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.

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.

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.

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.

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.

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.

Timing is everything: Event-related transcranial direct current stimulation improves motor adaptation.

BACKGROUND: There is a current discord between the foundational theories underpinning motor learning and how we currently apply transcranial direct current stimulation (TDCS): the former is dependent on tight coupling of events while the latter is conducted with very low temporal resolution. OBJECTIVE: Here we aimed to investigate the temporal specificity of stimulation by applying TDCS in short epochs, and coincidentally with movement, during a motor adaptation task. METHODS: Participants simultaneously adapted a reaching movement to two opposing velocity-dependent force-fields (clockwise and counter-clockwise), distinguished by a contextual leftward or rightward shift in the task display and cursor location respectively. Brief bouts (<3 s) of event-related TDCS (er-TDCS) were applied over M1 or the cerebellum during movements for only one of these learning contexts. RESULTS: We show that when short duration stimulation is applied to the cerebellum and yoked to movement, only those reaching movements performed simultaneously with stimulation are selectively enhanced, whilst similar and interleaved movements are left unaffected. We found no evidence of improved adaptation following M1 er-TDCS, as participants displayed equivalent levels of error during both stimulated and unstimulated movements. Similarly, participants in the sham stimulation group adapted comparably during left and right-shift trials. CONCLUSIONS: It is proposed that the coupling of cerebellar stimulation and movement influences timing-dependent (i.e. Hebbian-like) mechanisms of plasticity to facilitate enhanced learning in the stimulated context.

Effectiveness of transcranial direct current stimulation on hand dexterity in stroke patients: a protocol for a systematic review and meta-analysis.

INTRODUCTION: Hand dexterity is the ability to execute the skilful movements using the hand and fingers. It is commonly impaired poststroke resulting in a profound deterioration in the quality of life for patients with stroke. Transcranial direct current stimulation (tDCS) is a form of non-invasive brain stimulation, which has gained a popularity as an adjunct therapy in recovering motor dysfunction poststroke. Promising results have been gained from applying tDCS in combination with motor rehabilitation, however, the outcome of tDCS on the upper limb motor function poststroke has been varied. Different results are potentially related to the discrepancy of the area of brain stimulation. Therefore, we aim to enhance the application of tDCS to improve its effectiveness in recovering hand dexterity through testing our hypothesis that stimulating the primary motor cortex could improve fine dexterity more than gross dexterity. METHODS AND ANALYSIS: This protocol has been reported according to Preferred Reporting Items for Systematic Review and Meta-Analyses Protocols guidelines. CENTRAL, MEDLINE, EMBASE, SCOPUS, Web of Science and CINAHL databases will be searched with no restriction in language and publication date. The selected studies will be randomised controlled trial investigating the effect of tDCS alone or in combination with motor rehabilitation in improving hand dexterity of patients with stroke with upper limb hemiparesis. The outcomes of interest are fine and gross hand dexterity measures. Two independent reviewers will assess the eligibility of the study, extract data and appraise the methodological quality. The data will be pooled in a meta-analysis if applicable or interpreted narratively. Grading of Recommendations, Assessment, Development and Evaluation approach will be used to assess the overall quality of evidence for the fine and gross dexterity measures. ETHICS AND DISSEMINATION: Ethical approval is not required for this study. The dissemination plan is to publish the results in a peer-review journal and presenting results in a conference. PROSPERO REGISTRATION NUMBER: CRD42021262186.

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.

Dopamine genetic risk score predicts impulse control behaviors in Parkinson's disease.

