# Multimodality Imaging (MRI, PET, CT, etc..)

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Multimodality Imaging (MRI, PET, CT, etc..)
Jonathan Dyke, Ph.D. Assistant Research Professor of Physics in Radiology Citigroup Biomedical Imaging Center Weill Cornell Medical College Sackler Institute for Developmental Psychobiology Summer Lecture Series July 9, 2009 A college physics professor was explaining a particularly complicated concept to his class when a pre-med student interrupted him. "Why do we have to learn this stuff?" one young man blurted out. "To save lives," the professor responded before continuing the lecture. A few minutes later the student spoke up again.  "So how does physics save lives?" The professor stared at the student for a long time without saying a word. Finally the professor said, "Physics saves lives, because it keeps certain people out of medical school."

We’re going to explore step by step how one gets from a radioisotope to a metabolic uptake scan acquired using PET. Unlike anatomical MRI, PET requires injection of a radiotracer in order to obtain signal.

TR 19/9 Ebco Cyclotron facility that produces 19.2 MeV proton/9.5 MeV Deuterons.

Cyclotron design from Ernest Lawrence’s
The electrodes shown at the right would be in the vacuum chamber, which is flat, in a narrow gap between the two poles of a large magnet. In the cyclotron, a high-frequency alternating voltage applied across the "D" electrodes (also called "dees") alternately attracts and repels charged particles. The particles, injected near the center of the magnetic field, accelerate only when passing through the gap between the electrodes. The perpendicular magnetic field (passing vertically through the "D" electrodes), combined with the increasing energy of the particles forces the particles to travel in a spiral path. Cyclotron design from Ernest Lawrence’s 1934 patent application.

Atomic # = # protons (never changes)
Basic HS Chemistry is useful. What does the atomic # define? Atomic # = # protons (never changes) What does the atomic mass define? #protons + #neutrons = Mass # My apologies to those of you who excelled in chemistry, but a little review for the rest of us in regards to the periodic table of the elements. When producing a radioisotope using a cyclotron, one of the primary reactions occurs by bombarding a target with a beam of protons. What actually happens when you add a proton to an element? In order to conserve charge and mass, a neutron is also lost in the reactions changing the atomic mass number and producing a radioactive “isotope” of that nuclide.

The radius will increase until the particles hit a target at the perimeter of the vacuum chamber. Various materials may be used for the target, and the collisions will create secondary particles which may be guided outside of the cyclotron and into instruments for analysis. Orange box indicates target material used. Radioisotopes relate to the raw radionuclide prior to being bound to a specific compound. A radiotracer is the term used to describe the radioisotope after being bound to a specific amino acid, ligand or metabolically active compound.

16O + p -> 18F + n 8 9 Production of 18F precursor to FDG
Target Material: Purified Water 16O + p -> 18F + n 8 9

Positron Emission Tomography “PET” Scan (“DOG” Scan)
The PET scan

e+ + e- -> ga + gb Is a positron stuff of fiction?
Andersons cloud chamber picture of cosmic radiation from 1932 showing for the first time the existence of the anti-electron that we now call the positron. In the picture a charged particle is seen entering from the bottom at high energy. It then looses some of the energy in passing through the 6 mm thick lead plate in the middle. The cloud chamber is placed in a magnetic field and from the curvature of the track one can deduce that it is a positively charged particle. From the energy loss in the lead and the length of the tracks after passing though the lead, an upper limit of the mass of the particle can be made. In this case Anderson deduces that the mass is less that two times the mass of the electron. Ref. : Carl D. Anderson, Physical Review vol. 43, p. 491 (1933) e+ + e- -> ga + gb

PET: Coincidence Detection
As the radioisotope undergoes positron emission decay (also known as positive beta decay), it emits a positron, an antiparticle of the electron with opposite charge. After travelling up to a few millimeters the positron encounters an electron. The encounter annihilates them both, producing a pair of annihilation (gamma) photons moving in opposite directions. Courtesy: Brookhaven National Lab

Filtered Back Projection
(Key for both PET and CT!) When a positron decays into two back to back photons, you then only know the line of origin (LOR) or possibly a 10cm segment of that line with fast electronics. The analogy that my advisor taught me that I’ve carried is if you were to look in 4 windows of a house at a table, could you tell if it were square or round with only 4 angles?? Courtesy: Univ British Columbia

Clinical Applications of PET
Alzheimer’s Disease In practice, since the brain is normally a rapid user of glucose, and since brain pathologies such as Alzheimer's disease greatly decrease brain metabolism of both glucose and oxygen in tandem, standard FDG-PET of the brain, which measures regional glucose use, may also be successfully used to differentiate Alzheimer's disease from other dementing processes, and also to make early diagnosis of Alzheimer's disease.

Primate - 11C-Raclopride Imaging
11C-Raclopride is a dopamine antagonist that acts on D2 and D3 receptors. The majority of these receptors are located in the basal ganglia, which can be clearly seen in these images. This study in primates examines the effect of various opiates on the dopamine receptor areas of the brain. The close proximity of the production, radiochemistry and imaging facilities at CBIC allow synthesis and imaging of a 20 minute half life radiolabeled pharmaceutical to occur without loss of product due to decay. Courtesy: Shankar Vallabhajosula, Ph.D.

