Finding Normal

Wired magazine ran an article 'Finding Normal' in May 2008. Diagnostic techniques like MRI or CT are becoming tools of research for predictive medicine and any apparent smudge in images could be interpreted as a lesion, which, at surgery, is found to be benign. Mr. Goetz criticizes the field as a whole, all the way from the NIH down to the individual scientist.


It's tempting to believe that scientists pursue research this way: 'Eureka! A spot on MRI! Nobel, here I come!'. In general, scientists don't do this and most realize that their grant could never be funded this way.

The NIH does give priority scores to indicate a project's novelty, originality and scientific merit, but as any study group at the NIH will tell you, understanding what's normal is a key component to whether the research is funded. Normal, in this case, is the control group - and characterizing this group of people defines what's abnormal.

As an example, Dr. Subramanian hypothesizes that atherosclerotic plaques have higher tau-score on MRI. Dr. Subramanian has investigated tau-score in vitro and realizes that it correlates well with atherosclerotic fat content and suspects that high tau-score can be used to characterize plaque risk.

Should Dr. Subramanian...

A. Quantify tau-score among 40 patients with heart disease?
B. Correlate tau-score with the gold standard in patients with heart disease?
C. Quantify tau-score among 40 healthy normal subjects.

A, B and C are all necessary to fully characterize the disease and tau-score. In fact, scientists look at a healthy population all the time to estimate the sensitivity and specificity of the diagnostic technique. How specific and sensitive is the technique, if 40% of healthy normal subjects have an atherosclerotic plaque with high tau-score and apparently high fat content? Specificity and sensitivity scoring is ubiquitous to MRI and science in general.

It is true that we have actually surpassed our capacity to interpret the results of diagnostic imaging. This doesn't preclude scientists from doing good research, but suggests only that more scientists should use imaging as a tool.

Predictably T2

The white bread of MR imaging uses T2 to generate contrast between healthy and diseased tissues. What a surprise when boring, cookie-cutter T2, so overused and under-appreciated had a big boost in interest at the cardiac MR study session this year at ISMRM.

In a room that fit 500 people, about 20 (5000+ are at the ISMRM) made it to the early evening discussion led by Dr. Andrew Arai at the National Institutes of Health about a unique application for T2-weighted imaging. Buried under the glamour of delayed gadolinium enhanced MR, full-body magnetic resonance angiography and cine, T2-weighted imaging is the only one that apparently gives useful contrast for acute myocarditis. In this case, the infected area becomes brighter on MRI, likely because of edema and inflammation. A short discussion on the research appeared in Circulation recently.

This is especially nice because T2 contrast is endogeneous. It also doesn't require specialized hardware or pulse sequences to use. You could potentially quantify the tissue to monitor the muscle longitudinally or run a multisite/multivendor trial with reproducible results. The image to the right shows the inflammed tissue as bright signal on T2 MRI in a comprehensive study of several techniques.

Clearly, this is also an opportunity to use single-shot T1R, which would fit nicely in the RR interval of the cardiac cycle. It has improved dynamic range, reduced diffusion and would reduce any effect of cardiac muscle orientation on quantification. Also, anyone with a complicated T2-weighted sequence (T2-prepared bSSFP, variable flip angle fast spin echo, etc) looking for a useful non-brain application could find one.

Gridder

The International Society for Magnetic Resonance in Medicine is next week in Toronto. In our genuine (sarcastic?) excitement of scientific discovery we submitted an entire abstract on a feature depicted on p. 246 of maybe the best known MRI textbook - dark, regular bands, all artifacts, and not at all useful - until recently.

The balanced gradient echo sequence is exquisitely and annoyingly sensitive to magnetic field inhomogeneities. This unfortunate feature, together with a forgotten prephaser gradient, perversely kept us in the dark about a series of banding artifacts along the direction of slice excitation.

The bands are predictable and appear whenever the accumulated spin phase per TR is 180 degrees. For example, the balanced steady-state free precession (bSSFP) frequency response looks like this:

The large signal voids occur at +- N*180 degrees and are spectacularly troublesome when images are acquired at high field or in the presence of large magnetic field inhomogeneities.

Only a stubborn MR physicist would try to take advantage of the bands. Two applications that come to mind are using ferromagnetic materials to label cells using the balanced GRE as a probe. The other is fMRI. We're perverse too, so why not attempt our own application? We added an 'unbalancer' gradient to the pulse sequence.


The unbalancer creates uniform grids on the tissue. The grids can be modified predictably by changing the gradient direction or amplitude:


But how are the bands useful? Could they persist through an acquisition to track tissues like SPAMM or DANTE? If so, the persistence isn't obvious and likely won't last longer than 30-100 TRs prior to entering the next steady-state. But both conventional tagging techniques persist a similar duration (< T1). Oh - the dream of indefinitely persisting tags.

A Black Hole in Honor of Jack Leigh

Dr. John "Jack" Leigh, a scientific genius, prolific reader and oddball eccentric, sadly passed away last week. Jack's desk sits about 10 feet from my own and has an assortment of gadgets like bar magnets, canned beaver and a book of crude yiddish vocabulary. The corner of his filing cabinet has innumerable beer bottle caps which are suspended from bar magnets.



