Effects of High Definition-Transcranial Direct Current Stimulation on Local GABA and Glutamate Levels Among Older Adults with and without Mild Cognitive Impairment: An Exploratory Study

Abstract

Background: Prior research, primarily with young adults, suggests transcranial direct current stimulation (tDCS) effects are driven by the primary excitatory and/or inhibitory neurotransmitters, glutamate, and gamma-aminobutyric acid (GABA), respectively.

Objective: We examined the neurometabolic mechanisms of tDCS in older adults with and without mild cognitive impairment (MCI).

Methods: We used data from a double-blind, cross-over, randomized controlled trial (NCT01958437) in 32 older adults to evaluate high definition (HD)-tDCS-induced changes in glutamate and GABA via magnetic resonance spectroscopy (MRS). Participants underwent MRS following two counterbalanced HD-tDCS sessions (one active, one sham) that targeted the right superior parietal cortex (center anode at P2) and delivered 2mA for 20 minutes.

Results: Relative to sham, and when co-varying for MRS voxel overlap and right superior parietal volume, active HD-tDCS significantly increased GABA and decreased the ratio of glutamate to GABA. No changes were observed in a left prefrontal control MRS voxel. Although we did not find a significant correlation between strength of delivered current (measured via MRI-based computational modeling) and neurometabolite change, there was a robust positive relationship between the volume of right superior parietal cortex and neurometabolite change.

Conclusion: Our preliminary findings of increased GABA and reduced glutamate/GABA ratio raise the possibility that (HD-)tDCS effects differ by age. Moreover, age- and disease-related regional brain volume loss may be especially important to consider when planning future studies. Replication would emphasize the importance of developing population-specific tDCS parameters that consider structural and physiologic changes associated with "normal" and pathological aging.

Keywords: Aging; magnetic resonance spectroscopy; mild cognitive impairment; neuromodulation; neurotransmitters; transcranial electrical stimulation.

Figures

Figure 1.

Illustration of (a) experimental design, (b) electrode locations based on international 10–10 electrode system, and (c) electric field arising from the montage via ROAST. Note: Intended location of MRS voxels are depicted in red (P2) and green (F5 – control voxel) boxes in Figure 1b.

Figure 2.

Examples of left frontal (F5; top) and right parietal (P2; bottom) voxel locations. Example spectral data shown for full spectrum with GLX identified (left) and GABA (right) (note: only GABA was acquired at the F5 voxel).

Figure 3.

(a) Mean EF values within the P2 1 cm3 ROI across participants. (b) Percent differences in EF relative to participant with lowest EF. (c) ROAST EF models of two participants illustrating striking variability in EF values. (d) Relationships between EF and degree of change in excitatory to inhibitory neurotransmitters (i.e., glutamate/GABA ratio) for the Healthy Control and MCI groups, covarying for MRS overlap and P2 Volume. (e) Relationship between P2 Volume and degree of change in excitation (i.e., glutamate to GABA ratio) for the Healthy Older Adult (HOA) and MCI groups.