Impairment in processing visual information at the pre-attentive stage in patients with a major depressive disorder: a visual mismatch negativity study

Age-related declines in central processing may delay the facilitation of corticospinal (CS) tracts that underlie emergence of voluntary responses to external stimuli. To explore this effect, single pulse transcranial magnetic stimulation (TMS) was applied to the left motor cortex at different latencies from the go-signal (auditory tone) during a simple reaction time (SRT) task with the right or left thumb [i.e. right (RHM) or left hand move (LHM)]. Motor evoked potentials (MEPs) in the right abductor pollicis brevis (APB) were recorded from eleven healthy right-handed participants (aged 22-65; six young adults and five old adults). Both age groups showed significant facilitation of CS excitability approximately 100-120 ms from the onset of the go-signal in the RHM SRT that occurred before the onset of EMG voluntary burst, with no evidence for motor slowing in old adults. Old adults demonstrated a significant facilitation of MEPs in the time that preceded the go-signal for RHM SRT and a marked depression of CS excitability in preparation for the LHM SRT that was sustained up to 80 ms after the onset of the go-signal. Both effects were not seen in young adults. While the small number of participants may hinder the generality of the present observations, this pilot study suggests for the first time that old adults implemented selective tuning of CS excitability prior to the onset of the go command to speed up their response generation.     

Kinesthetic, but not visual, motor imagery modulates corticomotor excitability

The hypothesis that motor imagery and actual movement involve overlapping neural structures in the central nervous system is supported by multiple lines of evidence. The aim of this study was to examine the modulation of corticomotor excitability during two types of strategies for motor imagery: Kinesthetic Motor Imagery (KMI) and Visual Motor Imagery (VMI) in a phasic thumb movement task. Transcranial magnetic stimulation (TMS) was applied over the contralateral motor cortex (M1) to elicit motor evoked potentials (MEPs) in the dominant abductor pollicis brevis (APB) and abductor digiti minimi (ADM). In a separate experiment, transcutaneous electrical stimuli were delivered to the median nerve at the dominant wrist, to elicit F-waves from APB. Imagined task performance was paced with a 1 Hz auditory metronome, and stimuli were delivered either 50 ms before (ON phase), or 450 ms after (OFF phase), the metronome beeps. Recordings were also made during two control conditions: Rest, and a Visual Static Imagery (VSI) condition. Significant MEP amplitude facilitation occurred only in APB, and only during the ON phase of KMI. F-wave persistence and amplitude were unaffected by imagery. These results demonstrate that kinesthetic, but not visual, motor imagery modulates corticomotor excitability, primarily at the supraspinal level. These findings have implications for the definition of motor imagery, and for its therapeutic applications.     

A temporally asymmetric Hebbian rule governing plasticity in the human motor cortex

Synaptic plasticity is conspicuously dependent on the temporal order of the pre- and postsynaptic activity. Human motor cortical excitability can be increased by a paired associative stimulation (PAS) protocol. Here we show that it can also be decreased by minimally changing the interval between the two associative stimuli. Corticomotor excitability of the abductor pollicis brevis (APB) representation was tested before and after repetitively pairing of single right median nerve simulation with single pulse transcranial magnetic stimulation (TMS) delivered over the optimal site for activation of the contralateral APB. Following PAS, depression of TMS-evoked motor-evoked potentials (MEPs) was induced only when the median nerve stimulation preceded the TMS pulse by 10 ms, while enhancement of cortical excitability was induced using an interstimulus interval of 25 ms, suggesting an important role of the sequence of cortical events triggered by the two stimulation modalities. Experiments using F-wave studies and electrical brain stem stimulation indicated that the site of the plastic changes underlying the decrease of MEP amplitudes following PAS (10 ms) was within the motor cortex. MEP amplitudes remained depressed for approximately 90 min. The decrease of MEP amplitudes was blocked when PAS(10 ms) was performed under the influence of dextromethorphan, an N-methyl-d-aspartate-receptor antagonist, or nimodipine, an L-type voltage-gated calcium-channel antagonist. The physiological profile of the depression of human motor cortical excitability following PAS(10 ms) suggests long-term depression of synaptic efficacy to be involved. Together with earlier findings, this study suggests that strict temporal Hebbian rules govern the induction of long-term potentiation/long-term depression-like phenomena in vivo in the human primary motor cortex.     

