Nature Reviews Drug Discovery | AOP, published online 7 April 2006; doi:10.

1038/nrd2027 REVIEWS

A role for fMRI in optimizing CNS

drug development
David Borsook*, Lino Becerra* and Richard Hargreaves‡
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.

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.
*Imaging Center for
Drug Development (ICD),
Mclean Hospital Department
of Psychiatry, Massachusetts
General Hospital Department
of Radiology, Harvard
Medical School.
‡
Imaging, Merck & Co. Inc.,
West Point, Pennsylvania
19486, USA.
e-mails: dborsook@mclean.
harvard.edu; lbecerra@
mclean.harvard.edu;
richard_hargreaves@
merck.com
doi:10.1038/nrd2027
Published online 7 April 2006
There is a clear need to fundamentally change drug
discovery paradigms to meet today’s healthcare
needs1–3. The past 20 years, which included the ‘decade
of the brain’ (the 1990s), has seen the development of
few novel therapeutic agents for CNS disorders. Indeed,
many of the drugs coming to market have been derived
from the pharmacology of older agents with proven
clinical utility with the aim of improving potency,
tolerability or ease of administration. Drug develop-
ment in the CNS domain has to overcome a number
of challenging barriers, not the least of which is the
inaccessibility of the brain itself, when evaluating the
consequences of drug–target interactions. The lack of
facile surrogate endpoints for potential CNS therapeu-
tics means that making the right choice of targets and
molecules for development is crucial4. For the CNS, the
problem is also confounded by the paucity of processes
and technologies that can provide a true translational
bridge between preclinical studies and subsequent clin-
ical testing and evaluation5. A functional approach such
as functional magnetic resonance imaging (fMRI) provides a
‘systems neuroscience’ evaluation of the circuitry that
underlies the behavioural effects of a drug, independ-
ent of its specific biochemical mechanism of action.
Indeed, many CNS drugs have multiple mechanisms of
action and can vary in efficacy across the CNS targets
with which they interact. fMRI monitors the combined
or integrated effect of these interactions across multiple
brain systems and thereby reflects activity of the true
neural circuitry that drives behaviour.
fMRI of the brain measures changes in the blood
oxygenation levels in microcirculation. This provides
an indirect measure of neural activity (BOXES 1 , 2) .
It can be performed in awake animals and humans, and
provides information about neural circuit activity in
response to specific, reproducible and well-character-
ized stimuli that can serve as a ‘fingerprint’ of specific
function. Such fingerprinting can be applied to neural
circuits involved in drug action or disease states. The
big question is whether fMRI can help provide the
focus and level of specific functionality to guide CNS
drug development. This review critically evaluates the
potential of fMRI at different stages during the pre-
clinical-to-clinical drug development process (BOX 3)
to assess its potential to engender a paradigm shift in
CNS drug discovery by providing early knowledge that
validates therapeutic concepts and rationally endorses
candidate molecule choices.
Brain circuits — functional arrays
Gene-expression signatures have helped identify patterns
of cellular pathway control and dysregulation, thereby
opening the possibility of designing targeted thera-
pies that match disease mechanisms more precisely6.
Similarly, an understanding of the functional neural
circuits and the interactions between them that drive
CNS behaviour in health and disease could lead to the
development of novel circuit-specific drugs, rather than
today’s pharmacologically selective agents. This could
provide a rationale for the selection of combinations of

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neural circuits, including regions involved in emotion

