Increasing cortical excitability: a possible explanation for the proconvulsant role of sleep deprivation

STUDY OBJECTIVE: Sleep deprivation (SD) is known to facilitate both seizures and interictal epileptiform abnormalities. For this reason, it is often used in the routine diagnostic workup of epileptic patients as an activating procedure for eliciting epileptiform and/or seizure patterns in their EEGs. In order to evaluate the effects of SD on cortical excitability, we studied the effects of sleep loss on healthy subjects by transcranial magnetic stimulation (TMS). DESIGN AND PARTICIPANTS: Seven normal subjects underwent TMS examination in baseline condition and after total sleep deprivation. The TMS investigation included two protocols: a) the evaluation of motor evoked potential and silent period parameters recorded in response to single-pulse magnetic stimulation; and b) the evaluation of the time course of intracortical motor activity tested with paired-pulse TMS applied at inter-stimulus intervals of 1-6 ms. SETTING: Clinical neurophysiology laboratory in a general hospital. INTERVENTIONS: None. RESULTS: After SD, the principal finding observed using single-pulse TMS was a decrease of the silent period duration, whereas a reduction of the intracortical inhibition, in particular at inter-stimulus intervals 1 and 2 ms, was found, using the paired-pulse TMS. CONCLUSION: Our findings suggest that SD may modify cortical excitability, seen as the balance between inhibitory and excitatory cortical phenomena, which could reduce the epileptic threshold.     

The effect of test TMS intensity on short-interval intracortical inhibition in different excitability states

The paired-pulse transcranial magnetic stimulation (TMS) paradigm is increasingly employed to examine intracortical inhibitory processes in different motor tasks. Short-interval intracortical inhibition (SICI) has been shown to vary with the size of the MEP elicited by the test TMS pulse. This suggests that factors that alter MEP size, such as changes in cortical excitability, may confound the interpretation of SICI. However, the effect of excitability on SICI has not been systematically investigated. The present study examined SICI in 11 volunteers. The effect of test TMS intensities ranging from 90 to 150% resting motor threshold (RMT) on SICI was examined in three excitability states in the right first dorsal interosseous muscle: rest, isometric abduction of the left index finger (Contra) and isometric abduction of the right index finger (Active). For all excitability states SICI was not observed when test TMS intensity was less than 110% resting motor threshold. This was true even for the Active condition in which 90 and 100% test TMS intensities elicited large and consistent MEPs. For all conditions moderately suprathreshold test TMS intensities (110–120% RMT) yielded the greatest measure of SICI; increasing test TMS intensities resulted in a progressive reduction in the estimate of SICI. These results suggest that estimates of SICI are systematically affected by the intensity of the test TMS pulse, regardless of excitability state. The results suggest that SICI should be examined using a constant test TMS intensity regardless of changes in cortical excitability and test MEP size.     

Corticospinal excitability in human subjects during nonrapid eye movement sleep: single and paired-pulse transcranial magnetic stimulation study

The mechanisms responsible for changes in brain function during normal sleep are poorly understood. In this study, we aimed to investigate the effects of sleep on human corticospinal excitability by estimating resting motor threshold (RMT), and latency and amplitude of motor-evoked potentials (MEPs) after delivering transcranial magnetic stimulation (TMS) in ten healthy subjects. We also aimed to study short-interval intracortical inhibition (SICI) during sleep with paired-pulse TMS (pp-TMS). Ten healthy volunteers were studied. They were monitored immediately before, during and after a 3-h sleep (from 1 p.m. to 4 p.m., immediately after the mid-day meal). EEG was continuously recorded during sleep and the various sleep stages were identified off line. Every 10 min, subjects received ten single stimuli (to estimate RMT, MEP latency and amplitude) and six paired stimuli (to estimate SICI). MEP amplitude decreased and latency and RMT increased during the various sleep stages and returned to baseline values on awakening. Post hoc comparisons showed a significant difference in pp-TMS MEP amplitudes between the sleep and all the other conditions. The changes in TMS evoked variables during the different sleep stages indicate that during nonrapid eye movement sleep, cortical pyramidal neuron excitability (as measured by RMT, MEP latency and amplitude) progressively diminishes and the efficiency of the intracortical GABA-ergic network (as assessed by three pp-TMS) increases. On awakening, these sleep-induced changes in corticospinal excitability return rapidly to values observed during wakefulness.     