Task-dependent changes of intracortical inhibition

 The motor-evoked potential (MEP) to transcranial magnetic stimulation (TMS) is inhibited when preceded by a subthreshold TMS stimulus at short intervals (1–6 ms; intracortical inhibition, ICI) and is facilitated when preceded by a subthreshold TMS at longer intervals (10–15 ms; intracortical facilitation, ICF). We studied changes in ICI and ICF associated with two motor tasks requiring a different selectivity in fine motor control of small hand muscles (abductor pollicis brevis muscle, APB, and fourth dorsal interosseous muscle, 4DIO). In experiment 1 (exp. 1), nine healthy subjects completed four sets (5 min duration each) of repetitive (1 Hz) thumb movements. In experiment 2 (exp. 2), the subjects produced the same number of thumb movements, but complete relaxation of 4DIO was demanded. Following free thumb movements (exp. 1), amplitudes of MEPs in response to both single and paired TMS showed a trend to increase with the number of exercise sets in both APB and 4DIO. By contrast, more focal, selective thumb movementsinvolving APB with relaxation of 4DIO (exp. 2) caused an increase in MEP amplitudes after single and paired pulses only in APB, while a marked decrease in MEPs after paired pulses, but not after single TMS, in the actively relaxed 4DIO. This effect was more prominent for the interstimulus interval (ISI) of 1–3 ms than for longer ISIs (8 ms, 10 ms, and 15 ms). F-wave amplitudes reflecting excitability of the alpha motoneuron pool were unaltered in APB and 4DIO, suggesting a supraspinal origin for the observed changes. We conclude that plastic changes of ICI and ICF within the hand representation vary according to the selective requirements of the motor program. Performance of more focal tasks may be associated with a decrease in ICI in muscles engaged in the training task, while at the same time ICI may be increased in an actively relaxed muscle, also required for a focal performance. Additionally, our data further supports the idea that ICI and ICF may be controlled independently. Received: 20 September 1996 / Accepted: 1 October 1997     

Suppression of corticospinal excitability during negative motor imagery

To investigate the effect of negative motor imagery on corticospinal excitability, we performed transcranial magnetic stimulation (TMS) studies in seven healthy subjects during imagination of suppressing movements. Subjects were asked to imagine suppression of TMS-induced twitching movement of their nondominant left hands by attempting to increase the amount of relaxation after receiving an auditory NoGo cue (negative motor imagery), but to imagine squeezing hands after a Go cue (positive motor imagery). Single- and paired-pulse TMS were triggered at 2 s after Go or NoGo cues. Motor-evoked potentials (MEPs) were recorded in the first dorsal interosseus (FDI), abductor pollicis brevis (APB), and abductor digiti minimi (ADM) muscles of the left hand. Paired-pulse TMS with subthreshold conditioning stimuli at interstimulus intervals of 2 (short intracortical inhibition) and 15 ms (intracortical facilitation) and that with suprathreshold conditioning stimuli at interstimulus interval of 80 ms (long intracortical inhibition) were performed in both negative motor imagery and control conditions. Compared with the control state (no imagination), MEP amplitudes of FDI (but not APB and ADM) were significantly suppressed in negative motor imagery, but those from all three muscles were unchanged during positive motor imagery. F-wave responses (amplitudes and persistence) were unchanged during both negative and positive motor imagery. During negative motor imagery, resting motor threshold was significantly increased, but short and long intracortical inhibition and intracortical facilitation were unchanged. The present results demonstrate that excitatory corticospinal drive is suppressed during imagination of suppressing movements.     

Facilitatory effect of paired-pulse stimulation by transcranial magnetic stimulation with biphasic wave-form

Transcranial magnetic stimulation (TMS) is used to probe corticospinal excitability by stimulating the motor cortex. Our aim was to enhance the effects of biphasic TMS by coupling a suprathreshold test pulse and a following subthreshold priming pulse to induce short-interval intracortical facilitation (SICF), which is conventionally produced with monophasic TMS. Biphasic TMS could potentially induce the SICF effect with better energy-efficiency and with lower stimulus intensities. This would make the biphasic paired-pulses better applicable in patients with reduced cortical excitability.A prototype stimulator was built to produce biphasic paired-pulses. Resting motor thresholds (rMTs) from the right and left hand abductor pollicis brevis muscles, and the right tibialis anterior muscle of eight healthy volunteers were determined using single-pulse paradigm with neuronavigated TMS. The rMTs and MEPs were measured using single-pulses and three paired-pulse setups (interstimulus interval, ISI of 3, 7 or 15 ms).The rMTs were lower and MEPs were higher with biphasic paired-pulses compared to single-pulses. The SICF effect was greatest at 3 ms ISI. This suggests that the application of biphasic paired-pulses to enhance stimulation effects is possible.     