Box 1 | Functional MRI — the basics
or cognition, have been harder to evaluate. However,
Neuronal activity triggers an increase in blood supply to the surrounding capillary beds novel insights into these systems that were previously
that overcompensates for neuronal oxygen extraction, causing a relative change in not possible in humans have been gained using fMRI.
their oxy/deoxyhaemoglobin status; oxyhaemoglobin concentration increases while Chemical circuits (glutamate, GABA (γ-aminobutyric
deoxyhaemoglobin decreases (see FIGURE). Because oxyhaemoglobin is less acid), dopaminergic, cholinergic, serotonergic and
paramagnetic than deoxyhaemoglobin the MR signal intensities in the area around
noradrenergic) can also be construed as complex because
these capillary beds change; increased concentrations of oxyhaemoglobin result in
higher MR intensities. A net increase in MR signal intensity is therefore detected in areas
they generally project to many neuroanatomical brain
that become active and depends on the magnitude of the blood-flow changes evoked. regions8–10. Structural systems (such as neurons and glia)
For this reason, it has been defined as blood oxygenated level dependent (BOLD) fMRI. define functional brain activity by determining the net
The increased blood flow (which correlates with increased neural activity152) produces balance of numerous neurotransmitter/neuromodulators
fMRI signal changes of the order of 0.5–5%. that are found on cell bodies and terminals. Functional
neurological circuits can also be sub-categorized because
O2 they often differ in their activity in health and disease.
In the early stages of CNS drug development, the deliv-
Normal
activity ery of potential therapeutics and their actions are often
Normal flow studied in healthy individuals with normal neurocir-
cuitry. Although this can have great value in ensuring
O2 target engagement (using technologies such as nuclear
molecular imaging, positron-emission tomography (PET) and
Change
in single-photon-emission computed tomography (SPECT)) and
activity proof of biochemical mechanism, these studies usually
Increased flow = increased MRI signal
create baselines for the study of disease states and their
O2 Oxygen Oxyhaemoglobin therapeutic modulation — the holy grail of targeted CNS
Relative signal intensity Deoxyhaemoglobin therapies. In some cases, it is difficult to recapitulate key
aspects of psychiatric or neurological disease in healthy
therapies, which could improve the treatment of com- individuals, but their use is a rapid step towards the
plex CNS disorders. Understanding functional circuits development of paradigms for patients.
as ‘arrays’ or units that contribute to behaviour might Activation of specific neuroanatomical circuitry
provide novel signatures that can be used as endpoints within the brain defines the behavioural consequences
to define CNS disease processes or the effects of drugs of a drug effect or disease process. The patterns of
on the brain in health and disease. neuroactivation and their changes are therefore poten-
Functional circuits can be defined as simple or com- tial markers of disease state and therapeutic efficacy.
plex. It has been relatively easy to image simple circuits Targeting the pathological alterations in CNS process-
such as sensory systems (for example, vision and pain ing involved in CNS dysfunction in humans allows for
Molecular imaging
detection), and to define their functionality7. Complex a top-down approach to the evaluation of drug effects
An imaging technique in
which cellular/molecular
processes have been tagged
in such a way that they can
Box 2 | Functional MRI — the experiment
be non-invasively imaged. In an fMRI experiment, subjects are
inserted into the MRI scanner and a
Positron-emission
tomography
series of stimuli applied. Typically, the Statistical
(PET). A dual-photon nuclear stimuli are presented as ‘on’ and ‘off’ map
imaging technique in which periods (see FIGURE). During the
radioactive tracers are stimulus presentation several images of
administered in non- the brain are acquired. One approach to
pharmacologically active detecting activation consists of
doses to subjects and images correlating the temporal profile of the Time
are created that reveal brain stimulus with the temporal evolution of
blood flow, glucose
Pseudo-
each ‘point’ (voxel) in the image. Voxels colour
metabolism or fractional
that are highly correlated with the statistical
receptor binding by drugs. map over
stimulus receive a high statistical score.
fMRI anatomical
Single-photon-emission An image is created that reflects the signal image
computed tomography statistical score for each voxel, a
(SPECT). A nuclear imaging statistical map. The statistical map,
technique in which radioactive however, lacks any anatomical Stimulus
tracers generating single information that could define the Off On Off On Off On Off
photons of a specific energy structures with significant activation.
are administered to subjects to
Statistical maps are colour coded and overlaid on anatomical images (usually, statistical maps are displayed in such a
produce images. SPECT can
give information about blood
way that only voxels with a significance larger than a threshold are included and the rest are not considered/displayed).
flow to tissues, molecular The resulting combined image allows the identification of voxels that are significantly activated and the central nervous
targets, and chemical reactions system substrate that they belong to. fMRI resolution for standard clinical 3-Tesla scanners is typically about 10 mm3
(metabolism) in the body. (and could be as low as 1 mm3) and for 7-Tesla animal scanners as low as 0.05 mm3.

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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.
NATURE REVIEWS | DRUG DISCOVERY
Box 3 | Potential application of fMRI across drug development
Lead optimization
Off-target CNS effects
CNS ‘therapeutic window’
Preclinical
Drug discovery
development
Target validation
Experimental assays
Disease models
Transgenics
The figure shows the classic progress of the components of drug development (ovals) and the potential applications of
fMRI (boxes) at each point along this development line.
on disease states11–13. The circuits that control complex
behaviours have been approached using large-scale
genomic profiling approaches to define phenotypes
associated with altered neural circuits14. Clearly the
reverse process — defining circuits and then linking
back to genomics — is an alternative approach (FIG. 1).
Detailed mapping of brain circuits allows for the sys-
tematic evaluation of functional reorganization in, for
example, the neural plasticity seen following stroke15,
dyslexia16,17, alterations induced by drugs (such as tha-
lidomide-induced dysmelia18), reorganization of visual
processing in the condition macular degeneration19, and
chronic pain20,21. Functional neuroimaging provides an
objective, differential readout of CNS function (neuro-
informatics) that can inform neurobehavioural studies of
CNS disorders and provide a novel framework in which
to evaluate therapeutic hypotheses rapidly.
The approach we propose would develop standard-
ized methods that define the functional fingerprints or
fMRI signatures in animals and humans for drugs with
proven clinical efficacy. This undertaking would require
a long-term commitment and sustained investment, but is
potentially transforming as it would enable a true ‘systems
neuroscience’ approach to be applied to CNS drug dis-
covery. We envisage that these activities lie initially in the
‘pre-competitive space’, such that the resources needed to
establish reference databases could be shared by consor-
tia formed between government, academia and industry.
An excellent example of this approach is the Alzheimer’s
Disease Neuroimaging Initiative (see Further informa-
tion), a US$60-million programme. Once established,
the reference databases could be used by the biopharma-
ceutical industry in a proprietary confidential setting to
evaluate new molecules and hypotheses.
The simple and complex systems that are involved
in normal and pathological acute and chronic pain
states, and the response to analgesic drugs, have been
well defined by clinical and basic science research.
Pain and analgesia therefore provide a rational start-
ing point for exploring the current and potential uses
REVIEWS
Life-cycle management
Novel CNS indications
Expanded use
Approved drugs
Clinical
development
Failed, safe
CNS drugs
Early proof of CNS activity
Early support for concept Novel uses for safe molecules
Therapeutic index Recover development costs
Optimized dosing Mechanistically
Responder identification unprecedented targets
Patient stratification Breakthrough neuroscience
of fMRI in drug development22–24. Moreover, it is now
widely accepted that pain is not a unitary sensation
but, in its chronic form especially, has cognitive, moti-
vational and emotional valences. Chronic pain states
therefore provide a clinical model with co-morbid
psychophysical aspects. These can be studied to pro-
vide insight into other CNS diseases, such as anxiety
and depression, because there is a high incidence of
pain following the onset of depression 25 and a high
incidence of depression in chronic pain26. It is impor-
tant when considering fMRI as a top-down transla-
tional technology, that it can be used to evaluate and
focus selection of the most appropriate surrogate27
animal models of chronic pain28–30 to those most rel-
evant to the human state31,32. It should be noted that,
depending on the disease model, it might be necessary
to consider imaging in gyrencephalic species, especially
if the predicted changes are predominantly cortical.
The concept of functional neuropathomics is shown in
FIG. 2. fMRI can be used to integrate across core areas
of CNS research that are currently segregated bioinfor-
matically. These encompass normal systems (functional
neuromics ), disease states (functional pathology),
molecular-profiling genomic-based disease markers,
pharmacotherapy or molecular mechanisms directed
at novel targets. For example, in Parkinson’s disease33,
for which genetic variation has been evaluated in the
context of possible differences in functional neuro-
circuitry34, fMRI can be used to differentiate between
healthy and disease states and to evaluate the impact
of therapeutics.
fMRI: drug discovery to clinical trials
The path of traditional outcomes-based drug discovery
and development can be long, expensive and uncer-
tain35–37. Early knowledge that speeds decision-making
about candidate molecules and therapeutic concepts
will facilitate the development process by ensuring that
if we are to fail, we fail fast. This will enable resources to
be focused on more promising molecules or alternative
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Molecular imaging (PET) Molecular diagnostics

