Short-latency Intracortical Inhibition Research Articles

Motorcortical Excitability and Synaptic Plasticity Is Enhanced in Professional Musicians

Musicians not only have extraordinary motor and sensory skills, but they also have an increased ability to learn new tasks compared with non-musicians. We examined how these features are expressed in neurophysiological parameters of excitability and plasticity in the motor system by comparing the results of 11 professional musicians and 8 age-matched non-musicians. Parameters of motor excitability were assessed using transcranial magnetic stimulation (TMS) to measure motor-evoked potentials (MEPs) together with recruitment of corticospinal projections [input-output curve (IOcurve)] and of short-latency intracortical inhibition (SICIcurve). Plasticity, here defined as change of synaptic effectiveness, was tested by measuring MEPs and IOcurves after paired associative stimulation (PAS), which consists of an electric median nerve stimulus repeatedly paired (200 times at 0.25 Hz) with a TMS pulse over the hand motor area. Using an interstimulus interval of 25 ms (PAS25) or 10 ms (PAS10), this leads to long-term potentiation- or long-term depression-like plasticity, respectively. Musicians showed steeper recruitment of MEPs and SICI (IOcurve and SICIcurve). Additionally, PAS25 increased and PAS10 decreased the MEP amplitudes and the slope of the IOcurves significantly more in musicians than in non-musicians. This is consistent with a wider modification range of synaptic plasticity in musicians. Together with the steeper recruitment of corticospinal excitatory and intracortical inhibitory projections, this suggests that they regulate plasticity and excitability with a higher gain than normal. Because some of these changes depend on age at which instrumental playing commenced and on practice intensity, they may reflect an increase in number and modifiability of synapses within the motor area caused by long-term musical practice.

Cortical excitability predicts seizures in acutely drug-reduced temporal lobe epilepsy patients

To test the hypothesis that cortical excitability changes prior to seizures, using transcranial magnetic brain stimulation (TMS). We studied 18 patients with unilateral temporal lobe epilepsy (TLE) twice using TMS: prior to (day 1) and following (day 3) reduction of antiepileptic drugs in a monitored inpatient setting. Short-latency intracortical inhibition (SICI) and intracortical facilitation (ICF) were measured. Time since most recent seizure prior to day 1, and time until next seizure after day 3, were recorded. On day 1, prior to antiepileptic drug withdrawal, there were no correlations with recent or next seizures. On day 3, patients who had seizures in the subsequent 48 hours had weaker SICI and ICF in the hemisphere ipsilateral to seizure onset, vs patients who did not have seizures in the next 48 hours (p = 0.033). Additionally on day 3, there was a strong correlation between the difference between ICF and SICI in the ipsilateral hemisphere and time to next seizure (p < 0.001). Change in cortical excitability, measured with transcranial magnetic brain stimulation, may reflect a long-lasting and widespread pre-ictal state.

Motor cortex inhibitory circuits in dementia with Lewy bodies and in Alzheimer’s disease

To determine whether a peculiar neurophysiological profile may contribute to characterize dementia with Lewy bodies (DLB) vs. Alzheimer disease (AD), we used transcranial magnetic stimulation to examine the excitability of two different inhibitory systems of the motor cortex, short latency intracortical inhibition (SICI) and short latency afferent inhibition (SAI) in 10 patients with DLB, in 13 patients with AD and in 15 healthy subjects. SICI and SAI were significantly reduced in AD patients, while both were not significantly different from the controls in DLB patients. The differential pattern of SICI and SAI exhibited by AD vs. DLB may have diagnostic significance in discriminating DLB from AD. Furthermore, this technique may help to clarify the pathophysiological entity of DLB; since SAI is a cortical phenomenon that depends on central cholinergic activity, our findings suggest that the mechanisms of cholinergic depletion in DLB may be different from that in AD, while normal SICI may reflect a less pronounced dysregulation of the intracortical GABAergic inhibitory circuitries in DLB.