Effects of a high-frequency,low-intensity,biphasic conditioning train of TMS pulses on the human motor cortex

Intracortical circuit excitability of the human motor cortex has been studied by measuring effects of some conditioning TMS stimulus on the succeeding test TMS stimulus in the motor cortex, such as short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF). A single-pulse TMS was used as a conditioning stimulus (CS) in these techniques, but a train of several TMS pulses might induce some intracortical changes in the motor cortex more effectively. For nine healthy volunteers, we compared the SICI and ICF induced by a single conditioning biphasic TMS pulse with those induced by a train of 10 biphasic TMS pulses of the same intensity. As a conditioning stimulus, we delivered a subthreshold single biphasic pulse (CS1) or 10, 10-Hz biphasic pulses (CS10) before a suprathreshold monophasic test stimulus at several interstimulus intervals (ISIs) of 3–40 ms over the hand motor area. The CS intensity was 50–100% of the active motor threshold (AMT). We compared the motor cortical excitability after the conditioning stimulus (single pulse or a train of ten pulses) at the intervals for SICI and ICF. A train of ten 10-Hz pulses elicited greater inhibition at short ISIs than a single conditioning pulse did. The facilitation at ISIs around 10 ms corresponding to the ICF was evoked by CS1 only at an intensity of 80% AMT; CS10 evoked no ICF. Furthermore, CS10 evoked MEP inhibition at longer intervals. Results show that a train of high-frequency, low-intensity, biphasic TMS pulses can have a strong inhibitory effect on the motor cortex.     

Differences between Han Chinese and Caucasians in transcranial magnetic stimulation parameters

The study was conducted to investigate the difference between Han Chinese and Caucasians on various parameters measured from responses to transcranial magnetic brain stimulation (TMS). Sixteen subjects were studied in each group. A circular coil at the vertex was used for stimulation, whilst recording surface electromyograms from right first dorsal interosseous. In the passive state, motor-evoked potential (MEP) threshold, MEP recruitment, short-interval intracortical inhibition (SICI) and intracortical facilitation were measured. The MEP threshold, recruitment and silent period were also measured in the active state. Chinese subjects showed significantly higher passive thresholds (P < 0.005), less inhibition of the motor response (SICI, P < 0.0005) and a shorter silent period (P < 0.05). Differences in SICI appeared to be a consequence of the differences in passive threshold and were not seen when active threshold was used to determine the conditioning stimulus intensity. Differences in silent period may also reflect differences in cortical excitability rather than inhibitory processes, as they were not seen when the silent-period duration was expressed as a function of MEP size, rather than TMS intensity. There appears to be a significant difference in some TMS parameters between Han Chinese and Caucasian subjects. This may reflect an underlying difference in cortical excitability.     

Riluzole suppresses motor cortex facilitation in correlation to its plasma level

The aim of our study was to measure the effects of the glutamate antagonist riluzole on different parameters of motor excitability, using transcranial magnetic stimulation (TMS) during 7 days of riluzole administration, and to correlate these effects with riluzole plasma levels. Nine healthy volunteers received a dose of 100 mg riluzole from day 1 to 7 of the study period. Electrophysiological examinations were performed on day 1 before and 2 h, 5 h and 8 h after riluzole administration, on day 2, day 3 and day 5 before riluzole administration, and on day 8. Plasma samples were taken simultaneously. The excitability of the motor cortex, supraspinal and spinal motor pathways was tested by studying intracortical facilitation and inhibition, the cortical silent period and motor threshold after TMS, as well as the peripheral silent period and F-wave amplitudes after electrical peripheral nerve stimulation. We found a significant reduction of intracortical facilitation, which correlated significantly with riluzole plasma levels. To a lesser extent, intracortical inhibition was enhanced on day 1, motor threshold was increased on day 8 and F-wave amplitudes were reduced. These changes did not correlate with riluzole plasma levels. We conclude that the main effect of riluzole in vivo is a reduction of intracortical facilitation, which is closely related to the drug's level in the plasma. The most probable mechanism involves an effect on glutamatergic synaptic transmission.     

