Long Intracortical Inhibition Research Articles

Prolonged continuous theta burst stimulation increases motor corticospinal excitability and intracortical inhibition in patients with neuropathic pain: An exploratory, single-blinded, randomized controlled trial

ObjectivesA new paradigm for Transcranial Magnetic Stimulation (TMS), referred to as prolonged continuous theta burst stimulation (pcTBS), has recently received attention in the literature because of its advantages over high frequency repetitive TMS (HF-rTMS). Clinical advantages include less time per intervention session and the effects appear to be more robust and reproducible than HF-rTMS to modulate cortical excitability. HF-rTMS targeted at the primary motor cortex (M1) has demonstrated analgesic effects in patients with neuropathic pain but their mechanisms of action are unclear and pcTBS has been studied in healthy subjects only. This study examined the neural mechanisms that have been proposed to play a role in explaining the effects of pcTBS targeted at the M1 and DLPFC brain regions in neuropathic pain (NP) patients with Type 2 diabetes. MethodsForty-two patients with painful diabetic neuropathy were randomized to receive a single session of pcTBS targeted at the left M1 or left DLPFC. pcTBS stimulation consisted of 1,200 pulses delivered in 1 min and 44 s with a 35–45 min gap between sham and active pcTBS stimulation. Both the activity of the descending pain system which was examined using conditioned pain modulation and the activity of the ascending pain system which was assessed using temporal summation of pain were recorded using a handheld pressure algometer by measuring pressure pain thresholds. The amplitude of the motor evoked potential (MEP) was used to measure motor corticospinal excitability and GABA activity was assessed using short (SICI) and long intracortical inhibition (LICI). All these measurements were performed at baseline and post-pcTBS stimulation. ResultsFollowing a single session of pcTBS targeted at M1 and DLPFC, there was no change in BPI-DN scores and on the activity of the descending (measured using conditioned pain modulation) and ascending pain systems (measured using temporal summation of pain) compared to baseline but there was a significant improvement of >13% in perception of acute pain intensity, increased motor corticospinal excitability (measured using MEP amplitude) and intracortical inhibition (measured using SICI and LICI). ConclusionIn patients with NP, a single session of pcTBS targeted at the M1 and DLPFC modulated the neurophysiological mechanisms related to motor corticospinal excitability and neurochemical mechanisms linked to GABA activity, but it did not modulate the activity of the ascending and descending endogenous modulatory systems. In addition, although BPI-DN scores did not change, there was a 13% improvement in self-reported perception of acute pain intensity.

117 The role of the cerebellum in cortical myoclonus: a neurophysiological study

ObjectiveTo investigate whether primary writing tremor (PWT) and dystonia share a common pathophysiology.BackgroundPWT is probably the most common form of task-specific tremor. Its pathophysiology is still debated and there is controversy about it being a type of focal dystonia, a variant of essential tremor or a separate entity.MethodsWe recruited 7 patients with PWT, who underwent the following neurophysiological tests: blink recovery cycle (BRC), eye-blink classical conditioning (EBCC), short and long-intracortical inhibition (SICI-LICI). Moreover, motor-evoked potentials (MEP), SICI and LICI were measured pre and post paired associative stimulation (PAS) plasticity paradigm. Data were compared with those obtained in 7 dystonic patients (DYT).ResultsData analysis for BRC showed a similar inhibition between DYT and PWT. There was no difference between DYT and PWT in the number of conditioned response (CR) during. Baseline SICI and LICI were similar in the two patients’ group, but whereas they were unchanged in PWT after PAS, they were reduced in DYT.ConclusionsThe present results suggest that PWT and DYT have similar brainstem excitability and associative learning. Cortical plasticity induced by PAS had a different effect on SICI and LICI in the two groups. Overall this data suggests that PWT and DYT share some pathophysiological mechanisms.a.latorre@ucl.ac.uk

