Transcutaneous auricular vagus nerve stimulation modifies cortical excitability in middle-aged and older adults.

There is a growing interest in the clinical application of transcutaneous auricular vagus nerve stimulation (taVNS). However, its effect on cortical excitability, and whether this is modulated by stimulation duration, remains unclear. We evaluated whether taVNS can modify excitability in the primary motor cortex (M1) in middle-aged and older adults and whether the stimulation duration moderates this effect. In addition, we evaluated the blinding efficacy of a commonly reported sham method. In a double-blinded randomized cross-over sham-controlled study, 23 healthy adults (mean age 59.91 ± 6.87 years) received three conditions: active taVNS for 30 and 60 min and sham for 30 min. Single and paired-pulse transcranial magnetic stimulation was delivered over the right M1 to evaluate motor-evoked potentials. Adverse events, heart rate and blood pressure measures were evaluated. Participant blinding effectiveness was assessed via guesses about group allocation. There was an increase in short-interval intracortical inhibition (F = 7.006, p = .002) and a decrease in short-interval intracortical facilitation (F = 4.602, p = .014) after 60 min of taVNS, but not 30 min, compared to sham. taVNS was tolerable and safe. Heart rate and blood pressure were not modified by taVNS (p > .05). Overall, 96% of participants detected active stimulation and 22% detected sham stimulation. taVNS modifies cortical excitability in M1 and its effect depends on stimulation duration in middle-aged and older adults. taVNS increased GABAAergic inhibition and decreased glutamatergic activity. Sham taVNS protocol is credible but there is an imbalance in beliefs about group allocation.

Repetitive paired-pulse TMS increases motor cortex excitability and visuomotor skill acquisition in young and older adults.

Transcranial magnetic stimulation (TMS) over primary motor cortex (M1) recruits indirect (I) waves that can be modulated by repetitive paired-pulse TMS (rppTMS). The purpose of this study was to examine the effect of rppTMS on M1 excitability and visuomotor skill acquisition in young and older adults. A total of 37 healthy adults (22 young, 18-32 yr; 15 older, 60-79 yr) participated in a study that involved rppTMS at early (1.4 ms) and late (4.5 ms) interstimulus intervals (ISIs), followed by the performance of a visuomotor training task. M1 excitability was examined with motor-evoked potential (MEP) amplitudes and short-interval intracortical facilitation (SICF) using posterior-anterior (PA) and anterior-posterior (AP) TMS current directions. We found that rppTMS increased M1 excitability in young and old adults, with the greatest effects for PA TMS at the late ISI (4.5 ms). Motor skill acquisition was improved by rppTMS at an early (1.4 ms) but not late (4.5 ms) ISI in young and older adults. An additional study using a non-I-wave interval (3.5 ms) also showed increased M1 excitability and visuomotor skill acquisition. These findings show that rppTMS at both I-wave and non-I-wave intervals can alter M1 excitability and improve visuomotor skill acquisition in young and older adults.

Effect of current direction and muscle activation on motor cortex neuroplasticity induced by repetitive paired-pulse transcranial magnetic stimulation.

Repetitive paired-pulse transcranial magnetic stimulation (TMS) at indirect (I)-wave periodicity (iTMS) can increase plasticity in primary motor cortex (M1). Both TMS coil orientation and muscle activation can influence I-wave activity, but it remains unclear how these factors influence M1 plasticity with iTMS. We therefore investigated the influence of TMS coil orientation and muscle activation on the response to iTMS. Thirty-two young adults (24.2 ± 4.8 years) participated in three experiments. Each experiment included two sessions using a modified iTMS intervention with either a posterior-anterior orientation (PA) or anterior-posterior (AP) coil orientation over M1. Stimulation was applied in resting (Experiments 1 and 3) or active muscle (Experiments 2 and 3). Effects of iTMS on M1 excitability were assessed by recording motor evoked potentials (MEPs) and short-interval intracortical facilitation (SICF) with PA and AP orientations in both resting (all experiments) and active (Experiment 2) muscle. For the resting intervention, MEPs were greater after AP iTMS (Experiment 1, P = .046), whereas SICF was comparable between interventions (all P > .10). For the active intervention, responses did not vary between PA and AP iTMS (Experiment 2, all P > .14), and muscle activation reduced the effect of AP iTMS during the intervention (Experiment 3, P = .002). Coil orientation influenced the MEP response after iTMS, and muscle activation reduced the response during iTMS. While this suggests that AP iTMS may be beneficial in producing a neuroplastic modulation of I-wave circuits in resting muscle, further exploration of factors such as dosing is required.

