Different mechanisms contribute to motor cortex hyperexcitability in amyotrophic lateral sclerosis.

OBJECTIVES: Different physiological approaches demonstrated motor system hyperexcitability in amyotrophic lateral sclerosis (ALS), probably reflecting excitotoxic mechanisms. Transcranial magnetic stimulation (TMS) showed that both increased excitability of corticomotoneurons and reduced intracortical inhibition (ICI) contribute to motor cortex hyperexcitability, but the importance of these factors in inducing this cortical dysfunction is unknown. The aim of the study was to establish how different mechanisms interact to promote motor system hyperexcitability in ALS in relation to clinical features. METHODS: The resting motor threshold (RMT), the motor evoked potential (MEP) recruitment curve and the cortical silent period (CSP) to single-pulse TMS were evaluated in 35 patients with ALS. Early ICI and intracortical facilitation (ICF) and late ICI were evaluated by paired TMS. RESULTS: The main abnormal TMS findings were: (a) a steeper MEP recruitment curve associated with a lowering of the RMT; (b) reduced or even absent early and late ICI; (c) reduced CSP lengthening with increasing TMS intensity. ICF was not affected. RMT increased and the MEP recruitment curve became less steep with longer disease duration, but they did not correlate with the motor deficit, the type of motoneuron affection and the decrease of ICI. Impairment of early and late ICI were significantly correlated to each other, to disease severity and to clinical evidence of upper motor neuron involvement. CONCLUSIONS: Different and partially independent mechanisms contribute to motor cortex hyperexcitability in ALS. The increased gain in MEP recruitment with a lowering of the RMT appears to be a primary event reflecting an increase in the strength of corticospinal projections, probably related to changes in the ion-channel permeability of the neuronal membrane. On the other hand, inhibitory functions linked to multiple neurotransmitter systems decline with disease progression. Both depletion of specific subpopulations of intracortical GABAergic neurons and mechanisms involved in motor cortex reorganization following progressive neuronal loss have been considered to account for the impaired inhibition. The clarification of the importance of these factors in the pathogenesis of ALS may have diagnostic and therapeutic implications.     

Motor cortex excitability in patients with focal epilepsy

We studied the excitability of the motor cortex using, transcranial magnetic stimulation (TMS) in patients with temporal and extratemporal epilepsy. We applied single and paired-pulse TMS to 15 patients with temporal (n = 7), extratemporal (n = 6) and focal epilepsy lateralised to one hemisphere (n = 2). Patients had no antiepileptic drugs in the last 48 h and were seizure free for 4 h prior to testing. We determined the threshold for EMG responses at rest (RMT), the cortically evoked silent period (CSSP) and intracortical inhibition (ICI, intervals of 2-4 ms) and facilitation (ICF, 7-15 ms) and compared the results to those obtained in 17 normal controls. ICI and ICF was reduced in both hemispheres (P < 0.01. ANOVA) compared to the controls. In the hemisphere of seizure origin ('abnormal') there was a reduction of ICF (P < 0.01) and normal ICI, in the 'normal' hemisphere there was a reduced ICI (P < 0.01) and a slight reduction of ICF (P < 0.05). ICF on the 'abnormal' side was reduced (P < 0.05) compared to the 'normal' hemisphere. RMT was increased in two patients, but group comparison of RMT and CSSP showed no significant differences between patients and controls. The results suggest a remote effect of epileptic activity onto the motor cortex leading to an alteration of activity in local inhibitory circuits.     

