ARTICLE IN BRIEF
At the Society for Neuroscience annual meeting, neuroscientists presented an overview of new findings that are emerging from the application of connectomics, the mapping of multiple neural connections made possible by refined MRI imaging and histological techniques.
No one doubts that mapping the human connectome will lead to a profound new understanding of how the brain produces thought, emotion, and behavior.
But when Jeffrey Lichtman, MD, PhD, laid out the “What, How, and Why” of connectomics at the recent Society for Neuroscience (SfN) meeting in San Diego, his enthusiasm for upcoming discoveries slammed up against his animation showing a piece of mouse connectome no larger than a grain of salt.
That speck of tissue, massively enlarged on a screen behind him, contained 680 axons, 774 synapses — most of them excitatory — and 79 dendrites, according to Dr. Lichtman, professor of molecular and cellular biology at Harvard. Another view of the animated image revealed clouds of synaptic vesicles filled with neurotransmitters ready for release.
Refined MRI imaging techniques — diffusion tensor imaging — coupled with histological techniques are enabling neuroscientists to increase the speed, efficiency, and resolution of maps of the multiple neural connections in a nervous system.
“There's so much stuff in this trivially small area,” Dr. Lichtman observed — an understatement that captures both the excitement and the daunting challenge of connectomics.
Actually, connectomics currently represents two parallel endeavors. Dr. Lichtman is mapping what might be called the microconnectome —– the millions of synaptic connections that form the circuits that enable the human brain to learn. The microconnectome is another story, but for basic tractography, MRI diffusion tensor imaging is useful.
“We come into world knowing almost nothing,” he said. “You can trace almost all of your behaviors to learning as opposed to genes. Language, riding a bicycle, how you button your shirt — basically everything is learned, which means once that information gets into the brain it has to be turned into a stable form. There must be rules for that. It's like chess — each game is unique, but the rules are always the same. So the immense complexity (of the human brain) isn't as daunting as it seems.”
MAPPING C. ELEGANS
Another explorer of the microconnectome, Scott W. Emmons, PhD, described his quest in a presentation at the SfN meeting titled, “The Mind of a Worm.” Although the subject of his research — C. elegans — may be small and simple, it represents the first complete mapping of an actual nervous system.
“C. elegans is so tiny we can identify all the connections in the nervous system,” said Dr. Emmons, the Siegfried Ullmann professor of genetics, and a professor of neuroscience at the Albert Einstein College of Medicine. “C. elegans is the first natural neural network to be mapped. Now theorists can reverse engineer the network and figure out how it functions.”
The other branch of connectomics involves mapping the pathways that transport signals from one brain region to another. Aberrations in neuronal transmissions, often called “connectopathies,” are believed to produce the symptoms of some of the most perplexing neurological and psychiatric conditions, including schizophrenia, autism, attention deficit hyperactivity disorder (ADHD), depression, and epilepsy. Therefore, a rapidly growing realm of research is dedicated to understanding how those signals function and malfunction.
For example, at the Society for Neuroscience meeting, Damien Fair, PhD, of the Oregon Health & Science University, discussed the application of connectomics to ADHD and autism spectrum disorders during a symposium titled “The Human Connectome in Health and Disease.” Dr. Fair is confident that a large, focused research effort into brain connections will reveal the roots of such problems.
“No part of the brain is not connected to some other part of the brain, either directly or indirectly,” said Dr. Fair, assistant professor in the department of behavioral neuroscience and psychiatry, and an assistant scientist in the Advanced Imaging Research Center. “For many years those of us studying these disorders have focused on atypical patterns in specific brain regions. Now we've begun to supplement that work with investigations of how those regions communicate more broadly with other parts of brain.”
He credits this change in perspective to the bird's-eye view provided by a better understanding of brain networks.
PATHWAYS IN SCHIZOPHRENIA
Olaf Sporns, PhD, Provost professor in the department of psychological and brain sciences at Indiana University in Bloomington, has been studying the connectivity of brain pathways in schizophrenia.
