Long-interval Intracortical Inhibition Research Articles

Effect of acupuncture at ST36 on motor cortical excitation and inhibition.

BackgroundAcupuncture at Zusanli (ST36) is often used to facilitate motor recovery after stroke. However, the effect of acupuncture at ST36 on motor cortical excitation and inhibition remains unclear. This study aimed to explore the effect of acupuncture at ST36 on motor cortical excitation and inhibition.MethodsTwenty healthy volunteers were recruited to receive acupuncture treatment. We selected the acupoint ST36 and its respective sham point as the experimental acupoint. Transcranial magnetic stimulation (TMS) was used to measure motor‐evoked potentials (MEP) at 7 time points—before acupuncture (Pre), acupuncture (T0), 4 and 8 min after acupuncture (T4; T8), needle removal (T12), 4 and 8 min after needle removal (T16; T20). Simultaneously, paired TMS (pTMS) was employed to measure short‐ and long‐interval intracortical inhibition (SICI [short latency intracortical inhibition]; LICI [long latency intracortical inhibition]), respectively, at three time points—before acupuncture (Pre), acupuncture (T0), needle removal (T12). After removing the acupuncture needle, all subjects were asked to quantify their Deqi sensation using a Gas table.ResultsThe average Deqi sensation score of all subjects during acupuncture at ST36 was higher than that observed at the sham point. With acupuncture at ST36, the MEP amplitude was higher at three time points (T0, T4, T8) than at Pre, although the MEP amplitude tended toward Pre after needle removal. The MEP amplitude was also higher at the same time points (T0, T4, T8) than at the sham point. Furthermore, the Deqi sensation score was correlated with MEP amplitude. With acupuncture at ST36, SICI and LICI at T0 were higher than those at Pre, and SICI and LICI at T0 were higher than those at the sham point.ConclusionAcupuncture at ST36 increased motor cortical excitation and had an effect on the remaining needle phase. Deqi sensation was correlated with MEP amplitude. Acupuncture at ST36 also decreased motor cortical inhibition.

Transcranial Magnetic Stimulation-Electroencephalography Measures of Cortical Neuroplasticity Are Altered after Mild Traumatic Brain Injury.

While the potential long-term side effects of mild traumatic brain injury (mTBI) are becoming increasingly recognized, the associated neurophysiological mechanisms remain poorly understood. However, changes in cortical inhibitory function and neuroplasticity have been suggested as possible contributing factors. The current study applied transcranial magnetic stimulation (TMS) in conjunction with electroencephalography (combined TMS-EEG) to investigate further the effects of mTBI on these processes. In 17 patients with a history of mTBI and 15 healthy control subjects with no mTBI history, paired-pulse TMS-EEG measures of short- (SICI) and long-interval intracortical inhibition (LICI) were used to assess intracortical inhibitory function. Single-pulse TMS-EEG was used to assess neuroplastic changes in cortical excitability after application of continuous theta burst stimulation (cTBS, a plasticity inducing TMS paradigm). Inhibition of the TMS-evoked EEG potential after application of SICI and LICI was not different between groups. In contrast, the inhibitory effects of cTBS on both P30 (p < 0.05) and N45 (p = 0.04) TEP components was significantly increased in patients, with the modulation of N45 in patients significantly related to the time since injury (p = 0.04). While these results provide further evidence that inhibitory circuits involving γ-aminobutyric acid (GABA) are modified after mTBI, they place greater emphasis on the plasticity of inhibitory networks involving the GABAA receptor subtype.

Effects of Transcranial Static Magnetic Stimulation on Motor Cortex Evaluated by Different TMS Waveforms and Current Directions

