The nature of corticospinal paths driving human motoneurones during voluntary contractions

The properties of the human motor cortex can be studied non-invasively using transcranial magnetic stimulation (TMS). Stimulation at high intensity excites corticospinal cells with fast conducting axons that make direct connections to motoneurones of human upper limb muscles, while low-intensity stimulation can suppress ongoing EMG. To assess whether these cells are used in normal voluntary contractions, we used TMS at very low intensities to suppress the firing of single motor units in biceps brachii ( n = 14) and first dorsal interosseous (FDI, n = 6). Their discharge was recorded with intramuscular electrodes and cortical stimulation was delivered at multiple intensities at appropriate times during sustained voluntary firing at ∼10 Hz. For biceps, high-intensity stimulation produced facilitation at 17.1 ± 2.1 ms (lasting 2.4 ± 0.9 ms), while low-intensity stimulation (below motor threshold) produced suppression (without facilitation) at 20.2 ± 2.1 ms (lasting 7.6 ± 2.2 ms). For FDI, high-intensity stimulation produced facilitation at 23.3 ± 1.2 ms (lasting 1.8 ± 0.4 ms), with suppression produced by low-intensity stimulation at 25.2 ± 2.6 ms (lasting 7.5 ± 2.6 ms). The difference between the onsets of facilitation and suppression was short: 3.1 ± 1.2 ms for biceps and 2.0 ± 1.5 ms for FDI. This latency difference is much less than that previously reported using surface EMG recordings (∼10 ms). These data suggest that low-intensity cortical stimulation inhibits ongoing activity in fast-conducting corticospinal axons through an oligosynaptic (possibly disynaptic) path, and that this activity is normally contributing to drive the motoneurones during voluntary contractions.     

Paired-pulse transcranial magnetic stimulation protocol applied to visual cortex of anaesthetized cat: effects on visually evoked single-unit activity

In this study, we tested the paired-pulse transcranial magnetic stimulation (ppTMS) protocol – a conditioning stimulus (CS) given at variable intervals prior to a test stimulus (TS) – for visually evoked single-unit activity in cat primary visual cortex. We defined the TS as being supra-threshold when it caused a significant increase or decrease in the visually evoked activity. By systematically varying the interstimulus interval (ISI) between 2 and 30 ms and the strength of CS within the range 15–130% of TS, we found a clear dependence of the ppTMS effect on CS strength but little relation to ISI. The CS effect was strongest with an ISI of 3 ms and steadily declined for longer ISIs. A switch from enhancement of intracortical inhibition at short ISIs (2–5 ms, SICI) to intracortical facilitation (ICF) at longer ISIs (7–30 ms), as demonstrated for human motor cortex, was not evident. Whether the CS caused facilitation or suppression of the TS effect mainly depended on the strength of CS and the polarity of the TS effect: within a range of 60–130% a positive correlation between ppTMS and TS effect was evident, resulting in a stronger facilitation if the TS caused facilitation of visual activity, and more suppression if the TS was suppressive by itself. The correlation inverted when CS was reduced to 15–30%. The ppTMS effect was not simply the sum of the CS and TS effect, it was much smaller at weak CS strength (15–50%) but stronger than the sum of CS and TS effects at CS strength 60–100%. Differences in the physiological state between sensory and motor cortices and the interactions of paired synaptic inputs are discussed as possible reasons for the partly different effects of ppTMS in cat visual cortex and human motor cortex.     

Perceptual learning of line orientation modifies the effects of transcranial magnetic stimulation of visual cortex

Perceptual learning may be accompanied by physiological changes in early visual cortex. We used transcranial magnetic stimulation (TMS) to test the postulate that perceptual learning of a visual task initially performed at 60–65% accuracy strengthens visual processing in early visual cortex. Single pulse TMS was delivered to human occipital cortex at time delays of 70–154 ms after the onset of an odd-element, line orientation discrimination task. When TMS was delivered at a delay of 84 ms or later the accuracy of visual discrimination was transiently degraded in ten subjects. As visual performance in control trials without TMS improved with training, the absolute magnitude of TMS suppression of performance decreased in parallel. This result occurred both when TMS was delivered to broad areas of occipital cortex and when TMS was optimally delivered to early occipital cortex. No change in TMS suppression was observed when three new subjects were given feedback during an odd-element task that did not require substantial perceptual learning. Thus, perceptual learning improved visual performance and reduced TMS suppression of early visual cortex in parallel.     

