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.     

Increased facilitation of the primary motor cortex following 1 Hz repetitive transcranial magnetic stimulation of the contralateral cerebellum in normal humans

Connections between the cerebellum and the contralateral motor cortex are dense and important, but their physiological significance is difficult to measure in humans. We have studied a group of 10 healthy subjects to test whether a modulation of the excitability of the left cerebellum can affect the excitability of the contralateral motor cortex. We used repetitive transcranial magnetic stimulation (rTMS) at 1 Hz frequency to transiently depress the excitability of the left cerebellar cortex and paired-pulse TMS testing of intracortical inhibition (ICI) and intracortical facilitation (ICF) to probe the excitability of cortico-cortical connections in the right motor cortex. The cortical silent period was also measured before and after cerebellar rTMS. Motor evoked potentials (MEPs) were significantly larger after than before conditioning rTMS trains (p < 0.01). Moreover, left cerebellar rTMS increased the ICF of the right motor cortex as measured with paired-pulses separated by an interstimulus interval (ISI) of 15 ms. The effect lasted for up to 30 min afterward and was specific for the contralateral (right) motor cortex. The cortical silent period was unaffected by cerebellar rTMS. The implication is that rTMS of the cerebellar cortex can shape the flowing of inhibition from Purkinje cells toward deep nuclei, thereby increasing the excitability of interconnected brain areas.     

The effect of rTMS over the cerebellum in normal human volunteers on peg-board movement performance

Low frequency rTMS over the paramedian part of the right cerebellum was used to test the effects of TMS-induced disruption of the cerebellum on performance of the 10-hole pegboard task. A test group (n = 14) showed significantly increased movement times lasting about 3 min after the 5-min 1 Hz rTMS train, compared to a control group who received no rTMS (n = 14), tested in a parallel group design. The increase was greatest for the hand ipsilateral to the stimulation, but the difference between the two hands was not statistically significant. These results suggest that the rTMS affects cerebellar excitability and cause a short-lasting bilateral change in sensory-motor performance.     

Low frequency rTMS effects on sensorimotor synchronization

Previous studies using low frequency (1 Hz) rTMS over the motor and premotor cortex have examined repetitive movements, but focused either on motor aspects of performance such as movement speed, or on variability of the produced intervals. A novel question is whether TMS affects the synchronization of repetitive movements with an external cue (sensorimotor synchronization). In the present study participants synchronized finger taps with the tones of an auditory metronome. The aim of the study was to examine whether motor and premotor cortical inhibition induced by rTMS affects timing aspects of synchronization performance such as the coupling between the tap and the tone and error correction after a metronome perturbation. Metronome sequences included perturbations corresponding to a change in the duration of a single interval (phase shifts) that were either small and below the threshold for conscious perception (10 ms) or large and perceivable (50 ms). Both premotor and motor cortex stimulation induced inhibition, as reflected in a lengthening of the silent period. Neither motor nor premotor cortex rTMS altered error correction after a phase shift. However, motor cortex stimulation made participants tap closer to the tone, yielding a decrease in tap-tone asynchrony. This provides the first neurophysiological demonstration of a dissociation between error correction and tap-tone asynchrony in sensorimotor synchronization. We discuss the results in terms of current theories of timing and error correction.     

Effect of 1?Hz Repetitive Transcranial Magnetic Stimulation Over the Auditory Cortex on Audiometry and Otoacustic Emissions

Repetitive transcranial magnetic stimulation (rTMS) at low frequencies (≤1 Hz) delivered to the primary motor cortex for 15 min or longer has been shown to reduce motor cortex excitability. Over the visual cortex, 1 Hz rTMS led to increased phosphene thresholds and over the auditory cortex rTMS reduced auditory evoked potentials. rTMS above the auditory or temporo-parietal cortex has also been reported to reduce the severity of auditory hallucinations and the perception of tinnitus. However, possible unwanted effects on hearing function have not yet been investigated systematically. 12 right-handed normal hearing subjects (5 male, mean age 28.2 ± 4.3) received a single session of 18 min 1 Hz rTMS at 90% resting motor threshold intensity using an established coil positioning method targeting the Heschl's area of the left superior temporal gyrus. Standard pure tone audiometry and distortion-products otoacustic emissions (DPOAE) were performed before and immediately after stimulation. The main finding was that one session of 1 Hz rTMS over the temporal cortex modified neither the auditory threshold meaningfully nor the presence of DPOAE in healthy subjects. In conclusion, we found in this pilot approach no obvious indication for auditory dysfunctions due to direct electromagnetic stimulation of the superior temporal gyrus after one session of rTMS in healthy controls that may be interpreted as unwanted side effects. Nevertheless monitoring of auditory functions is strongly recommended in future clinical trials stimulating the auditory cortex, as this has not been done systematically in the past.     