2-[fluorine-18] fluoro-2-deoxy-D-glucose (FDG)
18F-FDG Lymphoma Study: 2-[fluorine-18] fluoro-2-deoxy-D-glucose (FDG) 18F-FDG Lymphoma Study: PET with 2-[fluorine-18] fluoro-2-deoxy-D-glucose (FDG) may play an important role in the evaluation and management of malignant lymphoma. FDG uptake is predictive of therapeutic response during the course of treatment. The adjacent images show advanced progression of the disease with focal nodules showing increased glucose metabolic uptake throughout the body. PET in Oncology To differentiate between benign and malignant tumor tissue using [18F]FDG. HCFA approved indications: Solitary pulmonary nodule, Staging of Lung Cancer, Lymphoma, Breast Cancer, Colorectal cancer, Head and neck Cancer, Melanoma, Thyroid cancer [elevated Tgb; negative I-131] Quantitative dosimetry of readiolabeled monocloncal antibodies and small molecular weight ligands using Y-86, I-124. Investigational tumor imaging with [18F] fluorocholine, [18F]fluorotyrosine

11C-5-Hydroxytryptophan (5-HTP)
5-HTP is a naturally-occurring amino acid and is also a precursor to production of the neurotransmitter serotonin. 5-HTP is preferentially taken up by carcinoid tumors of the liver that produce serotonin. The radiolabeled 11C analog of 5-HTP is shown to aggregate in tumor nodules of the liver as well as several metastatic sites throughout the body.

Standard Uptake Value:
Image Analysis: Standard Uptake Value: Basically assumes that an even distribution of radioactivity within the entire body would results in an SUV of 1.0… An SUV of 5 means that this region of interest has 5 times the average uptake of radioactivity.. It is not an absolute measure of quantitation and varies for FDG scans with blood glucose level, % body fat ( as FDG does not enter fat). Compartmental modeling is a more accurate analysis tool. Pre-Tx SUV=15 Post-Tx SUV=2 Courtesy: PET/CT in clinical practice By T. B. Lynch, James Clarke

Computed Tomography “CAT Scan”

Creation of X-Rays Circa 1896
X-rays are electromagnetic waves of short wavelength, capable of penetrating some thickness of matter. Medical x-rays are produced by letting a stream of fast electrons come to a sudden stop at a metal plate;. Hand mit Ringen (Hand with Rings): print of Wilhelm Röntgen's first "medical" X-ray, of his wife's hand, taken on 22 December By 1896 an x-ray department had been set up at the Glasgow Royal Infirmary, one of the first radiology departments in the world. The head of the department, Dr John Macintyre, produced a number of remarkable x-rays: the first x-ray of a kidney stone; an x-ray showing a penny in the throat of a child,

X-Ray Tube Construction
Circa 1900 As with any vacuum tube, there is a (-) cathode, which emits electrons into the vacuum and an (+) anode to collect the electrons, thus establishing a flow of electrical current, known as the beam, through the tube. Filament serves as an electron source. A high voltage power source, for example 30 to 150 kilovolts (kV), is connected across cathode and anode to accelerate the electrons. The X-ray spectrum depends on the anode material and the accelerating voltage Electrons from the cathode collide with the anode material, usually tungsten, molybdenum or copper, and accelerate other electrons, ions and nuclei within the anode material. About 1% of the energy generated is emitted/radiated, usually perpendicular to the path of the electron beam, as X-rays. Circa 2000

Do the following appear Dark or light on an X-Ray image? Air Fat Bone
X-Ray Densities Do the following appear Dark or light on an X-Ray image? Air Fat Bone The images produced by X-rays are due to the different absorption rates of different tissues. X-ray film silver halide particles absorb Calcium in bones absorbs X-rays the most, so bones look white on a film recording of the X-ray image , called a radiograph. Fat and other soft tissues absorb less, and look gray. Air absorbs the least, so lungs look black on a radiograph.

CT Hounsfield Units

CT Hardware

In the ED it’s FAST! Advantages:
CT completely eliminates the superimposition of images of structures outside the area of interest. because of the inherent high-contrast resolution of CT, differences between tissues that differ in physical density by less than 1% can be distinguished. data from a single CT imaging procedure consisting of either multiple contiguous or one helical scan can be viewed as images in the axial, coronal, or sagittal planes, depending on the diagnostic task. This is referred to as multiplanar reformatted imaging. In the ED it’s FAST!

CT Diagnostic Utility:
Head: Chest: Cardiac: Abdominal and pelvic: Extremities: Trauma, Stroke, Tumor, Biopsy Lungs, Pneumonia, Emphysema, Embolism Coronary artery disease (High Dose) Renal stones, appendicitis, pancreatitis, diverticulitis Fractures, dislocations.

CT - Stroke CT assessment of stroke is very rapid which allows intervention and salvage of tissue at risk in the ischemic penumbra. A new study suggests that magnetic resonance imaging (MRI) gives a more accurate early assessment of stroke than the more commonly used computed tomography (CT) imaging technique. MRI was especially effective in identifying patients with acute ischemic stroke, who can benefit from swift treatment with clot-busting interventions.

