MAGNETIC RESONANCE IMAGING

Methods and Applications in Neuroscience Research

Craig Ferris, Ph.D. Center for Translational NeuroImaging

Department of Psychology Northeastern University

Magnetic Resonance Imaging “Then & Now”

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

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

High Resolution Magnetic Resonance Image of Marmoset Monkey Brain

The Neuroscience Toolbox for In Vivo Studies

Adapted from Huettel, Song and McCarthy, In: Functional Magnetic Resonance Imaging, 2004 Sinauer Associates Inc.

Animal    fMRI    ≥4.7T  

Electromagnetic Waves

“The energy of MRI”

E B

C

E B C

E - electric field B - magnetic field C - speed of light

1sec

t = .5 sec

frequency (f) = 1/t f = 1/.5 = 2 cycles/sec = 2 Hertz

λ = 1 m

C = λf

Electromagne8c  Spectrum    

radiowaves   microwaves   visible  light  

X-­‐rays,  gamma  rays  

Frequency  (Hz)  

Energy  (eV)  

MR  imaging  

103   104  

1  kHz  

105   106   107   108   109  

100  MHz  1  MHz  

1013   1016  1014   1015  

visual  imaging  

1017   1018   1019   1020   1021   1022  

X-­‐ray  imaging  

106  103  100  10-­‐5  10-­‐8  10-­‐11  

1  MeV  1  keV  

Wavelength  (m)  103   100   10-­‐6   10-­‐9   10-­‐12  

1  km   1  m   1  µ 1  nm   1  pm  

Superconducting Magnets

•  Generate external magnetic field - B0 •  Field strength between 1.5 – 11.7 Tesla (T) •  Operate near absolute zero temperature

Safety  ferromagnetic projectiles

radiofrequency fields and specific absorption ratio (SAR)

static magnetic fringe field “5-guass line”

gradient coils and current induction Note: high performance gradients with

high rise times (T/s) can induce currents in body tissue. FDA limits scanners to 6.0T/sec

Note: the electrical component of a transmitted RF pulse can heat tissue. The SAR of RF energy deposited is measured in watts/kilogram (W/kg). FDA limits -

biological effects Note: there are no know adverse bio-

effects from the static fringe field – including pregnancy

“Proton Imaging” 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

•  The time constant that defines the rate

of equilibrium is T1

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 f = γ BO

•  γ = 42.6 MHz/T for hydrogen •  When 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

• Angiography

• Diffusion Weighted Tensor Imaging

• Diffusion/Perfusion Imaging

• Function Imaging CBF – cerebral blood flow CBV – cerebral blood volume BOLD imaging

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

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

anes

thes

ia

awak

e

baseline

saline vehicle

5 min post

EtOH

15 min post

EtOH

baseline

saline vehicle

5 min post

EtOH

15 min post

EtOH

Applications •  phenotyping transgenic mice •  developmental biology •  neurotoxicology

MR Spectroscopy: Quantifying Brain Chemistry

Brain EtOH Levels

Angiography

normal rat cerebral vasculature

Applications •  ischemic and hemorrhagic stroke •  tumor research •  biomarkers of disease progression

medial cerebral artery occlusion

Courtesy of Bruker BioiSpin, 4.7T

Diffusion Imaging

Application

•  Ischemic stroke

occlusion of medial cerebral artery

MR angiography T2-weighted image Diffusion-weighted

image (DWI)

infarcted area infarcted area

Diffusion Weighted Tensor Imaging

Applications •  brain myelination and

development •  neurodegeneration •  in vivo neuropathology

DT maps of marmoset

Transla:onal  NeuroImaging  

§   transgenics  §   inbred  strains  § behavioral        phenotypes    

§   development  

§   small  size    

Marmoset  Monkeys  Mice  and  Rats  

§   monogamous  

§   twins  §   development  

§   small  size  

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

•  Odors

•  Visual Images

•  Tactile Stimulation

•  Drug Challenges

•  Complex Environmental Cues “vivarium”

Predatory  Conditioned  Fear

sable ferret rat

Functional MRI in Awake Animals Set-up -animals are lightly anesthetized with 3% isoflurane, placed in the holder, allowed to awaken and moved to scanner.

Computer Console

7.0T MR Scanner

Set-up takes ca 10 min to start of image acquisition.

Custom Radiofrequency Technology

restrainer  

head  coil  Quad transmit/receive volume coil built into the head holder

Optimal signal-to-noise and field homogeneity

Spatial and Temporal Resolution Twenty-two 1 mm thick slices of the brain are acquired in 6 sec with a HASTE pulse sequence (Half Fourier Acquisition Single Shot Turbo Spin Echo)

Field of View: 3.0 cm

Data Matrix: 96 x 96

voxel size

312 µm2 X 1000 µm

sagittal view

axial view

A measure of signal intensity is collected in each of ca. 15,000 voxels every six seconds.

