Corticospinal Silent Period Research Articles

Neurophysiological effects of a combined treatment of lovastatin and minocycline in patients with fragile X syndrome: Ancillary results of the LOVAMIX randomized clinical trial.

Fragile X syndrome (FXS) is the primary hereditary cause of intellectual disability and autism spectrum disorder. It is characterized by exacerbated neuronal excitability, and its correction is considered an objective measure of treatment response in animal models, a marker albeit rarely used in clinical trials. Here, we used an extensive transcranial magnetic stimulation (TMS) battery to assess the neurophysiological effects of a therapy combining two disease-modifying drugs, lovastatin (40 mg) and minocycline (100 mg), administered alone for 8 weeks and in combination for 12 weeks, in 19 patients (mean age of 23.58 ± 1.51) with FXS taking part in the LOVAmix trial. The TMS battery, which included the resting motor threshold, short-interval intracortical inhibition, long-interval intracortical inhibition, corticospinal silent period, and intracortical facilitation, was completed at baseline after 8 weeks of monotherapy (visit 2 of the clinical trial) and after 12 weeks of dual therapy (visit 4 of the clinical trial). Repeated measure ANOVAs were performed between baseline and visit 2 (monotherapy) and visit 3 (dual therapy) with interactions for which monotherapy the participants received when they began the clinical trial. Results showed that dual therapy was associated with reduced cortical excitability after 20 weeks. This was reflected by a significant increase in the resting-motor threshold after dual therapy compared to baseline. There was a tendency for enhanced short-intracortical inhibition, a marker of GABAa-mediated inhibition after 8 weeks of monotherapy compared to baseline. Together, these results suggest that a combined therapy of minocycline and lovastatin might act on the core neurophysiopathology of FXS. This trial was registered at clinicaltrials.gov (NCT02680379).

Weak grip strength among persons with multiple sclerosis having minimal disability is not related to agility or integrity of the corticospinal tract

IntroductionMobility impairment is common in multiple sclerosis (MS); however, agility has received less attention. Agility requires strength and neuromuscular coordination to elicit controlled propulsive rapid whole-body movement. Grip strength is a common method to assess whole body force production, but also reflects neuromuscular integrity and global brain health. Impaired agility may be linked to loss of neuromuscular integrity (reflected by grip strength or corticospinal excitability). ObjectivesWe aimed to determine whether grip strength would be associated with agility and transcranial magnetic stimulation (TMS)-based indices of corticospinal excitability and inhibition in persons with MS having low disability. We hypothesized that low grip strength would predict impaired agility and reflect low corticospinal excitability. MethodsWe recruited 34 persons with relapsing MS (27 females; median [range] age 45.5 [21.0-65.0] years) and mild disability (median [range] Expanded Disability Status Scale 2.0 [0-3.0]), as well as a convenience sample of age- and sex-matched apparently healthy controls. Agility was tested by measuring hop length during bipedal hopping on an instrumented walkway. Grip strength was measured using a calibrated dynamometer. Corticospinal excitability and inhibition were examined using TMS-based motor evoked potential (MEP) and corticospinal silent period (CSP) recruitment curves, respectively. ResultsMS participants had significantly lower grip strength than controls independent of sex. Females with and without MS had weaker grip strength than males. There were no statistically significant sex or group differences in agility. After controlling for sex, weaker grip strength was associated with shorter hop length in controls only (r = 0.645, p < .05). Grip strength did not significantly predict agility in persons with MS, nor was grip strength predicted by corticospinal excitability or inhibition. ConclusionsIn persons with MS having low disability, grip strength (normalized to body mass) was reduced despite having intact agility and walking performance. Grip strength was not associated with corticospinal excitability or inhibition, suggesting peripheral neuromuscular function, low physical activity or fitness, or other psychosocial factors may be related to weakness. Low grip strength is a putative indicator of early neuromuscular aging in persons with MS having mild disability and normal mobility

Sub-concussive head impacts from heading footballs do not acutely alter brain excitability as compared to a control group.