Intra- and inter-cortical motor excitability in Alzheimer’s disease

Transcranial magnetic stimulation (TMS) provides evidence for facilitatory and inhibitory motor dysfunctions in Alzheimer's disease (AD). The corpus callosum (CC) is affected in AD already at early stages consistent with the hypothesis that AD patients exhibit alterations in transcallosally mediated motor inhibition (ipsilateral silent period, iSP). Therefore, here we aimed at investigating the integrity not only of intra-, but also of inter-hemispheric mechanisms of cortical motor excitability in AD. We determined the iSP, the resting motor threshold (RMT), and the amplitude of motor evoked potentials (MEP) in 19 AD patients and 19 healthy controls using single-pulse TMS. Furthermore, we used paired-pulse TMS to study the intra-cortical inhibition (ICI) and intra-cortical facilitation (ICF). All subjects underwent comprehensive neuropsychologic, clinical, and laboratory testing, and neuroimaging to exclude significant co-morbidity. In AD patients, the RMT was significantly reduced (Oneway-ANOVA). An analysis of covariance (ANCOVA) revealed a strong group specific interaction of the inhibitory interstimulus intervals (p = 0.005) with a reduced ICI in AD. Furthermore, we found a significantly prolonged iSP-latency (p = 0.003) in AD compared to controls, whereas the iSP-duration was not different. The iSP-latency correlated significantly with the ICI (ANCOVA) (p = 0.02). The ICF did not differ significantly between groups. Our data suggest comprehensive but still subclinical dysfunctions of motor cortical inhibition in mild to moderate clinical stages of AD with strong interactions of intra- and inter-hemispheric inhibitory phenomena. Future studies are needed to show the potential prognostic relevance of these findings for the further course of the disease.     

Zonisamide decreases cortical excitability in patients with idiopathic generalized epilepsy.

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

Motor cortical excitability in patients with poststroke epilepsy

PURPOSE: To gain insight into the mechanisms underlying poststroke epilepsy (PSE), we evaluated motor cortical function in chronic stroke patients with (N = 18) and without (N = 18) PSE. METHODS: We measured resting motor threshold (RMT), motor evoked potential (MEP) amplitudes, cortical silent period (CSP), intracortical inhibition (ICI), influenced by GABAergic neurotransmission, and intracortical facilitation (ICF), influenced by glutamatergic activity, to transcranial magnetic stimulation. RESULTS: We found (1) larger MEP amplitudes and ICF, in the affected than unaffected hemispheres of patients in the PSE group but not in patients without epilepsy, and (2) comparably higher RMT and longer CSP in the absence of differences in ICI, H-reflexes or F-waves in the affected and unaffected hemispheres of both PSE and non-PSE patients. CONCLUSIONS: Enhanced cortical excitability in the affected hemisphere, possibly related to increased glutamatergic activity, could be one of the mechanisms contributing to the development of poststroke epilepsy.     

Cyclical excitability of the motor cortex in patients with catamenial epilepsy: A transcranial magnetic stimulation study

PURPOSE: The pathophysiology of catamenial epilepsy is still unclear. Therefore, we investigated the cortical excitability of women with catamenial epilepsy during different phases of the menstrual cycle. METHODS: Using transcranial magnetic stimulation, six patients suffering from catamenial epilepsy were investigated during ovulatory cycles. On days 8, -14, -7 and 2 of the cycle (day 1 being the first day of menstrual bleeding), resting motor threshold (RMT), cortical silent period (CSP), intracortical inhibition (ICI) and intracortical facilitation (ICF) were investigated. The non-parametric Friedman-test for multiple comparisons and Wilcoxon signed rank test were used for statistical analysis. RESULTS: Five patients suffered from focal epilepsy (three right hemispheric, one bitemporal, one unknown origin) and one patient had idiopathic generalized epilepsy. All patients experienced perimenstrual seizure clustering and two also showed an increased seizure frequency during the luteal phase. In the right hemispheres there was a significant change of CSP duration in the course of the menstrual cycle (chi(2)=8.3, P=0.041), due to a shorter CSP during the luteal phase (Z=-2.0, P=0.043) and menstruation (Z=-2.2, P=0.028) as compared to the follicular phase. There was no significant variation of CSP in the left hemispheres. RMT, ICI and ICF showed no significant changes in the course of the menstrual cycle. CONCLUSIONS: The CSP changes suggest a decreased inhibition involving GABA-ergic neurotransmission during the luteal phase and menstruation. These TMS alterations correlated with the clinical course of the epilepsies and were found in the hemispheres containing the majority of the epileptogenic zones.     

Cortical excitability and age-related volumetric MRI changes.

