A TMS Paradigm to Measure Visual Cortical Inhibition and Its Application to Aging

Abstract

The neurotransmitter GABA (γ-aminobutyric acid) is the major inhibitory neurotransmitter in the adult human brain. Deficits in GABA-mediated inhibitory function are associated with various motor and psychiatric disorders and may also play a role in age-related cognitive decline. However, there are limited ways of probing GABA and inhibitory function in vivo. While Magnetic Resonance Spectroscopy (MRS) can assess the concentration of GABA, this measure may not be indicative of local inhibitory functioning. Instead, techniques such as paired-pulse Transcranial Magnetic Stimulation (ppTMS) are often used to probe local GABA-mediated inhibitory function. However, ppTMS is almost exclusively used in motor cortex due to the ease-of-measurement and sensitivity of the resulting muscle twitch response. The ability to investigate inhibitory function outside of motor cortex would require adaptation of this technique for use in other cortical regions. While TMS of the motor cortex elicits muscle-twitches, stimulation of primary visual cortex elicits short-lived visual percepts called phosphenes. Previous studies were unable to elicit inhibitory phenomena in visual cortex using phosphenes (Kammer & Baumann, 2010; Ray et al., 1998; Sparing et al., 2005), likely due to a less sensitive measurement system and non-optimal stimulation parameters derived from motor cortex. The objective of this dissertation is to implement and test a new tracing paradigm as a method of measuring the phosphene response, as well as apply this new technique in the realm of aging research.

In the first study of this dissertation, I developed a reliable method of assessing cortical inhibition in visual cortex using phosphenes and ppTMS. Specifically, I demonstrated that a phosphene-tracing procedure can capture subtle increases or decreases in phosphene size. I also determined the proper conditioning stimulus intensity setting (i.e. the magnitude of the first stimulus in each pulse pair) to elicit the strongest inhibitory response.

In the second study, I utilized the ppTMS phosphene-tracing paradigm developed in the first study to explore the temporal dynamics of local inhibitory and facilitatory networks in visual cortex. I determined that certain time intervals between pulse-pair stimuli do not elicit the same response (i.e. inhibition versus facilitation) in visual cortex as it does in motor cortex. Together, the first and second studies pinpoint the optimal paired pulse parameters for measuring cortical inhibition in visual cortex, and suggest that these parameters differ from what is optimal in motor cortex.

In the final study, I conducted a multimodal investigation using ppTMS and MRS to probe both inhibitory function and GABA in the same group of older and younger adults. I determined that ppTMS measures of visual inhibitory activity are reduced with age. Furthermore, I found that MRS measures of GABA and ppTMS measures of cortical inhibition are significantly positively correlated in primary visual cortex. This pattern of results is different from what is observed in primary sensorimotor cortex, where GABAA-mediated inhibitory function remains stable (Bhandari et al., 2016), and ppTMS and MRS measures are uncorrelated (Cuypers et al., 2021; Dyke et al., 2017; Tremblay et al., 2013).

Together, this dissertation demonstrates the feasibility of using ppTMS to assess corticocortical inhibition in a brain region outside of motor cortex. It also provides further insight into how GABAergic signaling changes with age in primary visual cortex, as well as highlights that age-related changes in GABAergic signaling differ in different brain regions.