Pharmaco fMRI: Determining the functional anatomy of the effects of medication.

Britta Wandschneider,Matthias J Koepp

doi:10.1016/j.nicl.2016.10.002

Britta Wandschneider, Matthias J Koepp

Open Access

https://doi.org/10.1016/j.nicl.2016.10.002

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Abstract

Functional MRI studies have helped to elucidate underlying mechanisms in complex neurological and neuropsychiatric disorders. Disease processes often involve complex large-scale network interactions, extending beyond the presumed main disease focus. Given both the complexity of the clinical phenotype and the underlying dysfunctional brain circuits, so called pharmaco-fMRI (ph-MRI) studies probe pharmacological effects on functional neuro-anatomy, and can help to determine early treatment response, mechanisms of drug efficacy and side effects, and potentially advance CNS drug development. In this review, we discuss recent ph-MRI research in three major neuropsychiatric and neurological disorders and associated network alterations, namely selective serotonin and noradrenergic reuptake inhibitors in affective disorders and emotional processing circuits; antiepileptic drugs in epilepsy and cognitive networks; and stimulants in attention-deficit/hyperactivity disorder and networks of attention control. We conclude that ph-MRI studies show consistent and reproducible changes on disease relevant networks, and prove sensitive to early pharmacological effects on functional anatomy associated with disease. Further CNS drug research and development would benefit greatly from improved disease phenotyping, or biomarkers, using advanced imaging techniques.

Highlights

In functional MRI, reproducible patterns of activation or deactivation elicited by motor, cognitive or other tasks could be identified, such as the default mode network, a set of brain regions, which are commonly deactivated during goal-directed tasks (Bullmore, 2012; Raichle et al, 2001)
A rewarded working memory functional MRI (fMRI) study in healthy controls contrasting the effects of methylphenidate and the noradrenaline reuptake inhibitor atomoxetine demonstrated that both drug effects were context-dependent and showed an interaction with the degree of incentive: In the reward context, both drugs lead to attenuation of working memory networks and enhanced task-dependent deactivation in the default mode network in comparison to placebo
Beyond trials for potentially new CNS drugs, longitudinal imaging studies can capture long-term drug effects on brain circuits, in order to understand whether chronic drug exposure can eventually lead to normalization of brain function, and mechanisms in non-responders, as well as the evolution of treatment resistance to a substance that previously lead to long-term symptom benefit, as e.g. observed in epilepsy

Summary

Introduction

In functional MRI (fMRI), reproducible patterns of activation or deactivation elicited by motor, cognitive or other tasks could be identified, such as the default mode network, a set of brain regions, which are commonly deactivated during goal-directed tasks (Bullmore, 2012; Raichle et al, 2001). This enables to explore disease effects on regional and network functional anatomy, and vice versa, may help to establish consistent (functional) imaging phenotypes of CNS diseases. Imaging phenotypes may provide surrogate markers to, firstly, investigate drug effects at a network level in so called pharmaco-fMRI (ph-MRI) studies and, secondly, to early establish treatment efficacy, dose-response relationships and cognitive side-effects of CNS drugs (Nathan et al, 2014)

Pharmaco-fMRI: concept and challenges

Pharmaco fMRI: functional networks and specific medication effects

Antiepileptic drugs and higher cognitive networks

Stimulants and networks involved in attention control

The use of ph-MRI in CNS drug development

Conclusion