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. 2021 Feb 1:226:117536.
doi: 10.1016/j.neuroimage.2020.117536. Epub 2020 Nov 10.

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

Koen Cuypers  1 , Melina Hehl  2 , June van Aalst  3 , Sima Chalavi  2 , Mark Mikkelsen  4 , Koen Van Laere  3 , Patrick Dupont  5 , Dante Mantini  6 , Stephan P Swinnen  7
Affiliations

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

Koen Cuypers et al. Neuroimage. .

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.

Keywords: Aging; GABA; MRS; PET; TMS.

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Figures

Fig. 1.
Fig. 1.
Overview of the magnetic resonance spectroscopy (MRS) [and similar for positron emission tomography (PET)] voxel positions and raw spectra for older and young adults. The color bar indicates the overlap of the individual voxels, with bright color indicating a high overlap and dark color a low overlap. The GABA+ peak is expected at 3.0 parts per million (ppm) of the proton frequency and is highlighted in gray.
Fig. 2.
Fig. 2.
Gamma-aminobutyric acid type A (GABAAR) availability for the left primary sensorimotor (SM1) voxel expressed in distribution volume ratio (DVR) values of [11C]flumazenil in older (yellow bar) and young (blue bar) adults. Black dots represent the individual median DVR values. Bar plots refer to the median values; error bars represent the standard deviation.
Fig. 3.
Fig. 3.
Tissue-corrected gamma-aminobutyric acid with the contribution of macromolecules (GABA+) levels [institutional units (I.U.)] in the left primary sensorimotor (SM1) voxel in older (yellow bar) and young (blue bar) adults. Black dots represent the individual GABA+ levels. Bar plots refer to the mean values; error bars represent the standard deviation.
Fig. 4.
Fig. 4.
short-interval intracortical inhibition (SICI) in the left primary motor cortex (M1) in older (yellow bar) and young (blue bar) adults. Black dots represent individual SICI values. Bar plots refer to the mean values; error bars represent the standard deviation. SICI was defined as: (1 − [Motor evoked potential (MEP)paired-pulse/MEPsingle-pulse]) * 100. Higher positive values indicate higher inhibition, while higher negative values indicate higher disinhibition. The right part of the figure illustrates the SICI principle. MEPsingle-pulse is assessed after administering a single test stimulus (TS) (visualized as the green ‘lightning’). MEPpaired-pulse is obtained when the TS is preceded by a conditioning stimulus (CS) (visualized as the red ‘lightning’).
Fig. 5.
Fig. 5.
Illustration of the associations between positron emission tomography (PET)-based gamma-aminobutyric acid type A (GABAAR) availability in left primary sensorimotor (SM1) voxel, magnetic resonance spectroscopy (MRS)-based GABA with the contribution of macromolecules (GABA+) levels [institutional units (I.U.)] in the left SM1 voxel and TMS-based GABAAR activity in the left primary motor cortex (M1) in young and older adults. The critical p-value is 0.025 (based on the Bonferroni correction for multiple comparisons). $ indicates that a Spearman correlation test was used instead of a Pearson correlation test.
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