“A number of studies point to problems with structural connections in highly connected brain regions such as the parietal cortex and prefrontal cortex,” said Dr. Sporns, author of Networks of the Brain (MIT Press, 2010) and, more recently, Discovering the Human Connectome (MIT Press, 2012). “Schizophrenia has long been conceptualized as a disorder of integration — of not being able to bring information together in the brain — and these long-distance pathways in the brain appear to be weaker in brains of patients with schizophrenia than in healthy controls. That is an exciting finding that might lead to better understand of what capacities of the brain have been perturbed, and that will lead to better diagnostic and therapeutic methods.”
At the Society for Neuroscience meeting, Dr. Sporns and Martijn van der den Heuvel, PhD, of the University Medical Center Utrecht, Netherlands, also participated in a the symposium titled “The Human Connectome in Health and Disease.” Together they discussed the brain's “connectivity rich club” and its role in integrating neural signals.
“In plain English we ask, are highly connected nodes in the network more highly connected with each other than would be predicted by chance?” Dr. Sporns said. “That appears to be the case, which is an interesting feature of brain connectivity. It means that not only does information come together in specific nodes in the brain, but also those highly connected hubs are exchanging information among each other, which we think is crucially important for integrating signals.”
Now, Dr. Sporns wants to apply computational methods to the study of connectivity problems in the brain.
“We can do things with a model we can't do in humans, such as make lesions and create disturbances in connectivity by deleting or enhancing pathways or gray matter regions, or even adding new pathways,” he said. “It's a little like doing computational studies in other fields such as physics or climatology or ecology, and trying to understand how a system responds to challenge. This approach will be clinically useful when we can model a patient's brain and manipulate that model in a computer to find a good way for that brain to recover. This is not going to happen in the next few years, but it's something that is a very valuable long-term goal for connectomics.”
And a study published in the Dec. 6 issue of Science demonstrates how an awareness of the connections among brain regions can redefine a seemingly well-understood disorder such as dyslexia.
A group of Belgian researchers led by Bart Boets, PhD, a clinical psychologist at the Catholic University of Leuven, used fMRI with functional and connectivity analysis capabilities to examine the widespread belief that dyslexics have trouble deciphering phonetic representations. They found that 23 dyslexic subjects performed just as well as 22 controls in their ability to discriminate phonemes, but did not display normal connectivity between the left inferior frontal gyrus, involved in phonological processing, and others brain regions involved in deciphering phonemes.
“Our results suggest that a dysfunctional connection between frontal and temporal language areas impedes efficient access to otherwise intact representations of speech sounds, thus hampering a person's ability to manipulate them fluently,” the researchers concluded. [See the Feb. 6 issue for an in-depth analysis of this study: http://bit.ly/1dg1KwW.]
SUPPORT FOR CONNECTOMICS
The European Union's Human Brain Project has committed $1.6 billion over 10 years to a similar endeavor — creating a supercomputer simulation of the human brain. “This is expected to lead to technological innovation and a better understanding of the human brain, new treatments for brain diseases, and new brain-inspired computing technologies,” said Dr. Daniel Pasini, PhD, of the European Commission, based in Brussels.
In the United States, the NIH is coordinating the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative, announced by President Obama in April. Aimed at developing technologies that will reveal the brain at work, the BRAIN Initiative is expected to include generous funding for connectomics research, although specific projects are still under review.
The NIH first announced a $40 million grants program in 2010 for the Human Connectome Project — supporting efforts to map the human brain's connections in high resolution — under its Blueprint for Neuroscience initiative.
Some fear that connectomics will soak up vast amounts of funding that could be put to better use elsewhere. Dr. Lichtman addressed some of those concerns in a recent article in Nature Methods titled, “Why not Connectomicsconnectomics?” which he co-authored with Joshua L. Morgan, PhD.
“We listed 10 arguments against connectomics,” Dr. Lichtman said. “We could have listed 20. People are constantly giving us reasons why it won't work, and they're not poorly informed reasons. We're dealing with a degree of complexity that seems impossible, but I don't think it is impossible.”
Dr. Sporns is also confident that the human connectome, like the human genome, will produce innovations and insights beyond the imagination of today's researchers. He expects that such progress will make his most recent book, Discovering the Human Connectome (MIT Press, 2012), out of date very soon.
“Two years ago the field already was developing rapidly,” he said, “but now it's taking off like a rocket. I should write an update.”