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Abstract Background Spinocerebellar ataxia type 3 (SCA3), also known as Machado–Joseph disease, is an autosomal dominant neurodegenerative disorder caused by CAG repeat expansion in exon 10 of ATXN3. Extra-cerebellar manifestations, including external ophthalmoplegia, dystonia, Parkinsonism, and peripheral neuropathy, are predominantly present in SCA3 cases. Here, we report a case of SCA3 presenting with a split hand and minipolymyoclonus. Case presentation A 73-year-old female patient presented with a 5-year history of ataxic gait. Neurological examination revealed cerebellar ataxia and minipolymyoclonus in the digits on both sides and muscle atrophy in the right hand, consistent with the split hand pattern. Electrodiagnostic studies demonstrated decreased amplitude of compound muscle action potentials and neurogenic motor unit potentials, indicating lower motor neuron involvement. Conclusions Our patient’s case indicated a split hand and minipolymyoclonus in SCA3. Clinicians should consider these extra-cerebellar manifestations in patients with SCA3. Although neither split hand nor minipolymyoclonus are likely to directly result in a specific etiological diagnosis, a common pathophysiological mechanism for both may be lower motor neuron involvement. This extracerebellar manifestation contributes to narrowing down the diagnostic possibilities for cases presenting with progressive cerebellar ataxia.

Background: Spinocerebellar ataxia type 3 (SCA3), also known as Machado–Joseph disease, is an autosomal dominant neurodegenerative disorder caused by CAG repeat expansion in exon 10 of ATXN3. Extra-cerebellar manifestations, including external ophthalmoplegia, dystonia, Parkinsonism, and peripheral neuropathy, are predominantly present in SCA3 cases. Here, we report a case of SCA3 presenting with a split hand and minipolymyoclonus. Case presentation: A 73-year-old female patient presented with a 5-year history of ataxic gait. Neurological examination revealed cerebellar ataxia and minipolymyoclonus in the digits on both sides and muscle atrophy in the right hand, consistent with the split hand pattern. Electrodiagnostic studies demonstrated decreased amplitude of compound muscle action potentials and neurogenic motor unit potentials, indicating lower motor neuron involvement. Conclusions: Our patient's case indicated a split hand and minipolymyoclonus in SCA3. Clinicians should consider these extra-cerebellar manifestations in patients with SCA3. Although neither split hand nor minipolymyoclonus are likely to directly result in a specific etiological diagnosis, a common pathophysiological mechanism for both may be lower motor neuron involvement. This extracerebellar manifestation contributes to narrowing down the diagnostic possibilities for cases presenting with progressive cerebellar ataxia. [ABSTRACT FROM AUTHOR]

Short-interval intracortical inhibition (SICI) is a common paired-pulse transcranial magnetic stimulation (TMS) measure used to assess primary motor cortex (M1) interneuron activity in healthy populations and in neurological disorders. Many of the parameters of TMS stimulation to most accurately measure SICI have been determined. However, one TMS parameter that has not been investigated is the time between SICI trials (termed inter-trial interval; ITI). This is despite a series of single-pulse TMS studies which have reported that motor evoked potential (MEP) amplitude were suppressed for short, but not long ITIs in approximately the initial ten trials of a TMS block of 20–30 trials. The primary purpose was to examine the effects of ITI on the quantification of SICI at rest. A total of 23 healthy adults completed an experimental session that included four SICI trial blocks. Each block utilized a different ITI (4, 6, 8, and 10 s) and was comprised of a total of 26 SICI trials divided into three epochs. ANOVA revealed that the main effects for ITI and epoch as well as their interaction were all non-statistically significant for SICI. We conclude that the shorter (4–6 s) ITIs used in studies investigating SICI should not alter the interpretation of M1 activity, while having the advantages of being more comfortable to participants and reducing the experimental time needed to evaluate perform single and paired-pulse TMS experiments. [ABSTRACT FROM AUTHOR]

Humans display automatic action tendencies toward emotional stimuli, showing faster automatic behavior (i.e., approaching a positive stimulus and avoiding a negative stimulus) than regulated behavior (i.e., avoiding a positive stimulus and approaching a negative stimulus). Previous studies have shown that the primary motor cortex is involved in the processing of automatic actions, with higher motor evoked potential amplitudes during automatic behavior elicited by single-pulse transcranial magnetic stimulation. However, it is unknown how intracortical circuits are involved with automatic action tendencies. Here, we measured short-interval intracortical inhibition and intracortical facilitation within the primary motor cortex by using paired-pulse transcranial magnetic stimulation protocols during a manikin task, which has been widely used to explore approaching and avoiding behavior. Results showed that intracortical facilitation was stronger during automatic behavior than during regulated behavior. Moreover, there was a significant negative correlation between reaction times and intracortical facilitation effect during automatic behavior: individuals with short reaction times had stronger faciliatory activity, as shown by higher intracortical facilitation. By contrast, no significant difference was found for short-interval intracortical inhibition between automatic behavior and regulated behavior. The results indicated that the intracortical facilitation circuit, mediated by excitatory glutamatergic neurons, in the primary motor cortex, plays an important role in mediating automatic action tendencies. This finding further supports the link between emotional perception and the action system. [ABSTRACT FROM AUTHOR]

Objective: Insufficient sleep is linked to several health problems. Previous studies on the effects of sleep deprivation on cortical excitability using conventional transcranial magnetic stimulation (TMS) included a limited number of modalities, and few inter-stimulus intervals (ISIs) and showed conflicting results. This study aimed to investigate the effects of sleep deprivation on cortical excitability through threshold-tracking TMS, using a wide range of protocols at multiple ISIs. Methods: Fifteen healthy subjects (mean age ± SD: 36 ± 3.34 years) were included. The following tests were performed before and after 24 h of sleep deprivation using semi-automated threshold-tacking TMS protocols: short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) at 11 ISIs between 1 and 30 ms, short interval intracortical facilitation (SICF) at 14 ISIs between 1 and 4.9 ms, long interval intracortical inhibition (LICI) at 6 ISIs between 50 and 300 ms, and short-latency afferent inhibition (SAI) at 12 ISIs between 16 and 30 ms. Results: No significant differences were observed between pre- and post-sleep deprivation measurements for SICI, ICF, SICF, or LICI at any ISIs (p

Introduction/Aims: The transcranial magnetic stimulation tests of short‐interval intracortical inhibition (SICI) by both conventional amplitude measurements (A‐SICI) and threshold‐tracking (T‐SICI) are important methods to investigate intracortical inhibitory circuits, and T‐SICI has been proposed to aid the diagnosis of amyotrophic lateral sclerosis. Beverages containing caffeine are widely consumed, and caffeine has been reported to affect cortical excitability. The aim of this study was to determine whether these SICI tests are affected by caffeine. Methods: Twenty‐four healthy subjects (13 females, 11 males, aged from 19 to 31, mean: 26.2 ± 2.4 years) were studied in a single fixed‐dose randomized double‐blind placebo‐controlled cross‐over trial of 200 mg caffeine or placebo ingested as chewing gum. A‐SICI and T‐SICI, using parallel tracking (T‐SICIp), were performed before and after chewing gum. Results: There was no significant change in SICI parameters after placebo in A‐SICI (p >.10) or T‐SICIp (p >.30), and no significant effect of caffeine was found on A‐SICI (p >.10) or T‐SICIp (p >.50) for any of the interstimulus intervals. Discussion: There is no need for caffeine abstention before measurements of SICI by either the T‐SICI or A‐SICI measurements. [ABSTRACT FROM AUTHOR]