Modulation of motor cortex excitability by median nerve and digit stimulation

We investigated the time course of changes in motor cortex excitability after median nerve and digit stimulation. Although previous studies showed periods of increased and decreased corticospinal excitability following nerve stimulation, changes in cortical excitability beyond 200 ms after peripheral nerve stimulation have not been reported. Magnetoencephalographic studies have shown an increase in the 20-Hz rolandic rhythm from 200 to 1000 ms after median nerve stimulation. We tested the hypothesis that this increase is associated with reduced motor cortex excitability. The right or left median nerve was stimulated and transcranial magnetic stimulation (TMS) was applied to left motor cortex at different conditioning-test (C-T) intervals. Motor-evoked potentials (MEPs) were recorded from the right abductor pollicis brevis (APB), first dorsal interosseous (FDI), and extensor carpi radialis (ECR) muscles. Right median nerve stimulation reduced test MEP amplitude at C-T intervals from 400 to 1000 ms for APB, at C-T intervals from 200 to 1000 ms for FDI, and at C-T intervals of 200 and 600 ms for ECR, but had no effect on FDI F-wave amplitude at a C-T interval of 200 ms. Left median nerve (ipsilateral to TMS) stimulation resulted in less inhibition than right median nerve stimulation, but test MEP amplitude was significantly reduced at a C-T interval of 200 ms for all three muscles. Digit stimulation also reduced test MEP amplitude at C-T intervals of 200–600 ms. The time course for decreased motor cortex excitability following median nerve stimulation corresponds well to rebound of the 20-Hz cortical rhythm and supports the hypothesis that this increased power represents cortical deactivation. Received: 11 December 1998 / Accepted: 30 April 1999     

Mechanisms of enhancement of human motor cortex excitability induced by interventional paired associative stimulation

Associative stimulation has been shown to enhance excitability in the human motor cortex ( Stefan et al. 2000 ); however, little is known about the underlying mechanisms. An interventional paired associative stimulation (IPAS) was employed consisting of repetitive application of single afferent electric stimuli, delivered to the right median nerve, paired with single pulse transcranial magnetic stimulation (TMS) over the optimal site for activation of the abductor pollicis brevis muscle (APB) to generate approximately synchronous events in the primary motor cortex. Compared to baseline, motor evoked potentials (MEPs) induced by unconditioned, single TMS pulses increased after IPAS. By contrast, intracortical inhibition, assessed using (i) a suprathreshold test TMS pulse conditioned by a subthreshold TMS pulse delivered 3 ms before the test pulse, and (ii) a suprathreshold test TMS pulse conditioned by afferent median nerve stimulation delivered 25 ms before the TMS pulse, remained unchanged when assessed with appropriately matching test stimulus intensities. The increase of single-pulse TMS-evoked MEP amplitudes was blocked when IPAS was performed under the influence of dextromethorphan, an N -methyl- d -aspartate (NMDA) receptor antagonist known to block long-term potentiation (LTP). Further experiments employing the double-shock TMS protocol suggested that the afferent pulse, as one component of the IPAS protocol, induced disinhibition of the primary motor cortex at the time when the TMS pulse, as the other component of IPAS, was delivered. Together, these findings support the view that LTP-like mechanisms may underlie the cortical plasticity induced by IPAS.     

Reduction of cortico-spinal excitability by transcranial magnetic stimulation at predictable timing

Electrophysiological studies have shown that cortico-spinal excitability increases during the motor preparation period in reaction time (RT) paradigms. However, there is a line of contradictory evidence with transcranial magnetic stimulation (TMS) showing that its excitability is reduced during the preparation period. In these studies, the subjects can predict the TMS timings. Thus we investigated how the predictability of TMS timing affects cortico-spinal excitability. A single-pulse TMS was delivered to the hand section of the left motor cortex while seven right-handed subjects relaxed their hands in a flexed position. We prepared three conditions: (i) in the semi-PREDICTABLE condition, two visual stimuli at 500 ms interval were presented and the TMS was delivered either 0, 125, 250, 375, or 500 ms after the first stimulus; (ii) in the PREDICTABLE condition, the TMS was provided only at 500 ms after the first stimulus; (iii) in the UNPREDICTABLE condition, no visual cue preceded the TMS. We recorded motor evoked potentials (MEPs) from the wrist flexor and extensor muscles. We found a significant reduction of MEP amplitude in the flexor muscles in both the PREDICTABLE and semi-PREDICTABLE conditions, but not in the UNPREDICTABLE condition. These results showed that the predictability of TMS per se, without the preparation of motor outputs, can reduce cortico-spinal excitability.     

