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Wednesday, October 1, 2014

i-fMRI: My initial thoughts on the BRAIN Initiative proposals

So we finally have some grant awards on which to judge the BRAIN Initiative. What was previously a rather vague outline of some distant, utopian future can now be scrutinized for novelty, practicality, capability, etc. Let's begin!

The compete list of awards across six different sections is here. The Next Generation Human Imaging section has selected nine diverse projects to lead us into the future. Here are my thoughts (see Note 1) based mostly on the abstracts of these successful proposals.

Dissecting human brain circuits in vivo using ultrasonic neuromodulation

See 1-R24-MH106107-01 for the abstract.

Ultrasonic neuromodulation is a recent addition to the family of "minimally invasive" stimulation methods (TMS, tDCS) being used to prompt neurons (and other brain cells?) into doing something. In this case, ultrasound waves serve as an energy source to provoke some sort of neural response. The mechanism could be via localized heating, say, and one of the main goals of this project is to determine just how ultrasound interacts with brain tissue.

Strictly speaking, transcranial ultrasound isn't an imaging method per se, rather it's a manipulation designed to allow imaging methods to see something different after the manipulation. Combining methods - here, ultrasonic neuromodulation with fMRI or EEG - should enable some unique experiments, e.g. to test network modularity. In this regard it's akin to TMS-fMRI. Knockout models have always been critically important in neuroscience and neurology, I see this project as a logical extension of those approaches.

Path towards MRI with direct sensitivity to neuro-electro-magnetic oscillations

See 1-R24-MH106048-01 for the abstract.

This proposal extends prior attempts to use high field MRI to measure directly the electromagnetic activity associated with concerted neural firing. I generally refer to this family of methods as neuronal current imaging (NCI). To date, the only compelling demonstrations of NCI via MRI have involved bloodless preparations, because BOLD signal changes (as well as changes in cerebral blood volume, CBV) tend to overwhelm the tiny signal changes driven by electromagnetic fields associated with neurons working. This is still my biggest concern with this new proposal. I'm not saying it can't be done, only that BOLD is a ubiquitous weed that contaminates every fast imaging pulse sequence yet invented and applied at operating fields above a tesla or so. (My rule of thumb: in primary cortex, expect 1% change in BOLD per tesla of operating field.) CBV changes are also a huge concern when using amplitude changes in signals.

Then there's sensitivity. For Lorentz force-based contrast, as used previously by this group, the desired effect increases with the magnetic field used to induce it. The problem, however, is that BOLD also scales not less than linearly with operating magnetic field. In sum, then, I see this proposal as interesting but technically challenging in a way that is unlikely to find it displacing other methods any time soon. For such a project, it seems to me that the farther they can get from high field magnets and conventional MRI sequences for spatial encoding, the better off they might be. The group at Los Alamos tried NCI using their ultralow field MRI scanner. They may have circumvented the BOLD contamination issue but that just leaves the not inconsiderable sensitivity issue to address. (See Note 2.)

Imaging in vivo neurotransmitter modulation of brain network activity in real time

See 1-R24-MH106083-01 for the abstract.

This is a curious proposal. It's also the one I have the least background knowledge about. The abstract is scant on details, but it sounds like they are proposing to build transmitting agents that can be inserted into the brain - circulating in the blood, perhaps - and thence to report on the neurotransmitter status nearby. It does sound rather "Innerspace" to me, I have to say.

Photoacoustics are mentioned as part of one aim. This involves firing laser light at tissue such that an ultrasound pressure wave is generated from the rapid heating. The principles are well established. Whether they will be amenable to use in a "minimally invasive/non-invasive" manner, however, remains to be seen. Perhaps they can adapt magnetoacoustics to the task instead, to eliminate the laser light and its associated heating. I'll be watching this team with interest. I could see them making successful bench-top demonstrations and proofs of principle, but getting agents into brains and reporting signals out of brains will be a massive sensitivity and safety challenge, it seems to me.

Magnetic particle imaging (MPI) for functional brain imaging in humans

See 1-R24-MH106053-01 for the abstract.