Introduction: Gamma-aminobutyric acid (GABA) deficiency is suggested in depressive disorders, along with alterations in cortical excitability. However, whether these excitability changes are related to GABAA receptor availability is largely unknown. Our aim was to assess the correlation between these measures in depressed patients and healthy controls. Methods: Twenty-eight patients with a major depressive episode, measured before and after participating in a clinical trial with repetitive transcranial magnetic stimulation (TMS), and 15 controls underwent [11C]flumazenil positron emission tomography to assess GABAA receptor availability and paired pulse TMS (ppTMS) to evaluate cortical excitability. Both whole-brain voxel-wise GABAA receptor availability and mean values from left hand motor cortex and left paracentral lobule were correlated to the ppTMS outcomes: short-interval intracortical inhibition reflecting GABAA receptor activity, long-interval intracortical inhibition representing GABAB receptor activity, intracortical facilitation reflecting glutamate N-methyl-D-aspartate-receptor activity, as well as the resting motor threshold (rMT), considered a global measure of corticospinal excitability. Results: No significant differences in baseline GABAA receptor availability or cortical excitability were found between patients and controls. Additionally, no correlations were observed between baseline measurements of GABAA receptor availability and TMS outcomes. Changes in GABAA receptor availability in the hand motor cortex, between pre- and post-assessments, were inversely related to pre-post changes in hand rMT. Conclusion: We found that a change in GABAA receptor availability was inversely related to a change in rMT, suggesting a link between GABA deficiency and increased rMT previously observed in depressive episodes. The results highlight the complex mechanisms governing cortical excitability measures and offer new insight into their properties during the depressive state. [ABSTRACT FROM AUTHOR]

Intracortical facilitation (ICF) is a paired-pulse transcranial magnetic stimulation (TMS) measurement used to quantify interneuron activity in the primary motor cortex (M1) in healthy populations and motor disorders. Due to the prevalence of the technique, most of the stimulation parameters to optimize ICF quantification have been established. However, the underappreciated methodological issue of the time between ICF trials (inter-trial interval; ITI) has been unstandardized, and different ITIs have never been compared in a paired-pulse TMS study. This is important because single-pulse TMS studies have found motor evoked potential (MEP) amplitude reductions over time during TMS trial blocks for short, but not long ITIs. The primary purpose was to determine the influence of different ITIs on the measurement of ICF. Twenty adults completed one experimental session that involved 4 separate ICF trial blocks with each utilizing a different ITI (4, 6, 8, and 10 s). Two-way ANOVAs indicated no significant ITI main effects for test MEP amplitudes, condition-test MEP amplitudes, and therefore ICF. Accordingly, all ITIs studied provided nearly identical ICF values when averaged over entire trial blocks. Therefore, it is recommended that ITIs of 4–6 s be utilized for ICF quantification to optimize participant comfort and experiment time efficiency. [ABSTRACT FROM AUTHOR]

Aims: By performing three transcranial magnetic stimulation (TMS) experiments, we measured the motor‐specific modulatory mechanisms in the primary motor cortex (M1) at both the intercortical and intracortical levels when smokers actively approach or avoid smoking‐related cues. Design, Setting and Participants: For all experiments, the design was group (smokers versus non‐smokers) × action (approach versus avoidance) × image type (neutral versus smoking‐related). The study was conducted at the Shanghai University of Sport, CHN, TMS Laboratory. For experiment 1, 30 non‐smokers and 30 smokers; for experiment 2, 16 non‐smokers and 16 smokers; for experiment 3, 16 non‐smokers and 16 smokers. Measurements: For all experiments, the reaction times were measured using the smoking stimulus–response compatibility task. While performing the task, single‐pulse TMS was applied to the M1 in experiment 1 to measure the excitability of the corticospinal pathways, and paired‐pulse TMS was applied to the M1 in experiments 2 and 3 to measure the activity of intracortical facilitation (ICF) and short‐interval intracortical inhibition (SICI) circuits, respectively. Findings Smokers had faster responses when approaching smoking‐related cues (F1,58 = 36.660, P < 0.001, ηp2 = 0.387), accompanied by higher excitability of the corticospinal pathways (F1,58 = 10.980, P = 0.002, ηp2 = 0.159) and ICF circuits (F1,30 = 22.187, P < 0.001, ηp2 = 0.425), while stronger SICI effects were observed when they avoided these cues (F1,30 = 10.672, P = 0.003, ηp2 = 0.262). Conclusions: Smokers appear to have shorter reaction times, higher motor‐evoked potentials and stronger intracortical facilitation effects when performing approach responses to smoking‐related cues and longer reaction times, a lower primary motor cortex descending pathway excitability and a stronger short‐interval intracortical inhibition effect when avoiding them. [ABSTRACT FROM AUTHOR]

Objectives: To compare the utility of conventional amplitude measurements of short-interval intracortical inhibition (A-SICI) with two threshold-tracking (T-SICI) methods, as aids to early diagnosis of amyotrophic lateral sclerosis (ALS). The new parallel threshold-tracking method (T-SICIp) was compared with the previously used serial tracking method (T-SICIs). Methods: 112 consecutive patients referred with the suspicion of ALS and 40 healthy controls were prospectively included. Based on clinical follow-up, patients were divided into 67 patients with motor neuron disease (MND) comprising progressive muscular atrophy (PMA) as well as ALS, and 45 patient controls. SICI was recorded from first dorsal interosseus muscle using the three different protocols. Results: MND patients had significantly reduced T-SICIp, T-SICIs and A-SICI, compared with healthy controls and patient controls, while healthy and patient controls were similar. Paradoxically, T-SICIp was least affected in MND patients with the most upper motor neuron (UMN) signs (Spearman ρ = 0.537, P < 0.0001) whereas there was no correlation for T-SICIs or A-SICI. T-SICIp also provided the best discrimination between patient controls and MND as determined by the receiver operating characteristic (ROC) curves. For patients with no UMN signs, area under ROC curve for 2-3ms inter-stimulus intervals was 0.931 for T-SICIp, 0.771 for T-SICIs and 0.786 for A-SICI. Conclusions: SICI is a sensitive measure for detection of cortical involvement in ALS patients. T-SICIp has higher sensitivity and specificity than T-SICIs and A-SICI, particularly in patients without any upper motor neuron signs. [ABSTRACT FROM AUTHOR]

Motor imagery (MI) refers to the mental simulation of an action without overt movement. While numerous transcranial magnetic stimulation (TMS) studies provided evidence for a modulation of corticospinal excitability and intracortical inhibition during MI, the neural signature within the primary motor cortex is not clearly established. In the current study, we used directional TMS to probe the modulation of the excitability of early and late indirect waves (I‐waves) generating pathways during MI. Corticospinal responses evoked by TMS with posterior–anterior (PA) and anterior–posterior (AP) current flow within the primary motor cortex evoke preferentially early and late I‐waves, respectively. Seventeen participants were instructed to stay at rest or to imagine maximal isometric contractions of the right flexor carpi radialis. We demonstrated that the increase of corticospinal excitability during MI is greater with PA than AP orientation. By using paired‐pulse stimulations, we confirmed that short‐interval intracortical inhibition (SICI) increased during MI in comparison to rest with PA orientation, whereas we found that it decreased with AP orientation. Overall, these results indicate that the pathways recruited by PA and AP orientations that generate early and late I‐waves are differentially modulated by MI. [ABSTRACT FROM AUTHOR]

