The effects of intermittent theta burst stimulation over dorsal premotor cortex on primary motor cortex plasticity in young and older adults.

Previous transcranial magnetic stimulation (TMS) research suggests that the dorsal premotor cortex (PMd) influences neuroplasticity within the primary motor cortex (M1) through indirect (I) wave interneuronal circuits. However, it is unclear how the influence of PMd on the plasticity of M1 I-waves changes with advancing age. This study therefore investigated the neuroplastic effects of intermittent theta burst stimulation (iTBS) to M1 early and late I-wave circuits when preceded by iTBS (PMd iTBS-M1 iTBS) or sham stimulation (PMd sham-M1 iTBS) to PMd in 15 young and 16 older adults. M1 excitability was assessed with motor evoked potentials (MEP) recorded from the right first dorsal interosseous using posterior-anterior (PA) and anterior-posterior (AP) current TMS at standard stimulation intensities (PA1mV, AP1mV) and reduced stimulation intensities (PA0.5mV, early I-waves; AP0.5mV, late I-waves). PMd iTBS-M1 iTBS lowered the expected facilitation of PA0.5mV (to M1 iTBS) in young and older adults (P = 0.009), whereas the intervention had no effect on AP0.5mV facilitation in either group (P = 0.305). The modulation of PA0.5mV following PMd iTBS-M1 iTBS may reflect a specific influence of PMd on different I-wave circuits that are involved in M1 plasticity within young and older adults.

Investigating the Effects of Repetitive Paired-Pulse Transcranial Magnetic Stimulation on Visuomotor Training Using TMS-EEG.

I-wave periodicity repetitive paired-pulse transcranial magnetic stimulation (iTMS) can modify acquisition of a novel motor skill, but the associated neurophysiological effects remain unclear. The current study therefore used combined TMS-electroencephalography (TMS-EEG) to investigate the neurophysiological effects of iTMS on subsequent visuomotor training (VT). Sixteen young adults (26.1 ± 5.1 years) participated in three sessions including real iTMS and VT (iTMS + VT), control iTMS and VT (iTMSControl + VT), or iTMS alone. Motor-evoked potentials (MEPs) and TMS-evoked potentials (TEPs) were measured before and after iTMS, and again after VT, to assess neuroplastic changes. Irrespective of the intervention, MEP amplitude was not changed after iTMS or VT. Motor skill was improved compared with baseline, but no differences were found between stimulus conditions. In contrast, the P30 peak was altered by VT when preceded by control iTMS (P < 0.05), but this effect was not apparent when VT was preceded by iTMS or following iTMS alone (all P > 0.15). In contrast to expectations, iTMS was unable to modulate MEP amplitude or influence motor learning. Despite this, changes in P30 amplitude suggested that motor learning was associated with altered cortical reactivity. Furthermore, this effect was abolished by priming with iTMS, suggesting an influence of priming that failed to impact learning.

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.

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.

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 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.

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.

Does predictive cueing of presentation time modulate alpha power and facilitate visual working memory performance in younger and older adults?

Selective attention and working memory (WM) are vulnerable to age-related decline. Older adults perform worse on, and are less able to modulate alpha power (8-12 Hz) than younger adults in tasks involving cues about 'where' or 'when' a memory set will appear. However, no study has investigated whether alpha power is modulated by cues predicting the presentation time of a memory set. Here, we recorded electroencephalography while 24 younger (18-33 years) and 23 older (60-77 years) adults completed a modified delay match-to-sample task where participants were cued to the duration of a memory set (0.1 s or 0.5 s). We found: (1) predictive cues increased WM storage; (2) no differences in preparatory alpha power between predictive and neutral cue types, but preparatory alpha suppression was weaker in older adults; (3) retention period oscillatory power differed between presentation times, but these differences were no longer present when comparing trial types from the onset of the memory set; and (4) oscillatory power in the preparatory and retention periods were unrelated to performance. Our results suggest that preparatory alpha power is not modulated by predictive cues towards presentation time, however, reductions in alpha/beta power during visual WM retention may be linked to encoding, rather than retention.

