MRI - functional MRI, spectroscopy, etc

Lecture 24

Functional MRI: Principles

Prerequisites: Oxyhemoglobin (oxygen rich hemoglobin) which delivers oxygen in arteries to brain cell is diamagnetic χ > 0

Deoxyhemoglobin (oxygen poor hemoglobin) which gave some of its oxygen molecules to brain cells is paramagnetic: χ <0

Paramagnetic substance produces microscopic field inhomogeneities that decreases the transverse relaxation time T2 of the blood and surrounding tissues.

Magnetic susceptibility χ: M = χ HM is the magnetization of the material, H is the strength of the external magnetic field

χdeoxy>>χoxy ratio ~ 65

T2* images and blood oxygen level depend (BOLD) contrast

(Ogawa, 1990)Oxygenated

bloodDe-oxygenated

blood

Diamagnetic Paramagnetic

Neuron

Oxyhemoglobin Oxyhemoglobin and and Deoxyhemoglobin Deoxyhemoglobin ininVeins during Brain ActivationVeins during Brain Activation

OxyhemoglobinDeoxyhemoglobin

Rest Activation

Normal blood flow High blood flow

Neural activation increased demand for oxygen=)=)=)=)

increased flowincreased blood flowaltered oxi /dioxi ratio

Naively, this would lead to decrease of T2. However the blood flow overcompensates the demand so T2 actually increases in the area of the neural activity.

One studies the difference between on and off task.

Perspectives: Mapping of brain function in health and disease in response to various stimulation paradigm

BOLD fMRI

Time

Inte

nsity

Rest

Task

BOLD effect

Statistical map

thresholded

activation

Activation and structural image

Clinical applications

• Mapping motor and language areas in patients with brain tumors

• Neurosurgeon guided by fMRI

tumor

Activation upon Perception of Disgust

Faces from a standard set were computer-transformed, to create two levels of intensity of expressed fear and disgust. Examples of faces depicting 100% neutral, 75 and 150% disgust, and 75 and 150% fear are demonstrated, together with an example of a stimulus depicting a mildly happy expression (75% neutral and 25% happy) which was used as the neutral baseline.

Phillips et al, Nature 389:495 (1997)

Figure 1 (next slide) Generic brain activations in seven right-handed normal subjects during perception of faces depicting 75% (top row) and 150% (bottom row) disgust intensity. The grey-scale template was calculated by voxel-by-voxel averaging of the individual EPI images of all subjects, following transformation into Talairach space. The transverse sections in each experiment are at 2 mm below (left) and 9 mm above (right) the AC-PC line (right side of the brain on the left side of each section, and vice versa). Major regions of activation (probability of false activation <0.004) for perception of faces depicting 75% disgust versus a neutral expression are demonstrated in the right insula (I) and right medial frontal cortex (BA 32); those for faces depicting 150% disgust versus a neutral expression are demonstrated in the right and left anterior insula (I), right anterior insula bordering on inferior frontal cortex (BA 44), right putamen (P), and right middle temporal gyrus (BA 21).Figure 2 (next slide) The difference image demonstrating significant (P < 0.004) differences in activation for perception of faces depicting 150% intensity of disgust (versus a neutral expression) and faces depicting 75% intensity of disgust (versus a neutral expression). The grey-scale template was as for Fig. 1. The largest region of activation was in the right anterior insula (Talairach coordinates 38, 17, 9), with twice the number of activated voxels compared with other regions of the difference image. Transverse (z = 9) and coronal (y = 17) sections are shown depicting this activation in the right insula.

Activation upon Perception of Disgust

Phillips et al, Nature 389:495 (1997)

difference

75%

150%

Figure 1 (next slide) A representative axial slice from a 'late' bilingual subject (A) shows all voxels that pass the multistage statistical criteria at P < 0.0005 as either red (native language) or yellow (second acquired language). An expanded view of the pattern of activity in the region of interest (inferior frontal gyrus, Brodmann's area 44, corresponding to Broca's area) indicates separate centroids (+) of activity for the two languages. Centre-of-mass calculations indicate that the centroids are separated on this plane by 7.9 mm. The green line on the upper right mid-sagittal view indicates the plane location. R indicates the right side of the brainFigure 2 (next slide) A representative axial slice from an 'early' bilingual subject (G) who learned English and Turkish simultaneously during early childhood shows all voxels that pass the multistage statistical criteria at P < 0.0005. Red indicates the Turkish language task and yellow indicates the English language task. An expanded view of the region of interest (Broca's area) indicates multiple common voxels between the two language areas. The geometric centers-of-mass indicate that the centroids are within 1.5 voxels. R indicates the right side of the brain

Late vs. Early Second Language

Early-learned 2nd language

Late-learned 2nd language

Kim et al, Distinct cortical areas associated with native and second languages, Nature 388:171 (1997)

Functional MR imaging of the primary motor cortex, activated when the subject’s hand repeatedly opens and closes. Note - this is NOT a real time filming. It is produced by subtraction of measurements at rest and during the activity.

The physical basis of the MRS. Protons in lipids have slightly different resonance frequency than in water. This is because electrons in the molecule interact with external magnetic field. They have magnetic moments 1860 times larger than protons and may screen a bit the external field as their orbitals are modified by the external field.

where is the shielding constant expressed in units of 10-6 . Spectra are plotted as a function of with area under the peak proportional to the number of protons in this state.