250 Is primary writing tremor a forme fruste of dystonia?

ObjectiveTo investigate whether primary writing tremor (PWT) and dystonia share a common pathophysiology.BackgroundPWT is probably the most common form of task-specific tremor. Its pathophysiology is still debated and there is controversy about it being a type of focal dystonia, a variant of essential tremor or a separate entity.MethodsWe recruited 7 patients with PWT, who underwent the following neurophysiological tests: blink recovery cycle (BRC), eye-blink classical conditioning (EBCC), short and long-intracortical inhibition (SICI-LICI). Moreover, motor-evoked potentials (MEP), SICI and LICI were measured pre and post paired associative stimulation (PAS) plasticity paradigm. Data were compared with those obtained in 7 dystonic patients (DYT).ResultsData analysis for BRC showed a similar inhibition between DYT and PWT. There was no differ- ence between DYT and PWT in the number of conditioned response (CR) during. Baseline SICI and LICI were similar in the two patients’ group, but whereas they were unchanged in PWT after PAS, they were reduced in DYT.ConclusionsThe present results suggest that PWT and DYT have similar brainstem excitability and associa- tive learning. Cortical plasticity induced by PAS had a different effect on SICI and LICI in the two groups. Overall this data suggests that PWT and DYT share some pathophysiological mechanisms.a.latorre@ucl.ac.uk

Intracortical Inhibition in the Affected Hemisphere in Limb Amputation.

Phantom limb pain (PLP) affects up to 80% of amputees. Despite the lack of consensus about the etiology and pathophysiology of phantom experiences, previous evidence pointed out the role of changes in motor cortex excitability as an important factor associated with amputation and PLP. In this systematic review, we investigated changes in intracortical inhibition as indexed by transcranial magnetic stimulation (TMS) in amputees and its relationship to pain. Four electronic databases were screened to identify studies using TMS to measure cortical inhibition, such as short intracortical inhibition (SICI), long intracortical inhibition (LICI) and cortical silent period (CSP). Seven articles were included and evaluated cortical excitability comparing the affected hemisphere with the non-affected hemisphere or with healthy controls. None of them correlated cortical disinhibition and clinical parameters, such as the presence or intensity of PLP. However, most studies showed decreased SICI in amputees affected hemisphere. These results highlight that although SICI seems to be changed in the affected hemisphere in amputees, most of the studies did not investigate its clinical correlation. Thus, the question of whether they are a valid diagnostic marker remains unanswered. Also, the results were highly variable for both measurements due to the heterogeneity of study designs and group comparisons in each study. Although these results underscore the role of inhibitory networks after amputation, more studies are needed to investigate the role of a decreased inhibitory drive in the motor cortex to the cause and maintenance of PLP.

Spatiotemporal Dynamics of Single and Paired Pulse TMS-EEG Responses

For physiological brain function a particular balance between excitation and inhibition is essential. Paired pulse transcranial magnetic stimulation (TMS) can estimate cortical excitability and the relative contribution of inhibitory and excitatory networks. Combining TMS with electroencephalography (EEG) enables additional assessment of the spatiotemporal dynamics of neuronal responses in the stimulated brain. This study aims to evaluate the spatiotemporal dynamics and stability of single and paired pulse TMS-EEG responses, and assess long intracortical inhibition (LICI) at the cortical level. Twenty-five healthy subjects were studied twice, approximately one week apart. Manual coil positioning was applied in sixteen subjects and robot-guided positioning in nine. Both motor cortices were stimulated with 50 single pulses and 50 paired pulses at each of the five interstimulus intervals (ISIs): 100, 150, 200, 250 and 300 ms. To assess stability and LICI, the intraclass correlation coefficient and cluster-based permutation analysis were used. We found great resemblance in the topographical distribution of the characteristic TMS-EEG components for single and paired pulse TMS. Stimulation of the dominant and non-dominant hemisphere resulted in a mirrored spatiotemporal dynamics. No significant effect on the TMS-EEG responses was found for either stimulated hemisphere, time or coil positioning method, indicating the stability of both single and paired pulse TMS-EEG responses. For all ISIs, LICI was characterized by significant suppression of the late N100 and P180 components in the central areas, without affecting the early P30, N45 and P60 components. These observations in healthy subjects can serve as reference values for future neuropsychiatric and pharmacological studies.

