Rapid-rate paired associative stimulation of the median nerve and motor cortex can produce long-lasting changes in motor cortical excitability in humans

Repetitive transcranial magnetic stimulation (rTMS) or repetitive electrical peripheral nerve stimulation (rENS) can induce changes in the excitability of the human motor cortex (M1) that is often short-lasting and variable, and occurs only after prolonged periods of stimulation. In 10 healthy volunteers, we used a new repetitive paired associative stimulation (rPAS) protocol to facilitate and prolong the effects of rENS and rTMS on cortical excitability. Sub-motor threshold 5 Hz rENS of the right median nerve was synchronized with submotor threshold 5 Hz rTMS of the left M1 at a constant interval for 2 min. The interstimulus interval (ISI) between the peripheral stimulus and the transcranial stimulation was set at 10 ms (5 Hz rPAS_10ms) or 25 ms (5 Hz rPAS_25ms). TMS was given over the hot spot of the right abductor pollicis brevis (APB) muscle. Before and after rPAS, we measured the amplitude of the unconditioned motor evoked potential (MEP), intracortical inhibition (ICI) and facilitation (ICF), short- and long-latency afferent inhibition (SAI and LAI) in the conditioned M1. The 5 Hz rPAS_25ms protocol but not the 5 Hz rPAS10_ms protocol caused a somatotopically specific increase in mean MEP amplitudes in the relaxed APB muscle. The 5 Hz rPAS_25ms protocol also led to a loss of SAI, but there was no correlation between individual changes in SAI and corticospinal excitability. These after-effects were still present 6 h after 5 Hz rPAS_25ms. There was no consistent effect on ICI, ICF and LAI. The 5 Hz rENS and 5 Hz rTMS protocols failed to induce any change in corticospinal excitability when given alone. These findings show that 2 min of 5 Hz rPAS_25ms produce a long-lasting and somatotopically specific increase in corticospinal excitability, presumably by sensorimotor disinhibition.     

Physiology of modulation of motor cortex excitability by low-frequency suprathreshold repetitive transcranial magnetic stimulation

Many studies show consistently that repetitive transcranial magnetic stimulation (rTMS) with a frequency of 1 Hz and an intensity above the resting motor threshold (RMT) performed for several minutes over the primary motor cortex (M1) leads to a depression of cortical excitability. Furthermore, most studies concur on a facilitation of the non-stimulated contralateral M1. Little is known, however, about the physiological mechanisms underlying these effects. In 11 healthy volunteers, we stimulated the left M1 for 15 min with 1 Hz-rTMS of 115% RMT. Before, immediately after, and 30 min after the rTMS train, we examined short-interval intracortical inhibition (SICI; interstimulus interval (ISI) of 2 and 4 ms), intracortical facilitation (ICF; ISI 10 ms), and short-interval intracortical facilitation (SICF; ISI 1.5 ms) with established paired-pulse protocols. Mean unconditioned motor evoked potential (MEP) amplitudes and RMT were also measured. Two sessions were run at least 1 week apart, in one excitability of the stimulated M1 was tested, in the other one excitability of the non-stimulated M1. rTMS led to the expected reduction of MEP amplitude of the stimulated M1, which was significant only immediately after the rTMS train. rTMS increased MEP amplitude of the non-stimulated M1, which lasted for at least 30 min. RMT, SICI, ICF and SICF did not show any significant change in either M1, except for a long lasting increase of SICF in the non-stimulated M1. In conclusion, the MEP increase in the non-stimulated M1 lasted longer than the MEP decrease in the stimulated M1. Only the long-lasting MEP increase was associated with a specific change in intracortical excitability (increase in SICF). Modulation of motor cortical inhibition did not play a role in explaining the rTMS induced changes in MEP amplitude.     

Increased corticospinal excitability after 5 Hz rTMS over the human supplementary motor area