CT Perfusion CBF CBV MTT AJNR 2000;21:1441–1449.
CBF maps predicted the extent of cerebral infarction with a sensitivity of 93% and a specificity of 98%. In contrast, CBV maps were less sensitive and TTP maps were less specific and also showed areas of collateral flow. Infarction occurred in all of the patients with CBF reduction of more than 70% and in half of the patients with CBF reduction of 40% to 70%. CONCLUSION: Dynamic CT perfusion imaging safely detects tissue at risk in cases of acute stroke and is a feasible method for any clinic with a third-generation CT scanner.

Assumes linear relationship between radiation dose and cancer risk (Controversial). Risk for pediatric patients developing cancer from CT scan is greater than adults. ~ 500 in every 600,000 scans. “CT is an extremely valuable tool, and nobody should hesitate to undergo CT when it is indicated.” These calculations are based on the assumption of a linear relationship between radiation dose and cancer risk; this claim is controversial, as some but not all evidence shows that smaller radiation doses are less harmful

Advanced MRI Applications CONTRAST ENHANCEMENT DIFFUSION IMAGING
FAST IMAGING METHODS FUNCTIONAL IMAGING PERFUSION IMAGING SPECTROSCOPY BASICALLY, I’M GOING TO COVER PAGES IN HUDA IN 2 HOURS. So we’re going to go at a breakneck speed of a page an hour. There are also only a handful of questions on the board exam relating to MRI applications. They are behind the times. Depending on the time we take, please feel free to ask questions about previous MR topics that were a bit fuzzy as well. Or if I’ve left out something that strikes your interest we can also talk about this at the end as well.

As tough to get volunteers for this one as the endorectal coil.

Magnetism of Materials
Dia Weakest c~-1 Para Weak c~10 Ferro Strong c~25,000 Super Strong c~5000 What materials are magnetic in nature? ALL MATERIALS!! Diamagnetism is the weakest category of mag materials but all biological materials possess this property. As long as the magnetic force equals the gravitational force something can levititate in a mag field. They have negative mag susceptibilities and divert the field lines making them weaker. [water, organics] Paramagnetism concentrate field lines in postive way [ions, salts, Chelates Gd, Cu, deoxyhemoglobin] – unpaired outer shell electron align with field! Ferromagnetic – [Fe, Ni, Co] large Fe3SO4 particles multiple domains or memory. Superparamagnetic – small Fe3SO4 particles – small iron oxide particles Single domain particles. No magnetic memory MENTAL NOTE: these mag suscept vary between air & tissues and Cause artifacts in images as Henning mentioned.

How does it affect the signal?
What type of material is Gadolinium? How many unpaired e- does in Gd-DTPA? What compound do we detect the effect of contrast on? Gd is a very toxic metal in its pure form but is bound in a chelate and FDA approved since 1988. The larger the number of unpaired electrons, the larger the magnetic moment of the contrast agent. Gd has 7 – how many does hydrogen have? 1! Gd also has a very large magnetic susceptibility.. Making it paramagnetic and aiding in aligning spins. Gd-DTPA interacts/binds directly with water which is the primary signal source for MRI. Gd thereby polarizes the binding between hydrogen and oxygen. “This causes an enhanced dipole moment of water, which results in an enhanced magnetic moment! Due to thermal motion the gadolinium does not increase the magnetic moment of just one water molecule but of all water molecules that are present in its vicinity! “

1 = 1 + R1,2 C T1,2 T10,20 Contrast Mechanisms Dictate Method of Study
in Magnetic Resonance Imaging How does an agent affect relaxation times? 1 = R1,2 C T1,2 T10,20 Solomon-Bloembergen Equations (1955) As the concentration in a voxel increases, both T1 & T2 relaxation times decrease. Positive agents = shorten T1 Negative agents = shorten T2 USPIO agents – super paramag iron oxide Used by Berlex – Feridex in liver imaging where a decrease in signal indicates cancer Gd-DTPA shortens T1 more than T2.

What factors influence whether the T1 or T2 effect will dominate the MRI signal?
Both time curves were taken with a T1W GRE on the same animal with a single dose of contrast. The Gd leaks out of the vasculature in the muscle and slowly diffuses back allowing the T1 effect to dominate. This is a long range spin-lattice effect that takes place when the Gd leaves the capillary bed & goes into the extracellular space. The BBB in this mouse is intact and the Gd is quickly cleared by the capillaries allowing the T2* effect to dominate. This effect is a short range spin-spin relaxation effect seen when the Gd stays in the capillary bed.

Tumor, Stroke, Angiography CNS disease
Clinical Apps: Why are contrast agents necessary given the excellent resolution of un-enhanced MRI images? When is a contrast scan prescribed? Relaxation props of normal vs. pathology do not always allow maximal contrast or sensitivity (i.e. small tumor may be isointense on T1) If I had a brain tumor and got no Gd I would scream! Contrast adds functional info about uptake kinetics CLINICALLY PRESCRIBED EXAM PROTOCOLS Brain (infections(difficult to detect along the ependyma or meninges ), inflammations, tumors) MR Angiography – vessel patency/stenosis note angio is not perfusion but flow!! Stroke – diffusion perfusion mismatch – PWI show regions at risk for infract. Tumor, Stroke, Angiography CNS disease

But.. Talk is cheap.. The microvasculature in the lesion takes up the Gd-DTPA to a greater degree than the surrounding tissue. These are static images taken 90 seconds apart using a 3D GRE imaging sequence. Gd-DTPA contrast studies are of use in assessing angiogenesis and neovasculature and we have actually correlated dynamic MRI uptake parameters with markers such as VEGF.

