Abstract
The Center for Magnetic Resonance (CMRR) at the University of Minnesota was one of the laboratories where the work that simultaneously and independently introduced functional magnetic resonance imaging (fMRI) of human brain activity was carried out. However, unlike other laboratories pursuing fMRI at the time, our work was performed at 4. T magnetic field and coincided with the effort to push human magnetic resonance imaging to field strength significantly beyond 1.5. T which was the high-end standard of the time. The human fMRI experiments performed in CMRR were planned between two colleagues who had known each other and had worked together previously in Bell Laboratories, namely Seiji Ogawa and myself, immediately after the Blood Oxygenation Level Dependent (BOLD) contrast was developed by Seiji. We were waiting for our first human system, a 4. T system, to arrive in order to attempt at imaging brain activity in the human brain and these were the first experiments we performed on the 4. T instrument in CMRR when it became marginally operational. This was a prelude to a subsequent systematic push we initiated for exploiting higher magnetic fields to improve the accuracy and sensitivity of fMRI maps, first going to 9.4. T for animal model studies and subsequently developing a 7. T human system for the first time. Steady improvements in high field instrumentation and ever expanding armamentarium of image acquisition and engineering solutions to challenges posed by ultrahigh fields have brought fMRI to submillimeter resolution in the whole brain at 7. T, the scale necessary to reach cortical columns and laminar differentiation in the whole brain. The solutions that emerged in response to technological challenges posed by 7. T also propagated and continues to propagate to lower field clinical systems, a major advantage of the ultrahigh fields effort that is underappreciated. Further improvements at 7. T are inevitable. Further translation of these improvements to lower field clinical systems to achieve new capabilities and to magnetic fields significantly higher than 7. T to enable human imaging is inescapable.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 726-735 |
| Number of pages | 10 |
| Journal | NeuroImage |
| Volume | 62 |
| Issue number | 2 |
| DOIs | |
| State | Published - Aug 15 2012 |
Bibliographical note
Funding Information:In the endeavor to achieve even higher fields for human fMRI (as well as spectroscopy) a critical partnership evolved with David Rayner and his magnet company Magnex. David was willing to assume the financial risk for the development of ultrahigh fields; he agreed to build and install ultrahigh field magnets in CMRR before the funding was in place, in exchange for a promise on our part to seek funding through grant applications. In each case, the magnets were installed before the funding ultimately materialized from NIH and the Keck Foundation. It is commendable that these organizations were willing to fund these magnets even though they were already in place. But without David's contribution, the development of ultrahigh fields would have been significantly delayed. Our first project with David Rayner was a 9.4 T/33 cm bore magnet for animal model studies. This was the first magnet at such a high field with such a bore size. It was successfully built and provided a plethora of fMRI as well as spectroscopy data to warrant the exploration of similar fields for human studies. We also used this magnet to obtain an image of an intact porcine chest, approximating the size of the human head, demonstrating that RF problems can be tackled to achieve human head imaging even at such high fields ( ). This may be one of the first uses of multichannel transmit and receive concept since we essentially employed a four loop coil to make a volume coil (arranged as two “quadrature” coils each of which was made up of two loops coupled through a 90° hybrid); we did not have multiple transmitters or receive channels but obtained images first with one quadrature pair and then the other, and subsequently combined them. Multichannel transmit is of course a bit more complex due to the simultaneity of the transmission; nonetheless, the approach anticipated the multichannel transmit and receive array technology we developed many years later for 7 and 9.4 T human imaging (e.g. T, in anticipation of such a development. Fig. 3 Adriany et al., 2005; Vaughan et al., 2006 ). I showed this porcine chest data that year (1995) in