Basal condition

BLO

OD

FLO

WΔ 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

Functional Imaging Using BOLD

BOLD Imaging: A Critical Tool for Studying Brain Function

•  Since Ogawa’s original paper there have been 5,408 publications on BOLD imaging.

•  Only 234 have used animals – why?

They  don’t  sit  s:ll.  

Acclimating Animals to the Imaging Protocol

Physiology and Stress Hormone

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

Atlas

Three Dimensional Segmented Atlases

Registration “Group Statistics”

Segmentation

Activation Maps

3D Visualization

GUI

Quantifying MRI Signal – Volume of Activation & Percent Change

Marmoset atlas has 234 brain regions

-2

0

2

4

6

8

10

12

60 0 60 120 180 240 300

% C

hang

e in

BO

LD S

igna

l

% C

hang

e in

BO

LD S

igna

l

Time (sec) Time (sec)

Hippocampus Cortex68 µg/kg cort 68 µg/kg cort17 µg/kg cort 17 µg/kg cortvehicle vehicle

Bar Graphs Showing Volume of Activation Between Groups

Time Course Plots Showing BOLD Signal Change Between Groups

Rat atlas has 174 brain regions

Mouse atlas has 140 brain

regions

Vole atlas has 140 brain

regions

Nursing  

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  …  

Brain  ac:vity  suggests  suckling  is  a  rewarding  experience.    

•  Mesocor:colimbic  dopaminergic  pathways  are  ac:vated.    

•  Previous  studies  show  suckling  has  many  of  the  proper:es  of    addic:ve  drugs.  Suckling  mo:vates  bar  pressing  for  pups  and  condi:oned  place  preference.  

 (Fleming,  Spear,  and  Morrell  labs)    

Ferris  et  al.,  J  Neurosci  25:149-­‐156  (2005)  

Is  motherhood  more  rewarding  than  cocaine?  

…  it  would  seem  so.  

How do you interpret these findings ?

• The salience of reinforcing stimuli is state dependent.

• The maternal brain has evolved to favor the reinforcing experience of pup suckling over other hedonic stimuli.

• Can this notion of prioritizing one hedonic stimulus over another in the context of evolution and survival be tested for another behavior like sex?

Pain  

5 min baseline 10 min capsaicin or formalin stimulation

50 40 90 60 110

100

120

70 10 20 30 80 150 image acquisition (10/min)

130

140

150

Data Analysis for Pain

Acute Pain – Experimental Design

Constructing a Template of the Pain Neural Circuit

Constructing a Template of the Habenular Neural Circuit “Imaging the anticipation and prediction of aversive

events.”

Negative BOLD Over Time: Engagement of the Diffuse Noxious Inhibitory Control

System?

DNIC provides a long lasting, inhibitory modulation of dorsal horn and trigeminal nuclear activity involved in transmitting nociceptive signals to the pain neural circuit

Dissociation of Cortex and Basal Ganglia

Does the Brain Process Pain Under Anesthesia?

General anesthetics activate a nociceptive ion channel to enhance pain and inflammation

Jose´ A. Matta*, Paul M. Cornett*, Rosa L. Miyares*, Ken Abe†, Niaz Sahibzada*, and Gerard P. Ahern*‡

PNAS June 24, 2008 vol. 105 General anesthetics (GAs) have transformed surgery through their actions to depress the central nervous system and blunt the perception of surgical insults. Counterintuitively, many of these agents activate peripheral nociceptive neurons. However, the underlying mechanisms and significance of these effects have not been explored. Here, we show that clinical concentrations of noxious i.v. and inhalation GAs excite sensory neurons by selectively activating TRPA1, a key ion channel in the pain pathway. Further, these GAs induce pain-related responses in mice that are abolished in TRPA1-null animals. Significantly, TRPA1-dependent neurogenic inflammation is greater in mice anesthetized with pungent compared with nonpungent anesthetics. Thus, our results show that TRPA1 is essential for sensing noxious GAs. The pronociceptive effects of GAs combined with surgical tissue damage could lead to a paradoxical increase in postoperative pain and inflammation.

While general anesthetics suppress CNS activity and induce unconsciousness

through activation of GABA receptors, do they suppress pain by enhancing pain?

Question?

Is pain a remedy for pain?

Thanks  Praveen  Kulkarni  Thom  Barchet  William  Kenkel    Seth  Finklestein    Martha  Shenton  Zora  Kinkinis    Mark  Nedelman    

Awake  Animal  Imaging  Has  Its  Limits  

Thank  You