Transcranial magnetic stimulation (TMS) can produce effects not only at the site of stimulation but also at distant sites to which it projects. Here we examined the connection between supplementary motor area (SMA) and the hand area of the primary motor cortex (M1_Hand) by testing whether prolonged repetitive TMS (rTMS) over the SMA can produce changes in excitability of the M1_Hand after the end of the stimulus train. We evaluated motor-evoked potentials (MEPs) and the cortical silent period (CSP) evoked by a single-pulse TMS, short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) produced by a paired-pulse TMS, and forearm flexor H reflexes before and after 750 pulses of 5 Hz rTMS over SMA at an intensity of 110% active motor threshold (AMT) for the first dorsal interosseous (FDI) muscle. The amplitude of MEPs recorded from the right FDI muscle at rest as well as during voluntary contraction increased for at least 10 min after the end of rTMS, although the duration of the CSP, SICI and ICF did not change. There was no effect on H reflexes in the flexor carpi radialis muscle, even though the amplitude of the MEP obtained from the same muscle increased after rTMS. The effects on MEPs depended on the intensity of rTMS and were spatially specific to the SMA proper. We suggest that 5 Hz rTMS over SMA can induce a short-lasting facilitation in excitability of the M1_Hand compatible with the anatomical connections between SMA and the M1_Hand.     

Paired-pulse repetitive transcranial magnetic stimulation of the human motor cortex

In nine healthy humans we modulated corticospinal excitability by using conditioning-test paired-pulse transcranial magnetic stimulation in a repetitive mode (rTMS), and we compared its effect to conventional single-pulse rTMS. We applied 80 single pulses or 80 paired pulses to the motor cortex at frequencies ranging from 0.17 to 5 Hz. The conditioning-test intervals were 2, 5, or 10 ms. Motor evoked potential (MEP) amplitudes from the abductor digiti minimi (ADM) as target muscle and extensor carpi radialis (ECR) indicated the excitability changes during and after rTMS. During paired-pulse rTMS at a facilitatory conditioning-test interval of 10 ms, we observed a facilitation of MEPs at 1, 2, and 5 Hz. A similar facilitation was found during single-pulse rTMS, when stimulus intensity was adjusted to evoke MEPs of comparable size. Using an inhibitory conditioning-test interval of 2 ms, paired-pulse rTMS at frequencies of 1 and 2 Hz caused no change in MEP size during the train. However, paired-pulse rTMS at 5 Hz caused a strong enhancement of MEP size, indicating a loss of paired-pulse inhibition during the rTMS train. Since no facilitatory effect was observed during single-pulse rTMS with an adjusted stimulus intensity, the MEP enhancement during 5 Hz rTMS was specific for "inhibitory" paired-pulse rTMS. After 5 Hz rTMS MEPs were facilitated for 1 min, and this effect was not substantially different between paired-pulse rTMS and single-pulse rTMS. The correlation between ADM and ECR was most pronounced at 5 Hz rTMS. We conclude that paired-pulse rTMS is a suitable tool to study changes in corticospinal excitability during the course of rTMS. In addition, our data suggest that short trains of paired-pulse rTMS are not superior to single-pulse rTMS in inducing lasting inhibition or facilitation. Electronic Publication     

Effects on the right motor hand-area excitability produced by low-frequency rTMS over human contralateral homologous cortex

Repetitive transcranial magnetic stimulation (rTMS) has long lasting effects on cortical excitability at the site of stimulation, on interconnected sites at a distance and on the connections between them. In the present experiments we have used the technique of transcallosal inhibition between the motor cortices to examine all three effects in the same protocol. Ten healthy subjects received 900 rTMS stimuli at 1 Hz from a figure of eight coil over the left motor hand area. The intensity of rTMS was above the threshold for inducing short latency interhemispherical inhibition with a single stimulus (equivalent to 115–120 % resting motor threshold). Before and after the rTMS we evaluated: (1) in the left hemisphere, the amplitude of motor-evoked potentials (MEPs), and contralateral and ipsilateral cortical silent periods (CSP, ISP); (2) in the right hemisphere, MEP, CSP, ISP and short-interval intracortical inhibition and intracortical facilitation (SICI/ICF), and (3) interhemispherical inhibition (IHI) from the left-to-right hemisphere using a paired-pulse method. There were two main effects after rTMS to the left hemisphere: first, the amplitude of MEPs from the right hemisphere increased; second, there was a reduction in the IHI from the left-to-right hemisphere at interstimulus intervals of 7 and 10 ms but not at longer intervals (15–75 ms). Control experiments showed that these effects were not due to afferent inputs produced by the muscle twitches induced during the rTMS. The data are compatible with the notion that rTMS to the left hemisphere leads to reduced interhemispherical inhibition of the right hemisphere and a consequent increase in corticospinal excitability in that hemisphere.     