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.

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.

Single joint fatiguing exercise decreases long but not short-interval intracortical inhibition in older adults.

Ageing is accompanied by neuromuscular changes which may alter fatigue in older adults. These changes may include changes in corticospinal excitatory and inhibitory processes. Previous research has suggested that single joint fatiguing exercise decreases short-(SICI) and long-(LICI) interval intracortical inhibition in young adults. However, this is yet to be established in older adults. In 19 young (23 ± 4 years) and 18 older (69 ± 5 years) adults, SICI (2 ms interstimulus interval; ISI) and LICI (100 ms ISI) were measured in a resting first dorsal interosseous (FDI) muscle using transcranial magnetic stimulation (TMS) before and after a 15 min sustained submaximal contraction at 25% of their maximum EMG. Subsequent ten 2-min contractions held at 25% EMG were also performed to sustain fatigue for a total of 30 min, while SICI and LICI were taken immediately after each contraction. There was no change in SICI post-fatiguing exercise compared to baseline in both young and older adults (P = 0.4). Although there was no change in LICI post-fatiguing exercise in younger adults (P = 1.0), LICI was attenuated in older adults immediately post-fatiguing exercise and remained attenuated post-fatigue (PF)1 and PF2 (P < 0.05). Contrary to previous studies, the lack of change in SICI and LICI in young adults following a sustained submaximal EMG contraction suggests that GABA modulation may be dependent on the type of fatiguing task performed. The reduction in LICI in older adults post-fatiguing exercise suggests an age-related decrease in GABAB-mediated activity with sustained submaximal fatiguing exercise.

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.

The Role of Alpha Power in the Suppression of Anticipated Distractors During Verbal Working Memory.

As working memory (WM) is limited in capacity, it is important to direct neural resources towards processing task-relevant information while ignoring distractors. Neural oscillations in the alpha frequency band (8-12 Hz) have been suggested to play a role in the inhibition of task-irrelevant information during WM, although results are mixed, possibly due to differences in the type of WM task employed. Here, we examined the role of alpha power in suppression of anticipated distractors of varying strength using a modified Sternberg task where the encoding and retention periods were temporally separated. We recorded EEG while 20 young adults completed the task and found: (1) slower reaction times in strong distractor trials compared to weak distractor trials; (2) increased alpha power in posterior regions from baseline prior to presentation of a distractor regardless of condition; and (3) no differences in alpha power between strong and weak distractor conditions. Our results suggest that parieto-occipital alpha power is increased prior to a distractor. However, we could not find evidence that alpha power is further modulated by distractor strength.

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.

Primary motor cortex function and motor skill acquisition: insights from threshold-hunting TMS.

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.

Intermittent single-joint fatiguing exercise reduces TMS-EEG measures of cortical inhibition.

