The pathobiology of psychomotor slowing in psychosis: altered cortical excitability and connectivity.

Psychomotor slowing is a frequent symptom of schizophrenia. Short-interval intracortical inhibition assessed by transcranial magnetic stimulation demonstrated inhibitory dysfunction in schizophrenia. The inhibitory deficit results from additional noise during information processing in the motor system in psychosis. Here, we tested whether cortical inhibitory dysfunction was linked to psychomotor slowing and motor network alterations. In this cross-sectional study, we included 60 patients with schizophrenia and psychomotor slowing determined by the Salpêtrière Retardation Rating Scale, 23 patients without slowing and 40 healthy control participants. We acquired single and double-pulse transcranial magnetic stimulation effects from the left primary motor cortex, resting-state functional connectivity and diffusion imaging on the same day. Groups were compared on resting motor threshold, amplitude of the motor evoked potentials, as well as short-interval intracortical inhibition. Regression analyses calculated the association between motor evoked potential amplitudes or cortical inhibition with seed-based resting-state functional connectivity from the left primary motor cortex and fractional anisotropy at whole brain level and within major motor tracts. In patients with schizophrenia and psychomotor slowing, we observed lower amplitudes of motor evoked potentials, while the short-interval intracortical inhibition/motor evoked potentials amplitude ratio was higher than in healthy controls, suggesting lower cortical inhibition in these patients. Patients without slowing also had lower amplitudes of motor evoked potentials. Across the combined patient sample, cortical inhibition deficits were linked to more motor coordination impairments. In patients with schizophrenia and psychomotor slowing, lower amplitudes of motor evoked potentials were associated with lower fractional anisotropy in motor tracts. Moreover, resting-state functional connectivity between the primary motor cortex, the anterior cingulate cortex and the cerebellum increased with stronger cortical inhibition. In contrast, in healthy controls and patients without slowing, stronger cortical inhibition was linked to lower resting-state functional connectivity between the left primary motor cortex and premotor or parietal cortices. Psychomotor slowing in psychosis is linked to less cortical inhibition and aberrant functional connectivity of the primary motor cortex. Higher neural noise in the motor system may drive psychomotor slowing and thus may become a treatment target.

Direct interrogation of cortical interneuron circuits in amyotrophic lateral sclerosis.

Cortical hyperexcitability is a key pathogenic feature of amyotrophic lateral sclerosis (ALS), believed to be mediated through complex interplay of cortical interneurons. To date, there has been no technological approach to facilitate the direct capture of cortical interneuron function. Through combination of transcranial magnetic stimulation (TMS) with advanced EEG, the present study examined GABA-ergic dysfunction in ALS, through recording focussed cortical output whilst applying TMS over the primary motor cortex contralateral to the site of symptom onset. Using both a single pulse and novel inhibitory paired-pulse paradigms, TMS-EEG studies were undertaken on 21 ALS patients and results compared to healthy controls. TMS responses captured by EEG form a discrete waveform known as the transcranial evoked potential (TEP), with positive (P) or upward deflections occurring at 30ms (P30), 60 ms (P60) and 190 ms (P190) after TMS stimulus. Negative (N) or downward deflections occur at 44 ms (N44), 100 ms (N100) and 280ms (N280) after T,MS stimulus. The single pulse TEPs recorded in ALS patients demonstrated novel differences suggestive of cortical GABA-ergic dysfunction. When compared to controls, the N100 component was significantly reduced (P<0.05) while the P190 component increased (P<0.05) in ALS patients. Additionally, the N44 component correlated with muscle weakness (r=-0.501, P<0.05). These finding were supported by reduced paired pulse inhibition of TEP components in ALS patients (P60, P<0.01; N100, P<0.005), consistent with dysfunction of cortical interneuronal GABAA-ergic circuits. Further, the reduction in SICI, as reflected by changes in paired-pulse inhibition of the N100 component, was associated with longer disease duration in ALS patients (r=-0.698, P<0.001). In conclusion, intensive and focussed interrogation of the motor cortex utilising novel TMS-EEG combined technologies has established localised dysfunction of GABA-ergic circuits, supporting the notion that cortical hyperexcitability is mediated by cortical disinhibition in ALS. Dysfunction of GABA-ergic circuits correlated with greater clinical disability and disease duration implying pathophysiological significance.

