Age-related GABAergic differences in the primary sensorimotor cortex: A multimodal approach combining PET, MRS and TMS

Dante Mantini,Patrick Dupont,Melina Hehl,Koen Van Laere,Koen Cuypers,Sima Chalavi,Mark Mikkelsen,June van Aalst,Stephan P. Swinnen

doi:10.1016/j.neuroimage.2020.117536

Abstract

Healthy aging is associated with mechanistic changes in gamma-aminobutyric acid (GABA), the most abundant inhibitory neurotransmitter in the human brain. While previous work mainly focused on magnetic resonance spectroscopy (MRS)-based GABA+ levels and transcranial magnetic stimulation (TMS)-based GABAA receptor (GABAAR) activity in the primary sensorimotor (SM1) cortex, the aim of the current study was to identify age-related differences in positron emission tomography (PET)-based GABAAR availability and its relationship with GABA+ levels (i.e. GABA with the contribution of macromolecules) and GABAAR activity. For this purpose, fifteen young (aged 20–28 years) and fifteen older (aged 65–80 years) participants were recruited. PET and MRS images were acquired using simultaneous time-of-flight PET/MR to evaluate age-related differences in GABAAR availability (distribution volume ratio with pons as reference region) and GABA+ levels. TMS was applied to identify age-related differences in GABAAR activity by measuring short-interval intracortical inhibition (SICI). Whereas GABAAR availability was significantly higher in the SM cortex of older as compared to young adults (18.5%), there were neither age-related differences in GABA+ levels nor SICI. A correlation analysis revealed no significant associations between GABAAR availability, GABAAR activity and GABA+ levels. Although the exact mechanisms need to be further elucidated, it is possible that a higher GABAAR availability in older adults is a compensatory mechanism to ensure optimal inhibitory functionality during the aging process.

Highlights

Gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the human brain, plays a crucial role in human motor behavior [1,2,3,4]
An increase in GABAA receptors (GABAAR) availability was observed in fibromyalgia patients [49], and this finding was suggested to demonstrate that the GABAARs might even shift functionality from inhibitory to excitatory, a disease mechanism that has been associated with epilepsy [89]
This explanation is rather unlikely in the context of healthy aging as the current study found a positive association between GABAAR availability and GABAAR activity in older adults

Summary

Introduction

Gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the human brain, plays a crucial role in human motor behavior [1,2,3,4]. Aging results in alterations of the GABAergic system and these have been linked with deficits in inhibitory control [5,6,7,8,9,10], such as increased reaction times [11,12,13], impaired motor coordination [1416] and reduced sensorimotor function [17, 18]. Whereas local GABA levels can be accurately quantified using magnetic resonance spectroscopy (MRS), the amount of GABA receptor activity can be assessed by transcranial magnetic stimulation (TMS) [26]. Activity of the fast ionotropic GABAA receptors (GABAAR) or slower acting metabotropic GABABR can be measured with TMS [27,28,29,30]

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