Investigating TMS–EEG indices of long-interval intracortical inhibition at different interstimulus intervals

Available online 8 August 2016Abstract not availableGeorge M. Opie, Nigel C. Rogasch, Mitchell R. Goldsworthy, Michael C. Ridding, John G. Semmle

The role of GABAAergic neurotransmission in the human brain probed by paired-pulse TMS-EEG

Cortical inhibitory processes can be measured by paired-pulse transcranial magnetic stimulation (TMS). Until recently, short-interval intracortical inhibition (SICI) and longinterval intracortical inhibition (LICI) were quantified as motor evoked potential (MEP) inhibition in the hand muscle. Pharmacological experiments consider them as a measure of GABAA and GABAB receptor-mediated neurotransmission, respectively. The effect of SICI on TMS-evoked EEG potentials (TEPs) and its pharmacological properties using combined TMS and electroencephalography (TMS-EEG) have not been systematically studied. Thus, the present study aims to investigate the physiological underpinnings of TEPs modulated by SICI, to examine its pharmacological characteristics and to compare SICI with a separate paired-pulse paradigm LICI. Sixteen healthy male subjects participated in three sessions of the pseudo-randomized, placebo-controlled, double-blinded crossover study. Paired-pulse TMS was tested over the left motor cortex and the evoked brain responses were recorded by a high-density 64-channel EEG. Neuroactive drugs acting as positive modulator at GABAA-(diazepam, 20mg) or as specific agonist at GABAB (baclofen, 50mg) receptors were applied, probing the pharmacological characteristics of SICI. We analyzed the effects of a conditioning stimulus (CS) applied 2 ms prior to a test stimulus (TS) on TEPs. Here, SICI was calculated as the difference between pairedpulse TEPs (corrected for late EEG responses evoked by the conditioning pulse) and single-pulse TEPs. Cluster-based permutation analysis showed that SICI before drugintake significantly suppressed late TEPs (N100 and P180, both p < 0.001). Whereas diazepam reduced SICI of the N100 over the non-stimulated hemisphere (p = 0.03), baclofen increased SICI of the N100 over frontal sites of both hemispheres (p = 0.007). The comparison of the effects of two paired-pulse paradigms with differing interstimulus intervals (ISI), SICI (ISI = 2 ms) and LICI (ISI = 100 ms), showed a largely similar modulation on TEPs irrespective of the interstimulus interval. These findings demonstrate for the first time that cortical inhibitory mechanisms are explained insufficiently by TMS-EMG studies testing corticospinal activity; TEPs of SICI and LICI cannot be deduced directly from MEP amplitudes. Furthermore, we demonstrated a tight interaction between GABAergic receptor subtypes controlling the balance between inhibitory and excitatory activity at the level of human cortex. The modulation by paired-pulse paradigms increases our knowledge of TMS-EEG measurements identifying functional abnormalities with altered inhibitory mechanisms

No difference in motor cortical inhibition between young and Middle-Aged adults: A TMS-EEG Study

It is well established that ageing is associated with a decline in manual dexterity. An important neural process for the control of manual dexterity is motor cortical inhibition, which is the process by which neural activity within the motor cortex is supressed. Reductions in motor cortical inhibition may contribute to the age-related decline in manual dexterity. Paired-pulse transcranial magnetic stimulation (TMS) can be used to measure long-interval intracortical inhibition (LICI) in the motor cortex. Previous literature examining differences in LICI between young and older adults have produced conflicting results. In addition, none have included a middle-aged group of participants. The purpose of the current study was to determine whether there are differences in LICI between young and middle-aged adults. An emerging technique that combines TMS with electroencephalography (EEG) was used to measure LICI. In 12 young and 13 middle-aged participants, the TMS-evoked potential (TEP; recorded from EEG) reflected the motor cortical response to sham TMS, single-pulse TMS, and paired-pulse TMS. The TEPs generated by single- and paired-pulse TMS did not differ between young and middle-aged adults. Therefore, there is no evidence from the current study to suggest differences in motor cortical inhibition between young and middle-aged adults. However, these results are speculative as the TEPs generated by sham and single-pulse TMS were highly similar, suggesting that artefacts heavily influenced the TEPs. It is critical that future studies are able to minimise the artefacts during TMS-EEG recording, and reliably identify and remove artefacts from the EEG data

Investigating cortical excitability and inhibition in patients with schizophrenia: A TMS-EEG study.

