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Objectives: Non-invasive brain stimulation (NIBS) is beneficial to many neurological and psychiatric disorders by modulating neuroplasticity and cortical excitability. However, recent studies evidence that single type of NIBS such as transcranial direct current stimulation (tDCS) does not have meaningful clinical therapeutic responses due to their small effect size. Transcranial near-infrared stimulation (tNIRS) is a novel form of NIBS. Both tNIRS and tDCS implement its therapeutic effects by modulating cortical excitability but with different mechanisms. We hypothesized that simultaneous tNIRS and tDCS is superior to single stimulation, leading to a greater cortical excitability., Methods: Sixteen healthy subjects participated in a double-blind, sham-controlled, cross-over designed study. Motor evoked potentials (MEPs) were used to measure motor cortex excitability. The changes of MEP were calculated and compared in the sham condition, tDCS stimulation condition, tNIRS condition and the simultaneous tNIRS and anodal tDCS condition., Results: tDCS alone and tNIRS alone both elicited higher MEP after stimulation, while the MEP amplitude in the simultaneous tNIRS and tDCS condition was significantly higher than either tNIRS alone or tDCS alone. The enhancement lasted up to at least 30 minutes after stimulation, indicating simultaneous 820 nm tNIRS with 2 mA anodal tDCS have a synergistic effect on cortical plasticity., Conclusions: Simultaneous application of tNIRS with tDCS produces a stronger cortical excitability effect., Significance: The simultaneous tNIRS and tDCS is a promising technology with exciting potential as a means of treatment, neuro-enhancement, or neuro-protection., Competing Interests: Declaration of Competing Interest None of the authors has any conflict of interest to disclose., (Copyright © 2021 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Objective: The objective of this study is to investigate how transcranial magnetic intermittent theta burst stimulation (iTBS) with a prolonged protocol affects human cortical excitability and movement-related oscillations., Methods: Using motor-evoked potentials (MEPs) and movement-related magnetoencephalography (MEG), we assessed the changes of corticospinal excitability and cortical oscillations after iTBS with double the conventional stimulation time (1200 pulses, iTBS1200) over the primary motor cortex (M1) in 10 healthy subjects. Continuous TBS (cTBS1200) and sham stimulation served as controls., Results: iTBS1200 facilitated MEPs evoked from the conditioned M1, while inhibiting MEPs from the contralateral M1 for 30 min. By contrast, cTBS1200 inhibited MEPs from the conditioned M1. Importantly, empirical mode decomposition-based MEG analysis showed that the amplitude of post-movement beta synchronisation (16-26 Hz) was significantly increased by iTBS1200 at the conditioned M1, but was suppressed at the nonconditioned M1. Alpha (8-13 Hz) and low gamma-ranged (35-45 Hz) rhythms were not notably affected. Movement kinetics remained consistent throughout., Conclusions: TBS1200 modulated corticospinal excitability in parallel with the direction of conventional paradigms with modestly prolonged efficacy. Moreover, iTBS1200 increased post-movement beta synchronisation of the stimulated M1, and decreased that of the contralateral M1, probably through interhemispheric interaction., Significance: Our results provide insight into the underlying mechanism of TBS and reinforce the connection between movement-related beta synchronisation and corticospinal output., (Copyright © 2011 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

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.

Objective: Stimulation frequency has been considered the most important factor in conventional repetitive transcranial magnetic stimulation (rTMS) for determining the direction of after effects on corticospinal excitability. Here, we examined the functional relevance of breaks during high-frequency subthreshold rTMS for the induction of facilitatory after effects., Methods: The after effects on corticospinal excitability of a standard 5Hz rTMS protocol in a block design were compared to a continuous rTMS protocol using the same number of pulses. In addition the effect of current direction both for rTMS and single pulse TMS was included in the study design., Results: While 5Hz rTMS in a standard block design induces facilitatory after effects on corticospinal excitability, the continuous protocol does not induce facilitation but rather inhibition. In our study only rTMS using an initially posterior-anterior current direction in the brain leads to significant neuroplastic effects at all., Conclusions: Breaks during conventional high-frequency rTMS are a crucial factor determining the direction of induced neuroplastic changes., Significance: These results contribute to the understanding of rTMS-induced neuroplasticity and are important for the design of rTMS protocols both for experimental and clinical studies.

