The influence of pain and kinesiophobia on motor control of the upper limb: how pointing task paradigms can point to new avenues of understanding.

ABSTRACT: People experiencing kinesiophobia are more likely to develop persistent disabilities and chronic pain. However, the impact of kinesiophobia on the motor system remains poorly understood. We investigated whether kinesiophobia could modulate shoulder pain-induced changes in (1) kinematic parameters and muscle activation during functional movement and (2) corticospinal excitability. Thirty healthy, pain-free subjects took part in the study. Shoulder, elbow, and finger kinematics, as well as electromyographic activity of the upper trapezius and anterior deltoid muscles, were recorded while subjects performed a pointing task before and during pain induced by capsaicin at the shoulder. Anterior deltoid cortical changes in excitability were assessed through the slope of transcranial magnetic stimulation input-output curves obtained before and during pain. Results revealed that pain reduced shoulder electromyographic activity and had a variable effect on finger kinematics, with individuals with higher kinesiophobia showing greater reduction in finger target traveled distance. Kinesiophobia scores were also correlated with the changes in deltoid corticospinal excitability, suggesting that the latter can influence motor activity as soon as the motor signal emerges. Taken together, these results suggest that pain and kinesiophobia interact with motor control adaptation.

Cross-cultural translation and psychometric validation of the French version of the Fear-Avoidance Components Scale (FACS).

BACKGROUND: The Fear-Avoidance Components Scale (FACS) is a reliable and valid instrument widely used to assess fear-avoidance beliefs related to pain and disability. However, there is a scarcity of validated translations of the FACS in different cultural and linguistic contexts, including the French population. This study aimed to translate and validate the French version of the FACS (FACS-Fr/CF), examining its psychometric properties among French-speaking individuals. METHODS: A cross-cultural translation process-including forward translation, backward translation, expert committee review, and pre-testing-was conducted to develop the FACS-Fr/CF. The translated version was administered to a sample of French-speaking adults (n = 55) with chronic musculoskeletal pain. Internal consistency (including confirmatory analyses of the 2 factors identified in the Serbian version), test-retest reliability and convergent validity were then assessed. RESULTS: The FACS-Fr/CF demonstrated high global internal consistency (α = 0.94, 95% CI: 0.91-0.96) as well as high internal consistency of the 2 factors identified in the Serbian version (α = 0.90, 95% CI: 0.86-0.94 and α = 0.90, 95% CI: 0.85-0.94, respectively). Test-retest analysis revealed a moderate (close to high) reliability (ICC = 0.89; 95% CI: 0.82-0.94 and r = 0.89; p<0.005). Convergent validity was supported by significant correlations between the FACS-Fr/CF scores and the Tampa Scale for Kinesiophobia (r = 0.82; p < 0.005), the Pain Catastrophizing Scale (r = 0.72; p < 0.005) and the Hospital Anxiety and Depression Scale (r = 0.66; p < 0.005). CONCLUSION: The present study provides evidence for the cross-cultural translation and psychometric validation of the FACS-Fr/CF. The FACS-Fr/CF exhibits a high internal consistency, a moderate (close to high) test-retest reliability, and good construct validity, suggesting its utility in assessing fear-avoidance beliefs in the French-speaking population. This validated tool can enhance the assessment and understanding of fear-avoidance behaviors and facilitate cross-cultural research in pain-related studies.

Late cortical disinhibition in focal hand dystonia.