Short-interval paired-pulse inhibition and facilitation of human motor cortex: the dimension of stimulus intensity

Paired transcranial magnetic stimulation has greatly advanced our understanding of the mechanisms which control excitability in human motor cortex. While it is clear that paired-pulse excitability depends on the exact interstimulus interval (ISI) between the first (S1) and second stimulus (S2), relatively little is known about the effects of the intensities of S1 and S2, and the effects of manipulating neurotransmission through the GABA_A receptor. When recording the motor evoked potential (MEP) from the resting abductor digiti minimi (ADM) muscle, using a fixed ISI of 1.5 ms, and expressing the interaction between S1 and S2 as MEP_S1+S2/(MEP_S1+ MEP_S2), then a systematic variation of the intensities of S1 and S2 revealed short-interval intracortical facilitation (SICF) if S1 and S2 were approximately equal to MEP threshold (RMT), or if S1 > RMT and S2 < RMT. In contrast, short-interval intracortical inhibition (SICI) occurred if S1 < RMT and S2 > RMT. Contraction of the ADM left SICI unchanged but reduced SICF. The GABA_A receptor agonist diazepam increased SICI and reduced SICF in the resting ADM while diazepam had no effect during ADM contraction. Surface EMG and single motor unit recordings revealed that during ADM contraction SICI onset was at the I3-wave latency of S2, whereas SICF typically 'jumped up' by one I-wave and started with the I2-wave latency of S2. Findings suggest that SICI is mediated through a low-threshold GABA_A receptor-dependent inhibitory pathway and summation of IPSP from S1 and EPSP from S2 at the corticospinal neurone. In contrast, SICF originates through non-synaptic facilitation at the initial axon segment of interneurones along a high-threshold excitatory pathway.     

Modulatory effects of low- and high-frequency repetitive transcranial magnetic stimulation on visual cortex of healthy subjects undergoing light deprivation

The aim of the present study was to explore further the effects of light deprivation (LD) on visual cortex excitability. Healthy subjects reporting reliable induction of phosphenes by occipital transcranial magnetic stimulation (TMS) underwent 60 min of complete LD. Phosphene threshold (PT) was measured before ( T ₀), after 45 min ( T ₁) and 60 min ( T ₂) of LD, and then every 10 min after light re-exposure until recovery to T ₀ values. Repetitive TMS (rTMS) (at 1 or 10 Hz) was applied in separate sessions during the last 15 min of LD. PTs significantly decreased after 45 min of LD. rTMS differentially modified the effects of 60 min LD on PTs depending on stimulation frequency. One hertz rTMS did not change the decreasing of PT values as observed in baseline condition, but significantly prolonged the time to recover T ₀ PT values after light re-exposure. By contrast, 10 Hz rTMS significantly increased PT and the time to recover T ₀ PT values after light re-exposure was shortened. The results of this study show that the modulatory effects of different rTMS frequencies on visual cortex critically depend on the pre-existing excitability state of inhibitory and facilitatory circuits, and provide novel insights into the neurophysiological changes that take place in the visual cortex following functional visual deafferentation.     

Neural correlates of encoding and expression in implicit sequence learning

It has been shown that high-frequency repetitive transcranial magnetic stimulation (rTMS) to the human primary motor hand area (M1-HAND) can induce a lasting increase in corticospinal excitability. Here we recorded motor evoked potentials (MEPs) from the right first dorsal interosseus muscle to investigate how sub-threshold high-frequency rTMS to the M1-HAND modulates cortical and spinal excitability. In a first experiment, we gave 1500 stimuli of 5 Hz rTMS. At an intensity of 90% of active motor threshold, rTMS produced no effect on MEP amplitude at rest. Increasing the intensity to 90% of resting motor threshold (RMT), rTMS produced an increase in MEP amplitude. This facilitatory effect gradually built up during the course of rTMS, reaching significance after the administration of 900 stimuli. In a second experiment, MEPs were elicited during tonic contraction using weak anodal electrical or magnetic test stimuli. 1500 (but not 600) conditioning stimuli at 90% of RMT induced a facilitation of MEPs in the contracting FDI muscle. In a third experiment, 600 conditioning stimuli were given at 90% of RMT to the M1-HAND. Using two well-established conditioning-test paradigms, we found a decrease in short-latency intracortical inhibition (SICI), and a facilitation of the first peak of facilitatory I-waves interaction (SICF). There was no correlation between the relative changes in SICI and SICF. These results demonstrate that subthreshold 5 Hz rTMS can induce lasting changes in specific neuronal subpopulations in the human corticospinal motor system, depending on the intensity and duration of rTMS. Short 5 Hz rTMS (600 stimuli) at 90% of RMT can selectively shape the excitability of distinct intracortical circuits, whereas prolonged 5 Hz rTMS (900 stimuli) provokes an overall increase in excitability of the corticospinal output system, including spinal motoneurones.     