Functional imaging (fMRI) Genomic profiling

Disease Function Targets Pathways Structure

Function Organ Tissue Receptors Cellular Genomic

Figure 1 | Locus of imaging in drug development — from disease to genomics and back again. The figure
shows the spectrum that imaging covers from molecular (for example, positron-emission tomography (PET)) and
functional (for example, fMRI) imaging to its use in molecular diagnostics and a link to genomic profiling in the
clinical and preclinical domains. Potential targets (circuits or specific regions) can be evaluated in the context of
the role they play in functional pathways, and can be studied in the preclinical domains using more invasive
processes, including molecular and cellular imaging, before detailed evaluation using high-field and high-resolution
functional, neuroanatomical and microimaging techniques. (Thanks to K. Moldoff for permission to use some of
these graphics)

hypotheses. This is becoming increasingly important, as
there are burgeoning numbers of molecules to choose
between and no shortage of potential therapeutic tar-
gets that are being revealed by genomics in health and
disease. Indeed, it can be argued that the more novel the
target chosen, the lower the probability of successfully
using the target to treat a particular disease.
Below we discuss how fMRI can enhance every level
of drug development from drug discovery through
preclinical and clinical development. Indeed, fMRI
might provide novel insights suggesting new uses for
marketed drugs, and could help rescue safe and well-
tolerated CNS agents that have failed in their primary
endpoint by revealing hitherto unknown therapeutic
potential. An overview of the incorporation of fMRI into
drug discovery is shown in BOX 3. A number of reviews
have focused on pharmacological fMRI38,39 of the CNS
in humans40 and animals in drug discovery41, and we
recommend these as additional reading.
fMRI in preclinical development
In preclinical phases, fMRI can be used to focus the selec-
tion of clinically relevant CNS animal assays, enhance
target validation based on objective assessment of behav-
iour, increase the speed of lead optimization based on
functional CNS responses, and define circuits of action
based on the neuroanatomy of the functional signature.
The fMRI approach is circuit-based, and might therefore
also reveal activation that is cautionary for potential CNS
side effects, including mechanism-based or off-target
activities that could influence compound selection for
clinical trials.
fMRI has now been used to study rodents and primates
in both the anaesthetized and awake states42–44. Activation
in specific circuitry of the brain produces a dynamic
signature that can be used to define behaviours and the
functional consequences of a drug effect. Identification
and mapping of the specific brain structures that are
involved directly and indirectly in behavioural responses
(such as activation of sensory pathways) can be used to
reveal the involvement of previously unsuspected brain
regions. Mapping the effects of drugs with known clinical
properties can be used to generate an fMRI ‘fingerprint’
that is characteristic of their activity. Knowledge from
experiments such as these could provide a rational basis
for initiating novel research into the pharmacology of
the newly identified brain regions and a means to select
between novel drug molecules by comparing their
fingerprints against those with known clinical effects.
fMRI as a functional bioassay. Preclinical animal assays
have great mechanistic value for examining in vivo the
pharmacology and neurochemistry of CNS active agents,
but are often not true surrogates of human disease. There

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Integrative
neuroinformatics

Markers
Specific brain Disease Drug Novel
for disease
regions state development targets
and drug

Functional Functional Genetic Pharmaco- Molecular

neuromics pathology variations therapy mechanisms

Brain function

Figure 2 | Functional neuropathomics — integrating brain function. The figure summarizes the potential value of
the use of fMRI when integrated (integrative neuroinformatics) into other neuroscience core disciplines such as;
systems biology (functional neuromics), to contribute to basic understanding of how the brain or specific brain
regions are involved in a particular function; the evaluation of central nervous system (CNS) disease states (functional
pathology; for example, chronic pain and depression and so on), to define how these areas malfunction at a
functional level, including how these evolve over time; the contribution of genetic markers (for example, genes or
single-nucleotide polymorphism markers), to define specific functional markers for CNS disease or effects of specific
drugs on disease; drug evaluation (drug development) or the clinical evaluation of the efficacy of a drug; and finally,
the evaluation of mechanisms (molecular mechanisms) of potential novel targets or the early evaluation of drugs that
could have follow-on uses.