Fatiguing intermittent single-joint exercise causes an increase in corticospinal excitability and a decrease in intracortical inhibition when measured with peripherally recorded motor evoked potentials (MEPs) after transcranial magnetic stimulation (TMS). Combined TMS and electroencephalography (TMS-EEG) allows for more direct recording of cortical responses through the TMS-evoked potential (TEP). The aim of this study was to investigate the changes in the excitatory and inhibitory components of the TEP during fatiguing single-joint exercise. Twenty-three young (22 ± 2 yr) healthy subjects performed intermittent 30-s maximum voluntary contractions of the right first dorsal interosseous muscle, followed by a 30-s relaxation period repeated for a total of 15 min. Six single-pulse TMSs and one peripheral nerve stimulation (PNS) to evoke maximal M wave (Mmax) were applied during each relaxation period. A total of 90 TMS pulses and 5 PNSs were applied before and after fatiguing exercise to record MEP and TEP. The amplitude of the MEP (normalized to Mmax) increased during fatiguing exercise ( P < 0.001). There were no changes in local and global P30, N45, and P180 of TEPs during the development of intermittent single-joint exercise-induced fatigue. Global analysis, however, revealed a decrease in N100 peak of the TEP during fatiguing exercise compared with before fatiguing exercise ( P = 0.02). The decrease in N100 suggests a fatigue-related decrease in global intracortical GABAB-mediated inhibition. The increase in corticospinal excitability typically observed during single-joint fatiguing exercise may be mediated by a global decrease in intracortical inhibition. NEW & NOTEWORTHY Fatiguing intermittent single-joint exercise causes an increase in corticospinal excitability and a decrease in intracortical inhibition when measured with transcranial magnetic stimulation (TMS)-evoked potentials from the muscle. The present study provides new and direct cortical evidence, using TMS-EEG to demonstrate that during single-joint fatiguing exercise there is a global decrease in intracortical GABAB-mediated inhibition.

Age-related changes in late I-waves influence motor cortex plasticity induction in older adults.

KEY POINTS: The response to neuroplasticity interventions using transcranial magnetic stimulation (TMS) is reduced in older adults, which may be due, in part, to age-related alterations in interneuronal (I-wave) circuitry. The current study investigated age-related changes in interneuronal characteristics and whether they influence motor cortical plasticity in older adults. While I-wave recruitment was unaffected by age, there was a shift in the temporal characteristics of the late, but not the early I-waves. Using I-wave periodicity repetitive TMS (iTMS), we showed that these differences in I-wave characteristics influence the induction of cortical plasticity in older adults. ABSTRACT: Previous research shows that neuroplasticity assessed using transcranial magnetic stimulation (TMS) is reduced in older adults. While this deficit is often assumed to represent altered synaptic modification processes, age-related changes in the interneuronal circuits activated by TMS may also contribute. Here we assessed age-related differences in the characteristics of the corticospinal indirect (I) waves and how they influence plasticity induction in primary motor cortex. Twenty young (23.7 ± 3.4 years) and 19 older adults (70.6 ± 6.0 years) participated in these studies. I-wave recruitment was assessed by changing the direction of the current used to activate the motor cortex, whereas short-interval intracortical facilitation (SICF) was recorded to assess facilitatory I-wave interactions. In a separate study, I-wave periodicity TMS (iTMS) was used to examine the effect of I-wave latency on motor cortex plasticity. Data from the motor-evoked potential (MEP) onset latency produced using different coil orientations suggested that there were no age-related differences in preferential I-wave recruitment (P = 0.6). However, older adults demonstrated significant reductions in MEP facilitation at all 3 SICF peaks (all P values < 0.05) and a delayed latency of the second and third SICF peaks (all P values < 0.05). Using I-wave intervals that were optimal for young and older adults, these changes in the late I-waves were shown to influence the plasticity response in older adults after iTMS. These findings suggest that temporal characteristics are delayed for the late I-waves in older adults, and that optimising TMS interventions based on I-wave characteristics may improve the plasticity response in older adults.

Increasing motor cortex plasticity with spaced paired associative stimulation at different intervals in older adults.