Objective: To evaluate changes in cortical excitability after long-term zonisamide (ZNS) administration., Methods: Fifteen drug-naïve idiopathic generalized epilepsy (IGE) patients (8 male, mean age 24.9 years) were enrolled. The transcranial magnetic stimulation (TMS) parameters obtained using two Magstim 200 stimulators were resting motor threshold (RMT), motor evoked potential (MEP) amplitudes, cortical silent period (CSP), intracortical inhibition (ICI), and intracortical facilitation (ICF). TMS parameters were compared before and after ZNS administration., Results: All patients were administered ZNS monotherapy (200 mg/day) for 8 weeks. No patient reported seizures during the study period. After ZNS treatment MEP amplitudes were significantly reduced in right (-34.2%) and left hemispheres (-37.0%) (Wilcoxon's signed rank test after Bonferroni's correction for multiple comparisons, P < 0.05). Mean RMT, CSP, and ICI/ICF were not changed by ZNS (P > 0.05)., Conclusions: These findings suggest that ZNS decreases cortical excitability in patients with IGE and a MEP amplitude is a useful TMS parameter for evaluating changes in cortical excitability induced by ZNS., Significance: The findings in this study are helpful to understand how ZNS affects the excitability of the motor cortex in patients with IGE.

Objective: To determine whether a single hemisphere exerts distinct inhibitory influences over masseter muscles on each side, and to compare features of the masseter cortical silent period (CSP) evoked by transcranial magnetic stimulation (TMS) with previous reports from limb and other cranial muscles., Methods: Focal TMS was applied over the motor cortex jaw area in 14 normal subjects. In one experiment, TMS intensity was constant (1.1 or 1.3x active motor threshold, T) and masseter muscle activation varied from 10% to 100% of maximal. In another experiment, muscle activation was constant (20% maximal) and TMS intensity varied from 0.7 to 1.3T., Results: In all subjects, TMS evoked a silent period of similar duration in masseter muscles on both sides. Masseter CSP duration increased at higher TMS intensities, but was not affected by muscle activation level or the size of the excitatory response evoked by TMS. Weak TMS produced a bilateral CSP without short-latency excitation. The masseter CSP was short ( approximately 100ms at 1.3T), yet this was not due to maintenance of excitatory drive from the unstimulated hemisphere, as the masseter CSP was not prolonged with dual-hemisphere TMS., Conclusions: Intracortical inhibitory circuits activated by TMS have a relatively weak effect on corticotrigeminal neurons supplying masseter, and effects are equivalent for corticobulbar efferents directed to contralateral and ipsilateral masseter motoneuron pools., Significance: Trigeminally innervated masseter muscles exhibit weak, bilaterally symmetric inhibition following focal TMS. This method can be used to investigate abnormalities of intracortical inhibition in movement disorders or focal lesions affecting the masticatory muscles in humans.

