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.     

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     

Preconditioning repetitive transcranial magnetic stimulation of premotor cortex can reduce but not enhance short-term facilitation of primary motor cortex

Short trains of suprathreshold 5-Hz repetitive transcranial magnetic stimulation (rTMS) over primary motor cortex (M1) evoke motor potentials (MEPs) in hand muscles that progressively increase in amplitude via a mechanism that is thought to be similar to short-term potentiation described in animal preparations. Long trains of subthreshold rTMS over dorsal premotor cortex (PMd) are known to affect the amplitude of single-pulse MEPs evoked from M1. We tested whether PMd-rTMS affects short-term facilitation in M1. We also explored the effect of PMd-rTMS on M1 responses evoked by single-pulse TMS of different polarities. We tested in 15 healthy subjects short-term facilitation in left M1 (10 suprathreshold TMS pulses at 5 Hz) after applying rTMS to left PMd (1,500 subthreshold pulses at 1 and 5 Hz). In a sample of subjects we delivered single-pulse TMS with different polarities and paired-pulse TMS at short intervals (SICI) after PMd-rTMS. Short-term facilitation in M1 was reduced after applying 1 Hz to PMd, but was unaffected after 5-Hz PMd-rTMS. PMd-rTMS with 1 Hz reduced the amplitude of MEPs evoked by monophasic posteroanterior (PA) or biphasic anteroposterior (AP)-PA but had little effect on MEPs by monophasic AP or biphasic PA-AP single-pulse TMS. PMd-rTMS left SICI unchanged. PMd-rTMS (1 Hz) reduces short-term facilitation in M1 induced by short 5-Hz trains. This effect is likely to be caused by reduced facilitation of I-wave inputs to corticospinal neurons.     

Associative plasticity in human motor cortex during voluntary muscle contraction

TMS pulses over the hand area of motor cortex activate different subpopulations of synaptic connections if the direction of the induced current in the brain is reversed from posterior-anterior (PA) direction to anterior-posterior (AP). We tested whether this also made a difference to the after-effects of paired associative stimulation (PAS: ulnar nerve stimulation followed 25 ms later by a transcranial magnetic stimulation pulse). If 50 pairs of stimuli (0.1 Hz) were applied using conventional suprathreshold PA-PAS in resting subjects, there was no effect on motor-evoked potentials (MEPs) in the first dorsal interosseous muscle. In contrast if the same number of pulses were given while subjects made a small tonic (5% maximum) contraction, MEPs were facilitated and resting motor threshold reduced when AP but not PA pulses were used. Subsequent experiments employed subthreshold TMS (95% of the active motor threshold) during voluntary muscle contraction. MEP facilitation accompanied by reduced AP threshold occurred when PAS was given using AP pulses (AP-Sub-PAS), whereas PAS using PA pulses (PA-Sub-PAS) had no excitatory effect. There was no facilitation if the ulnar nerve stimulus was replaced by digital nerve stimulation. There was a tendency for short interval intracortical inhibition (SICI) to decrease and intracortical facilitation (ICF) to increase after AP-Sub-PAS. We propose that the increased effectiveness of AP-Sub-PAS over PA-Sub-PAS is due to the fact that AP TMS more readily activates I3 inputs to corticospinal neurons and hence that these are an important component of associative plasticity in the human motor cortex.     

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.     

Electrical stimulation of the human common peroneal nerve elicits lasting facilitation of cortical motor-evoked potentials