Repeated sub-concussive head impacts are a growing brain health concern, but their possible biomarkers remain elusive. One impediment is the lack of a randomised controlled human experimental model to study their effects on the human brain. This work had two objectives. The first one was to provide a randomised controlled human experimental model to study the acute effects of head impacts on brain functions. To achieve this, this work's second objective was to investigate if head impacts from heading footballs acutely alter brain excitability by increasing corticospinal inhibition as compared to a control group. In practised and unpractised young healthy adults, transcranial magnetic stimulation was used to assess corticospinal silent period (CSP) duration and corticospinal excitability (CSE) before and immediately after performing headings by returning 20 hand-thrown balls directed to the head (Headings; n = 30) or the dominant foot (Control; n = 30). Moreover, the Rivermead Post-Concussion Questionnaire (RPQ) was used to assess the symptoms of head impacts. Head acceleration was also assessed in subgroups of participants. The intervention lengthened CSP duration in both the Headings (6.4 ± 7.5%) and Control groups (4.6 ± 2.6%), with no difference in lengthening between the two groups. Moreover, CSE was not altered by the intervention and did not differ between groups. However, performing headings increased headaches and dizziness symptoms and resulted in greater head acceleration upon each football throw (12.5 ± 1.9g) as compared to the control intervention (5.5 ± 1.3g). The results suggest that head impacts from football headings do not acutely alter brain excitability as compared to a control intervention. However, the results also suggest that the present protocol can be used as an experimental model to investigate the acute effects of head impacts on the human brain.

Corticospinal Responses Following Gait-Specific Training in Stroke Survivors: A Systematic Review

Corticospinal excitability is subject to alterations after stroke. While the reversal of these alterations has been proposed as an underlying mechanism for improved walking capacity after gait-specific training, this has not yet been clearly demonstrated. Therefore, the objective of this review is to evaluate the effect of gait-specific training on corticospinal excitability in stroke survivors. We conducted an electronic database search in four databases (i.e., Medline, Embase, CINAHL and Web of Science) in June 2022. Two authors screened in an independent way all the studies and selected those that investigated the effect of gait-specific training on variables such as motor-evoked potential amplitude, motor threshold, map size, latency, and corticospinal silent period in stroke survivors. Nineteen studies investigating the effect of gait-specific training on corticospinal excitability were included. Some studies showed an increased MEP amplitude (7/16 studies), a decreased latency (5/7studies), a decreased motor threshold (4/8 studies), an increased map size (2/3 studies) and a decreased cortical silent period (1/2 study) after gait-specific training. No change has been reported in terms of short interval intracortical inhibition after training. Five studies did not report any significant effect after gait-specific training on corticospinal excitability. The results of this systematic review suggest that gait-specific training modalities can drive neuroplastic adaptation among stroke survivors. However, given the methodological disparity of the included studies, additional clinical trials of better methodological quality are needed to establish conclusions. The results of this review can therefore be used to develop future studies to better understand the effects of gait-specific training on the central nervous system.

Comparison between Eccentric-Only and Coupled Concentric-Eccentric Contractions for Neuromuscular Fatigue and Muscle Damage.

Eccentric contractions induce muscle damage, but less is known about the effects of preceding concentric contractions to eccentric contractions on muscle damage. We compared eccentric-only (ECC) and coupled concentric and eccentric contractions (CON-ECC) of the knee extensors for parameters of neuromuscular fatigue and muscle damage. Twenty participants (age, 19-36 yr) were randomly placed into an ECC or a CON-ECC group (n = 10 per group), without significant (P > 0.06) differences in baseline neuromuscular variables between groups. The ECC group performed six sets of eight ECC at 80% of ECC one-repetition maximum (1-RMecc), whereas the CON-ECC group performed six sets of eight alternating concentric (CON) and ECC (16 contractions per set) at 80% of CON 1-RM and 1-RMecc, respectively. Maximal voluntary isometric contraction force, rate of force development, resting twitch force, maximal M-wave (MMAX), voluntary activation, motor evoked potentials, corticospinal silent period, short interval intracortical inhibition, and muscle soreness were measured before, immediately after, and 1-3 d after exercise. No significant (P ≥ 0.09) differences between ECC and CON-ECC were observed for changes in any variables after exercise. However, maximal voluntary isometric contraction force decreased immediately after exercise (ECC: -20.7% ± 12.8%, CON-ECC: -23.6% ± 23.3%) and was still reduced 3 d after exercise (ECC: -13.6% ± 13.4%, CON-ECC: -3.3% ± 21.2%). Rate of force development at 0-30 ms reduced immediately after exercise (ECC: -38.3% ± 33.9%, CON-ECC: -30.7% ± 38.3%). Voluntary activation, resting twitch force, and motor evoked potential/MMAX decreased and corticospinal silent period increased after exercise (all P ≤ 0.03), but short interval intracortical inhibition and MMAX did not change. Muscle soreness developed (P < 0.001) similarly for both groups (peak, 38.5 ± 29.5 mm). CON-ECC did not exacerbate neuromuscular fatigue and muscle damage when compared with ECC, despite twice as many contractions performed. Thus, eccentric contractions (n = 48 in both groups) seemed to mainly mediate the neuromuscular responses observed.