Inhibitory and excitatory intracortical circuits across the human sleep–wake cycle using paired-pulse transcranial magnetic stimulation

Studies using single-pulse transcranial magnetic stimulation (TMS) have shown that excitability of the corticospinal system is systematically reduced in natural human sleep as compared to wakefulness with significant differences between sleep stages. However, the underlying excitatory and inhibitory interactions on the corticospinal system across the sleep–wake cycle are poorly understood. Here, we specifically asked whether in the motor cortex short intracortical inhibition (SICI) and facilitation (ICF) can be elicited at all in sleep using the paired-pulse TMS protocol, and if so, how SICI and ICF vary across sleep stages. We studied 28 healthy subjects at interstimulus intervals of 3 ms (SICI) and 10 ms (ICF), respectively. Magnetic stimulation was performed over the hand area of the motor cortex using a focal coil and evoked motor potentials were recorded from the contralateral first dorsal interosseus muscle (1DI). Relevant data was obtained from 13 subjects (NREM 2: n = 7; NREM 3/4: n = 7; REM: n = 7). Results show that both SICI and ICF were present in NREM sleep. SICI was significantly enhanced in NREM 3/4 as compared to wakefulness and all other sleep stages whereas in NREM 2 neither SICI nor ICF differed from wakefulness. In REM sleep SICI was in the same range as in wakefulness, but ICF was entirely absent. These results in humans support the hypothesis derived from animal experiments which suggests that intracortical inhibitory mechanisms are involved in the control of neocortical pyramidal cells in NREM and REM sleep, but along different intraneuronal circuits. Further, our findings suggest that cortical mechanisms may additionally contribute to the inhibition of spinal motoneurones in REM sleep.     

Excitability of the motor cortical representation of the external anal sphincter

This study was designed to assess the excitability of the motor cortical representation of the external anal sphincter by using transcranial magnetic stimulation (TMS). In six healthy volunteers, the rest motor threshold and the duration of the cortical silent period were determined with single TMS pulses, and the intracortical inhibition and facilitation were measured with paired TMS pulses. Values obtained from the anal sphincter were compared with those obtained from a muscle in the right hand. All subjects completed the study. Rest motor threshold and intracortical facilitation were similar in both muscles. In contrast, cortical silent period duration and intra-cortical inhibition were less for the anal sphincter than for hand muscle. This study has opened new perspectives for the investigation of anal sphincter cortical control in humans.     

Changes in motor cortical excitability in humans following orally administered theophylline

The effects of theophylline on human corticospinal excitability were studied using transcranial magnetic stimulation (TMS) before and after double-blind oral administration of theophylline or placebo in 20 healthy volunteers. TMS measurements included resting and active motor threshold, silent period, intracortical inhibition (ICI), and intracortical facilitation. F-wave and compound muscle action potential (CMAP) were also measured. Theophylline produces a reduction in ICI, while other parameters of corticospinal excitability remained unaffected. Since ICI is thought to depend on GABAA intracortical inhibitory mechanisms, our data suggest that the increase of human motor cortex excitability is the result of a decrease in GABAergic transmission. Our results further support the hypothesis that theophylline might induce convulsions by inhibiting GABAA receptor binding.     

Effects on the right motor hand-area excitability produced by low-frequency rTMS over human contralateral homologous cortex

Repetitive transcranial magnetic stimulation (rTMS) has long lasting effects on cortical excitability at the site of stimulation, on interconnected sites at a distance and on the connections between them. In the present experiments we have used the technique of transcallosal inhibition between the motor cortices to examine all three effects in the same protocol. Ten healthy subjects received 900 rTMS stimuli at 1 Hz from a figure of eight coil over the left motor hand area. The intensity of rTMS was above the threshold for inducing short latency interhemispherical inhibition with a single stimulus (equivalent to 115–120 % resting motor threshold). Before and after the rTMS we evaluated: (1) in the left hemisphere, the amplitude of motor-evoked potentials (MEPs), and contralateral and ipsilateral cortical silent periods (CSP, ISP); (2) in the right hemisphere, MEP, CSP, ISP and short-interval intracortical inhibition and intracortical facilitation (SICI/ICF), and (3) interhemispherical inhibition (IHI) from the left-to-right hemisphere using a paired-pulse method. There were two main effects after rTMS to the left hemisphere: first, the amplitude of MEPs from the right hemisphere increased; second, there was a reduction in the IHI from the left-to-right hemisphere at interstimulus intervals of 7 and 10 ms but not at longer intervals (15–75 ms). Control experiments showed that these effects were not due to afferent inputs produced by the muscle twitches induced during the rTMS. The data are compatible with the notion that rTMS to the left hemisphere leads to reduced interhemispherical inhibition of the right hemisphere and a consequent increase in corticospinal excitability in that hemisphere.     