Modulation of dorsal premotor cortex differentially influences I-wave excitability in primary motor cortex of young and older adults.

Previous research using transcranial magnetic stimulation (TMS) has demonstrated weakened connectivity between dorsal premotor cortex (PMd) and motor cortex (M1) with age. While this alteration is probably mediated by changes in the communication between the two regions, the effect of age on the influence of PMd on specific indirect (I) wave circuits within M1 remains unclear. The present study therefore investigated the influence of PMd on early and late I-wave excitability in M1 of young and older adults. Twenty-two young (mean ± SD, 22.9 ± 2.9 years) and 20 older (66.6 ± 4.2 years) adults participated in two experimental sessions involving either intermittent theta burst stimulation (iTBS) or sham stimulation over PMd. Changes within M1 following the intervention were assessed with motor-evoked potentials (MEPs) recorded from the right first dorsal interosseous muscle. We applied posterior-anterior (PA) and anterior-posterior (AP) current single-pulse TMS to assess corticospinal excitability (PA1mV ; AP1mV ; PA0.5mV , early; AP0.5mV , late), and paired-pulse TMS short intracortical facilitation for I-wave excitability (PA SICF, early; AP SICF, late). Although PMd iTBS potentiated PA1mV and AP1mV MEPs in both age groups (both P < 0.05), the time course of this effect was delayed for AP1mV in older adults (P = 0.001). Furthermore, while AP0.5mV , PA SICF and AP SICF were potentiated in both groups (all P < 0.05), potentiation of PA0.5mV was only apparent in young adults (P < 0.0001). While PMd influences early and late I-wave excitability in young adults, direct PMd modulation of the early circuits is specifically reduced in older adults. KEY POINTS: Interneuronal circuits responsible for late I-waves within primary motor cortex (M1) mediate projections from dorsal premotor cortex (PMd), but this communication probably changes with advancing age. We investigated the effects of intermittent theta burst stimulation (iTBS) to PMd on transcranial magnetic stimulation (TMS) measures of M1 excitability in young and older adults. We found that PMd iTBS facilitated M1 excitability assessed with posterior-anterior (PA, early I-waves) and anterior-posterior (AP, late I-waves) current TMS in young adults, with a stronger effect for AP TMS. M1 excitability assessed with AP TMS also increased in older adults following PMd iTBS, but there was no facilitation for PA TMS responses. We conclude that changes in M1 excitability following PMd iTBS are specifically reduced for the early I-waves in older adults, which could be a potential target for interventions that enhance cortical excitability in older adults.

Modulation of I-Wave Generating Pathways With Repetitive Paired-Pulse Transcranial Magnetic Stimulation: A Transcranial Magnetic Stimulation-Electroencephalography Study.

OBJECTIVES: Repetitive paired-pulse transcranial magnetic stimulation (iTMS) at indirect (I) wave intervals increases motor-evoked potentials (MEPs) produced by transcranial magnetic stimulation (TMS) to primary motor cortex (M1). However, the effects of iTMS at early and late intervals on the plasticity of specific I-wave circuits remain unclear. This study therefore aimed to assess how the timing of iTMS influences intracortical excitability within early and late I-wave circuits. To investigate the cortical effects of iTMS more directly, changes due to the intervention were also assessed using combined TMS-electroencephalography (EEG). MATERIAL AND METHODS: Eighteen young adults (aged 24.6 ± 4.2 years) participated in four sessions in which iTMS targeting early (1.5-millisecond interval; iTMS1.5) or late (4.0-millisecond interval; iTMS4.0) I-waves was applied over M1. Neuroplasticity was assessed using both posterior-to-anterior (PA) and anterior-to-posterior (AP) stimulus directions to record MEPs and TMS-evoked EEG potentials (TEPs) before and after iTMS. Short-interval intracortical facilitation (SICF) at interstimulus intervals of 1.5 and 4.0 milliseconds was also used to index I-wave activity. RESULTS: MEP amplitude was increased after iTMS (p < 0.01), and this was greater for PA responses (p < 0.01) but not different between iTMS intervals (p = 0.9). Irrespective of iTMS interval and coil current, SICF was facilitated after the intervention (p < 0.01). Although the N45 produced by AP stimulation was decreased by iTMS1.5 (p = 0.04), no other changes in TEP amplitude were observed. CONCLUSIONS: The timing of iTMS failed to influence which I-wave circuits were potentiated by the intervention. In contrast, decreases in the N45 suggest that the neuroplastic effects of iTMS may include disinhibition of intracortical inhibitory processes.