Microglial activation induces cell death,inhibits neurite outgrowth and causes neurite retraction of differentiated neuroblastoma cells

We investigated the changes in intracortical neuronal circuits of the hand motor cortex following sensory stimulation of the fingers in 11 healthy subjects. Motor evoked potentials (MEPs) were recorded from intrinsic hand muscles (right first dorsal interosseous and abductor digiti minimi muscles). Electrical stimulation was applied to a digit near (homotopic) or distant (heterotopic stimulation) from each muscle. The right index or little finger was stimulated electrically, followed by single- or paired-pulse transcranial magnetic stimulation (TMS) at an interval of 25, 200, 600, 1,000 or 1,400 ms. Paired-pulse TMS was applied with interstimuli intervals of 2 ms or 12 ms and was expected to stimulate inhibitory or facilitatory intracortical circuits, respectively. MEPs induced by single-pulse TMS were significantly suppressed 200, 600, and 1,000 ms after heterotopic and homotopic stimuli. Intracortical facilitation was significantly enhanced only after homotopic stimuli and such enhancement was maximal 200 ms after digit stimulation. Intracortical inhibition was slightly weakened after homotopic stimulation but this effect did not reach statistical significance (P=0.25). Our results show that sensory feedback can modify intracortical and corticospinal motor excitability and that intracortical facilitation can be enhanced in a topographic-specific way especially at long latencies. These findings suggest that indirect pathways, probably through somatosensory cortex and other areas, enhance intracortical motor excitability in a somatotopically organized manner. Electronic Publication     

Role of sustained excitability of the leg motor cortex after transcranial magnetic stimulation in associative plasticity

Changes in the strength of corticospinal projections to muscles in the upper and lower limbs are induced in conscious humans after paired associative stimulation (PAS) to the motor cortex. We tested whether an intervention of PAS consisting of 90 low-frequency (0.1-Hz) stimuli to the common peroneal nerve combined with suprathreshold transcranial magnetic stimulation (TMS) produces specific changes to the motor-evoked potentials (MEPs) in lower leg muscles if the afferent volley from peripheral stimulation is timed to arrive at the motor cortex after TMS-induced firing of corticospinal neurons. Unlike PAS in the hand, MEP facilitation in the leg was produced when sensory inputs were estimated to arrive at the motor cortex over a range of 15 to 90 ms after cortical stimulation. We examined whether this broad range of facilitation occurred as a result of prolonged subthreshold excitability of the motor cortex after a single pulse of suprathreshold TMS so that coincident excitation from sensory inputs arriving many milliseconds after TMS can occur. We found that significant facilitation of MEP responses (>200%) occurred when the motor cortex was conditioned with suprathreshold TMS tens of milliseconds earlier. Likewise, it was possible to induce strong MEP facilitation (85% at 60 min) when afferent inputs were directly paired with subthreshold TMS. We argue that in the leg motor cortex, facilitation of MEP responses from PAS occurred over a large range of interstimulus intervals as a result of the paired activation of sensory inputs with sustained, subthreshold activity of cortical neurons that follow a pulse of suprathreshold TMS.     

Cerebral blood-flow changes induced by paired-pulse transcranial magnetic stimulation of the primary motor cortex

Positron emission tomography (PET) was used to assess changes in regional cerebral blood flow (CBF) induced by paired-pulse transcranial magnetic stimulation (TMS) of primary motor cortex (M1). The study was performed in eight normal volunteers using two Magstim-200 stimulators linked with a Bistim module. A circular TMS coil was held in the scanner by a mechanical arm and located over the left M1. Surface electrodes were used to record motor evoked potentials (MEPs) from the contralateral first dorsal interosseous muscle (FDI). Cortical excitability was evaluated in the relaxed FDI using a paired conditioning-test stimulus paradigm with two interstimulus intervals (ISIs): 3 and 12 ms. The subjects were scanned three times during each of the following four conditions: 1) baseline with no TMS (BASE); 2) single-pulse TMS (TMSsing); 3) 3-ms paired-pulse TMS (TMS3); and 4) 12-ms paired-pulse TMS (TMS12). CBF and peak-to-peak MEP amplitudes were measured over each 60-s scanning period. To assess TMS-induced changes in CBF, a t-statistic map was generated by first subtracting the single-pulse TMS condition from the 3- and 12-ms paired-pulse TMS conditions and then correlating the CBF differences, respectively, with the amount of suppression and facilitation of the EMG responses. A significant positive correlation was observed between the CBF difference (TMS3-TMSsing) and the amount of suppression of EMG response, as well as between the CBF difference (TMS12-TMSsing) and the amount of facilitation of EMG response. This positive correlation was observed in the left M1, left lateral premotor cortex, and right M1 in the case of 3-ms paired-pulse TMS, but only in the left M1 in the case of 12-ms paired-pulse TMS. The above pattern of CBF response to paired-pulse TMS supports the possibility that suppression and facilitation of the EMG response are mediated by different populations of cortical interneurons.     