A TMS study on non-consciously triggered response tendencies in the motor cortex

Non-consciously perceived arrow stimuli can speed up responses to similar stimuli that are shortly presented after a masked prime. Yet response facilitation may turn into a delay at particular intervals between masked primes and targets. In this case, the lateralized readiness potential, as a measure of the time course of differential activation between the primed and the unprimed motor cortices, consistently yielded two consecutive maxima of opposite polarity, at 250 and at 350 ms after prime onset. To further explore the mechanisms underlying inverse priming, we used single-pulse transcranial magnetic stimulation (TMS) of the left or right primary motor hand area (M1). Lateralized changes in corticomotor excitability induced by the masked prime were probed by assessing the effect of priming on the amplitude of the TMS-induced motor-evoked potentials (MEPs). In two experiments, MEPs increased and decreased, respectively, in the hand primed by the masked arrows when TMS was given at 250 and at 350 ms after prime onset, confirming the expectation that MEP changes may indicate the response tendencies induced by the masked primes. Both effects were more distinct with TMS of the left M1. However, there were also some differences between the patterns of results in the two experiments. We propose that the left M1 is activated for preparation of both right- and left-hand movements, and we relate the present results to current hypotheses about the nature of inverse priming.     

Short-interval intracortical inhibition is modulated by high-frequency peripheral mixed nerve stimulation

Cortical excitability can be modulated by manipulation of afferent input. We investigated the influence of peripheral mixed nerve stimulation on the excitability of the motor cortex. Motor evoked potentials (MEPs), short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) in the right abductor pollicis brevis (APB), extensor carpi radialis (ECR) and first dorsal interosseous (FDI) muscles were evaluated using paired-pulse transcranial magnetic stimulation (TMS) before and after high-frequency peripheral mixed nerve stimulation (150Hz, 30min) over the right median nerve at the wrist. The MEP amplitude and SICI of the APB muscle decreased transiently 0-10min after the intervention, whereas the ICF did not change. High-frequency peripheral mixed nerve stimulation reduced the excitability of the motor cortex. The decrement in the SICI, which reflects the function of GABA(A)ergic inhibitory interneurons, might compensate for the reduced motor cortical excitability after high-frequency peripheral mixed nerve stimulation.     

Intracortical inhibition during volitional inhibition of prepared action

Volitional inhibition is the voluntary prevention of a prepared movement. Here we ask whether primary motor cortex (M1) is a site of convergence of cortical activity associated with movement preparation and volitional inhibition. Volitional inhibition was studied by presenting a stop signal before execution of an anticipated response that requires a key lift to intercept a revolving dial. Motor evoked potentials (MEPs) were elicited in intrinsic hand muscles by transcranial magnetic stimulation (TMS) to assess corticomotor excitability and short interval intracortical inhibition (sICI) during task performance. The closer the stop cue was presented to the anticipated response, the harder it was for subjects to inhibit their response. Corticomotor pathway excitability was temporally modulated during volitional inhibition. Using subthreshold TMS, corticomotor excitability was reduced for Stop trials relative to Go trials from 140 ms after the cue. sICI was significantly greater for Stop trials compared with Go trials at a time that preceded the onset of muscle activity associated with the anticipated response. These results provide evidence that volitional inhibition is exerted at a cortical level and that inhibitory networks within M1 contribute to volitional inhibition of prepared action.     

