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Transcranial direct current stimulation (tDCS) has been used as a useful interventional brain stimulation technique to improve unilateral upper-limb motor function in healthy humans, as well as in stroke patients. Although tDCS applications are supposed to modify the interhemispheric balance between the motor cortices, the tDCS after-effects on interhemispheric interactions are still poorly understood. To address this issue, we investigated the tDCS after-effects on interhemispheric inhibition (IHI) between the primary motor cortices (M1) in healthy humans. Three types of tDCS electrode montage were tested on separate days; anodal tDCS over the right M1, cathodal tDCS over the left M1, bilateral tDCS with anode over the right M1 and cathode over the left M1. Single-pulse and paired-pulse transcranial magnetic stimulations were given to the left M1 and right M1 before and after tDCS to assess the bilateral corticospinal excitabilities and mutual direction of IHI. Regardless of the electrode montages, corticospinal excitability was increased on the same side of anodal stimulation and decreased on the same side of cathodal stimulation. However, neither unilateral tDCS changed the corticospinal excitability at the unstimulated side. Unilateral anodal tDCS increased IHI from the facilitated side M1 to the unchanged side M1, but it did not change IHI in the other direction. Unilateral cathodal tDCS suppressed IHI both from the inhibited side M1 to the unchanged side M1 and from the unchanged side M1 to the inhibited side M1. Bilateral tDCS increased IHI from the facilitated side M1 to the inhibited side M1 and attenuated IHI in the opposite direction. Sham-tDCS affected neither corticospinal excitability nor IHI. These findings indicate that tDCS produced polarity-specific after-effects on the interhemispheric interactions between M1 and that those after-effects on interhemispheric interactions were mainly dependent on whether tDCS resulted in the facilitation or inhibition of the M1 sending interhemispheric volleys.

Objective: Ageing is accompanied by diminished practice-dependent plasticity. We investigated the effect of age on another plasticity inducing paradigm, repetitive transcranial magnetic stimulation (rTMS)., Methods: Healthy young (n=15; 25+/-4 years) and old (n=15; 67+/-5 years) adults participated in two experiments. Motor evoked potentials (MEPs) were measured in the target muscle (first dorsal interosseus, FDI) and a remote muscle (abductor digiti minimi) during a set of single stimuli. Subjects then received real or sham inhibitory rTMS (intermittent subthreshold trains of 6Hz stimulation for 10min). MEPs were measured for 30min after rTMS., Results: In young adults, MEPs in the target FDI muscle were approximately 15% smaller in the real rTMS experiment than in the sham rTMS experiment (P<0.026). In old adults, FDI MEP size did not differ between experiments., Conclusions: Advancing age is associated with reduced efficacy of inhibitory rTMS., Significance: This work has important implications for the potential therapeutic use of rTMS in stroke and neurological disease.

Using transcranial magnetic stimulation (TMS), disturbed facilitatory and inhibitory motor functions were recently found to correlate with motor hyperactivity in children with ADHD. Since hyperactivity seems to become reduced in ADHD during the transition to adulthood, a normalization of motor cortical excitability might be assumed. Therefore, we investigated the same inhibitory and facilitatory TMS paradigms in ADHD adults as we had previously examined in children. Motor cortical excitability was tested with TMS paired-pulse protocols in 21 ADHD adults and 21 age- and gender-matched healthy controls. In contrast to our results in ADHD children, no group-specific differences in amplitude changes of motor evoked potentials for inhibitory inter-stimulus intervals (ISI) (3, 100, 200 and 300 ms) or for facilitatory ISIs (13, 50 ms) could be detected. In ADHD adults, disturbed facilitatory and inhibitory motor circuits as found in ADHD children could not be shown, probably due to a development-dependent normalization of motor cortical excitability.

1 Hz rTMS applied over primary motor cortex (M1) reduces cortical excitability outlasting the stimulation period. Healthy right-handed subjects performed finger and hand tapping and a reach-to-grasp movement prior to (baseline) and after 1 Hz rTMS applied over (1) M1 of either the right or the left hemisphere, and (2) the vertex (control stimulation). 1 Hz rTMS applied over the left M1, but not over the vertex, improved movement kinematics of finger and hand tapping as well as grasping with the left hand. 1 Hz rTMS applied over the right M1, but not over the vertex, improved only the kinematics of hand tapping performed with the right hand. These data suggest that 1 Hz rTMS induced inhibition of ipsilateral M1 reduces transcallosal inhibition of contralateral M1 and thereby improves motor performance at the ipsilateral hand. The impact on motor performance of the ipsilateral hand is most pronounced after 1 Hz rTMS over the left M1.