In writer's cramp (WC), a form of focal hand dystonia, cortical GABAergic inhibitory mechanisms are altered and may cause involuntary tonic contractions while writing. The objective of this study was to explore the time course of long-interval intracortical inhibition (LICI) that involves gamma-amino butyric acid (GABA)-B transmission and late cortical disinhibition (LCD) (that combines GABA-A and GABA-B mechanisms) in patients with WC and in control subjects. A double pulse transcranial magnetic stimulation protocol was used to evoke LICI and LCD while the subjects either gripped a cylinder between their thumb and index fingers or relaxed all their upper limb muscles. We measured the ratio between primed and unprimed motor evoked potential in the first dorsal interosseous at interstimulus intervals ranging between 60 and 300 ms. Though the cortical silent period was not different between the groups, LICI lasted longer in patients with WC, that is, LCD was delayed for more than 30 ms and reached a higher level. In addition to the alteration of inhibitory mechanism mediated by GABA-B transmission, LCD which probably involves presynaptic inhibition is also modified in patients with WC with possible consequences on the activity of primary motor cortex inhibitory and excitatory circuits which control the hand muscles.caus.

Influence of Motor Deficiency and Spatial Neglect on the Contralesional Posterior Parietal Cortex Functional and Structural Connectivity in Stroke Patients.

The posterior parietal cortex (PPC) is a key structure for visual attention and upper limb function, two features that could be impaired after stroke, and could be implied in their recovery. If it is well established that stroke is responsible for intra- and interhemispheric connectivity troubles, little is known about those existing for the contralesional PPC. In this study, we aimed at mapping the functional (using resting state fMRI) and structural (using diffusion tensor imagery) networks from 3 subparts of the PPC of the contralesional hemisphere (the anterior intraparietal sulcus), the posterior intraparietal sulcus and the superior parieto-occipital cortex to bilateral frontal areas and ipsilesional homologous PPC parts in 11 chronic stroke patients compared to 13 healthy controls. We also aimed at assessing the relationship between connectivity and the severity of visuospatial and motor deficiencies. We showed that interhemispheric functional and structural connectivity between PPCs was altered in stroke patients compared to controls, without any specificity among seeds. Alterations of parieto-frontal intra- and interhemispheric connectivity were less observed. Neglect severity was associated with several alterations in intra- and interhemispheric connectivity, whereas we did not find any behavioral/connectivity correlations for motor deficiency. The results of this exploratory study shed a new light on the influence of the contralesional PPC in post-stroke patients, they have to be confirmed and refined in further larger studies.

Contribution of transcranial magnetic stimulation in assessing parietofrontal connectivity during gesture production in healthy individuals and brain-injured patients.

Parietofrontal (PF) networks link the posterior parietal cortex to premotor and prefrontal areas, and are involved in the control of many motor and cognitive behaviors in healthy humans. In recent years, electrophysiological experiments have provided a better understanding of the functional specificity and temporal involvement of the PF networks' different components during the planning of visually guided upper limb movements. In particular, transcranial magnetic stimulation has been used to temporarily inactivate a cortical area (virtual lesions) or to assess connectivity using paired-pulse protocols)). This approach has shed new light on the neural mechanisms that underlie the planning stages of the reaching and grasping phases of transitive movements. Reaching and grasping were often presented as two distinct processes; in fact, the respective involvement of dorsolateral and dorsomedial networks may depend on the movement's complexity and the need for precise coordination between the two phases. The dorsolateral parietofrontal network (linking the anterior part of the intraparietal sulcus to the ventral premotor cortex) is involved in the grasping phase (i.e. hand shape and grip force scaling), whereas the dorsomedial part (from the posterior part of the intraparietal sulcus and the superior parieto-occipital cortex to the dorsal premotor cortex) appears to be involved not only in the reaching phase but also in more complex visually guided grasping movements. Changes in parietofrontal connectivity following brain injury might explain the impairments in visually guided upper limb movements observed in patients (such as optic ataxia and the motor component of spatial neglect). Lastly, parietofrontal changes may reflect neuronal plasticity in motor function recovery.

A 15-day course of donepezil modulates spectral EEG dynamics related to target auditory stimuli in young, healthy adult volunteers.