P07-S Multimodal TMS has the potential to improve the diagnostic process in epilepsy

Background In epilepsy, a disturbed cortical excitability results in a predisposition to generate seizures. The limited diagnostic sensitivity of the electroencephalogram motivates the search for a novel biomarker. Transcranial magnetic stimulation (TMS) is a technique to assess cortical excitability. We used a multimodal TMS approach to evaluate differences between healthy controls, first seizure patients diagnosed with epilepsy and those without epilepsy. Methods We included twenty-one healthy subjects and twenty-one first seizure patients, of which seven were diagnosed with epilepsy. Both motor cortices were stimulated with 50 single pulses and 50 paired pulses at six interstimulus intervals (ISIs) between 50–300 As single pulse TMS readouts we analyzed amplitudes of the motor evoked potential (MEP) and TMS evoked potential (TEP). For paired pulse stimulation, we assessed long intracortical inhibition (LICI) of the MEP and TEP. Results We found no significant differences in MEP or TEP amplitudes using single pulse TCompared to healthy controls, epilepsy patients showed significantly increased LICI of the N100 and P180 components for ISI 200 Furthermore, we found facilitation at ISI 100 ms in epilepsy patients and inhibition in patients without epilepsy. Conclusions Multimodal TMS has the potential to improve the diagnostic process in epilepsy. Biomarkers include increased LICI at ISI 200 ms and facilitation at ISI 100 At a group level, paired pulse TMS differentiated between healthy controls, patients with epilepsy and patients without epilepsy. To establish the true potential, data of more patients is needed, which may enable analysis at the individual level.

Intracortical facilitation within the migraine motor cortex depends on the stimulation intensity. A paired-pulse TMS study

IntroductionConnectivity within the primary motor cortex can be measured using the paired-pulse transcranial magnetic stimulation (TMS) paradigm. This evaluates the effect of a first conditioning stimulus on the motor evoked potential (MEP) elicited by a second test stimulus when different interstimulus intervals are used. Aim of the present study was to provide, in patients suffering from migraine without aura (MwoA), additional information on intracortical facilitation (ICF), short intracortical inhibition (SICI), and long intracortical inhibition (LICI), using different intensities of the test stimulus (TS).MethodsWe enrolled 24 patients with episodic MwoA and 24 age- and sex-matched healthy volunteers. Both patients and controls were randomly assigned to two different experimental groups: the first group underwent evaluation of ICF, while in the second group we assessed SICI and LICI. All these measures were assessed by using three different suprathreshold intensities of the TS (110%, 130% and 150% of the resting motor threshold, RMT). Interstimulus intervals (ISIs) of 10 ms were used for testing ICF, while SICI and LICI were carried out by using 2 ms and 100 ms ISIs respectively. All migraine patients underwent the experimental protocol while in the interictal pain-free state.ResultsA main finding of the study was that an increased ICF could be seen in migraineurs as compared to the healthy subjects only by using a 110% intensity of the TS. Instead, no significant differences were observed between patients and controls as regards both measures of intracortical inhibition.ConclusionWe show that hyperresponsivity of the glutamatergic intracortical circuits can be detected in the migraine motor cortex only by applying a low suprathreshold intensity of stimulation. Our results strengthen the notion that, to be reliable, the assessment of cortical excitability in migraine should always include evaluation of the cortical response to different stimulation intensities.