Swapping one method reliant on vascular changes (present-day fMRI) for another doesn't, at first blush, seem very ambitious. Critics of fMRI are always lambasting the indirect view of "neural activity" provided by blood flow and volume changes. But the rationale for this project rests on the large potential gain in SNR compared to BOLD-based fMRI. The claim is that MPI would offer more than two orders of magnitude in sensitivity. This is likely true. However, there are some limitations to consider. First and foremost, MPI requires that the signaling agent - magnetic particles of iron oxide, or similar - be injected into the blood stream. This is immediately going to dissuade many people from volunteering for studies, and there is always the potential toxicity to consider. (The nice thing about hydrogen nuclear spin is that it's already everywhere in the brain and the blood, in the form of water. And it's non-toxic!) Perhaps a reduced subject pool is acceptable if it means that we can get better signals from those who do volunteer. Time will tell.

The other issue is imaging speed. As acquired at present, MPI needs a certain amount of rastering - usually the sample is moved relative to a field-free point or field-free line - which makes the acquisition of a full image considerably slower than for fMRI. Based on my experience with neuroscientists and fMRI to date, unless and until one can get whole brain MPI in two seconds or less, it will be a hard sell. So that is where I would want to see the biggest developments from present technology if I was to view this as a true potential replacement for fMRI.

Still, I find the whole premise that MPI could replace fMRI unlikely, given that fMRI scanners also make rather good anatomical MRI scanners, hence to permit reasonably good localization of those functional blobs in situ. MPI needs supporting anatomical information, such as that obtained by a separate MRI, in order to make sense of its signals. At best I would think that MPI and MRI might be made complimentary. I see the choice of one versus the other as a false dichotomy.

There is one possibility that I am very keen to see tested, however. In fMRI we have a huge number of different motion sensitivities, from T1 effects to receive field biases to magnetic susceptibility gradients. It's a complicated mess. If MPI could be made somehow less motion-sensitive than fMRI - perhaps motion would just blur an image and cause false negatives, without the chance of lots of false positives - then it might find a deserving role in mapping brain function, even if it is "just another" vascular method as presently envisaged.

Vascular interfaces for brain imaging and stimulation

See 1-R24-MH106075-01 for the abstract.

If proposal 1-R24-MH106083-01 eluded to the movie, "Innerspace," this one virtually hijacks the plot! The whole idea is to devise new imaging reporter systems that can be introduced via the vasculature "to deliver recording devices to the vicinity of neurons buried inside the brain parenchyma." It's invasive by definition, but that may not be the biggest obstacle by a long way. Getting the agents to go where they are required, to anchor for a while, and then to have sufficient power to transmit their signals to the surface of the head, are all truly massive difficulties.

Still, with any luck proposals like this one will cross-fertilize with those using optogenetics, photoacoustics and other sensor systems and who knows, perhaps some sort of mini-machine might be devised that can be used in the vasculature without killing either Martin Short or Dennis Quaid.

MRI corticography (MRCoG): micro-scale human cortical imaging

See 1-R24-MH106096-01 for the abstract.

Given that I have the most background knowledge on this proposal it isn't perhaps surprising that I might find it to be the most tractable of the nine. I would even go so far as to say that it is low risk. The premise is straightforward: given that large arrays of small coil loops have difficulty gaining depth penetration for the entire brain, don't aim for the entire brain. Aim to image just the cortex instead. Seen this way, the weak signals from deeper tissue are a contaminant to be eliminated - likely feasible - thereby facilitating smaller image fields-of-view and higher spatial resolution using essentially the same sort of spatial encoding as we use now. Granted there might be benefits to coupling these cortical coil arrays with faster and/or stronger gradients to push the resolution still further, but head gradient sets and even surface gradient sets are already out there.

Limited ambition on the fMRI contrast front is perhaps my main criticism. We know from a lot of animal work, e.g. from the lab of Seong-Gi Kim, that once one attains laminar specificity, CBF or CBV-based contrast attain much the same spatial localization. So, getting away from BOLD would help but the intrinsic biological limits have already been established, I think. That said, it would be a truly massive step from what we can do today, and I don't see any reason why it can't be done for fMRI purposes.