FC14.4 Short-latency intracortical inhibition preceding movement: Different time-course of modulation during simple and choice reaction time

Background: Motor preparation is associated with excitability changes along the corticospinal tract. In simple reaction time task (SRT), the motor-evoked potentials (MEP) to transcranial magnetic stimulation (TMS) are facilitated before onset of EMGactivity (EMGonset), and the short-latency intracortical inhibition (SICI) is reduced preceding the facilitatory changes.We examined the timing of those neural processes in choice reaction time task (CRT). Aim: To identify potential differences in SICI during SRT and CRT paradigms. Patients/Methods: Five subjects were requested to perform a hand pinch in response to a visual stimulus in the context of SRT/CRT paradigms. MEPs were recorded from the first dorsal interosseous. TMS was applied over the contralateral hand area at an intensity of 0.95 active motor threshold for conditioning stimuli and 1.2 resting motor threshold for test stimuli. We obtained sets of responses combining single and paired (interstimulus interval 2.5 ms) stimuli with control and movement trials. Test stimuli were applied at 100, 75, 50 and 25 ms with respect to EMGonset. We used ANOVA to determine the differences between control and test trials. Results: During SRT, significant reduction of SICI with respect to baseline values occurred at 50 ms before EMGonset, while MEP facilitation started 25 ms later. Reduction of SICI occurred significantly later during CRT than during SRT (p 0.05). Discussion: The time course of intracortical excitability changes before EMGonset is different in SRT and CRT. In SRT, with direct stimulus/response mapping, SICI reduction precedes MEP facilitation. In CRT, characterized by uncertain stimulus/response mapping, reduction of SICI and MEP facilitation occur in parallel. Conclusion: The timing of premovement modulation of SICI with respect to MEP facilitation before EMGonset depends on the behavioral context.

Cabergoline reverses cortical hyperexcitability in patients with restless legs syndrome

To reverse the profile of abnormal intracortical excitability in patients with restless legs syndrome (RLS) by administering the dopaminergic agonist cabergoline. The effects of this drug on motor cortex excitability were examined with a range of transcranial magnetic stimulation (TMS) protocols before and after administration of cabergoline over a period of 4 weeks in 14 patients with RLS and in 15 healthy volunteers. Measures of cortical excitability included central motor conduction time; resting and active motor threshold to TMS; duration of the cortical silent period; short latency intracortical inhibition (SICI) and intracortical facilitation using a paired-pulse TMS technique. Short latency intracortical inhibition was significantly reduced in RLS patients compared with the controls and this abnormal profile was reversed by treatment with cabergoline; the other TMS parameters did not differ significantly from the controls and remained unaffected after treatment with cabergoline. Cabergoline had no effect on cortical excitability of the normal subjects. As dopaminergic drugs are known to increase SICI, our findings suggest that RLS may be caused by a central nervous system dopaminergic dysfunction. This study demonstrates that the cortical hyperexcitability of RLS is reversed by cabergoline, and provides physiological evidence that this dopamine agonist may be a potentially efficacious option for the treatment of RLS.

Selective and nonselective benzodiazepine agonists have different effects on motor cortex excitability

Transcranial magnetic stimulation (TMS) is a useful method to study pharmacological effects on motor cortex excitability. Zolpidem is a selective agonist of the benzodiazepine receptor subtype BZ1 and has a distinct pharmacological profile compared to diazepam. To study the different effects of these two drugs on the cortical inhibitory system, TMS was performed before and after administration of a single oral dose of zolpidem (10 mg) and diazepam (5 mg) in six healthy volunteers. TMS tests included the determination of resting and active motor threshold (MT) and measurements of the amplitudes of motor evoked potentials, intracortical facilitation (ICF), short-latency intracortical inhibition (SICI), and long-latency intracortical inhibition (LICI), and determination of the cortical silent period (CSP). Both drugs were without effect on the active or resting MT and decreased the ICF. Prolongation of the CSP and enhancement of LICI only in the presence of zolpidem point to a specific BZ1-related mechanism underlying the long-lasting component of cortical inhibition. This selective modulation of the CSP and the LICI points to a specific role of BZ1 receptors in the control of inhibitory neuronal loops within the primary motor cortex.

Effects of sleep deprivation on cortical excitability in patients affected by juvenile myoclonic epilepsy: a combined transcranial magnetic stimulation and EEG study

Objective: To investigate the effect of sleep deprivation on corticospinal excitability in patients affected by juvenile myoclonic epilepsy (JME) using different transcranial magnetic stimulation (TMS) parameters. Methods: Ten patients with...

