The relationship between motor cortex excitability and severity of Alzheimer's disease: a transcranial magnetic stimulation study

Introduction

In Alzheimer's disease (AD), transcranial magnetic stimulation (TMS) studies have been limited to test motor cortical excitability. The aim of this study was to investigate the inhibitory circuits of the motor cortex and to relate these to measures of cognitive function in AD patients. Results were compared with those of a control group of healthy subjects matched for age, sex and education.

Patients and methods

Forty-five AD patients and 37 healthy volunteers were included in the study. Each participant received a neurological evaluation, Mini-Mental State Examination (MMSE), and Clinical Dementia Rating (CDR). Neurophysiological evaluations included resting and active motor threshold (rMT and aMT), motor evoked potential (MEP), cortical silent period (CSP), and transcallosal inhibition (TI).

Results

AD patients showed significantly reduced rMT, aMT and shorter MEP onset latency; in addition there was a prolongation of both CSP and TI. There was a significant positive correlation between the MMSE and CDR, on the one hand, and aMT and rMT, on the other hand, whereas the correlation was negative with CSP and TI durations.

Conclusion

AD is associated with hyperexcitability of the motor cortex, which supports the hypothesis that changes in GABAb and glutamate function are important factors in cognitive impairment.     

Alteration of motor cortex excitability in response to intermittent photic stimulation.

OBJECTIVE: To measure the duration of cortical silent period (C-SP) in response to different frequencies of intermittent photic stimulation (IPS). METHODS: Ten normal volunteers without a history of seizures were studied. First, using a magnetic stimulator we determined the resting motor threshold (RMT). The C-SP produced by a single magnetic shock at 120% of RMT was measured in the maximally contracted abductor pollicis brevis. C-SP was then measured while subjects were exposed to IPS at 5, 10, 15, 20, 30, 50, and 60 Hz with closed eyes. RESULTS: The average duration of C-SP was 135+/-33. 2 ms with no photic stimulation. This did not change significantly when subjects were exposed to IPS at 5, 10, 15, 20, and 30 Hz. The duration of C-SP, however, decreased significantly at higher frequencies. At 50 Hz it was 116.2+/-43 ms (P=0.003) and at 60 Hz it was 112.7+/-44.6 ms (P<0.001). CONCLUSION: Our findings suggest that motor cortex inhibition is altered in response to IPS at 50 and 60 Hz.     

Cortical excitability in cryptogenic localization-related epilepsy: interictal transcranial magnetic stimulation studies

PURPOSE: To assess whether single-and paired-pulse transcranial magnetic stimulation (TMS) can measure the interictal brain excitability of medicated patients with cryptogenic localization related epilepsy (CLE). Changes in the balance between excitation and inhibition are the core phenomena in focal epileptogenesis. TMS can assess this balance in the primary motor cortex. METHODS: We selected 18 patients with CLE and similar clinical features in whom we located the epileptogenic area reliably, with 11 age-and sex-matched healthy controls. For both motor cortices, we determined the threshold to TMS, the duration of the cortical silent period, and the corticocortical inhibition and facilitation curve. RESULTS: TMS was safe. The more antiepileptic drugs (AEDs) taken by the patients, the higher their threshold to TMS. The silent period duration failed to show significant changes. On paired TMS, a cluster analysis identified a homogeneous subgroup of patients (n = 7) who showed a significantly defective corticocortical inhibition and excess facilitation. With respect to the epileptogenic area, the phenomenon was bilateral in four of these patients, ipsilateral in two, and contralateral in one. The phenomenon was independent of AEDs and many other clinical variables. However, this patient group had a higher seizure frequency and a higher proportion of electroencephalograms (EEGs) showing interictal generalized epileptic discharges than the rest of the patients. CONCLUSION: Paired TMS provided a valuable pathophysiologic insight into the interictal excitatory state of the cortex in CLE. This method can potentially supply useful prognostic clinical information.     

Fatigue-induced motor cortex excitability changes in subjects with spinal cord injury

To further investigate the mechanisms of exercise-induced cortical plasticity after spinal cord injury (SCI), the cortical silent period (CoSP) evoked by transcranial magnetic stimulation (TMS) during a fatiguing muscle contraction was evaluated in 5 patients with incomplete cervical SCI and in 5 healthy subjects.The physiological lengthening of CoSP end latency during fatigue was not observed in the SCI patients.This reduced intracortical inhibition, probably secondary to decreased activity of the GABAergic inhibitory interneurons that modulate the corticomotoneuronal output, could represent a ‘positive’ neuroplastic response in an attempt to compensate for the loss of corticospinal axons.The investigation of motor cortex excitability during fatiguing exercise may shed light on the role of exercise therapy in promoting brain reorganization and functional recovery in humans.     

