The Effect of Theta-Gamma Coupling on Response to Cognitive Remediation Combined with Transcranial Direct Current Stimulation in Older Adults at High Risk for Dementia: a PACt-MD Secondary Analysis

The PACt-MD study demonstrated that combined cognitive remediation (CR) and transcranial direct current stimulation (tDCS) slows global cognitive decline in individuals with mild cognitive impairment (MCI) or remitted major depressive disorder (rMDD) over a median follow-up of four years. Prefrontal theta-gamma coupling (TGC), measured via electroencephalography (EEG), is a marker of prefrontal cortical function and may index cognitive compensation, the mechanism thought to underlie CR+tDCS effects. This secondary analysis investigated whether baseline TGC influenced the efficacy of CR+tDCS, hypothesizing that participants with high baseline TGC-indicating better prefrontal function-would benefit more from CR+tDCS than those with low baseline TGC. TGC was assessed during an N-back task at baseline in 260 participants (mean age=71.9, SD = 6.0) and dichotomized by median split into high vs low groups. Cognition was evaluated two months post-baseline and annually up to six years. Baseline TGC significantly moderated the effects of CR+tDCS on global cognition (χ²=12.46, p = 0.006), verbal memory (χ²=16.93, p = 0.0007), and executive function (χ²=18.57, p = 0.0003). In the high-TGC group, global cognition declined more slowly with active CR+tDCS compared to sham. No such difference was observed in the low-TGC group. Lower baseline TGC may reflect reduced capacity for cognitive compensation, limiting CR+tDCS effectiveness in at-risk older adults. Higher TGC may identify those most likely to benefit from this intervention. ClinicalTrials.gov Identifier: NCT02386670.