Reply from Vincenzo Di Lazzaro, Fabio Pilato, Michele Dileone, Pietro A. Tonali and Ulf Ziemann

We thank Pompeia and colleagues for their insightful comments on our recent paper (Di Lazzaro et al. 2005b) in which we demonstrate that measures of transcranial magnetic stimulation (TMS) provide an opportunity to segregate physiologically relevant differences of benzodiazepine action in the intact human brain. By using paired pulse TMS protocols, or by coupling of peripheral nerve stimulation with TMS of the contralateral motor cortex, it is possible to recruit specific neuronal circuits of the human brain and to evaluate in vivo the effects of drugs on several neurotransmitter systems (Ziemann, 2004). The short latency inhibitory effect produced by peripheral nerve stimulation on the excitability of the contralateral motor cortex is known as short latency afferent inhibition (SAI). SAI tests an inhibitory circuit in motor cortex (Tokimura et al. 2000) that is controlled by central cholinergic activity: SAI is decreased by the muscarinic receptor antagonist scopolamine in normal subjects (Di Lazzaro et al. 2000b), is significantly reduced in Alzheimer's disease patients and, in these patients, can be increased by acetylcholinesterase inhibitors (Di Lazzaro et al. 2005a). A particular paired pulse TMS protocol (Kujirai et al. 1993) elicits short latency intracortical inhibition (SICI). SICI tests an inhibitory circuit in motor cortex in which neurotransmission through the GABAA receptor is involved (Ziemann et al. 1996; Di Lazzaro et al. 2000a; Ilic et al. 2002) while, in contrast to SAI, this measure is not modified by scopolamine (Di Lazzaro et al. 2000b), and decreased by an acetylcholinesterase inhibitor (Korchounov et al. 2005). Thus, evaluation of the effects of benzodiazepines on SAI and SICI provides a novel and fascinating opportunity to evaluate their effects on distinct inhibitory circuits in human motor cortex. In our recent study (Di Lazzaro et al. 2005b), we provide evidence, for the first time, for a dissociation of lorazepam and a ‘classical benzodiazepine’ (diazepam) on these measures. While both drugs enhance SICI, lorazepam decreases SAI and diazepam increases it. This dissociation may contribute to our understanding of why these two benzodiazepines impair memory function differently. What makes lorazepam different from other benzodiazepines remains unknown though Pompeia and colleagues suggest in their letter that a possible explanation for the atypical effects of lorazepam might be that it has a unique binding profile, possibly to as yet uncharacterized benzodiazepine receptors. This idea bears much similarity with our as yet unproven proposal that lorazepam and diazepam differ in their affinity to subtypes of the GABAA receptor bearing different alpha-units (Di Lazzaro et al. 2005b). If we conceive SAI as a GABAergic cortical inhibition positively controlled by acetylcholine, then the dissociation between lorazepam and diazepam on SAI may be caused by the GABAA receptor that mediates inhibition in the GABAergic motor cortical SAI circuit, or the GABAA receptor that controls release of acetylcholine at brainstem or intracortical levels (Giorgetti et al. 2000). According to the first scenario, which we speculated upon in our recent paper (Di Lazzaro et al. 2005b), lorazepam and diazepam both reduce acetylcholine release to a similar extent, therefore exerting a similar depression on SAI, but diazepam is significantly more effective than lorazepam in enhancing inhibition in the GABAergic motor cortical SAI circuit. This could explain the observed net effect of increased SAI under diazepam but decreased SAI under lorazepam (Di Lazzaro et al. 2005b). The second scenario, which is equally possible, is that lorazepam decreases acetylcholine release more effectively than diazepam while both drugs have similar effects on inhibition in the GABAergic SAI circuit, again resulting in the same dissociating net effects on SAI as above. If true, this would indicate that measures of TMS can be applied to probe cortical inhibition at the level of different subtypes of GABAA receptors. This would be a major advance, not only in comparison to psychophysical studies and less specific electrophysiological studies (Itil et al. 1989; Pompeia et al. 2003), as quoted by Pompeia and colleagues in their letter to the editor, but also in comparison to all previous TMS drug studies (Ziemann, 2004). The significance of this research lies in the fact that cortical GABAergic interneurones are highly diverse and operate with a corresponding diversity of GABAA receptor subtypes in controlling developmental plasticity and behaviour (Fagiolini et al. 2004; Mohler et al. 2004). We agree with Pompeia and colleagues that much more needs to be done, including dose–response curves and testing of other atypical benzodiazepines, to corroborate the view that TMS can distinguish non-invasively and at the systems level of human cerebral cortex between neuronal circuits bearing different GABAA receptor subtypes. However, it appears that a first step towards this important goal has been achieved.