Objective: To investigate the changes in cortical excitability of the human motor cortex induced by high-frequency repetitive transcranial magnetic stimulation (rTMS) of different stimulation durations., Methods: Twenty healthy subjects participated in the study. Subjects received 20 trains of 10-Hz rTMS at 80% of the resting motor threshold (RMT) intensity with two different stimulation durations (5 and 1.5s) over the motor hot spot for left first dorsal interosseous (FDI) muscle. Electromyographic responses (motor-evoked potentials, MEPs) to single-pulse stimulation, and intracortical inhibition (ICI) and intracortical facilitation (ICF) by paired-pulse stimulation were measured bilaterally in the relaxed FDI muscles before, immediately after, and 30, 60, 90 and 120 min after rTMS., Results: After 5s of 10-Hz rTMS, the mean amplitude of MEP for the stimulated M1 cortex decreased for up to 90min (P=0.002) and that of the unstimulated M1 cortex decreased for up to 60 min (P=0.008). Enhancement of ICI and suppression of ICF were observed and sustained for more than 90 min in both stimulated (P=0.001) and unstimulated (P=0.003) M1 cortex after 5s of 10-Hz rTMS. After 1.5s of 10-Hz rTMS, the mean amplitude of MEP increased in stimulated cortex for up to 120 min (P=0.005)., Conclusions: With different stimulation durations, high-frequency subthreshold rTMS can produce different patterns of long-lasting changes in corticospinal and intracortical excitability in stimulated and unstimulated motor cortex in healthy subjects., Significance: The results have important implications for the selection of stimulation parameters other than the frequency of rTMS. The clinical application of rTMS for the purpose of motor enhancement should be considered along with the mechanism of different stimulation parameters.

Objective: To investigate the effect of high frequency rTMS (25 Hz at 90-100% of resting motor threshold) on the excitability of the motor cortex of healthy human subjects., Methods: Resting and active motor threshold, MEP recruitment curve (I/O curve), short interval intracortical inhibition (SICI) and facilitation (ICF), and the duration of the silent period (SP) were tested in the right first dorsal interosseous muscle (FDI) before and twice after the end of 1500 pulses in 16 normal young adult male volunteers., Results: Twenty-five Hertz rTMS decreased motor thresholds, reduced the duration of the silent period and had a tendency to increase the slope of the I/O curve. Most of these effects lasted for the duration of the two post-testing sessions (at least 30 min) and had returned to normal by 2h. There were no significant effects on SICI/ICF., Conclusion: Twenty-five Hertz rTMS can produce a long lasting increase in cortical excitability in healthy subjects., Significance: This method may prove useful for the study of normal human physiology and for therapeutic manipulation of brain plasticity.

Repetitive transcranial magnetic stimulation (rTMS) procedures are being widely applied in therapeutic and investigative studies. Numerous studies have investigated the effects of rTMS on cortical excitability and inhibition, yielding somewhat contradictory results. The purpose of this study was to comprehensively review this literature to guide the selection of methodology in therapeutic studies. We conducted a comprehensive review of all identified studies that investigated effects of low and/or high frequency rTMS on motor cortical excitability or inhibition. Low frequency rTMS appears to produce a transient reduction in cortical excitability as assessed by motor evoked potential (MEP) size and produces no substantial effect on cortical inhibition. High frequency rTMS appears to produce a persistent increase in MEP size and a reduction in cortical inhibition measured with paired pulse methods although few studies have investigated frequencies greater than 5Hz. A number of novel stimulation paradigms have significant potential for altering cortical excitability but require further investigation. Although commonly applied forms of rTMS have effects on cortical excitability, more substantial effects may be obtained through the use of novel stimulation paradigms or innovative approaches to the stimulation of areas connected to a potential target site. Further research is required, however, before these paradigms can be more widely adopted.

Objective: To determine whether low-frequency repetitive transcranial magnetic stimulation (rTMS) may modulate l-DOPA-induced dyskinesia (LID) in dyskinetic Parkinson's disease (PD) patients. LID is a severe motor complication in advanced PD patients. The neural mechanisms involved in LID are not clear, and it is apparent that both an excessive decrease in internal pallidus firing and a modification and overactivation of cortical motor and premotor areas are involved in its pathogenesis., Methods: Using low frequency 1Hz repetitive rTMS we investigated whether decrease of excitability of the supplementary motor area (SMA) may result in modification of LID in PD patients. Furthermore we tested whether it was possible to enhance and/or prolong the beneficial effects of the treatment with repeated sessions of stimulation., Results: We observed that 1Hz rTMS induced a transient reduction of dyskinesias. A single session of rTMS improved LID, while repeated sessions of stimulation failed to enhance and/or prolong the beneficial effects of the procedure, without causing motor deterioration or other adverse effects., Conclusions: These results suggest that LID may depend on an increased excitability of the SMA., Significance: SMA rTMS is effective in reducing transiently LID, although cannot yet be considered clinically useful.

