Wednesday, December 18, 2013

BRAIN Initiative Funding Opportunites at NIH


National Institutes of Health (NIH) has finally released detailed descriptions for six separate funding opportunities in support of the BRAIN Initiative. If you're big on cells, circuits, and/or technologies, one of these programs could be for you. NIH hopes to award $40 million by the end of the fiscal year (September 30, 2014). The application deadlines are all in March 2014.

In October, Defense Advanced Research Projects Agency (DARPA) announced that it would spend $70 million over the next five years to develop and improve deep brain stimulation (DBS) techniques. The approaches of the two agencies are quite different, as outlined in this post.

The NIH Director's BRAIN Advisory Committee issued its Interim Report (PDF) on September 16. The report focused on animal models, including improvement of technologies for recording neuronal activity and manipulating circuit function. The new Requests for Applications (RFAs) reflect the high-priority research areas for FY 2014. Here are concise summaries of the new funding opportunities from the White House:
  • Generate an inventory of the different types of cell types in the brain
  • Develop new tools to analyze the complex circuits that are responsible for brain function by delivering  genes, proteins and chemicals to particular cells
  • Develop new approaches to record the activity of large numbers of neurons in any location in the brain, and improve existing technologies so they can be widely adopted by neuroscientists
  • Understand large-scale neural circuits by integrating experimental, analytical, and theoretical approaches
  • Form teams to develop the next generation of non-invasive imaging technologies

As you can see, Cellular/Molecular and Systems/Circuits neuroscience researchers will benefit the most, along with engineers, physicists, and other technology-development types.

Here are the RFA summaries from NIH:
  • Transformative Approaches for Cell-Type Classification in the Brain (RFA-MH-14-215) – aims to pilot classification strategies to generate a systematic inventory/cell census of cell types in the brain, integrating molecular identity of cell types with connectivity, morphology, and location. These pilot projects and methodologies should be designed to demonstrate their utility and scalability to ultimately complete a comprehensive cell census of the human brain.

  • Development and Validation of Novel Tools to Analyze Cell-Specific and Circuit-Specific Processes in the Brain (RFA-MH-14-216) – aims to develop and validate novel tools that possess a high degree of cell-type and/or circuit-level specificity to facilitate the detailed analysis of complex circuits and provide insights into cellular interactions that underlie brain function. A particular emphasis is the development of new genetic and non-genetic tools for delivering genes, proteins and chemicals to cells of interest; new approaches are also expected to target specific cell types and or circuits in the nervous system with greater precision and sensitivity than currently established methods.

  • New Technologies and Novel Approaches for Large-Scale Recording and Modulation in the Nervous System (RFA-NS-14-007) – focuses on development and proof-of-concept testing of new technologies and novel approaches for large scale recording and manipulation of neural activity, with cellular resolution, at multiple spatial and/or temporal scales, in any region and throughout the entire depth of the brain. The proposed research may be high risk, but if successful could profoundly change the course of neuroscience research.

  • Optimization of Transformative Technologies for Large Scale Recording and Modulation in the Nervous System (RFA-NS-14-008) – aims to optimize existing and emerging technologies and approaches that have the potential to address major challenges associated with recording and manipulating neural activity. This FOA is intended for the iterative refinement of emergent technologies and approaches that have already demonstrated their transformative potential through initial proof-of-concept testing, and are appropriate for accelerated engineering development with an end-goal of broad dissemination and incorporation into regular neuroscience research.

  • Integrated Approaches to Understanding Circuit Function in the Nervous System (RFA-NS-14-009) – focuses on exploratory studies that use new and emerging methods for large scale recording and manipulation to elucidate the contributions of dynamic circuit activity to a specific behavioral or neural system. Applications should propose teams of investigators that seek to cross boundaries of interdisciplinary collaboration, for integrated development of experimental, analytic and theoretical capabilities in preparation for a future competition for large-scale awards.

  • Planning for Next Generation Human Brain Imaging (RFA-MH-14-217) – aims to create teams of imaging scientist together with other experts from a range of disciplines such as engineering, material sciences, nanotechnology and computer science, to plan for a new generation of non-invasive imaging techniques that would be used to understand human brain function. Incremental improvements to existing technologies will not be funded under this announcement.

Is this a call for DARPA-lite projects? Or for proposals as far-fetched as calcium imaging in humans? As the RFA explains...
The long-term objective is to develop tools for the precise imaging of molecules, cells, and circuits in the human brain.  Applications submitted in response to this R24 FOA should support the formation and development of interdisciplinary teams that will plan innovative approaches to substantively expand the ways by which brain structure and function can be imaged in humans.  These R24 awards will support planning activities such as meetings, prototype development projects and small scale pilot studies in mammals or humans that would provide proof of principle for transformative approaches to assessing human brain structure and function.  The proposed concepts are expected to be high-risk, high-impact, and disruptive (c.f. C. Christensen “The Innovator's Dilemma”, 1997; http://en.wikipedia.org/wiki/Disruptive_innovation).

What might these [post-]BOLD new BRAIN scanners of the future look like? This question was addressed by practiCal fMRI in September:
This week's interim report from the BRAIN Initiative's working group is an opportunity for all of us involved in fMRI to think seriously about our tools. We've come a long way with BOLD contrast to be sure, even though we don't fully understand its origins or its complexities. ...

I can't help but wonder what my fMRI scanner might look like if it was designed specifically for task. Would the polarizing magnet be horizontal or would a subject sit on a chair in a vertical bore? How large would the polarizing magnet be, and what would be its field strength? The gradient set specifications? And finally, if I'm not totally sold on BOLD contrast as my reporting mechanism for neural activity, what sort of signal do I really want? In all cases I am especially interested in why I should prefer one particular answer over the other alternatives.