Modulation of short-latency intracortical inhibition in human primary motor cortex during synchronised versus syncopated finger movements

Rhythmic movements are inherently more stable and easier to perform when they are synchronised with a periodic stimulus, as opposed to syncopated between the beats of a pacing stimulus. Although this behavioural phenomenon is well documented, its neurophysiological basis is poorly understood. In a first experiment, we demonstrated that all healthy subjects (N=8) performing index finger abduction in time with an auditory metronome exhibited transitions from syncopation to synchronisation when the metronome tempo was scaled from 0.8 to 2.0 Hz. Subjects' mean transition frequency was 1.7+/-0.2 Hz. In a second experiment, we used paired-pulse transcranial magnetic stimulation to examine short-latency intracortical inhibition (sICI) directed towards the first dorsal interosseous (FDI) muscle in healthy subjects (N=9) who made synchronised and syncopated phasic finger movements in time with metronome pacing of 1.0 Hz. Despite the equivalence between the patterns in terms of task performance and corticospinal excitability of FDI at this movement frequency, there was significantly greater sICI during syncopation than during synchronisation. From this result, we infer that the stability of movement patterns may be contingent upon excitability of inhibitory networks within primary motor cortex.

Effects of lorazepam on short latency afferent inhibition and short latency intracortical inhibition in humans

Experimental studies have demonstrated that the GABAergic system modulates acetylcholine release and, through GABA(A) receptors, tonically inhibits cholinergic activity. Little is known about the effects of GABA on the cholinergic activity in the human central nervous system. In vivo evaluation of some cholinergic circuits of the human brain has recently been introduced using a transcranial magnetic stimulation (TMS) protocol based on coupling peripheral nerve stimulation with TMS of the motor cortex. Peripheral nerve inputs have an inhibitory effect on motor cortex excitability at short intervals (short latency afferent inhibition, SAI). We investigated whether GABA(A) activity enhancement by lorazepam modifies SAI. We also evaluated the effects produced by lorazepam on a different TMS protocol of cortical inhibition, the short interval intracortical inhibition (SICI), which is believed to be directly related to GABA(A) activity. In 10 healthy volunteers, the effects of lorazepam were compared with those produced by quetiapine, a psychotropic drug with sedative effects with no appreciable affinity at cholinergic muscarinic and benzodiazepine receptors, and with those of a placebo using a randomized double-blind study design. Administration of lorazepam produced a significant increase in SICI (F(3,9) = 3.19, P = 0.039). In contrast to SICI, SAI was significantly reduced by lorazepam (F(3,9) = 9.39, P = 0.0002). Our findings demonstrate that GABA(A) activity enhancement determines a suppression of SAI and an increase of SICI.

Pathophysiological differences between musician's dystonia and writer's cramp

Focal hand dystonia (FHD) has been suggested to be a maladaptive response of the brain to repetitive performance of stereotyped and attentionally demanding hand movements. However, not all patients with FHD have a strict history of excessive hand use; for example, patients with musician's dystonia (MD) spend many hours per day with their attention focused on instrumental practice, whereas many patients with writer's cramp (WC) have a history of average hand use. The present experiments test whether seven MD and six WC patients have different pathophysiological deficits by examining the spatial pattern of sensorimotor organization in the motor cortex. Two control groups were used, eight healthy non-musicians and eight healthy musicians. The latter served to control for physiological adaptation of the brain to musical training. We used focal vibration of a single hand muscle to produce sensory input whilst the excitability of corticospinal outputs to the vibrated and other hand muscles was evaluated with transcranial magnetic stimulation. In healthy non-musicians, vibration increases the amplitude of motor-evoked potentials and decreases the short-latency intracortical inhibition (SICI) in the vibrated muscle, whilst having the opposite effect on the non-vibrated hand muscles. The pattern of sensorimotor interaction was abnormal in both patient groups. However, the nature of the deficit differed between them. While vibration had little effect on cortical excitability in WC, it strongly reduced SICI in all hand muscles irrespective of spatial organization in MD. In the healthy musicians we found an organization intermediate between that of healthy non-musicians and MD. The data are consistent with a model in which musical practice in healthy musicians leads to beneficial changes in organization of the motor cortex, but in MD these progress too far and begin to interfere with movement rather than assist it. The fact that sensory input had no effect on motor output in patients with WC suggests that sensory information from the hand may play a smaller role in provoking pathological changes in WC than in MD.