Distinct neuronal circuits mediate cortical hyperexcitability in amyotrophic lateral sclerosis.

Cortical hyperexcitability is an important pathophysiological mechanism in amyotrophic lateral sclerosis (ALS), reflecting a complex interaction of inhibitory and facilitatory interneuronal processes that evolves in the degenerating brain. The advances in physiological techniques have made it possible to interrogate progressive changes in the motor cortex. Specifically, the direction of transcranial magnetic stimulation (TMS) stimulus within the primary motor cortex can be utilized to influence descending corticospinal volleys and to thereby provide information about distinct interneuronal circuits. Cortical motor function and cognition was assessed in 29 ALS patients with results compared to healthy volunteers. Cortical dysfunction was assessed using threshold-tracking TMS to explore alterations in short interval intracortical inhibition (SICI), short interval intracortical facilitation (SICF), the index of excitation and stimulus response curves using a figure-of-eight coil with the coil oriented relative to the primary motor cortex in a posterior-anterior, lateral-medial and anterior-posterior direction. Mean SICI, between interstimulus interval of 1-7 ms, was significantly reduced in ALS patients compared to healthy controls when assessed with the coil oriented in posterior-anterior (P = 0.044) and lateral-medial (P = 0.005) but not the anterior-posterior (P = 0.08) directions. A significant correlation between mean SICI oriented in a posterior-anterior direction and the total Edinburgh Cognitive and Behavioural ALS Screen score (Rho = 0.389, P = 0.037) was evident. In addition, the mean SICF, between interstimulus interval 1-5 ms, was significantly increased in ALS patients when recorded with TMS coil oriented in posterior-anterior (P = 0.035) and lateral-medial (P < 0.001) directions. In contrast, SICF recorded with TMS coil oriented in the anterior-posterior direction was comparable between ALS and controls (P = 0.482). The index of excitation was significantly increased in ALS patients when recorded with the TMS coil oriented in posterior-anterior (P = 0.041) and lateral-medial (P = 0.003) directions. In ALS patients, a significant increase in the stimulus response curve gradient was evident compared to controls when recorded with TMS coil oriented in posterior-anterior (P < 0.001), lateral-medial (P < 0.001) and anterior-posterior (P = 0.002) directions. The present study has established that dysfunction of distinct interneuronal circuits mediates the development of cortical hyperexcitability in ALS. Specifically, complex interplay between inhibitory circuits and facilitatory interneuronal populations, that are preferentially activated by stimulation in posterior-to-anterior or lateral-to-medial directions, promotes cortical hyperexcitability in ALS. Mechanisms that underlie dysfunction of these specific cortical neuronal circuits will enhance understanding of the pathophysiological processes in ALS, with the potential to uncover focussed therapeutic targets.

The paired-pulse TMS paradigm of short intracortical inhibition is mediated by a reduction of repetitive motor neuron discharges.

Transcranial magnetic stimulation (TMS) causes repetitive spinal motoneuron discharges (repMNDs), but the effects of short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) on repMNDs remain unknown. Triple stimulation technique (TST) and the extended TST-protocols that include a fourth and fifth stimulation, the Quadruple (QuadS) and Quintuple (QuintS) stimulation, respectively, offer a precise estimate of cortical and spinal motor neuron discharges, including repMNDs. The objective of our study was to explore the effects of SICI and ICF on repMNDs. We explored conventional paired-pulse TMS protocols of SICI and ICF with the TMS, TST, the QuadS, and the QuintS protocols, in a randomized study design in 20 healthy volunteers. We found significantly less repMNDs in the SICI paradigm compared with a single-pulse TMS (SP-TMS). No significant difference was observed in the ICF paradigm. There was a significant inter- and intrasubject variability in both SICI and ICF. We demonstrate a significant reduction of repMNDs in SICI, which may result from the suppression of later I-waves and mediate the inhibition of motor-evoked potential (MEP). There is no increase in repMNDs in ICF suggesting another mechanism underlying facilitation. This study provides the proof that a reduction of repMNDs mediates the inhibition seen in SICI.NEW & NOTEWORTHY Significant reduction of repetitive motor neuron discharges (repMNDs) in short-interval intracortical inhibition (SICI) may result from the suppression of later I-waves and mediate the inhibition of motor-evoked potential (MEP). There is no change in the number of repMNDs in intracortical facilitation (ICF). There was a significant variability in SICI and ICF in healthy subjects.