OBJECTIVE: To identify possible electroencephalographic (EEG) markers of donepezil's effect on cortical activity in young, healthy adult volunteers at the group level. METHODS: Thirty subjects were administered a daily dose of either 5mg donepezil or placebo for 15days in a double-blind, randomized, cross-over trial. The electroencephalogram during an auditory oddball paradigm was recorded from 58 scalp electrodes. Current source density (CSD) transformations were applied to EEG epochs. The event-related potential (ERP), inter-trial coherence (ITC: the phase consistency of the EEG spectrum) and event-related spectral perturbation (ERSP: the EEG power spectrum relative to the baseline) were calculated for the target (oddball) stimuli. RESULTS: The donepezil and placebo conditions differed in terms of the changes in delta/theta/alpha/beta ITC and ERSP in various regions of the scalp (especially the frontal electrodes) but not in terms of latency and amplitude of the P300-ERP component. CONCLUSION: Our results suggest that ITC and ERSP analyses can provide EEG markers of donepezil's effects in young, healthy, adult volunteers at a group level. SIGNIFICANCE: Novel EEG markers could be useful to assess the therapeutic potential of drug candidates in Alzheimer's disease in healthy volunteers prior to the initiation of Phase II/III clinical studies in patients.

Brain imaging of locomotion in neurological conditions.

Impaired locomotion is a frequent and major source of disability in patients with neurological conditions. Different neuroimaging methods have been used to understand the brain substrates of locomotion in various neurological diseases (mainly in Parkinson's disease) during actual walking, and while resting (using mental imagery of gait, or brain-behavior correlation analyses). These studies, using structural (i.e., MRI) or functional (i.e., functional MRI or functional near infra-red spectroscopy) brain imaging, electrophysiology (i.e., EEG), non-invasive brain stimulation (i.e., transcranial magnetic stimulation, or transcranial direct current stimulation) or molecular imaging methods (i.e., PET, or SPECT) reveal extended brain networks involving both grey and white matters in key cortical (i.e., prefrontal cortex) and subcortical (basal ganglia and cerebellum) regions associated with locomotion. However, the specific roles of the various pathophysiological mechanisms encountered in each neurological condition on the phenotype of gait disorders still remains unclear. After reviewing the results of individual brain imaging techniques across the common neurological conditions, such as Parkinson's disease, dementia, stroke, or multiple sclerosis, we will discuss how the development of new imaging techniques and computational analyses that integrate multivariate correlations in "large enough datasets" might help to understand how individual pathophysiological mechanisms express clinically as an abnormal gait. Finally, we will explore how these new analytic methods could drive our rehabilitative strategies.

Parietomotor connectivity in the contralesional hemisphere after stroke: A paired-pulse TMS study.

OBJECTIVES: To assess the contralesional connectivity between the posterior parietal cortex (PPC) and the motor cortex (M1) in stroke patients, and to probe putative relationships with spatial neglect and motor impairment. METHODS: In 12 right-side stroke patients and 12 age-matched healthy controls, we used paired-pulse transcranial magnetic stimulation to assess the contralesional connectivity between three left-side PPC sites (the anterior intraparietal sulcus (aIPS), the posterior intraparietal sulcus and the superior parieto-occipital cortex (SPOC)) and M1. The interstimulus interval (ISI) was set to 4 or 6ms. RESULTS: Although there were no differences between the stroke patient group and the controls, a subgroup analysis showed that stimulation over the SPOC with an ISI of 6ms facilitated motor-evoked potential responses in patients with neglect (and especially those with severe peripersonal neglect), relative to non-neglect patients. With an ISI of 4ms, the aIPS exerted an inhibitory influence on M1 in all subjects. The severity of motor impairment was not associated with PPC-M1 connectivity. CONCLUSIONS: aIPS-M1 connectivity seems to be unaffected in stroke patients, whereas connectivity from the most posterior parts of the parietal cortex depends on the patient's neglect status. SIGNIFICANCE: These results provide insight into post-stroke changes in contralesional PPC-M1 connectivity.

Single session intermittent theta-burst stimulation on the left premotor cortex does not alleviate freezing of gait in Parkinson's disease.