Distinct changes in cortical and spinal excitability following high-frequency repetitive TMS to the human motor cortex

It has been shown that high-frequency repetitive transcranial magnetic stimulation (rTMS) to the human primary motor hand area (M1-HAND) can induce a lasting increase in corticospinal excitability. Here we recorded motor evoked potentials (MEPs) from the right first dorsal interosseus muscle to investigate how sub-threshold high-frequency rTMS to the M1-HAND modulates cortical and spinal excitability. In a first experiment, we gave 1500 stimuli of 5 Hz rTMS. At an intensity of 90% of active motor threshold, rTMS produced no effect on MEP amplitude at rest. Increasing the intensity to 90% of resting motor threshold (RMT), rTMS produced an increase in MEP amplitude. This facilitatory effect gradually built up during the course of rTMS, reaching significance after the administration of 900 stimuli. In a second experiment, MEPs were elicited during tonic contraction using weak anodal electrical or magnetic test stimuli. 1500 (but not 600) conditioning stimuli at 90% of RMT induced a facilitation of MEPs in the contracting FDI muscle. In a third experiment, 600 conditioning stimuli were given at 90% of RMT to the M1-HAND. Using two well-established conditioning-test paradigms, we found a decrease in short-latency intracortical inhibition (SICI), and a facilitation of the first peak of facilitatory I-waves interaction (SICF). There was no correlation between the relative changes in SICI and SICF. These results demonstrate that subthreshold 5 Hz rTMS can induce lasting changes in specific neuronal subpopulations in the human corticospinal motor system, depending on the intensity and duration of rTMS. Short 5 Hz rTMS (600 stimuli) at 90% of RMT can selectively shape the excitability of distinct intracortical circuits, whereas prolonged 5 Hz rTMS (> or =900 stimuli) provokes an overall increase in excitability of the corticospinal output system, including spinal motoneurones.

Primary writing tremor: motor cortex reorganisation and disinhibition

Primary writing tremor (PWT) is a task-specific tremor of uncertain origin. There has been debate as to whether PWT represents a variant of essential tremor or a tremulous form of focal dystonia related to writer's cramp. In writer's cramp there is evidence of changes in intracortical inhibition (ICI), as well as cortical motor reorganisation. To study corticomotor organisation and short-latency ICI in a patient with typical task-specific PWT. Transcranial magnetic stimulation mapping of the corticomotor representation of the hand and studies of ICI using paired-pulse stimulation were performed in a 47-year-old right-handed woman with a pure task-specific writing tremor. The motor maps for the hand were displaced posteriorly on both sides and reverted to a normal position after treatment with botulinum toxin. Short-latency ICI was reduced for the dominant hand. The findings indicate reorganisation and disinhibition of the corticomotor projection to the hand and point to the participation of cortical centres in the origin of PWT.

Short-term modulation of regional excitability and blood flow in human motor cortex following rapid-rate transcranial magnetic stimulation

Repetitive transcranial magnetic stimulation (rTMS) of the human primary motor cortex (M1) provides a means of inducing lasting changes in cortical excitability and synaptic activity. Here we combined rTMS with positron emission tomography of regional cerebral blood flow (rCBF) to examine how an rTMS-induced change in intracortical excitability of inhibitory circuits affects regional synaptic activity. In a first set of experiments, we gave 150 biphasic pulses of 5 Hz rTMS at 90% of active motor threshold to left M1 and used single- and paired-pulse TMS to assess the conditioning effects of rTMS on motor cortical excitability at rest. rTMS conditioning led to a selective decrease in short-latency intracortical inhibition (SICI) without affecting short-latency intracortical facilitation or corticospinal excitability. The decrease in SICI lasted for approximately 8 min. In a second experiment, we used the same rTMS protocol and measured changes in regional synaptic activity (as indexed by rCBF) during and for up to 14 min after the end of rTMS. Subthreshold 5 Hz rTMS induced a region-specific increase in resting rCBF in the stimulated M1 lasting approximately 8 min. These \\ suggest that in the stimulated M1, temporary attenuation of SICI is paralleled by an increase in synaptic activity, consistent with reduced efficacy of intracortical GABA A-ergic synapses. The present findings demonstrate that short trains of low-intensity 5 Hz rTMS can be used to induce a transient change in function within a distinct cortical area. This opens up new possibilities for studying acute reorganization at the systems level in the intact human brain.