Motor facilitation while observing hand actions: specificity of the effect and role of observer's orientation

Action observation enhances cortico-spinal excitability. Here we tested the specificity of this effect and the role played by the orientation of the observer. Ten normal subjects observed video clips of right hand performing three different finger movements (thumb ab-/adduction, index ab-/adduction, index extens-/flexion) in two different orientations (Away, i.e., natural hand-orientation facing out from the observer; or Toward, i.e., unnatural hand-orientation facing toward the observer). Motor-evoked potentials (MEPs) induced by transcranial magnetic stimulation (TMS) were recorded from the abductor pollicis brevis (APB) and the first dorsal interosseus (FDI) muscles. Movement direction of the index finger was recorded using force transducers. Facilitation of MEP size was significantly greater for APB during observation of thumb movements and for FDI during observation of index finger movements. Facilitation of MEP size was significantly greater when the hand presented on screen was facing out from and corresponding to that of the observer (Away orientation). The direction of the index finger movement evoked by TMS shifted toward extension/flexion versus ab-/adduction matching the observed movement. Our results give further evidence that observation of a movement enhances motor output to the muscles involved in the movement and facilitates the observed action. In addition, we provide novel evidence about the high degree of specificity of this observation-induced motor cortical modulation. The degree of modulation depends on hand orientation. The modulation is maximal when the observed action corresponds to the orientation of the observer.     

The effect of ballistic thumb contractions on the excitability of the ipsilateral motor cortex

We investigated how ballistic contractions of the left thumb affect the excitability of the ipsilateral motor cortex using transcranial magnetic stimulation (TMS). TMS was applied at the motor hotspot for the right abductor pollicis brevis (APB) muscle. In ‘self-triggered’ trials, participants made targeted, isometric, contractions of the left APB. The right APB was either relaxed or maintained a tonic contraction. TMS was administered as soon as possible after electromyographic onset in the left APB. In ‘control’ trials, the left thumb remained quiescent and TMS was triggered by the computer. In each condition, 20–24 trials were conducted. Half these trials involved a single test stimulus, TS (130% APB resting motor threshold, RMT). In the other trials, short-interval intracortical inhibition (SICI) was investigated by applying a conditioning stimulus (70% APB RMT) 3 ms prior to the TS. SICI ratios were not significantly different in self-triggered and control trials. However, when the right APB was active, significantly shorter silent periods (SPs) were observed in self-triggered trials when compared with control trials. Our results support the view that SICI and SP are mediated by different inhibitory circuits, and that ipsilateral GABA_B-ergic circuits (assessed by SP), but not GABA_A-ergic circuits (assessed by SICI), are affected in the period immediately following voluntary ballistic contractions.     

Mapping of direction and muscle representation in the human primary motor cortex controlling thumb movements

Larger body parts are somatotopically represented in the primary motor cortex (M1), while smaller body parts, such as the fingers, have partially overlapping representations. The principles that govern the overlapping organization of M1 remain unclear. We used transcranial magnetic stimulation (TMS) to examine the cortical encoding of thumb movements in M1 of healthy humans. We performed M1 mapping of the probability of inducing a thumb movement in a particular direction and used low intensity TMS to disturb a voluntary thumb movement in the same direction during a reaction time task. With both techniques we found spatially segregated representations of the direction of TMS-induced thumb movements, thumb flexion and extension being best separated. Furthermore, the cortical regions corresponding to activation of a thumb muscle differ, depending on whether the muscle functions as agonist or as antagonist for flexion or extension. In addition, we found in the reaction time experiment that the direction of a movement is processed in M1 before the muscles participating in it are activated. It thus appears that one of the organizing principles for the human corticospinal motor system is based on a spatially segregated representation of movement directions and that the representation of individual somatic structures, such as the hand muscles, overlap.     

Focal depression of cortical excitability induced by fatiguing muscle contraction: a transcranial magnetic stimulation study

Motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS) and transcranial electrical stimulation (TES) of the motor cortex were recorded in separate sessions to assess changes in motor cortex excitability after a fatiguing isometric maximal voluntary contraction (MVC) of the right ankle dorsal flexor muscles. Five healthy male subjects, aged 37.4±4.2 years (mean±SE), were seated in a chair equipped with a load cell to measure dorsiflexion force. TMS or TES was delivered over the scalp vertex before and after a fatiguing MVC, which was maintained until force decreased by 50%. MEPs were recorded by surface electrodes placed over quadriceps, hamstrings, tibialis anterior (TA), and soleus muscles bilaterally. M-waves were elicited from the exercised TA by supramaximal electrical stimulation of the peroneal nerve. H-reflex and MVC recovery after fatiguing, sustained MVC were also studied independently in additional sessions. TMS-induced MEPs were significantly reduced for 20 min following MVC, but only in the exercised TA muscle. Comparing TMS and TES mean MEP amplitudes, we found that, over the first 5 min following the fatiguing MVC, they were decreased by about 55% for each. M-wave responses were unchanged. H-reflex amplitude and MVC force recovered within the 1st min following the fatiguing MVC. When neuromuscular fatigue was induced by tetanic motor point stimulation of the TA, TMS-induced MEP amplitudes remained unchanged. These findings suggest that the observed decrease in MEP amplitude represents a focal reduction of cortical excitability following a fatiguing motor task and may be caused by intracortical and/or subcortical inhibitory mechanisms.     