Modulation of steady-state auditory evoked potentials by cerebellar rTMS

Steady-state auditory evoked responses (SSAER) obtained via electroencephalography (EEG) co-vary in amplitude with blood flow changes in the auditory area of the cerebellum. The aim of the present EEG study was to probe the cerebellar role in the control of such SSAER. For this purpose, we investigated changes in SSAERs due to transient disruption of the cerebellar hemisphere by repetitive transcranial magnetic stimulation (rTMS). SSAERs to click-trains of three different frequencies in the gamma-band (32, 40 and 47 Hz) were recorded from 45 scalp electrodes in six healthy volunteers immediately after 1-Hz rTMS and compared to baseline SSAERs assessed prior to magnetic stimulation. Cerebellar rTMS contralateral to the stimulated ear significantly reduced the amplitude of steady-state responses to 40-Hz click-trains and showed a tendency to reduce the amplitude to 32-Hz click-trains. No effects were observed for 47-Hz click-trains, nor for magnetic stimulation of the cerebellum ipsilateral to auditory stimulation or after sham stimulation. Our results suggest that interference with cerebellar output by rTMS modifies functional activity associated with cortical auditory processing. The finding of maximum effects on 40-Hz SSAERs provides support to the notion that the cerebellum is part of a distributed network involved in the regulation of cortical oscillatory activity and points at some frequency-specificity for the control of auditory-driven neuronal oscillations.     

Perturbation of visuospatial attention by high-frequency offline rTMS

The contribution of different cortical regions to visuospatial attention can be probed with the help of perturbation techniques, such as transcranial magnetic stimulation (TMS). Repetitive TMS (rTMS) has also been suggested as a tool for the therapy of brain injuries, by adjusting the neural excitability of injured or intact brain regions. Low- and high-frequency rTMS have been shown to result in subsequent (offline) reductions or increases of local cortical excitability, respectively. Previous studies demonstrated that low-frequency (1 Hz) rTMS of posterior parietal cortex (PPC) produced significantly reduced detection of stimuli in the visual hemifield contralateral to the stimulation site, as well as increased ipsilateral detection. We here explored the functional impact of high-frequency (20 Hz) rTMS with an attention task similar to that of a previous low-frequency study (Hilgetag et al. in Nat Neurosci 4:953–957, 2001). Normal healthy subjects (N = 14) received high-frequency rTMS (20 Hz, 10 min, 50% stimulator output) over right or left PPC (coordinate points P4 or P3). After stimulation of the right PPC, detection of single visual stimuli in the contralateral hemifield was significantly impaired. Generally, rTMS of right and left PPC produced mirror-symmetric trends in reduced contralateral detection. These effects were still present after post-TMS sham stimulation (more than 20 min after the end of active rTMS). The results suggest that attentional function can be perturbed by high-frequency rTMS as well as by low-frequency rTMS, despite potential differences in the underlying neural mechanisms. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Contributions of human parietal and frontal cortices to attentional control during conflict resolution: a 1-Hz offline rTMS study

Various brain regions contribute to aspects of attentional control in conflict resolution. Here, we used transcranial magnetic stimulation (TMS) to examine the functions of posterior parietal cortex (PPC) and dorsal medial frontal cortex (dMFC) in a visual flanker task. Participants responded to a central target that was flanked by congruent, neutral or incongruent stimuli on the left or right. Offline low-frequency repetitive TMS (1 Hz, 110% motor threshold, 20 min) was applied to right PPC or dMFC. Performance, as measured by reaction times and accuracy, was established at baseline, after rTMS, and sham stimulation before or after active rTMS. After rTMS to right PPC, the interference of flankers presented in the left visual hemispace diminished selectively. By contrast, after rTMS over the right dMFC, flanker effects in both visual fields remained. Our results suggest that right PPC specifically contributes to the assignment of spatial attention during stimulus encoding.     