Ballistic motor training induces plasticity changes and imparts a cross-transfer effect. However, whether there are age-related differences in these changes remain unclear. Thus, the purpose of this study was to perform a meta-analysis to determine the corticospinal responses and cross-transfer of motor performance following ballistic motor training in young and older adults. Meta-analysis was performed using a random-effects model. A best evidence synthesis was performed for variables that had insufficient data for meta-analysis. There was strong evidence to suggest that young participants exhibited greater cross-transfer of ballistic motor performance than their older counterparts. This meta-analysis showed no significant age-related differences in motor-evoked potentials (MEPs), short-interval intracortical inhibition (SICI) and surface electromyography (sEMG) for both hands following ballistic motor training. [ABSTRACT FROM AUTHOR]

Several studies have reported the effects of short-term immobilization of the upper limb on the excitability of the primary motor cortex. In a report examining the effects of upper limb immobilization on somatosensory information processing using somatosensory-evoked potentials (SEPs), short-term upper limb immobilization reduced the amplitude and increased the latency of the P45 component recorded over the contralateral sensorimotor cortex of SEPs. However, the effects of upper limb immobilization on other regions involved in somatosensory information processing are unknown. Therefore, we investigated the effects of short-term right upper limb immobilization on sensory information processing, particularly in motor-related areas, by measuring the cortical components of SEPs. We also evaluated the excitability of the primary motor cortex and corticospinal tract as well as motor performance (visual simple reaction time and pinch force) related to these areas. All subjects were divided into two groups: the SEP group, in which the effects of upper limb immobilization on the excitability of somatosensory processing were investigated, and the transcranial magnetic stimulation (TMS) group, in which the effects of upper limb immobilization on the excitability of the corticospinal tract and primary motor cortex were investigated. Motor performance was evaluated in all subjects. We showed that 10-h right upper limb immobilization increased the cortical component of SEPs (N30) in the SEP group and decreased the excitability of the corticospinal tract, but not of the primary motor cortex, in the TMS group. The pinch force decreased after upper limb immobilization. However, the visual simple reaction time did not change between pre- and post-immobilization. The supplementary motor area and premotor cortex are believed to be the source of the N30. Therefore, these results suggest that upper limb immobilization affected somatosensory information processing in motor-related areas. Moreover, 10-h right upper limb immobilization reduced the excitability of corticospinal tracts but not that of the primary motor cortex, suggesting that circuits outside the M1, such as the intra- and inter-hemispheric inhibitory and facilitatory circuits rather than circuits within the M1, may be responsible for the reduced excitability of the central nervous system after restraint. [ABSTRACT FROM AUTHOR]

Background: Short-interval intracortical inhibition (SICI), as measured by threshold-tracking as a function of inter-stimulus interval (ISI), has been proposed as a useful biomarker for amyotrophic lateral sclerosis (ALS), but its relationship to conventional amplitude measurements has not been established. Methods: Serial tracking of SICI at increasing ISIs from 1 to 7 ms (T-SICIs) was compared in 50 healthy control subjects with the same ISIs tracked in parallel (T-SICIp), and with conventional amplitude measurements (A-SICI). For T-SICIp and A-SICI, pairs of conditioning and test stimuli with different ISIs were pseudo-randomised and interspersed with test-alone stimuli given at regular intervals. Thresholds were estimated by regression of log peak-to-peak amplitude on stimulus. Results: T-SICIp and A-SICI were closely related: a ten-fold reduction in amplitude corresponding to an approximately 18% increase in threshold. Threshold increases were greater for T-SICIs than for T-SICIp at 3.5–5 ms (P

Reduced short-interval intracortical inhibition (SICI) in motor neuron disease has been demonstrated by amplitude changes (A-SICI) and threshold-tracking (T-SICI) using 10 stimuli per inter-stimulus interval (ISI). To test whether fewer stimuli would suffice, A-SICI and T-SICI were recorded twice from 30 healthy subjects using 6 and 10 stimuli per ISI. Using fewer stimuli increased mean A-SICI variances by 23.8% but the 7.3% increase in T-SICI variance was not significant. We conclude that our new parallel threshold-tracking SICI protocol, with 6 stimuli per ISI, can reduce time and stimulus numbers by 40% without appreciable loss of accuracy. [ABSTRACT FROM AUTHOR]

We examined the effects of lower limb segmental muscle vibration (SMV) on intracortical and spinal excitability in 13 healthy participants (mean age: 34.9 ± 7.8 years, 12 males, 1 female). SMV at 30 Hz was applied to the hamstrings, gastrocnemius, and soleus muscles for 5 min. Paired-pulse transcranial magnetic stimulation protocols were used to investigate motor-evoked potential (MEP) amplitude, short-interval intracortical inhibition (SICI) and short-interval intracortical facilitation (SICF) from the abductor hallucis muscle (AbdH). These assessments were compared to the results of a control experiment (i.e., non-vibration) in the same participants. F-waves were evaluated from the AbdH on the right (vibration side) and left (non-vibration side) sides, and we calculated the ratio of the F-wave amplitude to the M-response amplitude (F/M ratio). These assessments were obtained before, immediately after, and 10, 20, and 30 min after SMV. For SICI, there was no change immediately after SMV, but there was a decrease over time (before vs. 30 min after, p = 0.021; immediately after vs. 30 min after, p = 0.015). There were no changes in test MEP amplitude, SICF, or the F/M ratio. SMV causes a gradual decrease in SICI over time perhaps owing to long-term potentiation. The present results may have implications for the treatment of spasticity. [ABSTRACT FROM AUTHOR]

A previous study using traditional paired-pulse TMS methods (amplitude-tracking) has reported differences in resting motor threshold (RMT) and short-interval intracortical inhibition (SICI) between healthy subjects of Caucasian and Han Chinese backgrounds, probably due to differences in the skull shape. The amplitude-tracking method delivers stimuli with constant intensity and causes substantial variabilities in motor-evoked potential amplitudes. To overcome this variability, threshold tracking transcranial magnetic stimulation (TT-TMS) has been developed. The present study aimed to investigate whether racial differences in motor cortical function exist, using TT-TMS. A total of 83 healthy volunteers (30 Caucasians, 25 Han Chinese, and 28 Japanese) were included in the present series. In TT-TMS and nerve conduction studies, electrodes were placed on the dominant limb, with measures recorded from the abductor pollicis brevis muscle. Stimulations were delivered with a circular coil, directly above the primary motor cortex. There were no significant differences at all the SICI intervals between races. Similarly, there were no significant differences in other measures of excitability including mean RMT, intracortical facilitation, and cortical silent period. Contrary to traditional amplitude-tracking TMS, motor cortical excitability and thereby motor cortical function is minimally influenced by racial differences when measured by TT-TMS. Recent studies have disclosed that SICI measured by TT-TMS differentiates amyotrophic lateral sclerosis (ALS) from ALS mimic disorders, with high sensitivity and specificity, in Caucasians. This study suggested that TT-TMS can be applied for the ALS diagnosis in Asian patients, as well as Caucasians. [ABSTRACT FROM AUTHOR]

