Effects of citalopram on the excitability of the human motor cortex: a paired magnetic stimulation study

Several recent reports suggest the possibility of monitoring pharmacological effects on brain excitability through transcranial magnetic stimulation (TMS). Different drugs have been studied using paired magnetic stimulation in normal subjects and patients. In particular, it has been suggested that antidepressant drugs may have an appreciable effect on motor excitability. The aim of the present study was to investigate motor area excitability in normal subjects after oral administration of a single dose of citalopram, a selective serotonin reuptake inhibitor (SSRI) antidepressant. Motor cortex excitability was studied by single and paired transcranial magnetic stimulation before and 2.5 and 36 (t1/2=36 h) h after oral administration of 30 mg of citalopram. Cortical excitability was measured using different transcranial magnetic stimulation parameters: motor threshold (MT), motor-evoked potential (MEP) amplitude and latency, motor recruitment, duration of cortical silent period (CSP), intracortical inhibition and intracortical facilitation. Spinal excitability and peripheral nerve conduction were measured by F response and M wave. Temporary but significant increases in motor threshold, motor-evoked potentials, silent period and intracortical inhibition were observed 2.5 h after drug administration, without any significant changes in motor-evoked potential amplitude and latency and spinal excitability parameters. Our findings suggest that a single oral dose of citalopram can induce significant but transitory suppression of motor cortex excitability in normal subjects.     

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.     

Effects of low frequency and low intensity repetitive paired pulse stimulation of the primary motor cortex.

OBJECTIVE: Following a previous report [Bestmann et al. Clin Neurophysiol 2004;115:755-64] that pairs of subthreshold pulses of transcranial magnetic stimulation (TMS) can show temporal summation, we explored whether repeated application of pairs of stimulation could produce long-lasting after effects on the excitability of the human motor cortex. METHODS: Twelve healthy subjects received 25 min repetitive paired pulse magnetic stimulation (paired rTMS) given at a frequency of about 0.6 Hz over the left primary motor cortex (500 paired stimuli in total). The interval between the paired stimuli was 3 ms and the intensity of both stimuli was 80% of active motor threshold. The resting and active motor threshold, MEP recruitment curve, short interval intracortical inhibition (SICI) and facilitation, and the duration of the cortical silent period (SP) were tested for the right first interosseous muscle (FDI) before and two times after the end of 25 min paired rTMS. RESULTS: Prolonged subthreshold paired rTMS produced a significant decrease in excitability in the corticospinal projection to FDI: resting motor threshold was significantly increased and MEP recruitment was significantly decreased, SICI was significantly increased at 2 and 4 ms and the SP was significantly increased in duration. CONCLUSIONS: Prolonged low frequency paired rTMS at subthreshold intensity can modulate cortical excitability by producing inhibitory effects that outlast the period of stimulation.     

Mirtazapine increases cortical excitability in healthy controls and epilepsy patients with major depression

BACKGROUND: Epilepsy is often complicated by depression requiring antidepressant treatment. Such treatment might be proconvulsive. OBJECTIVE: To examine the effects of the noradrenergic and specific serotonergic antidepressant mirtazapine on motor cortex excitability in epilepsy patients with depression and in healthy controls, using transcranial magnetic stimulation (TMS). METHODS: Seven clinically depressed epilepsy patients treated with anticonvulsant drugs and six healthy volunteers were studied. Before intake of mirtazapine and 24 hours afterwards (and also three weeks afterwards in the patients), the active and resting motor threshold (AMT, RMT), the size of the motor evoked potential (MEP), the cortical silent period (SP), and intracortical inhibition/facilitation and intracortical facilitatory I wave interactions were determined using single and paired pulse TMS. RESULTS: At baseline, AMT and RMT were higher (p = 0.049 and p = 0.04, respectively) and the ratio SP duration/MEP area greater in patients (p = 0.041). In patients but not in healthy subjects AMT was lower 24 hours after intake of mirtazapine (p = 0.028). Mirtazapine had no significant effect on the MEP size, duration of the SP, or the ratio of SP duration to MEP size in patients. The duration of the SP was longer (p = 0.037) but the ratio of SP duration to MEP size remained similar in healthy subjects after mirtazapine. There were no significant differences in paired pulse measures between the two groups either at baseline or after mirtazapine. CONCLUSIONS: Mirtazapine increased neuronal excitability of pyramidal tract axons in an activated state in both healthy controls and epilepsy patients with major depression.     

