Reward During Arm Training Improves Impairment and Activity After Stroke: A Randomized Controlled Trial.

BACKGROUND: Learning and learning-related neuroplasticity in motor cortex are potential mechanisms mediating recovery of movement abilities after stroke. These mechanisms depend on dopaminergic projections from midbrain that may encode reward information. Likewise, therapist experience confirms the role of feedback/reward for training efficacy after stroke. OBJECTIVE: To test the hypothesis that rehabilitative training can be enhanced by adding performance feedback and monetary rewards. METHODS: This multicentric, assessor-blinded, randomized controlled trial used the ArmeoSenso virtual reality rehabilitation system to train 37 first-ever subacute stroke patients in arm-reaching to moving targets. The rewarded group (n = 19) trained with performance feedback (gameplay) and contingent monetary reward. The control group (n = 18) used the same system without monetary reward and with graphically minimized performance feedback. Primary outcome was the change in the two-dimensional reaching space until the end of the intervention period. Secondary clinical assessments were performed at baseline, after 3 weeks of training (15 1-hour sessions), and at 3 month follow-up. Duration and intensity of the interventions as well as concomitant therapy were comparable between groups. RESULTS: The two-dimensional reaching space showed an overall improvement but no difference between groups. The rewarded group, however, showed significantly greater improvements from baseline in secondary outcomes assessing arm activity (Box and Block Test at post-training: 6.03±2.95, P = .046 and 3 months: 9.66±3.11, P = .003; Wolf Motor Function Test [Score] at 3 months: .63±.22, P = .007) and arm impairment (Fugl-Meyer Upper Extremity at 3 months: 8.22±3.11, P = .011). CONCLUSIONS: Although neutral in its primary outcome, the trial signals a potential facilitating effect of reward on training-mediated improvement of arm paresis. TRIAL REGISTRATION: ClinicalTrials.gov (ID: NCT02257125).

Interhemispheric facilitation of gesturing: A combined theta burst stimulation and diffusion tensor imaging study.

BACKGROUND: Imaging studies point to a posture (finger vs. hand) and domain-specific neural basis of gestures. Furthermore, modulation of gestures by theta burst stimulation (TBS) may depend on interhemispheric disinhibition. OBJECTIVE/HYPOTHESIS: In this randomized sham-controlled study, we hypothesized that dual site continuous TBS over left inferior frontal gyrus (IFG-L) and right inferior parietal gyrus (IPL-R) predominantly affects pantomime of finger postures. Furthermore, we predicted that dual cTBS improves imitation of hand gestures if the effect correlates with measures of callosal connectivity. METHODS: Forty-six healthy subjects participated in this study and were targeted with one train of TBS in different experimental sessions: baseline, sham, single site IFG-L, dual IFG-L/IPL-R, single site IPL-R. Gestures were evaluated by blinded raters using the Test for Upper Limb Apraxia (TULIA) and Postural Imitation Test (PIT). Callosal connectivity was analyzed by diffusion tensor imaging (DTI). RESULTS: Dual cTBS significantly improved TULIAtotal (F [3, 28] = 4.118, p = .009), but did not affect TULIApantomime. The beneficial effect was driven by the cTBS over IPL-R, which improved TULIAimitation (p = .038). Furthermore, TULIAimitation significantly correlated with the microstructure (fractional anisotropy) of the splenium (r = 0.420, p = .026), corrected for age and whole brain volume. CONCLUSIONS: The study suggests that inhibition of IPL-R largely accounted for improved gesturing, possibly through transcallosal facilitation of IPL-L. Therefore, the findings may be relevant for the treatment of apraxic stroke patients. Gesture pantomime and postural gestures escaped the modulation by dual cTBS, suggesting a more widespread and/or variable neural representation.

Reduced striatal activation in response to rewarding motor performance feedback after stroke.