Transcranial static magnetic stimulation (tSMS) modulates cortical excitability probably by interacting with the GABA-glutamate intracortical balance. Different transcranial magnetic stimulation (TMS) waveforms probe distinct GABA-mediated cortical inhibition networks. The goal of the present work is to further characterize tSMS-induced changes in motor cortex reactivity and inhibition–excitation (I/E) balance. We hypothesized that tSMS affects particular cortical networks and thus, the effects of tSMS would be different depending on the TMS waveform used to assess its results. 23 healthy young adults completed two sessions of real or sham tSMS. The order of the sessions was randomized across participants. Motor evoked potentials (MEPs), cortical silent period (CSP), short- and long-interval intracortical inhibition (SICI and LICI), and intracortical facilitation (ICF) were assessed with TMS monophasic posterior–anterior (monoPA; n = 9), monophasic anterior–posterior (monoAP; n = 7), or biphasic (biAP-PA; n = 7) pulses. Repeated measures analyses of variance and appropriate pairwise comparisons were performed for each TMS measure. After 15 min of real tSMS, the MEP amplitudes decreased compared to sham and baseline, SICI and LICI showed greater inhibition, and a tendency towards longer CSPs and less facilitation was found. These results were only observed with monoPA TMS. MEP amplitude increased compared to sham with monoAP TMS, with no clear changes in general intracortical I/E balance. Biphasic TMS was not able to capture any effects of tSMS. The results show that the effects of tSMS on cortical excitability and inhibition involve specific interneuron circuits that are selectively activated by monoPA TMS.

Antidepressant-resistant depression is characterized by reduced short- and long-interval cortical inhibition.

Major depressive disorder (MDD) is highly heterogeneous and can be classified as treatment-resistant depression (TRD) or antidepressant-responsive depression (non-TRD) based on patients' responses to antidepressant treatment. Methods for distinguishing between TRD and non-TRD are critical clinical concerns. Deficits of cortical inhibition (CI) have been reported to play an influential role in the pathophysiology of MDD. Whether TRD patients' CI is more impaired than that of non-TRD patients remains unclear. Paired-pulse transcranial magnetic stimulation (ppTMS) was used to measure cortical inhibitory function including GABAA- and GABAB-receptor-related CI and cortical excitatory function including glutamate-receptor-related intracortical facilitation (ICF). We recruited 36 healthy controls (HC) and 36 patients with MDD (non-TRD, n = 16; TRD, n = 20). All participants received evaluations for depression severity and ppTMS examinations. Non-TRD patients received an additional ppTMS examination after 3 months of treatment with the SSRI escitalopram. Patients with TRD exhibited reduced short-interval intracortical inhibition (SICI) and long-interval intracortical inhibition (LICI), as shown by abnormally higher estimates, than those with non-TRD or HC (F = 11.030, p < 0.001; F = 10.309, p < 0.001, respectively). After an adequate trial of escitalopram treatment, the LICI of non-TRD reduced significantly (t = - 3.628, p < 0.001), whereas the ICF remained lower than that of HC and showed no difference from pretreatment non-TRD. TRD was characterized by relatively reduced CI, including both GABAA- and GABAB-receptor-mediated neurons while non-TRD preserved partial CI. In non-TRD, SSRIs may mainly modulate GABAB-receptor-related LICI. Our findings revealed distinguishable features of CI in antidepressant-resistant and responsive major depression.

GABA-ergic tone hypothesis in hepatic encephalopathy – Revisited

ObjectiveThe GABA hypothesis of hepatic encephalopathy (HE) proposes an increased cerebral GABA-ergic tone in HE but has not been investigated in vivo in HE-patients yet. Cortical GABA-ergic and glutamatergic neurotransmission in HE-patients were evaluated using transcranial magnetic stimulation. MethodsTwenty-one patients with HE grade 1 and 2 and age matched controls participated in the study. GABA-ergic (short- and long-interval intracortical inhibition (SICI and LICI)) and glutamatergic (intracortical and short-interval intracortical facilitation (ICF and SICF)) excitability of the primary motor cortex (M1) and global corticospinal excitability (motor threshold, motor evoked potential recruitment curve (MEP-RC) were compared between the groups. SICI and ICF were correlated to the critical flicker frequency (CFF) as measure for disease severity. ResultsIn HE-patients, the slope of MEP-RC was significantly shallower compared to healthy controls. SICI was significantly reduced in patients with HE grade 2 compared to healthy controls. In HE-patients, SICI and ICF was significantly correlated to CFF. ConclusionAlthough global corticospinal excitability was reduced in HE-patients, GABA-ergic inhibition was reduced in M1 depending on HE severity. Moreover CFF related alteration of GABAergic and glutamatergic neurotransmission in patients with HE could support the notion of a severity dependent alteration of cortical excitability. SignificanceThe decrease of cortical GABA-ergic tone challenges the classical GABA hypothesis in HE.