Facilitation of rhythmic events in progressive myoclonus epilepsy: a transcranial magnetic stimulation study.

Twelve subjects with progressive myoclonus epilepsy (PME) were studied with transcranial magnetic stimulation (TMS), using single and paired magnetic stimuli at different interstimulus intervals (ISIs), and polygraphic recording. Motor threshold (T) and silent period (SP) were normal. Paired TMS showed a loss of inhibition at 100-150 ms ISI and a marked facilitation at 50 ms ISI of conditioned motor evoked potential (MEP). Polygraphic analysis showed 20 Hz oscillatory activity over the sensorimotor area coupled to contralateral myoclonic jerks. These findings suggest a condition of increased supraspinal excitability and support the evidence of a cortical rhythm in the range of 20 Hz. No direct evidence exists that these findings are mediated by the same intracortical pathway. Furthermore, the normal SP and T suggest that the abnormal excitability is not a constant feature but is evident during rhythmic events.     

Effects of right unilateral electroconvulsive therapy on motor cortical excitability in depressive patients

Electroconvulsive therapy (ECT) is a widely acknowledged effective treatment for severe major depression. ECT produces considerable anticonvulsant effects that may be related to an increased GABA-ergic neurotransmission. We aimed to explore whether motor cortical excitability as assessed with single and paired pulse transcranial magnetic stimulation (TMS) could be used to investigate these anticonvulsant effects. Therefore, parameters of motor cortical excitability were investigated in 10 patients before and after 10 sessions of right unilateral ECT. After 10 sessions of right unilateral ECT, an enhanced activity of inhibitory circuits in human motor cortex had been observed, as measured by both increased intracortical inhibition and cortical silent period duration, whereas intracortical facilitation and resting motor threshold remained unchanged. The reduction of seizure duration in the course of ECT was associated with clinical improvement and an increase in intracortical inhibition. We interpret this finding as further indirect evidence for changes in inhibitory circuits in the course of ECT in patients with major depression.     

Assessment of cortical excitability using threshold tracking techniques

Conventional paired-pulse transcranial magnetic stimulation (TMS) techniques of assessing cortical excitability are limited by fluctuations in the motor evoked potential (MEP) amplitude. The aim of the present study was to determine the feasibility of threshold tracking TMS for assessing cortical excitability in a clinical setting and to establish normative data. Studies were undertaken in 26 healthy controls, tracking the MEP response from abductor pollicis brevis. Short-interval intracortical inhibition (SICI) occurred up to an interstimulus interval (ISI) of 7-10 ms, with two distinct peaks evident, at ISIs of < or =1 and 3 ms, followed by intracortical facilitation to an ISI of 30 ms. Long-interval intracortical inhibition (LICI) occurred at ISIs of 50-300 ms, peaking at 150 ms. The present study has confirmed the effectiveness of the threshold tracking TMS technique in reliably and reproducibly measuring cortical excitability. Simultaneous assessment of upper and lower motor neuronal function with threshold tracking techniques may help to determine the site of disease onset and patterns of progression in neurodegenerative diseases.     

Zonisamide Changes Unilateral Cortical Excitability in Focal Epilepsy Patients

Background and Purpose

To evaluate changes in cortical excitability induced by zonisamide (ZNS) in focal epilepsy patients.

Methods

Twenty-four drug-naїve focal epilepsy patients (15 males; overall mean age 29.8 years) were enrolled. The transcranial magnetic stimulation parameters obtained using two Magstim 200 stimulators were the resting motor threshold, amplitude of the motor-evoked potential (MEP), cortical silent period, short intracortical inhibition, and intracortical facilitation. These five transcranial magnetic stimulation parameters were measured before and after ZNS, and the findings were compared.