Caffeine and cortical excitability, as measured with paired-pulse transcranial magnetic stimulation.

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.

Reduction in short interval intracortical inhibition from the early stage reflects the pathophysiology in amyotrophic lateral sclerosis: A meta-analysis study.

BACKGROUND AND PURPOSE: Cortical hyperexcitability has been identified as a diagnostic and pathogenic biomarker of amyotrophic lateral sclerosis (ALS). Cortical excitability is assessed by transcranial magnetic stimulation (TMS), a non-invasive neurophysiological technique. The TMS biomarkers exhibiting highest sensitivity for cortical hyperexcitability in ALS remain to be elucidated. A meta-analysis was performed to determine the TMS biomarkers exhibiting the highest sensitivity for cortical hyperexcitability in ALS. METHODS: A systematic literature review was conducted of all relevant studies published in the English language by searching PubMed, MEDLINE, Embase and Scopus electronic databases from 1 January 2006 to 28 February 2023. Inclusion criteria included studies reporting the utility of threshold tracking TMS (serial ascending method) in ALS and controls. RESULTS: In total, more than 2500 participants, incorporating 1530 ALS patients and 1102 controls (healthy, 907; neuromuscular, 195) were assessed with threshold tracking TMS across 25 studies. Significant reduction of mean short interval intracortical inhibition (interstimulus interval 1-7 ms) exhibited the highest standardized mean difference with moderate heterogeneity (-0.994, 95% confidence interval -1.12 to -0.873, p < 0.001; Q = 38.61, p < 0.05; I2 = 40%). The reduction of cortical silent period duration along with an increase in motor evoked potential amplitude and intracortical facilitation also exhibited significant, albeit smaller, standardized mean differences. CONCLUSION: This large meta-analysis study disclosed that mean short interval intracortical inhibition reduction exhibited the highest sensitivity for cortical hyperexcitability in ALS. Combined findings from this meta-analysis suggest that research strategies aimed at understanding the cause of inhibitory interneuronal circuit dysfunction could enhance understanding of ALS pathogenesis.

Disruptive compensatory mechanisms in fibromyalgia syndrome and their association with pharmacological agents.

Fibromyalgia syndrome (FMS) is a chronic disorder characterized commonly by widespread musculoskeletal pain and fatigue, predominantly affecting women, with its complexity often leading to underdiagnosis and complicating treatment effectiveness. Transcranial magnetic stimulation (TMS) metrics are potential markers to optimize FMS treatments; however, evidence is limited. Our study aimed to explore the relationship between cortical excitability and inhibition, assessed through TMS markers, and clinical characteristics in patients with FMS. This presented cross-sectional study employed baseline data from a clinical trial with 108 FMS patients, mostly female (88.8%), and mean age of 47.3 years old (SD = 12.06). Our analysis showed that decreased short-intracortical inhibition (SICI) was associated with gabapentinoids use, nicotine history, and increased fatigue levels, suggesting its connection with compensatory mechanisms for non-painful FMS features. Increased motor intracortical facilitation (ICF) was linked with greater pain severity and shorter FMS duration, implying its relationship with a reorganization of sensorimotor pathways due to chronic pain. Additionally, higher resting motor threshold (rMT) was associated with less effective pain modulation (lower conditioned pain modulation [CPM]), indicating a disruption of pain compensatory mechanism. Given the role of SICI in indexing homeostatic brain mechanisms and its association with fatigue, a hallmark characteristic of FMS-induced behavioral changes, these results suggest that FMS likely has a deleterious effect on brain inhibitory function, thus providing a potential novel insight for FMS mechanisms. In addition, it seems that this compensatory mechanism's disruption is enhanced by pharmacological agents such as gabapentioids and nicotine.