The Influence of Primary Motor Cortex Inhibition on Upper Limb Impairment and Function in Chronic Stroke: A Multimodal Study

Background. Stroke is a leading cause of adult disability owing largely to motor impairment and loss of function. After stroke, there may be abnormalities in γ-aminobutyric acid (GABA)-mediated inhibitory function within primary motor cortex (M1), which may have implications for residual motor impairment and the potential for functional improvements at the chronic stage. Objective. To quantify GABA neurotransmission and concentration within ipsilesional and contralesional M1 and determine if they relate to upper limb impairment and function at the chronic stage of stroke. Methods. Twelve chronic stroke patients and 16 age-similar controls were recruited for the study. Upper limb impairment and function were assessed with the Fugl-Meyer Upper Extremity Scale and Action Research Arm Test. Threshold tracking paired-pulse transcranial magnetic stimulation protocols were used to examine short- and long-interval intracortical inhibition and late cortical disinhibition. Magnetic resonance spectroscopy was used to evaluate GABA concentration. Results. Short-interval intracortical inhibition was similar between patients and controls (P = .10). Long-interval intracortical inhibition was greater in ipsilesional M1 compared with controls (P < .001). Patients who did not exhibit late cortical disinhibition in ipsilesional M1 were those with greater upper limb impairment and worse function (P = .002 and P = .017). GABA concentration was lower within ipsilesional (P = .009) and contralesional (P = .021) M1 compared with controls, resulting in an elevated excitation-inhibition ratio for patients. Conclusion. These findings indicate that ipsilesional and contralesional M1 GABAergic inhibition are altered in this small cohort of chronic stroke patients. Further study is warranted to determine how M1 inhibitory networks might be targeted to improve motor function.

Age-related alterations in the modulation of intracortical inhibition during stopping of actions.

We investigated the effect of age on the ability to modulate GABAA-ergic and GABAB-ergic inhibitory activity during stopping of action (reactive inhibition) and preparation to stop (proactive inhibition). Twenty-five young and twenty-nine older adults performed an anticipated response version of the stop-signal task with varying levels of stop-signal probability. Paired-pulse transcranial magnetic stimulation was applied to left primary motor cortex to assess the modulation of GABAA-mediated short-interval intracortical inhibition (SICI) during stopping and GABAB-mediated long-interval intracortical inhibition (LICI) during the anticipation of a stop-signal. At the behavioral level, reactive inhibition was affected by aging as indicated by longer stop-signal reaction times in older compared to young adults. In contrast, proactive inhibition was preserved at older age as both groups slowed down their go response to a similar degree with increasing stop-signal probability. At the neural level, the amount of SICI was higher in successful stop relative to go trials in young but not in older adults. LICI at the start of the trial was modulated as a function of stop-signal probability in both young and older adults. Our results suggest that specifically the recruitment of GABAA-mediated intracortical inhibition during stopping of action is affected by aging.

Interindividual differences in both resting-state intracortical and interhemispheric inhibition predicts individual differences in relevant motor performance

Introduction: Evidence from studies where single and paired-pulse transcranial magnetic stimulation (TMS) was applied during the performance of unimanual and bimanual actions have suggested that the enactment and cessation of a motor response is dependent on a contextual modulation of corticospinal excitability and cortical inhibition within the primary motor cortex (M1). While these studies have certainly identified how neurophysiological markers such as short-interval intracortical inhibition (SICI), long-interval intracortical inhibition (LICI) and interhemispheric inhibition (IHI) are temporally modulated during various stages of movement (i.e., motor preparation, execution and cancellation), it remains unclear whether interindividual differences in these neurophysiological markers taken at rest are associated with individual differences in relevant motor performance (i.e., motor inhibition).

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.

Effects of eccentric versus concentric contractions of the biceps brachii on intracortical inhibition and facilitation.