Accurate Coil Positioning is Important for Single and Paired Pulse TMS on the Subject Level

Function-guided navigation is commonly used when assessing cortical excitability using transcranial magnetic stimulation (TMS). However, the required accuracy, stability and the effect of a change in coil positioning are not entirely known. This study investigates the accuracy of function-guided navigation for determining the hotspot. Furthermore, it evaluates the effect of a change in coil location on the single and paired pulse excitability measures: motor evoked potential (MEP) amplitude, TMS evoked potential (TEP) and long intracortical inhibition (LICI), and of a change in coil orientation on LICI. Eight healthy subjects participated in the single pulse study, and ten in the paired pulse study. A robot-guided navigation system was used to ensure accurate and stable coil positioning at the motor hotspot as determined using function-guided navigation. In addition, we targeted four locations at 2 mm and four at 5 mm distance around the initially defined hotspot, and we increased and decreased the coil orientation by 10°. In none of the subjects, the largest MEP amplitudes were evoked at the originally determined hotspot, resulting in a poor accuracy of function-guided navigation. At the group level, a change in coil location had no significant effect on the MEP amplitude, TEP, or LICI, and a change in coil orientation did not significantly affected LICI. However, at the subject level significant effects on MEP amplitude, TEP, and LICI were found for changes in coil location or orientation, although absolute differences were relatively small and did not show a consistent pattern. This study indicates that a high accuracy in coil positioning is especially required to measure cortical excitability reliably in individual subjects using single or paired pulse TMS.

S143. Brain plasticity marker in response to paired-pulse transcranial magnetic stimulation

Introduction Intracortical inhibition (ICI) and facilitation (ICF) in the primary motor cortex (M1) can be measured using a paired-pulse transcranial magnetic stimulation (ppTMS) protocol. The aim of the present study is to characterize the M1 connectivity (inhibition and facilitation) by means of navigated-ppTMS and cognitive assessment using the attention switching task (AST) through the Cambridge Neuropsychological Test Automated Battery. Methods We examined the responses of the left and right M1 to sub-threshold and supra-threshold single and pp stimulation in healthy (n = 50; 46% men; age, 35.5 ± 14.9 years) right-handed individuals using ppTMS. The subjects were evaluated using a combination of physiological motor evoked potentials (MEPs), motor threshold (MT), 3 ms intracortical inhibition (SICI), 7 ms and 12 ms ICF, and long intracortical inhibition (LICI) (100 ms). The cognitive function was evaluated using the AST. Results We report significant SICI (3 ms), ICF (12 ms), and LICI (100 ms) in the left and right hemispheres. We found significant differences in the right hemispheric cortico-spinal excitability (12 ms) between men and women. A correlation analysis revealed no significant relationship between AST performance and MEPs in subjects prior to and following ppTMS. Conclusion ppTMS is a promising tool to better characterize the regulation of the balance between inhibition and facilitation within the M1.

Neurophysiological and cognitive impairment following repeated sports concussion injuries in retired professional rugby league players

ABSTRACTBackground: Concussion is regarded as a common injury in rugby league, however no studies have explored the long-term neurophysiological and cognitive effects of repeated concussion injuries in this sport.Methods: Former professional rugby athletes (n = 25) were compared to 25 age-matched participants with no history of a concussion. All participants completed standardised motor dexterity, reaction time, and cognitive tasks for working memory, associative learning and rule acquisition and reversal. Single-pulse transcranial magnetic stimulation (TMS) acquired motor evoked potentials and cortical silent period (cSP), as well as paired-pulse TMS for short latency intracortical inhibition and long intracortical inhibition (LICI).Results: Compared to controls, dexterity and visuomotor reaction time was slower in the rugby group compared to controls (p = 0.02, p < 0.01, respectively). The rugby group also demonstrated poorer cognitive performance than controls (p range 0.02 to < 0.01). TMS revealed significantly reduced cSP at suprathreshold stimulation intensities (p range 0.02 to <0.01), and increased LICI (p = 0.03) in the rugby group.Discussion: These findings of motor and cognitive changes, along with neurophysiological alterations, particularly with intracortical inhibition, nearly two decades post-concussion provides evidence for long-term sequelae for athletes with a history of repeated head trauma in contact sports.

