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

Abstract

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.

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

“…Previous work from our group (Liao et al, 2023) and others (Meng et al, 2020) have reported that the application of iTBS to PMd broadly increases M1 excitability in young adults. This effect is thought to stem from the induction of LTP-like effects within PMd (Meng et al, 2020), resulting in increased excitability within M1 when assessed with PA and AP single-pulse TMS (PA 1mV , AP 1mV , PA 0.5mV , AP 0.5mV ) (Liao et al, 2023).…”

“…Sample size for the present study was determined using simulation-based power estimations on Rstudio (version 2023.12.1 + 402) (Team, 2015) using 'lme4' (Bates et al, 2015) and 'simr' (Green & MacLeod, 2016) packages. Our previous work assessing the effects of PMd iTBS on M1 excitability in young and older adults (Liao et al, 2023) revealed a fixed effects coefficient of À0.349 for the intervention that was used as an unstandardised measure of effect size (Green & MacLeod, 2016). This value was lowered by 15% (À0.297) to account for biases in power calculations derived from experimental data (Green & MacLeod, 2016) and revealed a required sample size of 25 total participants to observe a small to moderate effect of PMd iTBS on M1 excitability, given α = 0.05 and 1 -β = 0.9.…”

“…Previous studies have demonstrated that the application of repetitive TMS (rTMS) techniques (such as theta burst stimulation; TBS) over PMd has been reported to modify M1 excitability, plasticity and motor skill acquisition (Huang et al, 2018;Meng et al, 2020). Furthermore, while PMd influences both early and late I-wave excitability (Liao et al, 2023), there is a stronger effect of premotor areas on late I-waves (Aberra et al, 2020;Volz et al, 2015). Taken together, it is likely that the influence of late I-waves on M1 plasticity reflects inputs from PMd.…”

“…Importantly, this delay influences NIBSinduced plasticity and is associated with specific aspects of motor behaviour in older adults (Opie et al, 2018(Opie et al, , 2020. In addition, it is also known that PMd-M1 effective connectivity (Ni et al, 2015) and direct PMd modulation of early I-waves within M1 is reduced in older adults (Liao et al, 2023). Consequently, it is possible that the influence of PMd on M1 plasticity is altered with advancing age, but this remains to be tested.…”

Test-retest reliability of intrahemispheric dorsal premotor and primary motor cortex dual-site TMS connectivity measures

“…When stimulating M1 with TMS, distinct descending volleys can be measured in the corticospinal neurons and will summate at the level of the spinal cord to finally elicit an MEP in the muscle corresponding to the stimulated M1 area. When stimulating at higher intensities, this results in direct activation of the corticospinal neurons (i.e., D-wave), whereas lower intensities rather elicit an indirect activation of M1 via mono- and polysynaptic inputs of the local intracortical network (I-waves), to which PMd contributes (Di Lazzaro et al, 2001, Groppa et al, 2012, Liao et al, 2023, Rossini et al, 2015, Ziemann et al, 1996). Based on the emerging I-waves, choices in the dsTMS stimulation protocol such as the intensity of the CS and TS applied to PMd and M1 respectively, their timing (ISI), and the coil orientation (Di Lazzaro et al, 2001) can influence the pattern of activation in M1 and the subsequent muscle response.…”