The human neuromotor system is remarkably versatile and can quickly adapt complex visuomotor behaviour in response to the changing needs of the surrounding environment. An important region within the brain that mediates visuomotor adaption is dorsal premotor cortex (PMd), which is thought to select the appropriate action plan (Chouinard et al., 2005, Nowak et al., 2009, Parikh and Santello, 2017) before transmitting this information to primary motor cortex (M1) to form the final motor output (Koch et al., 2007). However, the capacity to adapt complex motor skills generally declines with age (Voelcker-Rehage, 2008), which can limit the ability of older adults to live independently. One possible reason for this decline is age-related changes in neuroplasticity, which refers to the ability of the brain to modify the strength of synaptic communication with long-term potentiation (LTP) and depression (LTD) (Burke and Barnes, 2006, Mahncke et al., 2006, Sanes and Donoghue, 2000). Previous studies using non-invasive brain stimulation (NIBS) have reported reduced M1 plasticity (Fathi et al., 2010, Freitas et al., 2011, Müller-Dahlhaus et al., 2008, Todd et al., 2010) and weaker PMd-M1 connectivity in older adults (Ni et al., 2015). These age-related changes within M1 likely affect PMd-M1 communication, but the mechanisms driving this decline, and how ageing modifies the influence of PMd on visuomotor adaptation, remain unclear.

Transcranial magnetic stimulation (TMS) is a type of NIBS that is useful for characterising the physiology within and between different motor networks with high temporal resolution. Application of TMS over M1 produces a complex descending volley that summates at the spinal cord, resulting in a motor evoked potential (MEP) in targeted muscles (Di Lazzaro et al., 1998; Rossini et al., 2015). The descending volley includes an early direct wave (D-wave), generated by direct activation of corticospinal neurons, followed by several indirect waves (I-waves) that are thought to stem from activation of local interneurons that are synaptically connected to corticospinal neurons (Di Lazzaro et al., 2012, Ziemann, 2020). I-waves can be further characterised as early (I1) and late (I2, I3), and follow each other at a periodicity of ~1.5 ms (Di Lazzaro et al., 2012, Ziemann, 2020). Early and late I-waves can be selectively recruited using single-pulse TMS by changing the direction of the applied current (Di Lazzaro et al., 2001; Ni et al., 2010; Sakai et al., 1997). For example, single-pulse TMS at perithreshold currents in the brain perpendicular to the central sulcus with a posterior-anterior (PA) direction preferentially recruit early I-waves, whereas anterior-posterior (AP) currents preferentially recruit late I-waves (Di Lazzaro et al., 2001; Ni et al., 2010; Sakai et al., 1997). Using this technique, TMS research in the past decade has shown that the ability to recruit late I-waves with single-pulse TMS specifically predicts the response of M1 to plasticity-inducing NIBS (Hamada et al., 2013, Volz et al., 2019, Wiethoff et al., 2014). Late I-waves have also been associated with visuomotor behaviour and are thought to originate from the premotor areas (Aberra et al., 2020, Hamada et al., 2014, Spampinato et al., 2020, Volz et al., 2015). Importantly, it is possible to modulate visuomotor adaptation by applying TMS to PMd (Lee and van Donkelaar, 2006, Parikh and Santello, 2017, Sugiyama et al., 2022), indicating that PMd is actively involved during visuomotor adaptation (Tzvi et al., 2020). Taken together, the late I-wave circuits likely reflect PMd inputs that modulate M1 plasticity and visuomotor adaptation.

Importantly, age-related changes in I-wave activity have also been reported using the paired-pulse TMS paradigm short-interval intracortical facilitation (SICF), which is able to specifically index I-wave excitability (Opie et al., 2018). Using this paired-pulse TMS protocol, previous studies have identified reduced I-wave excitability in older adults, and specific temporal alterations to the late I-waves that influence NIBS-induced plasticity, with these changes being predictive of motor behaviour in older adults (Opie et al., 2018, Opie et al., 2020). Furthermore, PMd-M1 connectivity and the influence of PMd on I-wave activity have been reported to weaken with age (W-Y. Liao et al., 2023; Ni et al., 2015). It may therefore be possible that age-related changes in the I-wave circuits can affect PMd-M1 communication, which is important for visuomotor adaptation.

Therefore, the present study aimed to investigate the influence of PMd on M1 I-wave circuits and visuomotor adaptation in young and older adults. As previous work in young adults has shown that continuous theta burst stimulation (cTBS; LTD-like paradigm) over PMd can disrupt visuomotor performance (Huang et al., 2018, Parikh and Santello, 2017), we wished to investigate whether intermittent TBS (iTBS; LTP-like paradigm) over PMd can improve visuomotor performance. We have shown previously that PMd iTBS has a stronger potentiating effect on late I-waves (W-Y. Liao et al., 2023), whose recruitment efficiency is related to the strength of premotor-M1 functional connectivity (Volz et al., 2015). Enhancing this communication may therefore improve visuomotor performance, which would be particularly beneficial for developing interventions that improve motor function in older adults. We assessed the effects of PMd iTBS on different I-wave circuits by varying the direction of TMS current applied over M1, and on performance during a visuomotor adaptation task (VAT) that is known to specifically engage PMd (Tzvi et al., 2020). We hypothesised that the influence of PMd on M1 I-waves would be related to changes in visuomotor behaviour within older adults, and enhancing this communication with iTBS can improve visuomotor adaptation in older adults.