Holger Rothkegel

Breaks during 5 Hz rTMS are essential for facilitatory after effects

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.

Right-shift for non-speech motor processing in adults who stutter

INTRODUCTION In adults who do not stutter (AWNS), the control of hand movement timing is assumed to be lateralized to the left dorsolateral premotor cortex (PMd). In adults who stutter (AWS), the network of speech motor control is abnormally shifted to the right hemisphere. Motor impairments in AWS are not restricted to speech, but extend to non-speech orofacial and finger movements. We here investigated the lateralization of finger movement timing control in AWS. METHODS We explored PMd function in 14 right-handed AWS and 15 age matched AWNS. In separate sessions, they received subthreshold repetitive transcranial magnetic stimulation (rTMS) for 20 min at 1Hz over the left or right PMd, respectively. Pre- and post-stimulation participants were instructed to synchronize their index finger taps of either hand with an isochronous sequence of clicks presented binaurally via earphones. Synchronization accuracy was measured to quantify the effect of the PMd stimulation. RESULTS In AWNS inhibition of left PMd affected synchronization accuracy of the left hand. Conversely, in AWS TMS over the right PMd increased the asynchrony of the left hand. CONCLUSIONS The present data indicate an altered functional connectivity in AWS in which the right PMd seems to be important for the control of timed non-speech movements. Moreover, the laterality-shift suggests a compensatory role of the right PMd to successfully perform paced finger tapping.

Dopaminergic potentiation of rTMS-induced motor cortex inhibition.

BACKGROUND Experiments in animal models suggest that neuronal plasticity can be enhanced by dopaminergic receptor activation. The present study tested whether stimulation-induced plasticity of human motor cortex after low-frequency repetitive transcranial magnetic stimulation (rTMS) could be potentiated by a single oral dose of the combined D1/D2 receptor agonist pergolide. METHODS In a randomized, double-blind, placebo-controlled cross-over design, nine healthy young volunteers received .125 mg pergolide or placebo 2 hours before 1 Hz rTMS was applied for 20 min to the left primary motor cortex. In a control experiment 7 subjects received .125 mg pergolide 2 hours before sham rTMS. We used single-pulse TMS at rest to assess corticospinal excitability before and up to 24 min after rTMS. RESULTS Suppression of corticospinal excitability by 1 Hz rTMS was more pronounced after pergolide intake compared with placebo and lasted approximately 20 min after pergolide but only 5 min after placebo. No change of corticospinal excitability could be observed when sham rTMS was performed after pergolide intake. CONCLUSIONS The results suggest a possible role for dopaminergic potentiation of rTMS-induced neuroplasticity in experimental or therapeutic applications and should be considered when rTMS is applied in patients under medication with dopamine agonists or antagonists.

Training effects outweigh effects of single-session conventional rTMS and theta burst stimulation in PD patients.

Background. Focal single-session repetitive transcranial magnetic stimulation (rTMS) of the primary motor cortex has been claimed to be capable of improving motor function in Parkinsons disease. Objective. The authors sought to determine which type of rTMS protocol holds the highest potential for future therapeutic application. Methods. Twenty-two patients with Parkinsons disease received 5 different rTMS protocols on 5 consecutive days in a pseudorandomized and counterbalanced order either in the defined OFF condition or with their usual medication. The protocols tested in the present study included 2 conventional rTMS protocols (0.5 and 10 Hz) as well as the recently introduced theta burst stimulation (cTBS, iTBS) and a sham condition. Cortical excitability, motor performance (pointing movement, pronation-supination, Purdue Pegboard Test, walking), and mood were assessed before and after each session. Results . The authors observed motor training from days 1 to 4, particularly in the group on dopaminergic medication. None of the rTMS paradigms excelled placebo stimulation. The only exception was the Purdue Pegboard Test, in which all active stimulation paradigms yielded slightly stronger effects than sham stimulation. Conclusions. Within a single session, no clinically relevant difference in the rTMS protocols could be detected. Training effects outweigh and may have masked rTMS effects, particularly in the group on dopaminergic mediation.