OBJECTIVE: To investigate the efficiency of intermittent theta-burst stimulation (iTBS) to alleviate the symptoms of freezing of gait (FoG) in Parkinson's disease (PD). METHODS: We performed a cross-over, sham-controlled study of patients with severe PD, bilateral motor signs and debilitating, severe FoG, that was levodopa-sensitive but not controlled by optimal dopatherapy. We applied iTBS to the left premotor cortex and measured FoG, gait initiation and continuous gait, before and immediately after the iTBS session. All patients received sham and true iTBS with a one-week interval and in randomized order. RESULTS: 15 patients were included in the study. Recordings were performed under usual medication and all patients always showed unresponsive freezing. The pre- and post-stimulation gait trajectories did not differ in terms of the mean trajectory completion time or the percent time with FoG. The percent time with FoG was 6% greater after sham stimulation and 3% lower after iTBS (p>0.05). Visual cueing modified gait initiation and continuous gait but these latter were not influenced by rTMS. CONCLUSIONS: The present study provides Class I evidence that iTBS of the left premotor cortex does not alleviate FoG in PD.

Influence of repetitive transcranial magnetic stimulation on tibialis anterior activity during walking in humans.

OBJECTIVE: To determine whether or not modulation of the excitability of the M1 region controlling the lower limb (using repetitive transcranial magnetic stimulation; TMS) would change the TA's activity during gait and the effect of aging on this change. METHODS: In three separate sessions, participants underwent different repetitive TMS (rTMS) protocols (sham stimulation, intermittent theta-burst stimulation (TBS) and continuous TBS) delivered over the M1 region controlling the lower limb muscles, using a focal, figure-of-eight coil. Before and after rTMS, the TA's activity was recorded using surface electrodes while participants walked at a freely chosen speed and at an imposed speed on a treadmill. Cortical excitability was assessed by characterizing input-output (IO) curves, after fitting the relationship between motor evoked potential amplitude and stimulus intensity with a Boltzmann sigmoidal equation. RESULTS: We did not observe any effects of rTMS in terms of TA activation during locomotion, gait parameters or IO curves in either healthy young adults or elderly adults. Elderly patients presented lower excitability of cortical TA representation area. CONCLUSION: Modulation of TA activity by TBS was ineffective contrary to what is observed for upper limbs. Interindividual variability in the effects of rTMS on TA activation, activation of the TA before the rTMS and/or differences in the depth of the cortical representation of the TA could have influenced the results and should be taken into account for further studies.

Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS).

A group of European experts was commissioned to establish guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS) from evidence published up until March 2014, regarding pain, movement disorders, stroke, amyotrophic lateral sclerosis, multiple sclerosis, epilepsy, consciousness disorders, tinnitus, depression, anxiety disorders, obsessive-compulsive disorder, schizophrenia, craving/addiction, and conversion. Despite unavoidable inhomogeneities, there is a sufficient body of evidence to accept with level A (definite efficacy) the analgesic effect of high-frequency (HF) rTMS of the primary motor cortex (M1) contralateral to the pain and the antidepressant effect of HF-rTMS of the left dorsolateral prefrontal cortex (DLPFC). A Level B recommendation (probable efficacy) is proposed for the antidepressant effect of low-frequency (LF) rTMS of the right DLPFC, HF-rTMS of the left DLPFC for the negative symptoms of schizophrenia, and LF-rTMS of contralesional M1 in chronic motor stroke. The effects of rTMS in a number of indications reach level C (possible efficacy), including LF-rTMS of the left temporoparietal cortex in tinnitus and auditory hallucinations. It remains to determine how to optimize rTMS protocols and techniques to give them relevance in routine clinical practice. In addition, professionals carrying out rTMS protocols should undergo rigorous training to ensure the quality of the technical realization, guarantee the proper care of patients, and maximize the chances of success. Under these conditions, the therapeutic use of rTMS should be able to develop in the coming years.