ω̄= γB(1�σ)σ

σ

MR Spectroscopy (MRS)

Since the shift is very small, MRS with fine tuning of the frequency to suppress signal from water. This can be done only without gradient field. Still localized measurements are possible - brain, kidneys, liver... . In addition to protons, several other nuclei are used 31P, 13C,...

a non-invasive tool for quantitative biochemical analysis

MRI vs. MRS

With MRI you depict

WATERand

Fat

Water; Intramyocellulae Lipids, Acetate; Alanine; Aspartate; Choline;

N-acetylaspartate; Creatine; myo-Inositol; Ethanol; Lactate;

Glutamate; Phosphoryl-choline; Glycerophosphoryl-choline; Keton

Bodies; γ-Aminobutyrate; Glucose; Glutamine; Glycine; scyllo-Inositol; Macromolecules;

N-Acetylaspartylglutamate; O-Phosphoethanolamine; Taurine; Threonine;

Glycogen; Carnosine, Carnitine, Acetylcarnitine, Phenylalanine; Succinate;

Phosphocreatine; Adenosinetriphosphate; pH; NAD; 2,3-Diphosphoglycerol; Deoxymyoglobin; Deoxyhemoglobin; Citrate; Betaine; Propanediol;

Homo-Carnosine; Glutathione; .....

With MRS you determine

Single-Voxel MRS Studies of Alzheimer’s Disease(Neurology 2001; 57: 626-632)

Single-Voxel MRS Studies of Alzheimer’s Disease

Choline Creatine

Citrate

ppm 3.5 3.0 2.5 2.0 1.5 ppm 3.5 3.0 2.5 2.0 1.5 ppm 3.5 3.0 2.5 2.0 1.5

Atrophy or Necrosis Benign Tissue CancerKurhanewicz et al, Radiology,1996; 200:489-96.

MRS: Evaluation of Prostate TumorsH

isto

logy

Creatine

CitrateCholine

1 H-M

RS

beforeCryo-Therapy successfull

Cryo-therapy

failed Cryo-Therapy

Judged by Cho/Citrate ratio

Kurhanewicz et al

MRS: Therapy Control for Prostate Tumors

Cho - choline compounds (phosphocholine, glucero-phosphocholine)

Choline is a quaternary saturated amine with the chemical formula: (CH3)3N+CH2CH2OHX−. where X− is a counterion such as chloride

Choline is a quaternary saturated amine with the chemical formula: (CH3)3N+CH2CH2OHX−. where X− is a counterion such as chloride

A counterion is the ion that accompanies an ionic species in order to maintain electric neutrality. In table salt the sodium cation is the counterion for the chlorine anion and vice versa. In a charged transition metal complex, a simple(i.e. non-coordinated) ionic species accompanying the complex is termed the counterion.

Localization of Spectroscopic Voxel for a Patient with MetastaticSquamous Cell Carcinoma

Pre-therapy Post-therapy

1H MRS for Monitoring Head and Neck Cancer Response to Therapy

Proton Spectra of a Patient with SquamousCell Carcinoma

Pre-therapy Post-therapy

MRI of Thin Air… but surely you can’t image air !

No, not thick air,

but if we add hyperpolarized gas,

… !

Hyperpolarized 129Xe ImagingPolarization is performed using a circularly polarized laser light (s+, the red wavy line in left picture) tuned to the specific transition in Rb. This causes population to build up in the 5S1/2 state of Rb. A collision will have a chance to exchange this polarization to the Xe. The N2 is present to keep fluorescence of the Rb to a minimum. Put all of this inside a weak magnet and one has polarized our xenon far greater then any magnet alone

MRI of the lung

129Xe

1H

Volume rendering of lungs using hyperpolarized He. 3A 3D FLASH sequence was used to obtain the 60 sections (4.33mmthickness,each). TR/TE = 5.85/2.5ms; Flip angle = 2.2 degrees; matrix = 70*128; FOV = 300*400 mm and time to acquire the entire 60 sections was 24.6 seconds.

http://imaging.med.virginia.edu/hyperpolarized/rendering.htmmovie:

Dynamic images of the human lung

during inhalation and expiration of 3He

Contrast Agent for MRI of Gene Expression

In vivo visualization of gene expression using MRIAngelique Y. Louie et al. Nature Biotechnology 18, 321 - 325 (2000)

Gd3+ hidden Gd3+ exposed

If galactosidaseis present (i.e.gene expressed),it cleaves asugar residue toexpose (activate)Gd3+, a MRIcontrast agent.

Schematic of the transition of EgadMe from a weak to a strong relaxivity state.

EgadMe, a contrast agent, consists of chelated gadolinium caged by a galactopyranose molecule. The cage door is removed only when EgadMe comes in contact with a beta-galactosidase enzyme.(A) Schematic diagram representing the site-specific placement of the galactopyranosyl ring on the tetraazamacrocycle (side view). Upon cleavage of the sugar residue by beta beta-galactosidase (at red bond), an inner sphere coordination site of the Gd3+ ion becomes more accessible to water. (B) Space-filling molecular model (top view, from above the sugar residue) of the complex before (left) and after cleavage by the beta-gal (right), illustrating the increased accessibility of the Gd3+ ion (magenta) upon cleavage: white, H; red, O; blue, N; gray, C.