Warren symposium follows legacy of geneticist giant

If we want to understand how the brain creates memories, and how genetic disorders distort the brain’s machinery, then the fragile X gene is an ideal place to start. That’s why the Stephen T. Warren Memorial Symposium, taking place November 28-29 at Emory, will be a significant event for those interested in neuroscience and genetics. Stephen T. Warren, 1953-2021 Warren, the founding chair of Emory’s Department of Human Genetics, led an international team that discovered Read more

Mutations in V-ATPase proton pump implicated in epilepsy syndrome

Why and how disrupting V-ATPase function leads to epilepsy, researchers are just starting to figure Read more

Tracing the start of COVID-19 in GA

At a time when COVID-19 appears to be receding in much of Georgia, it’s worth revisiting the start of the pandemic in early 2020. Emory virologist Anne Piantadosi and colleagues have a paper in Viral Evolution on the earliest SARS-CoV-2 genetic sequences detected in Georgia. Analyzing relationships between those virus sequences and samples from other states and countries can give us an idea about where the first COVID-19 infections in Georgia came from. We can draw Read more

seizures

Two birds with one stone: amygdala ablation for PTSD and epilepsy

The amygdala is a region of the brain known for its connections to emotional responses and fear memories, and hyperreactivity of the amygdala is associated with symptoms of PTSD (post-traumatic stress disorder). That said, it’s quite a leap to design neurosurgical ablation of the amygdala to address someone’s PTSD. This type of irreversible intervention could only be considered because of the presence of another brain disorder: epilepsy.

In a case series published in Neurosurgery, Emory investigators describe how for their first patient with both refractory epilepsy and PTSD, observations of PTSD symptom reduction were fortuitous. However, in a second patient, before-and-after studies could be planned. In both, neurosurgical ablation of the amygdala significantly reduced PTSD symptoms as well as reducing seizure frequency.

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Insane in the membrane – inflamed in the brain

Inflammation in the brain is a feature of several neurological diseases, ranging from Parkinson’s and Alzheimer’s to epilepsy. Nick Varvel, a postdoc with Ray Dingledine’s lab at Emory, was recently presenting his research and showed some photos illustrating the phenomenon of brain inflammation in status epilepticus (prolonged life-threatening seizures).

The presentation was at a Center for Neurodegenerative Disease seminar; his research was also published in PNAS and at the 2016 Society for Neuroscience meeting.green-red-brain

Varvel was working with mice in which two different types of cells are marked by fluorescent proteins. Both of the cell types come originally from the blood and can be considered immune cells. However, one kind – marked with green — is in the brain all the time, and the red kind enters the brain only when there is an inflammatory breach of the blood brain barrier.

Both markers, CX3CR1 (green) and CCR2 (red), are chemokine receptors. Green fluorescent protein is selectively produced in microglia, which settle in the brain before birth and are thought to have important housekeeping/maintenance functions.

Monocytes, a distinct type of cell that is not usually in the brain in large numbers, are lit up red. Monocytes rush into the brain in status epilepticus, and in traumatic brain injury, hemorrhagic stroke and West Nile virus encephalitis, to name some other conditions where brain inflammation is also seen.

In the PNAS paper, Varvel and his colleagues include a cautionary note about using these mice for studying situations of more prolonged brain inflammation, such as neurodegenerative diseases: the monocytes may turn down production of the red protein over time, so it’s hard to tell if they’re still in the brain after several days.

Targeting CCR2 – good or bad? Depends on the disease model

The researchers make the case that “inhibiting brain invasion of CCR2+ monocytes could represent a viable method for alleviating several deleterious consequences of status epilepticus.” Read more

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Four take-home thoughts on NGLY1

Please check out our feature in Emory Medicine magazine about two sisters with NGLY1 deficiency. This rare genetic disorder was identified only a few years ago, and now a surge of research is directed toward uncovering its mysteries.