is a general lack of understanding of what preclinical
behavioural responses are predictive of, as the func-
tional neuroanatomy of the response is unknown (FIG. 3).
Animal assays, especially those used in neuropsychiatric
drug discovery, can tend to be mechanism specific
and sometimes rediscover what was known already. A
consequence of the fact that fMRI measures functional
circuits that underlie behaviour is that it can be used to
probe the fundamental neuroanatomical basis of CNS
behavioural assays. This is an important consideration
because pharmacological manipulation of subconscious
processing can be of great significance in CNS drug
development, and this is difficult to objectively define
or evaluate in behavioural assays, many of which have
motor endpoints. Sometimes, however, fMRI might be
more sensitive than the behavioural assays it reports45.
Model selection and validation remains a key chal-
lenge in understanding or predicting drug efficacy46.
Current animal models have been relatively successful in
the discovery of anti-inflammatory analgesics but have
had limited success in predicting the activity of novel
agents for the pharmacotherapy of chronic pain. For
example, nerve growth factor (NGF) showed interesting
preclinical efficacy47, as did substance P neurokinin 1
(NK1) receptor antagonists, but failed in clinical
trials 48–50. Interestingly, substance P NK1 receptor
antagonists have been suggested to have multiple other
CNS applications51. They have failed comprehensively
in extensive Phase III trials for the treatment of depres-
sion52 but provide protection against chemotherapy-
induced nausea and vomiting through their actions in
the brainstem53,54. fMRI might be useful in assessing the
potential utility of NK1 receptor antagonists in other
CNS disease domains, and could reveal potentially novel
indications for follow-on drug development worthy of
more extensive clinical trials55,56.
We propose that the preclinical step in the early
evaluation of potential therapeutics can be improved
by using an objective fMRI circuit-based approach
to evaluate preclinical models instead of interpreting
‘binary’ type motor behavioural responses. Measuring
complex phenomena with single-focus behaviours
(for example, paw withdrawal) clearly has conceptual
limitations, as well as potential practical complications
based on interference with motor, motivational and
peripheral nociceptor systems. By using CNS circuits
as our measure, we can map laboratory models to
early clinical studies in healthy volunteers by examin-
ing the effects of therapy in activation paradigms that
produce similar global activation patterns in animals
and humans before more complex studies in patients
with chronic disease (FIG. 3). This is an iterative pro-
cess that allows functional bioassays of physiological
pain, inflammatory pain and neuropathic pain to be

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Species behaviour
? fied, novel animal assays with greater predictive value
Functional circuits
Somatosensory cortex
Sensory
Thalamus
Cingulate cortex
Emotional
Nucleus accumbens
Figure 3 | The language of translation — circuits not behaviour. fMRI brings
integrative processing to central nervous system (CNS) function and becomes the
‘language of translation’ between the human condition and preclinical models by
focusing on functional circuits and not behavioural assays. The top part of the
figure indicates that behaviours measured in humans and in animals are hard to
compare and difficult to interpret in terms of producing animal models of a disease
state (for example, chronic pain) that are truly predictive of the human condition in
terms of drug evaluation. Numerous candidate drugs fail in clinical trials with very
strong preclinical/behavioural results. The lower part of the figure shows fMRI data
from rats and humans exposed to the same thermal stimulus (46°C) that activates
nociceptors in a similar manner across mammalian species. Note that activations in
sensory and emotional systems are not only similar for structures and within
structures (medial and lateral thalamic activations) but also for strength of signal
(decreased signal in the nucleus accumbens). This approach requires animal and
human databases. Such databases would converge on a specific signature for a drug
or drug family. The specific signature or functional fingerprint is directly related to
physiological activity of the drug or class of drugs.
defined by their neurocircuitry, and for drug activity
to be defined by agonist/antagonist-induced changes
in these pathways rather than by behaviour alone57,58.
TABLE 1 summarizes reports on animal and human
fMRI of pain conditions. It is noteworthy that because
fMRI is non-invasive it can be repeated longitudinally
to follow the evolution of changes that are known to
occur temporally in the brain in many chronic pain
models. This improves the quality of data with intra-
subject design, and also reduces the number of subjects
needed for a study relative to discontinuous cross-
sectional terminal techniques that are often used to
probe brain function.
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fMRI-based drug profiling: fMRI fingerprinting. The
identification of specific areas of the brain that are
active in disease processes in combination with, or
through the actions of, a drug enables mechanistic
inferences to be drawn regarding how these processes
are mediated. Once a drug/disease profile is identi-
can be developed to test novel drug candidates. The
development of a preclinical fMRI profile database is
a prerequisite for this approach. For example, such a
database could be used to functionally define areas of
the brain that are implicated in neuropathic pain and
their interaction with drugs known to be clinically
effective and those known to have failed as analgesics
(that is, functional fingerprinting). These databases
must be able to be interrogated alongside parallel clini-
cal data-sets to establish the equivalence or lack thereof
of the animal and human data based on circuit function
(FIG. 4). Once defined, this behavioural and functional
‘efficacy fingerprint’ can be used translationally by drug
development groups to guide selection for clinical test-
ing of potentially effective drug candidates that have a
higher probability of success. fMRI evaluation of drug
effects on neuronal circuits might provide a unique way
to separate lead compound finalists that are equivalent
in simplified behavioural systems. There is emerging
preclinical and clinical fMRI literature on the direct
effects of drugs on CNS activity across a range of phar-
macological agents and targets (TABLE 2). It is notewor-
thy too that activation maps of the brain generated by
fMRI might be the only way to provide proof of target
and target engagement for full agonist, partial agonist
and inverse agonist drugs. Potent CNS agonists that
act at low-density receptor sites in small brain regions
cannot be tracked using PET neuroreceptor imaging
because the regional anatomy and fractional occu-
pancy required for pharmacological effects is beyond
the resolution of the technology. The use of fMRI in
combination with transgenic and knockout mouse
genetics could increase the value of both technolo-
gies in defining the links between genetics and CNS
function, and also provide a platform for CNS target
validation and drug candidate selection. It should
be noted that, although this approach might identify
drugs with a common mechanism of action (MOA), no
single, specific MOA is required because the fingerprint
predicts a therapeutic category of drug effect.
Integration: top-down approach. Non-invasive imaging
can provide specific insights into drug and disease phe-
notypes in humans that can be used to align preclinical
CNS models and to evaluate effective and ineffective
drug therapies, thereby improving early decision-
making on novel candidates (FIG. 5). Many CNS drugs
have been found serendipitously59 from astute clinical
observations in humans that have spawned drug devel-
opment programmes. A more rational approach is to use
imaging techniques such as fMRI to define the condition
in humans first. Indeed, the role of brain regions such as
the nucleus accumbens in pain processing was identified
in humans by fMRI prior to confirmation of their role in
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Table 1 | fMRI pain studies in animals and humans increasingly important in such commercially competi-
tive times in which there is considerable overlap across
Model Condition Refs the pharmaceutical industry in the therapeutic targets
Animal being pursued.
Formalin Tonic pain 104
fMRI in clinical drug development
Allodynia Capsaicin 105
The optimal use of fMRI in clinical drug development
Physiological pain Electrical stimulation 106,107 is early in Phase I or II trials (FIG. 6). Using relatively
Human small populations of healthy subjects, data relating
Allodynia Neuropathic pain 81,108,109 to efficacy (targeted circuits) and side effects can be
Capsaicin 110–112 determined. Indeed, it might be possible to develop
experimental models of some clinical conditions in
Pressure Back pain 113
Fibromyalgia 114,115 healthy subjects to facilitate the evaluation of drug effi-
cacy (FIG. 5)63. fMRI responses could also be useful for
Physiological Electrical stimulation 102,116 optimizing drug-dosing regimes. The accumulation of
Noxious heat 60,117–122
Noxious cold 122,123 objective fMRI data alongside traditional early clinical
data on novel drug candidates could provide a unique
Visceral pain Experimental 124–128
Irritable bowel 129,130 metric that affects go/no-go decisions. Indeed, early in
drug discovery and development it is essential to have
several orthogonal sources of information to increase
experimental models60, making evaluation of their roles confidence in decision-making. fMRI can contribute
in animal models more credible and useful61. It has been unique information about the potential success of a
argued that a hypothesis-driven MOA approach to drug drug candidate or therapeutic hypothesis that, when
development has limited utility because many drugs interwoven with traditional metrics such as safety and
that are effective have no clear MOA (for example, anti- tolerability, can provide an early matrix within which
epileptics62) and others have an unpredicted rich and to judge probability of success.
complex pharmacology that provides benefit through
multiple actions. In these cases, looking at the end of Therapeutic versus side effects. fMRI interweaved
the process — the functional consequences of CNS drug into early clinical trials, particularly safety and toler-
effects — to match key components of the brain fMRI ability studies involving dose escalation, could provide
fingerprints provides a unique opportunity to identify an early indicator of both therapeutic and side-effect
‘outside the box’ novel therapeutic approaches. This is potential. Indeed, incorporation of fMRI into early