Background and purpose: Short‐interval intracortical inhibition by threshold tracking (T‐SICI) has been proposed as a diagnostic tool for amyotrophic lateral sclerosis (ALS) but has not been compared directly with conventional amplitude measurements (A‐SICI). This study compared A‐SICI and T‐SICI for sensitivity and clinical usefulness as biomarkers for ALS. Methods: In all, 104 consecutive patients referred with suspicion of ALS were prospectively included and were subsequently divided into 62 patients with motor neuron disease (MND) and 42 patient controls (ALS mimics) by clinical follow‐up. T‐SICI and A‐SICI recorded in the first dorsal interosseus muscle (index test) were compared with recordings from 53 age‐matched healthy controls. The reference standard was the Awaji criteria. Clinical scorings, conventional nerve conduction studies and electromyography were also performed on the patients. Results: Motor neuron disease patients had significantly reduced T‐SICI and A‐SICI compared with the healthy and patient control groups, which were similar. Sensitivity and specificity for discriminating MND patients from patient controls were high (areas under the receiver operating characteristic curves 0.762 and 0.810 for T‐SICI and A‐SICI respectively at 1–3.5 ms). Paradoxically, T‐SICI was most reduced in MND patients with the fewest upper motor neuron (UMN) signs (Spearman ρ = 0.565, p = 4.3 × 10−6). Conclusions: Amplitude‐based measure of cortical inhibition and T‐SICI are both sensitive measures for the detection of cortical involvement in MND patients and may help early diagnosis of ALS, with T‐SICI most abnormal before UMN signs have developed. The gradation in T‐SICI from pathological facilitation in patients with minimal UMN signs to inhibition in those with the most UMN signs may be due to progressive degeneration of the subset of UMNs experiencing facilitation. [ABSTRACT FROM AUTHOR]

Abstract Background The development of diagnostic tools capable of accurately identifying the pathophysiology of mild cognitive impairment (MCI) has become a crucial target considering the claim that disease-modifying treatments should be administered as early as possible in the disease course. Transcranial magnetic stimulation (TMS) protocols have demonstrated analytical validity in discriminating different forms of dementia; however, its value in daily clinical practice in MCI subjects is still unknown. Objective To evaluate the clinical value of TMS compared to amyloid markers on diagnostic confidence and accuracy in MCI subjects, considering clinicians’ expertise. Methods One hundred seven MCI subjects were included and classified as MCI-Alzheimer disease (MCI-AD), MCI-frontotemporal dementia (MCI-FTD), MCI-dementia with Lewy bodies (MCI-DLB), or MCI-other in a three-step process based on (i) demographic, clinical, and neuropsychological evaluation (clinical work-up); (ii) clinical work-up PLUS amyloidosis markers or clinical work-up PLUS TMS measures; and (iii) clinical work-up PLUS both markers. Two blinded neurologists with different clinical expertise were asked to express a diagnostic confidence for each MCI subgroup, and ROC curve analyses were performed at each step. Results The addition of TMS markers to clinical work-up significantly increased the diagnostic confidence for MCI-AD (p = 0.003), MCI-FTD (p = 0.044), and MCI-DLB (p = 0.033) compared to clinical work-up alone, but not for MCI-other (p > 0.05). No significant differences between the add-on effect of TMS and the add-on effect of amyloid markers to clinical work-up were observed (p > 0.732), while the diagnostic confidence further increased when both markers were available. The greater the clinical expertise, the greater the flexibility in considering alternative diagnosis, and the greater the ability to modify diagnostic confidence with TMS and amyloid markers. Conclusions TMS in addition to routine clinical assessment in MCI subjects has a significant effect on diagnostic accuracy and confidence, comparable to well-established biomarkers of amyloidosis.

Short-interval intracortical inhibition (SICI), as measured by threshold-tracking as a function of inter-stimulus interval (ISI), has been proposed as a useful biomarker for amyotrophic lateral sclerosis (ALS), but its relationship to conventional amplitude measurements has not been established. Serial tracking of SICI at increasing ISIs from 1 to 7 ms (T-SICIs) was compared in 50 healthy control subjects with the same ISIs tracked in parallel (T-SICIp), and with conventional amplitude measurements (A-SICI). For T-SICIp and A-SICI, pairs of conditioning and test stimuli with different ISIs were pseudo-randomised and interspersed with test-alone stimuli given at regular intervals. Thresholds were estimated by regression of log peak-to-peak amplitude on stimulus. T-SICIp and A-SICI were closely related: a ten-fold reduction in amplitude corresponding to an approximately 18% increase in threshold. Threshold increases were greater for T-SICIs than for T-SICIp at 3.5–5 ms (P < 0.001). This divergence depended on the initial settings and whether ISIs were progressively increased or decreased, and was attributed to the limitations of the serial tracking protocol. SICI variability between subjects was greatest for T-SICIs estimates and least for A-SICI, and only A-SICI estimates revealed a significant decline in inhibition with age. The serial tracking protocol did not accurately show the dependence of inhibition on ISI. Randomising ISIs gives corresponding SICI measures, whether tracking thresholds or measuring amplitude measurements. SICI variability suggested that A-SICI measurements may be the most sensitive to loss of inhibition. • SICI at ISIs from 1 to 7 ms has been recorded from 50 healthy subjects by 3 methods. • A-SICI used amplitudes, T-SICIs tracked thresholds at sequentially increasing ISIs. • T-SICIp tracked the randomised 9 ISIs in parallel (new method). • A-SICI and T-SICIp were well correlated, but T-SICIs results were not accurate. • A-SICI provided the least variable measures of inhibition across subjects. [ABSTRACT FROM AUTHOR]

Modulation of GABA-mediated inhibition in primary motor cortex (M1) is important for the induction of training-induced plasticity. The downregulation of inhibition during acquisition may promote cortical reorganization, whereas an upregulation once performance has plateaued may promote consolidation of the newly acquired skill. GABA-related inhibition in human M1 is routinely assessed using the paired-pulse transcranial magnetic stimulation (TMS) paradigm of short-interval intracortical inhibition (SICI). However, modulation of SICI with motor skill learning is not a consistent finding and may be influenced by TMS parameters. The aim of this study was to compare the modulation of SICI by motor skill learning between conventional and adaptive threshold-hunting techniques with an anterior–posterior and posterior–anterior induced current. Sixteen participants (21–33 years) trained with their dominant (right) hand on a sequential visual isometric pinch task. Electromyographic recordings were obtained from the right first dorsal interosseous muscle. Corticomotor excitability and SICI were examined before and immediately after 12 blocks of training. Skill increased throughout the training, with performance plateauing before completion. Corticomotor excitability increased after motor training for both current directions. The amount of SICI was greater with anterior–posterior stimulation than posterior–anterior for both conventional and adaptive threshold-hunting techniques. SICI increased after motor training, but only for adaptive threshold-hunting with an anterior–posterior-induced current. The increased GABA-mediated inhibition evident after motor skill learning may promote consolidation of the newly acquired skill. The findings also support the notion that adaptive threshold-hunting SICI using an anterior–posterior current provides an effective assessment in interventional studies. [ABSTRACT FROM AUTHOR]