Differences in the neural mechanisms underpinning eccentric (ECC) and concentric (CON) contractions exist; however, the acute effects of fatiguing muscle contractions on intracortical and corticospinal excitability are not well understood. Therefore, we compared maximal ECC and CON contractions of the right biceps brachii (BB) muscle for changes in corticospinal excitability, short- (SICI) and long-interval intracortical inhibition (LICI) and intracortical facilitation (ICF) up to 1hour post-exercise. Fourteen right-handed adults (11M/3F; 26.8±2.9year) undertook a single session of 3 sets of 10 maximal ECC or CON contractions (180-second rest between sets) on an isokinetic dynamometer (40°/s) separated by 1week, in a randomized crossover study. Maximum voluntary isometric contraction torque (MVIC), maximal muscle compound waves (MMAX ), and motor-evoked potentials elicited through transcranial magnetic stimulation (TMS) were recorded via surface electromyography from the right BB. MVIC decreased (P<0.001) immediately after ECC and CON contractions similarly, but the decrease was sustained at 1hour post-ECC contractions only. MMAX was reduced immediately (P=0.014) and 1hour post-exercise (P=0.019) only for ECC contractions. SICI and ICF increased immediately after ECC and CON contractions (P<0.001), but LICI increased only after ECC contractions (P<0.001), and these increases remained at 1hour post-ECC contractions only. These findings suggest that ECC contractions induced a longer-lasting neuromodulatory effect on intracortical inhibition and facilitation, which could indicate a central compensatory response to peripheral fatigue.

Cortical excitability affects mood state in patients with idiopathic generalized epilepsies (IGEs)

Previously, we demonstrated an association between cortical hyperexcitability and mood disturbance in healthy adults. Studies have documented hyperexcitability in patients with idiopathic generalized epilepsies (IGEs; long-interval intracortical inhibition [LICI]) and high prevalence of mood comorbidities. This study aimed to investigate the influences of cortical excitability and seizure control on mood state in patients with IGEs. Single and paired-pulse transcranial magnetic stimulation (TMS) was applied to 30 patients with IGEs (16 controlled IGEs [cIGEs], 14 with treatment-resistant IGEs [trIGEs]), and 22 healthy controls (HCs) to assess cortical excitability with LICI. The Profile of Mood Sates (POMS) questionnaire was used to assess total mood disturbance (TMD), as well as, six mood domains: Depression, Confusion, Anger, Anxiety, Fatigue, and Vigor. To assess the effects of seizure control (HC vs. cIGEs vs. trIGEs) and LICI response (inhibitory vs. excitatory) on TMD, a two-way multivariate analysis of variance (MANOVA) was performed. Analyses revealed a significant main effect of long-interval intracortical inhibition (LICI) response on TMD (F(1, 46) = 4.69, p = 0.04), but not seizure control (F(2, 46) = 0.288, p = 0.75). Excitatory responders endorsed significantly higher TMD scores, indicating greater mood disturbance, than inhibitory responders (MD = −2.12; T (50) = −2.47, p = 0.04). Also, excitatory responders endorsed more items than inhibitory responders on the Depression (MD = −2.12; T (50) = −2.47, p = 0.04) and Fatigue (MD = −3.42; T (50) = −2.96, p = 0.03) subscales of the POMS. These findings provide further evidence of a relationship between hyperexcitability and mood disturbance, and indicate that cortical excitability may have greater influence on mood state than seizure control in patients with IGEs. Results also support theories for the underlying role of gamma-aminobutyric acid (GABA) network dysfunction in the etiology of depression. To better understand the clinical relevance and causal nature of these relationships, further investigation is warranted.

Cortical excitability and seizure control influence attention performance in patients with idiopathic generalized epilepsies (IGEs)

We recently found that higher cortical excitability is associated with poorer attention performance in healthy adults. While patients with idiopathic generalized epilepsies (IGEs), previously termed genetic generalized epilepsies, are known to demonstrate increased cortical excitability and cognitive deficits, a relationship between these variables in IGEs has not been investigated. Therefore, we aimed to characterize the effects of cortical excitability and seizure control on cognitive performance in IGEs. We studied 30 patients with IGEs (16 patients with controlled IGEs (cIGEs) and 14 patients with treatment-resistant IGEs (trIGEs)) and 24 healthy controls (HCs). Transcranial magnetic stimulation (TMS) was used to measure cortical excitability, including long-interval intracortical inhibition (LICI). Attention was assessed with the Digit Span Forwards, Digit Span Backwards, Trails A, and Flanker tasks. Executive functioning was assessed using Trails B, Stroop Color and Word, and the Wisconsin Card Sorting Task. Two-way multivariate analyses of variance (MANOVAs) were conducted to assess the influences of seizure control (HCs vs. cIGEs vs. trIGEs) and cortical excitability (inhibitory vs. excitatory) on composite measures of attention and executive functions. Attention performance was significantly affected by cortical excitability and seizure control. Participants with primarily excitatory LICI responses, indicating higher cortical excitability, performed worse than inhibitory responders on composite attention (Wilks' lambda = 0.748, F(4, 44) = 3.72, p = 0.011). While participants with cIGEs and trIGEs did not significantly differ in attention performance, participants with trIGEs performed worse on the Digit Forwards (False Discovery Rate (FDR)p < 0.001), Digit Backwards (FDRp = 0.015), and Flanker (FDRp = 0.0075) tasks compared with HCs. These results provide support for the relationship between cortical excitability and attention dysfunction in IGEs. Further investigation is needed to determine whether there is a causal relationship between these variables and whether intracortical gamma-aminobutyric acid (GABA)B networks may be targeted to improve attention deficits in clinical populations with decreased LICI. Findings also suggest that additional research directly comparing cognition in patients with cIGEs and trIGEs is warranted.