Motor cortex plasticity is greater in endurance-trained cyclists following acute exercise.

Previous research using transcranial magnetic stimulation (TMS) has shown that plasticity within primary motor cortex (M1) is greater in people who undertake regular exercise, and a single session of aerobic exercise can increase M1 plasticity in untrained participants. This study aimed to examine the effect of an acute bout of exercise on M1 plasticity in endurance-trained (cyclists) and untrained individuals. Fourteen endurance-trained cyclists (mean ± SD; 23 ± 3.8 yr) and 14 untrained individuals (22 ± 1.8 yr) performed two experimental sessions. One session included an acute bout of high-intensity interval training (HIIT) exercise involving stationary cycling, whereas another session involved no-exercise (control). Following exercise (or control), I-wave periodicity repetitive TMS (iTMS) was used (1.5-ms interval, 180 pairs) to induce plasticity within M1. Motor evoked potentials (MEPs) induced by single and paired-pulse TMS over M1 were recorded from a hand muscle at baseline, after HIIT (or control) exercise and after iTMS. Corticospinal and intracortical excitability was not influenced by HIIT exercise in either group (all P > 0.05). There was an increase in MEP amplitude after iTMS, and this was greater after HIIT exercise (compared with control) for all subjects (P < 0.001). However, the magnitude of this response was larger in endurance cyclists compared with the untrained group (P = 0.049). These findings indicate that M1 plasticity induced by iTMS was greater in endurance-trained cyclists following HIIT. Prior history of exercise training is, therefore, an important consideration for understanding factors that contribute to exercise-induced plasticity.NEW & NOTEWORTHY We use a novel form of repetitive transcranial magnetic stimulation to show that motor cortex plasticity is increased after acute exercise and that this effect is bolstered in endurance-trained cyclists. These findings indicate that participation in regular endurance exercise (involving lower limb muscles) has widespread effects on cortical plasticity (assessed in unexercised upper limb muscles) following acute lower-limb cycling exercise. It also highlights that exercise history is an important factor in exercise-induced cortical plasticity.

Cerebellar transcranial direct current stimulation disrupts neuroplasticity of intracortical motor circuits.

While previous research using transcranial magnetic stimulation (TMS) suggest that cerebellum (CB) influences the neuroplastic response of primary motor cortex (M1), the role of different indirect (I) wave inputs in M1 mediating this interaction remains unclear. The aim of this study was therefore to assess how CB influences neuroplasticity of early and late I-wave circuits. 22 young adults (22 ± 2.7 years) participated in 3 sessions in which I-wave periodicity repetitive transcranial magnetic stimulation (iTMS) was applied over M1 during concurrent application of cathodal transcranial direct current stimulation over CB (tDCSCB). In each session, iTMS either targeted early I-waves (1.5 ms interval; iTMS1.5), late I-waves (4.5 ms interval; iTMS4.5), or had no effect (variable interval; iTMSSham). Changes due to the intervention were examined with motor evoked potential (MEP) amplitude using TMS protocols measuring corticospinal excitability (MEP1mV) and the strength of CB-M1 connections (CBI). In addition, we indexed I-wave activity using short-interval intracortical facilitation (SICF) and low-intensity single-pulse TMS applied with posterior-anterior (MEPPA) and anterior-posterior (MEPAP) current directions. Following both active iTMS sessions, there was no change in MEP1mV, CBI or SICF (all P > 0.05), suggesting that tDCSCB broadly disrupted the excitatory response that is normally seen following iTMS. However, although MEPAP also failed to facilitate after the intervention (P > 0.05), MEPPA potentiated following both active iTMS sessions (both P < 0.05). This differential response between current directions could indicate a selective effect of CB on AP-sensitive circuits.