OBJECTIVE: Normative data on transcranial magnetic stimulation (TMS)-derived measures of cortical excitability in the elderly is sparse. Nevertheless, elderly subjects are included as controls in studies utilizing TMS to investigate disease states. Age-associated increased ventricular cerebrospinal fluid CSF (vCSF) and white matter hyperintensity (WMH) MRI volumes have uncertain significance in non-demented elderly. Information regarding cortical excitability in neurologically intact elderly would augment our understanding of the pathophysiology of aging and assist in the interpretation of TMS studies involving elderly subjects. METHODS: Twenty-four healthy elderly subjects underwent TMS testing to determine outcomes of resting motor threshold (RMT) cortical silent period (cSP) and central motor conduction time for examination in relation to WMH, vCSF, and CNS volumes. RESULTS: Increased vCSF and WMH volumes were associated with decreased right and left hemisphere RMT. Smaller CNS volumes were associated with decreased right hemisphere RMT and shorted cSP. CONCLUSIONS: Commonly observed age-associated MRI changes are associated with findings consistent with increased cortical excitability. SIGNIFICANCE: Age-related MRI findings likely reflect changes at a cellular level, and may influence cognitive and motor integrity in the elderly. Future TMS studies investigating cortical excitability may wish to consider neuroimaging markers of neurodegeneration prior to enrolling elderly subjects as controls.     

Motor cortex dysfunction revealed by cortical excitability studies in Parkinson's disease: influence of antiparkinsonian treatment and cortical stimulation.

Single or paired pulse paradigms of transcranial magnetic stimulation (TMS) provide several parameters to test motor cortex excitability, such as motor threshold (MT), motor evoked potential (MEP) amplitude, electromyographic silent period to cortical stimulation (CSP) and intracortical facilitation (ICF) or inhibition (ICI). Various changes in TMS parameters, revealing motor cortex dysfunction, were found in patients with Parkinson's disease (PD). For instance, low MT and increased MEP size disclosed an enhanced corticospinal motor output at rest, while reduced ICF and failure of MEP size increase during contraction suggested defective facilitatory cortical inputs, particularly for movement execution. Inhibitory cortical pathways were also found less excitable at rest (reduced ICI) and sometimes during contraction (shortened CSP). By restoring cortical inhibition, dopaminergic drugs and deep brain stimulation probably overcome the difficulty to focus neuronal activity onto the appropriate network required for a specific motor task. The application of repetitive TMS trains over motor cortical areas also showed some effect on cortical excitability, opening perspectives to consider the motor cortex as a target for therapeutic neuromodulation in PD. However, systematic studies of cortical excitability remained to be performed in large series of patients with PD, taking into account disease stage, clinical symptoms and medication influence.     

Inter- and intra-individual variability of paired-pulse curves with transcranial magnetic stimulation (TMS).

OBJECTIVES: Previous studies have evaluated the variability of motor thresholds (MTs) and amplitude of motor-evoked potentials (MEPs) to transcranial magnetic stimulation (TMS) within and across individuals. Here we evaluate the reproducibility and inter-hemispheric variability of measures of cortical excitability using the 'conventional' paired-pulse (PP) TMS technique. METHODS: We studied PP curves of the left and right hemisphere in 10 healthy subjects on two separate days 2 weeks apart. The inter-stimulus intervals studied were 1, 3, 6, 8, 10 and 12 ms with the conditioning stimulus being 80% of the resting MT, and a single test stimulus producing MEPs of approximately 0.8 mV peak-to-peak amplitude. RESULTS: As a group, the PP curves of the left and right hemispheres, and of Day 1 and Day 2 were not significantly different. The intracortical inhibition (ICI), but not the intracortical facilitation, showed a good correlation across days within the individuals. CONCLUSIONS: Cortical excitability, particularly ICI, measured by PP TMS shows no inter-hemispheric asymmetry and is reproducible within individuals.     

Effect of levetiracetam on cortical excitability: a transcranial magnetic stimulation study

Background and purpose:  We studied the effect of levetiracetam (LEV), an anticonvulsant with a novel mechanism of action, on cortical excitability, measured using transcranial magnetic stimulation (TMS). For this purpose, 38 healthy volunteers were assessed in two TMS sessions, before and after an oral dose of 3000 mg LEV.
Methods:  Resting motor threshold (RMT), intracortical facilitation (ICF) and intracortical inhibition (ICI), cortical silent period (CSP) threshold and duration and motor-evoked potential (MEP) amplitude were calculated.
Results:  After treatment with LEV, RMT was increased (mean ± SD: 63 ± 14% of the maximum stimulator output) compared with baseline (58 ± 11%). CSP threshold was decreased after LEV (54 ± 10%; baseline, 57 ± 11%). CSP duration was increased after LEV (116 ± 37 ms; baseline: 102 ± 33 ms). LEV did not affect ICF or ICI or mean MEP amplitude significantly.
Conclusions:  Our results indicate that LEV modulates some aspects of cortical excitability. Whereas the increase in the RMT most probably reflects the effect of LEV on ion channel activity, effects on the CSP might represent a modulation of GABA receptors at cortical and spinal level.     