The Effects of Waveform and Current Direction on the Efficacy and Test–Retest Reliability of Transcranial Magnetic Stimulation

The pulse waveform and current direction of transcranial magnetic stimulation (TMS) influence its interactions with the neural substrate; however, their role in the efficacy and reliability of single- and paired-pulse TMS measures is not fully understood. We investigated how pulse waveform and current direction affect the efficacy and test–retest reliability of navigated, single- and paired-pulse TMS measures. 23 healthy adults (aged 18–35 years) completed two identical TMS sessions, assessing resting motor threshold (RMT), motor-evoked potentials (MEPs), cortical silent period (cSP), short- and long-interval intra-cortical inhibition (SICI and LICI), and intracortical facilitation (ICF) using either monophasic posterior–anterior (monoPA; n = 9), monophasic anterior–posterior (monoAP; n = 7), or biphasic (biAP-PA; n = 7) pulses. Averages of each TMS measure were compared across the three groups and intraclass correlation coefficients were calculated to assess test–retest reliability. RMT was the lowest and cSP was the longest with biAP-PA pulses, whereas MEP latency was the shortest with monoPA pulses. SICI and LICI had the largest effect with monoPA pulses, whereas only monoAP and biAP-PA pulses resulted in significant ICF. MEP amplitude was more reliable with either monoPA or monoAP than with biAP-PA pulses. LICI was the most reliable with monoAP pulses, whereas ICF was the most reliable with biAP-PA pulses. Waveform/current direction influenced RMT, MEP latency, cSP, SICI, LICI, and ICF, as well as the reliability of MEP amplitude, LICI, and ICF. These results show the importance of considering TMS pulse parameters for optimizing the efficacy and reliability of TMS neurophysiologic measures.

Effects of bilateral priming on motor cortex function in healthy adults.

Bilateral priming is a rehabilitation adjuvant that can improve upper limb motor recovery poststroke. It uses a table-top device to couple the upper limbs together such that active flexion and extension of one wrist leads to passive movement of the opposite wrist in a mirror symmetric pattern. Bilateral priming increases corticomotor excitability (CME) in the primary motor cortex (M1) of the passively driven wrist; however, the neurophysiological mechanisms underlying this increase remain unclear. This study explored these mechanisms by using transcranial magnetic stimulation over the right M1 and recording motor-evoked potentials from the passively driven left extensor carpi radialis of healthy adults. Intracortical measures were recorded before and 5 and 35 min after a single 15-min session of priming. One-millisecond short-interval intracortical inhibition, long-interval intracortical inhibition, late cortical disinhibition (LCD), and intracortical facilitation were recorded with a posterior-anterior (PA) intracortical current, whereas CME and short-interval intracortical facilitation (SICF) were recorded with both PA and anterior-posterior (AP) currents. CME with PA stimulation was also recorded ~1 h postpriming. PA CME was elevated 35 min postpriming and remained elevated ~1 h postpriming. LCD decreased, and AP SICF increased at both 5 and 35 min postpriming. However, these changes in LCD and AP SICF are unlikely to be the cause of the increased PA CME because of the differing timelines of their effects and AP and PA currents activating separate interneuron circuits. These results suggest that bilateral priming does not increase CME through alterations of the intracortical circuits investigated here. NEW & NOTEWORTHY This is the first study to measure how bilateral priming modulates corticomotor excitability with posterior-anterior and anterior-posterior intracortical currents, 1-ms short-interval intracortical inhibition, late cortical disinhibition, intracortical facilitation, and short-interval intracortical facilitation. We found corticomotor excitability with a posterior-anterior current increased by 35 min until ~1 h postpriming. Short-interval intracortical facilitation with an anterior-posterior current was greater for at least 35 min postpriming. This provides further insight into the neurophysiological mechanisms underlying bilateral priming.