Results

All 24 patients were treated with ZNS monotherapy (200-300 mg/day) for 8-12 weeks. After ZNS, MEP amplitudes decreased (-36.9%) significantly in epileptic hemispheres (paired t-test with Bonferroni''s correction for multiple comparisons, p<0.05), whereas the mean resting motor threshold, cortical silent period, short intracortical inhibition, and intracortical facilitation were unchanged (p>0.05). ZNS did not affect cortical excitability in nonepileptic hemispheres.

Conclusions

These findings suggest that ZNS decreases cortical excitability only in the epileptic hemispheres of focal epilepsy patients. MEP amplitudes may be useful for evaluating ZNS-induced changes in cortical excitability.     

Serum levels of carbamazepine and cortical excitability by magnetic brain stimulation

Abstract. We investigated the correlation between serum levels of carbamazepine (CBZ) and motor excitability studied by different parameters of transcranial magnetic stimulation (TMS) in patients at the beginning of antiepileptic treatment. A total of 10 patients with complex partial seizures following stroke were treated with loading doses of CBZ. Motor evoked potential (MEP) was recorded from the thenar eminence (TE) muscles of the unaffected arm. In all patients, we studied rest and active motor threshold (rMT, aMT), MEP amplitude and cortical silent period (CSP). In three patients, intracortical inhibition (ICI) and intracortical facilitation (ICF) were measured using paired TMS at short interstimulus intervals (1–25 ms). The recording sessions were performed before treatment and after 7, 15 and 60 days (SD=16 days). Serum level of CBZ were monitored at each recording session. We observed a progressive increase in rMT and aMT until the serum levels of CBZ reached a steady state condition. No significant changes were observed in MEP amplitude, CSP, ICI and ICF. This study documents the increase of both motor threshold and drug serum levels in patients treated with loading doses of CBZ, suggesting a relationship between drug metabolism and the effect on motor cortical excitability.     

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 JME and 10 normal subjects underwent partial sleep deprivation. Motor threshold (MT), motor evoked potential amplitude (MEP), and silent period (SP) were recorded from the thenar eminence (TE) muscles. Short latency intracortical inhibition (SICI) and short latency intracortical facilitation (SICF) were studied using paired magnetic stimulation. TMS was performed before and after sleep deprivation; EEG and TMS were performed simultaneously. RESULTS: In patients with JME, sleep deprivation induced a significant decrease in SICI and an increase in SICF, which was associated with increased paroxysmal activity. A significant decrease in the MT was observed. No significant changes in any TMS parameters were noted in normal subjects after sleep deprivation. The F wave was unchanged by sleep deprivation in both control subjects and in patients with JME. CONCLUSIONS: In patients with JME, sleep deprivation produces increases in corticospinal excitability in motor areas as measured by different TMS parameters.     

Methylphenidate facilitates and disinhibits the motor cortex in intact humans

Animal experiments show that motor recovery after focal brain injury is accelerated by the indirect norepinephrine agonist methylphenidate (MPH). The underlying mechanisms are unknown, but an MPH-induced increase in cortical excitability has been advocated. Here, we tested the acute effects of a single oral dose of 40 mg MPH (Ritalin) on motor cortical excitability in eight healthy subjects using focal transcranial magnetic stimulation. MPH increased the slope of the motor evoked potentials (MEP) intensity curve in a hand muscle, reduced short-interval intracortical inhibition, and increased I-wave facilitation. MEP threshold, cortical silent period and measures of spinal and neuromuscular excitability remained unaffected. Findings support the idea that MPH promotes accelerated motor recovery after lesion through facilitation and disinhibition.     

