A high-density theta burst paradigm enhances the aftereffects of transcranial magnetic stimulation: Evidence from focal stimulation of rat motor cortex.

BACKGROUND: Theta burst stimulation (TBS) is an efficient noninvasive neuromodulation paradigm that has been widely adopted, clinically. However, the efficacy of TBS treatment remains similarly modest as conventional 10 Hz repetitive transcranial magnetic stimulation (rTMS). OBJECTIVE/HYPOTHESIS: To develop a new TBS paradigm that enhances the effects of TMS administration while maintaining high time-efficiency. METHODS: We describe here a new TMS paradigm, named High-Density Theta Burst Stimulation (hdTBS). This paradigm delivers up to 6 pulses per burst, as opposed to only 3 in conventional TBS, while maintaining the inter-burst interval of 200 ms (or 5 Hz) - a critical parameter in inducing long-term potentiation. This paradigm was implemented on a TMS stimulator developed in-house; its physiological effects were assessed in the motor cortex of awake rats using a rodent specific focal TMS coil. Microwire electrodes were implanted into each rat's limb muscles to longitudinally record motor-evoked potential (MEP). Four different TBS paradigms (3, 4, 5 or 6 pulses per burst, 200 s per session) were tested; MEP signals were recorded immediately before (baseline) and up to 35 min post each TBS session. RESULTS: We developed a stimulator based on a printed-circuit board strategy. The stimulator was able to deliver stable outputs of up to 6 pulses per burst. Animal experiments (n = 15) revealed significantly different aftereffects induced by the four TBS paradigms (Friedman test, p = 0.018). Post hoc analysis further revealed that, in comparison to conventional 3-pulse TBS, 5- and 6-pulse TBS enhanced the aftereffects of MEP signals by 56% and 92%, respectively, while maintaining identical time efficiency. CONCLUSION(S): A new stimulation paradigm is proposed, implemented and tested in the motor cortex of awake rats using a focal TMS coil developed in the lab. We observed enhanced aftereffects as assessed by MEP, with no obvious adverse effects, suggesting the translational potentials of this paradigm.

Focal transcranial magnetic stimulation in awake rats: Enhanced glucose uptake in deep cortical layers.

BACKGROUND: Transcranial magnetic stimulation (TMS) is an emerging neuromodulation tool. However, preclinical models of TMS are limited. OBJECTIVE: To develop a method for performing TMS in awake rats and to characterize neuronal response to TMS by mapping glucose uptake following TMS administration. METHODS: A headpost was implanted into rat skull serving as a refence to guide TMS target. Motor threshold measurement was used as the metric to assess the consistency in TMS delivery across animals and across sessions. Using a fluorescent glucose analogue (2-NBDG) as a marker of neuronal activity, we mapped glucose uptake in response to TMS of the rat motor cortex. RESULTS: The average motor threshold (n = 41) was 34.6 ± 6.3 % of maximum stimulator output (MSO). The variability of motor threshold across animals was similar to what has been reported in human studies. Furthermore, there was no significant difference in motor threshold measured across 3 separate days. Enhancement in fluorescent signals were TMS dose (power)-dependent, which centered around the motor cortex, covering an area medial-laterally 2 mm, rostral-caudally 4 mm at 55 % MSO, and 3 mm at 35 % MSO. The count of total cells with significant fluorescent signal was: 107 ± 23 (55 % MSO), 73 ± 11 (35 % MSO) and 42 ± 11 (sham, 5% MSO). CONCLUSIONS: Our method allows for consistent motor threshold assessment for longitudinal studies. Notably, cells with fluorescent signal enhancement were consistently aggregated in deep cortical layers, with minimal enhancement in superficial layers COMPARISONS WITH EXISTING METHOD(S): To our knowledge, this is the first study of focal TMS in awake rodents.