Abstract
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.
Highlights
The efficacy of psychopharmacological treatment is often considerably restricted by the fact that drugs reach both pathologically relevant and irrelevant brain areas in a non-selective manner, causing desired and unwanted effects
Cognitive performance in executive functions tasks was measured according to the NeuroTrax attention index, which did not differ between MPH and Placebo [97.216 and 100.441, respectively, t(12) = −1.04, p = 0.32], suggesting that the cognitive challenge was effective in both drug conditions
To examine the potential of this concept in the case of MPH, we coupled the administration of the drug with a demanding cognitive task and tested drug targeting effects with executive function task performance and its related right dorsolateral prefrontal cortex (rDLPFC) fMRI BOLD activity
Summary
The efficacy of psychopharmacological treatment is often considerably restricted by the fact that drugs reach both pathologically relevant and irrelevant brain areas in a non-selective manner, causing desired and unwanted effects. We coupled drug administration with the introduction of external psychological stimuli that activate the drug’s target brain regions We hypothesized that this coupling (termed hereby Functional Pharmacology) would result in the enhancement of the expected drug effect. In light of the involvement of the DLPFC in performance of the cognitive task we employed (Berridge and Devilbiss, 2011), and considering evidence that MPH may produce sustained increases in extracellular levels of dopamine (Berridge et al, 2006) and indirectly stimulate D1 receptors in the prefrontal cortex (Gamo et al, 2010), we regard rDLPFC activation as a relevant neural index for functionalpharmacological coupling in this case
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