Excitability profile of motor evoked potentials and silent periods

The aim of this study was to confirm the excitability profile of human cortical circuits on the motor evoked potential (MEP) and the silent period (SP) after paired transcranial magnetic stimulation (TMS) with variable interstimulus intervals (ISI), and to compare the time courses of MEP and SP after paired TMS at variable ISIs. MEPs were elicited at the hypothenar muscles at rest, and during tonic muscle contraction by applying paired TMS to the motor cortex. The authors measured the MEP amplitude during rest and the duration of SP during tonic muscle contraction at various ISIs. The response to paired stimuli was inhibited by an ISI of 15 ms and facilitated by an ISI of 1020 ms. The SP at an ISI of 15 ms was shorter than that at the single suprathreshold stimulus, but the SP at an ISI of 1525 ms was longer than this. A significant correlation was observed between the MEP amplitude and the duration of SP at ISIs of 120 ms and for a CS of 80% of threshold. These results may provide useful data for the study of the function of cortical excitability in disease states and suggest that the neural circuits underlying MEP and SP differ partly.     

Modulation of cortical excitability during action observation: a transcranial magnetic stimulation study

Paired-pulse transcranial magnetic stimulation (TMS) was used to examine changes in cortical excitability during action observation. We stimulated the left primary motor cortex (M1) of eight healthy volunteers during rest, observation of handwriting and observation of arm movements. Motor evoked potentials (MEP) were recorded from the first dorsal intereosseous (FDI) and biceps (BIC) muscles. Our results showed that action observation induced a facilitation of the MEP amplitude evoked by the single test stimulus and reduced intracortical inhibition and facilitation at 3 ms and 12 ms interstimulus intervals (ISIs), respectively, during paired-pulse stimulation. These changes were specific for the muscle involved in the observed action. Our study presents further evidence that motor excitability is significantly modified when the subject observes an action performed by another individual.     

Direct demonstration of the effect of lorazepam on the excitability of the human motor cortex.

OBJECTIVES: The present study explored the effects of lorazepam, a benzodiazepine with agonist action at the GABA(A) receptor, on human motor cortex excitability as tested using transcranial magnetic stimulation. METHODS: We recorded directly the descending volley evoked by single and paired transcranial magnetic stimulation from the spinal cord of a conscious subject with a cervical epidural electrode before and after a single oral dose of lorazepam. We evaluated the effects of lorazepam on the descending volleys evoked by a single magnetic stimulation and paired cortical stimulation using the intracortical inhibition paradigm (subthreshold conditioning stimulus) and the short latency intracortical facilitation paradigm (suprathreshold conditioning stimulus). RESULTS: Using a single magnetic stimulus lorazepam decreased the amplitude of the later I waves in the descending volley; this was accompanied by a decrease in the amplitude of the evoked EMG response. Using the intracortical inhibition paradigm lorazepam increased the amount of corticocortical inhibition, particularly at 4 and 5 ms interstimulus intervals. There was no effect on the amount of facilitation observed in the short latency intracortical facilitation paradigm. CONCLUSIONS: The present findings provide direct evidence that lorazepam increases the excitability of inhibitory circuits in the human motor cortex.     

Changes of cortical excitability of human motor cortex in spinocerebellar ataxia type 2. A study with paired transcranial magnetic stimulation

The aim of this study was to evaluate motor cortex excitability in spinocerebellar ataxia type 2 (SCA2). Cortical silent period (CSP), motor thresholds, and intracortical inhibition and facilitation by paired transcranial magnetic stimulation (TMS) were investigated in 18 SCA2 patients and in 20 controls. The mean CSP duration and motor threshold after TMS were significantly increased in the patient group. Intracortical inhibition by paired TMS at short interstimulus intervals (ISIs) showed no significant differences between patients and controls; at longer ISIs, the expected facilitation of test responses, observed in control subjects, resulted significantly less marked in SCA2 patients at all the tested intervals. Our findings extend previous findings on cerebellar dysfunctions of varying aetiologies by investigating intracortical excitability in SCA2. In addition, this study demonstrates that the cortical excitability involvement found in SCA2 is independent on the cytosine-adenine-guanine repeat expansion. The neurophysiological alterations seen in our patients relate to the worsening of general clinical condition. Thus, we might speculate that changes of motor cortex excitability in SCA2 represent a slow neurodegenerative process characterized by gradual loss of cerebellar neurons leading to an increasing disturbance of the balance between inhibitory and excitatory circuits in the motor system.     