Effect of Maximal and Submaximal Muscle Activation on Corticospinal Excitability in Humans

IntroductionFollowing short duration (5‐10s), high intensity (≥70%MVC) muscle activation, there is an enhancement of muscle contractile properties, termed post action potentiation (PAP). During PAP induced by voluntary or electrically stimulated conditioning contractions (CC) it has been reported that the corticospinal silent period (SP), assessed by transcranial magnetic stimulation (TMS), is elongated. Although a coexistence between the two occurs, the direct effect of PAP on corticospinal excitability has not been systematically evaluated to help determine whether a direct link exists. The purpose was to assess SP duration following potentiating and non‐potentiating voluntary and electrically stimulated contractions. We hypothesized that maximal and submaximal CCs inducing PAP and those not inducing PAP enhancement, respectively, will prolong SP durations albeit to a lesser degree at submaximal intensities.MethodsTen healthy young (three females; 18‐35y) individuals free of neurological issues to date have participated in the study. Subjects were seated with their right forearm pronated and their hand was fixed to a custom finger abduction force dynamometer. Monopolar surface electromyography signals were recorded from the first dorsal interosseous muscle (FDI) with self‐adhering Ag/AgCl electrodes. Peripheral stimulated twitches and tetani (50Hz) were evoked over the ulnar nerve at the wrist via a pair of small readjustable electrodes. Maximal M‐waves (M‐max) and baseline levels of (voluntary and stimulated) PAP and force were obtained for each subject. Electrically stimulated and voluntarily induced CCs of 10s were performed at ~95% MVC and ~35% MVC for a total of four contraction conditions. Before and after these contractions SP times were obtained during the plateau of ~25% MVC held for three seconds. To obtain SP times the TMS output was set to elicit a response ~75% of M‐max. The four conditions of voluntary or stimulated, maximal and submaximal CCs were pseudo‐randomized and repeated four times per subject. The nearest three values from each subject were averaged and compared as a normalized percent change from baseline.ResultsFollowing both maximal voluntary and stimulated CCs, mean twitch torque was enhanced similarly (PAP ~180%) with no PAP at the submaximal levels. Mean change in SP duration following maximal voluntary CCs was ~14% longer than control values, while maximal tetanic CCs similarly prolonged the SP by ~13%. Both voluntary and stimulated submaximal contractions prolonged SP duration similarly by ~5% and ~6%, respectively.ConclusionThese findings indicate that corticospinal inhibition assessed as SP elongation is present not only when the muscle is enhanced under PAP but also occurs following contractions inducing no PAP. This suggests that the muscle activation required to induce PAP likely causes the observed corticospinal inhibition, not the enhanced muscle properties of PAP per se.

Hyperexcitability and impaired intracortical inhibition in patients with fragile-X syndrome

Fragile-X syndrome (FXS) is characterized by neurological and psychiatric problems symptomatic of cortical hyperexcitability. Recent animal studies identified deficient γ-aminobutyricacid (GABA) inhibition as a key mechanism for hyperexcitability in FXS, but the GABA system remains largely unexplored in humans with the disorder. The primary objective of this study was to assess GABA-mediated inhibition and its relationship with hyperexcitability in patients with FXS. Transcranial magnetic stimulation (TMS) was used to assess cortical and corticospinal inhibitory and excitatory mechanisms in 18 patients with a molecular diagnosis of FXS and 18 healthy controls. GABA-mediated inhibition was measured with short-interval intracortical inhibition (GABAA), long-interval intracortical inhibition (GABAB), and the corticospinal silent period (GABAA+B). Net intracortical facilitation involving glutamate was assessed with intracortical facilitation, and corticospinal excitability was measured with the resting motor threshold. Results showed that FXS patients had significantly reduced short-interval intracortical inhibition, increased long-interval intracortical inhibition, and increased intracortical facilitation compared to healthy controls. In the FXS group, reduced short-interval intracortical inhibition was associated with heightened intracortical facilitation. Taken together, these results suggest that reduced GABAA inhibition is a plausible mechanism underlying cortical hyperexcitability in patients with FXS. These findings closely match those observed in animal models, supporting the translational validity of these markers for clinical research.

Determining the early corticospinal-motoneuronal responses to strength training: a systematic review and meta-analysis.