  1. The Stinchcombs are amazing. Seth Mnookin’s July 2014 piece in the New Yorker, and especially, his comments at the end of an interview with The Open Notebook drove me to contact them. “The father cares for the two girls with this disease full time. The mother is working insane hours. And while all this is going on, they’re the most good-natured … I don’t know, they just seem like they’re happy.”
  1. Several research teams around the world are investigating NGLY1 deficiency and potential remedies. For the magazine article, I talked with Emory geneticist Michael Gambello, Hudson Freeze at Sanford Burnham and Lynne Wolfe at the NIH Undiagnosed Diseases Program. Even more: the Grace Science Foundation, established by the Wilsey family, is supporting research at Retrophin/Notre Dame and Gladstone/UCSF. The independent Perlstein lab is investigating NGLY1 deficiency in fruit flies (reminiscent of Emory research from a decade ago on Fragile X syndrome).
  1. There’s a long road ahead for rare genetic disorders such as NGLY1 deficiency. That’s why the title that EM editor Mary Loftus came up with, “In time to help Jessie,” is so poignant. When I read Abby Goodnough’s New York Times piece on RCDP, which is a rare inherited bone disease that also involves seizures, I thought: “That could be NGLY1 in ten years.” Still, progress is possible, as demonstrated by this recent NEJM report on exome sequencing and neurometabolic disorders from British Columbia.

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Gabbing about GABA — implications for hypersomnia treatments

Anesthesiologist Paul Garcia and his colleagues are presenting two posters at the Society of Neuroscience meeting this week, whose findings may raise concerns about two non-stimulant drugs Emory sleep specialists have studied for the treatment of hypersomnia: flumazenil and clarithromycin.

For both, the data is in vitro only, so caution is in order and more investigation may be needed.

With flumazenil, Garcia and colleagues found that when neurons are exposed to a low dose for 24 hours, the cells increase expression of some GABA receptor forms.

This could be part of a mechanism for tolerance. I heard some anecdotes describing how flumazenil’s wake-promoting effects wear off over time at the Hypersomnia Foundation conference in July, but it’s not clear how common the phenomenon is.

Flumazenil’s utility in hypersomnia became known after the pioneering experience of Anna Sumner, who has reported being able to use the medicine for years. See this 2013 story in Emory Medicine. Read more

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The buzz of consciousness and how seizures disrupt it

These days, it sounds a bit old-fashioned to ask the question: “Where is consciousness located in the brain?” The prevailing thinking is that consciousness lives in the network, rather than in one particular place. Still, neuroscientists sometimes get an intriguing glimpse of a critical link in the network.

A recent paper in the journal Epilepsy & Behavior describes an epilepsy patient who had electrodes implanted within her brain at Emory University Hospital, because neurologists wanted to understand where her seizures were coming from and plan possible surgery. Medication had not controlled her seizures and previous surgery elsewhere had not either.

ElectrodesSmaller

MRI showing electrode placement. Yellow outline indicates the location of the caudate and thalamus. Image from Leeman-Markowsi et al, Epilepsy & Behavior (2015).

During intracranial EEG monitoring, implanted electrodes detected a pattern of signals coming from one part of the thalamus, a central region of the brain. The pattern was present when the patient was conscious, and then stopped as soon as seizure activity made her lose awareness.

The pattern of signals had a characteristic frequency – around 35 times per second – so it helps to think of the signal as an auditory tone. Lead author Beth Leeman-Markowski, director of EUH’s Epilepsy Monitoring Unit at the time when the patient was evaluated, describes the signal as a “buzz.”

“That buzz has something to do with maintenance of consciousness,” she says. Read more

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Brain surgery with a light touch

As part of reporting on neurosurgeon Robert Gross’s work with patients who have drug-resistant epilepsy, I interviewed a remarkable woman, Barbara Olds. She had laser ablation surgery for temporal lobe epilepsy in 2012, which drastically reduced her seizures and relieved her epilepsy-associated depression.

Emory Medicine’s editor decided to focus on deep brain stimulation, rather than ablative surgery, so Ms. Olds’ experiences were not part of the magazine feature. Still, talking with her highlighted some interesting questions for me.