a plenary session at the annual meeting of the Radiological Society of North America (RSNA) to demonstrate the feasibility of imaging the human brain at even higher magnetic field strength than 4 David Rayner and I started discussing this prospect in the ISMAR meeting in Sydney in 1995, where I gave a talk. We looked at many designs, starting conservatively with a small-bore “head only” human magnet ( ); this first exploration was completed by August 1995 ( T/90 cm bore. David reported the results to us on 1 April 1996 ( T/90 cm bore magnet because we did not want to compromise on the bore size; we anticipated that gradients will be a major challenge at this field strength and we did not want the bore size to limit gradient design. This system was installed in 1999 in CMRR. The installation was problematic because of an asymmetric passive shield design that was used to contain the stray field, leading to many months of delays. The complete system was put together by our group from parts we obtained from various manufacturers, with the “console” coming from Varian, gradient amplifiers donated by Siemens (arranged by Franz Schmitt), RF amplifiers from CPC, etc. Fig. 4 Fig. 4 ). Subsequently, we expanded the search up to 7 Fig. 4 , lower Fax). In 1996, we decided ultimately on a 7 This “lego” 7 T system is the first ever 7 T MR instrument established for human studies; it did not emerge because a manufacturer one day decided to offer a 7 T system. It came about based on a large body of work, first with 4 T human studies and subsequently with 9.4 T animal model experiments, mainly driven by functional imaging and T is the “mother” of all 7 T human systems. Until 2011, all 7 T magnets were based on the exact magnet that David Rayner and we had finally agreed upon. The system we put together was far less than optimal and significantly inferior to contemporary 7 T instruments offered by the three major manufacturers; but, before another 7 T paper on humans from another lab appeared in press, approximately thirty papers came from this “lego” 7 T demonstrating the unusual physics of ultrahigh fields in the human body (i.e. the traveling wave behavior) (e.g. T systems ( ). in vivo spectroscopy. If you like, the CMRR 7 Collins et al., 2002; Yang et al., 2002 ), the signal-to noise gains ( Vaughan et al., 2001 ), feasibility of excellent anatomical imaging ( Vaughan et al., 2001 ), and of course the unique advantages for fMRI in the human brain (e.g., Yacoub et al., 2001; Duong et al., 2002; Pfeuffer et al., 2002a, 2002b; Shmuel et al., 2002; Duong et al., 2003; Yacoub et al., 2003 ), starting the trend for rapidly increasing number of 7 Fig. 5 An 8 T/80 cm bore human magnet was delivered and installed at Ohio State shortly before our 7 T was delivered. Beautiful gradient recalled echo images of the brain were produced from this system (e.g. T work that defined the path of the ultrahigh field MR. On the way, several new technologies and image acquisition methods were developed that impact not only 7 T but also lower field strength clinical instruments. This benefit of pushing the ultrahigh field technology is generally underappreciated. Parallel transmit was developed for overcoming the 7 T problems of unusual B T. Slice accelerated ultrafast whole brain imaging, i.e. the Multiband technique, that is becoming increasingly popular at all field strengths has found its first driving biological utility in ultrahigh field fMRI, thus starting its current popularity; the gains at 7 T permitted us to aspire for obtaining whole brain functional maps with submillimeter isotropic resolution but it took too long to cover the entire human brain at such high resolutions. To overcome this problem, we proposed the Multiband fMRI approach for the competitive renewal application of our P41 Biotechnology Research Resource grant in 2007 and reported it first at the 2008 ISMRM annual meeting ( T, both in our and in the MGH-UCLA Human Connectome Project consortium ( Abduljalil et al., 1999; Bourekas et al., 1999; Burgess et al., 1999; Norris et al., 1999; Robitaille et al., 2000 ). Ultimately, however, it was the 7 1 fields in the human body and is now used for improved torso imaging at 3 Moeller et al., 2008 ), later publishing it at the beginning of 2010 ( Moeller et al., 2010 ). Only subsequently, the Multiband technique and a version of it where we combined it with the SIR approach for greater acceleration ( Feinberg et al., 2010 ) became the solution to the needs of