Inhibitory silent period (SP) is a transient suppression of voluntary muscle activity after depolarization of representative motor neuronal populations following transcranial magnetic stimulation (TMS). Our aim was to evaluate and present an optimal protocol for the measurement of SP by (1) determining the impact of muscle activation level and stimulus intensity (SI) on the duration of SP, and, (2) studying the relationship between motor evoked potential (MEP) and SP, using targeted stimulus delivery. Single magnetic pulses were focused on the optimal representation area of the thenar musculature on primary motor cortex. We utilized real-time 3D-positioning of TMS-evoked electric field on anatomical structures derived from individual MR-images. The SI varied from 80% to 120% of individual resting motor threshold (MT). Muscle activation levels varied from 20% to 80% of the maximal voluntary contraction (MVC). Contralateral SP lengthened significantly with increasing SI independent of target muscle activation. The peak amplitude of the MEP was affected by SI and force. Latency and duration of the MEP were practically unaffected by SI or force. Focal stimulation at 110-120% MT and approximately 50% MVC (with only negligible need for control) provides most stable and informative SP. MEP should be included in SP as the error from marking the onset diminishes. This study provides a guideline for the consistent measurement of SP, which is applicable when using navigated or traditional TMS.

Background: Previous investigations using transcranial magnetic stimulation (TMS) have shown that neural inhibitory motor circuits are disturbed in ADHD children. We sought to investigate the influence of methylphenidate (MPH) on inhibitory and facilitatory motor circuits of ADHD children with TMS paired pulse protocols using surplus long interval inter-stimulus intervals (ISI) not investigated so far., Methods: Motorcortical modulation was tested with TMS paired pulse protocols employing ISI of 3, 13, 50, 100, 200, and 300 msec in 18 ADHD children before and on treatment with MPH. Clinical improvement by MPH was measured by the Conners score., Results: Analysis of variance (ANOVA) revealed a significant three-way interaction "Group x Amplitude x ISI," p = .001. Subsequent two-factorial ANOVAs and t-tests showed group specific differences of motor evoked potential (MEP) amplitudes for inhibitory ISIs of 3 and 100 msec, and for facilitatory ISIs of 13 and 50 msec. Compared to controls, an adjustment of these parameters by MPH could be shown. On MPH, a significant bivariate correlation was found between the Conners score reduction and averaged MEP amplitude changes only for inhibitory ISIs (3 and 100 msec)., Conclusions: In ADHD children, MPH modulates disturbed facilitatory and inhibitory motor circuits, which for the latter is associated with clinical improvement.

It has been suggested that the therapeutic effects of repetitive transcranial magnetic stimulation (rTMS) are mediated through changes in cortical inhibition (CI). However, in healthy human subjects the effects of rTMS on CI have been inconsistent. Therefore, this study sought to improve on the methodological limitations of previous studies by exploring several different rTMS-stimulus conditions on inhibition in the human motor cortex. In the first experiment, 12 healthy control subjects were randomly assigned to receive regular 1, 10 or 20 Hz rTMS in a counterbalanced order with sessions separated by at least 1 week. In the second experiment, 10 of these 12 subjects received priming rTMS (600 stimuli at 6 Hz followed by 600 stimuli at 1 Hz). Cortical inhibition was indexed using short-interval intracortical inhibition (SICI) and cortical silent period (CSP). Corticospinal excitability was indexed using motor threshold and MEP amplitude. We found no significant overall change in SICI, although there was a significant correlation between changes in SICI with baseline SICI. Subjects with greater SICI at baseline tended to have reduction in SICI post-rTMS, whereas subjects with less SICI tended to have increase in SICI post-rTMS. There was also a significant lengthening of the CSP with higher stimulation frequencies compared to lower stimulation frequencies. These findings suggest that rTMS increases CI, particularly in subjects with reduced baseline inhibition, a finding consistent with the concept of homeostatic plasticity. Baseline physiological characteristics may be further explored as a method to select patients who may benefit from rTMS treatment.