Task-dependent changes in late inhibitory and disinhibitory actions within the primary motor cortex in humans.

The objective of the present study was to investigate the time course of long-interval intracortical inhibition (LICI) and late cortical disinhibition (LCD) as a function of the motor task (index abduction, thumb-index precision grip). Motor-evoked potentials were recorded from the first dorsal interosseus (FDI) muscle of the dominant limb in 13 healthy subjects. We used paired-pulse transcranial magnetic stimulation (TMS) paradigms in which a test pulse was preceded by a suprathreshold priming pulse (130% of the resting motor threshold) with varying interstimulus intervals (ISIs). In each task, double pulses were delivered with ISIs ranging from 30% of the corresponding silent period (SP; ~ 45 ms) to 220% of the SP (~ 330 ms). In both tasks, we found that LICI was followed by LCD (namely a period of increased cortical excitability lasting until ~ 200% of the SP). The time-dependent modulation of LICI and LCD differed in the two tasks; LICI was shorter (i.e. disinhibition occurred earlier) and LCD was more intense during precision grip than during index abduction. Long-interval intracortical inhibition disappeared well before the end of the SP in the precision grip task, suggesting that the mechanisms underlying these two inhibitory phenomena are distinct. Our data suggest that disinhibition might reflect adaptation of neural circuit excitability to the functional requirements of the motor task.

Effect of intermittent theta-burst stimulation on akinesia and sensorimotor integration in patients with Parkinson's disease.

High-frequency (HF) repetitive transcranial magnetic stimulation (rTMS) over the primary motor cortex (M1) has been shown to reduce akinesia in Parkinson's disease (PD). Given that the processing of sensory afferents is deficient in PD and might be involved in akinesia, we sought to determine whether or not the application of very HF rTMS [intermittent theta-burst stimulation (iTBS) protocol] over the M1 affected sensorimotor integration (SMI) and akinesia. The experiments were carried out in: (i) 11 patients taking their usual dopaminergic treatment ('on-drug'); (ii) eight of the latter patients after withdrawal of dopaminergic treatment ('off-drug'); and (iii) 10 de novo (drug-naive) patients. Sham stimulation was applied in 11 other patients in the 'on-drug' condition. SMI was investigated by conditioning a supra-threshold transcranial magnetic stimulation pulse in the motor region controlling the abductor pollicis brevis with a nerve shock over the median nerve at time intervals corresponding to short- and long-latency afferent inhibition (SAI and LAI) and afferent-induced facilitation (AIF). Akinesia was assessed with a pointing test. In on-drug, off-drug and de novo patients, akinesia in the contralateral arm was lower after iTBS. Sham stimulation had no effect. In on-drug patients (but not other groups), SMI was also influenced by iTBS, with an increase in AIF. No changes in SAI and LAI were observed. Our data suggest that iTBS might improve both akinesia and sensory processing in patients with PD taking levodopa.

Task-dependent changes of motor cortical network excitability during precision grip compared to isolated finger contraction.

The purpose of this study was to determine whether task-dependent differences in corticospinal pathway excitability occur in going from isolated contractions of the index finger to its coordinated activity with the thumb. Focal transcranial magnetic stimulation (TMS) was used to measure input-output (I/O) curves--a measure of corticospinal pathway excitability--of the contralateral first dorsal interosseus (FDI) muscle in 21 healthy subjects performing two isometric motor tasks: index abduction and precision grip. The level of FDI electromyographic (EMG) activity was kept constant across tasks. The amplitude of the FDI motor evoked potentials (MEPs) and the duration of FDI silent period (SP) were plotted against TMS stimulus intensity and fitted, respectively, to a Boltzmann sigmoidal function. The plateau level of the FDI MEP amplitude I/O curve increased by an average of 40% during the precision grip compared with index abduction. Likewise, the steepness of the curve, as measured by the value of the maximum slope, increased by nearly 70%. By contrast, all I/O curve parameters [plateau, stimulus intensity required to obtain 50% of maximum response (S(50)), and slope] of SP duration were similar between the two tasks. Short- and long-latency intracortical inhibitions (SICI and LICI, respectively) were also measured in each task. Both measures of inhibition decreased during precision grip compared with the isolated contraction. The results demonstrate that the motor cortical circuits controlling index and thumb muscles become functionally coupled when the muscles are used synergistically and this may be due, at least in part, to a decrease of intracortical inhibition and an increase of recurrent excitation.