Histaminergic and glycinergic modulation of GABA release in the vestibular nuclei of normal and labyrinthectomised rats

We explored interhemispheric facilitation (IHF) between (a) left and right primary motor cortex (M1) and (b) left dorsal premotor (dPM) and right M1 in 20 right-handed healthy human subjects using a paired pulse transcranial magnetic stimulation (TMS) protocol. A conditioning TMS pulse (CP) applied to left M1 or dPM with an intensity of 80% and 60% active motor threshold (CP_80%AMT and CP_60%AMT, respectively) was followed by a test pulse (TP) over right M1 induced by anterior–posterior- or posterior–anterior- (TP_AP, TP_PA) directed currents in the brain at interstimulus intervals (ISIs) of 3–8 and 10 ms. EMG was recorded from left first dorsal interosseous muscle. In the main experimental condition IHF was evoked by CP_80%AMT over left M1 and TP_AP at ISIs of 6 and 8 ms. The same CP_80%AMT produced IHF at an ISI of 8 ms when applied over left dPM but only with TP_PA. In addition, when CP_60%AMT was given to M1, IHF was present at an ISI of 6 ms (but not 8 ms) when followed by TP_PA, indicating that IHF elicited over dPM was not caused by current spread of the conditioning pulse to M1. We conclude that IHF can be induced differentially by conditioning M1 and dPM using subthreshold CP. These facilitatory interactions depended on the intensity and ISI of the CP as well as the current flow direction of the TP. We suggest that not only do the CPs activate separate anatomical pathways but also that these pathways project to different populations of interneurons in the receiving M1. These may correspond to elements involved in the generation of I3 and I1 waves, respectively.     

Different modulation of the cortical silent period by two phases of short interval intracortical inhibition

PURPOSE: To investigate the influence of 2 phases of short interval intracortical inhibition (SICI) on the cortical silent period (SP). MATERIALS AND METHODS: Single- and paired-pulse transcranial magnetic stimulations (TMSs) at 1 and 2.5ms interstimulus intervals (ISIs) were applied to the left motor cortex in 12 healthy subjects while their right hand muscles were moderately activated. Conditioning stimulation intensity was 90% of the active motor threshold (AMT). Test stimulation intensities were 120, 140, 160, 180, 200, 220, 240, 260% of the AMT and at 100% of the maximal stimulator output, the order of which was arranged randomly. The rectified electromyography area of motor evoked potential (MEP) and duration of the SP were measured off-line using a computerized program. RESULTS: At high-test stimulation intensities, MEP areas were saturated in both single- and paired-pulse stimulations, except that saturated MEPs were smaller for the paired-pulse TMS at 1ms ISI than for the other conditions. As the test stimulation intensity increased, SP was progressively prolonged in both single- and paired-pulse stimulations but was shorter in paired-pulse than single-pulse TMS. Overall, the ratio of SP duration/MEP area was comparable between single- and paired-pulse TMS except for the paired-pulse TMS at 1 ms ISI with a test stimulation intensity at 140-180% of the AMT, in which the ratio was significantly higher than in the single pulse TMS. CONCLUSION: These results suggest that 2 phases of SICI modulate MEP saturation and SP duration differently and provide additional evidence supporting the view that 2 phases of SICI are mediated by different inhibitory mechanisms.     

Spread of electrical activity at cortical level after repetitive magnetic stimulation in normal subjects