P149 Reproducibility of the long intracortical inhibition curve in healthy subjects

Introduction Over the last decades, transcranial magnetic stimulation (TMS) has been used to assess cortical excitability in a variety of neuropsychiatric conditions, e.g. epilepsy, dementia and depression. To detect changes in excitability in longitudinal studies, it is important to validate the repeatability of TMS outcomes for the same subject between different sessions. Previous studies in healthy subjects found mixed degrees of reproducibility, ranging from poor to good agreement Badawy et al., 2012 , Du et al., 2014 . Especially, the long intracortical inhibition (LICI) curve showed a large variability across sessions (Du et al., 2014) . Objective To evaluate the reproducibility of the LICI curve in healthy subjects using paired pulse TMS. Subjects & methods Twenty-seven healthy subjects were studied two times ( ± 1 week apart) with paired pulse TMS combined with electromyography. Both motor hot spots (abductor digiti minimi) were stimulated with 50 paired pulses (intensity 120% of resting motor threshold) at interstimulus intervals (ISIs): 100, 150, 200, 250 and 300 ms. In nineteen subjects a figure-of-eight coil was positioned and held in place manually during both sessions, while in eight subjects a robotic arm was used. The concordance correlation coefficient (rho-c) was used to estimate the agreement between repeated sessions (Lin, 1989) . Results The average LICI curve among all subjects showed a close agreement between TMS sessions for manual (rho-c = 0.88) and robot-guided (rho-c = 0.95) positioning. However, the reproducibility decreased when individual LICI curves were compared; manual (rho-c = 0.66) and robot-guided (rho-c = 0.86). There was a large variation in reproducibility between subjects, ranging from poor to good levels of agreement. Additionally, moderate levels of agreement and a large variation was found for individual ISIs: manual (range rho-c: 0.42–0.55) versus robot-guided (range rho-c: 0.62–0.89). Conclusion Reproducibility of LICI curves was highly variable between healthy subjects. Good levels of agreement were found for analysis on group levels, but reproducibility decreased for the level of individual subjects or ISIs. Overall, reproducibility of the LICI curve was higher for robot-guided than for manual coil positioning.

P235 Variation during the day of the TMS-EEG evoked potential

Introduction When applying concurrent TMS-EEG, a characteristic waveform – the TMS evoked potential (TEP) – can be measured. The amplitude of an early TEP component (∼20 ms) increased with time awake in healthy subjects ( Huber et al., 2012 ), and long intracortical inhibition (LICI) decreased ( Lang et al., 2011 ), both suggesting an increase in excitability during the day. Excitability was found to be higher in the morning compared to the evening in generalized epilepsy patients ( Badawy et al., 2009 ). For TMS to be of clinical diagnostic use, these diurnal changes should be smaller than the difference in response between epilepsy patients and controls. We studied the influence of the time of day on the overall TEP in healthy controls, using five sessions on one day. Objectives To study the variation of the TEP during the day when stimulating the motor and visual cortex. Subjects and methods TMS-EEG was recorded in 15 healthy subjects using a Magstim Rapid2 stimulator and a 64-channel EEG amplifier (ANT Neuro, Enschede). TMS was targeted at four brain regions: left and right motor cortex (MC), and left and right Brodmann area 19 (B19). At each target, we administered 75 pulses at an intensity of 110% resting motor threshold. Subjects were stimulated during five sessions in one day (8:00 AM, 10:30 AM, 13:00 PM, 15:30 PM and 18:00 PM) while keeping the stimulation intensity constant. Trials were averaged to obtain the TEP. We compared the TEP waveforms between the five sessions with a cluster-based permutation analysis using a dependent t-test and correcting for multiple comparisons (Bonferroni). Results TEPs with components N15, P30, N45, P60, N100 and P180 were present in all subjects after stimulating the MC. The TEP after B19 stimulation consisted of the components N5, P25, N40, P50, N75, P120, N160 and P200. There were no significant differences between the five sessions for both MC and B19 stimulation. Conclusion The TEP is highly reproducible during the day. We found no significant variation of the overall TEP between multiple sessions on one day.

