GABAERGIC MODULATION OF CORTICAL EXCITABILITY ASSESSED VIA TRANSCRANIAL MAGNETIC STIMULATION IN NON-HUMAN PRIMATES

Cortical excitability (CE) is defined as the general responsiveness of the cortex to incoming stimuli. Utilising non-invasive brain stimulation in a translational research framework, we quantified multiple comparable CE indices in awake rhesus macaque monkeys via motor threshold (MT) and recruitment curve (RC) protocols. Additionally, we tested the pharmacological modulation of CE by inhibitory GABA-receptor-specific agents. Using neuronavigation-guided single-pulse TMS on the primary motor cortex with motor-evoked potential (MEP) readout measured from the flexor muscle of the thumb, we implemented both the traditional relative-frequency motor threshold (tradMT) and the Stochastic Approximator of Motor Threshold (SAMT) methods. Then, recruitment curves (RC) were acquired at nine stimulation intensities (50-150% of MT) with 8-10 single-pulses per intensity level in a randomised order. Both MT and RC-derived MT values were stable, reliable and replicable. Systemic administration of GABA_A receptor modulator diazepam (0.1, 0.3, 1 mg/kg, n=4) or GABA_B receptor agonist baclofen (1 or 3 mg/kg, n=5) revealed distinct inhibitory profiles. Diazepam dose-dependently shifted RC to the right at 10 min post-administration (p<0.001). A similar but weaker inhibitory effect was present in only the large dose of RS-baclofen and at much longer waiting times (2 or 4 hrs, p<0.001). Here we demonstrated that human-relevant CE metrics can be successfully implemented in awake monkeys and that RCs highlight differences in the mechanism of GABA_A and GABA_Breceptor modulation. The system-level evaluation of pharmacological interventions supports the development of therapies targeting CE alterations in psychiatric and neurocognitive diseases.