Several studies have used transcranial magnetic stimulation to probe the corticospinal-motoneuronal responses to a single session of strength training; however, the findings are inconsistent. This systematic review and meta-analysis examined whether a single bout of strength training affects the excitability and inhibition of intracortical circuits of the primary motor cortex (M1) and the corticospinal-motoneuronal pathway. A systematic review was completed, tracking studies between January 1990 and May 2018. The methodological quality of studies was determined using the Downs and Black quality index. Data were synthesised and interpreted from meta-analysis. Nine studies (n=107) investigating the acute corticospinal-motoneuronal responses to strength training met the inclusion criteria. Meta-analyses detected that after strength training compared to control, corticospinal excitability [standardised mean difference (SMD), 1.26; 95% confidence interval (CI), 0.88, 1.63; p<0.0001] and intracortical facilitation (ICF) (SMD, 1.60; 95% CI, 0.18, 3.02; p=0.003) were increased. The duration of the corticospinal silent period was reduced (SMD, -17.57; 95% CI, -21.12, -14.01; p=0.00001), but strength training had no effect on the excitability of the intracortical inhibitory circuits [short-interval intracortical inhibition (SICI) SMD, 1.01; 95% CI, -1.67, 3.69; p=0.46; long-interval intracortical inhibition (LICI) SMD, 0.50; 95% CI, -1.13, 2.13; p=0.55]. Strength training increased the excitability of corticospinal axons (SMD, 4.47; 95% CI, 3.45, 5.49; p<0.0001). This systematic review and meta-analyses revealed that the acute neural changes to strength training involve subtle changes along the entire neuroaxis from the M1 to the spinal cord. These findings suggest that strength training is a clinically useful tool to modulate intracortical circuits involved in motor control.

The Reliability of Neurological Measurement in the Vastus Medialis: Implications for Research and Practice.

The integrity of the corticomotor pathway is paramount in the optimal functioning of skeletal muscle. However, variability of neurophysiological assessment via peripheral nerve and transcranial magnetic stimulation can render interpretation difficult. Seldom evidence exists regarding the reliability of such measurements in the leg extensors, which have important locomotive and functional roles. This study aimed to assess the test-retest reliability of peripheral, corticospinal and intracortical responses in the vastus medialis. Transcranial magnetic and direct current electrical nerve stimulation were delivered to sixteen healthy young adults (8M and 8F) on two separate occasions. The Hoffmann reflex, maximal compound wave, motor evoked potential, corticospinal silent period, intracortical facilitation, and short-interval intracortical inhibition were recorded from the vastus medialis at rest, and during controlled submaximal voluntary contraction. Relative reliability was quantified using intra-class correlation coefficient (ICC2,1). Absolute reliability was quantified using standard error of measurement (SEm) and minimal detectable change (MDC). Corticospinal silent period, corticospinal silent period/motor evoked potential ratio, active motor evoked potential, maximal Hoffman reflex, and passive short-interval intracortical inhibition demonstrated “good to excellent” relative reliability (ICC ≥ 0.643). Intracortical facilitation demonstrated the lowest relative reliability (ICC = 0.420–0.908). Corticospinal silent period displayed the lowest absolute reliability (SEm ≤ 18.68%). Good reliability of the maximal compound wave, Hoffman reflex, motor evoked potential, and corticospinal silent period allow for reliable neurological evaluation of peripheral and corticospinal pathways in the vastus medialis. Future research should investigate reliability of the intracortical (short-interval intracortical inhibition and intracortical facilitation) measures by using different paired-pulse stimulus parameters. These findings hold important implications for neurophysiological assessment conducted in the leg extensor group.

High-intensity exhaustive exercise reduces long-interval intracortical inhibition.

The development of fatigue during single-joint isolated muscle contractions is accompanied by an increase in long-interval intracortical inhibition (LICI). However, the effect of whole-body locomotor endurance exercise on LICI is unknown. Eighteen healthy men completed three exercise trials on a cycle ergometer. The first trial was completed to determine the lactate threshold (LT) and maximal oxygen uptake ([Formula: see text]). The remaining two trials (familiarisation and experimental) involved cycling to volitional exhaustion at an intensity equivalent to halfway between the LT and [Formula: see text] (50%Δ). Responses to stimulation of the femoral nerve [motor nerve stimulation (MNS)] and motor cortex [transcranial magnetic stimulation (TMS)] were determined pre- and post-exercise to determine the level of peripheral fatigue [potentiated quadriceps twitch (Qtw,pot)] and central fatigue [voluntary activation measured by MNS and TMS (VAMNS and VATMS, respectively)]. Corticospinal excitability (motor evoked potentials) and intracortical inhibition [LICI and corticospinal silent period (SP)] were also measured from electromyography recordings on the vastus lateralis. There were exercise-induced reductions in maximal voluntary contraction torque (- 21 ± 10%), Qtw,pot (- 37 ± 18%), VAMNS (- 7 ± 7%) and VATMS (- 8 ± 10) (all P < 0.01). There were increases in the LICI ratio and reductions in SP duration from pre- to post-exercise (mean absolute change of 16 ± 14% and - 31 ± 28s, respectively) (both P < 0.01). The pre- and post-exercise MEP amplitudes were not different (P = 0.86). The neural inhibitory circuits that mediate the LICI and SP became less excitable with fatigue following high-intensity exhaustive cycling, which could be important in the aetiology of central fatigue during whole-body locomotor endurance exercise.

