Impaired Cerebellum to Primary Motor Cortex Associative Plasticity in Parkinson's Disease and Spinocerebellar Ataxia Type 3

Abstract

Background: Functional perturbation of the cerebellum (CB)-motor cortex (M1) interactions may underlie pathophysiology of movement disorders, such as Parkinson's disease (PD) and spinocerebellar ataxia type 3 (SCA3). Recently, M1 motor excitability can be bidirectionally modulated in young subjects by corticocortical paired associative stimulation (PAS) on CB and contralateral M1 with transcranial magnetic stimulation (TMS), probably through the cerebello-dentato-thalamo-cortical (CDTC) circuit. In this study, we investigated the CB to M1-associative plasticity in healthy elderly PD and SCA3.

Methods: Ten right-handed PD patients, nine gene-confirmed SCA3 patients, and 10 age-matched healthy controls (HC) were studied. One hundred and twenty pairs of TMS of the left M1 preceded by right lateral CB TMS at an interstimulus interval of 2 (CB → M1 PAS_2ms) and 6 ms (CB → M1 PAS_6ms) were, respectively, applied with at least 1-week interval. M1 excitability was assessed by motor-evoked potential (MEP) amplitude, short-interval intracortical inhibition (SICI), intracortical facilitation (ICF), and cerebellar inhibition (CBI) at the first dorsal interosseous muscle of the right hand before and after the CB → M1 PAS.

Results: The M1 excitability represented by MEP amplitude was significantly facilitated and suppressed in the HC group by CB → M1 PAS_2ms and CB → M1 PAS_6ms, respectively. The bidirectional modulation on MEP amplitude was absent in the PD and SCA3 groups. SICI and the baseline CBI were significantly reduced in the SCA3 group compared to those of the HC group irrespective of the CB → M1 PAS protocols. There was a significant reduction of CBI immediately and 60 min after the CB → M1 PAS protocols in the HC group but not in the patient groups. No significant change of ICF was found.

Conclusion: Corticocortical CB → M1 PAS can induce bidirectional motor cortical plasticity in M1 for healthy aged subjects. The modulation may be independent of the inhibitory neurocircuits, such as SICI and CBI, and the facilitatory mechanism like ICF. Both patients with PD and SCA3 showed impairment of such plasticity, suggesting significant functional perturbation of the CDTC circuit.

Keywords: Parkinson’s disease; cerebellar inhibition; motor cortex; paired associative stimulation; spinocerebellar ataxia type 3.

Figure 1

(A) Motor-evoked potential (MEP) amplitudes (mean ± SEM in mV) recorded from the right first dorsal interosseus muscle in the healthy control (HC), Parkinson’s disease (PD), and spinocerebellar ataxia 3 (SCA3) groups. Comparisons between pre- (B0), immediate (P1), 30 min (P2), and 60 min (P3) post-CB → M1 PAS_2ms vs. CB → M1 PAS_6ms were shown. A significant MEP facilitation at P1 after CB → M1 PAS_2ms and MEP suppression at P1 and P2 after CB → M1 PAS_6ms were noted for the HC group (*P < 0.05 by non-parametric Mann–Whitney U test with Bonferroni’s correction). (B) The averaged MEP waveforms for the 10 subjects in the HC group. (C) Individual MEP data of the HC group (n = 10).

Figure 2

Mean short-interval intracortical inhibition (SICI) [given as percentage of the conditioned motor-evoked potential (MEP)/unconditioned MEP] in the three groups. Note that the spinocerebellar ataxia type 3 (SCA3) group showed a significant reduction of SICI compared to the healthy control (HC) group (*P < 0.05 by non-parametric Mann–Whitney U test).

Figure 3

Mean cerebellar inhibition (CBI) [given as percentage of the conditioned motor-evoked potential (MEP)/unconditioned MEP] in the three groups. In the healthy control (HC) group, there was a significant reduction of CBI at P1 and P3 compared to B0 (*P < 0.05 by non-parametric Mann–Whitney U test). The spinocerebellar ataxia type 3 (SCA3) group showed a significant reduction of the mean CBI compared with the HC group at B0 (^#P < 0.05 by non-parametric Mann–Whitney U test). Compared to the PD group, the HC group showed a significant reduction of the mean CBI at P3 (^#P < 0.05 by non-parametric Mann–Whitney U test).