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Experiment with Nerv

On Friday night, I tried a commercial relaxant/dietary supplement called "Nerv", which I obtained as a gift from Michael Jiang, a young entrepreneur who visited Emory a couple weeks ago.

 

Jiang, a former Emory graduate student in the Neuroscience program, spoke at a Neuroethics seminar about how he came up with the idea for Nerv. It was intended to occupy the space somewhere between an alcoholic drink and a cup of chamomile tea, he said.

 

Coffee, sodas and other drinks containing caffeine are common consumer products. Similarly, many college students and young people are used to the idea of taking stronger stimulants as study aids or temporary performance boosters. Often diverted from prescriptions to people with ADHD diagnoses, methylphenidate and amphetamines are available to those determined to get them. This recent Nature article and the Netflix documentary Take Your Pills explore the topic.

 

For the opposite purpose of stimulants, when it comes time to take the edge off and relax, Jiang said he wanted to create something relatively accessible like coffee. Prescription medications such as Xanax have undoubtedly strong effects, but they create the risk of dependence. Alcohol is also widely available, although for children, not legally.

 

In contrast, Jiang seemed to be aiming for a product that was gentler, self-limiting and thus less risky. Now that I know more about the precise components of his concotion, I am not so sure about whether that is achievable. He was coy during his talk, mentioning only a dietary supplement that is a GABA-B agonist. Nerv's website is clear about what this is: phenibut. The blog Science-Based Medicine has a round-up of information floating around on phenibut. Just this year, the Australian government designated it as a controlled substance.

 

When Jiang said GABA, it grabbed my attention immediately. I have been taking a deep dive into GABA neurobiology as part of The Woman Who Couldn't Wake Up. Benzodiazepines such as Valium and Xanax, as well as sleep aids such as Ambien, target GABA-A receptors. Other examples of GABA-B agonists are the muscle relaxant baclofen and (possibly) the highly controlled sleep aid sodium oxybate.

 

On Friday, I was concerned that if I did take something with a mild relaxant/depressant effect, it would make me sleepy or groggy, so I waited until a quiet time in the evening. I was simply watching a movie after the rest of my family had gone to bed. Jiang mentioned that the active ingredient by itself has an unpleasant taste, which he has to cover up with a citrus flavor. In the drink, the underlying medicinal taste was noticeable but not off-putting.

 

It was an uncontrolled, single subject experiment. Nerv didn't make me sleepy enough that I was dropping off while watching the movie (Roger Dodger). I did feel relaxed – similar to what I feel a few hours after I take ibuprofen for a headache and the anti-inflammatory effect lasts after the headache disappears. However, there may have been a placebo effect as well.

 

I wish Jiang well. It was amusing to hear him discuss his plans after his talk with a retired cancer researcher, who insisted that randomized controlled trials were necessary before he could make any claims about the effects of his drink.

 

While she would be correct if Nerv was being developed as a drug for FDA approval, dietary supplement marketers can and do make vague claims, sometimes referring to preclinical research for back-up. Jiang said he was not comfortable with the role of huckster, but the dietary supplement path he has chosen allows him more flexibility. He said he wanted to conduct larger studies someday, and he needs to get his business off the ground first.

 

Nerv reminded me of the sleep enhancement devices now being sold by Dreem and Philips, which I wrote about for Proto earlier this year. Those devices have substantial research on the acoustic enhancement of slow wave sleep behind them, but at this point, all their manufacturers can do is subtly present that research without asserting that the devices will address specific medical complaints. They are, right now, fancy brain toys for sleep aficionados.

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Emory blog posts on idiopathic hypersomnia #IHAW2018

Measuring sleepiness: alternatives to five naps June 29, 2018

For diagnosis of narcolepsy type 1, the MSLT (Multiple Sleep Latency Test) works well. Not so for other sleep disorders such as IH. At the Baltimore sleep meeting, researchers discussed alternatives.

 

Post-anesthetic inertia in IH April 20, 2018

General anesthesia pushes GABA buttons hard. It may be that in some people, their neural circuitry takes a long time to recover.

 

How much does IH overlap with ME/CFS? April 16, 2018

Sleepiness versus muscle fatigue.

 

Journey of a marathon sleeper Dec. 1, 2017

The myotonic dystrophy connection to GABA-related sleepiness.

 

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Notes on Mercies in Disguise and prion biology

Mercies in Disguise, by New York Times science reporter Gina Kolata, is a compelling look at a family from South Carolina, some of whose members have GSS, a rare inherited neurodegenerative disease. The central issue driving the book is: if an inherited disease runs in your family, would you find out your genetic status before the disease begins to affect you?

 

In her book, Kolata interposes some chapters about the discovery of prions and the research of Nobel Prize winners Carleton Gajdusek and Stanley Prusiner. Prions are, briefly, aggregates of warped proteins. They seduce other proteins with a similar makeup into taking the same warped 3D shape. The aggregates are infectious and toxic, and are thought to drive rare neurodegenerative diseases like GSS (Gerstmann-Sträussler-Scheinker) as well as playing a role in more common ones like Alzheimer's and Parkinson's.

 

I think that the story of Mercies in Disguise does not really hinge upon prion biology. In terms of decision-making and genetic tests now available to affected families, GSS could be some other inherited disease. It does not need to be a prion disease. Pre-implantation genetic diagnosis with exclusion testing has been performed for Huntington's disease, for example, since 2002.

 

The uncertainty comes when a younger person in an affected family don't know their status. Throughout half of the book, Amanda Baxley doesn't know what fate holds for her. The probability of inheritance, if one of your parents had the disease, are straightforward: 50 percent. It's a Mendelian disorder, meaning just one gene is involved. Compare this to Alzheimer's or inherited breast cancer, in which the picture is more complicated. In any case, because of advances in genetics and reproductive biology, Amanda Baxley has the option of PGD-IVF. Some relatives before her did not.

