Genetic influences on the variability of response to repetitive transcranial magnetic stimulation in human pharyngeal motor cortex

Background: Recent studies have reported substantial variability in response to repetitive transcranial magnetic stimulation (rTMS). We hypothesized that an individual's genetic predisposition may contribute to such variability in the pharyngeal motor cortex. This study aimed to investigate the response to 1 and 5 Hz rTMS paradigms on pharyngeal motor cortex in healthy participants and its relationship with genetic predisposition.Methods: Forty-one healthy participants (25.4 ± 4.6 years old) received either or both 1 Hz (n = 39) and 5 Hz rTMS (n = 40) over pharyngeal motor cortex. Pharyngeal and thenar motor–evoked potentials were recorded at baseline and for 1 hour post-rTMS. The participants were then classified according to their response. The associations between rTMS response and gender, time of day of the stimulation, and eight prespecified single nucleotide polymorphisms (SNPs) were analyzed.Key Results: There was no direction-specific response to either paradigm (1 Hz: F[3.69, 129.21] = 0.78, P = 0.56; 5 Hz: F[4.08, 146.85] = 1.38, P = 0.25). Only 13% of participants showed the expected bidirectional response (inhibition for 1 Hz and excitation for 5 Hz). Significant associations were found between response and COMT (1 Hz: P = 0.03) and DRD2 (1 Hz: P = 0.02; 5 Hz: P = 0.04) polymorphisms. Carriers of minor allele G from SNP rs6269 (COMT) were more likely to show inhibitory or excitatory outcomes after 1 Hz rTMS. By contrast, carriers of minor allele A from SNP rs1800497 (DRD2) were more likely to show no response to 1 Hz rTMS and inhibition after 5 Hz rTMS.Conclusions & Inferences: Two SNPs from COMT and DRD2 genes may partially explain the response variability to rTMS in the pharyngeal motor system. Further research should focus on stratified approaches for neurostimulatory dysphagia treatment using rTMS

Active Zone Protein Bassoon Co-Localizes with Presynaptic Calcium Channel, Modifies Channel Function, and Recovers from Aging Related Loss by Exercise

The P/Q-type voltage-dependent calcium channels (VDCCs) are essential for synaptic transmission at adult mammalian neuromuscular junctions (NMJs); however, the subsynaptic location of VDCCs relative to active zones in rodent NMJs, and the functional modification of VDCCs by the interaction with active zone protein Bassoon remain unknown. Here, we show that P/Q-type VDCCs distribute in a punctate pattern within the NMJ presynaptic terminals and align in three dimensions with Bassoon. This distribution pattern of P/Q-type VDCCs and Bassoon in NMJs is consistent with our previous study demonstrating the binding of VDCCs and Bassoon. In addition, we now show that the interaction between P/Q-type VDCCs and Bassoon significantly suppressed the inactivation property of P/Q-type VDCCs, suggesting that the Ca2+ influx may be augmented by Bassoon for efficient synaptic transmission at NMJs. However, presynaptic Bassoon level was significantly attenuated in aged rat NMJs, which suggests an attenuation of VDCC function due to a lack of this interaction between VDCC and Bassoon. Importantly, the decreased Bassoon level in aged NMJs was ameliorated by isometric strength training of muscles for two months. The training increased Bassoon immunoreactivity in NMJs without affecting synapse size. These results demonstrated that the P/Q-type VDCCs preferentially accumulate at NMJ active zones and play essential role in synaptic transmission in conjunction with the active zone protein Bassoon. This molecular mechanism becomes impaired by aging, which suggests altered synaptic function in aged NMJs. However, Bassoon level in aged NMJs can be improved by muscle exercise