Motor-evoked potentials (MEP) in the tibialis anterior (TA) muscle were shown to be facilitated by repetitive electrical stimulation of the common peroneal (CP) nerve at intensities above motor threshold. The TA electromyogram (EMG) and ankle flexion force were recorded in response to transcranial magnetic stimulation (TMS) of the leg area of the motor cortex to evaluate the excitability of cortico-spinal-muscular pathways. Repetitive stimulation of the CP nerve at 25 Hz for 30 min increased the MEP by 50.3 ± 13.6% (mean ± S.E.) at a TMS intensity that initially gave a half-maximum MEP (MEP_h). In contrast the maximum MEP (MEP_max) did not change. Ankle flexion force (103 ± 21.9%) and silent period duration (75.3 ± 12.9%) also increased. These results suggest an increase in corticospinal excitability, rather than total connectivity due to repetitive CP stimulation. Facilitation was evident after as little as 10 min of stimulation and persisted without significant decrement for at least 30 min after stimulation. The long duration of silent period following CP stimulation (99.2 ± 14.8 ms) suggests that this form of stimulation may have effects on the motor cortex. To exclude the possibility that MEP_h facilitation was primarily due to sensory fibre activation, we performed several control experiments. Preferentially activating Ia muscle afferents by vibration in the absence of motor activity had no significant effect. Cutaneous afferent activation via stimulation of the superficial peroneal nerve increased the amplitude of responses at MEP_max rather than MEP_h. Concurrent tendon vibration and superficial peroneal nerve stimulation failed to facilitate TA MEP responses. In summary, repetitive electrical stimulation of the CP nerve elicits lasting changes in corticospinal excitability, possibly as a result of co-activating motor and sensory fibres.Due to an error in the citation line, this revised PDF (published in December 2003) deviates from the printed version, and is the correct and authoritative version of the paper.     

Corticospinal contributions to lower limb muscle activity during cycling in humans

The purpose of the current study was to investigate corticospinal contributions to locomotor drive to leg muscles involved in cycling. We studied 1) if activation of inhibitory interneurons in the cortex via subthreshold transcranial magnetic stimulation (TMS) caused a suppression of EMG and 2) how the responses to stimulation of the motor cortex via TMS and cervicomedullary stimulation (CMS) were modulated across the locomotor cycle. TMS at intensities subthreshold for activation of the corticospinal tract elicited suppression of EMG for approximately one-half of the subjects and muscles during cycling, and in matched static contractions in vastus lateralis. There was also significant modulation in the size of motor-evoked potentials (MEPs) elicited by TMS across the locomotor cycle (P < 0.001) that was strongly related to variation in background EMG in all muscles (r > 0.86; P < 0.05). When MEP and CMEP amplitudes were normalized to background EMG, they were relatively larger prior to the main EMG burst and smaller when background EMG was maximum. Since the pattern of modulation of normalized MEP and CMEP responses was similar, the data suggest that phase-dependent modulation of corticospinal responses during cycling in humans is driven mainly by spinal mechanisms. However, there were subtle differences in the degree to which normalized MEP and CMEP responses were facilitated prior to EMG burst, which might reflect small increases in cortical excitability prior to maximum muscle activation. The data demonstrate that the motor cortex contributes actively to locomotor drive, and that spinal factors dominate phase-dependent modulation of corticospinal excitability during cycling in humans.     

Factors influencing the magnitude and reproducibility of corticomotor excitability changes induced by paired associative stimulation

Several paired-associative stimulation (PAS) protocols induce neuroplastic changes in human motor cortex (M1). To understand better the inherent variability of responses to PAS, we investigated the effectiveness and reproducibility of two PAS paradigms, and neurophysiological and experimental variables that may influence this. Motor evoked potentials (MEPs) were elicited by transcranial magnetic stimulation (TMS) of right M1, and recorded from surface EMG of left abductor pollicis brevis (APB) and first dorsal interosseous before and after PAS. PAS consisted of electrical stimulation of left median nerve paired with TMS over right M1 25 ms later. Twenty subjects were given one of two PAS protocols: short (132 paired stimuli at 0.2 Hz) or long (90 paired stimuli at 0.05 Hz), and were re-tested with the same protocol on 3 separate occasions, with 11 subjects tested in the morning and 9 in the afternoon. Neurophysiological variables assessed included MEP amplitude, resting and active motor threshold, short-interval intracortical inhibition, intracortical facilitation and cortical silent period duration. The short PAS protocol produced greater APB MEP facilitation (51%) than the long protocol (11%), and this did not differ between sessions. The neurophysiological variables did not consistently predict responses to PAS. Both PAS protocols induced more APB MEP facilitation, and greater reproducibility between sessions, in experiments conducted in the afternoon. The mechanism for this is unclear, but circadian rhythms in hormones and neuromodulators known to influence neuroplasticity warrant investigation. Future studies involving PAS should be conducted at a fixed time of day, preferably in the afternoon, to maximise neuroplasticity and reduce variability.     