Increased corticospinal excitability after 5 Hz rTMS over the human supplementary motor area

Transcranial magnetic stimulation (TMS) can produce effects not only at the site of stimulation but also at distant sites to which it projects. Here we examined the connection between supplementary motor area (SMA) and the hand area of the primary motor cortex (M1_Hand) by testing whether prolonged repetitive TMS (rTMS) over the SMA can produce changes in excitability of the M1_Hand after the end of the stimulus train. We evaluated motor-evoked potentials (MEPs) and the cortical silent period (CSP) evoked by a single-pulse TMS, short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) produced by a paired-pulse TMS, and forearm flexor H reflexes before and after 750 pulses of 5 Hz rTMS over SMA at an intensity of 110% active motor threshold (AMT) for the first dorsal interosseous (FDI) muscle. The amplitude of MEPs recorded from the right FDI muscle at rest as well as during voluntary contraction increased for at least 10 min after the end of rTMS, although the duration of the CSP, SICI and ICF did not change. There was no effect on H reflexes in the flexor carpi radialis muscle, even though the amplitude of the MEP obtained from the same muscle increased after rTMS. The effects on MEPs depended on the intensity of rTMS and were spatially specific to the SMA proper. We suggest that 5 Hz rTMS over SMA can induce a short-lasting facilitation in excitability of the M1_Hand compatible with the anatomical connections between SMA and the M1_Hand.     

Stable motor cortex excitability in red and green lighting conditions

Illumination science has long established effects of coloured light on emotional state, cognitive performance, plus tactile, gustatory and olfactory perception. To explore the neurobiological mechanisms underlying these crossmodal phenomena, cortical excitability was addressed by single and paired-pulse transcranial magnetic stimulation (TMS) in 23 men with normal colour vision, and in 10 subjects with red–green blindness. Using a sequential challenge, excitability measures were recorded at baseline and during exposure to either red or green light. Dichromacy did not predict any of the electrophysiological parameters under study regardless of the spectral paradigm. In both dichromats and trichromats, red and green illumination did not induce any significant effects on resting motor threshold, short intracortical inhibition, intracortical facilitation and cortical silent periods. Our results suggest that motor cortex excitability as assessed by TMS is not sensitive to the modulatory effects of context-independent red and green light.     

The effects of repetitive transcranial magnetic stimulation on cortical inhibition in healthy human subjects

It has been suggested that the therapeutic effects of repetitive transcranial magnetic stimulation (rTMS) are mediated through changes in cortical inhibition (CI). However, in healthy human subjects the effects of rTMS on CI have been inconsistent. Therefore, this study sought to improve on the methodological limitations of previous studies by exploring several different rTMS-stimulus conditions on inhibition in the human motor cortex. In the first experiment, 12 healthy control subjects were randomly assigned to receive regular 1, 10 or 20 Hz rTMS in a counterbalanced order with sessions separated by at least 1 week. In the second experiment, 10 of these 12 subjects received priming rTMS (600 stimuli at 6 Hz followed by 600 stimuli at 1 Hz). Cortical inhibition was indexed using short-interval intracortical inhibition (SICI) and cortical silent period (CSP). Corticospinal excitability was indexed using motor threshold and MEP amplitude. We found no significant overall change in SICI, although there was a significant correlation between changes in SICI with baseline SICI. Subjects with greater SICI at baseline tended to have reduction in SICI post-rTMS, whereas subjects with less SICI tended to have increase in SICI post-rTMS. There was also a significant lengthening of the CSP with higher stimulation frequencies compared to lower stimulation frequencies. These findings suggest that rTMS increases CI, particularly in subjects with reduced baseline inhibition, a finding consistent with the concept of homeostatic plasticity. Baseline physiological characteristics may be further explored as a method to select patients who may benefit from rTMS treatment.     

