Investigation and modulation of cortical excitability in awake rhesus macaques with non-invasive transcranial magnetic stimulation and electroencephalography

Disruption in the excitatory and inhibitory (E/I) balance of cortical networks is well-characterised in age-related neurocognitive disorders (NCD), impacting functional cognitive decline. Thus, utilising non-invasive transcranial magnetic stimulation (TMS) and electroencephalography (EEG) methods, similarly applicable in both patients and translationally relevant preclinical animal models, we established baseline cortical excitability in rhesus macaques, followed by modulation of the E/I balance by diazepam (GABAA PAM).We recorded scalp-EEG from 27 electrodes by a telemetric amplifier system determining baseline state based on minimum 20 sessions. In parallel, after establishing reliable individual motor thresholds (MT) using electromyography (within-subject SD: 2.12%, Intraclass Correlation Coefficient: 0.801), we recorded two consecutive input-output (I/O) curves with 8 single-pulses at multiple stimulation intensities (50-150% of MT) semi-randomly ordered.Following intramuscular administration of diazepam in 3 doses (0.1, 0.3 and 1mg/kg), a marked dose-dependent increase in low-frequency (alpha-beta) oscillatory power and a decrease in high-frequency (gamma) power was observed in scalp-EEG, indicating an inhibitory shift of the E/I balance. Correspondingly, the first I/O curve (10min post-administration) shifted to the right, showing a similarly pronounced decrease in excitability with statistically significant main effects (stimulation levels (F1,382=84.12, p<0.001), the treatment (F3,382=28.00, p<0.001)), and no interaction (F 3,382=1.11, p=0.344).In summary, combining data analysis of scalp-EEG and single-pulse TMS offers a complementary and reliable preclinical research method for investigating physiological baseline state and modulations of cortical excitability and E/I balance. Furthermore, by deepening our understanding in a translational context, a potential way for improved treatment options in NCDs is paved.