Assessment of cortical inhibition depends on inter individual differences in the excitatory neural populations activated by transcranial magnetic stimulation.

Transcranial magnetic stimulation (TMS) is used to probe inhibitory intracortical neurotransmission and has been used to infer the neurobiological dysfunction that may underly several neurological disorders. One technique, short-interval intracortical inhibition (SICI), indexes gamma-aminobutyric acid (GABA) mediated inhibitory activity and is a promising biomarker. However emerging evidence suggests SICI does not exclusively represent GABAergic activity because it may be influenced by inter-individual differences in the specific excitatory neural populations activated by TMS. Here we used the latency of TMS motor evoked potentials (MEPs) to index these inter-individual differences, and found that a significant proportion of the observed variability in SICI magnitude was accounted for by MEP latency, r = - 0.57, r2 = 0.33, p = .014. We conclude that SICI is influenced by inter-individual differences in the excitatory neural populations activated by TMS, reducing the precision of this GABAergic probe. Interpreting SICI measures in the context of MEP latency may facilitate a more precise assessment of GABAergic intracortical inhibition. The reduced cortical inhibition observed in some neuropathologies could be influenced by reduced activity in specific excitatory neural populations. Including MEP latency assessment in research investigating SICI in clinical groups could assist in differentiating the cortical circuits impacted by neurological disorders.

Threshold Tracked Short-Interval Intracortical Inhibition More Closely Predicts the Cortical Response to Transcranial Magnetic Stimulation.

OBJECTIVES: Short-interval intracortical inhibition (SICI) is a paired-pulse transcranial magnetic stimulation (TMS) technique that is commonly used to quantify intracortical inhibitory tone in the primary motor cortex. Whereas conventional measures of SICI (C-SICI) quantify inhibition by the amplitude of the motor evoked potential (MEP), alternative measures involving threshold tracked SICI (TT-SICI) instead record the TMS intensity required to maintain a consistent MEP amplitude. Although both C-SICI and TT-SICI are thought to reflect inhibition mediated by γ-aminobutyric acid type A (GABAA) receptors, recent evidence suggests that the mechanisms involved with each measure may not be equivalent. This study aimed to use combined TMS-electroencephalography (TMS-EEG) to investigate the cortical mechanisms contributing to C-SICI and TT-SICI. MATERIALS AND METHODS: In 20 young adults (30.6 ± 8.1 years), C-SICI and TT-SICI were recorded with multiple conditioning intensities, using both posterior-to-anterior (PA) and anterior-to-posterior (AP) induced currents, and this was compared with the TMS-evoked EEG potential (TEP). RESULTS: We found no relationship between the magnitude of C-SICI and TT-SICI within each current direction. However, there was a positive relationship between the slope (derived from multiple conditioning intensities) of inhibition recorded with C-SICI and TT-SICI, but only with a PA current. Furthermore, irrespective of conditioning intensity or current direction, measures of C-SICI were unrelated to TEP amplitude. In contrast, TT-SICI was predicted by the P30 generated with AP stimulation. CONCLUSIONS: Our findings further demonstrate that C-SICI and TT-SICI likely reflect different facets of GABAA-mediated processes, with inhibition produced by TT-SICI appearing to align more closely with TMS-EEG measures of cortical excitability.

Interactions Between Cerebellum and the Intracortical Excitatory Circuits of Motor Cortex: a Mini-Review.

Interactions between cerebellum (CB) and primary motor cortex (M1) are critical for effective motor function. Although the associated neurophysiological processes are yet to be fully characterised, a growing body of work using non-invasive brain stimulation (NIBS) techniques has significantly progressed our current understanding. In particular, recent developments with both transcranial magnetic (TMS) and direct current (tDCS) stimulation suggest that CB modulates the activity of local excitatory interneuronal circuits within M1. These circuits are known to be important both physiologically and functionally, and understanding the nature of their connectivity with CB therefore has the potential to provide important insight for NIBS applications. Consequently, this mini-review provides an overview of the emerging literature that has investigated interactions between CB and the intracortical excitatory circuits of M1.

Motor cortex plasticity and visuomotor skill learning in upper and lower limbs of endurance-trained cyclists.

