tDCS-Induced Modulation of GABA Levels and Resting-State Functional Connectivity in Older Adults

Abstract

Transcranial direct current stimulation (tDCS) modulates human behavior, neuronal patterns, and metabolite concentrations, with exciting potential for neurorehabilitation. However, the understanding of tDCS-induced alterations on the neuronal level is incomplete, and conclusions from young adults, in whom the majority of studies have been conducted, cannot be easily transferred to older populations. Here, we investigated tDCS-induced effects in older adults (N = 48; age range, 50-79 years) using magnetic resonance spectroscopy to quantify GABA levels as well as resting-state functional magnetic resonance imaging to assess sensorimotor network strength and interhemispheric connectivity. In a randomized, counterbalanced, crossover design, we applied anodal tDCS (atDCS), cathodal tDCS (ctDCS), and sham tDCS (stDCS) over the left sensorimotor region. We observed a significant reduction of GABA levels after atDCS compared with stDCS, reflecting the preserved neuromodulatory effect of atDCS in older adults. Moreover, resting-state functional coupling was decreased during atDCS compared with stDCS, most likely indicating augmented efficiency in brain network functioning. Increased levels of interhemispheric connectivity with age were diminished by atDCS, suggesting stimulation-induced functional decoupling. Further, the magnitude of atDCS-induced local plasticity was related to baseline functional network strength. Our findings provide novel insight into the neuronal correlates underlying tDCS-induced neuronal plasticity in older adults and thus might help to develop tDCS interventions tailored to the aging brain.SIGNIFICANCE STATEMENT Transcranial direct current stimulation (tDCS) modulates human behavior, neuronal patterns, and metabolite concentrations, with exciting potential for neurorehabilitation. However, the understanding of tDCS-induced alterations on the neuronal level is incomplete, and conclusions from young adults cannot be easily transferred to older populations. We used a systematic multimodal imaging approach to investigate the neurophysiological effects of tDCS in older adults and found stimulation-induced effects on GABA levels, reflecting augmented local plasticity and functional connectivity, suggesting modulation of network efficiency. Our findings may help to reconcile some of the recent reports on the variability of tDCS-induced effects, not only implicating age as a crucial modulating factor, but detailing its specific impact on the functionality of neural networks.

Keywords: aging; magnetic resonance spectroscopy; plasticity; sensorimotor network; transcranial electrical stimulation.

Figure 1.

Illustration of experimental design, electrode montage for tDCS, and voxel positioning for MRS. A, Experimental design; all subjects underwent atDCS, ctDCS, and stDCS sessions separated by at least 1 week; the order of stimulation conditions was counterbalanced. GABA was measured immediately before and after tDCS, and resting-state fMRI was assessed during tDCS. B, tDCS montage; active electrode over the left sensorimotor cortex (according to the 10-20 EEG system; C3), reference electrode over the right supraorbital area (sizes, 5 × 7 and 10 × 10 cm²). C, MRS voxel positioning on an individual T1-weighted scan over the left sensorimotor area. Voxel size: 22 × 22 × 22 mm³. T1w, T1-weighted scan.

Figure 2.

Results from MRS acquisition for GABA and Glu levels. A, C, Sample magnetic resonance spectra from the sensorimotor voxel. MEGA-PRESS difference spectrum (A) and MEGA-PRESS unedited spectrum (C). Top lines of each figure box represent the original spectrum and the fit, respectively. Also shown are fits for GABA and Glu, as well as the background. The small residuals reflect the high quality of the fits. B, Change of GABA levels by condition. GABA levels after atDCS were significantly reduced compared with stDCS. D, Change of Glu levels by condition. GABA and Glu level changes as ratios to tCr normalized to sham condition (z-values). Error bars represent the 95% CI. *p ≤ 0.05.

Figure 3.

Results from rs-fMRI acquisition for interhemispheric functional connectivity and sensorimotor network strength. A, Illustration of left and right ROIs in the sensorimotor cortex. ROIs were derived individually from MRS voxel center coordinates (flipped around the midline for right ROI). B, Interhemispheric connectivity by condition (Fisher r to z values). C, Sensorimotor network as derived from ICA analysis. D, Strength in the sensorimotor network by condition (arbitrary units). Error bars represent the 95% CI. *p ≤ 0.05.

Figure 4.

Relationship between GABA and sensorimotor network strength. A, Association between baseline GABA levels and baseline SMN strength, separately for YO and OO adults (median split by 63 years of age). Note that for the YO group sensitivity analysis without the outlier yielded a similar Pearson's correlation coefficient (r₍₁₇₎ = −0.468, p = 0.058). B, Association between tDCS-induced change of local GABA levels (stDCS minus atDCS; larger numbers represent a higher disinhibitory effect produced by atDCS) and baseline SMN strength, separately for YO and OO adults. GABA level was given as a ratio to tCr. *p ≤ 0.05, **p ≤ 0.01, #p ≤ 0.10.