INTRODUCTION: Up to 40% of Parkinson's disease patients taking dopamine agonist medication develop impulse control behaviors which can have severe negative consequences. The current study aimed to utilize dopamine genetics to identify patients most at risk of developing these behaviors. METHODS: Demographic, clinical, and genetic data were obtained from the Parkinson's Progression Markers Initiative for de novo patients (n = 327), patients taking dopamine agonists (n = 146), and healthy controls (n = 160). Impulsive behaviors were identified using the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease. A dopamine genetic risk score was calculated for each patient according to polymorphisms in genes coding for dopamine D1, D2 and D3 receptors, and catechol-O-methyltransferase. A higher score reflected higher central dopamine neurotransmission. RESULTS: Patients on agonists with a low dopamine genetic risk score were over 18 times more likely to have an impulsive behavior compared to higher scores (p = 0.04). The 38% of patients taking agonists who had at least one impulsive behavior were more likely to be male and report higher Unified Parkinson's Disease Rating Scale I&II scores. With increasing time on dopamine agonists (range 92-2283 days, mean 798 ± 565 standard deviation), only patients with a high dopamine genetic risk score showed an increase in number of impulsive behaviors (p = 0.033). Predictive effects of the gene score were not present in de novo or healthy control. CONCLUSIONS: A dopamine genetic risk score can identify patients most at risk of developing impulsive behaviors on dopamine agonist medication and predict how these behaviors may worsen over time.

Age-Related Differences in Corticospinal Excitability and Anticipatory Postural Adjustments of the Trunk.

Anticipatory postural adjustments (APAs) are a feedforward mechanism for the maintenance of postural stability and are delayed in old adults. We previously showed in young adults that APAs of the trunk induced by a fast shoulder movement were mediated, at least in part, by a cortical mechanism. However, it remains unclear the relationship between delayed APAs and motor cortical excitability in ageing. Using transcranial magnetic stimulation we examined motor evoked potentials (MEPs) of the erector spinae (ES) muscles in healthy young and old adults prior to a fast shoulder flexion task. A recognition reaction time (RRT) paradigm was used where participants responded to a visual stimulus by flexing their shoulders bilaterally as fast as possible. The activity of bilateral anterior deltoid (AD) and ES muscles was recorded using electromyography (EMG). The onset of AD and ES EMG was measured to represent RRT and APAs, respectively. We found increases in amplitudes of ES MEPs at 40 ms than 50 ms prior to the EMG onset of the AD in both groups. The amplitude of ES MEPs at 40 ms prior to the onset of AD EMG correlated with the onset of ES activity counterbalancing the perturbation induced by the shoulder task in the elderly participants only. Our findings suggest that timing of increasing corticospinal excitability prior to a self-paced perturbation becomes more relevant with ageing in modulating postural control of the trunk.

Direct and indirect effects of cathodal cerebellar TDCS on visuomotor adaptation of hand and arm movements.

Adaptation of movements involving the proximal and distal upper-limb can be differentially facilitated by anodal transcranial direct current stimulation (TDCS) over the cerebellum and primary motor cortex (M1). Here, we build on this evidence by demonstrating that cathodal TDCS impairs motor adaptation with a differentiation of the proximal and distal upper-limbs, relative to the site of stimulation. Healthy young adults received M1 or cerebellar cathodal TDCS while making fast 'shooting' movements towards targets under 60° rotated visual feedback conditions, using either whole-arm reaching or fine hand and finger movements. As predicted, we found that cathodal cerebellar TDCS resulted in impairment of adaptation of movements with the whole arm compared to M1 and sham groups, which proved significantly different during late adaptation. However, cathodal cerebellar TDCS also significantly enhanced adaptation of hand movements, which may reflect changes in the excitability of the pathway between the cerebellum and M1. We found no evidence for change of adaptation rates using arm or finger movements following cathodal TDCS directly over M1. These results are further evidence to support movement specific effects of TDCS, and highlight how the connectivity and functional organisation of the cerebellum and M1 must be considered when designing TDCS-based therapies.

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.

Targeted tDCS selectively improves motor adaptation with the proximal and distal upper limb.

BACKGROUND: The cerebellum and primary motor cortex (M1) are crucial to coordinated and accurate movements of the upper limbs. There is also appreciable evidence that these two structures exert somewhat divergent influences upon proximal versus distal upper limb control. Here, we aimed to differentially regulate the contribution of the cerebellum and M1 to proximal and distal effectors during motor adaptation, with transcranial direct current stimulation (tDCS). For this, we employed tasks that promote similar motor demands, but isolate whole arm from hand/finger movements, in order to functionally segregate the hierarchy of upper limb control. METHODS: Both young and older adults took part in a visuomotor rotation task; where they adapted to a 60° visuomotor rotation using either a hand-held joystick (requiring finger/hand movements) or a 2D robotic manipulandum (requiring whole-arm reaching movements), while M1, cerebellar or sham tDCS was applied. RESULTS: We found that cerebellar stimulation improved adaptation performance when arm movements were required to complete the task, while in contrast stimulation of M1 enhanced adaptation during hand and finger movements only. This double-dissociation was replicated in an independent group of older adults, demonstrating that the behaviour remains intact in ageing. CONCLUSIONS: These results suggest that stimulation of distinct motor areas can selectively improve motor adaptation in the proximal and distal upper limb. This also highlights new ways in which tDCS might be best applied to achieve reliable rehabilitation of upper limb motor deficits.