Deficit of sensorimotor integration in normal aging.

Sensorimotor performance declines with normal aging. The present study explored age-related changes in sensorimotor integration by conditioning a supra-threshold transcranial magnetic stimulation pulse with a peripheral nerve shock at different interstimulus intervals. Cortical motor threshold of the abductor pollicis brevis muscle, intracortical inhibition and facilitation were measured. We also assessed the influence of median nerve stimulation on motor cortex excitability at intervals which evoked short- and long-latency afferent inhibition (SAI and LAI, respectively) and afferent-induced facilitation (AIF). We observed a marked decrease of the long latency influence of proprioceptive inputs on M1 excitability in the elderly, with the loss of AIF and LAI. The SAI, motor thresholds and intracortical inhibition and facilitation were not age-related. Decreased sensorimotor performance with aging appears to be associated with a decrease in the influence of proprioceptive inputs on motor cortex excitability at longer intervals (probably via higher order cortical areas).

Perceiving what is reachable depends on motor representations: evidence from a transcranial magnetic stimulation study.

BACKGROUND: Visually determining what is reachable in peripersonal space requires information about the egocentric location of objects but also information about the possibilities of action with the body, which are context dependent. The aim of the present study was to test the role of motor representations in the visual perception of peripersonal space. METHODOLOGY: Seven healthy participants underwent a TMS study while performing a right-left decision (control) task or perceptually judging whether a visual target was reachable or not with their right hand. An actual grasping movement task was also included. Single pulse TMS was delivered 80% of the trials on the left motor and premotor cortex and on a control site (the temporo-occipital area), at 90% of the resting motor threshold and at different SOA conditions (50ms, 100ms, 200ms or 300ms). PRINCIPAL FINDINGS: Results showed a facilitation effect of the TMS on reaction times in all tasks, whatever the site stimulated and until 200ms after stimulus presentation. However, the facilitation effect was on average 34ms lower when stimulating the motor cortex in the perceptual judgement task, especially for stimuli located at the boundary of peripersonal space. CONCLUSION: This study provides the first evidence that brain motor area participate in the visual determination of what is reachable. We discuss how motor representations may feed the perceptual system with information about possible interactions with nearby objects and thus may contribute to the perception of the boundary of peripersonal space.

The comparable size and overlapping nature of upper limb distal and proximal muscle representations in the human motor cortex.

The purpose of this study was to determine the relative size and location of proximal and distal upper limb muscle representations in the human motor cortex. Motor-evoked potentials (MEPs) evoked by transcranial magnetic stimulation were recorded in the proximal muscle anterior deltoid (AD) and in the distal muscles extensor carpi radialis (ECR) and first dorsal interosseus (1DI). The coil was moved in steps of 1 cm along a grid drawn on a tight-fitting polyester cap placed on the subject's head. At each location, four stimuli were delivered at 1.2 times the active motor threshold (AMT), and MEPs averaged in real-time. The peak-to-peak amplitude of each muscle's mean MEP was measured at each stimulation site. The area of a muscle's representation was measured by a pixel-counting algorithm. The optimal point of each muscle's areal representation, which corresponds to the locus near which the largest MEPs are obtained, was determined by fitting a 3D Lorentzian function to the data points. The optimal point of distal muscles tended to be situated more laterally along the motor strip than that of proximal muscles. However, there was no statistically significant difference between the size of the areal representations and they overlapped considerably. Additionally, in another five subjects, using a small 45-mm coil placed in a hyper-focal orientation, maps were obtained at a stimulus intensity of 1.1-1.15 times the AMT of the muscle with the lowest threshold, usually the 1DI. Even in this very stringent condition, the mapped representations of the AD, ECR and 1DI overlapped, notwithstanding that sharp demarcations between borders were also apparent. These observations demonstrate that stimulus spread alone does not explain the overlap of muscle representations. These results show that commonly used proximal and distal upper-limb muscles, taken individually, are controlled by motor cortical territories of approximately equal size that significantly overlap despite differences in the location of their optimal points.