During fatiguing exercise, previous studies have employed transcranial magnetic stimulation (TMS) paradigms eliciting either maximal or submaximal short-interval intracortical inhibition (SICI) and silent period (SP) durations. However, the effect of using either approach on the change in these variables with fatigue is unknown. This study examined the effects of using conditioning stimulus (CS, experiment A) and single-pulse TMS intensities (experiment B) that elicit maximal and submaximal SICI and SP duration (MaxSICI vs. SubmaxSICI in experiment A, MaxSP vs. SubmaxSP in experiment B) on the change in these measures with fatigue. In both experiments, participants performed a 10-min sustained isometric knee-extension contraction at a constant level of EMG, with measurements taken with maximal and submaximal intensities at baseline and every 2.5 min throughout the task. Immediately after the 10-min contraction (i.e., without recovery), responses were also measured at the same absolute force level as at baseline. In experiment A, no change in SICI was observed with either CS intensity throughout the EMG task (P > 0.05). However, an 18% decrease in SICI (i.e., less inhibition) was observed at the same absolute force only with the MaxSICI CS intensity (P < 0.01), with no change in SubmaxSICI (P = 0.72). In experiment B, the magnitude of increase in SP with fatigue was similar for both stimulus intensities (stimulus time interaction: P = 0.44). These results suggest that CS intensities eliciting maximum SICI are more sensitive in detecting fatigue-induced reductions in SICI, whereas increases in SP are detectable with TMS intensities evoking maximal or submaximal SPs. [ABSTRACT FROM AUTHOR]

Background. Motor information in the brain is transmitted from the dorsal premotor cortex (PMd) to the primary motor cortex (M1), where it is further processed and relayed to the spinal cord to eventually generate muscle movement. However, how information from the PMd affects M1 processing and the final output is unclear. Here, we applied intermittent theta burst stimulation (iTBS) to the PMd to alter cortical excitability not only at the application site but also at the PMd projection site of M1. We aimed to determine how PMd iTBS altered information changed M1 processing and the corticospinal output. Methods. In total, 16 young, healthy participants underwent PMd iTBS with 600 pulses (iTBS600) or sham-iTBS600. Corticospinal excitability, short-interval intracortical inhibition (SICI), and intracortical facilitation (ICF) were measured using transcranial magnetic stimulation before and up to 60 min after stimulation. Results. Corticospinal excitability in M1 was significantly greater 15 min after PMd iTBS600 than that after sham-iTBS600 (p=0.012). Compared with that after sham- iTBS600, at 0 (p=0.014) and 15 (p=0.037) min after iTBS600, SICI in M1 was significantly decreased, whereas 15 min after iTBS600, ICF in M1 was significantly increased (p=0.033). Conclusion. Our results suggested that projections from the PMd to M1 facilitated M1 corticospinal output and that this facilitation may be attributable in part to decreased intracortical inhibition and increased intracortical facilitation in M1. Such a facilitatory network may inform future understanding of the allocation of resources to achieve optimal motion output. [ABSTRACT FROM AUTHOR]

The purpose of this study was to determine whether the increases in corticospinal excitability (CSE) observed after one session of unilateral isometric strength training (ST) are related to changes in intracortical excitability measured by magnetic brain stimulation (TMS) in the trained and the contralateral untrained biceps brachii (BB) and whether such changes scale with training intensity. On three separate days, 15 healthy young men performed one ST session of 12 sets of eight isometric contractions of the right elbow flexors at 0% (control session), 25%, or 75% of the maximal voluntary contraction (MVC) in a random order. Before and after each session separated at least by 1 week, motor evoked potential (MEP) amplitude, short‐interval intracortical inhibition (SICI), contralateral silent period (SP), and intracortical facilitation (ICF) generated by TMS were measured in the trained and the untrained BBs. Compared with baseline, MEPs recorded from the trained BB increased by ~47% after training at 75% of MVC (P <.05) but not after training at 0% (~4%) or 25% MVC (~5%, both P >.05). MEPs in the untrained BB and SICI, SP, and ICF in either BB did not change. Therefore, acute high‐intensity but not low‐intensity unilateral isometric ST increases CSE in the trained BB without modifications in intracortical inhibition or facilitation. Thus, increases in corticospinal neurons or α‐α‐motoneuron excitability could underlie the increases in CSE. Regardless of contraction intensity, acute isometric ST did not modify the excitability of the ipsilateral primary motor cortex measured by TMS. [ABSTRACT FROM AUTHOR]

Cycling exercise is commonly used in rehabilitation to improve lower extremity (LE) motor function and gait performance after stroke. Motor learning is important for regaining motor skills, suggesting that training of motor skills influences cortical plasticity. However, the effects of motor skill learning in dynamic alternating movements of both legs on cortical plasticity remain unclear. Here, we examined the effects of skillful cycling training on cortical plasticity of the LE motor area in healthy adults. Eleven healthy volunteers participated in the following three sessions on different days: skillful cycling training, constant-speed cycling training, and rest condition. Skillful cycling training required the navigation of a marker up and down curves by controlling the rotation speed of the pedals. Participants were instructed to fit the marker to the target curves as accurately as possible. Amplitudes of motor evoked potentials (MEPs) and short-interval intracortical inhibition (SICI) evoked using transcranial magnetic stimulation (TMS) were assessed at baseline, after every 10 min of the task (a total of 30 min), and 30 min after the third and final trial. A decrease in tracking errors was representative of the formation of motor learning following skillful cycling training. Compared to baseline, SICI was significantly decreased after skillful cycling training in the tibialis anterior (TA) muscle. The task-induced alterations of SICI were more prominent and lasted longer with skillful cycling training than with the other conditions. The changes in SICI were negatively correlated with a change in tracking error ratio at 20 min the task. MEP amplitudes were not significantly altered with any condition. In conclusion, skillful cycling training induced long-lasting plastic changes of intracortical inhibition, which corresponded to the learning process in the LE motor cortex. These findings suggest that skillful cycling training would be an effective LE rehabilitation method after stroke.

Abstract Background Acupuncture 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. Methods Twenty 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. Results The 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. Conclusion Acupuncture 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.

Objective: To establish if induced current direction across the motor cortex alters the sensitivity of transcranial magnetic stimulation (TMS)-evoked short-interval intracortical inhibition (SICI) as an ALS biomarker., Methods: Threshold tracking-TMS was undertaken in 35 people with ALS and 39 controls. Using a coil orientation which induces posterior-anterior (PA)-directed current across the motor cortex, SICI (1 ms and 3 ms interstimulus intervals) and intracortical facilitation (ICF, 10 ms interstimulus interval) were recorded. SICI 3ms was also recorded using a coil orientation which induces anterior-posterior (AP)-directed current across the motor cortex., Results: At group level, SICI 3ms-PA (AUROC = 0.7), SICI 3ms-AP (AUROC = 0.8) and SICI 1ms (AUROC = 0.66) were substantially lower in those with ALS, although there was considerable interindividual heterogeneity. Averaging across interstimulus intervals (ISIs) marginally improved SICI PA sensitivity (AUROC = 0.76). Averaging SICI values across ISIs and orientations into a single SICI measure did not substantially improve sensitivity (AUROC = 0.81) compared to SICI 3ms-AP alone. SICI 3ms-AP and SICI 3ms-PA did not significantly correlate (rho = 0.19, p = 0.313), while SICI 1ms-PA and SICI 3ms-PA did (rho = 0.37, p = 0.006). Further, those with ALS with the lowest SICI 3ms-PA were not those with the lowest SICI 3ms-AP . ICF was similar between groups (AUROC = 0.50)., Conclusions: SICI PA and SICI AP are uncorrelated measures of motor cortical inhibitory functions which are useful as distinct, unequally affected, measures of disinhibition in ALS., Significance: Examining both SICI PA and SICI AP may facilitate more comprehensive characterisation of motor cortical disinhibition in ALS., (© 2024 International Federation of Clinical Neurophysiology. Published by Elsevier B.V.)

