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fMRI Studies in the Pharmaceutical Industry: Turning Data into Information. Paul M. Matthews Imaging, Genetics and Neurology Clinical Imaging Centre, Hammersmith Hospital GlaxoSmithKline Clinical Neurosciences, Imperial College, London FMRIB Centre, University of Oxford.

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Fmri studies in the pharmaceutical industry turning data into information

fMRI Studies in the Pharmaceutical Industry: Turning Data into Information

Paul M. Matthews

Imaging, Genetics and Neurology

Clinical Imaging Centre, Hammersmith Hospital

GlaxoSmithKline

Clinical Neurosciences, Imperial College, London

FMRIB Centre, University of Oxford


The gsk clinical imaging centre
The GSK Clinical Imaging Centre into Information

  • Established with joint planning and funding from GSK, Imperial College and the Medical Research Council

  • A centre equipped with state-of-the-art imaging systems for PET/CT and MRI

  • A centre with expertise in radiochemistry/biology, image analysis and modelling, imaging physics and clinical research applications

  • A centre for collaborative research in key areas of interest (especially neurosciences and oncology)

  • A centre to drive disease understanding and new therapeutics development


Gsk clinical imaging centre operations
GSK Clinical Imaging Centre: operations into Information

  • CIC began operations in a staged fashion from 2Q07

  • Progressive increase to full capacity over 3 years (end 2Q10)

  • Goals:

    • In-house image analysis and curation: adding value

    • Asset-specific molecular imaging

    • Development, evaluation and validation of novel PD measures

  • The CIC effort is supported by strong academic partnerships, including aninternational network for molecular imaging

  • Hardware/IT needs are being addressed in high value partnership with Siemens


Why is the pharmaceutical industry interested in fmri

Experimental medicine into Information

Disease

selection

Gene

function

to target

assoc’n

PoC to

commit to

Phase III

Target to

Lead

Lead to

Candidate

Pre-

clinical

FTIH to

PoC

File and

launch

Life cycle

man’ment

Phase III

Target family

selection

Why is the pharmaceutical industry interested in fMRI?

GENETICS/’OMICS

BIOMARKERS

IMAGING


Introduction to the workshop
Introduction to the workshop into Information

  • Applications of functional MRI in drug development

  • The peculiar nature of fMRI data

  • Optimising the outcome measure


Potential applications of fmri to drug development
Potential applications of fMRI to drug development into Information

  • Patient stratification

  • Pharmacodynamic response

  • Proof of mechanism

  • Early phase outcome study

  • Surrogate marker of outcome


Stratification a specific functional intermediate phenotype for schizophrenia
Stratification: a specific, functional “intermediate phenotype” for schizophrenia?

MacDonald et al., Am J Psychiatry, 2003


Pharmacodynamics of pain responses to remifentanil
Pharmacodynamics of pain responses to remifentanil phenotype

Courtesy of Dr. R. Wise, I. Tracey (Oxford)


pHMRI as a tool for proof of mechanism in translational studies

Sagittal plane, x=1.4mm

Sagittal plane, x=3.0mm

SSctx

Mctx

thal

PrL

thal

Sagittal plane, x=1.0mm

PrL

AcbSh

VTA

Rat metamphetamine response

Schwarz et al. NeuroImage 34, 1627-1636 (2007)


Phmri as a tool for proof of mechanism in translational studies
pHMRI as a tool for proof of mechanism in translational studies

Vollm et al., 2005

Human metamphetamine response


Early phase outcome measure providing a reason to believe
Early phase outcome measure: providing a “reason to believe”

Brain activation in the Stroop task

Anterior cingulate

Right inferior frontal cortex

Basal ganglia


MS patients have reduced right prefrontal activity in the Stroop task

MS patients recruit additional left prefrontal cortex during the Stroop task


Early phase outcome measure providing a reason to believe1
Early phase outcome measure: providing a “reason to believe”

Abnormal brain activition in MS transientlynormalises after rivastigmine administration

Patients

Healthy controls


Mri as a surrogate marker for disease activity in multiple sclerosis
MRI as a surrogate marker for disease activity in multiple sclerosis

Reprinted with permission from Elsevier

Compston A, Coles A. Lancet 2002;359:1221–31


Mri as a surrogate marker for disease activity in multiple sclerosis1
MRI as a surrogate marker for disease activity in multiple sclerosis

T2-weighted

Gadoliunium enhanced


The peculiar nature of fmri data
The peculiar nature of fMRI data sclerosis

  • fMRI is an indirect measure of neuronal activity

  • fMRI relies on small, voxel-associated signal changes

    • Changes are small relative to intrinsic contrast in image

  • fMRI generates a statistical image

    • Outcome is probabilistic, not binary

  • The brain works through networks, not individual regions


Fmri is sensitive to changes in local blood oxygenation
fMRI is sensitive to changes in local blood oxygenation sclerosis

With presynaptic neuronal activity, blood flow increases and the proportion of red blood cells carrying oxygen increases in the small blood vessels, enhancing the MRI signal specifically in that region of brain

See Jezzard, Matthews, Smith, Functional Magnetic Resonance Imaging: an Introduction to Methods (OUP)



The peculiar nature of fmri data1
The peculiar nature of fMRI data correlation of activity

  • fMRI is an indirect measure of neuronal activity

  • fMRI relies on small, voxel-associated signal changes

    • Changes are small relative to intrinsic contrast in image

  • fMRI generates a statistical image

    • Outcome is probabilistic, not binary

  • The brain works through networks, not individual regions


Resting state networks directly reflect network based activity in the brain
“Resting state networks” directly reflect network-based activity in the brain

Mean BOLD signal change

Coefficient of variation

0.5%

3%

0.1%

50%


A new way forward network based patient stratification
A new way forward? activity in the brainNetwork-based patient stratification

RSN

MMSE


Summary and outline of the day
Summary and outline of the day activity in the brain

  • fMRI is based on indirect measures, subject to modulation by vasoactive factors (Jezzard)

  • Signal changes are small- multiple subject, instrument and site factors contribute to variance (deCrespigny)

  • Perfusion provides an alternative to BOLD, potentially less subject to non-specific time-dependent effects (Woolrich)

  • Multiple metrics can be used as outcomes- specifying the question is critical (Smith)

  • Multivariate methods are powerful for exploratory analyses and may offer a new primary outcomes measure (Beckman)

  • Matching brains to provide summary measures and neuroanatomical contextualisation need as much thought as functional signal acquisition (Jenkinson)

  • Promising work suggests there is a way forward, but the community must work together to ensure that we are taking it (Smith)


Acknowledgements
Acknowledgements activity in the brain

Steve Smith, Irene Tracey, Richard Wise, Christian Beckmann, Alison Perry, Sarah Cader, Jackie Palace, Peter Jezzard, Phil Cowen, Angelo Bifone


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