Neural mechanisms involved in the functional linking of motor cortical points.

We sought to understand the basic neural processes involved in the functional linking of motor cortical points. We asked which of the two basic neural mechanisms, excitation or inhibition, is required to functionally link motor cortical points. In the ketamine-anaesthetized cat, a microstimulation electrode was positioned at a point (control point) that was identified by the following three characteristics of the EMG responses: the muscle(s) activated at threshold, any additional muscles recruited by supra-threshold stimulation, and their relative latency. A second distinct point (test point) producing activation of a muscle at a different joint was then identified. At this test cortical point the GABA(A) receptor antagonist bicuculline was ejected iontophoretically, while stimulating the control point near threshold. A combined response was elicited consisting of the response normally elicited at the control point plus that elicited at the test point. Thus, an artificial muscle synergy was produced following disinhibition of the test point. This was never the case when glutamate was ejected at the test point, even when supra-threshold stimuli were used at the control point. Therefore, simply increasing the excitability of a cortical point was not sufficient to release the muscle(s) represented at that point into a muscle synergy. Kynurenate, a broadly acting excitatory amino acid receptor antagonist, ejected at the bicuculline point reversed the effect of bicuculline. This shows that the release phenomenon was mediated synaptically and was not due to spread of the stimulating current. We suggest that release from inhibition may be one of the neural mechanisms involved in functionally linking motor cortical points. This functional linking may be part of the ensemble of motor cortical mechanisms involved in recruitment of muscle synergies.

Integrated motor cortical control of task-related muscles during pointing in humans.

A large body of compelling but indirect evidence suggests that the motor cortex controls the different forelimb segments as a whole rather than individually. The purpose of this study was to obtain physiological evidence in behaving human subjects on the mode of operation of the primary motor cortex during coordinated movements of the forelimb. We approached this problem by studying a pointing movement involving the shoulder, elbow, wrist, and index finger as follows. Focal transcranial magnetic stimulation (TMS) was used to measure the input-output (I/O) curves-a measure of the corticospinal pathway excitability-of proximal (anterior deltoid, AD, and triceps brachii, TB) and distal muscles (extensor carpi radialis, ECR, and first dorsal interosseus, 1DI) during isolated contraction of one of these muscles or during selective co-activation with other muscles involved in pointing. Compared to an isolated contraction of the ECR, the plateau-level of the ECR sigmoid I/O curve increased markedly during co-activation with the AD while pointing. In contrast, the I/O curve of AD was not influenced by activation of the more distal muscles involved in pointing. Moreover, the 1DI I/O curve was not influenced by activation of the more proximal muscles. Three arguments argue for a cortical site of facilitation of ECR motor potentials. First, ECR motor potentials evoked by a near threshold TMS stimulus were facilitated when the AD and ECR were co-activated during pointing but not those in response to a near threshold anodal electrical stimulus. Second, the ECR H reflex was not found to be task dependent, indicating that the recruitment gain of the ECR alpha-motoneuron pool did not differ between tasks. Finally, in comparison with an isolated ECR contraction, intracortical inhibition tested at the ECR cortical site was decreased during pointing. These results suggest that activation of shoulder, elbow, and wrist muscles involved in pointing appear to involve, at least in part, common motor cortical circuits. In contrast, at least in the pointing task, the motor cortical circuits involved in activation of the 1DI appear to act independently.