Functional Magnetic Resonance Imaging

Bridging the Science Between Animal and Human Research

Craig Ferris, Ph.D. DirectorCenter for Comparative Neuroimaging

Department of PsychiatryUniversity of Massachusetts Medical School

Center For Comparative Neuroimaging

mouse rat

marmoset rhesus

University Massachusetts Medical School

Magnetic Resonance Spectrometer(4.7 T)

RF Probes

Computer Console

Passive Shielding

Magnetic Resonance Imaging “Then & Now”

Damadian et al., Science 194:1431,’76 CCNI, 9.4T

Kramer et al., Neuroradiology 21:239 ’81 - Lauterbur

High Resolution Magnetic Resonance Image Of Marmoset Monkey Brain

Superconducting Magnets

Generate External Magnetic Field - B0

Field Strength Between 1.5 – 11.7 Tesla (T)Operate Near Absolute Zero Temperature

Manipulating Hydrogen Atoms

MRI is non-invasive and uses the protons from mobil hydrogen in water and fat to generate signals

The hydrogen nucleus spins creating a local magnetic field causing the charged nucleus to act like little magnet aligning in BO.

Over time (2-3 sec) protons come to equilibrium or net magnetization MO

Hydrogen Protons “Wobble”Not only does the nucleus of the hydrogen atom spin like a top but it also precesses or “wobbles.”The precessional frequency is defined by the Larmor Equation ω = γ BO

γ = 42.6 MHz/T for hydrogenWhen the field strength increases so does the precessional frequency

Flipping Hydrogen Protons To Get MR Signal

An RF pulse with the same precessional frequency can “flip” the proton into the transverse plane

Protons precess around the transverse plane giving off an oscillating signal

Protons are initially in phase but rapdily dephase and signal decays in 20 to 30 msec.

The time constant that defines the rate of decay is T2

•Spectroscopy

•Quantitative Anatomy

•Tract Tracing with Manganese Chloride

•Angiography

•Diffusion Weighted Tensor Imaging

•Diffusion/Perfusion Imaging

•Function ImagingCBF – cerebral blood flowCBV – cerebral blood volumeBOLD imaging

What can a neuroscientist learn about the brain using a magnet?

Ferris et al., J Neuroendocrinology 18:307, 2006

Diffusion Weighted Tensor Imaging

Applications• brain myelination and

development• neurodegeneration

unpublished data, CCNI 9 4T

DT maps of marmoset

Applications• phenotyping transgenic mice • developmental biology • neurotoxicology

MR Spectroscopy Quantifying Brain Chemistry

unpublished data, CCNI 4.7T

Brain EtOH Levels

Tract Tracing with Manganese Chloride

unpublished data, CCNI 9.4T

Absence Status Seizure

Application• tracing functional

neural circuits

MnCl2injection site

Mn2+ accumulation 8 hr after injection

in-plane resolution 50 µm2T1-weighted contrast

Basal condition

BLO

OD

FLO

W

Δ BOLD SIGNAL

4 Sec

HbFe2+O2

HbFe2+O2

HbFe2+

HbFe2+

O2

Initial increase in metabolism

Reactive hyperemia

Ogawa et al., MRM 14: 68-78 1990

O2

Functional Imaging Using BOLD BOLD Signal

Blood Oxygen Level Dependent

BOLD Imaging and Psychiatry: A Critical Tool for Studying Brain Function

Since Ogawa’s original publication there have been close to 1,800 publications on BOLD imaging.Only around 300 have used animals – why?

They don’t sit still.

Why Conscious Animals?

Tenney et al., Epilepsia 44:995, 2003

• BOLD Signal is depressed with anesthesia

S1FL

S2FL

CPu

Awake Anesthetized (α-chloralose)

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BOLD Signal Changes In Awake vsAnesthetized Rats

Sicard et al., Cereb Blood Flow Metab 23:472, 2003

Getting Started: Acclimating Animals to the Imaging Protocol

Physiology and Stress Hormone

King et al., J Neurosci Methods 148:154-60; 2005

Atlas

Three Dimensional Segmented Rat Atlas

Registration “Group Statistics”

Segmentation

Activation Maps

3D Visualization

GUI

Stimulation Paradigms“How do you talk to an animal in a magnet?”

• Odors

• Visual Images

• Tactile Stimulation

• Drug Challenges

• Complex Environmental Cues

“vivarium”

Applications In Neuroscience

Imaging emotional states, e.g. sexual arousal, hunger, fear, etc.

Developmental studies on neurological disorders, e.g. stroke, seizure, dementia, etc.

Drugs and brain function, e.g. cocaine, MDMA, anxiolytics, neuroleptics, etc.

Learning and memory

PRESENT AREAS OF RESEARCH

Maternal BehaviorStressDrugs of Abuse• MDMA “ecstasy” • Cocaine• Nicotine

AggressionFear and AnxietyDrug Discovery

MOTHER/INFANT BONDING

Early maternal care is critical for the psychosocial development of infants.

With the evolution of mammals, nursing has helped strengthen the mother/infant bond and extend the period of parental investment in young.Courtesy of Steve Suomi

a

b c

Volume coil

Body tube opening exposes the ventrum

Weigh boat cradle padded with gauze 4 pups inside cradle

under the ventrum

Can We Image the Nursing Brain?

Yes …

Interestingly, the Brain Activity Suggests Suckling is a Rewarding Experience

• Mesocorticolimbic dopaminergic pathways are activated.

• Previous studies show suckling has many of the properties of addictive drugs. Suckling motivates bar pressing for pups and conditioned place preference.

(Fleming, Spear, and Morrell labs)

Is motherhood more rewarding than cocaine?

… it would seem so.

MARMOSET FAMILIES

“MOM, DAD, & THE KIDS”

MONOGAMOUS

TWINS

AFFILIATION

DEVELOPMENT

SMALL SIZE

Courtesy of Nancy Shultz-Darken

Primatologists and collaborators:

•Charles Snowdon

•Toni Zeigler

•Nancy Shultz-Darken

•Melinda Novak

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habituation baseline

habituation post-restraint

unstable peer group*

*Wisconsin Marmoset Colony

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Stress-Induced Changes in Plasma Cortisol

simulated imaging session

Habituating Marmosets to the Stress of Restraint and Imaging

Choice of Anesthetic

• sodium pentobarbital

• chloral hydrate

• propofol

• isoflurane

• medetomidine/atipamezole

(Domitor/Antiseden)

Marmoset imaging restrainer and RF

electronics

Brain Activity and Recreational MDMA “Ecstasy”

To date, no one has done fMRI studies on humans or monkeys to observe changes in brain activity following oral MDMA.

post imaging

Brain Activation Following Oral MDMA (1mg/kg)

Activation of Limbic Circuitry Following Oral MDMA

N=6

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Adolescence vs Adulthood

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Pre-MDMA

Post MDMA

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A Special Thanks to…

Tara Messenger

Praveen Kulkarni

Marcelo Febo

Josie Harder

Mathew Brevard

SUPPORT

National Institute of Mental HealthNational Institute on Drug Abuse

&Insight Neuroimaging Systems (INSL)* Booth #1610

&Azevan Pharmaceuticals**

*Disclosure: Craig Ferris has a financial interest in INSL, the bioengineering company that produces the RF electronics and holders for animal imaging.

**Disclosure: Craig Ferris has a financial interest in Azevan, the pharmaceutical company developing drugs for the treatment of psychiatric disorders.

Animal Imaging Has Its Limits

Thank You