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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


The Brain Ripples Before We Remember

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Ripple brain
Credit: Thinkstock

Throw a stone into a quiet pond, and you’ll see ripples expand across the water from the point where it went in. Now, neuroscientists have discovered that a different sort of ripple—an electrical ripple—spreads across the human brain when it strives to recall memories.

In memory games involving 14 very special volunteers, an NIH-funded team found that the split second before a person nailed the right answer, tiny ripples of electrical activity appeared in two specific areas of the brain [1]. If the volunteer recalled an answer incorrectly or didn’t answer at all, the ripples were much less likely to appear. While many questions remain, the findings suggest that the short, high-frequency electrical waves seen in these brain ripples may play an unexpectedly important role in our ability to remember.

The new study, published in Science, builds on brain recording data compiled over the last several years by neurosurgeon and researcher Kareem Zaghloul at NIH’s National Institute of Neurological Disorders and Stroke (NINDS). Zaghloul’s surgical team often temporarily places 10-to-20 arrays of tiny electrodes into the brains of a people with drug-resistant epilepsy. As I’ve highlighted recently, the brain mapping procedure aims to pinpoint the source of a patient’s epileptic seizures. But, with a patient’s permission, the procedure also presents an opportunity to learn more about how the brain works, with exceptional access to its circuits.

One such opportunity is to explore how the brain stores and recalls memories. To do this, the researchers show their patient volunteers hundreds of pairs of otherwise unrelated words, such as “pencil and bishop” or “orange and navy.” Later, they show them one of the words and test their memory to recall the right match. All the while, electrodes record the brain’s electrical activity.

Previously published studies by Zaghloul’s lab [2, 3] and many others have shown that memory involves the activation of a number of brain regions. That includes the medial temporal lobe, which is involved in forming and retrieving memories, and the prefrontal cortex, which helps in organizing memories in addition to its roles in “executive functions,” such as planning and setting goals. Those studies also have highlighted a role for the temporal association cortex, another portion of the temporal lobe involved in processing experiences and words.

In their data collected in patients with epilepsy, Zaghloul’s team’s earlier studies had uncovered some telltale patterns. For instance, when a person correctly recalled a word pair, the brain showed patterns of activity that looked quite similar to those present when he or she first learned to make a word association.

Alex Vaz, one of Zaghloul’s doctoral students, thought there might be more to the story. There was emerging evidence in rodents that brain ripples—short bursts of high frequency electrical activity—are involved in learning. There was also some evidence in people that such ripples might be important for solidifying memories during sleep. Vaz wondered whether they might find evidence of ripples as well in data gathered from people who were awake.

Vaz’s hunch was correct. The reanalysis revealed ripples of electricity in the medial temporal lobe and the temporal association cortex. When a person correctly recalled a word pair, those two brain areas rippled at the same time.

Further analysis showed that the ripples appeared in those two areas a few milliseconds before a volunteer remembered a word and gave a correct answer. Your brain is working on finding an answer before you are fully aware of it! Those ripples also appear to trigger brain waves that look similar to those observed in the association cortex when a person first learned a word pair.

The finding suggests that ripples in this part of the brain precede and may help to prompt the larger brain waves associated with replaying and calling to mind a particular memory. For example, hearing the words, “The Fab Four” may ripple into a full memory of a favorite Beatles album (yes! Sgt. Pepper’s Lonely Hearts Club Band) or, if you were lucky enough, a memorable concert back in the day (I never had that chance).

Zaghloul’s lab continues to study the details of these ripples to learn even more about how they may influence other neural signals and features involved in memory. So, the next time you throw a stone into a quiet pond and watch the ripples, perhaps it will trigger an electrical ripple in your brain to remember this blog and ruminate about this fascinating new discovery in neuroscience.

References:

[1] Coupled ripple oscillations between the medial temporal lobe and neocortex retrieve human memory. Vaz AP, Inati SK, Brunel N, Zaghloul KA. Science. 2019 Mar 1;363(6430):975-978.

[2] Cued Memory Retrieval Exhibits Reinstatement of High Gamma Power on a Faster Timescale in the Left Temporal Lobe and Prefrontal Cortex. Yaffe RB, Shaikhouni A, Arai J, Inati SK, Zaghloul KA. J Neurosci. 2017 Apr 26;37(17):4472-4480.