INTRODUCTION: Motor skill learning can help stroke survivors to cope with motor function deficits but requires many repetitions. One factor that keeps patients motivated is obtaining reward upon successfully completing a motor task. It has been suggested that stroke survivors have deficits in reward processing which may negatively impact skill learning. OBJECTIVE: To test the hypothesis that stroke survivors have deficient reward processing during motor skill learning evident in reduced activation in the striatum and its subdivisions in functional magnetic resonance imaging as compared with healthy, age-matched control subjects. METHODS: Striatal activity in response to performance dependent feedback and monetary reward was measured in 28 subacute stroke patients and 18 age-matched healthy control subjects during the training of visuomotor tracking an arc-shaped trajectory using the wrist (unimpaired side in patients, dominant side in controls) in an fMRI scanner. RESULTS: Despite comparable monetary rewards, stroke patients showed reduced activation in the ventral part (p < 0.01), but not in the dorsal part of the striatum (p = 0.11). 14 patients had their lesion extending into the striatum. The nucleus accumbens as part of the ventral striatum was unlesioned in all participants and still showed a marked hypoactivation in stroke patients as compared with controls (p < 0.001), a finding that could not be explained by motivational differences between the groups. CONCLUSION: Striatal hypoactivation in stroke survivors may cause impaired consolidation of motor skills. Stronger rewarding stimuli or drug-mediated enhancement may be needed to normalize reward processing after stroke with positive effects on recovery.

Effects of an In-home Multicomponent Exergame Training on Physical Functions, Cognition, and Brain Volume of Older Adults: A Randomized Controlled Trial.

Aging is associated with a decline in physical functions, cognition and brain structure. Considering that human life is based on an inseparable physical-cognitive interplay, combined physical-cognitive training through exergames is a promising approach to counteract age-related impairments. The aim of this study was to assess the effects of an in-home multicomponent exergame training on [i] physical and cognitive functions and [ii] brain volume of older adults compared to a usual care control group. Thirty-seven healthy and independently living older adults aged 65 years and older were randomly assigned to an intervention (exergame training) or a control (usual care) group. Over 16 weeks, the participants of the intervention group absolved three home-based exergame sessions per week (à 30-40 min) including Tai Chi-inspired exercises, dancing and step-based cognitive games. The control participants continued with their normal daily living. Pre- and post-measurements included assessments of physical (gait parameters, functional muscle strength, balance, aerobic endurance) and cognitive (processing speed, short-term attention span, working memory, inhibition, mental flexibility) functions. T1-weighted magnetic resonance imaging was conducted to assess brain volume. Thirty-one participants (mean age = 73.9 ± 6.4 years, range = 65-90 years, 16 female) completed the study. Inhibition and working memory significantly improved post-intervention in favor of the intervention group [inhibition: F (1) = 2.537, p = 0.046, n p 2 = 0.11, working memory: F (1) = 5.872, p = 0.015, n p 2 = 0.02]. Two measures of short-term attentional span showed improvements after training in favor of the control group [F(1) = 4.309, p = 0.038, n p 2 = 0.03, F (1) = 8.504, p = 0.004, n p 2 = 0.04]. No significant training effects were evident for physical functions or brain volume. Both groups exhibited a significant decrease in gray matter volume of frontal areas and the hippocampus over time. The findings indicate a positive influence of exergame training on executive functioning. No improvements in physical functions or brain volume were evident in this study. Better adapted individualized training challenge and a longer training period are suggested. Further studies are needed that assess training-related structural brain plasticity and its effect on performance, daily life functioning and healthy aging.

Functional brain anatomy of exercise regulation.

Knowledge about possible brain mechanisms involved in the regulation of exercise intensity has vastly grown over the last decade. The current review attempts to condense this knowledge currently published with a focus on brain imaging studies. A number of psychological manipulations known to influence exercise intensity are discussed with respect to their possibly underlying brain structures. Although far from forming a complete picture, current knowledge allows to speculate on various possible influences and their corresponding neural bases. Especially, the roles of the insular cortex, anterior cingulate cortex, basal ganglia and prefrontal cortex structures are discussed. Interoceptive signals processed in the insular cortex can influence motor activity likely via anterior cingulate cortex with themselves being influenced by higher order prefrontal cortical regions (e.g., when mediating expectancy effects). Such higher order prefrontal regions can also modulate motivation and thus motor activity by influencing valuation processes in the midbrain and other structures.

Predicting the ergogenic response to methylphenidate.