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.     

Interaction between finger opposition movements and aftereffects of 1Hz-rTMS on ipsilateral motor cortex

One-hertz repetitive transcranial magnetic stimulation (1Hz-rTMS) over ipsilateral motor cortex is able to modify up to 30 min the motor performance of repetitive finger opposition movements paced with a metronome at 2 Hz. We investigated whether the long-lasting rTMS effect on motor behavior can be modulated by subsequent engagement of the contralateral sensorimotor system. Motor task was performed in different experimental conditions: immediately after rTMS, 30 min after rTMS, or when real rTMS was substituted with sham rTMS. Subjects performing the motor task immediately after rTMS showed modifications in motor behavior < or =30 min after rTMS. On the other hand, when real rTMS was substituted with sham stimulation or when subjects performed the motor task 30 min after the rTMS session, the effect was no longer present. These findings suggest that the combination of ipsilateral 1Hz-rTMS and voluntary movement is crucial to endure the effect of rTMS on the movement itself, probably acting on synaptic plasticity-like mechanism. This finding might provide some useful hints for neurorehabilitation protocols.     

High frequency repetitive transcranial magnetic over the medial cerebellum induces a shift in the prefrontal electroencephalography gamma spectrum: a pilot study in humans

In the present study the anatomical projections from the medial cerebellum to the prefrontal cortex (PFC) were investigated in healthy human subjects, using high frequency repetitive transcranial magnetic (rTMS) stimulation and electroencephalography (EEG). Medial cerebellar rTMS, compared to placebo induced a significant shift in anterior asymmetry, from left to right dominance in the fast (30-50 Hz) EEG spectrum, whereas occipital and lateral cerebellum stimulation did not show such an effect. Moreover elevations in mood and alertness were reported again after medial cerebellar stimulation only. Taken together, these data confirm and further specify the assumed cerebellar modulation of PFC activity and affect.     

Facilitating visuospatial attention for the contralateral hemifield by repetitive TMS on the posterior parietal cortex

Previous studies have demonstrated that repetitive transcranial magnetic stimulation (rTMS) could modulate the visuospatial functions. In this study, we investigated the effect of off-line high frequency subthreshold rTMS, when applied over the right or left posterior parietal cortex (PPC), on the visuospatial attention of the bilateral hemispaces. The subjects underwent visuospatial tasks before and immediately after receiving 1000 pulses of 10 Hz rTMS for a period of 20 min, and their responses were recorded. Our results demonstrated that the high frequency rTMS applied over the PPC produced facilitative effects on the visuospatial attention to the contralateral hemispace. The inhibitory effect to the ipsilateral hemispace was noticeable only in the left PPC.     

Repetitive TMS of cerebellum interferes with millisecond time processing

Time processing is important in several cognitive and motor functions, but it is still unclear how the human brain perceives time intervals of different durations. Processing of time in millisecond and second intervals may depend on different neural networks and there is now considerable evidence to suggest that these intervals are possibly measured by independent brain mechanisms. Using repetitive transcranial magnetic stimulation (rTMS), we determined that the cerebellum is essential in explicit temporal processing of millisecond time intervals. In the first experiment, subjects’ performance in a time reproduction task of short (400–600 ms) and long (1,600–2,400 ms) intervals, were evaluated immediately after application of inhibitory rTMS trains over the left and right lateral cerebellum (Cb) and the right dorsolateral prefrontal cortex (DLPFC). We found that rTMS over the lateral cerebellum impaired time perception in the short interval (millisecond range) only; for the second range intervals, impaired timing was found selectively for stimulation of the right DLPFC. In the second experiment, we observed that cerebellar involvement in millisecond time processing was evident when the time intervals were encoded but not when they were retrieved from memory. Our results are consistent with the hypothesis that the cerebellum can be considered as an internal timing system, deputed to assess millisecond time intervals.     