Repeatability of long intracortical inhibition in healthy subjects

ObjectivesTranscranial magnetic stimulation (TMS) is widely used to assess cortical excitability. To detect changes in excitability with longitudinal studies, it is important to validate the repeatability of excitability measures within a subject between different sessions. Repeatability studies on long intracortical inhibition (LICI) are limited and reported agreement ranges from poor to good. This study aims to evaluate the repeatability of LICI in healthy subjects using paired pulse TMS. In addition, it investigates whether LICI repeatability differs for manual and robot-guided coil positioning. MethodsThirty healthy subjects (10 males, mean age 28.4±8.2years) were studied twice, approximately one week apart. Both motor cortices were stimulated with 50 paired pulses (intensity 120% of resting motor threshold) at interstimulus intervals (ISIs): 50, 100, 150, 200, 250 and 300ms. In twenty subjects a figure-of-eight coil was positioned and held in place manually during both sessions, while in ten subjects a robot-navigated arm was used. LICI repeatability was assessed using the intraclass correlation coefficient (ICC). ResultsFor manual and robot-guided coil positioning we found a large variation in repeatability at the subject level and ISI level, ranging from poor to good agreement. On a group level, we found good repeatability for averaged LICI curves (manual: ICC=0.91, robot-guided: ICC=0.95), which decreased when individual curves were correlated between sessions (manual: ICC=0.76, robot-guided: ICC=0.84). ConclusionFor a correct interpretation of longitudinal study outcomes it is important to know the subject specific LICI repeatability and to analyze each ISI individually. Furthermore, the added value of robot-guided coil positioning for paired pulse TMS seems limited. SignificanceThe large variation in LICI repeatability at the subject level and ISI level should be taken into account in longitudinal studies, while robot-guided coil positioning seems unnecessary.

Single and paired pulse transcranial magnetic stimulation in drug naïve epilepsy

Transcranial magnetic stimulation (TMS) measures cortical excitability and is therefore potentially suitable as an additional tool for epilepsy diagnostics and therapy evaluation. In this review we discuss the application of TMS in epilepsy research and systematically analyze single and paired pulse TMS outcomes from 31 drug naïve patient studies. Despite a large variety in used TMS protocols, there was no relation between specific protocol aspects and the occurrence of significant results. Protocols were often not in accordance with latest guidelines and recommendations. Cortical excitability, as measured by TMS, was increased in drug naïve epilepsy patients, being most prominent for generalized epilepsy. Single pulse TMS indicated a trend towards a lower resting motor threshold (rMT) and a prolonged cortical silent period (CSP) for generalized epilepsy, while inconclusive results were found for focal epilepsy. The paired pulse TMS outcomes, short intracortical inhibition (SICI) and long intracortical inhibition (LICI), showed the most consistent significant increase in cortical excitability in generalized and focal epilepsy patients. Future epilepsy research should especially focus on the interstimulus intervals 2 and 5ms for SICI, and 250 and 300ms for LICI. Furthermore, combining TMS with electroencephalography (EEG) may contribute to analysis on an individual patient level.