Neurophysiological Characterization of Autosomal Dominant Spinocerebellar Ataxia 17

Recently, trinucleotide expansion (critical limit 42±2) has been described in the TATA box binding protein gene in autosomal dominant spinocerebellar ataxia 17 (SCA 17, OMIM 600075). The clinical presentation is very variable with psychiatric disturbance, gait ataxia, dysarthria, bradykinesia and/or dystonia. We neurophysiologically characterized two families with SCA-17 using transcranial magnetic stimulation (TMS) and brain parenchyma sonography (BPS). The two families consisted of 14 individuals with genetically proven SCA-17 (trinucleotide expansion 45 to 54). 7 family members (4 male, mean age 44±9 years, mean disease duration 8±7 years) were characterized neurophysiologically. Our TMS measures comprised a routine investigation, the contralateral and ipsilateral silent period as well as analysis of short latency intracortical inhibition (PPI 3 ms) and facilitation (PPF 13 ms) using a paired-pulse paradigm. The echogenicity of several brain structures of the basal ganglia and the midbrain was investigated by BPS according to a standardized protocol. All patients showed a moderate to severe dementia and a wide spectrum of clinical symptoms including dyspraxia, atypical Parkinsonism as well as myoclonus, and ataxia in only one case. TMS revealed only one abnormal parameter with loss of PPF 13 ms in 6 patients. BPS demonstrated a reduced echogenicity of the brainstem raphe in all 7 individuals, a hyperechogenicity of the caudat nucleus in 5 patients (with correlation to the severity of dementia), and in all patients a dilatation of the IV. ventricle (7.4±1.9mm). Clinical features of SCA17 comprised a broad spectrum of more psychiatric and extrapyramidal symptoms than ataxia. A loss of short-latency intracortical facilitation measured by TMS was also reported previously in other types of SCA and may be the expression of a disturbed cerebello-thalamic-cortical connection. Hyperechogenicity of the caudate nucleus in the BPS was described also in other forms of dementia. The hypoechogenicity of the brainstem raphe, a serotonergic nucleus area, was described for patients with unipolar depression. Disturbances in the serotonergic system seem to play a role in patients with SCA suggesting that the hypoechogenicity of the brainstem raphe revealed by BPS may be of pathogenetic importance.

Motor cortex hyperexcitability to transcranial magnetic stimulation in Alzheimer’s disease

Objectives: Recent transcranial magnetic stimulation (TMS) studies demonstrate that motor cortex excitability is increased in Alzheimer’s disease (AD) and that intracortical inhibitory phenomena are impaired. The aim of the present...

Long-lasting increase in corticospinal excitability after 1800 pulses of subthreshold 5 Hz repetitive TMS to the primary motor cortex

Objective To study the after effects of high-frequency repetitive transcranial magnetic stimulation (rTMS) over the primary motor cortex (M1) on corticospinal excitability. Methods Eight healthy volunteers received either 150 or 1800 stimuli of 5 Hz rTMS on two separate days in a counterbalanced order. rTMS was given over the ‘motor hot spot’ of the right first dorsal interosseus (FDI) muscle using an intensity of 90% of resting motor threshold (referred to as subthreshold rTMS). We evaluated the amplitude of the motor-evoked potential (MEP), short-latency intracortical inhibition (SICI), short-latency intracortical facilitation (SICF), and cortical silent period (CSP) before and for about 30 min after rTMS. MEPs were recorded from the right FDI muscle and abductor digiti minimi (ADM) muscle. Results 1800 stimuli induced an increase in MEP amplitude in the relaxed FDI muscle, but not in the relaxed ADM muscle. This facilitatory after effect was stable for at least 30 min. Prolonged 5 Hz rTMS had no effect on the relative magnitude of SICI and SICF. 150 stimuli caused no lasting modulation of MEP amplitudes in either muscle. In a subgroup of 5 subjects, 900 conditioning stimuli caused only a short-lived MEP facilitation. 5 Hz rTMS did not modify the duration of the CSP during tonic contraction. Conclusions A single session of subthreshold 5 Hz rTMS to the M1 can induce a long-lasting and muscle-specific increase in resting corticospinal excitability. However, a sufficient number of conditioning stimuli is necessary to produce persistent corticospinal facilitation.