[3] Human Cortical Neurons in the Anterior Temporal Lobe Reinstate Spiking Activity during Verbal Memory Retrieval. Jang AI, Wittig JH Jr, Inati SK, Zaghloul KA. Curr Biol. 2017 Jun 5;27(11):1700-1705.e5.

Links:

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

Brain Basics (NINDS)

Zaghloul Lab (NINDS)

NIH Support: National Institute of Neurological Disorders and Stroke; National Institute of General Medical Sciences


Can a Mind-Reading Computer Speak for Those Who Cannot?

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Credit: Adapted from Nima Mesgarani, Columbia University’s Zuckerman Institute, New York

Computers have learned to do some amazing things, from beating the world’s ranking chess masters to providing the equivalent of feeling in prosthetic limbs. Now, as heard in this brief audio clip counting from zero to nine, an NIH-supported team has combined innovative speech synthesis technology and artificial intelligence to teach a computer to read a person’s thoughts and translate them into intelligible speech.

Turning brain waves into speech isn’t just fascinating science. It might also prove life changing for people who have lost the ability to speak from conditions such as amyotrophic lateral sclerosis (ALS) or a debilitating stroke.

When people speak or even think about talking, their brains fire off distinctive, but previously poorly decoded, patterns of neural activity. Nima Mesgarani and his team at Columbia University’s Zuckerman Institute, New York, wanted to learn how to decode this neural activity.

Mesgarani and his team started out with a vocoder, a voice synthesizer that produces sounds based on an analysis of speech. It’s the very same technology used by Amazon’s Alexa, Apple’s Siri, or other similar devices to listen and respond appropriately to everyday commands.

As reported in Scientific Reports, the first task was to train a vocoder to produce synthesized sounds in response to brain waves instead of speech [1]. To do it, Mesgarani teamed up with neurosurgeon Ashesh Mehta, Hofstra Northwell School of Medicine, Manhasset, NY, who frequently performs brain mapping in people with epilepsy to pinpoint the sources of seizures before performing surgery to remove them.

In five patients already undergoing brain mapping, the researchers monitored activity in the auditory cortex, where the brain processes sound. The patients listened to recordings of short stories read by four speakers. In the first test, eight different sentences were repeated multiple times. In the next test, participants heard four new speakers repeat numbers from zero to nine.

From these exercises, the researchers reconstructed the words that people heard from their brain activity alone. Then the researchers tried various methods to reproduce intelligible speech from the recorded brain activity. They found it worked best to combine the vocoder technology with a form of computer artificial intelligence known as deep learning.

Deep learning is inspired by how our own brain’s neural networks process information, learning to focus on some details but not others. In deep learning, computers look for patterns in data. As they begin to “see” complex relationships, some connections in the network are strengthened while others are weakened.

In this case, the researchers used the deep learning networks to interpret the sounds produced by the vocoder in response to the brain activity patterns. When the vocoder-produced sounds were processed and “cleaned up” by those neural networks, it made the reconstructed sounds easier for a listener to understand as recognizable words, though this first attempt still sounds pretty robotic.

The researchers will continue testing their system with more complicated words and sentences. They also want to run the same tests on brain activity, comparing what happens when a person speaks or just imagines speaking. They ultimately envision an implant, similar to those already worn by some patients with epilepsy, that will translate a person’s thoughts into spoken words. That might open up all sorts of awkward moments if some of those thoughts weren’t intended for transmission!

Along with recently highlighted new ways to catch irregular heartbeats and cervical cancers, it’s yet another remarkable example of the many ways in which computers and artificial intelligence promise to transform the future of medicine.

Reference:

[1] Towards reconstructing intelligible speech from the human auditory cortex. Akbari H, Khalighinejad B, Herrero JL, Mehta AD, Mesgarani N. Sci Rep. 2019 Jan 29;9(1):874.

Links:

Advances in Neuroprosthetic Learning and Control. Carmena JM. PLoS Biol. 2013;11(5):e1001561.