Note that I'm not suggesting we all dream of voltage-sensitive contrast agents. That's the point of the BRAIN Initiative according to my reading of it. All I'm suggesting is that we spend a few moments considering what we are currently doing, and whether there might be a better way...

Further Reading

DARPA allocates $70 million for improving deep brain stimulation technology

A Tale of Two BRAINS: #BRAINI and DARPA's SUBNETS

New Deep Brain Stimulation System Measures Neurotransmitter Release


Anyone who is awarded one of these #BRAINI grants is free to use this nifty badge on all their promotional materials and publications.


The BRAIN Initiative badge is awarded by President Obama to research supported by his $100 million #BRAINI. This bold new research effort will include advances in nanotechnology and purely exploratory efforts to record from thousands of neurons simultaneously.

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4 Comments:

At December 18, 2013 8:12 PM, Blogger practiCal fMRI said...

So I've been thinking a lot about human brain imaging, in particular how far we've come with endogenous signals. Not so bad, really. I won't bore you with the details but the prospects of detecting directly neuronal currents with MRI are pretty lousy at the moment. Specifically, they are lousy if your goal is to detect neuronal currents in a normal, awake human brain and you have a high field magnet. Why? BOLD. It's a weed that is really, really hard to overcome.

I know this because I've been attempting to do fMRI at 130 uT for nearly ten years. Using as a rough rule of thumb "1% per tesla" for BOLD, the BOLD contamination will be around 0.00013%. Pretty good. Except that the neuronal currents are really, really small, probably still around two to three orders of magnitude below the BOLD changes. Now, there may be other ways to do vascular fMRI at ultralow fields - we've been trying a CBV-based method - but they are still exceedingly challenging. I won't go into the details here but our estimates are that we are about an order of magnitude below the detection threshold for CBV-based fMRI. Except, of course, that this doesn't offer anything new in the way of fMRI mechanisms. (There is a project in Finland attempting to combine MEG with MRI; MEG with fMRI might be super interesting, but it is also super challenging.)

Which brings me to exogenous contrast. What can we stick into normal humans that will signal something more interesting than the vasculature? We can use blood-based contrast agents, such as superparamagnetic nanoparticles, but these relatively large beasts will (hopefully) stay in the blood. The blood-brain barrier should prevent their migration into parenchyma. So, what on earth can we do that would (a) deliver to the brain cells, (b) be non-toxic, and (c) would signal something interesting in the brain that we can't see today? I can only think of molecular tracers, such as 13-C labeled substrates, or 17-O, or 23-Na.... Anyone got any better ideas?

 
At December 19, 2013 1:47 PM, Blogger The Neurocritic said...

Thanks so much for your comment. I wish I had something scientifically useful to add, but this topic is well beyond my area of expertise. Taking a closer look at the RFA (below), it seems like the BBB is actually a target area of interest:

"This FOA promotes the development of breakthrough technology to measure brain processes that were formerly inaccessible to imaging, including but not limited to:

- Dynamic cellular processes in the brain, including gene expression and regulation, metabolism, proteomics and other molecular processes
- Local and micro-circuits in the nervous system
- Non-neuronal (glial) structure and function
- Glymphatic (non-cerebrovascular) flow
- Blood brain barrier (targeted, regional) permeability and function in the human brain
- Mechanisms linking single cell or circuit activity to hemodynamic or macro-electromagnetic signals
- Neurotransmitter release dynamics and receptor/ion channel function at the scale of synaptic transmission, that do not use radioactive tracers
- Dynamic local drug distribution, pharmacokinetics and metabolism"


And it also seems that some of the desired technologies (e.g., the last two) are not non-invasive. "Neurotransmitter release dynamics" overlaps with the DARPA DBS mandate. Except the DARPA program is very clinically focused. Clearly, much of this work will be done in pilot studies with animal models. At any rate, NIH isn't expecting immediate translation to humans:

"By the completion of the R24 award period [3 yrs], investigators should be prepared to fully develop next-generation brain imaging technology within 5 years, for use in humans."

And within these 3 yrs, NIH will support things like investigator meetings, data-sharing and information exchange, standardization, prototype development, and pilot studies to provide proof of concept. I hope you'll be on one of the funded teams!

 
At December 19, 2013 10:36 PM, Blogger practiCal fMRI said...

Yes, if invasive procedures are considered then the options seem to get a lot better. Like you, I'm not qualified to comment on those. I am passably qualified to talk about MRI-based measures but that's it.

I'd forgotten this gem of a publication, the first demonstration of non-vascular fMRI that's likely to be a valid result:

http://www.ncbi.nlm.nih.gov/pubmed/23618601

I don't believe the previous claimed results based on neuronal currents, neuronal swelling or rapid diffusion responses. Seong-Gi Kim is a really thorough scientist and the data in this paper seem compelling to me. So much so that I'll do a review of it on my blog at some point soon. Note here, however, that to get their non-hemodynamic fMRI contrast they had to employ one trick: knock out all the signal (including BOLD) from blood! This may be possible in a minimally invasive way in humans, using intravascular contrast agents (such as superparamagnetic nanoparticles) to reduce the blood signal to near zero. Some CBV-based signal changes may persist, but these may be separable based on their longer response time than the tissue-based signals. More details in a future blog post!

"I hope you'll be on one of the funded teams!"

Mmmm. Thanks for the vote of confidence anyway. I'm not much of a fan of meetings generally, and I tend to keep away from debating societies in particular. But maybe I can contribute from the sidelines. Someone needs to ask the nasty questions!

 
At December 20, 2013 9:42 AM, Blogger The Neurocritic said...

Ah. Well, hopefully you can contribute from the sidelines...

Looking forward to your future blog posts!

 

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