The present study used short interval intracortical inhibition (SICI), intracortical facilitation (ICF), and short latency afferent inhibition (SAI) to evaluate motor cortex excitability in 16 diffuse axonal injury (DAI) patients with memory impairment and compared the data with those of 16 healthy controls. SAI was reduced in patients compared with controls (92+/-12 versus 39+/-11% of the test size; p<0.0001, unpaired t-test). DAI patients tended to have a high resting motor threshold (RMT) and less pronounced SICI and ICF than controls, but these differences were not significant. A single oral dose (3mg) of donepezil, an acetylcholinesterase inhibitor that is commonly used to treat Alzheimer's disease (AD), improved SAI in DAI patients with wide individual variations that ranged from an increase of 77-18% of test size. These findings suggest that measuring SAI may provide a means of probing the integrity of cholinergic networks in an injured human brain.

Paired-pulse transcranial magnetic stimulation was used in three experiments to measure the properties of long-latency intracortical inhibition (LICI) acting on the relaxed first dorsal interosseus muscle of the left and right hand in right-handed volunteers. The experiments show that LICI is asymmetrical: it emerges more rapidly and is greater in the dominant than non-dominant hand shortly after activation of the LICI circuits, and is greater with low-intensity conditioning stimulus intensities in the dominant than non-dominant hand. These findings suggest that asymmetrical function of long-latency inhibitory circuits in motor cortex might contribute to the asymmetrical dexterity between the hands, possibly through their inhibitory control of the circuits responsible for short-latency inhibition.

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.

Stimulant and norepinephrine (NE) reuptake inhibitor medications have different effects at the neuronal level, but both reduce symptoms of attention deficit hyperactivity disorder (ADHD). To understand their common physiologic effects and thereby gain insight into the neurobiology of ADHD treatment, we compared the effects of the stimulant methylphenidate (MPH) and NE uptake inhibitor atomoxetine (ATX) on inhibitory and excitatory processes in human cortex. Nine healthy, right-handed adults were given a single, oral dose of 30 mg MPH and 60 mg ATX at visits separated by 1 week in a randomized, double-blind crossover trial. We used paired and single transcranial magnetic stimulation (TMS) of motor cortex to measure conditioned and unconditioned motor-evoked potential amplitudes at inhibitory (3 ms) and facilitatory (10 ms) interstimulus intervals (ISI) before and after drug administration. Data were analyzed with repeated measures, mixed model regression. We also analyzed our findings and the published literature with meta-analysis software to estimate treatment effects of stimulants and NE reuptake inhibitors on these TMS measures. There were no significant pretreatment differences or effects of treatment order. Both agents produced a significant increase in facilitation and a decrease in inhibition. Effects of ATX and MPH did not differ significantly. Pooled estimates from published studies show similar results for stimulants and NE reuptake inhibitors. In conclusion, in healthy adults, both stimulant and nonstimulant medications for ADHD decrease cortical inhibition and increase cortical facilitation. Cortical inhibition, shown previously to be abnormal in ADHD, may play a key role producing behavioral pathology.

Objective: We hypothesised that facilitatory I-wave interaction set up by paired-pulse transcranial magnetic stimulation delivered with I-wave periodicity (iTMS) may reinforce trans-synaptic events and provide a means for modulating synaptic plasticity and cortical excitability. Our objective was to determine whether prolonged iTMS can increase corticospinal excitability, and whether this form of stimulation can have lasting aftereffects., Methods: Paired stimuli of equal strength with a 1.5 ms inter-stimulus interval were delivered for 30 min at a rate of 0.2 Hz. Motor threshold and motor evoked potential (MEP) amplitude to single-pulse TMS was compared before and after intervention., Results: Paired-pulse MEP amplitude increased linearly throughout the period of iTMS, and had increased five-fold by the end of the stimulation period. Single-pulse MEP amplitude was increased a mean of four-fold for 10 min after stimulation. Motor threshold was unaffected., Conclusions: iTMS is an effective method for increasing excitability of the human motor cortex, and probably acts by increasing synaptic efficacy., Significance: Reinforcement of trans-synaptic events by iTMS may provide a means to investigate and modulate synaptic plasticity in the brain.

Objective: The perirolandic regions were studied by extensive electrical stimulation to clarify the topography and somatotopic distribution of negative motor areas (NMAs) and examine the clinical significance of these areas., Methods: We evaluated the cortical function elicited by electrical stimulation in 30 patients with tumors or intractable epilepsy. The somatotopic distribution of NMAs was examined by localizing these regions using Talairach's bicommissural reference system. NMAs within the lesions of two patients were removed under local anesthesia., Results: We obtained negative motor responses following the stimulation of 30 electrodes in 15 patients. On the lateral brain surface, the majority of NMAs for the upper extremities were distributed broadly throughout the premotor cortex, while NMAs for the tongue were only found in the inferior frontal gyrus of the dominant hemisphere. During removal of the NMAs within the lesions of two patients, we documented transient hand clumsiness in one patient., Conclusions: NMAs were widely distributed throughout the perirolandic area, as well as the previously reported regions in the inferior frontal gyrus. These areas likely function in the control of skilled movements; dysfunction of such movements transiently follows resection of these regions, but is subsequently well compensated for after surgery., Significance: The localization and consequences of resection of NMAs suggests their clinical significance in motor control.