Short- and long-interval intracortical inhibition in EPM1 is related to genotype.

OBJECTIVE: Progressive myoclonic epilepsy type 1 (EPM1) is caused by biallelic alterations in the CSTB gene, most commonly dodecamer repeat expansions. Although transcranial magnetic stimulation (TMS)-induced long-interval intracortical inhibition (LICI) was previously reported to be normal in EPM1, short-interval intracortical inhibition (SICI) was reduced. We explored the association between these measures and the clinical and genetic features in a separate group of patients with EPM1. METHODS: TMS combined with electromyography was performed under neuronavigation. LICI was induced with an inter-stimulus interval (ISI) of 100 ms, and SICI with ISIs of 2 and 3 ms, and their means (mSICIs) were expressed as the ratio of conditioned to unconditioned stimuli. LICI and mSICI were compared between patients and controls. Nonparametric correlation was used to study the association between inhibition and parameters of clinical severity, including the Unified Myoclonus Rating Scale (UMRS); among patients with EPM1 due to biallelic expansion repeats, also the association with the number of repeats was assessed. RESULTS: The study protocol was completed in 19 patients (15 with biallelic expansion repeats and 4 compound heterozygotes), and 7 healthy, age- and sex-matched control participants. Compared to controls, patients demonstrated significantly less SICI (median mSICI ratio 1.18 vs 0.38; p < .001). Neither LICI nor SICI was associated with parameters of clinical severity. In participants with biallelic repeat expansions, the number of repeats in the more affected allele (greater repeat number [GRN]) correlated with LICI (rho = 0.872; p < .001) and SICI (rho = 0.689; p = .006). SIGNIFICANCE: Our results strengthen the finding of deranged γ-aminobutyric acid (GABA)ergic inhibition in EPM1. LICI and SICI may have use as markers of GABAergic impairment in future trials of disease-modifying treatment in this condition. Whether a higher number of expansion repeats leads to greater GABAergic impairment warrants further study.

Normal parameters for diagnostic transcranial magnetic stimulation using a parabolic coil with biphasic pulse stimulation.

BACKGROUND: TMS is being used to aid in the diagnosis of central nervous system (CNS) illnesses. It is useful in planning rehabilitation programs and setting appropriate goals for patients. We used a parabolic coil with biphasic pulse stimulation to find normal values for diagnostic TMS parameters. OBJECTIVES: 1. To determine the normal motor threshold (MT), motor evoked potentials (MEP), central motor conduction time (CMCT), intracortical facilitation (ICF), short-interval intracortical inhibition (SICI), and silent period (SP) values. 2. To measure the MEP latencies of abductor pollicis brevis (APB) and extensor digitorum brevis (EDB) at various ages, heights, and arm and leg lengths. STUDY DESIGN: Descriptive Study. SETTING: Department of Rehabilitation Medicine, Chiang Mai University, Thailand. SUBJECTS: Forty-eight healthy participants volunteered for the study. METHODS: All participants received a single diagnostic TMS using a parabolic coil with biphasic pulse stimulation on the left primary motor cortex (M1). All parameters: MT, MEP, CMCT, ICF, SICI, and SP were recorded through surface EMGs at the right APB and EDB. Outcome parameters were reported by the mean and standard deviation (SD) or median and interquartile range (IQR), according to data distribution. MEP latencies of APB and EDB were also measured at various ages, heights, and arm and leg lengths. RESULTS: APB-MEP latencies at 120% and 140% MT were 21.77 ± 1.47 and 21.17 ± 1.44 ms. APB-CMCT at 120% and 140% MT were 7.81 ± 1.32 and 7.19 ± 1.21 ms. APB-MEP amplitudes at 120% and 140% MT were 1.04 (0.80-1.68) and 2.24 (1.47-3.52) mV. EDB-MEP latencies at 120% and 140% MT were 37.14 ± 2.85 and 36.46 ± 2.53 ms. EDB-CMCT at 120% and 140% MT were 14.33 ± 2.50 and 13.63 ± 2.57 ms. EDB-MEP amplitudes at 120% and 140% MT were 0.60 (0.38-0.98) and 0.95 (0.69-1.55) mV. ICF amplitudes of APB and EDB were 2.26 (1.61-3.49) and 1.26 (0.88-1.98) mV. SICI amplitudes of APB and EDB were 0.21 (0.13-0.51) and 0.18 (0.09-0.29) mV. MEP latencies of APB at 120% and 140% MT were different between heights < 160 cm and ≥ 160 cm (p < 0.001 and p < 0.001) and different between arm lengths < 65 and ≥ 65 cm (p = 0.022 and p = 0.002). CONCLUSION: We established diagnostic TMS measurements using a parabolic coil with a biphasic pulse configuration. EDB has a higher MT than APB. The 140/120 MEP ratio of APB and EDB is two-fold. The optimal MEP recording for APB is 120%, whereas EDB is 140% of MT. CMCT by the F-wave is more convenient and tolerable for patients. ICF provides a twofold increase in MEP amplitude. SICI provides a »-fold of MEP amplitude. SP from APB and EDB are 121.58 ± 21.50 and 181.01 ± 40.99 ms, respectively. Height and MEP latencies have a modest relationship, whereas height and arm length share a strong positive correlation.

