleus correlate with gait performance in parkinsonism.

The pedunculopontine nucleus, a component of the reticular formation, is topographically organized in animal models and implicated in locomotor control. In Parkinson's disease, pedunculopontine nucleus stimulation is an emerging treatment for gait freezing. Local field potentials recorded from pedunculopontine nucleus electrodes in such patients have demonstrated oscillations in the alpha and beta frequency bands, reactive to self-paced movement. Whether these oscillations are topographically organized or relevant to locomotion is unknown. Here, we recorded local field potentials from the pedunculopontine nucleus in parkinsonian patients during rest and unconstrained walking. Relative gait speed was assessed with trunk accelerometry. Peaks of alpha power were present at rest and during gait, when they correlated with gait speed. Gait freezing was associated with attenuation of alpha activity. Beta peaks were less consistently observed across rest and gait, and did not correlate with gait speed. Alpha power was maximal in the caudal pedunculopontine nucleus region and beta power was maximal rostrally. These results indicate a topographic distribution of neuronal activity in the pedunculopontine nucleus region and concur with animal data suggesting that the caudal subregion has particular relevance to gait. Alpha synchronization, proposed to suppress 'task irrelevant' distraction, has previously been demonstrated to correlate with performance of cognitive tasks. Here, we demonstrate a correlation between alpha oscillations and improved gait performance. The results raise the possibility that stimulation of caudal and rostral pedunculopontine nucleus regions may differ in their clinical effects.

Short duration event related cerebellar TDCS enhances visuomotor adaptation.

BACKGROUND: Transcranial direct current stimulation (TDCS) is typically applied before or during a task, for periods ranging from 5 to 30 min. HYPOTHESIS: We hypothesise that briefer stimulation epochs synchronous with individual task actions may be more effective. METHODS: In two separate experiments, we applied brief bursts of event-related anodal stimulation (erTDCS) to the cerebellum during a visuomotor adaptation task. RESULTS: The first study demonstrated that 1 s duration erTDCS time-locked to the participants' reaching actions enhanced adaptation significantly better than sham. A close replication in the second study demonstrated 0.5 s erTDCS synchronous with the reaching actions again resulted in better adaptation than standard TDCS, significantly better than sham. Stimulation either during the inter-trial intervals between movements or after movement, during assessment of visual feedback, had no significant effect. Because short duration stimulation with rapid onset and offset is more readily perceived by the participants, we additionally show that a non-electrical vibrotactile stimulation of the scalp, presented with the same timing as the erTDCS, had no significant effect. CONCLUSIONS: We conclude that short duration, event related, anodal TDCS targeting the cerebellum enhances motor adaptation compared to the standard model. We discuss possible mechanisms of action and speculate on neural learning processes that may be involved.

The role of the subthalamic nucleus in response inhibition: evidence from local field potential recordings in the human subthalamic nucleus.

Response inhibition as measured during a stop-signal task refers to the ability to halt an action that has already been set in motion. Cortical and sub-cortical structures, such as the subthalamic nucleus (STN), that are active during attempts to inhibit action are thought to contribute to a 'stop-process' that must gain dominance over a 'go-process' if inhibition is to be successful. We recorded local field potential activity from the STN of Parkinson's disease patients with implanted deep brain stimulation electrodes during a stop-signal task. In particular we measured activity in the STN that has traditionally been associated with motor action (gamma-band, 60-100 Hz) and inhibition (beta-band, 10-30 Hz). Our data support the idea that beta activity in the STN is related to the inhibition of motor action. Further, we report that gamma oscillatory activity responds robustly to stop-signals as well as go-signals. This unexpected finding might suggest that gamma activity supports a go-process that not only responds to go-signals, but is also sensitive to stimuli that signal stopping.

The fate of the oculomotor system in clinical bilateral anophthalmia.

The interdependence of the development of the eye and oculomotor system during embryogenesis is currently unclear. The occurrence of clinical anophthalmia, where the globe fails to develop, permits us to study the effects this has on the development of the complex neuromuscular system controlling eye movements. In this study, we use very high-resolution T2-weighted imaging in five anophthalmic subjects to visualize the extraocular muscles and the cranial nerves that innervate them. The subjects differed in the presence or absence of the optic nerve, the abducens nerve, and the extraocular muscles, reflecting differences in the underlying disruption to the eye's morphogenetic pathway. The oculomotor nerve was present in all anophthalmic subjects and only slightly reduced in size compared to measurements in sighted controls. As might be expected, the presence of rudimentary eye-like structures in the socket appeared to correlate with development and persistence of the extraocular muscles in some cases. Our study supports in part the concept of an initial independence of muscle development, with its maintenance subject to the presence of these eye-like structures.