LTD-like plasticity induced by paired associative stimulation: direct evidence in humans

Paired associative stimulation (PAS), in which peripheral nerve stimuli are followed by transcranial magnetic stimulation (TMS) of the motor cortex, may produce a long lasting change in cortical excitability. At an interstimulus interval slightly shorter than the time needed for the afferent inputs to reach cerebral cortex (10 ms), motor cortex excitability decreases. Indirect data support the hypothesis that PAS at this interval (PAS10) involves LTD like-changes in cortical synapses. The aim of present paper was to investigate more directly PAS10 effects. We recorded corticospinal descending volleys evoked by single pulse TMS before and after PAS10 in two conscious subjects who had a high cervical epidural electrode implanted for pain control. These synchronous volleys provide a measure of cortical synaptic activity. PAS10 significantly reduced the amplitude of later descending waves while the earliest descending wave was not modified. Present results confirm the cortical origin of the effect of PAS10.     

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.     

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.     

Single pulse stimulation of the human subthalamic nucleus facilitates the motor cortex at short intervals

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment for Parkinson's disease (PD). The mechanism is poorly understood. High-frequency STN DBS has been reported to affect motor cortex excitability in a complex way, but the timing between STN stimuli and changes in motor cortical (M1) excitability has not been investigated. We examined the time course of changes in motor cortical excitability following single pulse STN DBS. We studied 14 PD patients with implanted DBS electrodes in the STN, 2 patients with electrodes in internal globus pallidus (GPi), and 1 patient with an electrode in the sensory thalamus. Transcranial magnetic stimulation (TMS) was delivered to the M1 ipsilateral to the DBS with induced currents either in the anterior-posterior direction in the brain to evoke indirect (I) waves or in the lateral-medial direction to activate corticospinal axons directly. Single pulse stimulation through the DBS contacts preceded the TMS by 0-10 ms. Surface EMG was recorded from the contralateral first dorsal interosseous muscle. Three milliseconds after STN stimulation, the motor evoked potential (MEP) amplitudes produced by anterior-posterior current were significantly larger than control responses, while the responses to lateral-medial currents were unchanged. Similar facilitation also occurred after GPi stimulation, but not with thalamic stimulation. Single pulse STN stimulation facilitates the M1 at short latencies. The possible mechanisms include antidromic excitation of the cortico-STN fibers or transmission through the basal ganglia-thalamocortical pathway.     

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.     

Contralesional paired associative stimulation increases paretic lower limb motor excitability post-stroke

Following stroke, an abnormally high interhemispheric inhibitory drive from the contralesional to the ipsilesional primary motor cortex (M1) is evident during voluntary movement. Down-regulating motor excitability of the contralesional M1 using inhibitory neuromodulatory protocols has demonstrated a correlation between balanced interhemispheric interactions and increased motor recovery. In 2005, our laboratory first reported bidirectional modulation of healthy subjects’ tibialis anterior (TA) motor excitability during walking, using a stimulation paradigm known as paired associative stimulation (PAS). Suprathreshold transcranial magnetic stimulation (TMS) of the lower limb M1 paired with electrical stimulation of the common peroneal nerve produced a persistent modulation of TA corticomotor excitability. The present study tested the hypothesis that the excitability of the ipsilesional lower limb motor cortex during walking is increased when inhibitory PAS is applied to the contralesional motor cortex in chronic stroke survivors. We applied inhibitory PAS (120 pairs at 0.5 Hz) to the quiescent paretic TA of ten chronic stroke patients and the right TA of ten age-matched healthy subjects. Post intervention excitability measures were taken immediately following PAS, and again 5, 10 and 15 min later. When inhibitory PAS was applied to the non-paretic TA of chronic stroke subjects, the non-paretic TA motor evoked potential (MEP) amplitude decreased to 91% and paretic TA MEP amplitude increased to 130% (of pre-PAS values) during post-PAS walking. In healthy subjects, MEPs in response to TMS revealed that mean MEP amplitude from the stimulated TA decreased to 87% and the mean MEP amplitude from the non-stimulated TA increased to 126%. This is the first study to demonstrate that inhibitory PAS applied to the contralesional lower limb motor system of stroke survivors increases motor excitability of the paretic lower limb assessed during walking. This finding suggests that inhibitory PAS may be a useful tool to study how the human lower limb motor cortex recovers after neural injury, and that PAS may be a candidate adjuvant therapy for patients with neurological walking impairments.     