The ability of priming non-invasive brain stimulation (NIBS) to modulate neuroplasticity induction (i.e. metaplasticity) within primary motor cortex (M1) may be altered in older adults. Previous studies in young subjects suggest that consecutive NIBS protocols interact in a time-dependent manner and involve homoeostatic metaplasticity mechanisms. This was investigated in older adults by assessing the response to consecutive blocks of paired-associative stimulation (PAS) separated by different inter-PAS intervals (IPIs). Fifteen older (62-82 years) subjects participated in four sessions, with each session involving two PAS blocks separated by IPIs of 10 (IPI10 ) or 30 (IPI30 ) mins. For each IPI, the first (priming) PAS block was either PASLTP (N20 latency + 2 ms) or PASLTD (N20 latency - 10 ms), while the second (test) PAS block was always PASLTP . Changes in M1 excitability were assessed by recording motor evoked potentials from a muscle of the right hand. For both IPIs, the response produced by PASLTD -primed PASLTP was significantly greater than the response produced by PASLTP -primed PASLTP . Furthermore, the effects of PASLTD priming on PASLTP were significantly greater for IPI30 . These findings suggest that priming PAS can increase plasticity induction in older adults, and this occurs through mechanisms involving homoeostatic metaplasticity. They also demonstrate that the timing between priming and test NIBS is a crucial determinant of this effect, with a 30-min interval being most effective. Providing a 30-min delay between priming NIBS and motor training may improve the efficacy of NIBS in augmenting motor performance and learning in the elderly.

Task-related changes in intracortical inhibition assessed with paired- and triple-pulse transcranial magnetic stimulation.

Recent research has demonstrated a task-related modulation of postsynaptic intracortical inhibition within primary motor cortex for tasks requiring isolated (abduction) or synergistic (precision grip) muscle activation. The current study sought to investigate task-related changes in pre- and postsynaptic intracortical inhibition in motor cortex. In 13 young adults (22.5 ± 3.5 yr), paired-pulse transcranial magnetic stimulation (TMS) was used to measure short (SICI)- and long-interval intracortical inhibition (LICI) (i.e., postsynaptic motor cortex inhibition) in first dorsal interosseous muscle, and triple-pulse TMS was used to investigate changes in SICI-LICI interactions (i.e., presynaptic motor cortex inhibition). These measurements were obtained at rest and during muscle activation involving isolated abduction of the index finger and during a precision grip using the index finger and thumb. SICI was reduced during abduction and precision grip compared with rest, with greater reductions during precision grip. The modulation of LICI during muscle activation depended on the interstimulus interval (ISI; 100 and 150 ms) but was not different between abduction and precision grip. For triple-pulse TMS, SICI was reduced in the presence of LICI at both ISIs in resting muscle (reflecting presynaptic motor cortex inhibition) but was only modulated at the 150-ms ISI during index finger abduction. Results suggest that synergistic contractions are accompanied by greater reductions in postsynaptic motor cortex inhibition than isolated contractions, but the contribution of presynaptic mechanisms to this disinhibition is limited. Furthermore, timing-dependent variations in LICI provide additional evidence that measurements using different ISIs may not represent activation of the same cortical process.

Crossed motor innervation of the base of human tongue.

Muscle fibers of the genioglossus (GG) form the bulk of the muscle mass at the base of the tongue. The motor control of the tongue is critical for vocalization, feeding, and breathing. Our goal was to assess the patterns of motor innervation of GG single motor units (SMUs) in humans. Simultaneous monopolar recordings were obtained from four sites in the base of the tongue bilaterally at two antero-posterior levels from 16 resting, awake, healthy adult males, who wore a face mask with airway pressure and airflow sensors. We analyzed 69 data segments in which at least one lead contained large action potentials generated by an SMU. Such potentials served as triggers for spike-triggered averaging (STA) of signals recorded from the other three sites. Spontaneous activity of the SMUs was classified as inspiratory modulated, expiratory modulated, or tonic. Consistent with the antero-posterior orientation of GG fibers, 44 STAs (77%) recorded ipsilateral to the trigger yielded sharp action potentials with a median amplitude of 52 µV [interquartile range (IQR): 25-190] that were time shifted relative to the trigger by about 1 ms. Notably, 48% of recordings on the side opposite to the trigger also yielded sharp action potentials. Of those, 17 (29%) had a median amplitude of 63 µV (IQR: 39-96), and most were generated by tonic SMUs. Thus a considerable proportion of GG muscle fibers receive a crossed motor innervation. Crossed innervation may help ensure symmetry and stability of tongue position and movements under normal conditions and following injury or degenerative changes affecting the tongue.