Modification of motor cortical excitability by an acetylcholinesterase inhibitor

Acetylcholine powerfully modulates the excitability of neocortical neurones and networks. This study applied focal transcranial magnetic stimulation (TMS) to eight healthy subjects to test the effects of a single oral dose of 40 mg tacrine, an acetylcholinesterase inhibitor, on motor cortical excitability. It was found that tacrine decreased short-interval intracortical inhibition, and increased intracortical facilitation and short-interval intracortical facilitation. Motor thresholds, motor evoked potential amplitude, cortical silent period (CSP) duration, and measures of spinal and neuromuscular excitability remained unchanged. The effects peaked at 2–6 h and fully reversed after 24 h. All effects can be explained by a reduction of motor cortical GABAergic inhibitory neurotransmission via activation of presynaptic muscarinic M2 receptors, but other more complex mechanisms may also have contributed and are discussed. The findings predict that acetylcholine has the potential to promote plasticity and learning in human motor cortex.     

Cognitive alteration after carotid revascularization is correlated with cortical GABA(B)-ergic modulations

The present study evaluates the hypotheses that a GABAergic mechanism underlies neurobehavioral sequelae of carotid stenosis and that it can be reversed by carotid revascularization. We used the Rivermead Behavioural Memory Test (RBMT), short interval intracortical inhibition (SICI), intracortical facilitation (ICF), long interval intracortical inhibition (LICI), and cortical silent period (CSP) to evaluate cognitive function and cerebral cortical excitability in 16 carotid artery stenosis patients with cognitive impairment before carotid arterial stenting (CAS) and 1 month later. We compared the pre- and post-CAS results and those of 16 healthy controls. CSP was prolonged in patients compared with controls (195.8±18ms vs. 157.8±13.9ms; p<0.0001, unpaired t-test). Patients tended to a have high resting motor threshold and less pronounced SICI and ICF than controls, but differences were not significant. Decreased RBMT score was correlated with hyperperfusion and CSP increase after CAS. RBMT score increase was correlated with CSP normalization. LICI showed positive correlation with CSP. CSP may provide a means of probing the integrity of GABA(B)-ergic networks in an ischemic human brain. CSP and LICI are potential tools to explore neuronal function for improvement as well as impairment after carotid revascularization.     

Repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex (DLPFC) during capsaicin-induced pain: modulatory effects on motor cortex excitability

Evidence by functional imaging studies suggests the role of left DLPFC in the inhibitory control of nociceptive transmission system. Pain exerts an inhibitory modulation on motor cortex, reducing MEP amplitude, while the effect of pain on motor intracortical excitability has not been studied so far. In the present study, we explored in healthy subjects the effect of capsaicin-induced pain and the modulatory influences of left DLPFC stimulation on motor corticospinal and intracortical excitability. Capsaicin was applied on the dorsal surface of the right hand, and measures of motor corticospinal excitability (test-MEP) and short intracortical inhibition (SICI) and facilitation (ICF) were obtained by paired-pulse TMS on left motor cortex. Evaluations were made before and at different times after capsaicin application in two separate sessions: without and with high-frequency rTMS of left DLPF cortex, delivered 10 min. after capsaicin application. We performed also two control experiments to explore: 1: the effects of Left DLPFC rTMS on capsaicin-induced pain; 2: the modulatory influence of left DLPFC rTMS on motor cortex without capsaicin application. Capsaicin-induced pain significantly reduced test MEP amplitude and decreased SICI leaving ICF unchanged. Left DLPFC rTMS, together with the analgesic effect, was able to revert the effects of capsaicin-induced pain on motor cortex restoring normal MEP and SICI levels. These data support the notion that that tonic pain exerts modulatory influence on motor intracortical excitability; the activation of left DLPFC by hf rTMS could have analgesic effects, reverting also the motor cortex excitability changes induced by pain stimulation.     