PURPOSE: Methylphenidate (MPH) and other stimulants have been shown to enhance physical performance. However, stimulant research has almost exclusively been conducted in young, active persons with a normal BMI, and may not generalize to other groups. The purpose of this study was to determine whether the ergogenic response to MPH could be predicted by individual level characteristics. METHODS: We investigated whether weekly minutes of moderate-to-vigorous physical activity (MVPA), age, and BMI could predict the ergogenic response to MPH. In a double-blind, cross-over design 29 subjects (14M, 15F, 29.7 ± 9.68 years, BMI: 26.1 ± 6.82, MVPA: 568.8 ± 705.6 min) ingested MPH or placebo before performing a handgrip task. Percent change in mean force between placebo and MPH conditions was used to evaluate the extent of the ergogenic response. RESULTS: Mean force was significantly higher in MPH conditions [6.39% increase, T(25) = 3.09, p = 0.005 118.8 ± 37.96 (± SD) vs. 111.8 ± 34.99 Ns] but variable (coefficient of variation:163%). Using linear regression, we observed that min MVPA (T(25) = -2.15, ß = -0.400, p = 0.044) and age [T(25) = -3.29, ß = -0.598, p = 0.003] but not BMI [T(25) = 1.67, ß = 0.320 p = 0.109] significantly predicted percent change in mean force in MPH conditions. CONCLUSIONS: We report that lower levels of physical activity and younger age predict an improved ergogenic response to MPH and that this may be explained by differences in dopaminergic function. This study illustrates that the ergogenic response to MPH is partly dependent on individual differences such as habitual levels of physical activity and age.

Does motivation matter in upper-limb rehabilitation after stroke? ArmeoSenso-Reward: study protocol for a randomized controlled trial.

BACKGROUND: Fifty percent of all stroke survivors remain with functional impairments of their upper limb. While there is a need to improve the effectiveness of rehabilitative training, so far no new training approach has proven to be clearly superior to conventional therapy. As training with rewarding feedback has been shown to improve motor learning in humans, it is hypothesized that rehabilitative arm training could be enhanced by rewarding feedback. In this paper, we propose a trial protocol investigating rewards in the form of performance feedback and monetary gains as ways to improve effectiveness of rehabilitative training. METHODS: This multicentric, assessor-blinded, randomized controlled trial uses the ArmeoSenso virtual reality rehabilitation system to train 74 first-ever stroke patients (< 100 days post stroke) to lift their impaired upper limb against gravity and to improve the workspace of the paretic arm. Three sensors are attached to forearm, upper arm, and trunk to track arm movements in three-dimensional space while controlling for trunk compensation. Whole-arm movements serve as input for a therapy game. The reward group (n = 37) will train with performance feedback and contingent monetary reward. The control group (n = 37) uses the same system but without monetary reward and with reduced performance feedback. Primary outcome is the change in the hand workspace in the transversal plane. Standard clinical assessments are used as secondary outcome measures. DISCUSSION: This randomized controlled trial will be the first to directly evaluate the effect of rewarding feedback, including monetary rewards, on the recovery process of the upper limb following stroke. This could pave the way for novel types of interventions with significantly improved treatment benefits, e.g., for conditions that impair reward processing (stroke, Parkinson's disease). TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02257125 . Registered on 30 September 2014.

Elderly adults show higher ventral striatal activation in response to motor performance related rewards than young adults.

Feedback on motor performance activates the striatum and boosting ventral striatum activation with rewarding feedback during motor training supports the consolidation of the learned skill. Aging is associated with changes of the reward system, including striatal and extrastriatal loss of dopamine receptors. How these changes interact with the blood oxygenation level dependent (BOLD) response is, however, not yet fully understood. While it is known that reward prediction and reward-based decision-making differ between young and elderly healthy adults, the influence of age on the processing of rewarding feedback on motor performance have not been investigated so far. Nineteen young (26.42±2.84years) and 18 elderly (65.39±6.40years) healthy adults performed an arc-tracking task including performance feedback linked to a monetary reward after half of the trials, while undergoing functional magnetic resonance imaging (fMRI). The BOLD effect was compared in three predefined regions of interest: Ventral and dorsal striatum plus primary motor cortex. Our study demonstrates differences in the processing of motor performance related reward between young and elderly healthy adults. While both groups earned similar amounts of money linked to their own performance, the ventral striatal response to the rewarding feedback was higher in the older group. Deficient prediction about the rewarding feedback, a higher motivational status or compensation for a reduced number of dopamine receptors in the elderly might be possible explanations. How this interacts with the reward-induced improvement of motor skill consolidation, as observed in young subjects, has to be clarified.