Opposite Optimal Current Flow Directions for Induction of Neuroplasticity and Excitation Threshold in the Human Motor Cortex

BACKGROUND Directional sensitivity is relevant for the excitability threshold of the human primary motor cortex, but its importance for externally induced plasticity is unknown. OBJECTIVE To study the influence of current direction on two paradigms inducing neuroplasticity by repetitive transcranial magnetic stimulation (rTMS). METHODS We studied short-lasting after-effects induced in the human primary motor cortex of 8 healthy subjects, using 5 Hz rTMS applied in six blocks of 200 pulses each, at 90% active motor threshold. We controlled for intensity, frequency, waveform and spinal effects. RESULTS Only biphasic pulses with the effective component delivered in an anterioposterior direction (henceforth posteriorly directed) in the brain yielded an increase of motor-evoked potential (MEP) amplitudes outlasting rTMS. MEP latencies and F-wave amplitudes remained unchanged. Biphasic pulses directed posteroanterior (i.e. anteriorly) were ineffective, as were monophasic pulses from either direction. A 1 Hz study in a group of 12 healthy subjects confirmed facilitation after posteriorly directed biphasic pulses only. CONCLUSIONS The anisotropy of the human primary motor cortex is relevant for induction of plasticity by subtreshold rTMS, with a current flow opposite to that providing lowest excitability thresholds. This is consistent with the idea of TMS primarily targeting cortical columns of the phylogenetically new M1 in the anterior bank of the central sulcus. For these, anteriorly directed currents are soma-depolarizing, therefore optimal for low thresholds, whereas posteriorly directed currents are soma-hyperpolarizing, likely dendrite-depolarizing and bested suited for induction of plasticity. Our findings should help focus and enhance rTMS effects in experimental and clinical settings.

H-coil: Induced electric field properties and input/output curves on healthy volunteers, comparison with a standard figure-of-eight coil

OBJECTIVE To acquire information about the physical properties and physiological effects of the H-coil. METHODS We used a robotized system to measure the electric field (E-field) generated by a H-coil prototype and compared it with a standard figure-of-eight coil. To explore the physiological properties of the coils, input/output curves were recorded for the right abductor digiti minimi muscle (ADM) as target muscle. To explore focality of stimulation, simultaneous recordings were performed for the left ADM, right abductor pollicis brevis (APB), extensor digitorum communis (EDC) and biceps brachii (BB) muscles. RESULTS Physical measurements of the H-coil showed four potentially stimulating foci, generating different electric field intensities along two different spatial orientations. RMT was significantly lower for H-coil- as compared to figure-of-eight coil stimulation. When stimulation intensity for the input-output curve was determined by percent of maximum stimulator output, the H-coil produced larger MEPs in the right ADM, as compared to the figure-of-eight coil, due to the larger relative enhancement of stimulation intensity of the H-coil. When stimulation intensity was adjusted to RMT, MEPs elicited at the right ADM were larger for figure-of-eight coil than for H-coil stimulation, while this relation was reversed for distant non-target muscles, with low stimulation intensities. With high stimulation intensities, the H-coil elicited larger MEPs for all tested muscles. Onset latency of the MEPs was never shorter for H-coil than for figure-of-eight coil stimulation of the target muscles. CONCLUSIONS These results are in favor for a non-focal, but not deeper effect of the H-coil, as compared to a figure-of-eight coil. SIGNIFICANCE This is the first neurophysiological study exploring the focality and depth of stimulation delivered by the H-coil systematically in humans. We found no advantage of this coil with regard to depth of stimulation in comparison to the figure-of-eight coil. Future studies have to show if the non-focality of this coil differs relevantly from that of other non-focal coils, e.g. the round coil.