Reduced cortical inhibition in first-episode schizophrenia

Disturbances in cortico-cortical and cortico-subcortical circuits in schizophrenia have been described by previous neuroimaging and electrophysiological studies. Transcranial magnetic stimulation (TMS) provides a neurophysiological technique for the measurement of cortical excitability, especially of the motoneural system. Previous studies using paired-pulse TMS to investigate short-interval cortical inhibition (SICI) and intracortical facilitation (ICF), mainly involving chronic schizophrenia patients, have been inconsistent and only one study in first-episode patients has been conducted so far. We assessed SICI (interstimulus interval, ISI, 3 milliseconds, ms) and ICF (ISI 7 ms) in 29 first-episode schizophrenia patients (FE-SZ) with limited exposure to antipsychotic treatment against measures of 28 healthy controls (HC). Amplitudes of motor evoked potentials (MEPs) were measured from the left and right first dorsal interosseus muscle (FDI). The conditioning stimulus was set at 80% intensity of resting motor threshold (RMT) and the test stimulus (TS) was set at an intensity that produced an MEP amplitude of about 1 mV. For SICI conditions, FE-SZ demonstrated significantly higher MEP amplitudes from left motor cortex (right FDI) compared to HC, and for MEPs from right motor cortex (left FDI) a similar trend was observable (FE-SZ 41% vs. HC 21% of TS, p=0.017 for left motor cortex, and FE-SZ 59% vs. HC 31% of TS, p=0.059 for right motor cortex; Mann-Whitney U-test). No significant difference in MEPs could be detected for ICF on either hemisphere. In addition, there was no difference in left and right RMT comparing patients and control subjects. Our result of a reduced SICI in a large sample of well characterized first-episode schizophrenia patients suggests that a GABAergic deficit may be involved in schizophrenic pathophysiology, already early in the disease course, supporting the intracortical dysconnectivity hypothesis.     

Modification of cortical excitability induced by gabapentin: a study by transcranial magnetic stimulation

Transcranial magnetic stimulation (TMS) was employed before and after a single dose of gabapentin to evaluate how this drug affects the activity of excitatory and inhibitory circuits within the motor cortex. Eleven healthy volunteers were studied. For the evaluation of cortical excitability, the following parameters were taken into account: resting and active motor threshold (RMT, AMT); cortical silent period (CSP); and intracortical inhibition (ICI) and facilitation (ICF). Peripheral silent period (PSP) was also detected. All parameters were measured before and 3 and 24 hours after 800 mg gabapentin was administered in a single oral dose. Gabapentin deepened the ICI and suppressed the ICF at 3 h but not at 5 h after dosing. We conclude that, in the normal human brain, gabapentin may act on intracortical excitability by shifting the balance towards less excitation and more inhibition. Received: 30 March 2001 / Accepted in revised form: 17 May 2001     

Cortical excitability in cocaine-dependent patients: a replication and extension of TMS findings

Cortical excitability can be assessed by transcranial magnetic stimulation (TMS). Previously we observed that TMS motor threshold (MT) was elevated in abstinent cocaine-dependent subjects. In the current study we aimed at replicating our initial finding, exploring other TMS-based measures of excitability, and examining association with personality characteristics. Nineteen cocaine-dependent and 12 healthy control subjects were examined. Resting and activated motor thresholds (RMT and AMT) and duration of the cortical silent period (CSP) were examined. The Cocaine Experience Questionnaire (CEQ) was administered to assess cocaine-induced psychotic symptoms. The relationship between Minnesota Multiphasic Personality Inventory (MMPI) scales and cortical excitability measures was also examined. AMT was significantly elevated in cocaine-dependent subjects on both hemispheres. RMT was also significantly elevated on the right hemisphere. No CSP changes were noted. Patients with cocaine-induced paranoia had longer CSPs on the right hemisphere compared to subjects reporting no paranoid experiences. The patients displayed significantly elevated scores on several MMPI scales, though the scale scores did not correlate with cortical excitability measures. These data support our initial finding of decreased cortical excitability in abstinent cocaine-dependent subjects. We interpret this finding as a compensatory mechanism against the stimulating and epileptogenic effects of cocaine.     