Methylphenidate Enhances Grip Force and Alters Brain Connectivity.

INTRODUCTION: A central fatigue theory proposes that force output during fatiguing exercise is limited to maintain homeostasis. The self-awareness of the body's homeostatic state is known as interoception. Brain regions thought to play a role in interoception, such as the insular and orbital frontal cortex, have been proposed as sites for the upstream regulation of fatiguing exercise. Methylphenidate (MPH) can improve force output during exercise and may alter central processes during fatiguing exercise. However, the ergogenic neural underpinnings of MPH are unknown. This study examines the effect of MPH on force output and brain functional connectivity during a muscle-fatiguing handgrip task. METHODS: In a double-blind, crossover design, 15 subjects (mean age = 28.4 ± 5.2; 9 males and 6 females) ingested MPH or placebo before performing a muscle-fatiguing handgrip task during functional magnetic resonance imaging. We examined force output and brain connectivity (psychophysiological interactions and functional connectivity) throughout the task as well as in the few seconds just before releasing the grip dynamometer (i.e., pretask failure). RESULTS: We show that in the MPH condition, subjects increased grip force throughout but not during pretask failure. Brain connectivity was altered throughout the task between the insular and the hand motor cortex, as well as between the insular and the orbital frontal cortex. There were no differences in connectivity during pretask failure. CONCLUSION: For the first time, we show that brain connectivity can be influenced by MPH during muscle-fatiguing exercise. This study provides additional support that the CNS acts to regulate motor drive subservient to homeostasis.

Structural brain correlates associated with professional handball playing.

BACKGROUND: There is no doubt that good bimanual performance is very important for skilled handball playing. The control of the non-dominant hand is especially demanding since efficient catching and throwing needs both hands. METHODOLOGY/HYPOTHESES: We investigated training-induced structural neuroplasticity in professional handball players using several structural neuroimaging techniques and analytic approaches and also provide a review of the literature about sport-induced structural neuroplastic alterations. Structural brain adaptations were expected in regions relevant for motor and somatosensory processing such as the grey matter (GM) of the primary/secondary motor (MI/supplementary motor area, SMA) and somatosensory cortex (SI/SII), basal ganglia, thalamus, and cerebellum and in the white matter (WM) of the corticospinal tract (CST) and corpus callosum, stronger in brain regions controlling the non-dominant left hand. RESULTS: Increased GM volume in handball players compared with control subjects were found in the right MI/SI, bilateral SMA/cingulate motor area, and left intraparietal sulcus. Fractional anisotropy (FA) and axial diffusivity were increased within the right CST in handball players compared with control women. Age of handball training commencement correlated inversely with GM volume in the right and left MI/SI and years of handball training experience correlated inversely with radial diffusivity in the right CST. Subcortical structures tended to be larger in handball players. The anatomical measures of the brain regions associated with handball playing were positively correlated in handball players, but not interrelated in control women. DISCUSSION/CONCLUSION: Training-induced structural alterations were found in the somatosensory-motor network of handball players, more pronounced in the right hemisphere controlling the non-dominant left hand. Correlations between handball training-related measures and anatomical differences suggest neuroplastic adaptations rather than a genetic predisposition for a ball playing affinity. Investigations of neuroplasticity specifically in sportsmen might help to understand the neural mechanisms of expertise in general.

Equal pain-Unequal fear response: enhanced susceptibility of tooth pain to fear conditioning.