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     

Automated-parameterization of the motor evoked potential and cortical silent period induced by transcranial magnetic stimulation

ObjectiveTo standardize the characterization of motor evoked potential (MEP) and cortical silent period (CSP) recordings elicited with transcranial magnetic stimulation (TMS).MethodsA computer-based, automated-parameterization program (APP) was developed and tested which provides a comprehensive set of electromyography (EMG) magnitude and temporal measures. The APP was tested using MEP, CSP, and isolated CSP (iCSP) TMS stimulus–response data from a healthy adult population (N = 13).ResultsThe APP had the highest internal reliability (Cronbach’s alpha = .98) for CSP offset time compared with two prominent automated methods. The immediate post-CSP EMG recovery level was 49% higher than the pre-TMS EMG level. MEP size (peak amplitude, mean amplitude, peak-to-peak amplitude, and area) correlated higher with effective E-field (E_eff) than other intensity measures (r ≈ 0.5 vs. r ≈ 0.3) suggesting that E_eff is better suited for standardizing MEP stimulus–response relationships.ConclusionsThe APP successfully characterized individual and mean epochs containing MEP, CSP, and iCSP responses. The APP provided common signal and temporal measures consistent with previous studies and novel additional parameters.SignificanceWith the use of the APP modeling method and the E_eff, a standard approach for the analysis and reporting of MEP–CSP complex and iCSP measurements is achievable.     

Effects of deep brain stimulation on the primary motor cortex: Insights from transcranial magnetic stimulation studies

Deep brain stimulation (DBS) implanted in different basal ganglia nuclei regulates the dysfunctional neuronal circuits and improves symptoms in movement disorders. However, the understanding of the neurophysiological mechanism of DBS is at an early stage. Transcranial magnetic stimulation (TMS) can be used safely in movement disorder patients with DBS, and can shed light on how DBS works. DBS at a therapeutic setting normalizes the abnormal motor cortical excitability measured with motor evoked potentials (MEP) produced by primary motor cortical TMS. Abnormal intracortical circuits in the motor cortex tested with paired-pulse TMS paradigm also show normalization with DBS. These changes are accompanied with improvements in symptoms after chronic DBS. Single-pulse DBS produces cortical evoked potentials recorded by electroencephalography at specific latencies and modulates motor cortical excitability at certain time intervals measured with MEP. Combination of basal ganglia DBS with motor cortical TMS at stimulus intervals consistent with the latency of cortical evoked potentials delivered in a repetitive mode produces plastic changes in the primary motor cortex. TMS can be used to examine the effects of open and closed loop DBS. Patterned DBS and TMS delivered in a repetitive mode may be developed as a new therapeutic method for movement disorder patients.     

帕金森病患者运动皮质兴奋性的经颅磁刺激研究

目的:本研究拟应用低频重复性经颅磁刺激(rTMS)分别刺激帕金森病(PD)患者M1手代表区(M1Hand)及运动前区(PMC),探讨不同干预手段对运动皮质兴奋性的影响,以及M1与PMC间的联系。方法:对18名确诊PD患者先后进行4种不同干预,即口服美多芭、低频rTMS刺激M1Hand(0.5Hz,100%静息阈值,共1600次脉冲)、低频rTMS刺激PMC(0.5Hz,100%静息阈值,共1600次脉冲)以及假刺激。于每次干预前后各进行临床评价并测定运动诱发电位(MEP)相关指标。结果:①口服美多芭后UPDRSⅢ(P=0.001)以及其中有关僵直(P=0.001)、运动迟缓(P<0.001)的评分均较服药前显著改善。三种不同磁刺激干预产生结果不同,M1Hand组UPDRSⅢ减低(P=0.015),僵直(P=0.010)、运动迟缓(P=0.004)亦有所改善;PMC组UPDRSⅢ较干预前减低(P=0.046),僵直评分亦减低,但无显著性意义(P=0.163);②口服美多芭1h后MEP120减低(P=0.002),CSP延长(P=0.006);M1Hand组MEP120无著变,而CSP延长(P=0.015);PMC组MEP120减低(P=0.004),而CSP无著变;假刺激组则均无显著性改变。结论:低频rTMS对不同脑区产生的效应不同:刺激M1可使CSP延长;而刺激PMC可使MEP波幅减低。     

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.     

