brain disorders
From Electrical Brain Maps to Learning More About Migraines
Posted on by Dr. Francis Collins
One of life’s greatest mysteries is the brain’s ability to encode something as complex as human behavior. In an effort to begin to unravel this mystery, neuroscientists often zoom in to record the activities of individual neurons. Sometimes they expand their view to look at a specific region of the brain. But if they zoom out farther, neuroscientists can observe many thousands of neurons across the entire brain firing at once to produce electrical oscillations that somehow translate into behaviors as distinct as a smile and a frown. The complexity is truly daunting.
Rainbo Hultman, University of Iowa Carver College of Medicine, Iowa City, realized years ago that by zooming out and finding a way to map all those emergent signals, she could help to change the study of brain function fundamentally. She also realized doing so offered her an opportunity to chip away at cracking the complicated code of the electrical oscillations that translate into such complex behaviors. To pursue her work in this emerging area of “electrical connectomics,” Hultman recently received a 2020 NIH Director’s New Innovator Award to study the most common human neurological disorder: migraine headaches.
A few years ago, Hultman made some impressive progress in electrical connectomics as a post-doctoral researcher in the lab of Kafui Dzirasa at Duke University, Durham, NC. Hultman and her colleagues refined a way to use electrodes to collect electrical field potentials across an unprecedented seven separate mouse brain regions at once. Using machine learning to help make sense of all the data, they uncovered a dynamic, yet reproducible, electrical brain network encoding depression [1].
What’s more, they found that the specific features of this brain-wide network could predict which mice subjected to chronic stress would develop signs of major depressive disorder. As Hultman noted, when measured and mapped in this way, the broad patterns of electrical brain activity, or “Electome factors,” could indicate which mice were vulnerable to stress and which were more resilient.
Moving on to her latest area of research, Hultman is especially intrigued by the fact that people who endure regular migraine attacks often pass through a characteristic sequence of symptoms. These symptoms can include a painful headache on one side of the head; visual disturbances; sensitivity to light, odors, or sound; mood changes; nausea; trouble speaking; and sometimes even paralysis. By studying the broad electrical patterns and networks associated with migraine in mice—simultaneously capturing electrical recordings from 14 brain regions on a millisecond timescale—she wants to understand how brain circuits are linked and work together in ways that produce the complex sequences of migraine symptoms.
More broadly, Hultman wants to understand how migraine and many other disorders affecting the brain lead to a state of heightened sensory sensitivity and how that emerges from integrated neural circuits in the brain. In her studies of migraine, the researcher suspects she might observe some of the same patterns seen earlier in depression. In fact, her team is setting up its experiments to ensure it can identify any brain network features that are shared across important disease states.
By the way, I happen to be one of many people who suffer from migraines, although fortunately not very often in my case. The visual aura of flashing jagged images that starts in the center of my visual field and then gradually moves to the periphery over about 20 minutes is pretty dramatic—a free light show! I’ve wondered what the electrical component of that must be like. But, even with treatment, the headache that follows can be pretty intense.
Hultman also has seen in her own life and family how debilitating migraines can be. Her goal isn’t just to map these neural networks, but to use them to identify where to target future therapeutics. Ultimately, she hopes her work will pave the way for more precise approaches for treating migraine and other brain disorders that are based on the emergent electrical characteristics of each individual’s brain activity. It’s a fascinating proposition, and I certainly look forward to where this research leads and what it may reveal about the fundamentals of how our brains encode complex behaviors and emotions.
Reference:
[1] Brain-wide electrical spatiotemporal dynamics encode depression vulnerability. Hultman R, Ulrich K, Sachs BD, Blount C, Carlson DE, Ndubuizu N, Bagot RC, Parise EM, Vu MT, Gallagher NM, Wang J, Silva AJ, Deisseroth K, Mague SD, Caron MG, Nestler EJ, Carin L, Dzirasa K. Cell. 2018 Mar 22;173(1):166-180.e14.
Links:
Migraine Information Page (National Institute of Neurological Disorders and Stroke/NIH)
Laboratory for Brain-Network Based Molecular Medicine (University of Iowa, Iowa City)
Hultman Project Information (NIH RePORTER)
NIH Director’s New Innovator Award (Common Fund)
NIH Support: Common Fund; National Institute of Mental Health
Could A Gut-Brain Connection Help Explain Autism?
Posted on by Dr. Francis Collins
You might think nutrient-sensing cells in the human gastrointestinal (GI) tract would have no connection whatsoever to autism spectrum disorder (ASD). But if Diego Bohórquez’s “big idea” is correct, these GI cells, called neuropods, could one day help to provide a direct link into understanding and treating some aspects of autism and other brain disorders.
Bohórquez, a researcher at Duke University, Durham, NC, recently discovered that cells in the intestine, previously known for their hormone-releasing ability, form extensions similar to neurons. He also found that those extensions connect to nerve fibers in the gut, which relay signals to the vagus nerve and onward to the brain. In fact, he found that those signals reach the brain in milliseconds [1].