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.

Nicotinamide Riboside Augments the Aged Human Skeletal Muscle NAD+ Metabolome and Induces Transcriptomic and Anti-inflammatory Signatures.

Nicotinamide adenine dinucleotide (NAD+) is modulated by conditions of metabolic stress and has been reported to decline with aging in preclinical models, but human data are sparse. Nicotinamide riboside (NR) supplementation ameliorates metabolic dysfunction in rodents. We aimed to establish whether oral NR supplementation in aged participants can increase the skeletal muscle NAD+ metabolome and if it can alter muscle mitochondrial bioenergetics. We supplemented 12 aged men with 1 g NR per day for 21 days in a placebo-controlled, randomized, double-blind, crossover trial. Targeted metabolomics showed that NR elevated the muscle NAD+ metabolome, evident by increased nicotinic acid adenine dinucleotide and nicotinamide clearance products. Muscle RNA sequencing revealed NR-mediated downregulation of energy metabolism and mitochondria pathways, without altering mitochondrial bioenergetics. NR also depressed levels of circulating inflammatory cytokines. Our data establish that oral NR is available to aged human muscle and identify anti-inflammatory effects of NR.

Memory deficits in Parkinson's disease are associated with reduced beta power modulation.

There is an increasing recognition of the significant non-motor symptoms that burden people with Parkinson's disease. As such, there is a pressing need to better understand and investigate the mechanisms underpinning these non-motor deficits. The electrical activity within the brains of people with Parkinson's disease is known to exhibit excessive power within the beta range (12-30 Hz), compared with healthy controls. The weight of evidence suggests that this abnormally high level of beta power is the cause of bradykinesia and rigidity in Parkinson's disease. However, less is known about how the abnormal beta rhythms seen in Parkinson's disease impact on non-motor symptoms. In healthy adults, beta power decreases are necessary for successful episodic memory formation, with greater power decreases during the encoding phase predicting which words will subsequently be remembered. Given the raised levels of beta activity in people with Parkinson's disease, we hypothesized that the necessary decrease in power during memory encoding would be diminished and that this would interfere with episodic memory formation. Accordingly, we conducted a cross-sectional, laboratory-based experimental study to investigate whether there was a direct relationship between decreased beta modulation and memory formation in Parkinson's disease. Electroencephalography recordings were made during an established memory-encoding paradigm to examine brain activity in a cohort of adults with Parkinson's disease (N = 28, 20 males) and age-matched controls (N = 31, 18 males). The participants with Parkinson's disease were aged 65 ± 6 years, with an average disease duration of 6 ± 4 years, and tested on their normal medications to avoid the confound of exacerbated motor symptoms. Parkinson's disease participants showed impaired memory strength (P = 0.023) and reduced beta power decreases (P = 0.014) relative to controls. Longer disease duration was correlated with a larger reduction in beta modulation during encoding, and a concomitant reduction in memory performance. The inability to sufficiently decrease beta activity during semantic processing makes it a likely candidate to be the central neural mechanism underlying this type of memory deficit in Parkinson's disease. These novel results extend the notion that pathological beta activity is causally implicated in the motor and (lesser appreciated) non-motor deficits inherent to Parkinson's disease. These findings provide important empirical evidence that should be considered in the development of intelligent next-generation therapies.

Author Correction: Sensorimotor adaptation as a behavioural biomarker of early spinocerebellar ataxia type 6.

A correction has been published and is appended to both the HTML and PDF versions of this paper. The error has been fixed in the paper.