Nephrogenic Systemic Fibrosis No cases reported before 1997.
A causal link with Gadolinium chelate based MRI contrast agents is apparent to cases of NSF. This disease is sometimes fatal and only patients with renal impairment, and traditionally on dialysis, were found to contract the disease in association with MR contrast agents Care must be taken in prescribing MR contrast for patients with renal failure at risk for contracting this disease for which there is no effective treatment. The cause of NSF is unclear and the link with gadodiamide is still speculative although more cases are becoming reported.

MRI DIFFUSION IMAGING

CLINICAL APPLICATIONS
BASIC DWI PHYSICS CLINICAL APPLICATIONS TRACTOGRAPHY Going to cover the definition and application of diffusion imaging. We’ll look at how diffusion occurs in various physiological systems and the MR sequences and measurements needed to detect it. I’ll close it off by dabbling in a little white matter tractography that our group here at the imaging center has put together. The onset of DWI is really something that came into clinical use only around 10 years ago and arrived hand in hand with echo planar imaging. The first clinical epi and then dwi-epi sequence available on our GE 1.5T scanners came when I first was at Memorial as a post-doc in 1998. Research in this area is a hot topic at most conferences.

What physical aspects or systems In nature exhibit diffusion?
What principles govern diffusion? 1827 – robert brown rubbed his eyes and observed random agitated motion of pollen molecules Same thing in effect when a drop of dye enters a bucket of water. 1905 – albert einstein proposes the principle of thermal brownian motion and postulates that liquids are composed of particles. 1926 – perrin verifies theory in experiment and receives nobel prize

How far does a drunk walk? <R(t)2>= 2 D t vs. R(t)= v t
The “Drunken” Walk Einstein – 1905 How far does a drunk walk? <R(t)2>= 2 D t vs. R(t)= v t DH O= 3x10-3 mm2/s Dbrain = 1x10-3 mm2/s So how far does a drunk walk.. It depends on whether he bumps into people and things right? (We’re also assuming he does not fall down and pass out) The analogy seems crude but I guarantee that you will not forget this concept. Why is Dbrain < DH2O? In the human brain, water diffusion is a three-dimensional process that is not truly random because the diffusional motion of water is impeded by natural barriers. These barriers are cell membranes, myelin sheaths, white matter fiber tracts, and protein molecules. 2

What affect does diffusion
have on the MRI signal? S=S0 e –b D DWI Atten Brain = 1/(2.782) DWI Atten CSF = 1/(2.782^3) So what % signal decrease do we expect for brain tissue and CSF using a standard b-value or diffusion gradient strength of 1000 s/mm2? S/S0 water = exp (-1000* 0.003) = 4.6% S/S0 brain = 36% This is why normal brain stays around in the DWI image but CSF or vasogenic edema drops out.

How can you image diffusion at the cellular level accounting
for patient motion? Patient motion ~ 1-2mm Diffusion length ~ mm This question is why DWI did not come onto the scene until echo planar imaging appeared.. When you are trying to measure something on the order of 10 to 100 times smaller in magnitude Than standard patient motion.. It presents a barrier. We’ll now take quick look at the DWI pulse sequence and show How part of this enigma is overcome.

Pulse Sequence: Spin-Echo Diffusion Weighting
RF Excitation G G Gx Image Acquisition Gy Diffusion weighting can be added to almost any Spin Echo pulse sequence.. In order to eliminate patient motion it must be utilized with the fastest possible acquisition method clinically available which is the echo planar imaging. EPI can acquire a whole image on the order of 200ms which reduces the effects of patient motion during that small time frame. Understanding this sequence will give you a better handle on DWI. A gradient is applied prior to the 180 RF pulse and dephases the signal. Brownian motion now occurs at the cellular level. The 180 refocuses the spins and the same gradient is re-applied. Molecules that are stationary will be returned to the same spin state while those that moved will give a reduced signal. Gz

Why the different contrast between a DWI & ADC image?
We now know that tissue with a high diffusion coefficient has the greatest amount of molecular motion and therefore the greatest dephasing or decreasing MR signal in a DWI image. The apparent diffusion coeffiecient is that parameter in units of mm2/s that then is derived from the image that contains no diffusion gradient as well as one with a diffusion gradient The increased sensitivity of diffusion-weighted MRI in detecting acute ischemia is thought to be the result of the water shift intracellularly restricting motion of water protons (cytotoxic edema), whereas the conventional T2 weighted images show signal alteration mostly as a result of vasogenic edema. The reduced ADC value also could be the result of decreased temperature in the nonperfused tissues, loss of brain pulsations leading to a decrease in apparent proton motion, increased tissue osmolality associated with ischemia, or a combination of these factors. DWI = ADC