Bohórquez has dedicated his lab to studying this direct, high-speed hookup between gut and brain and its impact on nutrient sensing, eating, and other essential behaviors. Now, with support from a 2019 NIH Director’s New Innovator Award, he will also explore the potential for treating autism and other brain disorders with drugs that act on the gut.
Bohórquez became interested in autism and its possible link to the gut-brain connection after a chance encounter with Geraldine Dawson, director of the Duke Center for Autism and Brain Development. Dawson mentioned that autism typically affects multiple organ systems.
With further reading, he discovered that kids with autism frequently cope with GI issues, including bowel inflammation, abdominal pain, constipation, and/or diarrhea [2]. They often also show unusual food-related behaviors, such as being extremely picky eaters. But his curiosity was especially piqued by evidence that certain gut microbes can influence abnormal behaviors in mice that model autism.
With his New Innovator Award, Bohórquez will study neuropods and the gut-brain connection in a mouse model of autism. Using the tools of optogenetics, which make it possible to activate cells with light, he’ll also see whether autism-like symptoms in mice can be altered or alleviated by controlling neuropods in the gut. Those symptoms include anxiety, repetitive behaviors, and lack of interest in interacting with other mice. He’ll also explore changes in the animals’ eating habits.
In another line of study, he will take advantage of intestinal tissue samples collected from people with autism. He’ll use those tissues to grow and then examine miniature intestinal “organoids,” looking for possible evidence that those from people with autism are different from others.
For the millions of people now living with autism, no truly effective drug therapies are available to help to manage the condition and its many behavioral and bodily symptoms. Bohórquez hopes one day to change that with drugs that act safely on the gut. In the meantime, he and his fellow “GASTRONAUTS” look forward to making some important and fascinating discoveries in the relatively uncharted territory where the gut meets the brain.
References:
[1] A gut-brain neural circuit for nutrient sensory transduction. Kaelberer MM, Buchanan KL, Klein ME, Barth BB, Montoya MM, Shen X, Bohórquez DV. Science. 2018 Sep 21;361(6408).
[2] Association of maternal report of infant and toddler gastrointestinal symptoms with autism: evidence from a prospective birth cohort. Bresnahan M, Hornig M, Schultz AF, Gunnes N, Hirtz D, Lie KK, Magnus P, Reichborn-Kjennerud T, Roth C, Schjølberg S, Stoltenberg C, Surén P, Susser E, Lipkin WI. JAMA Psychiatry. 2015 May;72(5):466-474.
Links:
Autism Spectrum Disorder (National Institute of Mental Health/NIH)
Bohórquez Lab (Duke University, Durham, NC)
Bohórquez Project Information (NIH RePORTER)
NIH Director’s New Innovator Award (Common Fund)
NIH Support: Common Fund; National Institute of Mental Health
Creative Minds: Opening a Window on Alzheimer’s Before It Strikes
Posted on by Dr. Francis Collins
While attending college in her native Colombia, Yakeel T. Quiroz joined the Grupo de Neurociencias de Antioquia. This dedicated group of Colombian researchers, healthcare workers, and students has worked for many years with a large extended family in the northwestern district of Antioquia that is truly unique.
About half of the more than 5,000 family members inherit a gene mutation that predisposes them to what is known locally as “la bobera,” or “the foolishness,” a devastating form of early-onset Alzheimer’s disease. Those born with the mutation are cognitively healthy through their 20s, become forgetful in their 30s, and descend into full-blown Alzheimer’s disease by their mid-to-late 40s. Making matters worse, multiple family members sometimes are in different stages of dementia at the same time, including the caregiver attempting to hold the household together.
Quiroz, now a researcher at Massachusetts General Hospital, Boston, vowed never to forget these families. She hasn’t, working hard to understand early-onset Alzheimer’s disease and helping to establish the Forget Me Not Initiative to raise money for affected families. With an NIH Director’s Early Independence Award, Quiroz also recently launched her own lab to pursue an even broader scientific opportunity: discover subtle pre-symptomatic changes in the brain years before they give rise to detectable Alzheimer’s. What she learns will have application not only to detect and possibly treat early-onset Alzheimer’s in Colombia but also to understand the late-onset forms of the dementia that affect an estimated 35.6 million people worldwide.
BRAIN: Launching America’s Next Moonshot
Posted on by Dr. Francis Collins
Some have called it America’s next moonshot. Indeed, like the historic effort that culminated with the first moon landing in 1969, the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative is a bold, ambitious endeavor that will require the energy of thousands of our nation’s most creative minds working together over the long haul.
Our goal? To produce the first dynamic view of the human brain in action, revealing how its roughly 86 billion neurons and its trillions of connections interact in real time. This new view will revolutionize our understanding of how we think, feel, learn, remember, and move, transforming efforts to help the more than 1 billion people worldwide who suffer from autism, depression, schizophrenia, epilepsy, traumatic brain injury, Parkinson’s disease, Alzheimer’s disease, and other devastating brain disorders.