Runners with mid-portion Achilles tendinopathy have greater triceps surae intracortical inhibition than healthy controls.

OBJECTIVES: This study aimed to investigate short-interval intracortical inhibition (SICI) and muscle function in the triceps surae of runners with mid-portion Achilles tendinopathy (AT). METHODS: Runners with (n = 11) and without (n = 13) AT were recruited. Plantar flexor isometric peak torque and rate of torque development (RTD) were measured using an isokinetic dynamometer. Triceps surae endurance was measured as single-leg heel raise (SLHR) to failure test. SICI was assessed using paired-pulse transcranial magnetic stimulation during a sustained contraction at 10% of plantar flexor isometric peak torque. RESULTS: Triceps surae SICI was 14.3% (95% CI: -2.1 to 26.4) higher in AT than in the control group (57.9%, 95% CI: 36.2 to 79.6; and 43.6% 95% CI: 16.2 to 71.1, p = 0.032) irrespective of the tested muscle. AT performed 16 (95% CI: 7.9 to 23.3, p < 0.001) fewer SLHR repetitions on the symptomatic side compared with controls, and 14 (95% CI: 5.8 to 22.0, p = 0.004), fewer SLHR repetitions on the non-symptomatic compared with controls. We found no between-groups differences in isometric peak torque (p = 0.971) or RTD (p = 0.815). PERSPECTIVE: Our data suggest greater intracortical inhibition for the triceps surae muscles for the AT group accompanied by reduced SLHR endurance, without deficits in isometric peak torque or RTD. The increased SICI observed in the AT group could be negatively influencing triceps surae endurance; thus, rehabilitation aiming to reduce intracortical inhibition should be considered to improve patient outcomes. Furthermore, SLHR is a useful clinical tool to assess plantar flexor function in AT patients.

Changes in corticospinal excitability during the preparation phase of ballistic and ramp contractions.

