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  • Review Article
  • Published:

A role for fMRI in optimizing CNS drug development

Nature Reviews Drug Discovery volume 5, pages 411–425 (2006)Cite this article

Key Points

  • Functional MRI (fMRI) has fundamentally changed the way that we can question brain systems because we can see them in action, bringing systems neuroscience to life. fMRI lets neuroscientists visualize the activity of neural networks that underlie human behaviour and development.

  • fMRI is an indirect measure of neural activity that can be used to evaluate disease states as well as drug function in awake humans and animals.

  • Current problems with the translation of animal behaviour (assays) to the human condition might be overcome by using a circuit-based approach to define objective changes in neural systems.

  • fMRI is able to dissect complex brain function in terms of temporally coordinated activation of related neurocircuits rather than dissociated events associated with disparate nuclei. fMRI has given new dimensions to many areas of complex brain function such as pain, sensory systems, psychiatric disorders and their co-morbidity with other central nervous system (CNS) conditions, cognition, language consciousness and neural mechanisms that underlie the developmental plasticity of the brain or its recovery of function after trauma.

  • fMRI can report on the functional neuroanatomy of the brain and, in combination with targeted therapeutic agents, provide novel insights into CNS neuropharmacology that could inform the drug development process from preclinical stages to clinical evaluation.

  • Whole-system effects allow for the evaluation of drug effects or disease states over time, conferring a better understanding of the long-term effects of drugs by objective measures of these circuits.

Abstract

Drug development today needs to balance agility, speed and risk in defining the probability of success for molecules, mechanisms and therapeutic concepts. New techniques in functional magnetic resonance imaging (fMRI) promise to be part of a sequence that could transform drug development for disorders of the central nervous system (CNS) by examining brain systems and their functional activation dynamically. The brain is complex and multiple transmitters and intersecting brain circuits are implicated in many CNS disorders. CNS therapeutics are designed against specific CNS targets, many of which are unprecedented. The challenge is to reveal the functional consequences of these interactions to assess therapeutic potential. fMRI can help optimize CNS drug discovery by providing a key metric that can increase confidence in early decision-making, thereby improving success rates and reducing risk, development times and costs of drug development.

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Figure 1: Locus of imaging in drug development ? from disease to genomics and back again.
Figure 2: Functional neuropathomics ? integrating brain function.
Figure 3: The language of translation ? circuits not behaviour.
Figure 4: Functional brain arrays.
Figure 5: Surrogate models in drug evaluation.
Figure 6: Clinical applications in Phase I studies: enhanced information for go/no-go decisions.
Figure 7: Application of a defined systems approach to models and disease in humans.

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Acknowledgements

We would like to thank K. Moldoff (www.galeriekirk.com) for kind permission to reproduce some of his graphics for this review.

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Authors and Affiliations

  1. Mclean Hospital Department of Psychiatry, Massachusetts General Hospital Department of Radiology, Imaging Center for Drug Development (ICD), Harvard Medical School,

    David Borsook & Lino Becerra

  2. Imaging, Merck & Co. Inc., West Point, Pennsylvania, 19486, USA

    Richard Hargreaves

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Competing interests

D.B. and L.B. have received unrestricted grant support from Merck Research Laboratories and a grant from the National Institutes of Neurological Diseases and Stroke. R.H. is a full-time employee of Merck & Co. Inc.

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Glossary

Functional magnetic resonance imaging

An MRI technique that uses metabolic-induced capillary blood flow changes caused by neuronal activity to produce images reflecting such activity. Activation can be correlated with brain structures as determined by these images.

Molecular imaging

An imaging technique in which cellular/molecular processes have been tagged in such a way that they can be non-invasively imaged.

Positron-emission tomography

(PET). A dual-photon nuclear imaging technique in which radioactive tracers are administered in non-pharmacologically active doses to subjects and images are created that reveal brain blood flow, glucose metabolism or fractional receptor binding by drugs.

Single-photon-emission computed tomography

(SPECT). A nuclear imaging technique in which radioactive tracers generating single photons of a specific energy are administered to subjects to produce images. SPECT can give information about blood flow to tissues, molecular targets, and chemical reactions (metabolism) in the body.

Neuroinformatics

A field that deals with data structure and software tools devoted to the analysis and integration of neuroscience.

Gyrencephalic species

Mammalian species that have developed cerebrums in which gyri and sulci can be defined.

Functional neuropathomics

Intended to define the underlying pathophysiology in neural conditions at a systems level.

Functional neuromics

Defining the functional components of normal neural function at a systems level.

Functional classifiers

Drugs can act on neural networks or systems in a particular fashion ? for example, produce sedation, euphoria or analgesia. Activation patterns that show specific regions of the brain known to be involved in a particular function allow for the segregation or functional classification of drug action.

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Borsook, D., Becerra, L. & Hargreaves, R. A role for fMRI in optimizing CNS drug development. Nat Rev Drug Discov 5, 411–425 (2006). https://doi.org/10.1038/nrd2027

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