Transcranial magnetic stimulation (TMS) combined with electromyography (EMG) has widely been used as a non-invasive brain stimulation tool to assess excitation/inhibition (E/I) balance. E/I imbalance is a putative mechanism underlying symptoms in patients with schizophrenia. Combined TMS-electroencephalography (TMS-EEG) provides a detailed examination of cortical excitability to assess the pathophysiology of schizophrenia. This study aimed to investigate differences in TMS-evoked potentials (TEPs), TMS-related spectral perturbations (TRSP) and intertrial coherence (ITC) between patients with schizophrenia and healthy controls. TMS was applied over the motor cortex during EEG recording. Differences in TEPs, TRSP and ITC between the patient and healthy subjects were analysed for all electrodes at each time point, by applying multiple independent sample t-tests with a cluster-based permutation analysis to correct for multiple comparisons. Patients demonstrated significantly reduced amplitudes of early and late TEP components compared to healthy controls. Patients also showed a significant reduction of early delta (50-160 ms) and theta TRSP (30-250ms),followed by a reduction in alpha and beta suppression (220-560 ms; 190-420 ms). Patients showed a reduction of both early (50-110 ms) gamma increase and later (180-230 ms) gamma suppression. Finally, the ITC was significantly lower in patients in the alpha band, from 30 to 260 ms. Our findings support the putative role of impaired GABA-receptor mediated inhibition in schizophrenia impacting excitatory neurotransmission. Further studies can usefully elucidate mechanisms underlying specific symptoms clusters using TMS-EEG biometrics. [Abstract copyright: Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.

Characterization of GABAB-receptor mediated neurotransmission in the human cortex by paired-pulse TMS–EEG

GABAB-receptor (GABABR) mediated inhibition is important in regulating neuronal excitability. The paired-pulse transcranial magnetic stimulation (TMS) protocol of long-interval intracortical inhibition (LICI) likely reflects this GABABergic inhibition. However, this view is based on indirect evidence from electromyographic (EMG) studies. Here we combined paired-pulse TMS with simultaneous electroencephalography (paired-pulse TMS–EEG) and pharmacology to directly investigate mechanisms of LICI at the cortical level. We tested the effects of a conditioning stimulus (CS100) applied 100 ms prior to a test stimulus (TS) over primary motor cortex on TS-evoked EEG-potentials (TEPs). Healthy subjects were given a single oral dose of baclofen, a GABABR agonist, or diazepam, a positive modulator at GABAARs, in a placebo-controlled, pseudo-randomized double-blinded crossover study. LICI was quantified as the difference between paired-pulse TEPs (corrected for long-lasting EEG responses by the conditioning pulse) minus single-pulse TEPs. LICI at baseline (i.e. pre-drug intake) was characterized by decreased P25, N45, N100 and P180 and increased P70 TEP components. Baclofen resulted in a trend towards the enhancement of LICI of the N45 and N100, and significantly enhanced LICI of the P180. In contrast, diazepam consistently suppressed LICI of late potentials (i.e. N100, P180), without having an effect on LICI of earlier (i.e. P25, N45 and P70) potentials. These findings demonstrate for the first time directly at the system level of the human cortex that GABABR-mediated cortical inhibition contributes to LICI, while GABAAR-mediated inhibition occludes LICI. Paired-pulse TMS–EEG allows investigating cortical GABABR-mediated inhibition more directly and specifically than hitherto possible, and may thus inform on network abnormalities caused by disordered inhibition, e.g. in patients with schizophrenia or epilepsy

Pharmaco-TMS-EEG as a new tool to characterize human cortical excitability and connectivity

Excitation and inhibition in human cortex can be measured by transcranial magnetic stimulation (TMS) combined with electromyography (EMG) and electroencephalography (EEG) by way of specific markers of TMS-evoked muscle and brain responses. It has been shown that this capacity can be strongly enhanced by combining TMS-EMG/EEG with central nervous system (CNS) active drugs. Early studies have systematically investigated the role of a wide variety of CNS active drugs on motor evoked potentials (MEPs) and this knowledge is now partially applied to clinical settings. However, pharmacological alteration of TMS evoked EEG potentials (TEPs), which can provide direct information on cortical excitability and connectivity, has not been systematically elucidated yet. Here, we complement previous findings by using pharmaco-TMSEEG/EMG approaches to explore the physiological signatures of TEPs. In Experiment 1, we studied the effects of the experimental compound S44819, a selective α5-GABAAR antagonist, on TEPs and MEPs in 18 healthy young adults in a phase I study. In experiment 2, we investigated the role of three anti-epileptic drugs (carbamazepine, brivaracetam and tiagabine) on TEPs and MEPs in 15 healthy male adults. 100 mg S44819 enhanced cortical excitability, as denoted by reduction of the amplitude of the N45 TEP component, as well as decrease of the motor threshold; carbamazepine decreased the amplitude of the P25 and P180 TEP components and increased motor threshold; brivaracetam decreased the N100 TEP amplitude and increased MEP threshold; tiagabine had no effect on TEPs and/or MEPs. Results of experiment 1 demonstrated for the first time effects of S44819 in the human cortex, that are relevant as S44819 showed potential to improve plasticity and learning in animal models of cerebral stroke. These findings led to further development of S44819 in a clinical phase II study to test its efficacy in enhancing recovery of function in stroke patients. Results of experiment 2 confirmed and extended previous findings that the P25 TEP component reflects axonal excitability of the corticospinal system, the N100 potential in the non-stimulated hemisphere propagated activity mediated by inhibition of presynaptic neurotransmitter release, and the P180 late activity dependent on voltage-gated sodium channels (VGSCs). We believe that these updated pharmacological characterization of TEPs will prove useful for the understanding of normal and dysfunctional cortical excitability and inhibition of the human brain

