Cerebellar Activity Affects Distal Cortical Physiology and Synaptic Plasticity in a Human Parietal-Motor Pathway Associated with Motor Actions

Abstract

Voluntary movement control depends on plasticity in several interconnected brain regions, including the cerebellum (CB), primary motor cortex (M1), and posterior parietal cortex (PPC). It is thought that one role of the CB is to regulate communication between PPC and M1, but causal evidence for this regulatory role in humans remains lacking. Here, we evaluated how transiently altering activity in CB via intermittent theta burst stimulation (iTBS) affects PPC-M1 connectivity and plasticity by assessing the effectiveness of subsequent Hebbian-like cortical paired associative stimulation (cPAS) to PPC and M1. Using a within-subject design, we administered four different single-session stimulation conditions to the CB and parietal-motor pathway of the motor network and measured the aftereffects on plasticity (both sexes). We administered iTBS to the right CB or right visual cortex, followed by cPAS of a parietal-motor circuit in the left hemisphere. In a subset of participants, we performed two additional control conditions to assess the effect of CB iTBS alone and Hebbian-like cPAS of the PPC-M1 circuit alone. We evaluated motor-evoked potentials (MEPs) using single-pulse transcranial magnetic stimulation as a measure of motor cortical excitability before and after each plasticity induction protocol. Cerebellar iTBS reduced cPAS-induced plasticity in the parietal-motor circuit, as evidenced by a decrease in MEPs. These responses were selective, as no decreases in excitability were observed during the control experiments. These findings suggest that CB activity can modify distal neural activity in a network-connected parietal-motor circuit through heterosynaptic metaplasticity.

Keywords: TMS; action; excitability; motor cortex; parietal cortex; plasticity.

Figure 1.

TMS target selection procedure. The M1 targets were selected based on the amplitude of MEP. A rs-fMRI analysis was then performed with the hand knob area as a seed. The maximum correlation with the parietal lobe was selected as our PPC target. A seed was then defined for this PPC area, and an additional rs-fMRI analysis was performed. A right hemisphere CB target was selected based on maximal correlation with the PPC seed. A right VC target with the lowest absolute correlation with left PPC was selected. Correlation maps and targets are depicted on cortical (fsLR; Glasser et al., 2013) and cerebellar (SUIT; Diedrichsen, 2006; Diedrichsen and Zotow, 2015) template surfaces for illustration purposes only. Actual targets were selected in Brainsight using native T1 space correlation maps.

Figure 2.

Experimental design. All participants underwent a rs-fMRI scan before the TMS experiments. The main experiment included 14 subjects who underwent iTBS in two different conditions: EXP_CB (dark blue boxes) and CTRL_VC (red boxes). The iTBS was delivered to a functionally connected CB region in the EXP_CB condition or a nonfunctionally connected VC region in the CTRL_VC condition. This was followed by cPAS to the PPC and the M1 with a 5 ms interstimulus interval (ISI) at 0.2 Hz for ∼8.3 min. Eight participants took part in two additional control experiments. In the CTRL_500ms (light blue boxes) experiment, iTBS was administered to CB and cPAS with a 500 ms ISI. In the CTRL_SHAM (gray boxes) experiment, iTBS was administered with the coil held close to the scalp but angled away from it, and cPAS was given at a 5 ms ISI. MEPs elicited by single-pulse TMS were measured at three different time points: baseline, 10 min after iTBS, and at six different time points for 1 h after cPAS (at 10, 20, 30, 40, 50, and 60 min). The sessions were conducted at least 5 d apart from each other.

Figure 3.

Stimulation targets for each participant are shown in stereotactic space overlaid on a template brain using the Brainsight software (N = 14). A, Dots indicate individual locations for the M1 (orange) and PPC (yellow) for cPAS. B, Dots indicate individual locations for the CB (blue) and VC (red) for iTBS.

Figure 4.

CB iTBS reverses the effect of subsequent parietal–motor plasticity induction protocol. A, Group (N = 14) average change in MEP amplitude for EXP_CB and CTRL_VC at each time point (expressed as percentage change from the average MEP amplitude recorded at the pre-iTBS time point). Error bars (pre-iTBS and post-iTBS) and shaded area (10–60 min Post-cPAS) indicate within-subject standard error (Morey, 2008). B, Sham CB iTBS and sham cPAS cannot explain the effect of CB priming on parietal–motor plasticity induction. Group (CTRL_500ms, N = 7; CTRL_SHAM, N = 8) average change in MEP amplitude at each time point (expressed as percentage change from the average MEP amplitude recorded at the pre-iTBS time point). Error bars (pre-iTBS and post-iTBS) and shaded area (10–60 min post-cPAS) indicate within-subject standard error (Morey, 2008).

Figure 5.

Individual participant time courses. A, Change in MEP amplitude (expressed as percentage change from the average MEP amplitude recorded at the pre-iTBS time point) across time for each subject (colored lines) and condition (EXP_CB and CTRL_VC). Black dots and lines indicate the group average across subjects (same as in Fig. 4A; Morey, 2008). B, Change in MEP amplitude across time for each subject (colored lines) and condition (CTRL_500ms and CTRL_SHAM). Black dots and lines indicate the group average across subjects (same as in Fig. 4B).

Figure 6.

Magnitude and consistency of cerebellar iTBS and PPC–M1 cPAS. Change in MEP amplitude (expressed as percentage change from the average MEP amplitude recorded at the pre-iTBS time point) for each subject who completed both the EXP_CB and the CTRL_SHAM condition (N = 8). The EXP_CB post-iTBS time point reflects the effect of cerebellar iTBS alone and the CTRL_SHAM post-cPAS time points reflect the effect PPC–M1 cPAS alone.