Objective: To assess, using a double-blind procedure, the pain-relieving effects of rTMS against placebo, and their predictive value regarding the efficacy of implanted motor cortex stimulation (MCS)., Methods: Three randomised, double-blinded, 25 min sessions of focal rTMS (1 Hz, 20 Hz and sham) were performed in 12 patients, at 2 weeks intervals. Effects on pain were estimated from daily scores across 5 days before, and 6 days after each session. Analgesic effects were correlated with those of subsequent implanted motor cortex stimulation (MCS)., Results: Immediately after the stimulating session, pain scores were similarly decreased by all rTMS modalities. Conversely, during the following week, 1 Hz stimulation provided significantly less analgesia than 20 Hz and placebo, and was pro-algesic in some patients. Placebo and 20 Hz rTMS were effective on different patients, and only 20 Hz rTMS predicted the efficacy of subsequent MCS, with no false positives., Conclusions: While 1Hz rTMS should not be used with analgesic purposes, high-frequency rTMS may become useful to select candidates for MCS. Placebo effects are powerful and should be controlled for. Immediate results after a single rTMS session are misleading., Significance: Defining rTMS parameters is a crucial step before proposing rTMS as predictive test of SCM efficacy in clinical practice.

Objective: Motor cortex plasticity may underlie motor recovery after stroke. Numerous studies have used transcranial magnetic stimulation (TMS) to investigate motor system plasticity. However, research on the reliability of TMS measures of motor cortex organization and excitability is limited. We sought to test the reliability of these TMS measurements., Methods: Twenty healthy volunteers were tested twice over a two-week period using TMS to determine motor threshold, map topography, and stimulus-response curves for first dorsal interosseous (FDI), abductor pollicis brevis (APB), extensor digitorum communis (EDC), and flexor carpi radialis (FCR) muscles., Results: We found moderate to good test-retest reliability TMS measurements of motor threshold (ICC=0.90-0.97), map area (ICC=0.63-0.86) and location (ICC=0.69-0.86), and stimulus-response curves (ICC=0.60-0.83)., Conclusions: TMS assessments of motor representation size, location, and excitability are generally reliable measures, although their reliability may vary according to the muscle under investigation., Significance: These results suggest that TMS measurements of motor cortex function are reliable enough to be potentially useful in investigation of motor system plasticity.

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 motor cortical representation in patients with complex regional pain syndrome type I (CRPS I) was determined under the assumption that the motor cortex undergoes representational adaptations in the course of CRPS., Methods: A total of 14 patients with CRPS I and a group of healthy subjects without any known neurological symptoms participated in the study. The motor cortical representation, i.e. the size of representation (cm2), motor-evoked potentials (MEP), the calculated volume (cm2 mV), and the center of gravity (CoG) were measured by transcranial magnetic stimulation. Recordings were made of the long extensor muscles of the forearm of the affected and unaffected hand., Results: Analyses of the results revealed a significant asymmetry between the two hemispheres: the motor cortical representation corresponding to the unaffected hand was significantly larger. While the CoG data did not differ statistically between the two hemispheres, the CoG coordinates corresponding to the affected hand indicated a larger variability., Conclusions: The presence of pain and other CRPS symptoms may induce lasting changes in motor cortical plasticity, as it also does in the sensory cortex., Significance: This could be of importance in rehabilitative strategies for the sensory motor system in CRPS I patients.

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.