Interaction of paired cortical and peripheral nerve stimulation on human motor neurons

This paper contrasts responses in the soleus muscle of normal human subjects to two major inputs: the tibial nerve (TN) and the corticospinal tract. Paired transcranial magnetic stimulation (TMS) of the motor cortex at intervals of 10–25 ms strongly facilitated the motor evoked potential (MEP) produced by the second stimulus. In contrast, paired TN stimulation produced a depression of the reflex response to the second stimulus. Direct activation of the pyramidal tract did not facilitate a second response, suggesting that the MEP facilitation observed using paired TMS occurred in the cortex. A TN stimulus also depressed a subsequent MEP. Since the TN stimulus depressed both inputs, the mechanism is probably post-synaptic, such as afterhyperpolarization of motor neurons. Presynaptic mechanisms, such as homosynaptic depression, would only affect the pathway used as a conditioning stimulus. When TN and TMS pulses were paired, the largest facilitation occurred when TMS preceded TN by about 5 ms, which is optimal for summation of the two pathways at the level of the spinal motor neurons. A later, smaller facilitation occurred when a single TN stimulus preceded TMS by 50–60 ms, an interval that allows enough time for the sensory afferent input to reach the sensory cortex and be relayed to the motor cortex. Other work indicates that repetitively pairing nerve stimuli and TMS at these intervals, known as paired associative stimulation, produces long-term increases in the MEP and may be useful in strengthening residual pathways after damage to the central nervous system.     

Facilitation of picture naming by focal transcranial magnetic stimulation of Wernicke’s area

On the basis of an evolutionary concept of language it was postulated that activation of the motor systems for arm movements, which are phylogenetically older, should facilitate language processes. In aphasic subjects picture naming can be improved by a concomitant movement of the dominant arm. In the present study it was investigated whether a similar facilitation can be observed in normal subjects by studying the effects of transcranial magnetic stimulation (TMS) on picture naming latencies. Suprathreshold focal TMS was applied to the left motor cortex for proximal arm muscles in right-handed subjects. The effects were compared with TMS of Wernicke’s area. While TMS of the motor cortex and the non-dominant temporal lobe had no facilitatory effects, TMS of Wernicke’s area decreased picture naming latencies significantly when TMS preceded picture presentation by 500 or 1000 ms. The observed effects depended on the intensity of the stimulus used. While clearly present with intensities of 35% and 55% of maximum output the facilitation disappeared with higher stimulation intensities. It is concluded that focal magnetic stimulation is able to facilitate lexical processes due to a general preactivation of language-related neuronal networks when delivered over Wernicke’s area. Received: 11 March 1997 / Accepted: 2 March 1998     

Modulation of intracortical facilitatory circuits of the human primary motor cortex by digital nerve stimulation

We investigated the effect of electrical digit stimulation on two different intracortical facilitatory phenomena. Paired-pulse transcranial magnetic stimuli (TMS) with different conditioning stimulus (CS) intensities were applied over the primary motor cortex (M1). Electromyographic (EMG) recordings were made from the relaxed right abductor digiti minimi muscle (ADM). The effect of preceding sensory stimulation applied to the ipsilateral digit V on the conditioning magnetic stimulus was examined. Changing the CS intensity affected the influence of peripheral electrical stimulation on motor evoked potential (MEP) amplitudes evoked by paired pulse TMS. Inhibition induced by ipsilateral digit stimulation was strongest with the lowest CS intensity if MEP amplitudes were evoked by a subthreshold CS followed by a suprathreshold test stimulus (TS) at an interstimulus interval (ISI) of 10 ms. In contrast, inhibition induced by digit stimulation in a paired-pulse paradigm with a suprathreshold first and a subthreshold second stimulus at ISI of 1.5 ms was strongest with the highest CS intensity. These findings suggest that appropriately timed peripheral electrical stimuli differentially modulate facilitatory interactions in the primary motor cortex. They further support the hypothesis that intracortical facilitation (ICF) and short-interval intracortical facilitation (SICF) are evoked through different mechanisms. An erratum to this article can be found at     