Excitability changes in human hand motor area dependent on afferent inputs induced by different motor tasks

Using the technique of transcranial magnetic stimulation (TMS) with a figure-of-eight-shaped coil in 16 normal volunteers, we studied the extents of motor evoked potentials (MEPs) induced by remote facilitation of voluntary teeth clenching (VTC) and by motor imagery (MI). In particular, we examined whether different excitability changes in the primary motor cortex (M1) induced by both facilitation methods occur between early (I1 and I2) and late (I3 and I4) components of I-waves elicited from a first dorsal interosseous (FDI) muscle. Both components of I-waves were induced by anterior-medially (AM) directed currents or posterior-laterally (PL) directed currents. Our hypothesis was that facilitatory effects of VTC and MI on M1 differ because the neural pathways of these afferent inputs differ. The present results indicate that during MI MEP amplitudes of late components are significantly larger than those of early ones, although both MEP amplitudes are enhanced. On the other hand, during VTC MEP amplitudes of early components are significantly enhanced, but those of late ones are rather depressed. We conclude that recruitment of early and late components of I-waves differ depending on the afferent inputs to the motor cortex.     

Short-interval intracortical inhibition blocks long-term potentiation induced by paired associative stimulation

Paired associative stimulation (PAS) of the motor cortex leads to increased motor evoked potential (MEP) amplitudes in the stimulated hand muscles. We hypothesized that evoking GABA(A) receptor-mediated short-interval intracortical inhibition (SICI) simultaneously with excitatory PAS would depress long-term potentiation plasticity in motor cortex. Four different PAS paradigms were tested, standard PAS (PAS25) and three conditioned PAS protocols (CS2-PAS25, CS2-PAS25adj, and CS10-PAS25adj). A subthreshold conditioning stimulus 2 ms (CS2) or 10 ms (CS10) before the test stimuli was added to the conditioned PAS protocols. Since CS2 has inhibitory and CS10 has facilitatory effect on cortical excitability, in the CS2-PAS25adj and CS10-PAS25adj protocols, TS intensity was adjusted to produce a 1-mV MEP in the presence of CS2 or CS10 to control for the degree of corticospinal excitation. As expected, MEP amplitudes after PAS25 were higher compared with that at baseline, but importantly, MEP amplitudes did not change after PAS was induced in the presence of SICI in either the CS2-PAS25 or CS2-PAS25adj condition. Furthermore, the CS10-PAS25adj protocol showed significantly increased MEP amplitude at 60 min after PAS compared with baseline. These results show that SICI blocked the induction of long-term potentiation-like plasticity in the motor cortex, indicating that GABAergic circuits play an important role in the regulation of cortical plasticity. The study demonstrates a noninvasive and nonpharmacological way to achieve focal modulation of plasticity.     

Corticospinal Facilitation Studied During Voluntary Contraction of Human Abdominal Muscles

Transcranial magnetic stimulation (TMS) of the human motor cortex was used to study facilitation of motor-evoked potentials (MEPs) in the rectus abdominis (RA) muscle, a trunk flexor, during voluntary activation. MEPs could be produced in the relaxed RA muscles of all six normal subjects studied. The MEPs had short latencies (18-22 ms) which are consistent with other studies suggesting a fast corticospinal input to the trunk muscles. Marked facilitation was observed in the MEPs when subjects were asked to produce graded levels of voluntary contractions. The two tasks used to produce voluntary contractions were a forced expiration during a breath-holding task (FEBH) and bilateral trunk flexion (BTF). Maximal voluntary EMG activity during the BTF task produced around 4.2 times more integrated EMG than during the FEBH task. Similarly the MEP amplitude at MVC was 2.3 times greater during BTF than FEBH. The pattern of MEP facilitation with increasing voluntary EMG was not linear and a maximal MEP amplitude was observed at a level of voluntary contraction around 30 % MVC in both tasks. There were some subtle differences in the pattern of facilitation in the two tasks. When TMS was applied to the right cortex only, MEPs were seen in both left and right RA muscles suggesting some ipsilateral corticospinal innervation. The latency of the right (ipsilateral) response was approximately 2 ms longer than the left. Comparison with studies in hand and leg muscles suggests that the facilitation pattern in RA may reflect a substantial degree of corticospinal innervation. Experimental Physiology (2001) 86.1, 131-136.     