The modulation of corticospinal excitability and inhibition following acute resistance exercise in males and females

Objective: The acute responses to resistance training (RT) between males and females are poorly understood, especially from a neural perspective. Therefore, we aimed to compare the corticospinal and intracortical responses during fatigue and recovery following RT.Methods: Twenty-two participants (12M, 10F) completed one-session of RT (3 × 12 repetition maximum) unilateral leg extensions with 60 s recovery. Single- and paired-pulse transcranial magnetic stimulation measured changes in the motor-evoked potential (MEP), corticospinal silent period (CSP), CSP/MEP ratio, and intracortical facilitation/inhibition (ICF, SICI). The maximal compound wave (MMAX) measured peripheral excitability of the rectus femoris (RF) and maximal voluntary isometric contraction (MVIC) neuromuscular function of the leg extensors. Measures were taken immediately post, 30 min, 1 and 6 h post-training.Results: A significantly greater increase in MEP/MMAX ratio (p = .005) was observed for females immediately post-training compared to males. While no sex differences in MEP/MMAX ratio was observed at 30 min and 1 h post-training, a greater MEP/MMAX ratio for males was observed at 30 min (p < .001), which remained elevated up until 1 h post-training for males when compared to baseline (p = .003). CSP trended to decrease for males compared to females immediately post-training (d = 1.93). MVIC was decreased post-training for males; 14.22% and females; 14.16% (P < .001), with MMAX reduced at 30 min for both groups (P < .001). No differences in the CSP/MEP ratio, SICI or ICF were observed (P > .05).Conclusion: The net output of corticospinal excitability is similar between males and females during fatigue. However, the mechanism in which this is modulated (increased MEP, decreased CSP) appears to be sex-specific.

Modulation of specific inhibitory networks in fatigued locomotor muscles of healthy males

Reduced maximal force capability of skeletal muscle, as a consequence of exercise, can be due to peripheral or central fatigue mechanisms. In upper-limb muscles, neuromuscular fatigue is concurrent with reduced corticospinal excitability and increased inhibition (lengthened corticospinal silent period [CSP]; reduced short-interval intracortical inhibition [SICI] ratio). However, it is unclear whether these adjustments occur in response to fatiguing exercise of locomotor muscles. This study examined the effect of fatiguing, maximal, knee-extensor exercise on motor cortical excitability and inhibition. Thirteen males performed three 30-s maximal, isometric contractions with the dominant knee-extensors (MVC1, MVC2 and MVC3), separated by 60 s. At the end of, and between each MVC, neuromuscular fatigue, corticospinal excitability, CSP and SICI were assessed with supramaximal stimulation of the femoral nerve, and motor cortical stimulation, respectively. Repeated MVCs caused progressive reductions in MVC (− 10, − 24 and − 29%, respectively, P ≤ 0.01), along with significant peripheral (reductions in potentiated twitch of − 23, −53 and − 60%, respectively, P < 0.001) and central (reductions in VA of − 10% and − 13% post-MVC2 and 3, respectively, P ≤ 0.01) fatigue. Following MVC1 corticospinal excitability was reduced, and remained depressed thereafter. CSP increased in duration and remained longer throughout the protocol; whereas, no change in SICI was observed. Repeated, sustained, maximal contractions of the knee-extensors elicited substantial peripheral and central fatigue that was accompanied by a concomitant reduction in corticospinal excitability. However, divergent responses exist between inhibitory networks within the motor cortex, the activity of inhibitory networks mediated by GABAB are increased, whereas those mediated by GABAA are not.

Effects of acute resistance training modality on corticospinal excitability, intra-cortical and neuromuscular responses.