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.     

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.     

The alpha2-adrenergic agonist guanfacine reduces excitability of human motor cortex through disfacilitation and increase of inhibition.

OBJECTIVE: To test the acute effects of the alpha2-adrenoceptor agonist guanfacine (GFC) on motor excitability in intact humans. METHODS: Eight healthy right-handed adults received a single oral dose of 2 mg of GFC. Motor cortex excitability was tested by focal transcranial magnetic stimulation of the hand area of the left motor cortex. Motor evoked potentials (MEP) were recorded from the right abductor pollicis brevis muscle. In addition, spinal and neuromuscular excitability were tested. All measures were obtained immediately before GFC intake (baseline), and 2, 6, and 24 h later. RESULTS: GFC decreased the slope of the MEP intensity curve, increased paired-pulse short-interval intracortical inhibition, and decreased paired-pulse intracortical facilitation and I-wave facilitation. These effects were maximal at 2-6 h and returned to baseline at 24 h. Motor threshold, cortical silent period, and the measures of spinal (peripheral silent period, F waves) and neuromuscular excitability (maximum M wave) remained unaffected. CONCLUSIONS: This is the first study on the effects of an anti-noradrenergic drug on human motor cortex excitability. GFC reduced cortical excitability by disfacilitation and increased inhibition. These findings support the idea that anti-noradrenergic drugs are detrimental for cortical plasticity and learning which are down-regulated by disfacilitation or increased inhibition.     

Cortical excitability and sleep deprivation: a transcranial magnetic stimulation study

The objective was to assess the changes in cortical excitability after sleep deprivation in normal subjects. Sleep deprivation activates EEG epileptiform activity in an unknown way. Transcranial magnetic stimulation (TMS) can inform on the excitability of the primary motor cortex. Eight healthy subjects (four men and four women) were studied. Transcranial magnetic stimulation (single and paired) was performed by a focal coil over the primary motor cortex, at the "hot spot" for the right first dorsal interosseous muscle. The following motor evoked potential features were measured: (a) active and resting threshold to stimulation; (b) duration of the silent period; (c) amount of intracortical inhibition on paired TMS at the interstimulus intervals of 2 and 3 ms and amount of facilitation at interstimulus intervals of 14 and 16 ms. The whole TMS session was repeated after a sleep deprivation of at least 24 hours. After the sleep deprivation, the threshold to stimulation (in the active and resting muscle), as well as the silent period, did not change significantly. By contrast, the paired stimulus study showed a significant (p<0.05) reduction in both intracortical inhibition and facilitation. Thus, TMS showed that sleep deprivation is associated with changes in inhibition-facilitation balance in the primary motor cortex of normal subjects. These changes might have a link with the background factors of the "activating" effects of sleep deprivation.     

Central effect of botulinum toxin type A in humans

This study investigated the changes in the cortical excitability with a paired-pulse transcranial magnetic stimulation (TMS) model after a botulinum toxin type A (BTA) injection in normal humans. Ten healthy subjects were enrolled in the study, which involved applying paired TMS to the motor cortex and recording the motor evoked potentials (MEP) before and after the BTA injection. BTA (2.5 mouse units) was injected into the right extensor digitorum brevis muscle. The amplitudes of MEP during rest and the cortical silent period (CSP) for the period of the tonic muscle contraction were measured at an interstimulus interval (ISI) of 3 ms and 20 ms. One month and three months after BTA injection, the level of intracortical inhibition increased significantly at an ISI of 3 ms and the intracortical facilitation decreased at an ISI of 20 ms. The duration of CSP shortened significantly at an ISI of 3 ms 1 month after BTA injection, which was also shortened significantly at an ISI of 20 ms. These findings were maintained until 3 months after the injection. It was concluded that cortical excitability could be modified by BTA injection in normal humans.