I wrote an article a couple of years ago on an infrequently used (overstatement) technique called an off-resonance rotary echo and its application to MR imaging. While writing, I had a conversation with Jack that went something like this:

Me: When you transform to the tilted rotating frame you can show that the off-resonance rotary echo refocuses the magnetization...
Jack: Tilted rotating frame? That's bullsh$t!

Dr. Ari Borthakur wrote to me his thoughts, 'Over the years, I have related several stories to you of his genius in topics such as physics (e.g. approximating how long a human can survive immersed in freezing water) to love ("You don't really want to be with a promiscuous girl. People just says these things. You want a girl that is happy being with you sometimes and is quite content being without you too.").

This year Siemens licensed from the University of Pennsylvania some awesome, endogenous contrast, technology that was developed by Jack and other clever Penn scientists called arterial spin labeling. Using slice selection and spin inversion, flowing blood is 'tagged' as it flows to the brain. The initial tagging alters blood flow contrast and is used for perfusion imaging. The Center for Functional Neuroimaging at Penn investigates many of these techniques for vascular disease, substance abuse and sleep studies.

Jack + brain will be sorely missed.

Unrelated, but interesting: There is a small chance - as in monkeys typing Shakespeare kinds of odds - that the world will end when CERN attempts to replicate the first several nanoseconds of the Universe's existence. The New York Times wrote an article about the two individuals who decided to sue CERN to protect humanity. Largely the issue is jurisdictional; a court in Hawaii cannot force a massive, multi-University/Institution organization in Europe to halt its experiments.

In general, scientists are driven by curiousity and not by evil intent. More likely, although not much more likely, are our chances of using the black hole as a nearly infinite renewable energy source or to travel rapidly to a solar system with a planet with clear blue water and soft sandy beaches. From a moral and recreational perspective, I think particle physicists are obligated to create the black hole.

Grab some popcorn, it's your heart - now at theaters everywhere.

Is it possible to make a film of the human heart beating without performing surgery? Today it can be common practice using an MRI technique called CINE.

Coming soon... cine of my heart.

To understand how this works, it helps to think about how you can make a movie out of set of single still images. Your digital camcorder collects single images at a given frame rate, usually measured in frames per second (fps). To make the 'jumps' between consecutive still images appear undetectable to the human eye, 24-30+ frames need to appear every second (24-30+ fps).

Cardiac movie-making is slightly more complicated. Using the fastest scanning techniques available, an MR scanner is capable of producing a single high resolution image once every 100-300 ms. This means we collect only 10 fps if we were scanning as fast as possible. Even more problematic is that the normal human heart beats slightly faster than once per minute. Contraction of the 4 chambers of the heart (systole) takes even less time.

To fully (time) resolve the heart beating, cine plays a trick on your eyes. Instead of acquiring single images over a single heart beat, it acquires fractions of images over multiple heart beats and reconstructs these images as a single heart beat afterwards. This is all well and good for predictable hearts, but if a heart beats asynchronously during a time period shorter than the total scan time (15 s - minutes), we're out of luck.

So what are the top researchers investigating now?

At the National Heart Lung and Blood Institute (NHLBI) at the National Institutes of Health (NIH) in Bethesda, Maryland, measurements of heart depolarization (electrical activity) are correlated with functional activity by EKG and cine MRI. Check out the work here.

Abroad, at the Institute for Biomedical Engineering at ETH in Zurich, Switzerland, the composition of plaques that develop during atherosclerosis is investigated using MRI. Check it out here.

Seven Tesla

The University of Pennsylvania became the proud owner of a Siemens 7T MRI system on Saturday. The magnet weighed in at a trim 36+ tons and was secured to 4 rigs each capable of holding 15 tons. The magnet arrived on a flatbed truck after being delivered on a ship from Germany. Check out the press here.


For nearly an hour, the riggers eyeballed the system of chains and platforms used to secure the device. Slowly the magnet creeped toward a hole where it would be lowered into the basement of labs where the MMRRCC facility is located. As the magnet approached the hole, the chief rigger decided the track along which the magnet rode was not secure. The magnet was brought out, the harness was secured and the creep continued. Each side of the magnet was lowered manually and asynchronously from the ground floor to the basement of Stellar-Chance. There was some (small) risk that overloading a single 15 ton capable pulley could send the magnet plummeting 20+ feet. Here is a view from the basement as the magnet is lowered from the ground floor.


So why 7T? There is a strong desire among researchers to acquire images at 7T because of the better resolution, the ability to separate resonances in separate chemical environments and changes in relaxation times. Several sites in the country have already installed full-body 7T or greater MR sytems, including OSU and UCSF.

It should be another 2 months before the magnet is ready to be used for research. And besides the magnet itself, RF coils need to be manufactured for nuclear excitation and image acquisition. Two such coils, designed for both proton and sodium imaging, are already in the works for the Penn site.