Although neural adaptations from strength training are known to occur, the acute responses associated with heavy-strength (HST) and hypertrophy training (HYT) remain unclear. Therefore, we aimed to compare the acute behaviour of corticospinal responses following a single session of HST vs HYT over a 72-h period. Fourteen participants completed a random counterbalanced, crossover study that consisted of a single HST session [5 sets×3 repetition maximum (RM)], a HYT session (3 sets×12 RM) of the leg extensors and a control session (CON). Single- and paired-pulse transcranial magnetic stimulation (TMS) was used to measure changes in motor-evoked potential (MEP) amplitude, corticospinal silent period (CSP), intra-cortical facilitation (ICF), short-interval intra-cortical inhibition (SICI) and long-interval intra-cortical inhibition (LICI). Additionally, maximal muscle compound wave (M MAX) of the rectus femoris (RF) and maximal voluntary isometric contraction (MVIC) of the leg extensors were taken. All measures were taken at baseline, immediately post and 2, 6, 24, 48 and 72h post-training. A significant condition x time interaction was observed for MVIC (P=0.001), M MAX (P=0.003), MEP amplitude (P<0.001) and CSP (P=0.002). No differences were observed between HST and HYT for all neurophysiological measures. No changes in SICI, ICF and LICI were observed compared to baseline. Our results suggest that: (1) the acute behaviour of neurophysiological measures is similar between HST and HYT; and (2) the increase in corticospinal excitability may be a compensatory response to attenuate peripheral fatigue.

ID 186 – Repetition suppression in resting motor evoked potentials evidenced by increase in intracortical inhibition

Objective To evaluate the repetition suppression (RS) in resting and active motor evoked potential (MEPs) and in corticospinal silent period (cSP) using navigated transcranial magnetic stimulation (nTMS). MEPs can be though to represent the activity of the excitatory system, whereas SPs represent the inhibitory effect of the GABAergic interneurons. Methods Seven healthy right-handed subjects (4 females, age: 24–35 years) were studied. nTMS was focused on the left cortical representation of first dorsal interosseous muscle by applying stimulus trials including 4 stimuli at 1s intervals. Total of 30 trials were given 20s apart. Resting MEPs were measured with a stimulation intensity of 120% of the resting motor threshold. Active MEPs and cSPs were measured during voluntary muscle contraction at 120% of the silent period threshold (SPT) with 20 trials. Results RS was evidenced in the resting MEPs (F = 44.11, p < 0.001), whereas no RS was observed with the active MEPs (p = 0.193). Instead of RS, the cSPs significantly lengthened during the stimulation trials (F = 19.97, p < 0.001). Conclusions While the resting MEPs demonstrate RS, active MEPs stay intact and SPs lengthen indicating potential intracortical inhibition as the mechanism of RS. Key message RS appears specific to resting MEPs and may occur due to increasing intracortical inhibition.

Input-Output Characteristics of Late Corticospinal Silent Period Induced by Transcranial Magnetic Stimulation.

Corticospinal silent period (SP) may be interrupted by a burst of muscle activity followed by a second (late) SP, generally assumed to be a continuation from the primary SP. Our objective was to characterize the input-output behavior of the late SP. Transcranial magnetic stimulation was applied on the cortical representation area of the right-hand muscles of 12 healthy subjects. Single-pulse transcranial magnetic stimulation was given with varying stimulation intensities normalized to the individual resting motor threshold (60% to 130% of the resting motor threshold) during voluntary muscle contraction. Electromyogram was recorded from first dorsal interosseous and abductor pollicis brevis muscles. Primary and late SPs were analyzed as absolute SPs, and input-output characteristics were assessed. The late SP exhibited fundamentally different input-output characteristics from that of the primary SP. The late SP most likely presented itself at stimulation intensities of 90% to 100% of the resting motor threshold. Different input-output characteristics of the late SP compared with the primary SP indicate that the late SP possess mechanisms different from the primary SP. The exact origin of the late SP remains unclear. Understanding the origins of the late SP could provide valuable insight on corticospinal inhibitory processes.

On the estimation of silent period thresholds in transcranial magnetic stimulation

ObjectiveWe evaluated the induction of corticospinal silent period (SP) using transcranial magnetic stimulation (TMS) at stimulation intensities normalized to resting motor threshold (rMT) or silent period thresholds (SPTs). The aim was to reduce the characteristic inter-individual variation in SP measurements in healthy population to improve the sensitivity of such measurements. MethodsThe cortical representation area of the right hand musculature of 12 healthy subjects was stimulated with navigated TMS with varying stimulating intensities. Subsequently, the individual SPTs for eliciting SPs of 20, 30, and 50ms in duration were determined from the input–output characteristics. ResultsWhile SPT for 20 and 50ms SPs differed from rMT, the SPT for 30ms was similar to rMT. Nevertheless, the inter-individual variation in SP duration was reduced significantly at 120% of SPT30 when compared with SP durations obtained at 120% of rMT. ConclusionsInter-individual variation in the SP duration decreases when applying TMS at stimulation intensities normalized to the individual SPTs instead to the rMT. This makes the SP duration more specific to inhibition and less affected by changes in cortical excitability. SignificanceUse of individual SPTs may improve the sensitivity of the SP measures in studies with inter-individual design.