Human motor associative plasticity induced by paired bihemispheric stimulation

Paired associative stimulation (PAS) is an effective non-invasive method to induce human motor plasticity by the repetitive pairing of peripheral nerve stimulation and transcranial magnetic stimulation (TMS) at the primary motor cortex (M1) with a specific time interval. Although the repetitive pairing of two types of afferent stimulation might be a biological basis of neural plasticity and memory, other types of paired stimulation of the human brain have rarely been studied. We hypothesized that the repetitive pairing of TMS and interhemispheric cortico-cortical projection or paired bihemispheric stimulation (PBS), in which the right and left M1 were serially stimulated with a time interval of 15 ms, would produce an associative long-term potentiation (LTP)-like effect. In this study, 23 right-handed healthy volunteers were subjected to a 0.1 Hz repetition of 180 pairings of bihemispheric TMS, and physiological and behavioural measures of the motor system were compared before, immediately after, 20 min after and 40 min after PBS intervention. The amplitude of the motor evoked potential (MEP) induced by the left M1 stimulation and its input–output function increased for up to ∼20 min post-PBS. Fine finger movements were also facilitated by PBS. Spinal excitability measured by the H-reflex was insensitive to PBS, suggesting a cortical mechanism. The associative LTP-like effect induced by PBS was timing dependent, occurring only when the interstimulus interval was 5–25 ms. These findings demonstrate that using PBS in PAS can induce motor cortical plasticity, and this approach might be applicable to the rehabilitation of patients with motor disorders.     

Proposed cortical and sub-cortical contributions to the long-latency stretch reflex in the forearm

The short- and long-latency (SLSR, LLSR) components of the stretch reflex response were investigated in the forearm using a paired transcranial magnetic stimulation (TMS)-stretch reflex protocol. Responses to TMS were recorded in the flexor and extensor carpi radialis muscles (FCR, ECR) after conditioning with a rapid wrist extension movement. The cortical stimuli were timed to elicit a motor-evoked potential (MEP) at either the SLSR or LLSR onset in the FCR muscle. Responses were also collected in TMS-alone and stretch reflex-alone conditions. Six intensities of magnetic stimulation were applied in all conditions. In the FCR muscle, MEP amplitude when timed to arrive at the LLSR onset was significantly greater than the sum of the MEP and stretch reflex responses when given separately. MEP amplitudes at the SLSR onset in the FCR muscle and in the ECR muscle at both SLSR and LLSR onset were not significantly different from that expected from the sum of the two stimuli given separately. This indicates heightened corticospinal excitability at a time corresponding to the passage of an afferent volley induced by the stretch, and raises the possibility of a transcortical loop of the LLSR in the forearm. The extent of MEP facilitation was generally consistent across all stimulus intensities tested. A reduced component of the LLSR was evident when the stretch response was timed to arrive during the silent period following the cortical stimulus, suggesting both cortical and sub-cortical components to the reflex response.     

Magnetic stimulation of motor and somatosensory cortices suppresses perception of ulnar nerve stimuli.

Magnetic stimulation of sensorimotor cortex interferes with the detection of electro-cutaneous stimulation. However, it is uncertain whether this interference is due to activation of the somatosensory or the motor cortex. Here, transcranial magnetic stimuli (TMS) were delivered separately over somatosensory and motor cortex contralateral to the right ulnar nerve in 12 subjects. In separate trials, TMS were given 100 ms before and 20 ms after 60 ms trains of electro-cutaneous ulnar nerve stimuli, and their effect on the subjective perception of peripheral stimuli was assessed. TMS of both motor and somatosensory cortex interfered with the perception of afferent stimuli when given before or after stimulation of the ulnar nerve. Perception was more strongly suppressed by motor cortex stimulation than by somatosensory cortex stimulation, when given before or after the peripheral stimulus. A similar proportion of errors was induced by sensory cortex stimulation between the two stimulus timing intervals. This study suggests that the inhibition of the afferent volley is unlikely to be the result of antidromic activation of thalamocortical connections or corticospinal gating. A phenomenon akin to sensory masking is the most plausible explanation for much of the suppression of sensory perception by stimulation of the motor or somatosensory cortex. The more powerful suppressive effect of motor cortex stimulation may be due to multiple mechanisms.