Inducing a Functional-Pharmacological Coupling in the Human Brain to Achieve Improved Drug Effect

Neuropharmacotherapy is substantially hindered by poor drug targeting, resulting in low specificity and efficacy. It is known that different behavioral tasks increase functional activity and cerebral blood flow (CBF), two key parameters controlling drug delivery and efficacy. Here, we tested a novel, non-invasive drug targeting approach (termed functional-pharmacological coupling), which couples drug administration with a task that is known to specifically activate the drug’s sites-of-action in the brain. In two studies we administered Methylphenidate (MPH) to neurotypical adults and to subjects with attention deficit hyperactivity disorder (ADHD). In study 1 we employed a within-subject factorial design and found that only following MPH administration, subjects that performed better in the cognitive induction task showed greater improvements in N-back performance. Moreover, only under MPH-Cognitive induction condition, this improvement correlated with concurrent N-Back rDLPFC activation. In Study 2, subjects with ADHD performed better on sustained attention when MPH administration was followed by a cognitive challenge rather than a control task. Again, those who were more attentive to the cognitive challenge scored higher. Our results provide preliminary support for the feasibility of functional-pharmacological coupling concept, hence opening a new horizon for patient-tailored, context-driven drug therapy.