脑血管病患者经颅磁刺激运动诱发电位的研究

采用经颅磁刺激运动诱发电位（ＭＥＰ）对７２例脑血管病（ＣＶＤ）患者和５０例正常人进行检测。结果：ＣＶＤ患者瘫痪侧上肢磁刺激无反应或皮层潜伏期和中枢传导时间（ＣＭＣＴ）较正常对照组和健侧显著延长（Ｐ＜０．００１）；瘫痪侧下肢磁刺激无反应或ＣＭＣＴ较正常对照组和健侧显著延长（Ｐ＜０．０５）。脑出血与脑梗塞患者ＭＥＰ异常率无显著差异（Ｐ＞０．０５），而与临床病情轻重和病变部位密切相关。提示ＭＥＰ能客观反映ＣＶＤ患者中枢运动传导通路功能受损的情况。     

Effects of lacosamide and carbamazepine on human motor cortex excitability: A double-blind,placebo-controlled transcranial magnetic stimulation study

PurposeLacosamide (LCM) and carbamazepine (CBZ) are antiepileptic drugs both acting on neuronal voltage-gated sodium channels. Patch-clamp studies demonstrated significant differences in how LCM and CBZ affect neuronal membrane excitability. Despite valuable information patch-clamp studies provide, they also comprise some constraints. For example, little is known about effects of LCM on intracortical synaptic excitability. In contrast, transcranial magnetic stimulation (TMS) can describe drug-induced changes at the system level of the human cerebral cortex.MethodsThe present study was designed to explore dose-depended effects of LCM and effects of CBZ on motor cortex excitability with TMS in a randomized, double-blind, placebo-controlled crossover trial in healthy human subjects. Subjects received 600 mg CBZ, 200 mg LCM, 400 mg LCM or placebo preceding TMS measurements.ResultsCompared to placebo, TMS motor thresholds were significantly increased after carbamazepine and lacosamide, with a trend for a dose dependent effect of lacosamide. Both, carbamazepine and lacosamide did not affect TMS parameters of intracortical synaptic excitability.ConclusionsTMS measurements suggest that lacosamide and carbamazepine predominantly act on neuronal membrane excitability.     

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.     

Repetitive transcranial magnetic stimulation of language function in patients with refractory epilepsy A preliminary functional magnetic resonance imaging study

To investigate whether repetitive transcranial magnetic stimulation （rTMS） can improve language function in patients with refractory epilepsy, three right-handed, refractory epilepsy patients who had complained of language dysfunction, were recruited. Over 1 month, 1-Hz rTMS treatment was performed every 3 days. A battery of language production and functional MRI were evaluated in the patients using a standard verb generation task both before and 1 month after rTMS treatment. Significant and lasting improvement in verb production was observed following rTMS treatment. Functional MRI results revealed that the left frontal lobes of two patients were more activated than they had been prior to therapy, and activation was primarily concentrated in the language-related areas. Results demonstrated that low frequency rTMS has potential to improve language function in patients with refractory epilepsy.     

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.     

Multi-modality mapping of motor cortex: comparing echoplanar BOLD fMRI and transcranial magnetic stimulation

Summary Multiple non-invasive methods of imaging brain function are now available for presurgical planning and neurobiological research. As these new methods become available, it is important to understand their relative advantages and liabilities, as well as how the information gained compares across different methods. A current and future trend in neurobiological studies as well as presurgical planning is to combine information from different imaging techniques. Multi-modal integration may perhaps give more powerful information than each modality alone, especially when one of the methods is transcranial magnetic stimulation (TMS), with its ability to non-invasively activate the brain. As an initial venture in cross comparing new imaging methods, we performed the following 2 studies, locating motor cortex with echoplanar BOLD fMRI and TMS. The two methods can be readily integrated, with concurring results, although each have important limitations.     

Cortical excitability in drug naive juvenile myoclonic epilepsy

PurposeTo evaluate the effect of diurnal variability on cortical excitability using single pulse transcranial magnetic stimulation (TMS), in drug naive patients with juvenile myoclonic epilepsy (JME) and to look for any differences in cortical excitability between males and females.MethodsThirty drug-naive patients with JME and 10 healthy controls were studied. Resting motor threshold (RMT), motor evoked potential (MEP), the duration of central motor conduction time (CMCT) and cortical silent period (CSP) were measured, twice, first early in the morning and again in the afternoon of the same day.ResultsDiurnal variation with higher evening values of CMCT and CSP were observed in the control group. In the study group, diurnal variation in RMT, CMCT and CSP was found with higher values in the morning than in control group. However, only the raised values of CSP [mean, 110.7 ms, morning and 96.44 ms, evening] were of statistical significance [p = 0.005, morning and 0.039, evening] as compared to controls. In the study group, males had higher values of RMT, CMCT and CSP than in females. However, the CMCT in males was lower in the evening study than in females. Further, RMT and morning CMCT was lower in females than in controls. In females, the morning CSP [mean, 100.91 ms, morning versus 87.86 ms, evening] was significantly prolonged [p = 0.017, morning versus 0.221, evening] as compared to controls.ConclusionThe study is suggestive of the existence of impaired supraspinal/intracortical inhibitory circuits which may account for the hyperexcitability of the motor system being prominent in the morning among drug naïve patients with JME. In this study, increased activity of cortical inhibitory networks, as evidenced by prolonged cortical silent period existed among drug naïve JME patients, but was found to be significant only in female patients. This may explain the increased seizure susceptibility in this cohort, at this time of the day and an increased manifestation of JME in females.