Therapeutic use of cerebellar transcranial theta burst magnetic stimulation in movement disorders. Mechanisms of action and biomarkers of efficacy

Movement disorders of different aetiology are characterized by an impairment in several interconnected areas of the motor system. Among the non-pharmacological options to improve motor symptoms, repetitive Transcranial Magnetic Stimulation (rTMS), represent a promising therapeutic tool due to its ability to induce long-term modulation of synaptic plasticity and its low incidence of side effects. Theta burst stimulation (TBS), a patterned protocol of rTMS, is able to induce long lasting excitatory (intermittent TBS) and inhibitory (continuous TBS) effects on cortical excitability and its very tolerable for patients due to its short duration. The high variability of response to TBS limits its use in clinical practice, thus research is focused on the characterization of predictors of response and biomarkers of efficacy. Among these, a common polymorphism of Brain Derived neurotrophic Factor (BDNF) gene, val66met, may influence the onset and progression of several neurodegenerative disorders and may alter the response to different TMS protocols, in particular TBS, but results are conflicting. Cerebellum is considered an interesting area of stimulation for rTMS protocols in movement disorders due to its ability to influence motor learning and control through its connections with all the areas of the motor system and its role in sensory-motor integration. Indeed, it is currently used as a target for neuromodulation in movement disorders involving different pathological mechanisms. The aim of the present study was to test the efficacy of inhibitory and excitatory cerebellar TBS in three movement disorders with different aetiology and to search possible biomarkers influencing its therapeutic effect. In the first project a single session of cerebellar continuous TBS (cTBS) was able to reduce levodopa-induced Dyskinesia in patients affected by Parkinson’s Disease (PD) and this effect was accompanied by a decrease in serum BDNF levels. Moreover, the presence of the Val66Met polymorphism of the BDNF gene was associated with a better response. In the second project 15 sessions of cerebellar intermittent TBS (iTBS) were able to improve motor symptoms in patients affected by Multiple system atrophy (MSA). No variations in serum BDNF levels after iTBS treatment were observed and apparently Val66Met polymorphism did not influence the clinical response. In the third project the excitability of primary motor cortex (M1) was increased by a single session of cerebellar iTBS in patients affected by Spino-Cerebellar ataxia 38 (SCA 38), an inherited disease characterized by mutation in the EVLOV-5 gene. iTBS was then applied for 10 sessions to the cerebellum of patients leading to an improvement of motor symptoms, especially postural stability. The Val66Met polymorphism did not influence the clinical response and the changes in motor cortex excitability. Overall, these data provide evidence for the use of cerebellar TBS in movement disorders; moreover, they suggest that BDNF Val66Met polymorphism may influence response to TBS but results vary depending on experimental model. Finally, they underline that measures of cortical excitability may provide information about the responsivity of the motor network to neuromodulation and may help to select an appropriate therapeutic protocol. Future studies will help to select other genetic, neurophysiological and imaging biomarkers leading to a better prediction and characterization of the clinical response to TBS.