Objective: To determine if there are steroid-dependent changes in transcallosal transfer during the menstrual cycle in normal women., Methods: We tested 13 normally cycling women during the menstrual, follicular and midluteal phases. Blood levels of estradiol (E) and progesterone (P) were determined by radioimmunoassay. Ipsilateral tonic voluntary muscle activity suppression, called ipsilateral silent period (iSP), was evoked by applying transcranial magnetic stimulation (TMS) over the left motor cortex and by measuring the EMG of the ipsilateral first dorsal interosseus (FDI) muscle. Both iSP-duration and transcallosal conduction times were measured and related to cycle phase and steroid levels., Results: Duration of iSPs varied over the cycle with largest differences between follicular and midluteal phases. During the midluteal phase high levels of P were significantly related to short iSPs. This relation also applied to E levels and iSPs during the follicular phase., Conclusions: Our study shows for the first time that the transcallosal transfer is modulated by E and P and changes over the menstrual cycle., Significance: It is suggested that gonadal steroid hormones affect the interhemispheric interaction and change the functional cerebral organization sex dependently via its neuromodulatory properties on GABAergic and glutamatergic neurons.

Objective: In this study, we tested the excitability of cortical motor areas in patients with Alzheimer's disease. Because repetitive transcranial magnetic stimulation (rTMS) modulates cortical excitability, possibly by inducing a short-term increase in synaptic efficacy, we used rTMS to investigate motor cortex excitability in patients with Alzheimer's disease., Methods: We tested the changes in the size and threshold of motor evoked potential (MEP) and cortical silent period (CSP) duration evoked by focal rTMS delivered in 10 trains of 10 stimuli at 5Hz frequency and 120% rMth intensity in a group of patients with Alzheimer's disease, and age-matched controls. In a further session, rTMS was also delivered at 1Hz frequency (trains of 10 stimuli, 120% rMth)., Results: Whereas in control subjects, 5Hz-rTMS elicited normal MEPs that progressively increased in size during the train, in patients, it elicited MEPs that decreased in size. The increase in the duration of the CSP was similar in patients and healthy controls. One hertz rTMS left the MEP amplitude unchanged in patients and healthy controls., Conclusions: The lack of MEP facilitation reflects an altered response to 5Hz-rTMS in patients with Alzheimer's disease., Significance: Our rTMS findings strongly suggest an altered cortical plasticity in excitatory circuits within motor cortex in patients with Alzheimer's disease.

Objective: To compare the heating behaviour of three figure-of-eight shaped coils during repetitive transcranial magnetic stimulation (rTMS)., Methods: A custom-made coil (referred to as test coil) with a resistance-optimized conductor geometry was compared with two commercially available eight-shaped coils. Each coil was attached to the same energy source, which generated trains of 50 biphasic magnetic pulses every 20s. Coil temperature was continuously measured during nine rTMS protocols using various combinations of stimulus frequencies (5, 10 or 20Hz) and intensities (40, 50 or 60% of maximum stimulator output). A heating curve relating coil temperature and the number of applied stimuli was generated for each coil and rTMS condition. In eleven healthy volunteers, we evaluated the effectiveness of motor cortex stimulation. For each coil, we determined the motor threshold (MT) in the right first dorsal interosseus muscle., Results: The slope of the heating curves of the test coil was markedly flattened relative to the heating curves of the two standard coils. This allowed the application of at least twice as many stimuli until the temperature of the coil reached 40 degrees C. Based on these data, we showed that a one-mass model could be used to accurately describe the heating behaviour of each coil. MTs determined with the test coil were comparable to or lower than the MTs that were determined with the standard coils., Conclusions: The efficacy of the test coil to stimulate the M1 was comparable to the efficacy of the two standard coils, yet thermal characteristics were markedly improved., Significance: Overheating of figure-of-eight shaped coils can be markedly delayed without reducing the efficacy of rTMS.

Transcranial stimulation of the human motor cortex can evoke several different kinds of descending activity depending on the type of stimulation, the intensity of stimulation and the area of the cortex being stimulated. Thus, transcranial magnetic stimulation preferentially activates different structures than transcranial electrical stimulation. In addition, the response to magnetic stimulation depends on the direction of the induced current in the brain, the waveform of the stimulating current, and the shape of the coil. Stimulation of the lower limb area of motor cortex recruits different elements than stimulation of the upper limb area. These differences occur because different structures in the motor cortex have a differential threshold to the different techniques of stimulation. We have had the opportunity to perform a series of direct recordings of the corticospinal volley evoked by the different techniques of transcranial stimulation from the epidural space of conscious patients with chronically implanted spinal electrodes. These recordings provide insights about the physiological basis of the excitatory and inhibitory phenomena produced by transcranial stimulation.