KEY POINTS: Changes in corticospinal excitability prior to a contraction may depend on its characteristics, including the rate of torque development. This study compared the specific modulation of cortical and spinal excitability during the preparation phase (last 500 ms before contraction) of fast (ballistic) and ramp contractions of ankle dorsiflexors, using transcranial magnetic stimulation and peripheral nerve stimulation. The results indicate earlier changes at the cortical than at the spinal level during the preparation phase of both contraction types. However, these adjustments are delayed prior to ballistic relative to ramp contractions. This study suggests that the time course of change in cortical and spinal excitability during the preparation phase of a voluntary action is specific to the intended rate of torque development of the upcoming contraction. ABSTRACT: The present study investigated cortical and spinal excitability during the preparation phase of ballistic (BAL) and ramp (RAMP) isometric contractions. To this end, young adults performed BAL and RAMP (1500 ms torque rise time) contractions, reaching a similar torque level, with the ankle dorsiflexor muscles. Transcranial magnetic stimulation of the motor cortex was randomly applied to record motor evoked potentials (MEP) in the tibialis anterior during the last 500 ms preceding the contraction (n = 16). Short-interval intracortical inhibition (SICI; n = 10) and spinal motor neurone excitability (F-wave occurrence; n = 8) were also assessed during this period. Data were averaged over 100 ms time windows beginning 500 ms prior to the onset of contractions. An increase in MEP amplitude and a decrease in SICI were observed from the 200-100 ms and 300-200 ms time windows prior to BAL and RAMP contractions (P < 0.05), respectively, with greater changes prior to RAMP than to BAL within the 300-200 ms time window (P < 0.05). F-wave occurrence, used to assess spinal motor neurone excitability, increased prior to RAMP (200-100 ms, P < 0.05) but not BAL contractions. Data obtained in a few participants during the last 100 ms confirmed a delayed and steeper rise in corticospinal excitability prior to BAL contractions. These results indicate earlier changes at the cortical than at the spinal level, with delayed changes prior to BAL contractions. This study suggests that the time course of change in cortical and spinal excitability during the preparation phase of a voluntary action is specific to the intended rate of torque development of the upcoming contraction.

Corticospinal properties are associated with sensorimotor performance in action video game players.

Notwithstanding the apparent demands regarding fine motor skills that are required to perform in action video games, the motor nervous system of players has not been studied systematically. In the present study, we hypothesized to find differences in sensorimotor performance and corticospinal characteristics between action video game players (Players) and Controls. We tested sensorimotor performance in video games tasks and used transcranial magnetic stimulation (TMS) to measure motor map, input-output (IO) and short intra-cortical inhibition (SICI) curves in the first dorsal interosseous (FDI) muscle of Players (n = 18) and Control (n = 18). Players scored higher in performance tests and had stronger SICI and higher motor evoked potential (MEP) amplitudes. Multiple linear regressions showed that Players and Control differed with respect to their relation between reaction time and corticospinal excitability. However, we did not find different motor map topography or different IO curves for Players when compared to Controls. Action video game players showed an increased efficiency of motor cortical inhibitory and excitatory neural networks. Players also showed a different relation of MEPs with reaction time. The present study demonstrates the potential of action video game players as an ideal population to study the mechanisms underlying visuomotor performance and sensorimotor learning.

What to train first: Balance or explosive strength? Impact on performance and intracortical inhibition.

Explosive strength and balance training are commonly applied to enhance explosive strength and balance performance. Even though both training methods are frequently implemented, ordering effects have largely been neglected. Therefore, the present study aimed to investigate ordering effects of balance and explosive strength training on explosive strength and balance performance as well as changes in short-interval intracortical inhibition (SICI). Two groups of subjects either participated in 4 weeks of balance training followed by 4 weeks of explosive strength training (BT-ET) or vice versa (ET-BT). Before, after 4 and 8 weeks, balance performance, as well as explosive strength, was tested. Additionally, SICI was tested during rest as well as during balance perturbations and explosive contractions. The results show a training specific increase in performance with an increase in balance control followed by an increase in explosive strength in the BT-ET, while the ET-BT increased its balance and explosive strength in the opposite order. There were no significant ordering effects. Both groups showed a significant decrease in SICI during the explosive contractions after the eight weeks of training. When SICI was tested during the balance perturbations, SICI initially increased after the first 4 weeks of training but returned to baseline until the end of the eight weeks. It is suggested that the decrease in SICI with prolonged training might show a disengagement of the motor cortex during the balance task. During the explosive contractions, the low SICI levels are beneficial to provide the necessary level of excitatory cortical drive.

Modulation of intracortical inhibition during physically performed and mentally simulated balance tasks.

