Objective: To test whether the non-responder or responder status of primary motor cortex (M1) to an LTP- inducing paired associative stimulation (PAS) protocol in healthy young adults is a fixed state or is reversible if primed by cerebellar stimulation.

Background: The average response of M1 to PAS is reportedly age-dependent but 15-30% of young adults are non responders which questions the role of age. The non responder status was also suggested to be influenced by genetic polymorphism in BDNF.

Method: 19 right-handed subjects were classified as 8 responders (25.5 ± 7.5 years) and 11 non responders (23.7± 2.1years) to PAS applied to left M1 in the session 1. In sessions 2 and 3 in random order, PAS protocol was preceded 5 minutes by either a continuous theta burst stimulation (cTBS CB-PAS) or intermittent theta burst stimulation (iTBS CB-PAS) applied to the right cerebellum. Motor thresholds and short interval intracortical inhibition (SICI) were tested at baseline and after each of these interventions.

Results: In non-responders, cTBS CB-PAS enhanced the MEPs (P<0.0001) while iTBS CB-PAS depressed the MEPs (P = 0.03 ). In responders, cTBS CB did not change the amplitude of the MEPs (P = 0.8) while iTBS CB depressed the MEPs (P<0.0001). Thus, non responders to PAS could convert to responders if cTBS CB preceded PAS. Similarly, responders to PAS could become non responders if iTBS CB preceded PAS. In the whole group, higher levels of LTP-like response to PAS was associated with higher level of SICI following PAS. Higher levels of LTP-like response to cTBS CB-PAS in non responders was also associated with a stronger SICI.

Conclusion: These results show that response or lack of it to PAS at M1 is not a fixed status as it is likely to be,among other factors, under cerebellar influence. Thus basal activities in the cerebello-cortical circuit can influence susceptibility of synapses in M1 to undergo LTP/LTD. Such a flexibility raises the issue of how to interpret a change in the amount of PAS response in pathophysiology studies as it may be related to a local (M1) or remote (cerebellum) pathology. In physiological conditions such a flexibility maybe relevant for motor learning and for consolidation of correct motor memories.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/to-respond-or-not-to-respond-to-paired-associative-stimulation-proof-of-intervention-by-cerebello-cortical-circuit/