Translational neuromodulation: approximating human transcranial magnetic stimulation protocols in rats

Abstract

Objective: Transcranial magnetic stimulation (TMS) is a well-established clinical protocol with numerous potential therapeutic and diagnostic applications. Yet, much work remains in the elucidation of TMS mechanisms, optimization of protocols, and in development of novel therapeutic applications. As with many technologies, the key to these issues lies in the proper experimentation and translation of TMS methods to animal models, among which rat models have proven popular. A significant increase in the number of rat TMS publications has necessitated analysis of their relevance to human work. We therefore review the essential principles for the approximation of human TMS protocols in rats as well as specific methods that addressed these issues in published studies.

Materials and methods: We performed an English language literature search combined with our own experience and data. We address issues that we see as important in the translation of human TMS methods to rat models and provide a summary of key accomplishments in these areas.

Results: An extensive literature review illustrated the growth of rodent TMS studies in recent years. Current advances in the translation of single, paired-pulse, and repetitive stimulation paradigms to rodent models are presented. The importance of TMS in the generation of data for preclinical trials is also highlighted.

Conclusions: Rat TMS has several limitations when considering parallels between animal and human stimulation. However, it has proven to be a useful tool in the field of translational brain stimulation and will likely continue to aid in the design and implementation of stimulation protocols for therapeutic and diagnostic applications.

Fig.1. I/O curves for rat TMS MEPs

Data averaged across 13 male adult rats demonstrating MEP metric discrepancy between the contralateral and ipsilateral brachioradialis muscle as a function of TMS intensity. Demonstrates the lower MT of the contralateral target muscle group as well as the ability to activate the contralateral limb without ipsilateral activation. Error bars represent the standard error of the mean; * p < 0.05, ** p < 0.01. Adapted from Rotenberg et al 2010 .

Fig.2. Long interval paired-pulse transcranial magnetic stimulation (LI-ppTMS) inhibitory profile in rats

Graph depicts the conditioned MEP size as a function of both anesthetic and ISI. Values were derived as the conditioned MEP peak-to-peak amplitude normalized to that of the unconditioned MEP. MEP inhibition is represented by values < 100%. Significant inhibition relative to baseline unconditioned MEP values is noted by asterisks (* p < 0.05, ** p < 0.02, *** p < 0.002, **** p ≤ 0.0002). ISIs demarcated with brackets indicate significant intergroup (e.g. interanesthetic) differences (δ < 0.05). Values indicate the mean ± se. Modified from Vahabzadeh-Hagh et al 2011 .

Fig.3. Recent growth in rodent TMS publications

PubMed search was performed from 1966 through December 2010 for “rat(s)”, “tcMMEP”, “TMS”, “rTMS”, “repetitive transcranial magnetic stimulation” and “transcranial magnetic stimulation.” Publications from 2012 were not included as the year was not yet complete at the time of submission.

Fig.4. Trends in stratified rat TMS publications

The articles from the above-mentioned PubMed search were used with the exception of those that did not detail their TMS protocol. 100 articles were used in total. A: Number of publications regarding focal and non-focal TMS over time. B: Number of publications that used TMS on anesthetized versus awake rats. C: Number of publications using single- or paired-pulse TMS, repetitive TMS, or some combination thereof. D: Number of publications stratified by their usage of a circular versus figure-of-eight coil.

Fig.5. Distribution of coil type utilized in rat TMS reports

This pie chart depicts the percentage of reports from among the 100 studies analyzed (supplemental Tables S1, S2, and S3), which utilized different types of TMS coils; namely, circular, figure-of-eight, Helmholtz, or teardrop coils. Since 1995, studies have mainly used the circular or figure-of-eight type coils at a near equal frequency.