Experimental fear conditioning in humans is widely used as a model to investigate the neural basis of fear learning and to unravel the pathogenesis of anxiety disorders. It has been observed that fear conditioning depends on stimulus salience and subject vulnerability to fear. It is further known that the prevalence of dental-related fear and phobia is exceedingly high in the population. Dental phobia is unique as no other body part is associated with a specific phobia. Therefore, we hypothesized that painful dental stimuli exhibit an enhanced susceptibility to fear conditioning when comparing to equal perceived stimuli applied to other body sites. Differential susceptibility to pain-related fear was investigated by analyzing responses to an unconditioned stimulus (UCS) applied to the right maxillary canine (UCS-c) vs. the right tibia (UCS-t). For fear conditioning, UCS-c and USC-t consisted of painful electric stimuli, carefully matched at both application sites for equal intensity and quality perception. UCSs were paired to simple geometrical forms which served as conditioned stimuli (CS+). Unpaired CS+ were presented for eliciting and analyzing conditioned fear responses. Outcome parameter were (1) skin conductance changes and (2) time-dependent brain activity (BOLD responses) in fear-related brain regions such as the amygdala, anterior cingulate cortex, insula, thalamus, orbitofrontal cortex, and medial prefrontal cortex. A preferential susceptibility of dental pain to fear conditioning was observed, reflected by heightened skin conductance responses and enhanced time-dependent brain activity (BOLD responses) in the fear network. For the first time, this study demonstrates fear-related neurobiological mechanisms that point toward a superior conditionability of tooth pain. Beside traumatic dental experiences our results offer novel evidence that might explain the high prevalence of dental-related fears in the population.

Development of ERN together with an internal model of audio-motor associations.

The brain's reactions to error are manifested in several event related potentials (ERP) components, derived from electroencephalographic (EEG) signals. Although these components have been known for decades, their interpretation is still controversial. A current hypothesis (first indicator hypothesis) claims that the first indication of an action being erroneous leads to a negative deflection of the EEG signal over frontal midline areas. In some cases this requires sensory feedback in the form of knowledge of results (KR). If KR is given, then the first negative deflection can be found around 250 ms after feedback presentation (feedback-related negativity, FRN). When KR is not required, a negative deflection is found already around 100 ms after action onset (ERN). This deflection may be evoked when a mismatch between required and actually executed actions is detected. To detect such a mismatch, however, necessitates knowledge about which action is required. To test this assumption, the current study monitored EEG error components during acquisition of an internal model, i.e., acquisition of the knowledge of which actions are needed to reach certain goals. Actions consisted of finger presses on a piano keyboard and goals were tones of a certain pitch to be generated, thus the internal model represented audio-motor mapping. Results show that with increasing proficiency in mapping goals to appropriate actions, the amplitude of the ERN increased, whereas the amplitude of the FRN remained unchanged. Thus, when knowledge is present about which action is required, this supports generation of an ERN around 100 ms, likely by detecting a mismatch between required and performed actions. This is in accordance with the first indicator hypothesis. The present study furthermore lends support to the notion that FRN mainly relies on comparison of sensory targets with sensory feedback.

Differential NMR spectroscopy reactions of anterior/posterior and right/left insular subdivisions due to acute dental pain.

OBJECTIVES: The insular cortex has an important role within the cerebral pain circuitry. The aim of this study was to measure metabolic alterations by MR spectroscopy due to experimentally induced trigeminal pain in the anterior/posterior and right/left insular subdivisions. METHODS: Sixteen male volunteers were investigated using magnetic resonance (MR) spectroscopy before, during and after experimentally induced dental pain. Biphasic bipolar electric current pulses of 1 ms duration were administered based on the subjectively determined pain threshold. Volunteers were instructed to rate every stimulus using a MR compatible rating scale. RESULTS: Due to the pain stimulation a significant absolute increase in glutamate (Glu, F = 6.1; P = 0.001), glutamine (Gln, F = 11.2; P = 0.001) as well as glutamate/glutamine (Glx, F = 17.7; P = 0.001) were observed, whereas myo-inositol (mI, F = 9.5;P = 0.001) showed a significant drop. Additionally, these metabolites showed a significant effect towards lateralisation, meaning that metabolic concentration differed either in left or right insular subdivision. Creatine demonstrated also an absolute significant decrease during stimulation (F = 2.8; P = 0.022) with a significant anterior-posterior difference (F = 40.7; P = 0.001). CONCLUSIONS: Results confirm that the insular cortex is a metabolically high active region in pain processing within the brain. Quantitative metabolic changes show that there is a distinct but locally diverse neurometabolic activity under acute pain. The known cytoarchitectonic subdivisions show different metabolic reactions and give new insights into pain-processing physiology.

The rewarding value of good motor performance in the context of monetary incentives.