The effects of inhibitory and facilitatory intracortical circuits on interhemispheric inhibition in the human motor cortex

Inhibitory and facilitatory intracortical pathways regulating motor cortical output can be studied non-invasively in humans with transcranial magnetic stimulation. These circuits include short-interval intracortical inhibition (SICI), long-interval intracortical inhibition (LICI) and intracortical facilitation (ICF). Stimulation of the motor cortex also inhibits the contralateral motor cortex (interhemispheric inhibition, IHI) at short (∼10 ms, IHI10) or long intervals (∼40 ms, IHI40). We investigated how SICI, ICF, and LICI influence IHI10 and IHI40. We hypothesize that intracortical circuits will have similar effects on IHI and cortical output neurons: SICI and LICI will decrease IHI, and ICF will increase it. Motor evoked potentials were recorded from the first dorsal interosseous muscles bilaterally in 10 healthy subjects. We compared IHI10 and IHI40 alone to IHI10 and IHI40 elicited in the presence of SICI, ICF, or LICI. Our results showed that SICI and LICI reduced IHI10, IHI40 and corticospinal output to a similar degree. ICF increased corticospinal output but had no effect on either IHI10 or IHI40. The different effects of ICF on corticospinal excitability and IHI suggest the transcallosal fibres mediating IHI and the corticospinal output system arise from different neuronal populations. SICI and LICI produce more global inhibition with similar effects on the transcallosal and descending corticospinal circuits.     

Influence of the N-methyl- -aspartate antagonist memantine on human motor cortex excitability

The aim of our study was to investigate the effect of the N-methyl- -aspartate (NMDA) antagonist memantine on motor excitability in humans. Seven healthy volunteers received memantine or placebo, respectively, over a period of 8 days. At day 8, transcranial magnetic stimulation (TMS) was performed using a paired pulses paradigm in order to assess intracortical inhibition and facilitation. Additionally, motor threshold and silent period duration after TMS were measured as well as M waves, F waves and peripheral silent period after electrical peripheral nerve stimulation. Intracortical inhibition was enhanced, and intracortical facilitation reduced after memantine ingestion in comparison to placebo, whereas no significant difference could be observed regarding the other neurophysiological parameters. We conclude that the NMDA receptor is involved in the regulation of excitability of intracortical interneuronal circuits.     

Short-interval intracortical inhibition is modulated by high-frequency peripheral mixed nerve stimulation

Cortical excitability can be modulated by manipulation of afferent input. We investigated the influence of peripheral mixed nerve stimulation on the excitability of the motor cortex. Motor evoked potentials (MEPs), short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) in the right abductor pollicis brevis (APB), extensor carpi radialis (ECR) and first dorsal interosseous (FDI) muscles were evaluated using paired-pulse transcranial magnetic stimulation (TMS) before and after high-frequency peripheral mixed nerve stimulation (150Hz, 30min) over the right median nerve at the wrist. The MEP amplitude and SICI of the APB muscle decreased transiently 0-10min after the intervention, whereas the ICF did not change. High-frequency peripheral mixed nerve stimulation reduced the excitability of the motor cortex. The decrement in the SICI, which reflects the function of GABA(A)ergic inhibitory interneurons, might compensate for the reduced motor cortical excitability after high-frequency peripheral mixed nerve stimulation.     

Short-term reduction of intracortical inhibition in the human motor cortex induced by repetitive transcranial magnetic stimulation

Ten healthy subjects and two patients who had an electrode implanted into the cervical epidural space underwent repetitive transcranial magnetic stimulation (rTMS; 50 stimuli at 5 Hz at active motor threshold intensity) of the hand motor area. We evaluated intracortical inhibition before and after rTMS. In healthy subjects, we also evaluated threshold and amplitude of motor evoked potentials (MEPs), duration of cortical silent period and short-latency intracortical facilitation. rTMS led to a short-lasting reduction in the amount of intracortical inhibition in control subjects with a high interindividual variability. There was no significant effect on other measures of motor cortex excitability. Direct recordings of descending corticospinal volleys from the patients were consistent with the idea that the effect of rTMS on intracortical inhibition occurred at the cortical level. Since the level of intracortical inhibition can be influenced by drugs that act on GABAergic systems, this may mean that low-intensity repetitive magnetic stimulation at 5 Hz can selectively modify the excitability of GABAergic networks in the human motor cortex. Electronic Publication