PURPOSE: Action observation (AO) during motor imagery (MI), so-called AO + MI, has been proposed as a new form of non-physical training, but the neural mechanisms involved remains largely unknown. Therefore, this study aimed to explore whether there were similarities in the modulation of short-interval intracortical inhibition (SICI) during execution and mental simulation of postural tasks, and if there was a difference in modulation of SICI between AO + MI and AO alone. METHOD: 21 young adults (mean ± SD = 24 ± 6.3 years) were asked to either passively observe (AO) or imagine while observing (AO + MI) or physically perform a stable and an unstable standing task, while motor evoked potentials and SICI were assessed in the soleus muscle. RESULT: SICI results showed a modulation by condition (F2,40 = 6.42, p = 0.009) with less SICI in the execution condition compared to the AO + MI (p = 0.009) and AO (p = 0.002) condition. Moreover, switching from the stable to the unstable stance condition reduced significantly SICI (F1,20 = 8.34, p = 0.009) during both, physically performed (- 38.5%; p = 0.03) and mentally simulated balance (- 10%, p < 0.001, AO + MI and AO taken together). CONCLUSION: The data demonstrate that SICI is reduced when switching from a stable to a more unstable standing task during both real task execution and mental simulation. Therefore, our results strengthen and further support the existence of similarities between executed and mentally simulated actions by showing that not only corticospinal excitability is similarly modulated but also SICI. This proposes that the activity of the inhibitory cortical network during mental simulation of balance tasks resembles the one during physical postural task execution.

Pulsed Facilitation of Corticospinal Excitability by the Sensorimotor µ-Alpha Rhythm.

Alpha oscillations (8-14 Hz) are assumed to gate information flow in the brain by means of pulsed inhibition; that is, the phasic suppression of cortical excitability and information processing once per alpha cycle, resulting in stronger net suppression for larger alpha amplitudes due to the assumed amplitude asymmetry of the oscillation. While there is evidence for this hypothesis regarding occipital alpha oscillations, it is less clear for the central sensorimotor µ-alpha rhythm. Probing corticospinal excitability via transcranial magnetic stimulation (TMS) of the primary motor cortex and the measurement of motor evoked potentials (MEPs), we have previously demonstrated that corticospinal excitability is modulated by both amplitude and phase of the sensorimotor µ-alpha rhythm. However, the direction of this modulation, its proposed asymmetry, and its underlying mechanisms remained unclear. We therefore used real-time EEG-triggered single- and paired-pulse TMS in healthy humans of both sexes to assess corticospinal excitability and GABA-A-receptor mediated short-latency intracortical inhibition (SICI) at rest during spontaneous high amplitude µ-alpha waves at different phase angles (peaks, troughs, rising and falling flanks) and compared them to periods of low amplitude (desynchronized) µ-alpha. MEP amplitude was facilitated during troughs and rising flanks, but no phasic suppression was observed at any time, nor any modulation of SICI. These results are best compatible with sensorimotor µ-alpha reflecting asymmetric pulsed facilitation but not pulsed inhibition of motor cortical excitability. The asymmetric excitability with respect to rising and falling flanks of the µ-alpha cycle further reveals that voltage differences alone cannot explain the impact of phase.SIGNIFICANCE STATEMENT The pulsed inhibition hypothesis, which assumes that alpha oscillations actively inhibit neuronal processing in a phasic manner, is highly influential and has substantially shaped our understanding of these oscillations. However, some of its basic assumptions, in particular its asymmetry and inhibitory nature, have rarely been tested directly. Here, we explicitly investigated the asymmetry of modulation and its direction for the human sensorimotor µ-alpha rhythm. We found clear evidence of pulsed facilitation, but not inhibition, in the human motor cortex, challenging the generalizability of the pulsed inhibition hypothesis and advising caution when interpreting sensorimotor µ-alpha changes in the sensorimotor system. This study also demonstrates how specific assumptions about the neurophysiological underpinnings of cortical oscillations can be experimentally tested noninvasively in humans.

Task-related measures of short-interval intracortical inhibition and GABA levels in healthy young and older adults: A multimodal TMS-MRS study.

