Concurrent assessment of neurometabolism and brain hemodynamics to characterize the functional brain response to psychotropic drugs: an S-ketamine study

Neuroimaging techniques offer valuable insights for understanding pharmacological treatment effects in neuropsychiatric disorders. Here, we present a novel approach that simultaneously assesses hemodynamic and neurometabolic brain responses to psychotropic drugs using interleaved pharmacological magnetic resonance imaging (phMRI) and pharmacological magnetic resonance spectroscopy (phMRS). This method was tested using a double-dose, placebo-controlled, randomized, crossover design using S-ketamine as the pharmacological agent. We acquired 7 Tesla phMRI and phMRS data to evaluate time- and dose-dependent effects of S-ketamine in 32 healthy controls. S-ketamine elicited robust phMRI responses in the dorsofrontal, cingulate, and insular cortices, which correlated with glutamate and opioid receptor maps and subjective dissociation scores. These hemodynamic changes were paralleled by increases in glutamate and lactate, especially at higher doses. Furthermore, accuracy in predicting received condition (placebo, a low, or a high S-ketamine dose) increased when combining both techniques. Here, we show for the first time that concurrent phMRI and phMRS assessments provide important complementary insights into the functional brain response to pharmacological interventions.