a Anatomical scan b Functional scan c Brain segmentation d Whole-brain parcellation

e ‘Brain array’ f Array fingerprint g Analysis/efficacy h Molecule

Figure 4 | Functional brain arrays. Anatomical scans (a) provide high-resolution details of the brain onto which
functional activation patterns can be mapped (b). By compartmentalizing anatomically defined brain regions
(parcellation/segmentation) (c), it is possible to obtain defined regional anatomy for the whole brain (d). e | A brain array
based on activations within anatomically defined regions of the brain can then be generated. Such an approach can
allow for differentiation of drugs or diseases by so-called ‘array fingerprinting’ (f) that allows for network reconstruction
and analysis steps to define neuroanatomically linked groups or neurocircuits in different ways, including efficacy (g).
h | Array fingerprinting can also be used to match different chemical compounds, because novel therapeutic compounds
can be recognized by their fMRI signature expression profiles.

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Table 2 | Pharmacological MRI: drug-induced CNS circuit activation It should also be noted that fMRI can detect unantici-
pated central effects of peripherally targeted analgesic
Drug(s) Mechanism Refs
drugs that could have side-effect liability. This is espe-
Animal cially important when selectivity is achieved through
d-Amphetamine Decrease dopamine reuptake 131 differential rather than absolute differences in receptor
Amphetamine Modulation of dopamine D2/D3 132 distribution between the peripheral and central compart-
function ments, or through manipulation of the physico-chemical
properties of a molecule to exclude it from the CNS. An
Dopamine Antagonism of amphetamine 133
example that preclinically had well-defined antinocic-
Bromocriptine and haloperidol D2 receptor agonist 134 eptive effects is the κ-opioid agonist ADL 10-010168,69,
Quinelorane D2/D3 receptor agonist 135 which was designed to be confined to peripheral recep-
Cocaine Dopamine reuptake inhibitor 136–138 tor sites. Experience with ADL-10-0101 is instructional
because it was found to produce dysphoria similar to
Bicuculine GABAA antagonist 139
other κ-agonists in later-stage clinical development70.
LY404187 AMPA receptor potentiator 140 Such unexpected surprises are to be avoided at all costs
GR-73632 NK1 receptor antagonist 141 as the failure is expensive. Had this drug been evalu-
Baroreceptor activation α-Adrenergic agonist 142 ated early using fMRI, perhaps preclinically at doses
Phenylephrine or sodium nitroprusside Nitric oxide release active in the pain assays, but almost certainly in early
clinical evaluation, then this unwanted and unexpected
Rivastigmine ACE inhibitor 143
side effect, which the drug was designed to avoid, might
Nicotine withdrawal Cholinergic agonist 144 have been predicted. Finally, it is also clear that fMRI
Heroin Opioid agonist 145 could be used to evaluate the central effects of therapies
Morphine withdrawal Naloxone reversal 146 that are targeted to diseases outside the CNS, because, if
present, they might prevent or limit the clinical utility of
HU210 Cannabinoid receptor agonist 147
potentially useful agents.
Human
Naloxone (N) µ-Opioid antagonist 148 fMRI to optimize drug dosing. Can drugs initially
Methamphetamine (N) Dopamine release 149 evaluated in healthy subjects in early clinical trials be
used as ‘smart’ indicators of drug efficacy in patient
Morphine (N) µ-Opioid agonist 58
populations, and will this index change with disease
Cocaine (P) Dopamine reuptake inhibitor 150 progression? In chronic pain, changes are now known to
Nicotine 151 take place along the entire neural axis, from peripheral
Note: these references are measures of the direct effect of a drug on CNS processing; for nerves to cortical regions. Insights show changes related
measures of effects of drugs on behavioural or other paradigms in humans see a recent review to pathological centralization of pain (hypersensitive
on human pharmacological MRI40. ACE, acetylcholinesterase; AMPA, α-amino-3-hydroxy-5- circuits), apparent loss of gray matter21 and altered func-
methyl-4-isoxazolepropionic acid; CNS, central nervous system; GABA, γ-aminobutyric acid;
NK1, neurokinin 1; N, normal/healthy volunteers; P, patients. tional connectivity71. It is also well known that there are
significant differences in the tolerability of several drug
classes (for example, antipsychotic, antidepressant and
low-dose clinical studies authorized under the experi- analgesic) used for the treatment of chronic undulating
mental Investigational New Drug (eIND) application CNS diseases at effective therapeutic doses when given
process could increase attrition of unsuitable drug can- to healthy volunteers rather than patients. Indeed, in
didates and mechanisms. Moreover, by focusing early some individuals the therapeutic dose makes no sense
on the best candidates and hypotheses there is greater in terms of simple receptor biology. How, then, do we
safety for human subjects in clinical trials. An example judge dosing to optimize benefits over side effects? We
case is an analgesic (for example, gabapentin, morphine suggest that fMRI has the potential to fulfill this need by
and amitryptiline) in which the desirable CNS effects providing an objective readout of CNS function during
are on sensory systems, descending pain control sys- drug dosing that could be correlated to drug exposure
tems and limbic structures including the amygdala64. and disease stage, and perhaps also used in experimen-
By contrast, major CNS side effects include sedation, tal paradigms conducted in the context of disease (for
dysphoria, possible addiction, and nausea and vomit- example, in analgesia and attention deficits72).
ing65,66 that can vary depending on the subject’s age,
sex or genetic make-up. fMRI can define the circuits Neurotransmitter status. fMRI has been used to evalu-
involved in these responses in a rational objective ate a number of neurotransmitter systems to study neu-
manner. For example, the neurocircuitry involved in ral processing in humans (TABLE 2), and this has been
sedation is known to involve intralaminar nuclei of the subject of a recent review40. Most of these studies
the thalamus and cortical regions. Reward circuitry, have, however, not evaluated direct effects of drugs on
particularly the accumbens and orbitofrontal lobe, are neural pathways but have instead used behavioural
involved in euphoria and dysphoria, and brainstem interventions. Nevertheless, clever study design allows