Impact of low frequency transcranial magnetic stimulation on event-related brain potentials

Contradictory findings exist concerning the inhibitory function of low frequency repetitive transcranial magnetic stimulation (rTMS). Therefore, the study examines the impact of different duration of low frequency rTMS on ERPs. In 17 subjects, auditory ERPs were measured before and after 1 Hz rTMS delivered over the left prefrontal cortex during 10 min (600 pulses) and 15 min (900 pulses). Results showed that 15 min of 1 Hz rTMS induced a significant increase of P300 latency. There was no effect for early ERP components (N100, P200 and N200). This study confirms and extends that 1 Hz rTMS produces a real inhibitory effect only when the duration of the stimulation is about 15 min. The data suggest that rTMS modifies the speed of cognitive processing rather than the energetical aspect of information processing, and that cortical inhibition induced by the magnetic stimulation affects principally the controlled cognitive processes and not the automatic ones.     

Persistent effects of high frequency repetitive TMS on the coupling between motor areas in the human

Repetitive transcranial magnetic stimulation (rTMS) shows promise as a treatment for various movement and psychiatric disorders. How rTMS may have persistent effects on cortical function remains unclear. We hypothesised that it may act by modulating cortico-cortical connectivity. To this end we assessed cortico-cortical coherence before and after high frequency rTMS of the motor cortex. Sixteen healthy subjects received a single train (5 Hz, active motor threshold, 50 stimuli) of rTMS to the left motor hand area. Spectral power and coherence estimates were calculated between different EEG signals at rest and while muscles of the distal upper limb were tonically contracted. Repetitive TMS over the left motor hand area caused a significant decrease in the intrahemispheric EEG-EEG coherence between motor and premotor cortex in the 10.7–13.6 Hz (upper alpha band) lasting a few minutes after stimulation. There was no significant change in interhemispheric EEG-EEG coherence between motor areas. Thus, high frequency rTMS of the motor cortex decreases ipsilateral cortico-cortical intrahemispheric in the upper alpha band. Electronic Publication     

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.     

Function of dog's auditory cortex in tests involving auditory location cues and directional instrumental response

Twenty one dogs, distributed into four groups, were trained pre-operatively in differentiation of auditory location or frequency cues. In each group instrumental responses, reinforced by food consisted in placing by the animal its right paw on the side levers. The first differentiation, go-left, go-right task with two location cues, required the animal to place its paw on the lever opposite to the source of the cue. The second differentiation task with the same location cues required placing the paw on the lever located close to the cue. The third task, involving 700 Hz vs. 1,000 Hz tone, required responding to one lever to the presentation of one tone and responding to the opposite lever to the presentation of the other. The last task was a symmetrically reinforced go, no-go differentiation with, again, auditory location cues: the animals were trained to place the paw on a lever to one location cue and to withhold this response to the other location cue. Bilateral ablation of the primary auditory cortex produced a considerable impairment of the performance of the two go-left, go-right tasks involving location cues. The go-left, go-right task employing frequency cues, and the symmetrically reinforced go, no-go task with location cues, were only slightly disturbed by this lesion.     

Repetitive transcranial magnetic stimulation interrupts phase synchronization during rhythmic motor entrainment

Rhythmic stimuli delivered through the auditory system can facilitate improved motor control following a motor impairment. The synchronization of movement to rhythmic auditory cues is characterized by quick, stable coupling of motor responses to rhythmic auditory cues. The exact neural sites responsible for this transformation of auditory input into timed rhythmic motor output are not clear. Neuroimaging studies have identified left ventral premotor cortex (vPMC) and left superior temporal-parietal (STP) activation during rhythmic auditory-motor synchronization. To investigate brain areas necessary for different types of rhythmic auditory-motor synchronization, we delivered repetitive transcranial magnetic stimulation (rTMS) to 15 healthy individuals prior to a rhythmic-auditory tapping task. Subthreshold rTMS was administered separately to the left vPMC and STP at a frequency of 0.9Hz for 15 min. Phase synchronization error (difference between auditory stimulus and response onsets) significantly increased after rTMS to STP as compared to baseline. Synchronization error also increased after rTMS to vPMC as compared to baseline, but not significantly. Absolute period error, (absolute difference between metronome interval and response interval) was not affected by rTMS. The significant effect of rTMS at the STP expands upon previous imaging research, suggesting that this area is part of the network responsible for rhythmic auditory-motor synchronization. The effect of rTMS on phase synchronization, but not period synchronization suggests these are separate neural processes controlled by different neural networks.     

