Low-dose ketamine tilts the cortical excitation--inhibition balance irrespective of systemic physiological response

Non-invasive proxies of cortical excitation--inhibition (E:I) balance, are increasingly used to understand human neural dynamics; especially so the aperiodic (1/f) electroencephalographic (EEG) exponent. Ketamine, an NMDA-receptor antagonist, is thought to shift this balance toward excitation. Propofol, a GABAA-receptor agonist, should behave oppositely. Here we show that these pharmacological manipulations at low doses tilt the noninvasive read-out of E:I balance as predicted, and we demonstrate this effect to be robust against potential mediation by the ketamine-related systemic cardiovascular response. In a single-blind, placebo-controlled crossover study, 25 healthy adults received low, subanesthetic doses of ketamine, propofol, or placebo by target-controlled infusion during resting-state EEG. We further analyzed electrocardiogram (ECG) and dissociating ratings. Ketamine flattened the aperiodic exponent (i.e., a shift toward excitation) and raised heart rate and blood pressure; propofol exerted its effects in the opposite direction, while both agents reduced alpha oscillatory power. Critically, the cardiovascular response did not mediate the cortical E:I shift. Controlling for heart rate left the ketamine effect not only intact but numerically stronger, suggesting that E:I balance findings might even be underestimated when ignoring the systemic physiological response.