nuclei (nucleus tractus solitarius) are known emetic for the functional dissection or modulation of neural
centres67. If these are activated, the decision not to pathways specific to a particular neurotransmitter
pursue further development might be taken. system (for example, dopamine73). In addition, there

8 | ADVANCE ONLINE PUBLICATION www.nature.com/reviews/drugdisc


Drugs Surrogate model fMRI Signal
differentiates
drug efficacy
Drug 1
Drug 2
Drug 1 Healthy subjects
Drug 2 +
Drug 3 stressor Placebo
Drug 4 + of patients with schizophrenia.
Placebo drug
Drug 3
Drug 4
Figure 5 | Surrogate models in drug evaluation. Because fMRI reflects neural activity,
and brain systems are by their very nature complex and interconnected, activation maps
provide a ‘picture’ of activation patterns in response to a perturbation (BOX 1) at a
particular time. For example, in response to pain stimuli, sensory, emotional, autonomic
and endogenous analgesic systems all process this information to evaluate and respond
to the perturbation. The complexity of the system is such that overall maps of the
patterns of activation might prove useful for interpreting drug action. This can be carried
out in healthy subjects to differentiate drugs that could have utility in a particular
disease, such as neuropathic pain63. Even in the diseased state, drugs also act on ‘normal’
or unaffected brain regions which may contribute to the distributed response. The
figure shows that, following different drug treatments, fMRI measures of a surrogate
model of stress produce different activation maps for each drug compared with placebo,
which might differentiate drug efficacy (that is, drugs 1 and 2 being useful for, and drugs
3 and 4 having no utility for, the condition).
are a few studies using fMRI with correlative plasma
levels72,74 to define a relationship between brain activation,
drug plasma levels and effect.
fMRI for marketed or failed yet safe drug candidates.
There are two broad areas of use of fMRI in this domain:
extending a known compound into a new therapeutic
area, and rescuing a CNS active compound that has failed
for its primary CNS indication by defining a new indica-
tion for which it was not originally designed51,55,56.
Few marketed CNS drugs have a well-defined MOA.
They are categorized simply on the basis of the cell sur-
face proteins with which they interact rather than the
neurobiological consequences of the interaction. Drugs
that were traditionally used in different domains have
serendipitously found uses for new indications55. This
has been obvious in the anti-epileptic domain, in which
many drugs have found off-label use in neuropathic pain,
post-traumatic stress disorder or other CNS diseases.
Functional classifiers A more defined method of evaluating these drugs is to
Drugs can act on neural identify circuit activation that is predictive of potential
networks or systems in a
use against a database established in this domain. This
particular fashion — for
example, produce sedation, could use the advanced bioinformatics approaches that
euphoria or analgesia. have been developed to define molecular signatures in
Activation patterns that show genomic profiling (FIG. 4).
specific regions of the brain
known to be involved in a
particular function allow for
fMRI studies of drug side effects. Some drug-induced
the segregation or functional side effects can be used as models for understanding
classification of drug action. disease symptoms and therapeutic drug effects. For
NATURE REVIEWS | DRUG DISCOVERY
REVIEWS
example, the antimalarial mefloquine (Larium) produces
psychosis as a side effect75 with an incidence rate of 33%
in a randomized controlled trial, even though only 6%
sought medical attention76. fMRI evaluation of this type
of drug can be used for a number of ends: to understand
circuitry activated during psychosis in otherwise healthy
subjects; as a model to discover drugs that ameliorate
this effect (compared with fMRI data on activation of
regions such as the hippocampus in schizophrenia77);
and to target investigations of drugs in small populations
Phenotyping for focused Phase II and III CNS clinical
trials. Mechanistic approaches to drug development
have been hampered by the lack of objective phenotypes
for diseases that are polygenetic or do not have specific
biomarkers. Studies to define a correlation between
genotype and phenotype have now begun using fMRI
in small focused groups of patients with known genetic
subtypes (for example, Parkinson’s disease) and in
larger cohorts using single-nucleotide polymorphism
(SNP) or related genotype mapping78–80. Phenotyping to
produce functional classifiers using a circuit-based fMRI
fingerprinting approach could yield novel experimental
imaging paradigms81 in which these markers are used
to evaluate novel drug candidates in defined patient
populations that are enriched and stratified on the basis
of brain function.
fMRI as an integrator. fMRI provides a hub for integrat-
ing the technologies and stages of CNS drug develop-
ment. fMRI can act as a key translational technology
for CNS research that provides a bridge from human to
animal and back again. Within the preclinical and clini-
cal arenas it can interface with other target validation
and MOA strategies to provide functional correlates of
drug action. fMRI signal change is thought to reflect
changes in field potentials82, and can therefore direct
drug discovery using in vitro slice electrophysiology
and in vivo electrophysiology to the correct brain regions
involved in a drug’s action and focus evaluation of drug
hits that come from mechanistic screens. fMRI-defined
pathways can inform the interpretation of clinical symp-
toms and drug effects, potentially helping to optimize
dose selection and therapeutic windows. fMRI can also
be leveraged by integration with genomic analyses at a
human level (for example, SNP mapping) to describe
the complex functional changes that occur in different
psychiatric and neurological diseases. Finally, fMRI
can be used with mouse genetic approaches to provide
novel mechanistic insights that link CNS dysfunction to
altered genes, thereby providing a segue from human
disease to animal models and back83,84.
A working example. Defining an objective model of
neural systems in humans allows for hypothesis-driven
evaluation of pain systems (physiological, inflammatory
and neuropathic conditions); the objective definition
of surrogate models for disease states or drug effects
(see below); and the evaluation of these effects over
time. Our group has begun to use this approach by
ADVANCE ONLINE PUBLICATION | 9
REVIEWS

