The Brain Activity Map: Answers for Alzheimer's and More?

In his state of the union address President Obama put his weight behind the goal of building a comprehensive map of the brain's activity, a Brain Activity Map or BAM. The administration is hoping to announce as soon as this spring how it plans to bring the plan together, including perhaps its most challenging aspect: funding.

How that plays out remains to be seen, but the term “brain mapping,” as it's being referred to in this project, really refers to developing tools and strategies to be able to monitor activity of all the neurons of the brain simultaneously, according to Rajiv R. Ratan, MD, PhD, Executive Director, Burke Medical Research Institute. This is so, “one can determine which areas of the brain are activated when humans are doing different actions, such as they're thinking of something pleasant or their walking,” he says.

Arriving Here

Historically, researchers, scientists, and physicians have conceptualized specific areas of the brain as serving specific functions. For example, a localized area of the brain is considered to be involved in speech, while another area is involved in motor function. “I think that there is a hypothesis that that sort of simple idea of anatomical functional correlates within different areas of the brain is overly simplistic,” Dr. Ratan said.

At the heart of the matter is a conflict between a static versus dynamic model: Where we are with our current wiring diagram that charts how neurons interconnect, and where we hope to be, Dr. Ratan suggests. A popular analogy Dr. Ratan says, is to look at a map of West Chester, NY. Scarsdale is south of White Plains and north of Bronxville. That's the static view. A dynamic view might show where all the residents of Scarsdale are at any one time in West Chest county. “So, you can see Scarsdale as not a geographical representation of where it is, but rather a representation of the people who live there.”

Writing for the technology web site io9.com, Robert Gonzalez observed: “Creating such a map will require nothing short of a technological revolution in the field of neuroscience. It is currently possible to insert electrodes into the brain that can both monitor and induce brain activity. But the resolution offered by these and less invasive techniques is poor. That means the first step toward a BAM will be to develop tools that can actually record the individual activity of every neuron in a brain circuit. The second step will be to create tools that can influence the activity of individual neurons.”

All of this brings somewhat of a natural, if often times unwanted, comparison to the Human Genome Project, which also serves as one of the two arguments against BAM: its conceptual goals remain less well-defined than those of the Human Genome Project.

“I think the conceptual goals are less clear but it's still worthwhile,” Dr. Ratan insists. “The current estimates are that the number of people with AD will go to almost 14 million people in 2050 and it will cost the United States, annually, $1.1 trillion.” Stroke and other neurological disorders will skyrocket as well. “These costs are going to bankrupt the United States. In some ways we would argue that an investment in a project like this is not an option, that it's a necessity.”

The Necessary Tools

The BAM project certainly has catching up to do. The technology to accomplish the Human Genome Project was available and was largely a matter of implementing the technology, distributing the effort among multiple different laboratories, and then just getting the job done, to put it simply.

“BAM's first aspiration is to develop technology that allows us to have the appropriate spatial temporal and temporal resolution to be able monitor the activity of all neurons in the brain,” Dr. Ratan explains. “Currently we use methods like EEG—not very sensitive, and it doesn't have good spatial resolution. You can't distinguish one neuron from another neuron because, essentially, the measurement integrates many thousands of neurons,” he adds.

“The dream would be to have a technique that allows us to simultaneously sample the billions and billions of neurons that exist in all the different regions of our brain so that we can have an understanding of when we do a complicated or simple task, what regions of the brain are actually being activated and have other techniques that allow us to understand if that activity is causally related to the task or is it just unrelated,” Dr. Ratan says.

Paying the Way

And then there's the matter of cost—the major second issue critics have with BAM. Something as large scale as BAM could cause a major diversion of existing neurology funds, siphoning research capital away from smaller projects and making it difficult for scientists to get their non- BAM projects funding, critics charge.

“It's like the moon shot of President Kennedy saying, ‘we're going to get the moon within the decade,' despite not having all the technological problems solved. If they could fund this like the HGP, where they can find additional money on top of what is invested in research through the NIH, and it doesn't compete with those resources than I would say this is a fantastic idea because I think that from the stand point,” Dr. Ratan said.

What's further troubling is how we spend on health care in the United States, he adds, particularly how dispersal of our almost $2 trillion yearly budget. Currently, the US is spending less than $30 billion on the NIH budget, meaning the government is spending less than two percent on research and development in health. And part of that reason is the failure to connect how that makes people healthier and reduces costs, Dr. Ratan said.

“Some people would argue with a R&D investment of less than two percent. You're never going to impact the human bedside. And if you look at the pharmaceutical industry, they invest about 25 percent of their annual budget in R&D. We have disproportionately small investment in research and development and one would argue that's going to negatively impact the United States' ability to be competitive,” he added.

New Developments

Brain mapping took a considerable step forward in March when researchers at the Howard Hughes Medical Institute published the first ever brain activity map of any creature. This achievement now suggests the possibility of recording larger animals, and even humans, as a real possibility.

For their study, Misha Ahrens, PhD, and Philipp Keller, PhD, started from the view that brain function relies on communication between large populations of neurons across multiple brain areas. “A full understanding of [this communication] would require knowledge of the time-varying activity of all neurons in the central nervous system,” they speculated. They used light-sheet microscopy to record activity, which was previously used to image developing embryos.

They reported through the genetically encoded calcium indicator GCaMP5G, from the entire volume of the brain of the larval zebrafish—a small transparent fish—in vivo at 0.8 Hz, capturing more than 80 percent of all neurons at singlecell resolution.

“Demonstrating how this technique can be used to reveal functionally defined circuits across the brain, we identify two populations of neurons with correlated activity patterns,” they wrote in their study published online March 18 in Nature Methods. “One circuit consists of hindbrain neurons functionally coupled to spinal cord neuropil. The other consists of an anatomically symmetric population in the anterior hindbrain, with activity in the left and right halves oscillating in antiphase, on a timescale of 20 seconds, and coupled to equally slow oscillations in the inferior olive,” they wrote.

“We were pleased to find the two functional networks--the hindbrain oscillator and the spinal-hindbrain circuit,” Dr. Ahrens said in an interview with Practical Neurology. “These sort-of ‘popped out' of the data in a very clear way. The other surprising finding was that brain areas which are anatomically far away from each other (on the scale of the zebra fish brain) still have strongly correlated activity: communication in the brain really seems to span the entire distance of the brain, in some cases.”

Dr. Ahrens says the most general message to take away from the study would be that their ability to image almost all neurons in the brain opens up the possibility to study how neural networks across many brain areas process sensory input and produce behavior. In this model system, they are not limited anymore by having to study a few neurons in a few brain areas at a time; instead, they can look at the entire system and see how the parts interact.

Where we on the map, so to speak, is a matter of perspective, he says, but “we can now look at how large populations of neurons across multiple brain areas interact and work in concert to process information and produce behavior.”

The Future Awaits

As a part of the popular TED (Technology, Education, Development) lecture series, Allan Jones, CEO of the Allen Institute for Brain Science, ended his talk on brain mapping with this note: “I'll just close by saying that the tools are there, and this is truly an unexplored, undiscovered continent. This is the new frontier, if you will. And so for those who are undaunted, but humbled by the complexity of the brain, the future awaits.”

In the meantime, neurologists and patients wait to see if the BAM comes to fruition and to determine if it offers answers to the challenges of diagnosing and treating neurological diseases.