Modulation of cerebellar–motor cortex pathways by cerebellar theta burst stimulation

The cerebellum is a brain region important for motor control and learning (Krakauer et al., 2019; Nguyen & Person, 2025). It is connected to the primary motor cortex (M1) via the cerebello-thalamocortical pathway (Dum & Strick, 2003). Purkinje cells carry the primary output of the cerebellum and inhibit the deep cerebellar nuclei, leading to a net inhibitory interaction between the cerebellum and M1, referred to as cerebellar brain inhibition (CBI) (Ugawa et al., 1995). CBI has been studied using transcranial magnetic stimulation (TMS) with a paired-pulse approach (Fernandez et al., 2018). Delivering a conditioning stimulus (CS) over the cerebellum 5-7ms before delivering a test stimulus (TS) over M1 reduces M1 excitability, measured as a decrease in the muscle response termed a motor evoked potential (MEP) relative to M1 stimulation alone. This effect is thought to reflect Purkinje cell activation. Previous research shows that CBI decreases following motor adaptation tasks (Jayaram et al., 2011; Schlerf et al., 2012; D. Spampinato et al., 2020) and aerobic exercise (Mang et al., 2016), suggesting that CBI reflects the plasticity of the cerebellar-M1 interaction. As this interaction is often disrupted in neurological conditions such as ataxia, Parkinson’s disease, and stroke (Carrillo et al., 2013; Schulz et al., 2017; Ugawa et al., 1994), manipulating its strength may support motor learning in rehabilitation settings (Mang et al., 2016). Theta burst stimulation (TBS), a repetitive TMS protocol, delivers bursts of high-frequency pulses that induce changes in brain excitability (Huang et al., 2005). Intermittent TBS (iTBS) and continuous TBS (cTBS), varying in stimulation pattern, transiently increase or decrease M1 excitability when delivered over M1, respectively. cTBS targeting the cerebellum reduces CBI (Popa et al., 2010; Strzalkowski et al., 2019), suggesting that cerebellar TBS can modulate the inhibitory effects of Purkinje cells. However, a recent meta-analysis shows that cerebellar cTBS also decreases M1 excitability (Behrangrad et al., 2019). This is opposite to the expected result given the cerebellum’s inhibitory influence on M1. This inconsistency illustrates that cerebellar-M1 interactions are not well understood. Since the cerebellum does not exclusively project to M1 (Dum & Strick, 2003), it is important to clarify which M1 pathways are modulated by cerebellar TBS. Using single-pulse TMS to induce current in different directions allows for probing different neuronal populations within M1 (Di Lazzaro & Rothwell, 2014; Hamada et al., 2014). TMS applied in a posterior-to-anterior (PA) direction preferentially recruits monosynaptic connections to M1 corticospinal neurons. In contrast, an anterior-to-posterior (AP) current preferentially recruits neurons with increased synaptic distance from corticospinal neurons, likely involving indirect inputs to M1 from other regions (Aberra et al., 2020; Di Lazzaro & Rothwell, 2014; Volz et al., 2015). CBI can be induced using an M1 stimulus applied in either the AP or PA direction (i.e., AP-CBI and PA-CBI), which shows different patterns of change associated with distinct motor learning tasks (D. Spampinato et al., 2020). This suggests that PA- and AP-sensitive neurons receive cerebellar inputs through different pathways and may have specialized functions (D. Spampinato, 2020). Because combining directional TMS with CBI may help delineate the neuromodulatory effects of cerebellar TBS, this project aims to: 1) characterize how cerebellar TBS influences excitability of AP and PA sensitive neurons in M1, and 2) assess its impact on cerebellar-M1 pathways by quantifying changes in CBI.