A conditioning electrical stimulus to a digital nerve can inhibit the motor-evoked potentials (MEPs) in adjacent hand muscles elicited by transcranial magnetic stimulation (TMS) to the contralateral primary motor cortex (M1) when given 25-50 ms before the TMS pulse. This is referred to as short-latency afferent inhibition (SAI). We studied inter-hemispheric differences (Experiment 1) and within-limb somatotopy (Experiment 2) of SAI in healthy right-handers. In Experiment 1, conditioning electrical pulses were applied to the right or left index finger (D2) and MEPs were recorded from relaxed first dorsal interosseus (FDI) and abductor digiti minimi (ADM) muscles ipsilateral to the conditioning stimulus. We found that SAI was more pronounced in right hand muscles. In Experiment 2, electrical stimulation was applied to the right D2 and MEPs were recorded from ipsilateral FDI, extensor digitorum communis (EDC) and biceps brachii (BB) muscles. The amount of SAI did not differ between FDI, EDC and BB muscles. These data demonstrate inter-hemispheric differences in the processing of cutaneous input from the hand, with stronger SAI in the dominant left hemisphere. We also found that SAI occurred not only in hand muscles adjacent to electrical digital stimulation, but also in distant hand and forearm and also proximal arm muscles. This suggests that SAI induced by electrical D2 stimulation is not focal and somatotopically specific, but a more widespread inhibitory phenomenon.

We studied the effects of 1-Hz repetitive transcranial magnetic stimulation (rTMS) on the excitability of interhemispheric connections in 13 right-handed healthy volunteers. TMS was performed using figure-eight coils, and surface electromyography (EMG) was recorded from both first dorsal interosseous (FDI) muscles. A paired-pulse method with a conditioning stimulus (CS) to the motor cortex (M1) followed by a test stimulus to the opposite M1 was used to study the interhemispheric inhibition (ppIHI). Both CS and TS were adjusted to produce motor-evoked potentials of approximately 1 mV in the contralateral FDI muscles. After baseline measurement of right-to-left IHI (pre-RIHI) and left-to-right IHI (pre-LIHI), rTMS was applied over left M1 at 1 Hz with 900 stimuli at 115% of resting motor threshold. After rTMS, ppIHI was studied using both the pre-rTMS CS (post-RIHI and post-LIHI) and an adjusted post-rTMS CS set to produce 1-mV motor evoked potentials (MEPs; post-RIHI(adj) and post-LIHI(adj)). The TS was set to produce 1-mV MEPs. There was a significant reduction in post-LIHI (P = 0.0049) and post-LIHI(adj) (P = 0.0169) compared with pre-LIHI at both interstimulus intervals of 10 and 40 ms. Post-RIHI was significantly reduced compared with pre-RIHI (P = 0.0015) but pre-RIHI and post-RIHI(adj) were not significantly different. We conclude that 1-Hz rTMS reduces IHI in both directions but is predominantly from the stimulated to the unstimulated hemisphere. Low-frequency rTMS may be used to modulate the excitability of IHI circuits. Treatment protocols using low-frequency rTMS to reduce cortical excitability in neurological and psychiatric conditions need to take into account their effects on IHI.

Specific stimulation of neuronal circuits may promote selective inhibition or facilitation of corticospinal tract excitability. Monophasic stimulation is more likely to achieve direction-specific neuronal excitation. In 10 healthy subjects, we compared four types of repetitive transcranial magnetic stimulation (rTMS), monophasic and biphasic stimuli with the initial current in the brain flowing antero-posteriorly ("posteriorly directed") or postero-anteriorly ("anteriorly directed"). We applied rTMS over the primary motor cortex contralateral to the dominant hand, using 80 stimuli at 5 Hz frequency at an intensity yielding baseline motor evoked potential (MEP) amplitudes of 1 mV. Monophasic stimulation was always more efficient than biphasic. Facilitation was induced by intracerebral anteriorly directed current flow and inhibition by posteriorly oriented current flow, although only initially for approximately 30 pulses. The early inhibition was absent when studied during a tonic muscle contraction. Several mechanisms could account for these findings. They include a more efficient excitation of inhibiting circuits by posteriorly oriented pulses, and a back-propagating D-wave inhibiting early I-waves and thus inducing early inhibition of MEP amplitude. In any case biphasic rTMS results can be explained by a mixture of monophasic opposite stimulations. We propose the use of monophasic pulses for maximizing effects during rTMS.