Clinical Apps: Acute AML pre/post Tx *Courtesy: Doug Ballon, 2003
Stroke is the routine clinical application for DWI but various tumors and haematopoetic diseases also benefit from DWI. Acute myelogenous leukemia Baseline study prior to myelosuppressive therapy 20 days later after remission. Water signal in the bone marrow is virtually absent after Tx. Only 2% myeloblasts in the differential blood count. Acute AML pre/post Tx *Courtesy: Doug Ballon, 2003

Isotropic vs. Anisotropic
We now turn our attention to how water diffuses preferentially along certain directions in the brain. Primarily, this can be seen in CSF that is alongside the pathway of the myelin sheaths. For a simple physicist like myself, I imagine the white matter tracts as cylinders surrounded by CSF wiring up our brain. If the fibers say run along the z axis, then the diffusion coefficient with be highest along z and lower along x and y. A.W. Song,

Diffusion Tensor Imaging
If diffusion gradients are applied in many directions, the direction of maximum anisotropy or greatest diffusion may then be calculated. Starting is a voxel at the base of the brain, one can then follow this Fractional Anisotropy value on a sub-voxel level until it dissipates. This is what is shown above. I acquired this DTI on a tumor patient at NYP. fMRI, DWI and standard FLAIR, 3DGRE sequences were also performed. One can see the displacement of the WM fiber tracts from the primary tumor site. Depending on the aggressiveness of the tumor, studies have been done monitoring displacement or destruction of the tracts through FA values. 3T MRI – NYP - Tumor

MR FUNCTIONAL IMAGING Traditionally MRI had previously only been thought of as an anatomical imaging modality. It’s strong point was that MRI used inherent tissue relaxivities to segment and discriminate soft tissues without the use of ionizing radiation. (which sets it apart from CT) The ability to detect function or metabolism of those tissues was left to those that manufactured radiotracers. With the onset of spectroscopy and later fMRI a niche has been formed that allows MRI to contribute to this field of research.

PHYSIOLOGICAL FACTORS
BOLD EFFECT PHYSICS PHYSIOLOGICAL FACTORS CLINICAL APPLICATIONS The inherent use of deoxyhemoglobin in the blood as an endogenous tracer in-vivo has presented some amazing results and launched the field of MRI into the area of brain mapping. What factors influence the detection of the BOLD effect? Are we really seeing what we think we are seeing? Some clinical examples of fMRI done here in the 3T.

100 years pass….. Roy, C.S., and Sherrington, C.S. 1890.
On the regulation of the blood supply of the brain. J. Physiol. 11: 100 years pass….. Ogawa, S., Lee, T.M., Nayak, A.S., and Glynn, P Oxygenation-sensitive contrast I magnetic resonance image of rodent brain at high magnetic fields. Magn. Reson. Med. 14:68-78. A bit of history here shows that the link between neuronal activity and increased blood flow had been around for 100 years.

How does BOLD really work?
Oxyhemoglobin is diamagnetic Deoxyhemoglobin is paramagnetic Neuronal activity->Less deoxyhemoglobin Less susceptibility difference between capillary vessel and brain tissue Longer T2* Signal increase in T2* Sequence How big an increase are we talking about? Blood Oxygenation Level Dependent (BOLD) effect is the source of contrast in fMRI images. When neurons are activated, the resulting increased need for oxygen is overcompensated by a large increase in perfusion. As a result, the venous oxyhemoglobin concentration increases and the deoxyhemoglobin concentration decreases. As the latter has paramagnetic properties, the intensity of the fMRI images increases in the activated areas. As the conditions are alternated, the signal in the activated voxels increases and decreases according to the paradigm. This is where having a 3T magnet really gets you some signal. On a 1.5T scanner, you get a 3-5% signal intensity change Between periods of rest and activation. On a 3T scanner is really Is around double that level of activation and is much cleaner as well As allows for thinner slices or detection of weaker activation centers.

Blood Oxygen Level Dependent Signal Source: Buxton book Ch 17
What factors contribute or confound the BOLD affect? CBV, CBF, CMRO2 all play a part.. Doing ASL measures CBF!! When nerve cells are active, they consume oxygen supplied by local capillaries. Approximately 4-6 seconds after a burst of neural activity, a haemodynamic response occurs and that region of the brain is infused with oxygen-rich blood. Are there any physiological validations of this effect? It appears that BOLD is well correlated with both local field potentials (caused by electrical activity in dendrites) and with action potentials (spiking), but the correlation with LFPs is slightly better Source: Buxton book Ch 17

Repeated Trials – Dale/Buckner 1997
Hemodynamic Response This is the response one gets from a single instantaneously applied stimuli. The stimuli is then repeated but the patient is now “conditioned” or “refractory” and is expecting the stimuli and the change in response can be seen as additive. Responses to consecutive presentations of a stimulus add in a “roughly linear” fashion but subtle departures from linearity are evident. Key point: What do we actually measure in the MRI signal change? We get a convolution of the response function with the block design and we see a resulting change in MR signal intensity. Dale & Buckner, 1997 Repeated Trials – Dale/Buckner 1997

Motor Activation in AFNI
shown here is a typical run on the NYP 3T magnet on a patient just prior to resective tumor surgery. It’s a team effort as the radiologist designs the paradigms and interprets the localization of the activation. The physicist acquires and processes the data and then the surgeon confers with the radiologist regarding regions of activation bordering the tumor. Clinically we typically do a simple block paradigm starting with 30 seconds off – 30 seconds on repeated 3 times total. You can see that although the signal is visually and statistically significant in correlating with the block paradigm step function. Each voxel in the image contains a separate time course and what is shown is a 3x3 grid of 9 voxels from the right motor strip. Slices are repeated for 111 time points yielding a 3:42 second scan time / fMRI paradigm. Data can also be overlaid on hi-res 3D SPGR sequences but do not accurately translate the distortion and susceptibility fallout seen in the acquired in the EPI images.