Repeatability of Corticospinal and Spinal Measures during Lengthening and Shortening Contractions in the Human Tibialis Anterior Muscle

Elements of the human central nervous system (CNS) constantly oscillate. In addition, there are also methodological factors and changes in muscle mechanics during dynamic muscle contractions that threaten the stability and consistency of transcranial magnetic stimulation (TMS) and perpherial nerve stimulation (PNS) measures.PurposeTo determine the repeatability of TMS and PNS measures during lengthening and shortening muscle actions in the intact human tibialis anterior.MethodsOn three consecutive days, 20 males performed lengthening and shortening muscle actions at 15, 25, 50 and 80% of maximal voluntary contraction (MVC). The amplitude of the Motor Evoked Potentials (MEPs) produced by TMS was measured at rest and during muscle contraction at 90° of ankle joint position. MEPs were normalised to Mmax determined with PNS. The corticospinal silent period was recorded at 80% MVC. Hoffman reflex (H-reflex) at 10% isometric and 25% shortening and lengthening MVCs, and V-waves during MVCs were also evoked on each of the three days.ResultsWith the exception of MEPs evoked at 80% shortening MVC, all TMS-derived measures showed good reliability (ICC = 0.81–0.94) from days 2 to 3. Confidence intervals (CI, 95%) were lower between days 2 and 3 when compared to days 1 and 2. MEPs significantly increased at rest from days 1 to 2 (P = 0.016) and days 1 to 3 (P = 0.046). The H-reflex during dynamic muscle contraction was reliable across the three days (ICC = 0.76–0.84). V-waves (shortening, ICC = 0.77, lengthening ICC = 0.54) and the H-reflex at 10% isometric MVC (ICC = 0.66) was generally less reliable over the three days.ConclusionAlthough it is well known that measures of the intact human CNS exhibit moment-to-moment fluctuations, careful experimental arrangements make it possible to obtain consistent and repeatable measurements of corticospinal and spinal excitability in the actively lengthening and shortening human TA muscle.

Exploring the pathophysiology of Mal de Debarquement

Mal de debarquement syndrome (MdDS) is a disorder of perceived motion most often occurring following a cruise. We report findings from a patient with MdDS who underwent a transcranial magnetic stimulation protocol to quantify cortical excitability. These data were compared to those from 40 controls. The patient with MdDS exhibited high levels of intracortical facilitation. These findings will provide insight on the pathophysiology of MdDS, and will help guide future work on this rare condition. Mal de debarquement syndrome (MdDS) occurs when habituation to passive background movement becomes resistant to readaptation to stable conditions and results in a phantom perception of self-motion. MdDS typically disappears quickly after return to stable ground; however, in rare instances the symptoms may persist for months to years (persistent MdDS). While the etiology of persistent MdDS is poorly understood, it does not appear to originate from vestibular dysfunction as vestibular tests are normal and the symptoms do not respond to vestibular therapy [2]. Rather, MdDS appears to be a disorder of neuroplasticity and sensory rearrangement [2]. To our knowledge, there have been no studies examining the neurophysiologic characteristics of the disorder. In this case study we report findings from a patient with persistent MdDS who underwent an extensive transcranial magnetic stimulation (TMS) protocol to quantify motor cortical excitability. Specifically, we quantified the duration of the corticospinal silent period using single-pulse TMS. The silent period is observed when a subject performs a slight contraction and a single TMS stimulus is applied to the motor cortex (Fig. 1a). Additionally, we quantified intracortical facilitation (ICF) and short-interval intracortical inhibition (SICI) using paired-pulse TMS. Paired-pulse TMS combines a conditioning stimulus (CP) with a test stimulus (TP) at different interstimulus intervals, and the relative change in motor evoked potential (MEP) size is expressed relative to an unconditioned test pulse. At a short interstimulus interval of 3 ms, the CP inhibits the MEP in comparison to the TP only (SICI), whereas at a longer interstimulus intervals of 15 ms it facilitates the MEP (ICF) (Fig. 1b). The patient was a 63-year-old female (160.2 cm, 77.3 kg) who complained of sensations of unsteadiness and a feeling of the floor moving under her feet after disembarking from a 7-day cruise *3.5 years ago (3/2007). She reported having to regularly reach out to steady herself against stationary objects, and that MdDS had greatly impacted her quality of life (subjective scoring of six out of ten on a visual analog scale for the impact of MdDS on her quality of life). Several other hallmark features of MdDS were present including mild cognitive slowing and transient improvement in symptoms with re-exposure to passive movement [2]. Physical examination was unremarkable. Diagnostic testing including sural sensory and peroneal motor conduction studies, needle EMG, and MRI of the brain were all normal. Additionally, the patient had unremarkable findings on Dix-Hallpike testing and the caloric reflex test. The patient did not have migraine or other primary headache as defined by the International B. C. Clark (&) Department of Biomedical Sciences, Ohio Musculoskeletal and Neurological Institute (OMNI), Ohio University, 211 Irvine Hall, Athens, OH 45701, USA e-mail: clarkb2@ohio.edu