The effect of rTMS over left and right dorsolateral premotor cortex on movement timing of either hand

It has been suggested that the left dorsolateral premotor cortex (dPMC) controls timing abilities of either hand. To further clarify its functional significance for movement timing, low‐frequency repetitive transcranial magnetic stimulation (rTMS) was applied over the left and right dPMC, respectively, while subjects performed an auditorily paced finger‐tapping task with each hand. rTMS over the left dPMC decreased tapping accuracy of both hands, whereas no behavioural effects occurred following right dPMC stimulation. To elucidate the time window in which left dPMC TMS disturbs synchronization abilities, pairs of TMS pulses were applied over the left dPMC and the left anterior parietal cortex serving as control condition. TMS pulses were applied randomly at 40 ms, 80 ms, 120 ms, 160 ms, 200 ms and 240 ms before pacer onset, as taps precede the pacing signal for about 20–60 ms. Again, the analysis revealed that TMS over the left dPMC disturbed synchronization abilities of either hand; however, this effect was shown at different times suggesting that the left dPMC affects the right M1 via at least one additional relay station. The present data support the hypothesis that the left dPMC is crucial for accurate timing of either hand. Additionally, they reveal a piece of evidence that the left dPMC affects the left hand not via a direct left dPMC–right M1 connection.

Impact of pulse duration in single pulse TMS

OBJECTIVE The intensity of transcranial magnetic stimulation (TMS) is typically adjusted by changing the amplitude of the induced electrical field, while its duration is fixed. Here we examined the influence of two different pulse durations on several physiological parameters of primary motor cortex excitability obtained using single pulse TMS. METHODS A Magstim Bistim(2) stimulator was used to produce TMS pulses of two distinct durations. For either pulse duration we measured, in healthy volunteers, resting and active motor thresholds, recruitment curves of motor evoked potentials in relaxed and contracting hand muscles as well as contralateral (cSP) and ipsilateral (iSP) cortical silent periods. RESULTS Motor thresholds decreased by 20% using a 1.4 times longer TMS pulse compared to the standard pulse, while there was no significant effect on threshold adjusted measurements of cortical excitability. The longer pulse duration reduced pulse-to-pulse variability in cSP. CONCLUSIONS The strength of a TMS pulse can be adjusted both by amplitude or pulse duration. TMS pulse duration does not affect threshold-adjusted single pulse measures of motor cortex excitability. SIGNIFICANCE Using longer TMS pulses might be an alternative in subjects with very high motor threshold. Pulse duration might not be relevant as long as TMS intensity is threshold-adapted. This is important when comparing studies performed with different stimulator types.

Increasing human leg motor cortex excitability by transcranial high frequency random noise stimulation.

PURPOSE Transcranial random noise stimulation (tRNS) can increase the excitability of hand area of the primary motor cortex (M1). The aim of this study was to compare the efficacy of tRNS and transcranial direct current stimulation (tDCS) on the leg motor cortex. METHOD Ten healthy subjects received anodal, cathodal tDCS, tRNS and sham stimulation for 10 min using 2 mA intensity during separate experimental sessions. Single pulse transcranial magnetic stimulation (TMS) induced motor evoked potential (MEP) measurements were used to assess motor cortical excitability changes after the stimulation. RESULTS Similar to the hand area, we found that both tRNS and anodal tDCS induced an increase of the amplitude of the MEPs. Anodal tDCS induced a constant gradual increase of corticospinal excitability until 60 min post-stimulation, whereas the effect of tRNS was immediate with a duration of 40 min following stimulation. The cathodal tDCS induced decrease in MEP amplitude did not reach statistical significance. CONCLUSION Our results suggest that although the leg area has a deeper position in the cortex compared to the hand area, it can be reached by weak transcranial currents. Both anodal tDCS and tRNS had comparable effect on cortical excitability.

Minocycline exerts acute inhibitory effects on cerebral cortex excitability in humans

Minocycline has efficacy to alleviate seizure activity in animal models of epilepsy. Among other mechanisms it has been postulated that minocycline can inhibit microglial activation and develop beneficial effects by decreasing glutamate excitotoxicity. To explore acute effects of minocycline on human motor cortex excitability we used single- and paired-pulse transcranial magnetic stimulation in 12 healthy subjects 4h after a single oral dose of 200mg minocycline or placebo was administered in a randomised, double-blind, placebo-controlled crossover design. Mean cortical silent period, an inhibitory parameter of predominantly intracortical origin, was prolonged after minocycline compared to placebo, while other TMS parameters of cortical excitability remained unchanged. The results demonstrate that a particular parameter of cortical inhibition is rapidly increased after a single oral dose of minocycline in humans.