Enhanced intracortical inhibition in cerebellar patients

Objective: The aim of the study was to examine intracortical excitability in cerebellar patients. Methods: Short-latency intracortical inhibition (SICI), long-latency intracortical inhibition (LICI) and intracortical facilitation (ICF) to paired transcranial magnetic stimulation (TMS) were investigated in 8 patients with ‘pure’ cerebellar syndromes and in 14 age-matched normal controls. The conditioning stimulus for short-latency intracortical inhibition and intracortical facilitation was set at 70% of the resting motor threshold (RMT) and preceded the test stimulus (110–120% of the resting motor threshold) by interstimulus intervals (ISIs) of 1–30 ms. For the long-latency intracortical inhibition determinations, the conditioning stimulus was set at 120% of the resting motor threshold and preceded the test stimulus (also 120% of the resting motor threshold) by interstimulus intervals of 30–500 ms. Results: No statistically significant differences were found between patients and controls as regards either short-latency intracortical inhibition or intracortical facilitation. A significant prevalence of long-latency intracortical inhibition was present in cerebellar patients at interstimulus intervals of 200–500 ms (conditioned MEP amplitude=29–41% of test MEP) as compared to controls (71–96% of test MEP). The amplitude of conditioned MEPs was persistently less than 45% of the test MEP in six patients, who were studied at interstimulus intervals up to 1000 ms. Conclusions: Long-latency intracortical inhibition was prevalent and abnormally longer-lasting in patients. Tonic hyperactivation of a subpopulation of GABAergic interneurons in the motor cortex of patients may be the mechanism responsible for this abnormality. Our findings seem to be specific to cerebellar diseases and are the opposite of those found in movement disorders such as dystonia and Parkinson's disease. These data suggest that the cerebellum and the basal ganglia may have opposite influences in tuning the excitability of the motor cortex.

Abnormal associative plasticity of the human motor cortex in writer's cramp.

Low-frequency median nerve stimulation, paired with suprathreshold transcranial magnetic stimulation (TMS) over the optimal site for activation of the abductor pollicis brevis (APB) muscle induces a long-lasting increase in the excitability of corticospinal output neurons, if median nerve stimulation is given 25 ms before TMS. Here we employed this protocol of stimulation to assess associative plasticity of the primary motor hand area in 10 patients with writer's cramp and 10 age-matched controls. Motor evoked potentials (MEPs) were recorded from right APB muscle and right first dorsal interosseus (FDI) muscle. Resting and active motor threshold, mean MEP amplitude at rest, short-latency intracortical inhibition (SICI) at an interstimulus interval of 2 ms and the duration of the cortical silent period (CSP) were assessed immediately before and after associative stimulation. In both groups, associative stimulation led to an increase in resting MEP amplitudes which was more pronounced in the right APB muscle. Compared with healthy controls, stimulation-induced facilitation of MEP amplitudes was stronger in patients with writer's cramp. In addition, only patients showed a slight decrease of resting and active motor thresholds after conditioning stimulation. In both groups, associative stimulation induced a prolongation of CSP in the APB and FDI muscles, which was significant only in the APB muscle in healthy controls. Associative stimulation had no effects on SICI in patients and healthy controls. Taken together, in patients with writer's cramp, the motor system exhibited an abnormal increase in corticospinal excitability and an attenuated reinforcement of intracortical inhibitory circuits that generate the CSP in response to associative stimulation. This altered pattern of sensorimotor plasticity may favour maladaptive plasticity during repetitive skilled hand movements and, thus, may be of relevance for the pathophysiology of writer's cramp and other task-specific dystonias.