the human connectome project at 3 Setsompop et al., 2011 ). Interestingly, we came on the Multiband technique because of breast imaging and spectroscopy studies that Mike Garwood and his colleagues were pursuing in CMRR at 4 T. They employed a separate coil for each breast, and aimed to collect data from both simultaneously using a dual band pulse to excite both breasts but using a field-of-view adjusted only for one breast in order to gain speed of acquisition. They expected to distinguish the images from the two breasts simply by the spatial separation of the two coils; however, there was residual coil coupling and consequently cross-contamination. The fMRI group in CMRR was at the time very much into regular parallel imaging (i.e. with reduction of field-of-view along the phase encode direction) (e.g. Wiesinger et al., 2004; Adriany et al., 2005; Van de Moortele et al., 2005 ) and following this line of thought we took care of Mike's problem by unaliasing the slices using the spatial sensitivity profile of the two coils. Then, we realized we could do something analogous in the brain to increase the speed of high resolution, whole brain multi-slice fMRI. At the time, we were not aware of the work by Larkman ( Larkman et al., 2001 ) or improved versions of that work which came somewhat later ( Breuer et al., 2005, 2006 ) (shows that we were not always good at following the field or recognizing important contributions). Only later, searching the literature for prior work, we found these papers. Larkman, thus, deserves the credit for the original discovery. Nevertheless, there is great merit in showing the power of a method that had otherwise failed to be recognized and failed to make it into mainstream imaging; in case of Multiband imaging, this came about by the aspirations made possible by ultrahigh field fMRI. The episode also underscores the importance of a diverse scientific environment where cross-pollination of ideas can occur, as we intentionally try to garner in CMRR. Functional imaging in the human brain, one of the main reasons we pushed to ultrahigh fields, reached new levels of spatial resolution and specificity at 7 T, yielding for the first time tonotopic maps of the human primary auditory cortex, revealing its mirror symmetric organization ( Formisano et al., 2003 ), presence of negative signal changes surrounding regions of increased neuronal activity ( Shmuel et al., 2002 ), robust functional maps associated largely with the microvasculature detected using spin-echo (SE) fMRI ( Duong et al., 2002; Yacoub et al., 2003, 2005 ), images of orientation columns ( Yacoub et al., 2008 ) defining the organizational relationship between these elementary computational units and the ocular dominance columns, and 3D functional maps of the axis-of-motion selective features in human area MT with laminar resolution ( Zimmermann et al., 2011 ). We worked towards the goal of imaging with columnar resolution from the very start of fMRI, and I personally felt fulfilled after the paper on orientation columns ( Yacoub et al., 2008 ) finally appeared in press. At the present, T with gradient echo EPI is feasible and in the near future we will see papers reporting studies with this capability with matching whole brain anatomy of exquisite detail. Critical technologies that make this possible are parallel imaging to accelerate along the phase encoding direction ( whole brain fMRI at isotropic columnar and laminar resolution, conducted at 7 Pruessmann et al., 1999; Sodickson et al., 1999; Griswold et al., 2002 ), improved EPI methods (e.g. Zaitsev et al., 2004; Speck et al., 2008; Chung et al., 2011 ), the use of slice accelerated whole brain imaging ( Moeller et al., 2008; Moeller et al., 2010; Feinberg et al., 2010 ), parallel transmission (e.g. Adriany et al., 2005; Van de Moortele et al., 2005; Vaughan et al., 2006; Metzger et al., 2008; Setsompop et al., 2008a, 2008b, 2008c, 2009 ) biased field correction methods in anatomical imaging (e.g. Duyn et al., 2007; Van de Moortele et al., 2009 ), and improved anatomical contrast (e.g. Duyn et al., 2007; Rooney et al., 2007; Budde et al., 2011; Henry et al., 2011 ). I believe when combined with recently developed decoding and encoding approaches for fMRI (e.g. Kamitani and Tong, 2005; Chaimow et al., 2011; Shmuel et al., 2010; Naselaris et al., 2011 ) the ability to obtain such detailed functional images together with the corresponding anatomical information will elevate to new heights the methods of