In normal subjects, focal repetitive transcranial magnetic stimulation (rTMS) of the hand motor area evokes muscle potentials (MEPs) from muscles in the hand (target muscles) and the arm (non-target muscles). In this study we investigated the mechanisms underlying the spread of MEPs induced by focal rTMS in non-target muscles. rTMS was delivered with a Magstim stimulator and a figure-of-eight coil placed over the first dorsal interosseus (FDI) motor area of the left hemisphere. Trains of 10 stimuli were given at a suprathreshold intensity (120% of motor threshold) and at frequencies of 5, 10 and 20 Hz at rest. Electromyographic (EMG) activity was recorded simultaneously from the FDI (target muscle) and the contralateral biceps muscle and from the FDI muscle ipsilateral to the side of stimulation (non-target muscle). rTMS delivered in trains to the FDI motor area of the left hemisphere elicited MEPs in the contralateral FDI (target muscle) that gradually increased in amplitude over the course of the train. Focal rTMS trains also induced MEPs in the contralateral biceps (non-target muscle) but did so only after the second or third stimulus; like target-muscle MEPs, in non-target muscle MEPs progressively increased in amplitude during the train. At no frequency did rTMS elicit MEPs in the FDI muscle ipsilateral to the site of stimulation. rTMS left the latency of EMG responses in the FDI and biceps muscles unchanged during the trains of stimuli. The latency of biceps MEPs was longer after rTMS than after a single TMS pulse. In conditioning-test experiments designed to investigate the cortical origin of the spread, a single TMS pulse delivered over the left hemisphere at an interstimulus interval (ISI) of 50, 100 and 150 ms reduced the amplitude of the test MEP evoked by a single TMS pulse delivered over the right hemisphere; and a conditioning rTMS train delivered over the left hemisphere increased the amplitude of the test MEP evoked by a single TMS pulse over the right hemisphere. A conditioning rTMS train delivered over the left hemisphere and paired magnetic shocks (test stimulus) at 3 and 13 ms ISIs over the right hemisphere reduced MEP inhibition at the 3-ms ISI but left the MEP facilitation at 13 ms unchanged. Using a control MEP size matched with that observed after a conditioning contralateral rTMS, we found that paired-pulse inhibition remained unchanged. Yet a single TMS conditioning pulse sufficiently strong to evoke a MEP in the contralateral FDI and biceps muscles simultaneously (as rTMS did) left paired-pulse inhibition unchanged. We conclude that the spread of EMG activity to non-target muscles depends on cortical mechanisms, mainly including changes in the excitability of the interneurones mediating intracortical inhibition. Electronic Publication     

The effects of low- and high-frequency repetitive TMS on the input/output properties of the human corticospinal pathway

The objective of this study was to characterize the effects of various parameters (notably the frequency and intensity) of repetitive transcranial magnetic stimulation (rTMS) applied over the primary motor (M1) and premotor (PMC) cortices on the excitability of the first dorsalis interosseus (FDI) corticospinal pathway. To this end, we applied a comprehensive input–output analysis after fitting the experimental results to a sigmoidal function. Twenty-six healthy subjects participated in the experiments. Repetitive TMS was applied either over M1 or PMC at 1 Hz (LF) for 30 min (1,800 pulses) or at 20 Hz (HF) for 20 min (1,600 pulses). In the HF condition, the TMS intensity was set to 90% (HF₉₀) of the FDI’s resting motor threshold (RMT). In the LF condition, the TMS intensity was set to either 90% (LF₉₀) or 115% (LF₁₁₅) of the RMT. The FDI input/output (I/O) curve was measured on both sides of the body before rTMS (the Pre session) and then during two Post sessions. For each subject, the I/O curves (i.e., the integral of the FDI motor-evoked potential (MEP) vs. stimulus intensity) were fitted using a Boltzmann sigmoidal function. The graph’s maximum slope, S ₅₀ and plateau value were then compared between Pre and Post sessions. LF₁₁₅ over M1 increased the slope of the FDI I/O curve but did not change the S ₅₀ and plateau value. This also suggested an increase in the RMT. HF₉₀ led to a more complex effect, with an increase in the slope and a decrease in the S ₅₀ and plateau value. We did not see a cross effect on the homologous FDI corticospinal pathway, and only PMC LF₉₀ had an effect on ipsilateral corticospinal excitability. Our results suggest that rTMS may exert a more complex influence on cortical network excitability than is usually reported (i.e. simple inhibitory or facilitatory effects). Analysis of the fitted stimulus response curve indicates a dichotomous influence of both low- and high-frequency rTMS on M1 cortical excitability; this may reflect intermingled effects on excitatory and inhibitory cortical networks.     