Objective: The aim of the study was to examine the stimulus-response properties of the excitatory and inhibitory components of corticospinal projections at rest and during voluntary contraction in cerebellar patients., Methods: We investigated motor evoked potential (MEP) and cortical silent period recruitment curves in response to increasing intensities of transcranial magnetic stimulation in 8 patients with 'pure' cerebellar syndromes and in 14 age-matched controls. The transcranial magnetic stimulation intensity was increased from 90 to 180% of the resting motor threshold. MEP recruitment curves were recorded at rest and during voluntary contraction in the right abductor pollicis brevis muscle., Results: No statistical differences were found between patients and controls in MEP recruitment curves in either the resting or active condition. A significant difference was found between patients and controls in the cortical silent period threshold (patients: 33.2+/-3.4% of maximal stimulator output; controls 39.4+/-3.2%; P=0.01) and recruitment curve, the duration of the cortical silent period being longer in patients at transcranial magnetic stimulation intensities ranging from 90 to 130% of the resting motor threshold (patients: 135-191 ms; controls: 53-158 ms). No changes were found in the silent period evoked by peripheral nerve stimulation., Conclusions: Inhibitory components of corticospinal projections were recruited with a lower threshold in patients. No abnormalities were found in the recruitment of the excitatory networks. Our data show a prevalence of inhibitory phenomena in the motor cortex of cerebellar patients. These findings would appear to be specific to cerebellar diseases and are the opposite of those previously documented in movement disorders such as dystonia and Parkinson's disease. Our results suggest that the cerebellum and the basal ganglia may counteract each other in modulating the level of motor system excitability.

Objective: The motor cortex may be subject to tonic inhibitory drive. One inhibitory mechanism is supported by activity at benzodiazepine (BZP) receptors. In this study we investigate whether or not the BZP antagonist, flumazenil, increases cortical motor excitability in humans., Methods: Eight healthy subjects received a 1 mg intravenous (i.v.) loading dose of flumazenil followed by a 0.5 mg i.v. infusion over the next 30 min. Before, during, and 1 h after flumazenil infusion, we measured cortical motor excitability using transcranial magnetic stimulation (TMS). This included resting motor threshold (rMT), paired-pulse measurements of intracortical inhibition and facilitation (ICI and ICF), recruitment curve (RC), and silent period (SP). We also measured F response and compound muscle action potential (CMAP) with peripheral nerve stimulation. The study was carried out using a randomized, double-blind crossover design controlled with a saline infusion., Results: None of the measures of cortical or peripheral excitability were significantly affected by drug administration., Conclusions: Our findings suggest that flumazenil has no effect on cortical motor excitability in normal humans., Significance: There does not appear to be any tonic activity at benzodiazepine receptors in the normal resting human motor cortex.

Objective: The authors studied amyotrophic lateral sclerosis (ALS) patients using triple stimulation technique (TST) to detect upper motor neuron (UMN) involvement., Methods: Nineteen ALS patients (aged 45-72 years) were enrolled in the study. According to the El Escorial criteria, 6 diagnoses were suspected or possible, 6 probable, and 7 definite. Patients were examined clinically, with conventional (single-pulse) transcranial magnetic stimulation (TMS), and with TST (on one side only)., Results: Among the whole group of patients, TST appeared to be more sensitive than conventional TMS techniques. In particular among suspected/possible ALS patients, TST area ratio was pathologic in 100%, while single-pulse TMS was abnormal only in 50% of cases. Overall, the use of TST area ratio was more sensitive than the analysis of TST amplitude ratio., Conclusions: The results suggest that TST might be more sensitive and useful in the diagnosis of subclinical UMN involvement than conventional TMS techniques, even if TST is performed on one side only.