 

Conservative Christians may sometimes feel that writers at the New York Times treat their views with contempt. However, I think that Kolata treats the concerns of Baxley family members with respect. For example, the central character's mother suggested the book's title, a reference to the song "Blessings" by Laura Story, which asks "What if trials of this life are your mercies in disguise?" Another of the Baxleys, Holly, is called upon to represent the conservative Christian world view:

 

Holly was married and had a son when she learned her father had GSS, but she and her husband decided that Holly's risk of getting ill herself and of passing on the gene was not going to deter them from having more children. Soon after, she got pregnant and gave birth to another son. The looming GSS threat was not Holly's focus; she would not let it be. She saw getting past her fears and her desire to control her fate as a test of her faith. Instead of dwelling on the uncertainty of GSS, she would concentrate on her children's relationship with God, on their eternal life. "Hope and knowledge are mutually exclusive in this situation," she declared with fixed certainty. "While I don't know, I have hope."

 

Kolata said that she learned from writing the book that "glib assumptions about people's motivations are often incomplete."

 

What set the ball rolling for the February 2014 New York Times story was a call from Duke, alerting Kolata to the first person to get PGD and IVF for a prion disease. A brief JAMA Neurology case report was published soon after that time. (Presymptomatic genetic diagnosis was reported in 1991.) The news story got more than 400 comments; an agent called her and prodded her to think about a book about the family. She noted that an editor told her to write like a novelist, and she hadn't written a book like that before. It made her ask the Baxleys lots of detail-oriented questions so that she could reconstruct scenes for readers, she said. She was grateful to the Baxleys, because she was asking them to "relive awful times." Also, in the acknowledgements, Kolata thanks a friend who told her that her prologue gave too much away.

 

GSS, fatal familial insomnia (FFI) and familial Creutzfeldt-Jakob disease (CJD) are caused by mutations in the same gene, which was identified in the early 1990s. Kolata's book does not deal with the last two decades of research since the identification of the prion precursor gene, and stops with Gajdusek, Prusiner, and Karen Hsiao. For example, it does not touch on how the prion protein interacts with troublemakers in both Alzheimer's (amyloid beta) and Parkinson's (alpha-synuclein), possibly mediating cognitive impairment. It does not deal with more adventurous theories, such as Susan Lindquist's ideas about how misfolded proteins and chaperonse are storehouses for evolutionary variation or Eric Kandel's proposals that prion-like proteins maintain long-term memories.

 

After her talk at the Decatur Book Festival, I asked Kolata whether she read DT Max's book The Family that Couldn't Sleep, which is about the discovery of FFI as well as the evolution of the idea of prions. She said no. It'd be like reading the Washington Post's version of a story before writing her own, she said. In contrast, she said that she did use some material from Prusiner's memoir, because she did not talk with him directly.

 

In The Family that Couldn't Sleep, prions hold the book together. His example is more instructive for me than Kolata's, because my book deals with various unrelated sleepy people, but scientific questions are what connect all my chapters. For me, there is not one family whose story is woven through everything, even if Anna Sumner plays a catalytic role at the beginning.

 

The recent flowering of prion science was perhaps beyond the scope of Mercies in Disguise. Still, in her talk, Kolata seemed to indicate that the connection between prions and more common neurodegenerative diseases like Alzheimer's was tenuous. So I consulted Emory neurologist Lary Walker, who was also listening.

 

"The basic mechanism of prion spread is pretty well accepted," he said. "But the idea that other diseases involve prion-like processes is still controversial, even though a lot of evidence has built up, In my view, it contributes to virtually every age-related neurodegenerative disease."

 

Walker showed me slides of brain tissue from GSS patients, in which amyloid plaques looked like Alzheimer's. Then he showed me slides from CJD, with large spongy vacuoles, but without lots of plaques. I was amazed that there was such a big contrast, when the diseases are so close to each other in genetic origin. There must be differences in how brain cells handle the toxic proteins, or the speed at which cells are killed.

 

 

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Studying sleep is big business

Wild Nights

I recently had the privilege of introducing Benjamin Reiss at the 2017 Decatur Book Festival. Here's what I said.

 

Studying sleep is big business. Perhaps you're one of the more than 3 million people in the United States who had a diagnostic sleep study last year.

 

I had one several years ago. A technician glues electrodes to your scalp-- it's quite cumbersome. And you spend the night in a lab, with all this stuff attached to your head. Now there are apps on your phone, and you can record and analyze yourself. You can even get your own portable EEG monitor.

 

Researchers at Emory, where I work, are harvesting data from heart rate monitors. They want to see whether they can reliably tell the difference between someone with PTSD or schizophrenia from healthy controls. It turns out that the time of day that is the most revealing, for heart rate variability, is the middle of the night.

 

Eventually they want to use this technology to monitor whether patients are doing better with treatment, without having them come into the doctor's office. They like to call this "objective" because it doesn't involve a conversation or having them fill out a questionnaire, just looking at their heart beats and activity logs.

 

This sounds intriguing, and it's an illustration of the flourishing state of sleep research. Still, doctors and big data researchers who think they are objectively measuring and studying sleep, or those people who are downloading sleep analysis apps, could do with a dose of cultural and historical perspective. That's what we can get from Benjamin Reiss.

 

There's a consensus that electricity and later computers altered the way in which we sleep in Western countries – Reiss' book in turn illuminates how to think about that change, reexamining work by authors such as Henry David Thoreau. Read More 

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