Nima Mesgarani (Columbia University, New York)

NIH Support: National Institute on Deafness and Other Communication Disorders; National Institute of Mental Health


Discovering a Source of Laughter in the Brain

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cingulum bundle
Illustration showing how an electrode was inserted into the cingulum bundle. Courtesy of American Society for Clinical Investigation

If laughter really is the best medicine, wouldn’t it be great if we could learn more about what goes on in the brain when we laugh? Neuroscientists recently made some major progress on this front by pinpointing a part of the brain that, when stimulated, never fails to induce smiles and laughter.

In their study conducted in three patients undergoing electrical stimulation brain mapping as part of epilepsy treatment, the NIH-funded team found that stimulation of a specific tract of neural fibers, called the cingulum bundle, triggered laughter, smiles, and a sense of calm. Not only do the findings shed new light on the biology of laughter, researchers hope they may also lead to new strategies for treating a range of conditions, including anxiety, depression, and chronic pain.

In people with epilepsy whose seizures are poorly controlled with medication, surgery to remove seizure-inducing brain tissue sometimes helps. People awaiting such surgeries must first undergo a procedure known as intracranial electroencephalography (iEEG). This involves temporarily placing 10 to 20 arrays of tiny electrodes in the brain for up to several weeks, in order to pinpoint the source of a patient’s seizures in the brain. With the patient’s permission, those electrodes can also enable physician-researchers to stimulate various regions of the patient’s brain to map their functions and make potentially new and unexpected discoveries.

In the new study, published in The Journal of Clinical Investigation, Jon T. Willie, Kelly Bijanki, and their colleagues at Emory University School of Medicine, Atlanta, looked at a 23-year-old undergoing iEEG for 8 weeks in preparation for surgery to treat her uncontrolled epilepsy [1]. One of the electrodes implanted in her brain was located within the cingulum bundle and, when that area was stimulated for research purposes, the woman experienced an uncontrollable urge to laugh. Not only was the woman given to smiles and giggles, she also reported feeling relaxed and calm.

As a further and more objective test of her mood, the researchers asked the woman to interpret the expression of faces on a computer screen as happy, sad, or neutral. Electrical stimulation to the cingulum bundle led her to see those faces as happier, a sign of a generally more positive mood. A full evaluation of her mental state also showed she was fully aware and alert.

To confirm the findings, the researchers looked to two other patients, a 40-year-old man and a 28-year-old woman, both undergoing iEEG in the course of epilepsy treatment. In those two volunteers, stimulation of the cingulum bundle also triggered laughter and reduced anxiety with otherwise normal cognition.

Willie notes that the cingulum bundle links many brain areas together. He likens it to a super highway with lots of on and off ramps. He suspects the spot they’ve uncovered lies at a key intersection, providing access to various brain networks regulating mood, emotion, and social interaction.

Previous research has shown that stimulation of other parts of the brain can also prompt patients to laugh. However, what makes stimulation of the cingulum bundle a particularly promising approach is that it not only triggers laughter, but also reduces anxiety.

The new findings suggest that stimulation of the cingulum bundle may be useful for calming patients’ anxieties during neurosurgeries in which they must remain awake. In fact, Willie’s team did so during their 23-year-old woman’s subsequent epilepsy surgery. Each time she became distressed, the stimulation provided immediate relief. Also, if traditional deep brain stimulation or less invasive means of brain stimulation can be developed and found to be safe for long-term use, they may offer new ways to treat depression, anxiety disorders, and/or chronic pain.

Meanwhile, Willie’s team is hard at work using similar approaches to map brain areas involved in other aspects of mood, including fear, sadness, and anxiety. Together with the multidisciplinary work being mounted by the NIH-led BRAIN Initiative, these kinds of studies promise to reveal functionalities of the human brain that have previously been out of reach, with profound consequences for neuroscience and human medicine.

Reference:

[1] Cingulum stimulation enhances positive affect and anxiolysis to facilitate awake craniotomy. Bijanki KR, Manns JR, Inman CS, Choi KS, Harati S, Pedersen NP, Drane DL, Waters AC, Fasano RE, Mayberg HS, Willie JT. J Clin Invest. 2018 Dec 27.

Links:

Video: Patient’s Response (Bijanki et al. The Journal of Clinical Investigation)

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

Jon T. Willie (Emory University, Atlanta, GA)

NIH Support: National Institute of Neurological Disease and Stroke; National Center for Advancing Translational Sciences


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.


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