Modulation of motor cortex excitability in obsessive-compulsive disorder: An exploratory study on the relations of neurophysiology measures with clinical outcome

Low-frequency repetitive transcranial magnetic stimulation (rTMS) to supplementary motor area (SMA) showed clinical benefit in obsessive-compulsive disorder (OCD). Here we tested whether clinical improvement was associated with enhanced cortical inhibition as measured by single and paired-pulse TMS variables. In 18 OCD patients receiving 4 weeks of either active or sham rTMS in a double-blind randomized trial, we assessed bilateral resting and active motor thresholds (RMT and AMT), cortical silent period (CSP), short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF). We tested correlations between changes in Yale-Brown Obsessive Compulsive Scale-Self-report (Y-BOCS-SR), Clinical Global Impression-Severity subscale (CGI-S) and cortical excitability measures. Active rTMS increased right hemisphere RMT whose change correlated with Y-BOCS-SR improvement. Baseline RMT hemispheric asymmetry, defined as the difference between left and right hemispheres RMT, and its normalization after active rTMS correlated with Y-BOCS-SR and CGI-S improvements. Active rTMS also increased right hemisphere SICI whose change correlated with Y-BOCS-SR and CGI-S at week 4, and with normalization of baseline RMT hemispheric asymmetry. Treatment-induced changes in cortical excitability measures are consistent with an inhibitory action of SMA rTMS on dysfunctional motor circuits in OCD. Correlations of neurophysiology measures with therapeutic outcome are supportive of the role of SMA in the modulation of OCD symptoms.     

Changes in motor cortex inhibition over time in patients with amyotrophic lateral sclerosis

Abnormal balance between intracortical inhibitory and excitatory mechanisms has been found to contribute to the genesis of motor cortex hyperexcitability in amyotrophic lateral sclerosis (ALS), but data are lacking on the role of these abnormalities in the pathophysiology of the disease. We evaluated the resting motor threshold (RMT), the cortical silent period (CSP) to single-pulse transcranial magnetic stimulation (TMS), early intracortical inhibition (ICI), early intracortical facilitation (ICF) and late ICI to paired-pulse TMS in 40 patients with ALS. These parameters were correlated with disease duration and clinical features. They were also monitored over time in selected patients.The main abnormal TMS findings were: (a). reduced or even absent early and late ICI; six out of 9 patients, with normal early ICI at the first recording, developed abnormal ICI after several months; (b). reduced cortical silent period duration with increasing TMS intensity. ICF and RMT were not affected. Impairment of early and late ICI correlated significantly with disease duration, the diagnostic categories and the clinical evidence of upper motor neuron involvement.The alteration of different cortical inhibitory functions seems to take place with disease progression, rather than being the primary event in the pathogenesis of ALS. The impaired inhibition is considered as being due to both depletion of specific subpopulations of intracortical GABAergic neurons and mechanisms involved in motor cortex reorganization following progressive neuronal loss. Clarification of the importance of these factors in the pathogenesis of the disease may have diagnostic and therapeutic implications.     

Impaired interhemispheric interactions in patients with major depression

Previous studies have shown that patients with major depression have an interhemispheric imbalance between right and left prefrontal and motor cortex. We aimed to investigate the interhemispheric interactions in patients with major depression using repetitive transcranial magnetic stimulation (rTMS). Thirteen patients with major depression and 14 age-matched healthy subjects participated in this study. Corticospinal excitability before and after 1 Hz rTMS (applied to the left primary motor cortex) was assessed in the left and right motor cortex and these results were compared with those in healthy subjects. There was a significant difference in the interhemispheric effects between patients with depression and healthy subjects. In healthy subjects, 1 Hz rTMS significantly decreased corticospinal excitability in the stimulated, left hemisphere and increased it in the contralateral, right hemisphere. In depressed subjects, 1 Hz rTMS also decreased corticospinal excitability in the left hemisphere; however, it induced no significant changes in corticospinal excitability in the contralateral, right hemisphere. In addition, there was a significant correlation between the degree of interhemispheric modulation and the severity of the depression as indexed by the Beck Depression Inventory scores. Our findings showing a decreased interhemispheric modulation in patients with major depression are consistent with the notion that mood disorders are associated with slow interhemispheric switching mechanisms.     