Short- and Long-Intracortical Inhibition in Incomplete Spinal Cord Injury

Short- (SICI) and long-interval intracortical inhibition (LICI) are involved in the control of movement and movement initiation. Alterations to the two circuits can result in direct alterations to the physiology of the muscles and can be used to explain the physiological changes to individuals with spinal cord injury (SCI). To probe changes in GABAergic function by characterizing the recruitment curves of SICI and LICI interval intracortical inhibition in an upper limb muscle in chronic SCI participants with injury between C3 and C7. Recruitment curves were elicited with conditioning stimulus intensities determined as a percentage of active motor threshold (AMT) (SICI, 60% to 110% AMT; LICI, 90% to 130% AMT) and recorded from the flexor carpi radialis muscle during an isometric contraction equal to 15% to 20% of maximum voluntary contraction. AMT was greater and motor-evoked potential sizes were lower in SCI compared with uninjured controls. SICI magnitude was not different between groups, although the range of conditioning stimulus intensities to evoke SICI was unique to each group. LICI was reduced in the control group during active contraction and remained present in SCI. LICI was increased in the actively contracted flexor carpi radialis muscle in individuals with SCI compared with age-matched controls. These findings indicate that GABAB function mediating LICI is different in SCI versus controls. Increased LICI in SCI may be attributed to the medication baclofen or to changes in the neural mechanisms controlling contraction-related modulation of the LICI circuit.

Neural mechanisms underlying the changes in ipsilateral primary motor cortex excitability during unilateral rhythmic muscle contraction

The aim of this study was to investigate the neural mechanisms underlying the changes in the ipsilateral primary motor cortex (ipsi-M1) excitability induced during the unilateral rhythmic muscle contraction of the first dorsal interosseous (FDI) (rhythmic contraction) muscle with three different frequencies of auditory cues (1, 2, and 3Hz). The effect of different frequencies of unilateral rhythmic contraction on changes in the ipsi-M1 excitability was assessed using a single-pulse transcranial magnetic stimulation (TMS) technique when subjects were performing the unilateral rhythmic contractions according to each auditory cue frequency. After that, the changes in short intracortical inhibition (SICI)/facilitation (ICF), long intracortical inhibition (LICI) within the ipsi-M1, and interhemispheric inhibition (IHI), as well as dorsal premotor cortex to M1 (PMd–M1), and dorsolateral prefrontal cortex to M1 (DLPFC-M1) connectivity from the contralateral hemisphere to the ipsi-M1 were assessed using paired-pulse TMS techniques. The motor evoked potentials (MEP) induced in the right FDI were recorded. In the results, the ipsi-M1 excitability induced in response to single-pulse TMS was significantly decreased in the 2Hz conditions, compared with the 1Hz and 3Hz conditions. Furthermore, PMd–M1 connectivity and LICI were significantly modulated depending on the frequency of the unilateral rhythmic contraction. In contrast, the changes in the SICI, ICF, IHI, and DLPFC–M1 were not directly associated with the rhythm frequency. These results suggest that PMd–M1 connectivity and LICI within the ipsi-M1 are likely to preferentially operate to modulate ipsi-M1 excitability during the performance of unilateral rhythmic contraction with different frequencies.

Non-homogeneous effect of levodopa on inhibitory circuits in Parkinson's disease and dyskinesia

IntroductionLevodopa-induced dyskinesia in patients with Parkinson's disease (PD) has been shown to be associated with an abnormal plasticity in the motor cortex. We investigated whether changes in the excitability of inhibitory and excitatory motor circuits could underlie maladaptive mechanisms associated with dyskinesia. MethodsUsing single and paired transcranial magnetic stimulation (TMS), we studied motor threshold, silent period (SP) duration, intracortical facilitation (ICF), short intracortical inhibition (SICI) and low- and high-intensity long intracortical inhibition (LICI) in 10 dyskinetic and 10 non-dyskinetic patients, matched for disease and treatment duration, before (OFF state) and after (ON state) levodopa, and in 10 healthy controls. ResultsIn the OFF state, the two groups of patients showed similar motor cortex excitability with a reduced SICI compared to controls. LICI was weaker and increasing stimulation intensity had a lower effect on SP duration in dyskinetic patients than in controls. In dyskinetic patients, in contrast to non-dyskinetic patients, levodopa failed to increase SICI and SP duration, and potentiated to a lesser extent the effect of increasing the stimulation intensity on LICI. Although levodopa improved motor symptoms to a similar extent in both dyskinetic and non-dyskinetic patients, it failed to activate effectively the excitability of the inhibitory systems in dyskinetic patients. DiscussionThese findings suggest that dyskinesia is associated with an abnormal effect of levodopa on cortical motor inhibitory circuits.

