Continuous Theta-Burst Stimulation Intensity Dependently Facilitates Motor-Evoked Potentials Following Focal Electrical Stimulation of the Rat Motor Cortex

Abstract

Although theta-burst stimulation (TBS) is known to differentially modify motor cortical excitability according to stimulus conditions in humans, whether similar effects can be seen in animals, in particular rats, remains to be defined. Given the importance of experimental rat models for humans, this study explored this stimulation paradigm in rats. Specifically, this study aimed to explore corticospinal excitability after TBS in anesthetized animals to confirm its comparability with human results. Both inhibitionfacilitation configurations using paired electrical stimulation protocols and the effects of the TBS paradigm on motor-evoked potentials (MEPs) in rat descending motor pathways were assessed. Paired-stimulation MEPs showed inhibition [interstimulus interval (ISI): 3 ms] and facilitation (11 ms) patterns under medetomidine/midazolam/butorphanol (MMB) anesthesia. Furthermore, while ketamine and xylazine (K/X) anesthesia completely blocked facilitation at 11-ms ISI, inhibition at a 3-ms ISI was preserved. Continuous and intermittent TBS strongly facilitated MEPs depending on stimulus intensity, persisting for up to 25 min under both MMB and K/X anesthesia. These findings are similar to the intracortical inhibition and facilitation observed in the human motor cortex using paired-pulse magnetic stimulation, particularly the glutamate-mediated facilitation phase. However, different TBS facilitatory mechanisms occur in the rat motor cortex. These different TBS facilitatory mechanisms affect the comparability and interpretations of TBS between rat and human models.

Blockade of Motor Cortical Long-Term Potentiation Induction by Glutamatergic Dysfunction Causes Abnormal Neurobehavior in an Experimental Subarachnoid Hemorrhage Model

“…Seven days before testing, the rats were deeply intraperitoneally anesthetized with a combination of medetomidine/midazolam/butorphanol anesthesia (0.15/2.0/5.0 mg/kg, respectively). The anesthetic conditions were continuously verified through the experiment (maintained during electrode implantation, SAH induction and during data recording 7 days after) in all animals (Fujiki et al, 2004(Fujiki et al, , 2020aQin et al, 2015;Mishra et al, 2017). Briefly, the absence of pedal withdrawal (''toe-pinch'') reflex was used for assessment of anesthesia and analgesia depth, and the body temperature was maintained at 37 • C intra-and postoperatively with a temperature-controlled heating pad.…”

“…MEPs were continuously recorded from the contralateral right biceps brachii muscle via wire-electrodes, as per previously described methods (Fujiki et al, 2004(Fujiki et al, , 2020aMishra et al, 2017). Electrode setting and base-MEP recordings were performed before the induction of SAH.…”

“…Intracortical inhibition or facilitation [short-latency intracortical inhibition (SICI) and intracortical facilitation (ICF)] were tested using a paired electrical and subthreshold conditioning stimulus (CS) preceding a suprathreshold test stimulus (TS) after resting motor threshold (RMT) determination (Kujirai et al, 1993;Rothwell, 1997;Fujiki et al, 2020a). The RMT was measured by varying the stimulator output by 0.1-mA-step until six stable peak-to-peak-50 µV-MEP elicitations were obtained for every FIGURE 1 | Schematic illustration of the experimental protocol and stimulus configurations.…”

“…12 trials. Two isolated stimulators connected with acustom-made single-stimulus-electrode switching unit were controlled for appropriate stimulus intervals (1,2,3,5,7,11,13, and 15 ms) and intensity (0.5-1.2 mA) in a similar manner as paired TMS (Vahabzadeh-Hagh et al, 2011;Hsieh et al, 2012;Fujiki et al, 2020a). The animals were humanely sacrificed after data collection with an overdose of anesthetic prior to decapitation.…”

“…The brains were then prepared for verification of electrode position and histological evaluation after SAH. High-frequency stimulation (QTS5, QPS5, and OPS2.5) was delivered at an intensity of 75%-RMT (0.5-1.2 mA; Yang et al, 2019;Fujiki et al, 2020a) for 1,440 pulses and post stimulus-continuous MEPs were recorded at 0.1 Hz for 60 or 180 min. The no-stimulation condition was produced by unplugging the electrodes while the high-frequency stimulation protocol was carried out.…”