Preliminary evidence of an association between increased cortical inhibition and reduced suicidal ideation in adolescents treated for major depression

BackgroundSuicide is a leading cause of death among youth. Prior research using transcranial magnetic stimulation (TMS) has implicated deficits in GABAergic cortical inhibition in adolescent suicidal behavior, yet no studies have assessed whether cortical inhibition varies over time in conjunction with changes in suicidal ideation (SI). This study examined dynamic changes in long-interval intracortical inhibition (LICI), a TMS measure of GABAB-mediated inhibition, and their relationship with changes in SI in a small sample of adolescents undergoing pharmacologic treatment for depression. MethodsTen depressed adolescents (aged 13–17) underwent clinical assessment and TMS testing at baseline and again at follow-up. All were treated with antidepressant medication in the interim. SI was measured with the Columbia Suicide Severity Rating Scale (C-SSRS) Intensity of Ideation subscale. LICI was measured at interstimulus intervals of 100 and 150 ms. ResultsThere was a significant partial correlation, controlling for change in depression severity, between ΔLICI-100 and change in SI as measured by ΔC-SSRS (ρ = .746, df = 7, p = .021), which remained after also controlling for time to follow-up assessment (ρ = .752, df = 6, p = .032). No significant correlation was observed between ΔLICI-150 and change in SI. LimitationsSample size; variable follow-up interval; inability to control for age, sex, and potential treatment effects. ConclusionsThese data offer preliminary signal of an association between increases in GABAB-mediated cortical inhibition and reduction in SI over time in adolescents treated for depression. Further studies are warranted to explore the role of cortical inhibition in adolescent suicidal ideation and behavior.

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.

In Standing, Corticospinal Excitability Is Proportional to COP Velocity Whereas M1 Excitability Is Participant-Specific.

Reductions in the base of support (BOS) make standing difficult and require adjustments in the neural control of sway. In healthy young adults, we determined the effects of reductions in mediolateral (ML) BOS on peroneus longus (PL) motor evoked potential (MEP), intracortical facilitation (ICF), short interval intracortical inhibition (SICI) and long interval intracortical inhibition (LICI) using transcranial magnetic stimulation (TMS). We also examined whether participant-specific neural excitability influences the responses to increasing standing difficulty. Repeated measures ANOVA revealed that with increasing standing difficulty MEP size increased, SICI decreased (both p < 0.05) and ICF trended to decrease (p = 0.07). LICI decreased only in a sub-set of participants, demonstrating atypical facilitation. Spearman’s Rank Correlation showed a relationship of ρ = 0.50 (p = 0.001) between MEP size and ML center of pressure (COP) velocity. Measures of M1 excitability did not correlate with COP velocity. LICI and ICF measured in the control task correlated with changes in LICI and ICF, i.e., the magnitude of response to increasing standing difficulty. Therefore, corticospinal excitability as measured by MEP size contributes to ML sway control while cortical facilitation and inhibition are likely involved in other aspects of sway control while standing. Additionally, neural excitability in standing is determined by an interaction between task difficulty and participant-specific neural excitability.

Connecting clinical aspects to corticomotor excitability in restless legs syndrome: a TMS study