Establishing the associations between magnetic resonance spectroscopy (MRS)-assessed gamma-aminobutyric acid (GABA) levels and transcranial magnetic stimulation (TMS)-derived 'task-related' modulations in GABAA receptor-mediated inhibition and how these associations change with advancing age is a topic of interest in the field of human neuroscience. In this study, we identified the relationship between GABA levels and task-related modulations in GABAA receptor-mediated inhibition in the dominant (left) and non-dominant (right) sensorimotor (SM) cortices. GABA levels were measured using edited MRS and task-related GABAA receptor-mediated inhibition was measured using a short-interval intracortical inhibition (SICI) TMS protocol during the preparation and premotor period of a choice reaction time (CRT) task in 25 young (aged 18-33 years) and 25 older (aged 60-74 years) adults. Our results demonstrated that GABA levels in both SM voxels were lower in older adults as compared to younger adults; and higher SM GABA levels in the dominant as compared to the non-dominant SM voxel pointed to a lateralization effect, irrespective of age group. Furthermore, older adults showed decreased GABAA receptor-mediated inhibition in the preparation phase of the CRT task within the dominant primary motor cortex (M1), as compared to young adults. Finally, results from an exploratory correlation analysis pointed towards positive relationships between MRS-assessed GABA levels and TMS-derived task-related SICI measures. However, after correction for multiple comparisons none of the correlations remained significant.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

A new parameter to discriminate amyotrophic lateral sclerosis patients from healthy participants by motor cortical excitability changes.

INTRODUCTION: We sought a combination of abnormalities to define a more sensitive measure of cortical excitability in amyotrophic lateral sclerosis (ALS). METHODS: The automatic threshold tracking method was employed to assess the resting motor threshold, intracortical facilitation (ICF), short-interval intracortical inhibition (SICI), and short-interval intracortical faciilitation (SICF) in patients and controls. RESULTS: SICF at interstimulus intervals (ISI) between 1 and 1.8 ms and 2 and 3 ms as well as average SICI and SICI at ISIs of 1 and 2.5 ms were significantly reduced in ALS. The SICI curve was altered, displaying a solitary peak. Discriminant analysis revealed that the combination of SICI 2.5 ms and the mean SICF between 1 and 1.8 ms ISIs was the most sensitive parameter to distinguish patients with ALS from healthy participants. DISCUSSION: Along with the reduced SICI and its altered shape, connectivity between motor cortical circuits is changed in ALS. Combination with SICF increases the diagnostic utility of SICI in ALS.

Superconditioning TMS for examining upper motor neuron function in MND.

We used transcranial magnetic stimulation (TMS) of motor cortex, including a novel four-pulse superconditioning (TMSsc) paradigm, in repeated examinations of motor-evoked potentials (MEPs) in eight subjects with motor neuron disease (MND), including seven with amyotrophic lateral sclerosis (ALS). The goals were: (1) to look for evidence of cortical hyperexcitability, including a reduction in short-interval intracortical inhibition (SICI); and (2) to examine the utility of using TMSsc for quantifying upper motor neuron function during MND progression. Testing of abductor pollicis brevis (APB) and tibialis anterior (TA) muscles bilaterally was carried out every 3 months in MND subjects for up to 2 years; results were compared to those from a cohort of 15 control subjects. Measures of SICI were not significantly different between control and MND subjects for either APB or TA muscles. Other measures of cortical excitability, including TMS threshold and MEP amplitude, were consistent with lowered cortical excitability in MND subjects. Certain combinations of superconditioning TMS were capable of causing stronger inhibition or facilitation of MEPs compared to dual-pulse TMS, for both APB and TA target muscles. Moreover, there were multiple cases in which target muscles unresponsive to strong single-pulse TMS, whether at rest or when tested with an active contraction, showed an MEP in response to TMSsc optimized for facilitation. Our findings suggest that a multi-faceted neurophysiologic protocol for examining upper motor neuron function in MND subjects might benefit from inclusion of TMSsc testing.

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 1 hour post-exercise. Fourteen right-handed adults (11 M/3F; 26.8 ± 2.9 year) 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 1 week, 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 1 hour post-ECC contractions only. MMAX was reduced immediately (P = 0.014) and 1 hour 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 1 hour 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.