Corticomotor threshold is a clinically useful concept for defining motor cortex excitability using transcranial magnetic stimulation. Although the silent period duration can be a quantitative measure of corticospinal inhibitory function, its threshold value has not been formally determined. The authors studied 20 right-handed normal subjects and found that silent period threshold was a reproducible parameter that did not vary with age and sex. Its value was significantly lower with left-sided transcranial magnetic stimulation and right-hand recordings. The silent period threshold may be a novel parameter useful for future studies of cortical inhibitory function.

Patients with writer's cramp (WC) show abnormalities of sensorimotor integration possibly contributing to their motor deficit. We studied sensorimotor integration by determining short-latency afferent inhibition (SAI) in 12 WC patients and 10 age-matched healthy controls. A conditioning electrical median nerve stimulus was followed 14 to 36 msec later by transcranial magnetic stimulation of the contralateral primary motor cortex, and motor evoked potentials (MEP) were recorded from the relaxed or contracting abductor pollicis brevis muscle (APB). SAI was normal in WC but during APB relaxation SAI was followed by abnormal MEP facilitation, which was absent during APB contraction and in the controls. These findings suggest that somatosensory short-latency inhibitory input into the primary motor cortex is normal in WC, whereas a later excitatory input, which very likely reflects the long-latency reflex II, is exaggerated., (Copyright 2004 Movement Disorder Society.)

Weak transcranial direct current stimulation (tDCS) can induce long lasting changes in cortical excitability. In the present study we asked whether tDCS applied to the left primary motor cortex (M1) also produces aftereffects distant from the site of the stimulating electrodes. We therefore tested corticospinal excitability in the left and the right M1 and transcallosal excitability between the two cortices using transcranial magnetic stimulation (TMS) before and after applying tDCS. Eight healthy subjects received 10 min of anodal or cathodal tDCS (1 mA) to the left M1. We examined the amplitude of contralateral motor evoked potentials (MEPs) and the onset latency and duration of transcallosal inhibition with single pulse TMS. MEPs evoked from the tDCS stimulated (left) M1 were increased by 32% after anodal and decreased by 27% after cathodal tDCS, while transcallosal inhibition evoked from the left M1 remained unchanged. The effect on MEPs evoked from the left M1 lasted longer for cathodal than for anodal tDCS. MEPs evoked from the right M1 were unchanged whilst the duration of transcallosal inhibition evoked from the right M1 was shortened after cathodal tDCS and prolonged after anodal tDCS. The duration of transcallosal inhibition returned to control values before the effect on the MEPs from the left M1 had recovered. These findings are compatible with the idea that tDCS-induced aftereffects in the cortical motor system are limited to the stimulated hemisphere, and that tDCS not only affects corticospinal circuits involved in producing MEPs but also inhibitory interneurons mediating transcallosal inhibition from the contralateral hemisphere.

Background: Focal transcranial magnetic stimulation (TMS) of the motor cortex was used to study two cortically activated inhibitory neuronal mechanisms that suppress ongoing tonic voluntary electromyographic activity in contralateral (postexcitatory inhibition [PI]) and ipsilateral (transcallosal inhibition [TI]) hand muscles. The PI follows the corticospinally mediated excitatory motor response (MEP) and is influenced by dopaminergic neurotransmission. TI reflects transcallosally mediated inhibition of the contralateral motor cortex, leading to motor inhibition in muscles ipsilateral to stimulation. PI and TI were studied to explore whether dopaminergic neurotransmission or interhemispheric transfers are altered in schizophrenia., Methods: TMS was performed in 16 patients with this disease and in 16 healthy control subjects. Surface electromyographic activity was recorded bilaterally from the first dorsal interosseous muscle during a sustained strong isometric contraction., Results: When compared with the findings in healthy subjects, patients with schizophrenia had a significantly longer PI and TI. The changes of the PI support the notion of an overactivity of the central dopaminergic system in schizophrenia., Conclusion: The prolonged TI suggests an abnormal activation of interhemispheric connections between the motor cortices and may be related to previously reported pathology of the corpus callosum in schizophrenic patients.