Objective: To investigate the after-effects of 0.3 Hz repetitive transcranial magnetic stimulation (rTMS) on excitatory and inhibitory mechanisms at the primary motor cortex level, as tested by single-pulse TMS variables., Methods: In 9 healthy subjects, we studied a wide set of neurophysiological and behavioral variables from the first dorsal interosseous before (Baseline), immediately after (Post 1), and 90 min after (Post 2) the end of a 30 min long train of 0.3 Hz rTMS delivered at an intensity of 115% resting motor threshold (RMT). Variables under investigation were: maximal M wave, F wave, and peripheral silent period after ulnar nerve stimulation; RMT, amplitude and stimulus-response curve of the motor evoked potential (MEP), and cortical silent period (CSP) following TMS; finger-tapping speed., Results: The CSP was consistently lengthened at both Post 1 and Post 2 compared with Baseline. The other variables did not change significantly., Conclusions: These findings suggest that suprathreshold 0.3 Hz rTMS produces a relatively long-lasting enhancement of the inhibitory mechanisms responsible for the CSP. These effects differ from those, previously reported, of 0.9-1 Hz rTMS, which reduces the excitability of the circuits underlying the MEP and does not affect the CSP. This provides rationale for sham-controlled trials aiming to assess the therapeutic potential of 0.3 Hz rTMS in epilepsy.

Objective: We investigated whether repetitive transcranial magnetic stimulation (rTMS) applied to the right motor cortex modified the excitability of the unstimulated left motor cortex., Methods: Interhemispheric effects of 0.5 and 5 Hz subthreshold rTMS over the right motor cortex were examined by single pulse and paired pulse TMS and by transcranial electrical stimulation (TES) applied to the unstimulated left motor cortex. The effects of (a) 1800 pulses real and sham rTMS with 5 Hz, (b) 180 pulses real and sham rTMS with 0.5 Hz and (c) 1800 pulses real rTMS with 0.5 Hz were studied., Results: Following 5 Hz right motor rTMS motor evoked potential (MEP) amplitudes induced by single pulse TMS over the left motor cortex increased significantly. Intracortical inhibition (ICI) and facilitation (ICF) and MEP amplitudes evoked by TES were unchanged. Sham stimulation had no influence on motor cortex excitability. After 180 pulses right motor cortex rTMS with 0.5 Hz a significant decrease of left motor ICF, but no change in single pulse MEP amplitudes was found. A similar trend was observed with 1800 pulses rTMS with 0.5 Hz., Conclusions: High frequency right motor rTMS can increase left motor cortex excitability whereas low frequency right motor rTMS can decrease it. These effects outlast the rTMS by several minutes. The underlying mechanisms mediating interhemispheric excitability changes are likely to be frequency dependent.

Objective: To determine whether the plastic changes induced in human motor cortex by afferent stimulation depend on stimulus frequency., Methods: Transcranial magnetic stimulation was used to examine changes in corticospinal excitability in 20 subjects before and after combined peripheral (motor point) and central stimulation. Peripheral stimuli were given as either low frequency (3 Hz) or high frequency (30 Hz) trains., Results: Low frequency stimulation induced prolonged depression of corticospinal excitability, while high frequency stimulation induced prolonged facilitation. These effects persisted for approximately 40-50 min after stimulation ceased., Conclusions: Corticospinal plasticity induced by dual peripheral and central stimulation is bi-directionally-modifiable in the adult human, with the direction of change being frequency-dependent., Significance: Therapies using peripheral stimulation to alter human motor cortex excitability could be tailored to exploit the differential effects of stimulus frequency on the direction of the excitability change.