Facilitatory I wave interaction in proximal arm and lower limb muscle representations of the human motor cortex

Transcranial magnetic stimulation (TMS) of the human motor cortex elicits direct and indirect (I) waves in the corticospinal tract. Facilitatory I wave interaction has been demonstrated with a suprathreshold first stimulus (S1) followed by a subthreshold to threshold second stimulus (S2). Intracortical inhibition (ICI) and intracortical facilitation (ICF) can be studied by another paired TMS paradigm with a subthreshold conditioning stimulus (CS) followed by a suprathreshold test stimulus. Facilitatory I wave interaction in motor representations other than the hand area and its relationship to ICI and ICF has not been studied. We studied I wave interaction, ICI and ICF in an intrinsic hand muscle (abductor pollicis brevis, APB), in a proximal arm muscle (biceps brachii, BB) and in a lower limb muscle (tibialis anterior, TA) in 11 normal subjects. I wave facilitation was studied by paired TMS at 24 interstimulus intervals (ISIs) from 0.5 to 5.1 ms. For APB and TA, facilitation occurred in three distinct peaks at ISIs of 0.9-1.7, 2. 5-3.5, and 4.1-5.1 ms. For BB, facilitation was significant for the first two peaks. The latencies of the peaks were similar among different muscles, but the magnitude of facilitation was much greater for APB and TA compared with BB. For all three muscles, changing the S2 to transcranial electrical stimulation (TES) resulted in much less facilitation of the first peak. For APB, there was significant I wave facilitation with S2 at 72% motor threshold (MT). The same stimulus used as the CS did not elicit ICF at ISI of 15 ms, suggesting that the threshold for eliciting I wave facilitation is lower than that for ICF. For BB and TA, there was no I wave facilitation with S2 at 90% of APB MT, and the same stimulus used as CS led to ICI. Thus in BB and TA the threshold for eliciting ICI is lower than that for I wave facilitation. We conclude that the circuits that mediate I wave interactions are present in the proximal arm and lower limb representations of the motor cortex. I wave facilitation occurs predominately in the cortex and may be primarily related to the monosynaptic corticomotoneuronal (CM) system. The reduced I wave facilitation for BB compared with APB and TA may be related to less extensive CM projection and involvement of other polysynaptic descending pathways. I wave facilitation, ICI, and ICF appears to be mediated by different neuronal circuits.     

Suppression of EMG activity by subthreshold paired-pulse transcranial magnetic stimulation to the leg motor cortex

Cortical activity driving a voluntary muscle contraction is inhibited by very low-intensity transcranial magnetic stimulation (TMS) and is reflected in the suppression of the average rectified EMG. This approach offers a method to test the contribution of cortical neurons actively involved in a motor task, but requires a large number of stimuli (~100) to suitably depress the average EMG. Here, we investigated whether two pulses of subthreshold TMS at interstimulus intervals (ISIs) ranging between 1 and 12 ms could enhance the amount of EMG suppression in the tibialis anterior muscle compared to a single pulse. Pairs of subthreshold TMS at an ISI of 7 ms produced the maximum EMG suppression that was 42% more than the inhibition elicited using a single pulse. In addition, the signal-to-noise ratio of the TMS-induced suppression was further increased by a second pulse, delivered 7 ms later. The reduction in the EMG at the 7 ms paired-pulse interval occurred without any short-latency excitation suggesting that the two stimuli increased the activation of cortical inhibitory neurons. Subthreshold paired-pulse TMS at ISIs of 1–3 ms was prone to EMG excitation in the period that immediately preceded the inhibition and is consistent with the recruitment of short-interval intracortical facilitation (SICF). We propose that pairs of subthreshold TMS outside the range of SICF with an inter-pulse interval of 7 ms is optimal to inhibit ongoing cortical activity during human motor movement.     