Where do we expect activation?
It is an amazing thing that fMRI can confirm or deny these assignments and in fact textbooks have been slightly modified to incorporate this information as well as in additional arenas such as white matter fiber tracking. Additionally, this scenario is also repeated for word generation, rhyming and picture naming to localize wernike’s and broca’s regions in relation to epileptic seizure foci or tumors. Where do we expect activation?

Cortical mapping in the surgical suite.
Historically how did the mapping of somatosensory and motor cortex to make diagrams like this take place? The alternative to fMRI is to map the motor cortex in the surgical suite as shown above.

Neuron, 2006,18;643-653. – Courtesy BJ Casey

Clinical Apps: Improving clinical procedures, e.g. presurgical planning for brain tumors Direct: Mapping of functional properties of adjacent tissue Indirect: Understanding of likely consequences of a treatment Understanding cognition Studying brain development Investigating brain physiology ** Henning – Minimally Conscious State

MR PERFUSION IMAGING So you may be thinking, we’ve already covered MRA what’s different about perfusion imaging from contrast enhanced MRA? How is perfusion different from flow? Perfusion is blood flow in the tissue. In MRA the flow is imaged in the large vessels.. Arteries/veins and the smaller arterioles/venules. This is a macroscopic flow like a garden hose measured in ml/min as in Doppler studies and quantitatively in phase contrast MRA. We’re now interested about flow in tumors, strokes and such. Let’s take a quick look at the path the contrast takes through the circulatory system.

Physiologically, what happens when a tracer enters the blood supply?
What factors influence the distribution and kinetics? Johns Hopkins – Dept Radiology In tissue, no exchange of tracers takes place in the arteries or veins where the walls are too thick. All transfer of the tracer from the blood supply outside the vessels takes place in the capillary bed. Capillaries have a HUGE surface area which facilitates rapid diffusion of substances from the blood to the surrounding tissue. ~ 25,000 miles, um in diameter ( 1 RBC Diam), They actually have to deform to get through the capillaries. Factors influencing how this occurs are: Size/weight of the tracer: Gd-albumin vs. Gd-DTPA Location of vessels -> permeability (BBB)

DYNAMIC CONTRAST ENHANCED IMAGING
T1W – DCE MRI DYNAMIC CONTRAST ENHANCED IMAGING Perfusion imaging is either categorized as positive or negative enhancing. As stated earlier, positive enhancement occurs with Gd-DTPA when it leaks out of a permeable vessel resulting in a long range spin-lattice effect on the surrounding water molecules evident on T1W images. Imaging utilizing the dominant T1 mechanism for contrast, results in positive signal enhancement due to the choice of contrast agent, pulse sequence and timing and vascular structure. DCE is basically the same thing as a cine sequence whereby a fast spoiled T1 weighted gradient echo just sequentially images slices over and over in time. Shown in the movie is a pediatric osteogenic sarcoma patient I imaged using DCE. The goal of this study was to determine a percent necrosis of the tumor via MR perfusion. We were able to correlate parameters from a pharmacokinetic model with % necrosis. 2D Fast Spoiled Gradient Echo, 12 mm slice, 8/0 slices, TR/TE 8 ms/2 ms, kHz RBW, 22 cm FOV, 256 x 128 matrix, 8.56 sec/resolution

Pediatric Osteogenic Sarcoma: Post-Chemotherapy
Grade IV Responder: 100% Necrotic 1 2 3 4 2 4 1 Key point is that different tissues exhibit different time intensity curves relating to flow, clearance and permeability of the tissue. The fastest enhancing tissue will always be that of the vasculature, in this case the popliteal artery, which delivers the contrast agent to the rest of the tumor. Highly vascularized tumor tissue will result in the next fastest uptake. A constant slow rise into normal muscle tissue can be seen in the 1st ROI and is being investigated by some groups as a reference by which the blood curve may be derived. The therapy induced necrotic central region of this Grade IV tumor exhibits a lack of uptake expected with a reduction in vasculature. 3

DCE-MRI & ANGIOGENESIS
What role does neovasculature fill in tumor growth? (Goldman,1907) How far from a vessel can a tumor cell survive? (Thomlinson & Gray,1955) Does DCE produce any physiologically significant parameters? A short digression here as this is one of my areas of interest. I’ve done some work in correlating DCE parameters with angiogenic factors such as VEGF. 100 years ago, scientists knew that vessels supplied substrates and oxygen to the tumor as well as eliminated toxic agents. Angiogenesis also somehow induced a mechanism of rapid growth. Though this was observed, the mechanism behind it remained mystery. To further illustrate the key role of angiogenesis, it is known that O2/nutrients can diffuse of 160 microns from the blood vessels, that the absence of vasculature promotes tumor necrosis! A tumor can grow to only 2-3mm in diameter beyond a blood supply before becoming hypoxic. * Physiological parameters are gained only through pharmacokinetic modeling of DCE uptake.