Whether an agent receives positive task feedback or a monetary reward, neural activity in their striatum increases. In the latter case striatal activity reflects extrinsic reward processing, while in the former, striatal activity reflects the intrinsically rewarding effects of performing well. There can be a "hidden cost of reward", which is a detrimental effect of extrinsic on intrinsic reward value. This raises the question how these two types of reward interact. To address this, we applied a monetary incentive delay task: in all trials participants received feedback depending on their performance. In half of the trials they could additionally receive monetary reward if they performed well. This resulted in high performance trials, which were monetarily rewarded and high performance trials that were not. This made it possible to dissociate the neural correlates of performance feedback from the neural correlates of monetary reward that comes with high performance. Performance feedback alone elicits activation increases in the ventral striatum. This activation increases due to additional monetary reward. Neural response in the dorsal striatum on the other hand is only significantly increased by feedback when a monetary incentive is present. The quality of performance does not significantly influence dorsal striatum activity. In conclusion, our results indicate that the dorsal striatum is primarily sensitive to optional or actually received external rewards, whereas the ventral striatum may be coding intrinsic reward due to positive performance feedback. Thus the ventral striatum is suggested to be involved in the processing of intrinsically motivated behavior.

Brain activation induced by dentine hypersensitivity pain--an fMRI study.

AIM: Dentine hypersensitivity (DH) is characterized by a short, sharp pain arising from exposed dentin. Most published literature reports on peripheral neural aspects of this pain condition. The current investigation focused on differential cerebral activity elicited by stimulation of sensitive and insensitive teeth by means of natural air stimuli. MATERIALS AND METHODS: Five graded stimulus strengths were randomly applied by means of a multi-injector air jet delivery system, each followed by an individual rating of perceived stimulus intensity. Brain activity was analysed by functional magnetic resonance imaging (fMRI). RESULTS: Stimulation of sensitive teeth induced significant activation in the thalamus, somatosensory cortices (SI & SII), anterior, middle and posterior insular cortices, anterior mid cingulate cortex, perigenual anterior cingulate cortex and frontal regions (BA10 and BA46). Differential responses to DH and painless perceptions were observed in the anterior insula and anterior midcingulate cortex. CONCLUSION: For the first time, this fMRI study demonstrates the feasibility of investigating cerebral processes related to DH evoked by natural (air) stimuli. Our neuroimaging data additionally provide evidence that differential activity in the anterior Insula (aIC) and anterior midcingulate cortex (aMCC) may represent clinically relevant pain experienced by DH patients.

Reducing the interval between volume acquisitions improves "sparse" scanning protocols in event-related auditory fMRI.

Sparse and clustered-sparse temporal sampling fMRI protocols have been devised to reduce the influence of auditory scanner noise in the context of auditory fMRI studies. Here, we report an improvement of the previously established clustered-sparse acquisition scheme. The standard procedure currently used by many researchers in the field is a scanning protocol that includes relatively long silent pauses between image acquisitions (and therefore, a relatively long repetition time or cluster-onset asynchrony); it is during these pauses that stimuli are presented. This approach makes it unlikely that stimulus-induced BOLD response is obscured by scanner-noise-induced BOLD response. It also allows the BOLD response to drop near baseline; thus, avoiding saturation of BOLD signal and theoretically increasing effect size. A possible drawback of this approach is the limited number of stimulus presentations and image acquisitions that are possible in a given period of time, which could result in an inaccurate estimation of effect size (higher standard error). Since this line of reasoning has not yet been empirically tested, we decided to vary the cluster-onset asynchrony (7.5, 10, 12.5, and 15 s) in the context of a clustered-sparse protocol. In this study sixteen healthy participants listened to spoken sentences. We performed whole-brain fMRI group statistics and region of interest analysis with anatomically defined regions of interest (auditory core and association areas). We discovered that the protocol, which included a short cluster-onset asynchrony (7.5 s), yielded more advantageous results than the other protocols, which involved longer cluster-onset asynchrony. The short cluster-onset asynchrony protocol exhibited a larger number of activated voxels and larger mean effect sizes with lower standard errors. Our findings suggest that, contrary to prior experience, a short cluster-onset asynchrony is advantageous because more stimuli can be delivered within any given period of time. Alternatively, a given number of stimuli can be presented in less time, and this broadens the spectrum of possible fMRI applications.