Background: The development of diagnostic tools capable of accurately identifying the pathophysiology of mild cognitive impairment (MCI) has become a crucial target considering the claim that disease-modifying treatments should be administered as early as possible in the disease course. Transcranial magnetic stimulation (TMS) protocols have demonstrated analytical validity in discriminating different forms of dementia; however, its value in daily clinical practice in MCI subjects is still unknown. Objective: To evaluate the clinical value of TMS compared to amyloid markers on diagnostic confidence and accuracy in MCI subjects, considering clinicians' expertise. Methods: One hundred seven MCI subjects were included and classified as MCI-Alzheimer disease (MCI-AD), MCI-frontotemporal dementia (MCI-FTD), MCI-dementia with Lewy bodies (MCI-DLB), or MCI-other in a three-step process based on (i) demographic, clinical, and neuropsychological evaluation (clinical work-up); (ii) clinical work-up PLUS amyloidosis markers or clinical work-up PLUS TMS measures; and (iii) clinical work-up PLUS both markers. Two blinded neurologists with different clinical expertise were asked to express a diagnostic confidence for each MCI subgroup, and ROC curve analyses were performed at each step. Results: The addition of TMS markers to clinical work-up significantly increased the diagnostic confidence for MCI-AD (p = 0.003), MCI-FTD (p = 0.044), and MCI-DLB (p = 0.033) compared to clinical work-up alone, but not for MCI-other (p > 0.05). No significant differences between the add-on effect of TMS and the add-on effect of amyloid markers to clinical work-up were observed (p > 0.732), while the diagnostic confidence further increased when both markers were available. The greater the clinical expertise, the greater the flexibility in considering alternative diagnosis, and the greater the ability to modify diagnostic confidence with TMS and amyloid markers. Conclusions: TMS in addition to routine clinical assessment in MCI subjects has a significant effect on diagnostic accuracy and confidence, comparable to well-established biomarkers of amyloidosis. [ABSTRACT FROM AUTHOR]

Background: Decreased short-interval intracortical inhibition (SICI) to transcranial magnetic stimulation (TMS) of the primary motor cortex was described in subjects with restless legs syndrome/Willis-Ekbom disease (RLS/WED). It remained to be determined whether the magnitude of SICI decrease would be similar across levels of RLS/WED severity. Moreover, it was unknown whether, in addition to decreases in SICI, changes in cortical thickness or area could be detected in subjects with RLS/WED compared to controls. The objective of this study was to compare SICI, cortical thickness, and cortical area in subjects with idiopathic mild to moderate RLS/WED, severe to very severe RLS/WED, and controls.Methods: The severity of RLS/WED was assessed by the International Restless Legs Syndrome Severity Scale (IRLSS). SICI and 3T magnetic resonance imaging (MRI) data of subjects with RLS/WED and controls were compared. A receiver operating characteristic curve for SICI was designed for discrimination of participants with RLS/WED from controls. Cortical thickness and area were assessed by automated surface-based analysis.Results: SICI was significantly reduced in patients with mild to moderate and severe to very severe RLS/WED, compared to controls (one-way analysis of variance: F = 9.62, p < 0.001). Receiver operating characteristic curve analysis predicted RLS/WED when SICI was above 35% (area under the curve = 0.79, 95% CI 0.67-0.91, p < 0.001). Analyses of the whole brain and of regions of interest did not reveal differences in gray matter thickness or area between controls and subjects with RLS/WED.Conclusion: SICI is an accurate cortical biomarker that can support the diagnosis of RLS/WED even in subjects with mild symptoms, but cortical thickness and area were not useful for discriminating subjects with this condition from controls. [ABSTRACT FROM AUTHOR]

Cycling exercise is commonly used in rehabilitation to improve lower extremity (LE) motor function and gait performance after stroke. Motor learning is important for regaining motor skills, suggesting that training of motor skills influences cortical plasticity. However, the effects of motor skill learning in dynamic alternating movements of both legs on cortical plasticity remain unclear. Here, we examined the effects of skillful cycling training on cortical plasticity of the LE motor area in healthy adults. Eleven healthy volunteers participated in the following three sessions on different days: skillful cycling training, constant-speed cycling training, and rest condition. Skillful cycling training required the navigation of a marker up and down curves by controlling the rotation speed of the pedals. Participants were instructed to fit the marker to the target curves as accurately as possible. Amplitudes of motor evoked potentials (MEPs) and short-interval intracortical inhibition (SICI) evoked using transcranial magnetic stimulation (TMS) were assessed at baseline, after every 10 min of the task (a total of 30 min), and 30 min after the third and final trial. A decrease in tracking errors was representative of the formation of motor learning following skillful cycling training. Compared to baseline, SICI was significantly decreased after skillful cycling training in the tibialis anterior (TA) muscle. The task-induced alterations of SICI were more prominent and lasted longer with skillful cycling training than with the other conditions. The changes in SICI were negatively correlated with a change in tracking error ratio at 20 min the task. MEP amplitudes were not significantly altered with any condition. In conclusion, skillful cycling training induced long-lasting plastic changes of intracortical inhibition, which corresponded to the learning process in the LE motor cortex. These findings suggest that skillful cycling training would be an effective LE rehabilitation method after stroke. [ABSTRACT FROM AUTHOR]

Objective: The study aimed to investigate short-interval intracortical inhibition (SICI) in burns survivors and non-injured controls, and establish whether paired-pulse transcranial magnetic stimulation (TMS) is a sensitive tool to investigate SICI after burn-injury.Methods: Burn survivors underwent experimental assessments at 6- and 12-weeks after injury, and control participants underwent two equivalent sessions 6 weeks apart. Single-pulse transcranial magnetic stimulation (TMS) was used to record motor-evoked potentials (MEPs) from a hand muscle and paired-pulse TMS was used to measure SICI. Functional measures were obtained for comparison at 12-weeks after injury.Results: There was no significant difference in SICI between burns survivors and non-injured controls at either 6- or 12-weeks after burn injury. There was no evidence of correlations between SICI and functional outcome measures in burns survivors.Conclusions: These results show that paired-pulse TMS is a useful method for investigating cortical inhibition following burn injury, and that SICI circuits in the primary motor cortex are not affected by minor burn injury. This study presents details for definitive future studies of primary motor cortex function after minor burn injury. [ABSTRACT FROM AUTHOR]