A-Type potassium currents active at subthreshold potentials in mouse cerebellar purkinje cells

Voltage-dependent and calcium-independent K⁺ currents were whole-cell recorded from cerebellar Purkinje cells in slices. Tetraethylammonium (TEA, 4 m m ) application isolated an A-type K⁺ current ( I _{k ( a )}) with a peak amplitude, at +20 mV, of about one third of the total voltage-dependent and calcium-independent K⁺ current. The I _{k ( a )} activated at about −60 mV, had a V _0.5 of activation of −24.9 mV and a V _0.5 of inactivation of −69.2 mV. The deactivation time constant at −70 mV was 3.4 ± 0.4 ms, while the activation time constant at +20 mV was 0.9 ± 0.2 ms. The inactivation kinetics was weakly voltage dependent, with two time constants; those at +20 mV were 19.3 ± 3.1 and 97.6 ± 9.8 ms. The recovery from inactivation had two time constants of 60.8 ms (78.4%) and 962.3 ms (21.6%). The I _{k ( a )} was blocked by 4-aminopyridine with an IC₅₀ of 67.6 μM. Agitoxin-2 (2 n m ) blocked 17.4 ± 2.1% of the I _{k ( a )}. Flecainide completely blocked the I _{k ( a )} with a biphasic effect with IC₅₀ values of 4.4 and 183.2 μM. In current-clamp recordings the duration of evoked action potentials was affected neither by agitoxin-2 (2 n m ) nor by flecainide (3 μM), but action potentials that were already broadened by TEA were further prolonged by 4-aminopyridine (100 μM). The amplitude of the hyperpolarisation at the end of depolarising steps was reduced by all these blockers.     

Paired-pulse rTMS at trans-synaptic intervals increases corticomotor excitability and reduces the rate of force loss during a fatiguing exercise of the hand

Previous studies have shown that the motor evoked potential (MEP) amplitude increases as force declines during a fatiguing muscle contraction, indicating that there is an increase in corticomotor excitability. In spite of this there is a progressive reduction in voluntary motor drive, as shown by an increase in the interpolated twitch force as fatigue develops. The aim of this study was to determine whether, by further increasing corticomotor excitability using a paired-pulse rTMS protocol designed to induce I-wave facilitation (iTMS), force loss during a sustained voluntary contraction could be reduced. We designed a cross-over study incorporating a 15-min period of iTMS (ISI 1.5 ms; 0.2 Hz; ∼AMT), following which MEP amplitude (first dorsal interosseous muscle) increased to 194 ± 38% of baseline (P < 0.05), compared to a control period of stimulation that did not increase MEP amplitude (single-pulse TMS; 0.2 Hz; ∼ 1.2 AMT). Eight right-handed healthy subjects received both iTMS and control stimulation, in a randomized order, a week apart. We measured percentage force loss at the end of a 10-s maximum right hand key-pinch task, and compared force loss before and after stimulation. There was an improvement in task performance following iTMS, with a reduction in force loss compared to pre-stimulation baseline (11.3 ± 2.0 vs. 17.6 ± 2.4%; post vs. pre; P < 0.05). There was no significant difference in force loss before and after control stimulation. The results indicate that by increasing corticomotor excitability using paired-pulse rTMS at trans-synaptic intervals, maximum voluntary force can be sustained at a higher level during a brief fatiguing maximal voluntary contraction.     

Modulatory effects of 1 Hz rTMS over the cerebellum on motor cortex excitability

Clinical observations and data from animal experiments point to a physiological facilitatory influence of the deep cerebellar structures on the motor system through the cerebello-thalamo-cortical pathways. The aim of the present study was to explore the long-term effects of low-frequency (1 Hz) repetitive transcranial magnetic stimulation (rTMS) over the cerebellum on short intracortical inhibition (SICI) and facilitation (ICF) of the motor cortex in normal subjects. Eight healthy subjects (mean age 26.9 ± 3.1) underwent 1 Hz frequency rTMS delivered on the right cerebellar hemisphere. Before and after cerebellar rTMS, SICI and ICF were assessed in the motor cortex contralateral to the stimulated cerebellar hemisphere by means of a paired pulse paradigm with a conditioning subthreshold stimulus set to 80% of the motor threshold (MT) followed by a testing stimulus at 120% of MT intensity. Five different interstimulus intervals (ISIs) were used to assess SICI (2 and 4 ms) and ICF (7, 10 and 15 ms). Amplitude of the responses was expressed as the percentage of motor evoked potential (MEP) to test stimulus alone. Results showed a significant decrease of ICF at 10 ms ISI that persisted up to 20 min after cerebellar rTMS. This was the only significant modulatory effect of cerebellar stimulation on intracortical motor excitability A suppressive effect of the low-frequency TMS on Purkinje cells could be supposed, even if, the lack of effects on other facilitatory ISIs, stands for more complex modulatory effects of rTMS over cerebellum. The study is a further demonstration that rTMS over the cerebellum induces a long-lasting modulatory effect on the excitability of the interconnected motor area.     