Changes in intracortical circuits of the human motor cortex following theta burst stimulation of the lateral cerebellum

Objective The cerebellum takes part in several motor functions through its influence on the motor cortex (M1). Here, we applied the theta burst stimulation (TBS) protocol, a novel form of repetitive Transcranial Magnetic Stimulation (rTMS) over the lateral cerebellum. The aim of this study was to test whether TBS of the lateral cerebellum could be able to modulate the excitability of the contralateral M1 in healthy subjects. Methods Motor-evoked potentials (MEPs) amplitude, short intracortical inhibition (SICI), long intracortical inhibition (LICI) and short intracortical facilitation (SICF) were tested in the M1 before and after cerebellar continuous TBS (cTBS) or intermittent TBS (iTBS). Results We found that cTBS induced a reduction of SICI and an increase of LICI. On the other hand, cerebellar iTBS reduced LICI. MEPs amplitude also differently vary following cerebellar stimulation with cTBS or iTBS, resulting in a decrease by the former and an increase by the latter. Conclusions Although the interpretation of these data remains highly speculative, these findings reveal that the cerebellar cortex undergoes bidirectional plastic changes that modulate different intracortical circuits within the contralateral primary motor cortex. Significance Long-lasting modifications of these pathways could be useful to treat various pathological conditions characterized by an altered cortical excitability.

Motor intracortical inhibition in PD: L-DOPA modulation of high-frequency rTMS effects

Dopaminergic drugs and deep brain stimulation restore cortical inhibition in Parkinson disease (PD) patients. High-frequency rTMS was also found to increase cortical inhibition in PD but its therapeutic effect is still controversial. Here we hypothesize that, if dopaminergic drugs reverse to normal cortical excitability in M1, the effect of high-frequency (hf)-rTMS in PD patients could depend on whether they are in a medicated or unmedicated state. The present study aims to explore the lasting effects of sub-threshold hf rTMS trains over M1 on cortical inhibition in patients with "on" and without "off" L-DOPA treatment. Fourteen PD patients were examined twice while "on" and "off" medication. In both conditions, a paired-pulse paradigm was used to evaluate short intracortical inhibition (SICI) and long intracortical inhibition (LICI) that were evaluated before and after hf rTMS trains applied on the motor cortex. The results were compared with those obtained from normal controls. In baseline condition, SICI and LICI were significantly reduced in "off" compared to "on" patients and controls. hf-rTMS over the motor cortex significantly increased SICI and LICI in "off" medication PD patients. Magnetic stimulation proved to be ineffective when the same patients were in "on" state. The results showed that hf-rTMS affected intracortical inhibition (ICI) only in unmedicated patients. By restoring cortical inhibitory circuits dopaminergic drugs, normalize the excitability changes in M1 subsequent to motor rTMS. Whether patients are in a medicated or an unmedicated state would therefore appear to be critical for rTMS effects in PD patients. If a positive correlation exists between increased cortical inhibition and clinical improvement, hf-rTMS during the "off" state could be regarded as a potential add-on treatment to reduce the need of L-dopa and thus delay the adverse effects of its chronic use.

Corticospinal disinhibition in paroxysmal kinesigenic dyskinesia

Objective To investigate the underlying mechanism responsible for paroxysmal kinesigenic dyskinesia (PKD). Methods We performed a transcranial magnetic stimulation (TMS) study in 12 drug-naïve patients with PKD and 10 healthy volunteers. TMS parameters included resting motor threshold, recruitment curve of motor evoked potential amplitudes, short intracortical inhibition and facilitation, long intracortical inhibition (LICI), and silent period. We also measured compound muscle action potential. Results LICI, representing GABA-mediated inhibition, was significantly reduced in the patients ( P=0.033), while results for all other TMS parameters tested were comparable between the two groups. Conclusions and significance These results suggest that a specific type of corticospinal inhibitory mechanism is impaired in patients with PKD.