Emory neuropsychologist Dan Drane, who probes the effects of epilepsy surgery on memory and language abilities, had identified Olds as a good example of how the more precise stereotactic laser ablation procedure pioneered by Gross can preserve those cognitive functions, in contrast to an open resection. Read more

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DBS for drug-resistant epilepsy

Space considerations in print forced us to slim down the feature on deep brain stimulation for drug resistant epilepsy, which appears in the Spring 2015 issue of Emory Medicine. While I encourage you to please read our story profiling playwright Paula Moreland, here are some take-away points:

*Surgery is a viable option for many patients with drug-resistant epilepsy, but not all of them, because the regions of the brain where the seizures start can have important functions. (Look for an upcoming post describing a patient I met for whom the surgical option was helpful.)

*Deep brain stimulation can reduce seizure frequency and improve quality of life for patients with drug-resistant epilepsy.

*In the large clinical trials on deep brain stimulation for epilepsy that have been run so far (SANTE and RNS), most participants do not see their seizures eliminated. Ms. Moreland is an exception.  Read more

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Recording seizures from within the brain

To go along with the (new) Spring 2015 Emory Medicine magazine set of features on deep brain stimulation for depression, movement disorders and epilepsy, here is a fascinating 2013 case report from Emory neurosurgeon Robert Gross and colleagues. The first author is electrical engineer Otis Smart.

It’s an example of the kinds of insights that can be obtained from implantable electrical stimulation devices, which can record signals from seizures inside the brain over long periods of time (more than a year).

As the authors write, “the technology can record brain activity while the patient is in a more naturalistic environment than a hospital, becoming an invasive ambulatory EEG.” Read more

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Exception from informed consent: what patients say

Informed consent is a basic principle of clinical research. Doctors are required to make sure that patients understand what’s involved with experimental treatments, and patients should only participate if they provide consent.

However, an important area of clinical research takes place outside of this general rule, because some life-threatening conditions – seizures, traumatic brain injury and cardiac arrest, as examples — make it impossible for the patient to learn about a clinical trial and make a decision about whether to participate. The urgency of treatment can also mean that seeking proxy consent from a relative is impractical.

A recent editorial in USA Today highlights this area of research, called EFIC (exception from informed consent). The author, Katherine Chretien from George Washington University, cites research from Emory investigators Neal Dickert and Rebecca Pentz.

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COX-2 and epilepsy: it’s complicated

How much is the development of epilepsy like arthritis?

More than you might expect. Inflammation, or the overactivation of the immune system, appears to be involved in both. In addition, for both diseases, inhibiting the enzyme COX-2 initially looked like a promising approach.

Ray Dingledine, PhD

COX-2 (cyclooxygenase 2) is a target of traditional non-steroid anti-inflammatory drugs like aspirin and ibuprofen, as well as more selective drugs such as Celebrex. With arthritis, selectively inhibiting COX-2 relieves pain and inflammation, but turns out to have the side effect of increasing the risk of heart attack and stroke.

In the development of epilepsy, inhibiting COX-2 turns out to be complicated as well. Ray Dingledine, chair of pharmacology at Emory, and colleagues have a new paper showing that COX-2 has both protective and harmful effects in mice after status epilepticus, depending on the timing and what cells the enzyme comes from. Status epilepticus is a period of continuous seizures leading to neurodegeneration, used as a model for the development of epilepsy.

Postdoc Geidy Serrano, now at the Banner Sun Health Research Institute in Arizona, is first author of the paper in Journal of Neuroscience. She and Dingledine were able to dissect COX-2’s effects because they engineered mice to have a deletion of the COX-2 gene, but only in some parts of the brain.
They show that deleting COX-2 in the brain reduces the level of inflammatory molecules produced by neurons, but this is the reverse effect of deleting it all over the body or inhibiting the enzyme with drugs.

Four days after status epilepticus, fewer neurons are damaged (bright green) in the neuronal COX-2 knockout mice.

Dingledine identified two take-home messages from the paper:
First, COX-2 itself is probably not a good target for antiepileptic therapy, and it may be better to go downstream, to prostaglandin receptors like EP2.
Second, the timing of intervention will be important, because the same enzyme has opposing actions a few hours after status epilepticus compared to a couple days later.

More of Dingledine’s thinking about inflammation in the development of epilepsy can be found in a recent review.

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