Shortening of simple reaction time by peripheral electrical and submotor-threshold magnetic cortical stimulation

 Subthreshold transcranial magnetic stimulation (TMS) over the motor cortex can shorten the simple reaction time in contralateral arm muscles if the cortical shock is given at about the same time as the reaction stimulus. The present experiments were designed to investigate whether this phenomenon is due to a specific facilitatory effect on cortical circuitry. The simple visual reaction time was shortened by 20–50 ms when subthreshold TMS was given over the contralateral motor cortex. Reaction time was reduced to the same level whether the magnetic stimulus was given over the bilateral motor cortices or over other points on the scalp (Cz, Pz). Indeed, similar effects could be seen with conventional electrical stimulation over the neck, or even when the coil was discharged (giving a click sound) near the head. We conclude that much of the effect of TMS on simple reaction time is due to intersensory facilitation, although part of it may be ascribed to a specific effect on the excitability of motor cortex. Received: 15 July 1996 / Accepted: 25 February 1997     

Impairment of visual perception and visual short term memory scanning by transcranial magnetic stimulation of occipital cortex

Summary Transcranial magnetic stimulation (TMS) of occipital cortex was performed using a magneto-electric stimulator with a maximum output of 2 Tesla in 24 normal volunteers. The identification of trigrams, presented for 14 ms in horizontal or vertical arrays was significantly impaired when the visual stimulus preceded the occipital magnetic shock by 40 to 120 ms. The extent of impairment was related to TMS intensity. The latency of perceptual impairment was shorter for more intense TMS. No perceptual impairment was obtained by sham stimulation when TMS shocks were applied to the upper cervical region rather than the occipital region to rule out unspecific startle reactions affecting attention possibly responsible for the observed reduction in performance. Occipital TMS did not evoke systematic eye movements except for blink responses at latencies beyond 40 ms which were too late to interfere with visual input. Depending on the required serial order of readout of the trigram perceptual impairment was more marked for the second and third part of the trigram. This demonstrates that TMS interferes with the internal serial processing of visual input. To elucidate this further, TMS was used in a Sternberg short term visual memory scanning task. TMS caused a marked decrease in memory scanning rates whereas visual stimulus encoding and storage remained unaffected when tested at various TMS delays. TMS appears to be a useful method to study processes of visual perception and short term memory handling in the occipital cortex. Advantages over classical visual masking techniques especially regarding topical localisation are discussed.This work was partially supported by a grant from the Deutsche Forschungs Gemeinschaft (SFB 200/B9) to V.H.     

Cortical activation during temporal preparation assessed by transcranial magnetic stimulation

Preparatory modulations relative to the timing of upcoming stimuli may involve activation or suppression mechanisms. Here, we assessed the interplay between these mechanisms with transcranial magnetic stimulation (TMS) of the motor cortex. Single- or paired-pulse TMS with 3- or 15-ms interstimulus intervals was delivered during the interval between the warning and the imperative stimuli (i.e., the foreperiod) of a choice reaction time task. Temporal uncertainty was manipulated through between-block variation of the foreperiod duration (500 or 2500 ms). The shortening of reaction time for the short foreperiod was accompanied with a decrease in amplitude of the single-pulse motor evoked potential (MEP), indicating corticospinal suppression. The co-occurring increase in amplitude of both paired-pulse MEPs (3 and 15 ms) expressed relative to single-pulse MEPs reveals released short intracortical inhibition (SICI) and enhanced intracortical facilitation (ICF). These results suggest that temporal preparation is associated with both corticospinal suppression and cortical activation.     

Exploring the connectivity between the cerebellum and motor cortex in humans

Animal studies have shown that cerebellar projections influence both excitatory and inhibitory neurones in the motor cortex but this connectivity has yet to be demonstrated in human subjects. In human subjects, magnetic or electrical stimulation of the cerebellum 5–7 ms before transcranial magnetic stimulation (TMS) of the motor cortex decreases the TMS-induced motor-evoked potential (MEP), indicating a cerebellar inhibition of the motor cortex (CBI). TMS also reveals inhibitory and excitatory circuits of the motor cortex, including a short-interval intracortical inhibition (SICI), long-interval intracortical inhibition (LICI) and intracortical facilitation (ICF). This study used magnetic cerebellar stimulation to investigate connections between the cerebellum and these cortical circuits. Three experiments were performed on 11 subjects. The first experiment showed that with increasing test stimulus intensities, LICI, CBI and ICF decreased, while SICI increased. The second experiment showed that the presence of CBI reduced SICI and increased ICF. The third experiment showed that the interaction between CBI and LICI reduced CBI. Collectively, these findings suggest that cerebellar stimulation results in changes to both inhibitory and excitatory neurones in the human motor cortex.     