Background The goal of this study was to examine baseline transcranial magnetic stimulation measures of cortical inhibition and excitability in depressed patients and characterize their longitudinal posttreatment changes. Methods Fifteen adolescents (age 13–17 years) with moderate to severe major depressive disorder and 22 healthy controls (age 9–17) underwent single- and paired-pulse transcranial magnetic stimulation and clinical assessments. Transcranial magnetic stimulation measures included short-interval intracortical inhibition (2 and 4 milliseconds), long-interval intracortical inhibition (100, 150, and 200 milliseconds), cortical silent period, and intracortical facilitation (10, 15, and 20 milliseconds). Ten participants with major depressive disorder initiated antidepressant treatment or had dose adjustments. These participants were reassessed after treatment. Depression symptom severity was measured with the Children's Depression Rating Scale, Revised. Robust regression modeling compared healthy and depressed adolescents at baseline. Relationships between changes in cortical inhibition and changes in depressive symptom severity were assessed in the depressed adolescents receiving antidepressant treatment. Results Our results revealed that at baseline, short-interval intracortical inhibition-2 was significantly reduced (P adj = .01) in depressed participants, suggesting impaired cortical inhibition compared with healthy controls. At follow-up, improvement in Children's Depression Rating Scale, Revised scores correlated with improvement in short-interval intracortical inhibition-4 amplitude (greater inhibition) after antidepressant treatment (R 2 = 0.63; P  = .01). Conclusions These results suggest that cortical inhibition measures may have promise as biomarkers in adolescents treated for depression. [ABSTRACT FROM AUTHOR]

Motor cortex (M1) paired-pulse TMS (ppTMS) probes excitatory and inhibitory intracortical dynamics by measurement of motor-evoked potentials (MEPs). However, MEPs reflect cortical and spinal excitabilities and therefore cannot isolate cortical function. Concurrent TMS-EEG has the ability to measure cortical function, while limiting peripheral confounds; TMS stimulates M1, whilst EEG acts as the readout: the TMS-evoked potential (TEP). Whilst varying preconditioning stimulus intensity influences intracortical inhibition measured by MEPs, the effects on TEPs is undefined. TMS was delivered to the left M1 using single-pulse and three, ppTMS paradigms, each using a different preconditioning stimulus: 70%, 80% or 90% of resting motor threshold. Corticospinal inhibition was present in all three ppTMS conditions. ppTMS TEP peaks were reduced predominantly under the ppTMS 70 protocol but less so for ppTMS 80 and not at all for ppTMS 90. There was a significant negative correlation between MEPs and N45 TEP peak for ppTMS 70 reaching statistical trends for ppTMS 80 and 90. Whilst ppTMS MEPs show inhibition across a range of preconditioning stimulus intensities, ppTMS TEPs do not. TEPs after M1 ppTMS vary as a function of preconditioning stimulus intensity: smaller preconditioning stimulus intensities result in better discriminability between conditioned and unconditioned TEPs. We recommend that preconditioning stimulus intensity should be minimized when using ppTMS to probe intracortical inhibition.

Post-movement beta synchronization is an increase of beta power relative to baseline, which commonly used to represent the status quo of the motor system. However, its functional role to the subsequent voluntary motor output and potential electrophysiological significance remain largely unknown. Here, we examined the reaction time of a Go/No-Go task of index finger tapping which performed at the phases of power baseline and post-movement beta synchronization peak induced by index finger abduction movements at different speeds (ballistic/self-paced) in 13 healthy subjects. We found a correlation between the post-movement beta synchronization and reaction time that larger post-movement beta synchronization prolonged the reaction time during Go trials. To probe the electrophysiological significance of post-movement beta synchronization, we assessed intracortical inhibitory measures probably involving GABAB (long-interval intracortical inhibition) and GABAA (short-interval intracortical inhibition) receptors in beta baseline and post-movement beta synchronization peak induced by index finger abduction movements at different speeds. We found that short-interval intracortical inhibition but not long-interval intracortical inhibition increased in post-movement beta synchronization peak compared with that in the power baseline, and was negatively correlated with the change of post-movement beta synchronization peak value. These novel findings indicate that the post-movement beta synchronization is related to forward model updating, with high beta rebound predicting longer time for the preparation of subsequent movement by inhibitory neural pathways of GABAA., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Abstract Background In human primary motor cortex (M1), the paired-pulse transcranial magnetic stimulation (TMS) paradigm of short-interval intracortical inhibition (SICI) can be expressed conventionally as a percent change in the relative amplitude of a conditioned motor evoked potential to non-conditioned; or adaptive threshold-hunting a target motor evoked potential amplitude in the absence or presence of a conditioning stimulus, and noting the relative change in stimulation intensity. The suitability of each approach may depend on the induced current direction, which probe separate M1 interneuronal populations. Objective To examine the influence of conditioning stimulus intensity, interstimulus interval (ISI) and current direction for adaptive threshold-hunting and conventional SICI using equivalent TMS intensities. Methods In 16 participants (21–32 years), SICI was examined using adaptive threshold-hunting and conventional paired-pulse TMS with posterior-anterior and anterior-posterior stimulation, ISIs of 2 and 3 ms, and a range of conditioning intensities. Results Inhibition with adaptive threshold-hunting was greater for anterior-posterior stimulation with an ISI of 3 ms (23.6 ± 9.0%) compared with 2 ms (7.5 ± 7.8%, P < 0.001) and posterior-anterior stimulation at both ISIs (2 ms 8.6 ± 8.7%, 3 ms 5.9 ± 4.8%; P < 0.001). There was an association between inhibition obtained with conventional and adaptive threshold-hunting for posterior-anterior but not anterior-posterior stimulation (2 ms only, r = 0.68, P = 0.03). Conclusions More inhibition was evident with anterior-posterior than posterior-anterior current for both adaptive threshold-hunting and conventional paired-pulse TMS. Assessment of SICI with anterior-posterior stimulation was not directly comparable between the two approaches. However, the amount of inhibition was dependent on conditioning stimulus intensity and ISI for both SICI techniques. Highlights • Greater intracortical inhibition can be obtained using anterior-posterior induced current in the brain compared with posterior-anterior for both conventional and adaptive threshold-hunting paired-pulse transcranial magnetic stimulation. • With both techniques, the amount of inhibition assessed with anterior-posterior induced current was dependent on the conditioning stimulus intensity and interstimulus interval. • Assessment of primary motor cortex short-latency inhibition using equivalent stimulation intensities may not be directly comparable between conventional and adaptive threshold-hunting techniques. [ABSTRACT FROM AUTHOR]

Background Inhibition 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. Methods PpTMS-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. Results We 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. Conclusions Findings 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. [ABSTRACT FROM AUTHOR]

Background Short-interval intracortical inhibition (SICI) is conventionally measured as the relative amplitude reduction of motor evoked potentials (MEPs) by subthreshold conditioning stimuli. In threshold-tracking SICI (T-SICI), stimulus intensity is instead adjusted repeatedly to maintain a constant MEP and inhibition is measured as the relative threshold increase . T-SICI is emerging as a useful diagnostic test, but its relationship to conventional amplitude SICI (A-SICI) is unclear. Objective To compare T-SICI and its reliability with conventional A-SICI measurements. Methods In twelve healthy volunteers (6 men, median age 30 years), conventional and T-SICI were recorded at conditioning stimuli (CS) of 50–80% resting motor threshold (RMT) and interstimulus interval of 2.5 ms. Measurements were repeated on the same day and at least a week later by a single operator. Results Across the CS range, mean group T-SICI showed a strong linear relationship to the mean group values measured by conventional technique (y = 29.7–0.3x, R 2  = 0.99), but there was considerable interindividual variability. At CS 60–80% RMT, T-SICI had excellent intraday (intraclass correlation coefficient, ICC, 0.81–0.92) and adequate-to-excellent interday (ICC 0.61–0.88) reproducibility. Conventional SICI took longer to complete (median of 5.8 vs 3.8 min, p < 0.001) and tended to have poorer reproducibility (ICC 0.17–0.42 intraday, 0.37–0.51 interday). With T-SICI, smaller sample sizes were calculated for equally powered interventional studies. Conclusion The close relationship between conventional and T-SICI suggests that both techniques reflect similar cortical inhibitory mechanisms. Threshold-tracking measurements of SICI may be able to improve reproducibility, to shorten acquisition time and to reduce sample sizes for interventional studies compared with the conventional technique. [ABSTRACT FROM AUTHOR]

