Functional Imaging with Endogenous Contrast

Ken Kwong, circa 1992

The NMR Center was flush with excitement in 1990-1991 following Jack Belliveau’s pioneering work with fMRI using external contrast agents (see [1]). Researchers throughout the center were inspired by the potential for brain mapping that the work revealed by the work. Kenneth Kwong wanted to take it a step further, though. He was interested in finding intrinsic MR contrast, and thus avoiding having to use external agents in human subjects. In developing this idea, Kwong was influenced by several earlier studies. First was Keith Thulborn’s 1982 study showing the impact of deoxyhemoglobin on the MR parameter T2 [2] (Kwong wasn’t yet aware of the results on blood oxygen level dependence (BOLD) contrast published in 1990 by Seiji Ogawa of Bell Laboratories in Murray Hill, N.J., and colleagues at the University of Minnesota [3]). Thulborn’s observations about deoxyhemoglobin and magnetic susceptibility suggested to Kwong that the gradient echo sequence, which was known to be highly sensitive to the susceptibility contrast, might offer a means to identify changes in blood signal following sensory and cognitive stimulation. Another important piece to the puzzle was a poster presented by Robert Turner, Denis Le Bihan, Chrit Moonen and Joe Frank at the April 1991 Society of Magnetic Resonance Imaging (SMRI) meeting in Chicago. Here, the researchers showed an association between perfusion and an overshoot in the deoxyhemoglobin signal in a hypoxia experiment with a cat (see [4]). This was a significant insight, Kwong said, one that would play an important role in his interpretation of the rising MR signal response in his experiments the following month. Kwong ran his first experiment seeking to demonstrate MRI imaging of cerebral activation with endogenous contrast on the evening of May 9, in what is now Bay 3 at the Martinos Center. He doesn’t recall if David Kennedy was at the scanner console with him, but he remembers learning from Kennedy that day the anatomical location of the visual cortex of the brain. Brigitte Poncelet may also have been present that evening; he was running her time course subtraction routine for image data analysis immediately after collecting the EPI time series.

For the experiment itself, Kwong borrowed the pair of visual stimulation goggles that Jack Belliveau had used for his Gd-DTPA fMRI experiments – the same goggles on loan from Peter Fox, who had used them in his seminal stimulation rate experiments in the early 1980s [5]. He ran a T2* weighted gradient echo EPI sequence as well as a T1 weighted inversion recovery spin echo EPI sequence while a volunteer watched the flickering stimulus in the goggles. He decided to use a block design paradigm for the latter, alternating a baseline OFF epoch with an ON epoch for a total of 70 time points. This was significant, Bruce Rosen explained in a 2012 lecture and paper, “fMRI at 20: Has it changed the world?” [6]. While the block design seems obvious now, he said, at the time all functional brain imaging studies were performed with single time-point injections, with analysis tools designed to identify the differences between the images acquired many minutes apart. “Ken’s block design represented a new paradigm for activation studies, requiring different timing and analysis techniques,” he continued, “and remains the most commonly used functional paradigm more than 20 years later.” The design can be seen on the left of the two pages from Kwong’s laboratory notebook from the day of the experiment reproduced here.

Ken Kwong's lab notes from the May 9, 1991, experiment (the name of the imaging volunteer has been crossed out)

After a quick analysis of the data, Kwong noted a clear difference in signal due to changes in blood oxygenation in the T2* images as well as blood flow-related changes in the T1 data. He also observed that oxygen delivery, blood flow and blood volume increased during neuronal activation, while the total paramagnetic deoxyhemoglobin content decreased. All of this suggested that he had successfully imaged cerebral activation based on endogenous contrast. He understood the potential significance of the results – he recalls joking with colleagues about having demonstrated cold fusion – but kept his enthusiasm in check, focusing instead on whether the signal differences he had seen were an artifacts. Indeed, this question occupied him for the next couple of months as he ran different experiments and analyzed the results, trying to confirm that the signal changes he observed – both in the original experiments and subsequently – were in fact due to visual activation. Finally, he was confident that they were. REFERENCES 1. Belliveau, J. W., D. N. Kennedy, Jr., R. C. McKinstry, B. R. Buchbinder, R. M. Weisskoff, M. S. Cohen, J. M. Vevea, T. J. Brady and B. R. Rosen (1991). "Functional mapping of the human visual cortex by magnetic resonance imaging." Science 254(5032): 716-719. 2. Thulborn, K. R., J. C. Waterton, P. M. Matthews and G. K. Radda (1982). "Oxygenation dependence of the transverse relaxation time of water protons in whole blood at high field." Biochim Biophys Acta 714(2): 265-270. 3. Ogawa, S., T. M. Lee, A. R. Kay and D. W. Tank (1990). "Brain magnetic resonance imaging with contrast dependent on blood oxygenation." Proc Natl Acad Sci U S A 87(24): 9868-9872. 4. Turner, R., D. Le Bihan, C. T. Moonen, D. Despres and J. Frank (1991). "Echo-planar time course MRI of cat brain oxygenation changes." Magn Reson Med 22(1): 159-166. 5. Fox, P. T., M. A. Mintun, M. E. Raichle and P. Herscovitch (1984). "A noninvasive approach to quantitative functional brain mapping with H2 (15)O and positron emission tomography." J Cereb Blood Flow Metab 4(3): 329-333. 6. Rosen, B. R. and R. L. Savoy (2012). "fMRI at 20: has it changed the world?" Neuroimage 62(2): 1316-1324.