Cortical excitability in adult patients with attention-deficit/hyperactivity disorder (ADHD)

Attention-deficit/hyperactivity disorder (ADHD) is more and more focused on, and the awareness of adult patients with ADHD increases. Deficits in inhibitory processes in cortical brain areas are discussed as possible causes for ADHD. An easy measurement of these processes is provided by transcranial magnetic stimulation (TMS). We applied single- and double-pulse TMS to the left motor cortex while an electromyogram (EMG) was taken at the abductor pollicis brevis muscle (APB) of the right hand. Intracortical inhibition (SICI) and facilitation (ICF) were measured in ten adult ADHD patients and ten healthy participants using inter-pulse intervals of 2 and 3ms (SICI), and 8 and 15ms (ICF). Furthermore, resting motor threshold (RMT) and latency of the motor evoked potential (MEP) following magnetic stimulation were compared. t-Tests were calculated for statistical analysis. TMS measurements resulted in impaired inhibition in ADHD patients, whereas there were no differences in facilitation, RMT and MEP-latency between groups. Large variability in the patient group was found. This study expands the findings of deficits in inhibition described in earlier studies in children to an adult population, which could be a hint for similar neurophysiological mechanisms underlying ADHD symptomatology in children and adults.     

Effects of low-frequency whole-body vibration on motor-evoked potentials in healthy men

The aim of this study was to determine whether low-frequency whole-body vibration (WBV) modulates the excitability of the corticospinal and intracortical pathways related to tibialis anterior (TA) muscle activity, thus contributing to the observed changes in neuromuscular function during and after WBV exercise. Motor-evoked potentials (MEPs) elicited in response to transcranial magnetic stimulation (TMS) of the leg area of the motor cortex were recorded in TA and soleus (SOL) muscles of seven healthy male subjects whilst performing 330 s continuous static squat exercise. Each subject completed two conditions: control (no WBV) and WBV (30 Hz, 1.5 mm vibration applied from 111 to 220 s). Five single suprathreshold and five paired TMS were delivered during each squat period lasting 110 s (pre-, during and post-WBV). Two interstimulus intervals (ISIs) between the conditioning and the testing stimuli were employed in order to study the effects of WBV on short-interval intracortical inhibition (SICI, ISI = 3 ms) and intracortical facilitation (ICF, ISI = 13 ms). During vibration relative to squat exercise alone, single-pulse TMS provoked significantly higher TA MEP amplitude (56 ± 14%, P = 0.003) and total area (71 ± 19%, P = 0.04), and paired TMS with ISI = 13 ms provoked smaller MEP amplitude (−21 ± 4%, P = 0.01) but not in SOL. Paired-pulse TMS with ISI = 3 ms elicited significantly lower MEP amplitude (TA, −19 ± 4%, P = 0.009; and SOL, −13 ± 4%, P = 0.03) and total area (SOL, −17 ± 6%, P = 0.02) during vibration relative to squat exercise alone in both muscles. Tibialis anterior MEP facilitation in response to single-pulse TMS suggests that WBV increased corticospinal pathway excitability. Increased TA and SOL SICI and decreased TA ICF in response to paired-pulse TMS during WBV indicate vibration-induced alteration of the intracortical processes as well.     

The site of saccadic suppression

During rapid eye movements, or saccades, stable vision is maintained by active reduction of visual sensitivity. The site of this saccadic suppression remains uncertain. Here we show that phosphenes--small illusory visual perceptions--induced by transcranial magnetic stimulation (TMS) to the human occipital cortex are immune to saccadic suppression, whereas phosphenes induced by retinal stimulation are not, thus providing direct physiological evidence that saccadic suppression occurs between the retina and the occipital visual cortex.     

Cortical activation during temporal preparation assessed by transcranial magnetic stimulation

Preparatory modulations relative to the timing of upcoming stimuli may involve activation or suppression mechanisms. Here, we assessed the interplay between these mechanisms with transcranial magnetic stimulation (TMS) of the motor cortex. Single- or paired-pulse TMS with 3- or 15-ms interstimulus intervals was delivered during the interval between the warning and the imperative stimuli (i.e., the foreperiod) of a choice reaction time task. Temporal uncertainty was manipulated through between-block variation of the foreperiod duration (500 or 2500 ms). The shortening of reaction time for the short foreperiod was accompanied with a decrease in amplitude of the single-pulse motor evoked potential (MEP), indicating corticospinal suppression. The co-occurring increase in amplitude of both paired-pulse MEPs (3 and 15 ms) expressed relative to single-pulse MEPs reveals released short intracortical inhibition (SICI) and enhanced intracortical facilitation (ICF). These results suggest that temporal preparation is associated with both corticospinal suppression and cortical activation.