PURPOSE: Studies with transcranial magnetic stimulation (TMS) show that both acute and long-term exercise can influence TMS-induced plasticity within primary motor cortex (M1). However, it remains unclear how regular exercise influences skill training-induced M1 plasticity and motor skill acquisition. This study aimed to investigate whether skill training-induced plasticity and motor skill learning is modified in endurance-trained cyclists. METHODS: In 16 endurance-trained cyclists (24.4 yrs; 4 female) and 17 sedentary individuals (23.9 yrs; 4 female), TMS was applied in 2 separate sessions: one targeting a hand muscle not directly involved in habitual exercise and one targeting a leg muscle that was regularly trained. Single- and paired-pulse TMS was used to assess M1 and intracortical excitability in both groups before and after learning a sequential visuomotor isometric task performed with the upper (pinch task) and lower (ankle dorsiflexion) limb. RESULTS: Endurance-trained cyclists displayed greater movement times (slower movement) compared with the sedentary group for both upper and lower limbs (all P < 0.05), but there was no difference in visuomotor skill acquisition between groups (P > 0.05). Furthermore, endurance-trained cyclists demonstrated a greater increase in M1 excitability and reduced modulation of intracortical facilitation in resting muscles of upper and lower limbs after visuomotor skill learning (all P < 0.005). CONCLUSION: Under the present experimental conditions, these results indicate that a history of regular cycling exercise heightens skill training-induced M1 plasticity in upper and lower limb muscles, but it does not facilitate visuomotor skill acquisition.

Age-related changes in motor cortex plasticity assessed with non-invasive brain stimulation: an update and new perspectives.

It is commonly accepted that the brains capacity to change, known as plasticity, declines into old age. Recent studies have used a variety of non-invasive brain stimulation (NIBS) techniques to examine this age-related decline in plasticity in the primary motor cortex (M1), but the effects seem inconsistent and difficult to unravel. The purpose of this review is to provide an update on studies that have used different NIBS techniques to assess M1 plasticity with advancing age and offer some new perspective on NIBS strategies to boost plasticity in the ageing brain. We find that early studies show clear differences in M1 plasticity between young and older adults, but many recent studies with motor training show no decline in use-dependent M1 plasticity with age. For NIBS-induced plasticity in M1, some protocols show more convincing differences with advancing age than others. Therefore, our view from the NIBS literature is that it should not be automatically assumed that M1 plasticity declines with age. Instead, the effects of age are likely to depend on how M1 plasticity is measured, and the characteristics of the elderly population tested. We also suggest that NIBS performed concurrently with motor training is likely to be most effective at producing improvements in M1 plasticity and motor skill learning in older adults. Proposed NIBS techniques for future studies include combining multiple NIBS protocols in a co-stimulation approach, or NIBS strategies to modulate intracortical inhibitory mechanisms, in an effort to more effectively boost M1 plasticity and improve motor skill learning in older adults.

Assessing cerebellar-cortical connectivity using concurrent TMS-EEG: a feasibility study.

Combined single-pulse transcranial magnetic stimulation (TMS) and electroencephalography (EEG) has been used to probe the features of local networks in the cerebral cortex. Here, we investigated whether we can use this approach to explore long-range connections between the cerebellum and cerebral cortex. Ten healthy adults received single-pulse suprathreshold TMS to the cerebellum and an occipital/parietal control site with double-cone and figure-of-eight coils while cerebral activity was recorded. A multisensory electrical control condition was used to simulate the sensation of the double-cone coil at the cerebellar site. Two cleaning pipelines were compared, and the spatiotemporal relationships of the EEG output between conditions were examined at sensor and source levels. Cerebellar stimulation with the double-cone coil resulted in large artifact in the EEG trace. The addition of SOUND filtering to the cleaning pipeline improved the signal such that further analyses could be undertaken. The cortical potentials evoked by the active TMS conditions showed strong relationships with the responses to the multisensory control condition after ∼50 ms. A distinct parietal component at ∼42 ms was found following cerebellar double-cone stimulation. Although evoked potentials differed across all conditions at early latencies, it is unclear as to whether these represented TMS-related network activation of the cerebellarthalamocortical tract, or whether components were dominated by sensory contamination and/or coil-driven artifact. This study highlights the need for caution when interpreting outcomes from cerebellar TMS-EEG studies.NEW & NOTEWORTHY This is the first study to systematically assess the feasibility of obtaining TMS-evoked potentials from cerebellar stimulation with concurrent EEG. An innovative control condition using electrical stimulation was modified to mimic the sensory aspects of cerebellar stimulation with a double-cone coil, and a state-of-the art cleaning pipeline was trialled. The extent of artifact contamination in signals from stimulation of a cerebellar and an occipital/parietal control site using two TMS coil types was highlighted.