We assessed corticomotor excitability in the primary motor cortex (M1) of participants with moderate-to-severe restless legs syndrome (RLS) symptoms using transcranial magnetic stimulation (TMS) in relation to the clinical and sleep aspects of the disease. Thirty-five participants (20 F; mean age: 59.23 ± 1.66 years; range: 42–78 years) affected by primary RLS (off medications) and 31 age-matched controls (19 F; mean age: 57.90 ± 1.50 years; range: 43–79 years) underwent TMS following two nights of polysomnography (PSG). Paired-pulse TMS measures [short-interval intracortical inhibition (SICI), long-interval intracortical inhibition (LICI), and intracortical facilitation (ICF)] of the dominant M1hand and M1leg muscles were collected and analyzed in relation to clinical features of RLS and PSG. We found decreased corticomotor excitability in M1hand, whereas it was increased in M1leg, which was greater in patients with more severe RLS. Participants with RLS with a history of dopamine-agonist–induced symptom augmentation showed decreased LICI (reduced inhibition) compared to nonaugmented participants with RLS for M1leg. None of the TMS measures (M1hand or M1leg) correlated with the PSG parameters. This study shows hyperexcitability in M1leg, and this appears related to RLS disease severity and decreased excitability in M1hand. The results provide new insight into the complex neurobiology of RLS, particularly in more advanced stages of the disease.

Short-interval and long-interval intracortical inhibition of TMS-evoked EEG potentials

BackgroundInhibition in the human motor cortex can be probed by means of paired-pulse transcranial magnetic stimulation (ppTMS) at interstimulus intervals of 2–3 ms (short-interval intracortical inhibition, SICI) or ∼100 ms (long-interval intracortical inhibition, LICI). Conventionally, SICI and LICI are recorded as motor evoked potential (MEP) inhibition in the hand muscle. Pharmacological experiments indicate that they are mediated by GABAA and GABAB receptors, respectively.Objective/Hypothesis: SICI and LICI of TMS-evoked EEG potentials (TEPs) and their pharmacological properties have not been systematically studied. Here, we sought to examine SICI by ppTMS-evoked compared to single-pulse TMS-evoked TEPs, to investigate its pharmacological manipulation and to compare SICI with our previous results on LICI. MethodsPpTMS-EEG was applied to the left motor cortex in 16 healthy subjects in a randomized, double-blind placebo-controlled crossover design, testing the effects of a single oral dose 20 mg of diazepam, a positive modulator at the GABAA receptor, vs. 50 mg of the GABAB receptor agonist baclofen on SICI of TEPs. ResultsWe found significant SICI of the N100 and P180 TEPs prior to drug intake. Diazepam reduced SICI of the N100 TEP, while baclofen enhanced it. Compared to our previous ppTMS-EEG results on LICI, the SICI effects on TEPs, including their drug modulation, were largely analogous. ConclusionsFindings suggest a similar interaction of paired-pulse effects on TEPs irrespective of the interstimulus interval. Therefore, SICI and LICI as measured with TEPs cannot be directly derived from SICI and LICI measured with MEPs, but may offer novel insight into paired-pulse responses recorded directly from the brain rather than muscle.

Cortical inhibitory markers of lifetime suicidal behavior in depressed adolescents

Although suicide is the second-leading cause of death in adolescents and young adults worldwide, little progress has been made in developing reliable biological markers of suicide risk and suicidal behavior. Converging evidence suggests that excitatory and inhibitory cortical processes mediated by the neurotransmitters glutamate and γ-aminobutyric acid (GABA) are dysregulated in suicidal individuals. This study utilized single- and paired-pulse transcranial magnetic stimulation (TMS) to assess excitatory and inhibitory cortical functioning in healthy control adolescents (n = 20), depressed adolescents without any history of suicidal behavior (“Depressed”, n = 37), and depressed adolescents with lifetime history of suicidal behavior (“Depressed+SB”, n = 17). In a fixed-effects general linear model analysis, with age, sex, and depression severity as covariates, no significant group main effects emerged for resting motor threshold, intracortical facilitation, short-interval intracortical inhibition, or cortical silent period. However, group main effects were significant for long-interval intracortical inhibition (LICI) at interstimulus intervals (ISIs) of 100 ms and 150 ms, but not 200 ms. Depressed+SB adolescents demonstrated impaired LICI compared to healthy control and Depressed adolescents, while healthy control and Depressed participants did not differ in LICI. Multiple linear robust regression revealed significant positive linear relationships between lifetime suicidal behavior severity and impairment in LICI at 100-ms and 150-ms ISIs. In a post hoc receiver operating characteristic analysis, LICI significantly discriminated Depressed from Depressed+SB youth in 100-ms and 150-ms paradigms. These findings suggest that GABAB receptor-mediated inhibition is distinctly dysregulated in depressed adolescents with histories of suicidal behavior. Further research is warranted to establish the utility of cortical inhibition in the assessment of suicide risk and as a target for treatment interventions.