Anticipatory control of hand and eye movements in humans during oculo-manual tracking

Anticipatory activity of hand and eye has been examined during oculo-manual tracking of a constant velocity visual target with a hand cursor. Both target and cursor were presented briefly (< 480 ms), but repeatedly, at regular inter-stimulus intervals (ISI). In Expt 1, the build-up of hand and eye responses was examined for target velocities varying from 10–40 deg s⁻¹ with an ISI of 2.4 s. The velocity 100 ms after target onset (i.e. prior to visual feedback) for both hand and eye ( V ₁₀₀) progressively increased over the first four presentations but then attained a steady state (SS). SS V ₁₀₀ values for eye and hand increased in proportion to target velocity and were thus predictive of forthcoming movement. Hand velocity exceeded eye velocity but both exhibited similar anticipatory trajectories. In Expt 2, target velocity was constant (40 deg s⁻¹) but ISI varied from 0.48–3.74 s. Subjects made anticipatory eye movements for all ISIs but hand movements were often reactive at the longest ISI. If the target failed to appear as expected, subjects initiated predictive hand and eye responses with timing appropriate for the prevailing ISI. In Expt 3, predictive responses were compared with responses to randomised presentation. Peak hand velocity was greater in the randomised mode than in the predictive condition, whereas the converse was true for peak eye velocity. This difference is discussed in terms of the mechanisms of positional error correction in hand and eye. Results provide evidence of similar anticipatory mechanisms in hand and eye, using storage of velocity and timing to achieve rapid prediction of target motion.     

Repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex (DLPFC) during capsaicin-induced pain: modulatory effects on motor cortex excitability

Evidence by functional imaging studies suggests the role of left DLPFC in the inhibitory control of nociceptive transmission system. Pain exerts an inhibitory modulation on motor cortex, reducing MEP amplitude, while the effect of pain on motor intracortical excitability has not been studied so far. In the present study, we explored in healthy subjects the effect of capsaicin-induced pain and the modulatory influences of left DLPFC stimulation on motor corticospinal and intracortical excitability. Capsaicin was applied on the dorsal surface of the right hand, and measures of motor corticospinal excitability (test-MEP) and short intracortical inhibition (SICI) and facilitation (ICF) were obtained by paired-pulse TMS on left motor cortex. Evaluations were made before and at different times after capsaicin application in two separate sessions: without and with high-frequency rTMS of left DLPF cortex, delivered 10 min. after capsaicin application. We performed also two control experiments to explore: 1: the effects of Left DLPFC rTMS on capsaicin-induced pain; 2: the modulatory influence of left DLPFC rTMS on motor cortex without capsaicin application. Capsaicin-induced pain significantly reduced test MEP amplitude and decreased SICI leaving ICF unchanged. Left DLPFC rTMS, together with the analgesic effect, was able to revert the effects of capsaicin-induced pain on motor cortex restoring normal MEP and SICI levels. These data support the notion that that tonic pain exerts modulatory influence on motor intracortical excitability; the activation of left DLPFC by hf rTMS could have analgesic effects, reverting also the motor cortex excitability changes induced by pain stimulation.     

Slow-oscillatory transcranial direct current stimulation can induce bidirectional shifts in motor cortical excitability in awake humans

Constant transcranial direct stimulation (c-tDCS) of the primary motor hand area (M1_HAND) can induce bidirectional shifts in motor cortical excitability depending on the polarity of tDCS. Recently, anodal slow oscillation stimulation at a frequency of 0.75 Hz has been shown to augment intrinsic slow oscillations during sleep and theta oscillations during wakefulness. To embed this new type of stimulation into the existing tDCS literature, we aimed to characterize the after effects of slowly oscillating stimulation (so-tDCS) on M1_HAND excitability and to compare them to those of c-tDCS. Here we show that so-tDCS at 0.8 Hz can also induce lasting changes in corticospinal excitability during wakefulness. Experiment 1. In 10 healthy awake individuals, we applied c-tDCS or so-tDCS to left M1_HAND on separate days. Each tDCS protocol lasted for 10 min. Measurements of motor evoked potentials (MEPs) confirmed previous work showing that anodal c-tDCS at an intensity of 0.75 mA (maximal current density 0.0625 mA/cm2) enhanced corticospinal excitability, while cathodal c-tDCS at 0.75 mA reduced it. The polarity-specific shifts in excitability persisted for at least 20 min after c-tDCS. Using a peak current intensity of 0.75 mA, neither anodal nor cathodal so-tDCS had consistent effects on corticospinal excitability. Experiment 2. In a separate group of ten individuals, peak current intensity of so-tDCS was raised to 1.5 mA (maximal current density 0.125 mA/cm2) to match the total amount of current applied with so-tDCS to the amount of current that had been applied with c-tDCS at 0.75 mA in Experiment 1. At peak intensity of 1.5 mA, anodal and cathodal so-tDCS produced bidirectional changes in corticospinal excitability comparable to the after effects that had been observed after c-tDCS at 0.75 mA in Experiment 1. The results show that so-tDCS can induce bidirectional shifts in corticospinal excitability in a similar fashion as c-tDCS if the total amount of applied current during the tDCS session is matched.     