Modulation of Motor Cortex Plasticity by Repetitive Paired-Pulse TMS at Late I-Wave Intervals Is Influenced by Intracortical Excitability.

The late indirect (I)-waves recruited by transcranial magnetic stimulation (TMS) over primary motor cortex (M1) can be modulated using I-wave periodicity repetitive TMS (iTMS). The purpose of this study was to determine if the response to iTMS is influenced by different interstimulus intervals (ISIs) targeting late I-waves, and whether these responses were associated with individual variations in intracortical excitability. Seventeen young (27.2 ± 6.4 years, 12 females) healthy adults received iTMS at late I-wave intervals (4.0, 4.5, and 5.0 ms) in three separate sessions. Changes due to each intervention were examined with motor evoked potential (MEP) amplitudes and short-interval intracortical facilitation (SICF) using both posterior-anterior (PA) and anterior-posterior (AP) TMS current directions. Changes in MEP amplitude and SICF were influenced by iTMS ISI, with the greatest facilitation for ISIs at 4 and 5 ms with PA TMS, and 4 ms with AP TMS. Maximum SICF at baseline (irrespective of ISI) was associated with increased iTMS response, but only for PA stimulation. These results suggest that modifying iTMS parameters targeting late I-waves can influence M1 plasticity. They also suggest that maximum SICF may be a means by which responders to iTMS targeting the late I-waves could be identified.

Preferential Activation of Unique Motor Cortical Networks With Transcranial Magnetic Stimulation: A Review of the Physiological, Functional, and Clinical Evidence.

OBJECTIVES: The corticospinal volley produced by application of transcranial magnetic stimulation (TMS) over primary motor cortex consists of a number of waves generated by trans-synaptic input from interneuronal circuits. These indirect (I)-waves mediate the sensitivity of TMS to cortical plasticity and intracortical excitability and can be assessed by altering the direction of cortical current induced by TMS. While this methodological approach has been conventionally viewed as preferentially recruiting early or late I-wave inputs from a given populations of neurons, growing evidence suggests recruitment of different neuronal populations, and this would strongly influence interpretation and application of these measures. The aim of this review is therefore to consider the physiological, functional, and clinical evidence for the independence of the neuronal circuits activated by different current directions. MATERIALS AND METHODS: To provide the relevant context, we begin with an overview of TMS methodology, focusing on the different techniques used to quantify I-waves. We then comprehensively review the literature that has used variations in coil orientation to investigate the I-wave circuits, grouping studies based on the neurophysiological, functional, and clinical relevance of their outcomes. RESULTS: Review of the existing literature reveals significant evidence supporting the idea that varying current direction can recruit different neuronal populations having unique functionally and clinically relevant characteristics. CONCLUSIONS: Further research providing greater characterization of the I-wave circuits activated with different current directions is required. This will facilitate the development of interventions that are able to modulate specific intracortical circuits, which will be an important application of TMS.

Characterising the influence of cerebellum on the neuroplastic modulation of intracortical motor circuits.

The cerebellum (CB) has extensive connections with both cortical and subcortical areas of the brain, and is known to strongly influence function in areas it projects to. In particular, research using non-invasive brain stimulation (NIBS) has shown that CB projections to primary motor cortex (M1) are likely important for facilitating the learning of new motor skills, and that this process may involve modulation of late indirect (I) wave inputs in M1. However, the nature of this relationship remains unclear, particularly in regards to how CB influences the contribution of the I-wave circuits to neuroplastic changes in M1. Within the proposed research, we will therefore investigate how CB effects neuroplasticity of the I-wave generating circuits. This will be achieved by downregulating CB excitability while concurrently applying a neuroplastic intervention that specifically targets the I-wave circuitry. The outcomes of this study will provide valuable neurophysiological insight into key aspects of the motor network, and may inform the development of optimized interventions for modifying motor learning in a targeted way.