Fatigue-induced increase in intracortical communication between mid/anterior insular and motor cortex during cycling exercise.

In the present study, intracortical communication between mid/anterior insular and motor cortex was investigated during a fatiguing cycling exercise. From 16 healthy male subjects performing a constant-load test at 60% peak oxygen consumption (VO(2peak)) until volitional exhaustion, electroencephalography data were analysed during repetitive, artefact-free periods of 1-min duration. To quantify fatigue-induced intracortical communication, mean intra-hemispheric lagged phase synchronization between mid/anterior insular and motor cortex was calculated: (i) at the beginning of cycling; (ii) at the end of cycling; and (iii) during recovery cycling. Results revealed significantly increased lagged phase synchronization at the end of cycling, which returned to baseline during recovery cycling after subjects' cessation of exercise. Following previous imaging studies reporting the mid/anterior insular cortex as an essential instance processing a variety of sensory stimuli and signalling forthcoming physiological threat, our results provide further evidence that during a fatiguing exercise this structure might not only integrate and evaluate sensory information from the periphery, but also act in communication with the motor cortex. To the best of our knowledge, this is the first study to empirically demonstrate that muscle fatigue leads to changes in interaction between structures of a brain's neural network.

Spinal opioid receptor-sensitive muscle afferents contribute to the fatigue-induced increase in intracortical inhibition in healthy humans.

We investigated the influence of spinal opioid receptor-sensitive muscle afferents on cortical changes following fatiguing unilateral knee-extensor exercise. On separate days, seven subjects performed an identical five sets of intermittent isometric right-quadriceps contractions, each consisting of eight submaximal contractions [63 ± 7% maximal voluntary contraction (MVC)] and one MVC. The exercise was performed following either lumbar interspinous saline injection or lumbar intrathecal fentanyl injection blocking the central projection of spinal opioid receptor-sensitive lower limb muscle afferents. To quantify exercise-induced peripheral fatigue, quadriceps twitch force (Q(tw,pot)) was assessed via supramaximal magnetic femoral nerve stimulation before and after exercise. Motor evoked potentials and cortical silent periods (CSPs) were evaluated via transcranial magnetic stimulation of the motor cortex during a 3% MVC pre-activation period immediately following exercise. End-exercise quadriceps fatigue was significant and similar in both conditions (Q(tw,pot) -35 and -39% for placebo and fentanyl, respectively; P = 0.38). Immediately following exercise on both days, motor evoked potentials were similar to those obtained prior to exercise. Compared with pre-exercise baseline, CSP in the placebo trial was 21 ± 5% longer postexercise (P < 0.01). In contrast, CSP following the fentanyl trial was not significantly prolonged compared with the pre-exercise baseline (6 ± 4%). Our findings suggest that the central effects of spinal opioid receptor-sensitive muscle afferents might facilitate the fatigue-induced increase in CSP. Furthermore, since the CSP is thought to reflect inhibitory intracortical interneuron activity, which may contribute to central fatigue, our findings imply that spinal opioid receptor-sensitive muscle afferents might influence central fatigue by facilitating intracortical inhibition.

Taking Sides with Pain - Lateralization aspects Related to Cerebral Processing of Dental Pain.

The current fMRI study investigated cortical processing of electrically induced painful tooth stimulation of both maxillary canines and central incisors in 21 healthy, right-handed volunteers. A constant current, 150% above tooth specific pain perception thresholds was applied and corresponding online ratings of perceived pain intensity were recorded with a computerized visual analog scale during fMRI measurements. Lateralization of cortical activations was investigated by a region of interest analysis. A wide cortical network distributed over several areas, typically described as the pain or nociceptive matrix, was activated on a conservative significance level. Distinct lateralization patterns of analyzed structures allow functional classification of the dental pain processing system. Namely, certain parts are activated independent of the stimulation site, and hence are interpreted to reflect cognitive emotional aspects. Other parts represent somatotopic processing and therefore reflect discriminative perceptive analysis. Of particular interest is the observed amygdala activity depending on the stimulated tooth that might indicate a role in somatotopic encoding.