Pharmacokinetic Modeling of Tracer Kinetics
(Kety, 1951) ve dCe(t) = Ktrans (Cp(t)-Ce(t)) dt Cp Cp This is a two compartment model with a uni-directional transfer rate Ktrans between compartments. Ktrans is actually the product of permeability and surface area of the vessel. Vp is the plasma volume or the fraction of blood in the plasma (vessel). Ve is the fraction of blood in the extracellular extravascular space.

kep k12 Brix/Hoffman 2 Compartment Model kel Intravascular Kin Plasma
Gd-DTPA 0.1 mM/kg kep Interstitial Lesion kel Kin k12 Plasma Intravascular Several excellent models exist for extracting physiologically relevant parameters from T1-weighted MR perfusion studies. The model proposed by Tofts & Kermode in 1991 has become highly used in the field but requires acquisition of a T1-map and some knowledge of an arterial input function to yield absolute measures of permeability and extravascular volume. Another model proposed by Brix & Hoffman assumes an exponential decay of the blood curve and provides relative measures of permeability and extraction without acquiring a T1 map.

Does this model actually fit real data?
Representative compartmental model fits of tumor ROI’s for two patients with differing chemotherapy responses are shown with their respective model parameters. The amplitude of the model fit is greater for the more viable tumor. The transfer coefficient between the vascular and extracellular space (kep) is also greater for the grade II responder. Note the negative value of kel means that the model cannot account for curves that do not plateau before the end of the time course.

CLINICAL APPS: Tumors: breast, brain, bone
Drug Trials: anti-angiogenic Arthritis: joint/synovium BBB leakage/permeability Tumor assessment is a key clinical app for DCE.. Here are just the applications we’ve used it for just beginning with the letter “B”. Assessing anti-angiogenic drugs that cut off the tumor blood supply is done using DCE as well. A totally different application we’re looking at is assessing joint pain and arthritic severity using DCE. Additionally, BBB leakage whether caused by tumor, stroke, lupus or another neurodegenerative disease may also be assessed using DCE.

DYNAMIC SUSCEPTIBILITY
T2*W – DSC MRI DYNAMIC SUSCEPTIBILITY CONTRAST Negative contrast enhancement occurs when the Gd-DTPA stays in the vessel and flow is greater than permeability. This produces a much faster, shorter range effect dominated by a T2* DEPHASING effect. Gd shortens both T1 and T2 and both occur in all situations, but the effects are competing and depend whether the situation if flow dominated or permeability dominated. As the Gd remains in the vessel is interacts with other spins and the shorter T2* produces a dephasing of signal within the vessel as well as in neighboring water molecules due to thermal motion. This results in a decrease in signal intensity or a negative enhancement.

Representative Perfusion Maps
CBV CBF The primary clinical application of DSC imaging is in neurovascular applications in patients presenting cerebrovascular disease, stroke, aphasia, etc. It has been used in other organs such as liver using T2* specific contrast agents such as Feridex but we’ll focus on Gado in the brain. Quantitative perfusion in MR or CT use the exact same principles for yielding CBV, CBF & MTT. MTT EPI 62 year old with left MCA territorial stroke. The perfusion maps show prolonged MTT with corresponding decreased CBF and CBV.

“Arterial Input Function”
-ln(S/S0) Raw SI Minutes Minutes The signal change in each tissue voxel is really the convolution of the bolus seen in the artery with the residual amount of contrast left in the voxel. We have to deconvolve these two to get the true tissue curve. It all starts by defining an arterial input function measured from a single voxel in the right internal cerebral. The AIF should be a delta function theoretically. Why is it not?

“CT Perfusion is for wimps.” Difficulties in MRP quantitation. Delay
Dispersion Saturation Effects Partial Volume Effects Susceptibility Masking Conversion to Concentration Partial Volume Effect Delay: curve gives false shifts in time Dispersion: contrast finds tortuous paths back, Also due to a non-finite bolus injection Saturation: signal falls to 0 ->underestimates Partial Volume: inclusion of GM in AIF Suscept: field distortion/AIF walks w=gB Concentration: linearity between R2,C Refs: van Osch,2000; Rausch,2001; Wu,2003

Central Volume Theorem
Cerebral Blood Volume Cerebral Blood Flow Mean Transit Time MTT=CBV/CBF Central Volume Theorem Quantitative perfusion parameters in MRI are possible although there are many factors that contribute to it not being ready for prime time. All of the MR vendors know this and very few have any decent software on their workstations. Also if your MTT > 6sec.. Something is amok. CBV (ml/100 gm ) Normal GM = 4.4%+/-0.9 Normal WM = 2.3%+/-0.4 Ischemia = >6 ml CBF (ml/100 gm/min) Normal GM = 39+/-10.3 Normal WM = 14.7+/-4.1 Ischemia < 10.0

DWI/PWI Services in Stroke: www.synarc.com
The central goal of therapy for many clinical trials in acute stroke is to salvage the ischemic penumbra. In these patients (perfusion deficit, but no DWI abnormality), blood flow appears to be impaired, but not severely enough to cause energy failure in the affected region, suggesting that most or all of the affected tissue is still potentially salvageable. Almost all recent studies show acute perfusion abnormalities larger than the DWI lesions, strongly suggesting that the “mismatch” represents viable tissue at risk, which may become recruited into the final infarct. Correlations of the PWI-DWI mismatch with the clinical impression (NIHSS and ESS) find that it is the larger of the two lesion volumes that provide the better correlation with the clinical scales.

