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Looking for Answers to Epilepsy in a Blood Test

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Gemma Carvill and lab members
Gemma Carvill (second from right) with members of her lab. Courtesy of Gemma Carvill

Millions of people take medications each day for epilepsy, a diverse group of disorders characterized by seizures. But, for about a third of people with epilepsy, current drug treatments don’t work very well. What’s more, the medications are designed to treat symptoms of these disorders, basically by suppressing seizure activity. The medications don’t really change the underlying causes, which are wired deep within the brain.

Gemma Carvill, a researcher at Northwestern University Feinberg School of Medicine, Chicago, wants to help change that in the years ahead. She’s dedicated her research career to discovering the genetic causes of epilepsy in hopes of one day designing treatments that can control or even cure some forms of the disorder [1].

It certainly won’t be easy. A recent paper put the number of known genes associated with epilepsy at close to 1,000 [2]. However, because some disease-causing genetic variants may arise during development, and therefore occur only within the brain, it’s possible that additional genetic causes of epilepsy are still waiting to be discovered within the billions of cells and their trillions of interconnections.

To find these new leads, Carvill won’t have to rely only on biopsies of brain tissue. She’s received a 2018 NIH Director’s New Innovator Award in search of answers hidden within “liquid biopsies”—tiny fragments of DNA that research in other forms of brain injury and neurological disease [3] suggests may spill into the bloodstream and cerebrospinal fluid (CSF) from dying neurons or other brain cells following a seizure.

Carvill and team will start with mouse models of epilepsy to test whether it’s possible to detect DNA fragments from the brain in bodily fluids after a seizure. They’ll also attempt to show DNA fragments carry telltale signatures indicating from which cells and tissues in the brain those molecules originate. The hope is these initial studies will also tell them the best time after a seizure to collect blood samples.

In people, Carvill’s team will collect the DNA fragments and begin searching for genetic alterations to explain the seizures, capitalizing on Carvill’s considerable expertise in the use of next generation DNA sequencing technology for ferreting out disease-causing variants. Importantly, if this innovative work in epilepsy pans out, it also can be applied to any other neurological condition in which DNA spills from dying brain cells, including Alzheimer’s disease and Parkinson’s disease.

References:

[1] Unravelling the genetic architecture of autosomal recessive epilepsy in the genomic era. Calhoun JD, Carvill GL. J Neurogenet. 2018 Sep 24:1-18.

[2] Epilepsy-associated genes. Wang J, Lin ZJ, Liu L, Xu HQ, Shi YW, Yi YH, He N, Liao WP. Seizure. 2017 Jan;44:11-20.

[3] Identification of tissue-specific cell death using methylation patterns of circulating DNA. Lehmann-Werman R, Neiman D, Zemmour H, Moss J, Magenheim J, Vaknin-Dembinsky A, Rubertsson S, Nellgård B, Blennow K, Zetterberg H, Spalding K, Haller MJ, Wasserfall CH, Schatz DA, Greenbaum CJ, Dorrell C, Grompe M, Zick A, Hubert A, Maoz M, Fendrich V, Bartsch DK, Golan T, Ben Sasson SA, Zamir G, Razin A, Cedar H, Shapiro AM, Glaser B, Shemer R, Dor Y. Proc Natl Acad Sci U S A. 2016 Mar 29;113(13):E1826-34.

Links:

Epilepsy Information Page (National Institute of Neurological Disorders and Stroke/NIH)

Gemma Carvill Lab (Northwestern University Feinberg School of Medicine, Chicago)

Carvill Project Information (NIH RePORTER)

NIH Director’s New Innovator Award (Common Fund)

NIH Support: Common Fund; National Institute of Neurological Disorders and Stroke


Distinctive Brain ‘Subnetwork’ Tied to Feeling Blue

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Woman looking distressed

Credit: :iStock/kieferpix

Experiencing a range of emotions is a normal part of human life, but much remains to be discovered about the neuroscience of mood. In a step toward unraveling some of those biological mysteries, researchers recently identified a distinctive pattern of brain activity associated with worsening mood, particularly among people who tend to be anxious.

In the new study, researchers studied 21 people who were hospitalized as part of preparation for epilepsy surgery,  and took continuous recordings of the brain’s electrical activity for seven to 10 days. During that same period, the volunteers also kept track of their moods. In 13 of the participants, low mood turned out to be associated with stronger activity in a “subnetwork” that involved crosstalk between the brain’s amygdala, which mediates fear and other emotions, and the hippocampus, which aids in memory.


A Scientist and Conservation Photographer

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These stunning images of animals were taken by Susan McConnell, whose photographs have appeared in Smithsonian Magazine, National Geographic, Nature’s Best Photography, Africa Geographic, and a number of other publications. But photography is just part of her professional life. McConnell is best known as a developmental neurobiologist at Stanford University, Palo Alto, CA, and an elected member of the U.S. National Academy of Sciences.

How did McConnell find the time while tracing the development of the brain’s biocircuitry to launch a second career as a nature photographer? Her answer: Every research career has its seasons. When McConnell launched her lab in 1989 at the age of 31, she was up to her eyeballs recruiting staff, writing research grants, and pursuing many different leads in her quest to understand how neurons in the brain’s cerebral cortex are produced, differentiated, and then wired together into functional circuits.


Brain in Motion

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Credit: Itamar Terem, Stanford University, Palo Alto, CA, and Samantha Holdsworth, University of Auckland, New Zealand

Though our thoughts can wander one moment and race rapidly forward the next, the brain itself is often considered to be motionless inside the skull. But that’s actually not correct. When the heart beats, the pumping force reverberates throughout the body and gently pulsates the brain. What’s been tricky is capturing these pulsations with existing brain imaging technologies.

Recently, NIH-funded researchers developed a video-based approach to magnetic resonance imaging (MRI) that can record these subtle movements [1]. Their method, called phase-based amplified MRI (aMRI), magnifies those tiny movements, making them more visible and quantifiable. The latest aMRI method, developed by a team including Itamar Terem at Stanford University, Palo Alto, CA, and Mehmet Kurt at Stevens Institute of Technology, Hoboken, NJ. It builds upon an earlier method developed by Samantha Holdsworth at New Zealand’s University of Auckland and Stanford’s Mahdi Salmani Rahimi [2].


Measuring Brain Chemistry

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Anne Andrews

Anne Andrews
Credit: From the American Chemical Society’s “Personal Stories of Discovery”

Serotonin is one of the chemical messengers that nerve cells in the brain use to communicate. Modifying serotonin levels is one way that antidepressant and anti-anxiety medications are thought to work and help people feel better. But the precise nature of serotonin’s role in the brain is largely unknown.

That’s why Anne Andrews set out in the mid-1990s as a fellow at NIH’s National Institute of Mental Health to explore changes in serotonin levels in the brains of anxious mice. But she quickly realized it wasn’t possible. The tools available for measuring serotonin—and most other neurochemicals in the brain—couldn’t offer the needed precision to conduct her studies.

Instead of giving up, Andrews did something about it. In the late 1990s, she began formulating an idea for a neural probe to make direct and precise measurements of brain chemistry. Her progress was initially slow, partly because the probe she envisioned was technologically ahead of its time. Now at the University of California, Los Angeles (UCLA) more than 15 years later, she’s nearly there. Buoyed by recent scientific breakthroughs, the right team to get the job done, and the support of a 2017 NIH Director’s Transformative Research Award, Andrews expects to have the first fully functional devices ready within the next two years.


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