TMS-evoked EEG potentials demonstrate altered cortical excitability in migraine with aura

Migraine is associated with altered sensory processing, that may be evident as changes in cortical responsivity due to altered excitability, especially in migraine with aura. Cortical excitability can be directly assessed by combining transcranial magnetic stimulation with electroencephalography (TMS-EEG). We measured TMS evoked potential (TEP) amplitude and response consistency as these measures have been linked to cortical excitability but were not yet reported in migraine. We recorded 64-channel EEG during single-pulse TMS on the vertex interictally in 10 people with migraine with aura and 10 healthy controls matched for age, sex and resting motor threshold. On average 160 pulses around resting motor threshold were delivered through a circular coil in clockwise and counterclockwise direction. Trial-averaged TEP responses, frequency spectra and phase clustering (over the entire scalp as well as in frontal, central and occipital midline electrode clusters) were compared between groups, including comparison to sham-stimulation evoked responses. Migraine and control groups had a similar distribution of TEP waveforms over the scalp. In migraine with aura, TEP responses showed reduced amplitude around the frontal and occipital N100 peaks. For the migraine and control groups, responses over the scalp were affected by current direction for the primary motor cortex, somatosensory cortex and sensory association areas, but not for frontal, central or occipital midline clusters. This study provides evidence of altered TEP responses in-between attacks in migraine with aura. Decreased TEP responses around the N100 peak may be indicative of reduced cortical GABA-mediated inhibition and expand observations on enhanced cortical excitability from earlier migraine studies using more indirect measurements

No hemispheric asymmetries in long-acting cortical inhibition in young adults using

It is well established that fine motor control is asymmetrical: this is known as handedness. Handedness is controlled by cortical motor processes, including long-acting inhibition. Long-acting cortical inhibition is asymmetric between the left and right hemispheres. Therefore, asymmetries of handedness may be attributable to asymmetries in long-acting inhibition. Asymmetries of long-acting inhibition have previously been tested using a measure of corticospinal excitability, but have not been previously investigated using combined transcranial magnetic stimulation (TMS) and electroencephalography (TMS-EEG), a measure of cortical inhibition not influenced by spinal excitability. This study aimed to determine if long-acting cortical inhibition is asymmetrical using TMS-EEG and to investigate any associations of asymmetrical inhibition with fine motor control. In young adults (n = 14) fine motor control was measured using the Purdue Pegboard task. EEG was used to record the cortical responses to paired-pulse, single-pulse and sham TMS. Results showed no asymmetry in fine motor control using the Purdue Pegboard task and no asymmetries of long-acting inhibition between the left and right hemispheres using TMS-EEG. There was no significant difference between the response to sham and single-pulse stimulation, suggesting that the cortical response to TMS was influenced by auditory or physiological artefacts. There were no associations between TEPs of long-acting inhibition and fine motor control. Overall, there were no conclusive results whether asymmetries of long-acting inhibition are replicable using TMS-EEG. Further investigation of the importance of LICI as a neural underpinning of handedness is important to better understanding the workings of handedness and fine motor control

Regional Precuneus Cortical Hyperexcitability in Alzheimer's Disease Patients

Objective: Neuronal excitation/inhibition (E/I) imbalance is a potential cause of neuronal network malfunctioning in Alzheimer's disease (AD), contributing to cognitive dysfunction. Here, we used a novel approach combining transcranial magnetic stimulation (TMS) and electroencephalography (EEG) to probe cortical excitability in different brain areas known to be directly involved in AD pathology. Methods: We performed TMS-EEG recordings targeting the left dorsolateral prefrontal cortex (l-DLPFC), the left posterior parietal cortex (l-PPC), and the precuneus (PC) in a large sample of patients with mild-to-moderate AD (n&nbsp;=&nbsp;65) that were compared with a group of age-matched healthy controls (n&nbsp;=&nbsp;21). Results: We found that patients with AD are characterized by a regional cortical hyperexcitability in the PC and, to some extent, in the frontal lobe, as measured by TMS-evoked potentials. Notably, cortical excitability assessed over the l-PPC was comparable between the 2 groups. Furthermore, we found that the individual level of PC excitability was associated with the level of cognitive impairment, as measured with Mini-Mental State Examination, and with corticospinal fluid levels of Aβ42 . Interpretation: Our data provide novel evidence that precuneus cortical hyperexcitability is a key feature of synaptic dysfunction in patients with AD. The current results point to the combined approach of TMS and EEG as a novel promising technique to measure hyperexcitability in patients with AD. This index could represent a useful biomarker to stage disease severity and evaluate response to novel therapies. ANN NEUROL 2022