Motor cortical physiology in patients and asymptomatic carriers of parkin gene mutations

Autosomal recessive parkin (PARK2) gene‐related parkinsonism may be phenotypically and pathophysiologically distinct from idiopathic Parkinson's disease (PD). Furthermore, asymptomatic subjects carrying a single parkin mutation (“parkin carriers”) may show striatal dopaminergic dysfunction and increased cortical movement‐related activation. Here, we used transcranial magnetic stimulation (TMS) to study corticospinal and intracortical excitability in manifesting parkin patients and asymptomatic carriers. We studied resting and active motor thresholds (RMT/AMT), central motor conduction time (CMCT), active recruitment curves, short‐interval intracortical inhibition (SICI) and facilitation (ICF), SICI recruitment curve, and cortical silent period (CSP) in 8 patients “off” medication, 7 carriers, and two groups of age‐matched controls (n = 21). Patients had longer CMCTs compared to controls with a significant negative correlation between CMCT duration and onset age (r = ?0.83, P = 0.04). Carriers had increased RMT/AMT; the time course of SICI/ICF and the duration of CSP were normal in both patients and carriers; however slight abnormalities in the recruitment of SICI were found in the carriers. Prolonged CMCT and normal cortical inhibitory mechanisms in parkin patients may be of value in the differentiation from idiopathic PD. The subclinical electrophysiological abnormalities found in carriers may represent underlying compensatory mechanisms. © 2008 Movement Disorder Society     

Anticipation and execution of a simple reading task enhance corticospinal excitability.

OBJECTIVE: Electromyographic responses (EMG) evoked in the right hand by transcranial magnetic stimulation (TMS) of the left motor cortex are enhanced during continuous reading. This enhancement is the result of increased excitability of the motor cortex. We proposed that anticipation and reading of single words would also enhance corticospinal excitability. We studied the temporal course of corticospinal excitability changes following left and right hemisphere TMS. METHODS: Ten normal volunteers were studied. A warning stimulus (S1) was followed by an imperative stimulus (S2) whereupon a word was presented. Subjects responded by reading the word aloud or reading it silently. In other conditions, no word was displayed and the subjects responded to S2 by saying the word 'Cat', pursing their lips, or doing nothing. EMG was recorded over the contralateral hand following a TMS pulse over the motor cortex during and after the S1-S2 period. RESULTS: Enhancement of EMG amplitudes was significantly greater following left hemisphere TMS. The enhancement in the S1-S2 period and that following S2 had a time course similar to several event-related brain potentials. CONCLUSIONS: There may be a common mechanism underlying both corticospinal excitability and the contingent negative variation, readiness potential and N400.     

The effect of modafinil on cortical excitability in patients with narcolepsy: A randomized,placebo-controlled,crossover study

ObjectiveTo investigate the effect of modafinil on cortical excitability in patients with narcolepsy using transcranial magnetic stimulation (TMS).MethodsNineteen drug-naïve narcolepsy patients with cataplexy (10 males, 9 females, and mean age 28.5 years) and 25 age- and sex-matched healthy controls were recruited. In this double-blind, randomized, crossover study, patients and controls received a single dose of 400 mg modafinil or placebo. Modafinil and placebo administrations were separated by a 2-week washout period. TMS parameters, such as resting motor thresholds (RMT), motor-evoked potential (MEP) amplitudes, cortical silent periods (CSP), short-interval intracortical inhibition (SICI), and intracortical facilitation (ICF), were measured before and 3 h after administering modafinil or placebo. The differences of TMS parameters were statistically tested between patients and controls and between before and after modafinil or placebo administration.ResultsNarcolepsy patients had significantly increased CSP durations compared to controls (independent t-test, P < 0.05), indicating decreased excitability of cortical networks in human narcolepsy. In patients after modafinil administration, MEP amplitudes, SICI, and ICF increased, and CSP duration shortened significantly, meaning enhanced motor excitability, whereas in controls modafinil did not change TMS parameters significantly. Placebo administration did not affect TMS parameters both in patients or controls.ConclusionsNarcolepsy patients with cataplexy showed decreased cortical excitability than normal healthy controls. Single dose modafinil significantly increased motor excitability in narcolepsy patients but had no effect in healthy controls.     

Interhemispheric effects of high and low frequency rTMS in healthy humans.

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