Objective: Slow frequency repetitive transcranial magnetic stimulation (rTMS) reduces motor cortex excitability, but it is unclear whether this has behavioural consequences in healthy subjects., Methods: We examined the effects of 1 Hz rTMS (train of 20 min; stimulus intensity 80% of active motor threshold) over left motor or left premotor cortex on performance in a visually cued choice reaction time task, using a 'masked prime' paradigm to assess whether rTMS might affect more automatic motor processes. Twelve healthy volunteers participated., Results: Motor cortex rTMS and, to a lesser extent, premotor cortex rTMS resulted in a slowing of right (stimulated) hand responses, but not of left (unstimulated) hand responses. In a control experiment, rTMS of the left somatosensory cortex did not lead to slower right hand responses., Discussion: We conclude that long trains of low intensity 1 Hz rTMS over the motor or premotor cortex can have subtle behavioural consequences outlasting the stimulation. rTMS did not affect the modulation of reaction times by subliminal primes, suggesting that priming effects triggered by subliminal primes are not generated at the level of motor or pre-motor cortex.

Objectives: Single-pulse transcranial magnetic stimulation (TMS) over the cerebellum affects corticospinal excitability by a cerebellar and a peripheral mechanism. We have investigated whether any of the long-lasting effects of repetitive TMS (rTMS) over cerebellum can also be attributed to peripheral effects., Methods: Five hundred conditioning stimuli at 1 Hz were given over either the right cerebellum using a double-cone coil, or over the right posterior neck using a figure-8-coil. Corticospinal excitability was assessed by measuring the amplitude of motor evoked potentials (MEPs) evoked in the right and left hand and forearm muscles. Hoffman reflexes (H-reflex) were also obtained in the right flexor carpi radialis muscle., Results: rTMS over either the right cerebellum or the right posterior neck significantly facilitated MEPs in hand and forearm muscles in the right but not in the left arm (n=8) for up to 30 min after the end of the train. rTMS (1 Hz) of the right neck area increased the amplitude of the H-reflex (n=5)., Conclusions: Much of the persisting effects of rTMS over the cerebellum on corticospinal excitability appear to be mediated through stimulation of peripheral rather than central structures. Moreover, the results show that rTMS over peripheral areas can cause long-lasting changes in spinal reflexes.

Objectives: Phosphene thresholds (PTs) to transcranial magnetic stimulation over the occipital cortex and motor thresholds (MTs) have been used increasingly as measures of the excitability of the visual and motor cortex. MT has been utilized as a guide to the excitability of other, non-motor cortical areas such as dorsolateral prefrontal cortex. The aims of this study were to compare the PTs to MTs; to assess their stability across sessions; and to investigate their relation to MTs., Methods: PTs and MTs were determined using focal transcranial magnetic stimulation over the visual and motor cortex., Results: PTs were shown to be significantly higher than MTs. Both PTs and MTs were stable across sessions. No correlation between PTs and MTs could be established., Conclusions: Phosphene threshold is a stable parameter of the visual cortex excitability. MTs were not related to the excitability of non-motor cortical areas.

Objective: Repetitive transcranial magnetic stimulation (rTMS) is able to modulate the corticospinal excitability and the effects appear to last beyond the duration of the rTMS itself. Different studies, employing different rTMS parameters, report different modulation of corticospinal excitability ranging from inhibition to facilitation. Intraindividual variability of these effects and their reproducibility are unclear., Methods: We examined the modulatory effects of rTMS to the motor cortex at various frequencies (1, 10, 20 Hz) and at different time-points in twenty healthy volunteers., Results: We observed significant inhibition of MEPs following 1 Hz rTMS and significant facilitation of MEPs following 20 Hz rTMS for both day1 and day 2. Interestingly, at 1 Hz and 20 Hz rTMS, the modulatory effect produced by rTMS was greater on day 2. However, there was no significant change in corticospinal excitability following 10 Hz rTMS neither on day 1 nor day 2., Conclusion: Our findings raise questions as to how stimulation parameters should be determined when conducting studies applying rTMS on multiple days, and in particular, studies exploring rTMS as a treatment modality in neuropsychiatric disorders.