High (15 Hz) and low (1 Hz) frequency transcranial magnetic stimulation have different acute effects on regional cerebral blood flow in depressed patients

BACKGROUND: High and low frequency repetititve transcranial magnetic stimulation (rTMS) are both effective in treating depression but have contrary effects on motor cortical activity. This study aimed to understand further the mechanisms of action of high and low frequency rTMS by examining their acute effects on regional cerebral blood flow (rCBF) in depressed patients. METHOD: Eighteen depressed subjects underwent brain single photon emission computerized tomography (SPECT) scanning using split-dose 99mTc-HMPAO, and were examined during sham and active rTMS to the left prefrontal cortex, at 15 Hz or 1 Hz (N=9 each). Relative rCBF changes were examined by statistical parametric mapping and by regions of interest analysis. RESULTS: High (15 Hz) frequency rTMS resulted in relative rCBF increases in the inferior frontal cortices, right dorsomedial frontal cortex, posterior cingulate and parahippocampus. Decreases occurred in the right orbital cortex and subcallosal gyrus, and left uncus. Low (1 Hz) frequency rTMS led to increased relative rCBF in the right anterior cingulate, bilateral parietal cortices and insula and left cerebellum. High frequency rTMS led to an overall increase, whereas low frequency rTMS produced a slight decrease, in the mean relative rCBF in the left dorsolateral prefrontal cortex. CONCLUSIONS: High (15 Hz) and low (1 Hz) frequency rTMS led to different frontal and remote relative rCBF changes, which suggests different neurophysiological and possibly neuropsychiatric consequences of a change in frequency of rTMS.     

Neuronavigation Increases the Physiologic and Behavioral Effects of Low-Frequency rTMS of Primary Motor Cortex in Healthy Subjects

Low-frequency repetitive transcranial magnetic stimulation (rTMS) can exert local and inter-hemispheric neuromodulatory effects on cortical excitability. These physiologic effects can translate into changes in motor behavior, and may offer valuable therapeutic interventions in recovery from stroke. Neuronavigated TMS can maximize accurate and consistent targeting of a given cortical region, but is a lot more involved that conventional TMS. We aimed to assess whether neuronavigation enhances the physiologic and behavioral effects of low-frequency rTMS. Ten healthy subjects underwent two experimental sessions during which they received 1600 pulses of either navigated or non-navigated 1 Hz rTMS at 90% of the resting motor threshold (RMT) intensity over the motor cortical representation for left first dorsal interosseous (FDI) muscle. We compared the effects of navigated and non-navigated rTMS on motor-evoked potentials (MEPs) to single-pulse TMS, intracortical inhibition (ICI) and intracortical facilitation (ICF) by paired-pulse TMS, and performance in various behavioral tasks (index finger tapping, simple reaction time and grip strength tasks). Following navigated rTMS, the amplitude of MEPs elicited from the contralateral (unstimulated) motor cortex was significantly increased, and was associated with an increase in ICF and a trend to decrease in ICI. In contrast, non-navigated rTMS elicited nonsignificant changes, most prominently ipsilateral to rTMS. Behaviorally, navigated rTMS significantly improved reaction time RT and pinch force with the hand ipsilateral to stimulation. Non-navigated rTMS lead to similar behavioral trends, although the effects did not reach significance. In summary, navigated rTMS leads to more robust modulation of the contralateral (unstimulated) hemisphere resulting in physiologic and behavioral effects. Our findings highlight the spatial specificity of inter-hemispheric TMS effects, illustrate the superiority of navigated rTMS for certain applications, and have implications for therapeutic applications of rTMS.