studying brain function as well as our understanding of it. Closing the circle on what was started in Bell Labs, spectroscopy experiments first performed on E. coli cells in suspension are now being performed in the human brain thanks to the gains provided by ultrahigh fields. The very same magnetization transfer experiment Truman Brown and I introduced to measure enzymatic rates in E. coli ( T, yielding a quantitative measure of the oxidative ATP synthesis rate ( T ( T systems mature and improve and the 10.5 T and 11.7 T systems planned for installation in 2011 and 2012 come into operation, hopefully in 2012. Brown et al., 1977 ), was finally accomplished approximately two and a half decades later in the human brain at 7 Lei et al., 2003 ), while spectroscopy with 1 H and low gyromagnetic ratio nuclei increasingly provide neurochemical and metabolic information in the human brain with unprecedented detail and biomedical relevance (e.g. Tkac et al., 2001; Mangia et al., 2006, 2007a, 2007b; Avdievich et al., 2009; Tkac et al., 2009; Atkinson and Thulborn, 2010; Oz et al., 2010 ) with more improvements expected as a consequence of the recent focus on higher order shimming techniques (e.g. ( Hetherington et al., 2006; Juchem et al., 2010 ). Until recently, all the high field studies were in the brain, but recently our group also showed for the first time that ultrahigh field imaging in the human torso, a more challenging goal due to the relative dimensions of the object versus the RF wavelength, is feasible at 7 Metzger et al., 2008, 2010; Snyder et al., 2009; Vaughan et al., 2009 ), thus starting a new burgeoning activity in several laboratories. New peaks are expected at ultrahigh field human MR as 9.4 At the 2002 annual meeting of the European Society of Magnetic Resonance in Medicine and Biology (ESMRMB) at Cannes, France, I was asked to take part in a “Hot Topics Debate” and argue against the motion that “there is only a niche market beyond 3 T” with David Norris acting as the proponent. The exact motion may have been worded slightly differently. As expected in a debate, we had to argue the position we were assigned irrespective of our true conviction. In my case this was simple; I defended my convictions. We debated with humor and scientific data. David Norris naturally focused on all the difficulties faced at high fields, particularly at 7 T, as evident in the sparse 7 T data available at the time. I argued based on the 4 T accomplishments and promises of 7 T as suggested even by the early data. I reproduce verbatim below my concluding summary slide from this debate. The text in brackets [ ] are added for clarification. My slide read: To CLAIM that BEYOND 3 T there is only but a NICHE MARKET is to • Deny all the experimentally demonstrated gains with [increasing] magnetic field magnitude • Deny that we are capable of creativity [to solve the problems of ultrahigh fields] • Deny the dynamism of MR research & development, and applications • Deny that there is clinical utility beyond todays clinical applications • Deny history • Deny that humans are fundamentally greedy! At the end, the audience voted and I won the debate. I believe that since that debate, a decade of fantastic technological developments and increasing number of biological results, especially in fMRI, on the 7 T platform has proven that I was right. Critical to the work on high and ultrahigh field MR conducted at CMRR is, of course, the large number of talented individuals I had and continue to have the pleasure of working with; some of these individuals have moved on to establish and lead high field centers of their own in the USA and abroad. They are too numerous to list here but their names appear in the large number of papers we have published on this journey. The contributions of our numerous collaborators throughout the world have also been indispensible and should be recognized; again, they are too numerous to list here but can be seen in our publications. Of course, without the funding from NIH (particularly our P41 Biotechnology Research Center grant (P41RR08079) and several High-end and Shared Instrumentation grants from the National Centers for Research Resources (NCRR)), the Keck Foundation and the University of Minnesota, this development would not have been possible.
Keywords
- 4Tesla
- 7T
- 7Tesla
- BOLD
- Brain imaging
- FMRI
- Functional imaging
- High field
- MRI
- Multiband
- Neuroimaging
- Slice accelerated imaging
- Slice acceleration
- Ultrahigh field