Human drug database

a d
Objective markers Objective markers
of drug action of drug efficacy
GO/NO GO and disease

Clinical drug
IND Phase I Phase II Phase III NDA Approval
development

Clinical
Repeat dose
pharmacology Safety
toxicology
&ADME/PK
b
Initial clinical Dose Manufacture
evaluation ranging QA methods

c
Repeat dose
Efficacy
toxicology

Long-term
toxicology

Manufacture Manufacture Manufacture

QA methods scaleup scaleup

Figure 6 | Clinical applications in Phase I studies: enhanced information for go/no-go decisions. fMRI has
applications in early-phase drug development in three principal domains. a | fMRI can provide objective markers of
drug action for go/no-go decisions. b | fMRI can provide additional information for central nervous system dose
ranging. c | fMRI can provide insights into efficacy of drug action in the healthy population normally used in Phase I
studies. d | fMRI can provide an objective marker of efficacy in Phase II and III trials once tools and standards are
developed to deal with the diversity of disease within clinical populations with a common diagnosis. ADME,
absorption, distribution, metabolism and excretion; IND, Investigational New Drug; NDA, New Drug Application;
PK, pharmacokinetics; QA, quality assurance.

defining activation in trigeminal pathways7,85,86 (FIG. 7).
This has allowed us to evaluate changes that occur in
clinical conditions affecting the trigeminal system, such
as neuropathic pain and migraine. With respect to the
latter, preclinical and clinical work has defined a model
of progressive central sensitization of the trigeminal
system that underlies allodynia associated with migraine
attacks87. Specifically, fMRI might provide insights into
inter-individual differences in responsiveness to triptan
5-hydroxytryptamine (5-HT1B/1D) agonist antimigraine
agents, as well as inter-attack differences within a patient,
and reveal their true clinical sites of action.
Challenges. fMRI is a relatively new field and its appli-
cations to drug development are still in their infancy.
fMRI holds great promise because it adds objective
methods for the measurement of CNS function in awake
animals and humans. However, like any technology,
there are limits and caveats that are worth noting. How
valid is the use of fMRI in CNS disease and drug evalu-
ation? How sensitive and reproducible is this? Is it a
population-based approach or an individual approach?
Global versus local changes produced by agents that
alter afferent inputs to the brain or affect cardiovascular
changes or nonspecific functional responses must be
investigated, and attention to experimental design and
data analysis is required41,88.
The on/off approach to stimuli for disease state or drug
evaluation is currently standard. This approach provides
provocative stimuli that can be used to evaluate differences
in the disease versus non-disease state with or without
pharmacological interventions. Novel approaches that use
resting fMRI have provided useful insights into process-
ing and connectivity in CNS disease89–91. These and other
technical developments, such as real-time imaging92,
could enhance the utility of magnetic resonance tech-
nologies by adding new dimensions to the study of brain
function in health and disease.
With all its potential to elucidate new paths and appli-
cations in drug discovery, we need to recognize that fMRI
is a relatively new technique and as such has yet to be
fully characterized. Several studies have looked at fMRI
reproducibility in terms of size (intensity) and focus of
activation93,94. Studies involving sensorimotor tasks,
working memory and other tasks have looked at how well
the signal intensity can be reproduced95–97. In general, for