MR SPECTROSCOPY

NMR Active Nuclei What can we see?
As mentioned in earlier lectures, only the nuclei with an odd number of proton and neutrons can be imaged via MRI. However, other factors come into play as to what can be seen in clinical practice. i.e. What is the natural abundance of the MR active isotope compared to it’s radioactive counterparts? Or What % of tissue will give us a signal? What is the inherent nuclear sensitivity compared to hydrogen? Is there a quadrupole moment that decreased T2?

Raw Signal “FID” FFT Shown on the left is what is called a free induction decay or FID. This is how a magnetic dipole returns to equillibrium after absorbing RF energy applied at the resonant frequency.. It is like a damped oscillator or spring system returning to rest. Contained in this simple curve are various metabolic peaks combined in an exponential summation in the time domain. In order to actually tease out what chemical

“Chemical Shift” Electron Shielding
Henning probably talked a bit about chemical shift artifacts in imaging. This is caused by the difference in frequency between the water and fat resonances and appears at the boundary between the 2 compounds. Electron currents produce a smaller magnetic field opposed to the main magnetic field that effectively shield the nuclei and therefore the decrease in magnetic field results in a frequency shift away from water. You can see the primary lipid peak results from the methyl group which can be seen in-vivo in this liver spectrum.

Water = 4.7ppm Lipid = 1.3 ppm Dn =(4.7-1.3) ppm*127.5MHz
= Tesla T=1/n = 2.3 ms (IP, OOP) A bit of math here to show you what the frequency shift between fat and water translates to into clinical imaging. The water peak is always referenced at 4.7ppm and the methyl peak from the lipid group at 1.3ppm. Note that the definition of ppm is parts per million and is field and frequency independent. The conversion between ppm and hertz involves multiplying by the resonant frequency of the scanner. The period of the frequency separation may actually then be used to vary the echo time (TE) of the sequence and produce in-phase and out-of-phase images with respect to fat and water. What would the variance in TE be at 1.5T for IP/OOP? (4.6ms) Note that In-phase images are EVEN multiples of this time. OOP=odd

1H Metabolites NAA CHO CRE LAC
So what metabolites other than fat or water may be studied in vivo with proton spectroscopy and have physiological relevance. Metabolites also have varying T1 and T2 values and may be optimized by specifying short or long echo times. If your shim was 20 Hz could you split the lactate doublet?

A sampling of 1H metabolites
Can you see all of these in-vivo? Why/why not? T2 may be too short, macromolecules, What kind of shim can you expect in-vivo? (~8-10Hz) = 0.06ppm i.e. lactate doublet, citrate quartet i.e. Can you separate two peaks that are close together? Where are some of these seen? Tumors, prostate, brain? Are all amino acids in all tissues??

What price is paid in detecting these signals?
Ex-vivo Mouse brain perchloric acid 11.4T This is an ex-vivo mouse brain perchloric extract that I had run off at 11.4 Tesla in the NMR core facility. The typical concentration of brain metabolites found in human subjects in on the order of 1 mM to 10 mM in comparison to 80 Molar.. There is then a difference in concentration of around 10,000 less in the metabolites compared to normal concentrations of water in the brain. Special water suppression and excitation pulses are used to detect these at lower spatial resolutions of approx 0.75 cm in volume compared to an imaging voxel of cc or (1mm x 1mm x 1mm). So then why can’t we see all of these metabolites in a typical brain spectra? The frequency separation of the metabolites is directly related to field strength and the splitting is then increased with magnetic field. Typically at 3.0 Tesla you’ll see the CRE/CHO/NAA in healthy brain tissue and LAC in pathology. Each metabolite has a specific biological function in the human body and provides information on that pathway or cycle in use. What price is paid in detecting these signals?

Grade III GBM Pre-Tx Dyke JP, Sanelli PC, Voss HU, Serventi JV, Stieg PE, Schwartz TH, Ballon D, Shungu DC, Pannullo SC. Monitoring the Effects of BCNU Chemotherapy Wafers (Gliadel®) in Glioblastoma Multiforme with Proton Magnetic Resonance Spectroscopic Imaging at 3.0 Tesla. J Neurooncol Mar;82(1):

31P Metabolites @ 3.0 Tesla Typical 31P NMR spectra from brain. The horizontal axis represents frequency in p.p.m. Resonance identifications are as follows: 1, phosphomonoesters (PME); 2, inorganic phosphate (Pi); 3, phosphodiesters (PDE); 4, phosphocreatine (PCr); 5, c-adenosine triphosphate (c-ATP); 6, a-adenosine triphosphate (a- ATP); 7, b-adenosine triphosphate (b-ATP).