Magnetic susceptibility contrast mapping of axon fibers is included as a way to improve white matter tractography. This method benefits from higher field, so this entire project would be tailor-made for 7 T, although more limited performance of both the fMRI and tractography could be obtained at 3 T.

Advancing MRI & MRS technologies for studying human brain function and energetics

See 1-R24-MH106049-01 for the abstract.

I'm way behind on the latest physics of high field MRI to assess this proposal in any detail, but as far as I can gather the aim is to use some new (dielectric) materials to squeeze every last drop of SNR out of existing whole body scanners operating at 7 T and higher. With the SNR enhanced over what's possible with today's transmission and reception systems, the hope would be to facilitate even higher resolution using conventional spatial encoding methods. (If novel methods are being considered they're not mentioned in the abstract.) Overall, then, it looks to be a logical extension of the path that's taken us to 7+ T today. Is that a bad thing? Probably not. Attaining maximum performance out of our existing polarizing fields is a laudable aim on its own. We might as well exploit the polarizing field as far as we possibly can, these are expensive beasts!

The real novelty would come after attaining the SNR gains. The hope would be to boost the performance of rare nuclei for imaging and spectroscopy. (Endogenous) 31-P and (exogenous) 17-O are the two nuclei mentioned in the abstract, but other nuclei would benefit and could become viable candidates for functional imaging in their own right. (Endogenous) 23-Na and (exogenous) 19-F come immediately to mind.

Imaging brain function in real world environments & populations with portable MRI

See 1-R24-MH105998-01 for the abstract.

In this proposal the drive is towards smaller, lower field polarizing magnets such that the smaller, lighter systems would then be transportable and could be deployed in environments quite different than today's MRI suite. It's an interesting proposal in that in some ways we've been here before. Prepolarized MRI systems using pulsed electromagnets at room temperature (with water cooling) have been around for a couple of decades and have already produced images that are rather good. Historically, the motivation claimed was to get cheaper MRI, but it has turned out that better trumps cheaper and there simply hasn't been the demand for producing a commercial product (sadly, imho).

Could this project reinvigorate the prepolarized MRI efforts as a side effect, then? I certainly hope so, because many of the problems faced by this proposal are common to prepolarized MRI systems aiming to do functional brain imaging, specifically the need to optimize functional contrast methods at magnetic fields that are generally lower than 1 tesla. BOLD could be used but it's a rather weak effect at low fields. CBF imaging is possible in principle, but arterial spin labeling of blood benefits from high field because the blood T1 increases with B0. So it would seem that CBV imaging (i.e. VASO and its ilk) would be the functional method of choice, if endogenous contrast is the goal. This could be done on prepolarized MRI systems with modest effort, no new magnet technology required.

To me, then, this proposal looks simultaneously ambitious and elementary. If another call goes out looking specifically for mobile MRI scanners, expect to see many more proposals with a lot more mature technology as their base.

Imaging the brain in motion: the ambulatory micro-dose, wearable PET brain imager

See 1-R24-MH106057-01 for the abstract.

This sounds like a laudable goal but whenever I've been involved in discussions about doing PET the first question asked is "How far away is the cyclotron?" Some radionuclides are amenable to transport, so perhaps an ambulatory cyclotron-PET combination isn't implied, but what does seem clear is that only certain species would be suitable for taking out into the big wide world.

Assuming that suitably long-lived radionuclides can be employed, and assuming that adequate imaging sensitivity can be achieved with the lower concentrations of radionuclides being considered, that just leaves the engineering challenge of building a portable, even wearable, PET scanner. I've no idea what they plan to do in this regard - the abstract focuses almost exclusively on the radionuclide issues - but one might think that lightweight disposable, "one-time use" technologies might be indispensable here. Way back in the last century we had this quaint photographic method that relied upon one-time use film to record pictures when a shutter was opened in the camera and the film was exposed to light. Perhaps something along these lines might replace the ring of scintillation crystals used in conventional PET scanners. Even so, to me it sounds like it would be a hefty piece of kit.