Ether-à-go-go-related gene K+ channels contribute to threshold excitability of mouse auditory brainstem neurons

The ionic basis of excitability requires identification and characterisation of expressed channels and their specific roles in native neurons. We have exploited principal neurons of the medial nucleus of the trapezoid body (MNTB) as a model system for examining voltage-gated K⁺ channels, because of their known function and simple morphology. Here we show that channels of the ether-à-go-go -related gene family (ERG, Kv11; encoded by kcnh ) complement Kv1 channels in regulating neuronal excitability around threshold voltages. Using whole-cell patch clamp from brainstem slices, the selective ERG antagonist E-4031 reduced action potential (AP) threshold and increased firing on depolarisation. In P12 mice, under voltage-clamp with elevated [K⁺]_o (20 m m ), a slowly deactivating current was blocked by E-4031 or terfenadine ( V _0.5,act=−58.4 ± 0.9 mV, V _0.5,inact=−76.1 ± 3.6 mV). Deactivation followed a double exponential time course (τ_slow= 113.8 ± 6.9 ms, τ_fast= 33.2 ± 3.8 ms at −110 mV, τ_fast 46% peak amplitude). In P25 mice, deactivation was best fitted by a single exponential (τ_fast= 46.8 ± 5.8 ms at −110 mV). Quantitative RT-PCR showed that ERG1 and ERG3 were the predominant mRNAs and immunohistochemistry showed expression as somatic plasma membrane puncta on principal neurons. We conclude that ERG currents complement Kv1 currents in limiting AP firing at around threshold; ERG may have a particular role during periods of high activity when [K⁺]_o is elevated. These ERG currents suggest a potential link between auditory hyperexcitability and acoustic startle triggering of cardiac events in familial LQT2.     

Reduced intracortical inhibition and facilitation of corticospinal neurons in musicians

Interhemispheric inhibition between motor cortices is reduced in musicians. In the present study we have assessed intracortical inhibition (ICI) and facilitation (ICF) within ipsilateral motor cortex in 15 musicians and 15 non-musician controls. Transcranial magnetic stimulation (TMS) was used to elicit muscle evoked potentials (MEPs) from left first dorsal interosseous (FDI) muscle at rest, and during voluntary index finger abduction (0.5 N). Paired TMS with subthreshold conditioning was used to test early ICI with interstimulus intervals (ISIs) 1-5 ms, and ICF with ISIs 8-15 ms. Suprathreshold conditioning was used to test late ICI with ISIs 100-200 ms. TMS thresholds were similar in musicians and controls both at rest and with weak voluntary activation of FDI, indicating that postsynaptic excitability of corticospinal neurons was similar in both groups. ICI was less effective in musicians with FDI at rest and active, but only with an ISI of 3 ms. ICF was less effective in musicians under both rest and active conditions, and this was independent of ISI. There were no differences in late ICI between musicians and controls. We conclude that ICI and ICF circuits which are activated by weak TMS have less influence on corticospinal neuron excitability in musicians. Because of the dependence on ISI, the most likely explanation for the reduced ICI in musicians is an alteration of the interaction between the ICI circuit and neural elements responsible for the later I-waves evoked in corticospinal neurons by TMS. Excitability of the neural elements producing early and late ICI is not altered in musicians. Reduced ICF in musicians could be due to reduced excitability of neurons responsible for ICF, or an altered balance of excitatory inputs to corticospinal neurons which favours neurons that are not acted upon by the ICF circuit. The reduced influence of ICI and ICF circuits on corticospinal neuron excitability in musicians is likely to reflect a training-induced adaptation. It is not clear at present whether these differences represent an adaptive change related to their extraordinary control of finger movements, or alternatively a maladaptive change induced by "overuse" of the hands from extensive training.