Paired-pulse transcranial magnetic stimulation (TMS) using fixed test stimuli suffers from marked variability of the motor evoked potential (MEP) amplitude. Threshold tracking TMS (TT-TMS) was introduced to overcome this problem. The aim of this work was to describe the absolute and relative reliability of short-interval intracortical inhibition (SICI) using TT-TMS. Cortical excitability studies were performed on twenty-six healthy subjects over three sessions (two recordings on the same day and one seven days apart), with MEPs recorded over abductor pollicis brevis. Reliability was established by calculating the standard error of the measurements (SEm), minimal detectable change (MDC) and intraclass correlation coefficient (ICC). Resting motor threshold and averaged SICI presented the lowest SEm and highest ICCs. SICI at 1 ms showed a higher SEm than SICI at 3 ms, suggesting different physiological processes, but averaging SICI over a number of intervals greatly increases the reproducibility. The variability was lower for tests undertaken at the same time of day seven days apart compared to tests performed on the same day, and in both instances the ICC for averaged SICI was ≥0.81. The MDC in averaged SICI was reduced from 6.7% to 2% if the number of subjects was increased from one to eleven. In conclusion, averaged SICI is the most reproducible variable across paired-pulse TT-TMS measures, showing an excellent ICC. It is recommended that, in longitudinal studies, testing be performed at the same time of day and that changes in cortical excitability should be measured and averaged over a number of interstimulus intervals to minimise variability. [ABSTRACT FROM AUTHOR]

A four-pulse pattern of transcranial magnetic stimulation (TMS) was compared to traditional dual-pulse TMS for its ability to modulate motor cortical excitability. This novel pattern consisted of a three-pulse train of subthreshold conditioning pulses followed by a suprathreshold test pulse (i.e., SC-T). The intervals between these superconditioning (SC) pulses (1, 3, or 6 ms) and the follow-on test pulse (1, 3, 10, or 25 ms) were varied, and the resultant MEPs were compared to those elicited by: (1) single-pulse TMS; and (2) dual-pulse conditioning-test (C-T) TMS with either short (3 ms) or long (10 ms) intervals to elicit short-interval intracortical inhibition (SICI) or intracortical facilitation (ICF), respectively. Testing included abductor pollicis brevis (APB) and tibialis anterior (TA) in 15 neurologically normal adults. For superconditioning inputs, 10 ms test intervals caused especially strong facilitation of the test MEP, while 1 ms test intervals were particularly effective at causing inhibition of the test response. For both muscles and across all subjects, the most effective of the 12 SC-T inputs tested for causing either facilitation or inhibition was—with rare exception—superior to the dual-pulse TMS input for causing facilitation (i.e., ICF) or inhibition (i.e., SICI), while the overall magnitude of effect was more pronounced in APB compared to TA. Nevertheless, after normalization, the impact of a superconditioning input train on the test MEP was similar in APB and TA muscles, suggesting similar mechanisms of action. Limited findings from a single subject with amyotrophic lateral sclerosis (ALS) are included to further illustrate the potential advantages of using a train of conditioning pulses preceding a TMS test pulse to selectively investigate abnormal motor cortical excitatory and inhibitory circuitry. [ABSTRACT FROM AUTHOR]

Vascular parkinsonism (VaP), type of lower body parkinsonism, occurs in relation to ischemic cerebrovascular disease. It can be associated with cognitive impairment. We aimed to study the cortical excitability changes in these patients using transcranial magnetic stimulation (TMS). We included 20 patients with VaP and 22 healthy controls (HC). All subjects underwent TMS over left motor cortex with recording of resting motor threshold (RMT), central motor conduction time (CMCT), short-interval intracortical inhibition (SICI), intracortical facilitation (ICF), contralateral and ipsilateral silent period (SP) along with RMT and CMCT in the contralateral lower limb. Cognitive assessments were done using Montreal cognitive assessment (MoCA) and Addenbrooke's cognitive evaluation III (ACE III). Mean age of patients (63.90 ± 7.36 years) was comparable with controls (59.77 ± 6.94 years; p = 0.07). Duration of disease was 2.58 ± 2.57 years. The upper and lower limb RMT of patients (32.45 ± 4.81%; 57.20 ± 11.54%) was significantly low compared to HC (43.64 ± 7.73%; 69.18 ± 14.27%; p < 0.001). There was a significant reduction in SICI in patients (1.87 ± 2.03) compared to HC (0.38 ± 0.29; p < 0.001). In addition, there was a significant prolongation of ipsilateral SP in patients (48.49 ± 24.49) compared to controls (32.04 ± 12.26, p = 0.01). However, there was no significant difference in contralateral SP (p = 0.66) and ICF (p = 0.25) between the two groups. There was a significant prolongation of lower limb CMCT in patients (p < 0.01). There was a positive correlation of SICI with MoCA (r = 0.45, p < 0.05) and ACE-III (r = 0.33, p < 0.05) scores. Reduction in RMT and SICI in patients with VaP suggests abnormalities in GABAergic neurotransmission that may underlie cognitive impairment observed in them. • Vascular parkinsonism (VaP) is a type of lower body parkinsonism occurring in relation to ischemic cerebrovascular disease. • A significant reduction in resting motor threshold (RMT) and short interval intracortical inhibition (SICI) was observed. • The ipsilateral silent period was also prolonged. • SICI correlated positively with MoCA and ACE-III score. • There is impaired GABAergic neurotransmission. [ABSTRACT FROM AUTHOR]

Neural adaptations to resistance training (RT) and their correlation with muscle strength remain partially understood. We conducted a systematic review and multivariate meta-analysis to examine the effects of metronome-paced (MP), self-paced (SP), and isometric (IM) training on M1 and corticospinal pathway activity. Following MP RT, a significant increase in corticospinal excitability was observed, correlating with increased strength. Conversely, no significant relationship was found after SP or IM training. RT also reduced the duration of the cortical silent period, but this change did not predict strength changes and was not specific to any training modality. No significant effects were found for short-interval intracortical inhibition. Our findings suggest that changes in corticospinal excitability may contribute to strength gains after RT. Furthermore, the relationship between these adaptations and strength appears dependent on the type of training performed. • RT increases strength, corticospinal excitability, and decreases inhibition significantly. • Changes in corticospinal excitability are good predictors of changes in strength after RT. • Changes in inhibitory corticospinal circuits after RT do not predict changes in strength. • Excitability and strength increase largely based on resistance exercise type. • Metronome-paced training boosts corticospinal excitability and strength more than self-paced and isometric training. [ABSTRACT FROM AUTHOR]