UPDATE, 3rd Oct 2014: photo of concept via Julie Brefczynski-Lewis,



1.  I am a colleague of some of the successful principal investigators, and I know personally several more from other groups. I have no interests that might conflict, however. I may bend a few people out of shape, but that's a risk I'm prepared to take. These are just my current scientific opinions on what has been proposed. Nothing more, nothing less.

2.  I got into ultralow field (ULF) MRI back in 2004 after reading a now largely discredited paper claiming to detect neuronal currents with MRI. My rationale was that if BOLD scales as a percent per tesla of operating field then reducing the operating field to the point where BOLD all but vanishes is a good start. But once we considered all the other contaminants we realized that CBV changes would persist and likely still be several orders of magnitude larger than anything we might hope to do with NCI. So we switched gears to trying to use the CBV change as a functional contrast mechanism at ULF. Even this less ambitious goal proved to be near-impossible with our setup; we had too much sensitivity to motion and, quite possibly, concomitant changes in cerebrospinal fluid (CSF) that offset our desired signal changes. So then we changed directions again and went after clinical goals instead. That's where we stand today. We haven't worked on functional imaging methods at ULF for several years now, and we have no plans to restart unless someone gives us a huge pot of money to rebuild the entire ULFMRI system to minimize subject motion. Sitting upright isn't gonna do it.


  1. Nice summary, PractiCal!!

    Given the wackiness of some of the successful proposals I wish I had submitted one on this speculative idea:

  2. I'm the PI on the wearable PET proposal. I wanted to first make a general comment about this RFA in that we were encouraged by our program officers to be a little 'out there' - the whole 'moon shot' concept of something practically (or should I say practiCal-ly) impossible. That said, I don't think the walk in the park is necessarily impossible, for example, if the park is relatively near a cyclotron (I recall the research PET days before fMRI in which O15 would be shuttled up 5 floors to the PET scanner), if 'table-top' cyclotron technologies advance in parallel (we did have a fig that actually did propose a combination but don't really have the funds to develop, except to include an outside consultant), and finally, as said in the last line of our Research Strategy 'Whether the ‘walk in the park’ is outside or in virtual reality..." I also wanted to encourage checking out the lightweight Silicon Photo-multiplier technology - much smaller than standard. We used it in our prototype and it weighed about 6 pounds, but whole brain coverage might be 10-15lbs, so we have a mechanical engineer on board for support/ registration logistics. Hope that helps! This blog is very helpful and idea inspiring, I do like the idea of disposable tech!

    1. Thanks, Julie! I'm glad it wasn't too critical a review based on a short abstract. Do you know if the full proposals will be made public at all? Not asking you personally to do anything that isn't de rigeur for the RFA, I'm really just curious to see more details on all the proposals.

      A 6 lb photomultiplier does sound a lot more portable, no doubt about it. Glad to be able to offer teeny ideas to inspire! It was the entire point of this post. (My usual posts are aimed at education.) Please do keep us all posted on your progress. Many of us are spectating with considerable interest.

  3. Yes, the whole ring is only 6 pounds, a ring of about 12 small detectors. Check out Ravi's (our GE partner's) demo and our little local news thing that shows our prototype helmet (we actually collected some piggyback patient data with the device.)

    This type of blog is exactly the spirit of these planning grant awards- to inspire discussion and have the neuroscience and neuroimaging be part of the development process. We plan to host symposia and satellite meetings on conferences for the same objectives. I'll keep you in the know.

    As for the whole grant, usually not - but if you'd like to have a phone chat about some details let me know! Keep the discussions rolling! I plan to read your posts about the other projects too- just was able to skim so far.

  4. Sorry, I just don't see the value in a wearable PET scanner. We need a noninvasive tool to measure brain signals on a fine spatial and temporal scale (mm and ms would be nice). How does wearing a tool that does not meet those requirements help understand brain function in a significant way?