10 | ADVANCE ONLINE PUBLICATION www.nature.com/reviews/drugdisc


Define functional system Apply functional system
d
Physiological model
c technology both in drug development and in the clinic.
Migraine
b Neuropathic pain
Surrogate models
Drug/analgesic effects
a ing of pain into clinical utility. Given that scanners
Figure 7 | Application of a defined systems approach to models and disease in
humans. This is an example of the use of functional imaging to define a neural system
(that is, trigeminal sensory pathway) that includes first-, second- and third-order neural
projections to the cortex. Activation can be measured in first-order (trigeminal
ganglion (a)); second-order (spinal nucleus of the trigeminal nerve (b)); third-order
(thalamus (c)); and fourth-order (primary sensory cortex (d)). Activations shown as
cutouts of the head (small white boxes) are shown in enlarged boxes. An understanding
of the connectivity and anatomical regions involved under baseline conditions
(physiological pain) can then be used to identify changes in these pathways in clinical
conditions such as migraine or neuropathic pain, applied to the development of
surrogate models such as capsacin induced sensitization of the system or used to
measure the effects of drugs on this pathway in health and disease. Modified, with
permission, from REF. 85 (C) Wiley (2004).
the same subjects, signals are found to be highly repro-
ducible. The variability among subjects, however, is sig-
nificantly larger. For population studies, a cohort size of
about 15 subjects is necessary to draw conclusions98. One
of the main obstacles for fMRI is the high-fidelity stand-
ardization of different brain anatomies across subjects
to a common anatomical template99. New approaches
to reduce variability use calibration techniques to adjust
each subject’s response to a standard obtained from the
same subject100. fMRI enjoys high specificity in activa-
tion patterns across tasks and subjects. fMRI sensitivity
varies with the brain structure under study, the specific
paradigm used and the scanner characteristics (such as
magnetic field and imaging coils). For cortical structures
involved in visual or sensorimotor tasks in a 3-Tesla scan-
ner, it is possible to detect activation in volumes as small
as 1 mm3. For subcortical structures the detectable vol-
ume is somewhat larger. The wide diversity of techniques
and instruments from different manufacturers used in
fMRI drives the need for common standards for routine
studies across imaging centres.
The example of pain and analgesia serves to validate
the use of fMRI in disease evaluation and drug develop-
ment101. Since the early fMRI studies in pain102,103 there
NATURE REVIEWS | DRUG DISCOVERY
REVIEWS
has been a significant contribution to the pain-imaging
literature from numerous laboratories around the world.
Indeed, the notion that other domains are using pain in
imaging studies speaks for the robustness of the stimulus
in imaging paradigms. As a result, the field has advanced
to a point that offers the exciting possibility of using this
For the technology to become valid as a diagnostic tool
(for drug/therapeutic effects of disease state), it needs
to satisfy the standard set of criteria for validity: face
validity (a reflection of the problem), construct valid-
ity (robustness/reproducibility of assay), and predictive
validity (defining or predicting a result in the context of
false-positive/-negative outcomes)101.
The revolution in imaging from a technological
and analytical point of view offers some exciting
prospects for clinical use. If one critically evaluates
progress being made in fulfilling the standards of
validity, based on the enormous breakthroughs that
the technology has provided within the past couple
of decades, then the future looks bright in terms of
a transition from basic research in functional imag-
are available at most academic institutions, access to
instruments to perform studies is not likely to be a
limiting factor. The main issue is the heterogeneity
of tools, technologies and techniques across imag-
ing centres that make fMRI studies, even in the
same domain, difficult to compare. Clearly what is
now needed are common standards that define the
populations included in imaging studies, ensure the
specificity of stimuli, data collection and analysis to
enable the field to advance.
Realizing the potential
The ability to realize the potential of fMRI in drug
development will be challenged by practical issues
including costs, validation and the need to define
new analytical mathematical approaches to evalu-
ate complex neurological and psychiatric diseases.
Issues include current evaluation of the disease at
baseline, medication use (including potential taper-
ing paradigms), appropriate ethical approaches to
human experimentation in these difficult populations,
and evaluation of novel clinically unproven drugs in
these conditions that could require withdrawal of best
practice usual care.
The benefit–cost relationship is difficult to predict,
but what is clear is that the traditional mechanism- and
target-based framework for CNS drug discovery has
recently not delivered truly novel approaches to com-
plex CNS diseases. Functional systems and circuit-based
approaches have the potential to provide a paradigm
shift that could advance the field of CNS drug discovery
beyond the roadblock that we have today.
Conclusions
Non-invasive functional imaging has fundamentally
changed the way that we can question brain systems
because we can see them in action. fMRI brings
systems neuroscience to life by showing how genes,
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REVIEWS

proteins, transmitters, neurons and neural networks
work togther to create brain responses in health and
disease. fMRI can be used in drug development in
new and exciting ways that provide valuable informa-
tion relating to drug and disease phenotype, using a
circuit-based approach to defining behaviours that
makes translational processes between the preclini-
cal and clinical domains more useful. Many of these
insights, such as ‘the language of translation’ across
species achieved by measuring neural circuit function
as a correlate of behaviour, might transform our cur-
rent thinking in neuroscience.
Ultimately, novel technologies need to prove their
value. The potential future for fMRI technology is to
contribute to decreasing risks and costs of CNS drug
development by increasing the ability to make focused
rational choices that help decision-making and so speed
the discovery of safe and cost-effective therapies.

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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.
Competing interests statement
The authors declare competing financial interests: see Web
version for details.
DATABASES
The following terms in this article are linked online to:
Entrez Gene:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene
NGF | NK1
OMIM:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM
Parkinson’s disease
FURTHER INFORMATION
Alzheimer’s Disease Neuroimaging Initiative:
http://www.loni.ucla.edu/ADNI/
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