Influence of transcranial magnetic stimulation on the execution of memorised sequences of saccades in man

Memorised sequences of saccades are cortically controlled by the supplementary motor area (SMA), as shown in animal experiments and in humans with isolated SMA lesions. We applied transcranial magnetic stimulation (TMS) in eight healthy subjects executing memorised sequences of saccades. Sequences of three targets were presented. Then, upon a go-signal, the subjects had to execute the appropriate sequences. Ten to fifteen sequences were performed in each experiment, and the number of errors were counted. The number of errors increased significantly if TMS was given 80 ms before or 60 ms after the go-signal, with the stimulation coil overlying the SMA. There was no significant increase in errors if different stimulation intervals were chosen (160ms and 120ms before the go-signal; 100 ms, 140 ms or 240 ms after the go-signal), if the coil was positioned inappropriately (e.g. over the occipital cortex), or if the stimulator output was too low. We conclude that TMS can interfere specifically with the function of the SMA during a critical time interval close to the go-signal.     

Extensive training of elementary finger tapping movements changes the pattern of motor cortex excitability

There is evidence of a strong capacity for functional and structural reorganization in the human motor system. However, past research has focused mainly on complex movement sequences over rather short training durations. In this study we investigated changes in corticospinal excitability associated with longer training of elementary, maximum-speed tapping movements. All participating subjects were consistent right-handers and were trained using either the right (experiment 1) or the left thumb (experiment 2). Transcranial magnetic stimulation was applied to obtain motor evoked potentials (MEPs) from the abductor pollicis brevis (APB) muscle of the right and the left hand before and after training. As a result of training, a significant increase was observed in tapping speed accompanied by increased MEPs, recorded from the trained APB muscle, following contralateral M1 stimulation. In the case of subdominant-hand training we additionally demonstrate increased MEP amplitudes evoked at the right APB (untrained hand) in the first training week. Enhanced corticospinal excitability associated with practice of elementary movements may constitute a necessary precursor for inducing plastic changes within the motor system. The involvement of the ipsilateral left M1 likely reflects the predominant role of the left M1 in the general control (modification) of simple motor parameters in right-handed subjects.     

Loss of short-latency afferent inhibition and emergence of afferent facilitation following neuromuscular electrical stimulation

Neuromuscular electrical stimulation (NMES) increases the excitability of corticospinal (CS) pathways by altering circuits in motor cortex (M1). How NMES affects circuits interposed between the ascending afferent volley and descending CS pathways is not known. Presently, we hypothesized that short-latency afferent inhibition (SAI) would be reduced and afferent facilitation (AF) enhanced when NMES increased CS excitability. NMES was delivered for 40 min over the ulnar nerve. To assess CS excitability, motor evoked potentials (MEPs) were evoked using transcranial magnetic stimulation (TMS) delivered at 120% resting threshold for first dorsal interosseus muscle. These MEPs increased by ∼1.7-fold following NMES, demonstrating enhanced CS excitability. SAI and AF were tested by delivering a “conditioning” electrical stimulus to the ulnar nerve 18–25 ms and 28–35 ms before a “test” TMS pulse, respectively. Conditioned MEPs were compared to unconditioned MEPs evoked in the same trials. TMS was adjusted so unconditioned MEPs were not different before and after NMES. At the SAI interval, conditioned MEPs were 25% smaller than unconditioned MEPs before NMES but conditioned and unconditioned MEPs were not different following NMES. At the AF interval, conditioned MEPs were not different from unconditioned MEPs before NMES, but were facilitated by 33% following NMES. Thus, when NMES increases CS excitability there are concurrent changes in the effect of afferent input on M1 excitability, resulting in a net increase in the excitatory effect of the ascending afferent volley on CS circuits. Maximising this excitatory effect on M1 circuits may help strengthen CS pathways and improve functional outcomes of NMES-based rehabilitation programs.