  5. Unfortunately I don't see a way to include figures, but we had one that showed potential uses that had a "Ambulatory" column and a "Microdose" column. The latter may have some bearing on your question, but not exactly mm or ms. The device is very close to the head and thus has high sensitivity - this means that we should be able to synthesize radioligands for targets that were previously off-limits like glia subtypes, pyramidal cell subtypes, ion channels, and other targets in concentrations too low for standard PET (that's what GE is especially excited about). Just developing the TOF technology, reconstruction and detectors will be useful, even without the ambulatory aspect (i.e. a seated subject). A dose comparable to a cross-country flight may also wipe the dust of PET brain research, which for some applications has advantages over fMRI - it doesn't require unnatural switching to a 'baseline', and one can use custom targets. Spatial resolution won't be better than fMRI (about 1mm), and certainly temporal will be low - a max of about a minute if using O15, 10 minutes for C11 compounds - but imaging things like balance, motor tasks, stroke recovery, more natural social interactions, unmedicated Parkinson's or other populations that can't stay still, emotional and other states that can't easily be switched on and off, virtual reality applications etc. I feel has value (sorry for the laundry list!). What other uses do people see for this and the technologies developed in the other proposals? One of the purposes of the planning grants is to brainstorm.

    1. I've always thought that in PET "you're only as good as your (bio)chemists." Meaning, identifying then synthesizing tracers is where the action has been. Dusting off research on detectors sounds like it is worthwhile, then, especially if it opens up the potential to different radionuclides. Sensitivity is a critical aspect of all imaging methodologies, and PET is operating with relatively old hardware designs to the best of my knowledge. (The exception might be the combined PET-MRI devices, but I was never totally sold on that premise to begin with.) One would think that new materials, and a fresh impetus to investigate, might bring some interesting developments. There could even be an argument that this project is more likely to develop useful medical applications before any of the other eight. One reliable tracer for Alzheimer's would do it.

      My scientific opinion (as opposed to my "PR-slash-grant-writing" opinion) is that a focus on sensitivity is laudable, and I would make the development of more sensitive hardware a higher priority than mobility or a low performance device capable of deployment in novel "real (or virtual) world" environments. If I do the thought experiment I choose a cumbersome machine capable of imaging something fundamentally new over a lightweight one that is portable but performs poorly. So I wouldn't constrain the project from the start with mass and size constraints. Make it the size of a 10.5 T MRI for all I care! If it sees something really new it's worthwhile.

    2. PS if you want to facilitate brainstorming, perhaps take some of the main parts of your application and create a Github on which to post them? That simultaneously solves the problem of sharing figures. Others may well have better ideas on internet resources to use, I'm not au fait with the latest, greatest web tools (as the design of this blog attests). In my limited experience, Github's a great way to foster collaborations.

  6. I can't tell which I love more - the microdose is the easy one to have clinical relevance, and yes, neural targets related to Alzheimer's and other disorders will be targets. When I did a GE site visit during grant prep, I spent a morning with their Biological and Organic Chem lab manager, Randy Carter. He showed me how they determine suitable targets, and how higher sensitivity basically shifts the curve in favor of some of the low concentration targets, like the rarer glia and pyramidal subtypes that I mentioned. This could be the real big deal, but I really love the portable/wearable aspect too for lots of reasons. We may even end up with more than one model, but we are unlikely to skimp on sensitivity. These kind of issues are part of what the 'planning' aspect will help ferret out - and we need input from lots of people like you, and from neuroscientists and clinicians in different disciplines with different needs. (Oh, as an aside, we were asked to minimize mention of clinical applications in the proposal, but they remained the pink elephant).

    Thanks by the way for the heads-up on Github - that looks great! For our long distant team, this looks like a great way to organize, and to get input from the larger community. And thanks for supporting my adventure into the Twittersphere. (for others I can be followed at JuliePEThelmet)

    1. Grand, I shall look forward to the Github. I'll be sure to pester my local PET folks to look at it, too.

      Until then, I'm taking the liberty of posting a link to the photo you tweeted of your mobile PET concept: I also added this link under the review paragraph on your successful proposal.