Influence Of Fatigue-induced Muscle Afferent Stimulation On Motor Evoked Potentials

Post-exercise muscle ischemia (PEMI)-induced stimulation of muscle afferents depresses motorneuron excitability (Martin et al., J Neurosci, 2006). However, little is known regarding the influence of muscle afferents on motor evoked potential (MEP) characteristics. PURPOSE: The purpose of this study is to determine the effect of a submaximal fatiguing elbow extensor muscle contraction followed by 2-min of PEMI on MEP amplitude and the duration of corticospinal silent period (SP). METHODS: Fifteen subjects (9 men and 6 women; 22.2±4.1 yrs) performed a submaximal elbow extensor fatigue task to failure at 15% of max strength. Immediately following the fatigue task, a 2-minute PEMI period was induced. Mean arterial blood pressure (MAP) and heart rate (HR) were measured on a beat-by-beat basis. Before, during, and after the exercise task, electromyographic responses were recorded from the lateral head of the triceps brachii in response to transcranial magnetic stimulation (TMS) pulses to the motor cortex and electrical stimulation of the brachial plexus to evoke a maximal muscle action potential (Mmax). MEP amplitude was normalized to the Mmax, and the SP duration was determined. RESULTS: The fatigue task was performed for 482±33.4 sec. MAP increased from 93±5.8 mmHg at rest to 148±8.9 mmHg at task failure (p<0.05), and remained elevated above resting conditions during PEMI (125±6.8 mmHg; p<0.05). HR also increased from 71±3.5 bpm at rest to 97±3.7 bpm at task failure (p<0.05); however, HR returned to resting levels during PEMI (75±2.3 bpm). MEP amplitude increased from 28±3.8% of Mmax at the start of exercise to 72±8.2% of Mmax at task failure (p<0.05), and remained elevated above pre-fatigue levels during PEMI (56±5.8% of Mmax; p<0.05). SP duration increased from 114±7.5 msec at the start of exercise to 176±14.0 msec at task failure (p<0.05); however, SP duration returned to pre-fatigue levels during PEMI (140±11.5 msec). CONCLUSIONS: These findings suggest that stimulation of muscle afferents via PEMI facilitates MEP amplitude without affecting the SP duration. Further work is required to determine the relative influence of spinal versus cortical modulation on these observations, as well as their functional implications on the mechanisms of muscle fatigue. Supported by SURF and PURF Awards from Ohio University.

Inter-hemispheric asymmetry of motor corticospinal excitability in major depression studied by transcranial magnetic stimulation

Background Imaging and electroencephalographic studies have reported inter-hemispheric asymmetries in frontal cortical regions associated with depression. This study aimed at comparing motor corticospinal excitability assessed by methods of transcranial magnetic stimulation (TMS) between the right and left hemispheres in patients with major depression and healthy controls. Method Patients with major depression ( n = 35) and healthy controls ( n = 35) underwent a bilateral study of various motor corticospinal excitability parameters, including rest motor threshold (RMT), corticospinal silent period (CSP) duration and intra-cortical inhibition (ICI) and facilitation (ICF). Indexes of asymmetry were calculated, and the relationships between excitability parameters and clinical scores of depression were statistically analyzed. Results Depressed patients showed a reduced excitability of both excitatory (RMT, ICF) and inhibitory (CSP, ICI) processes in the left hemisphere, compared to the right hemisphere and to healthy controls. Conclusion The present results confirmed the existence of inter-hemispheric asymmetries in frontal cortex activities of depressed patients in favor of a left-sided reduced excitability. This neurophysiological approach may help to guide repetitive TMS procedures in the treatment of depressive disorders.