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
In 2013, Brian Dias (at Yerkes) and Kerry Ressler (now at Harvard) describedÂ a surprising example of epigenetic inheritance.
They found that a mouse, exposed to a smell in combination with stress, could transmit the resulting sensitivity to that smell to its offspring. At the time, there wasn’t a lot of information about mechanism.
Now other scientistsÂ haveÂ substantiatedÂ a proposal that micro RNA in playing a role in sperm. See this story (“Sperm RNAs transmit stress”) from Kate Yandell in The ScientistÂ or this one from Rachel Zamzow at Spectrum, the Simons Foundation’s autism news site, for more. An added wrinkle is that thisÂ research showsÂ that descendantsÂ of stress-exposed mice show a muted response to stress.
Note for Emory readers: Dias is scheduled to give a Frontiers in Neuroscience talk on Friday.
This grant announcement from the American Heart Association caught Lab Land’s eye.Â All three of the scientists involved in this project, examining the connections between hypertension, inflammation and the sympathetic nervous system in PTSD, have Emory connections:
*Kerry Ressler, previously Emory Psychiatry/HHMI-supported/Yerkes-based lab/Grady Trauma Project, who moved this summer to Harvard’s McLean Hospital
Related findingÂ that emerged from the Grady Trauma Project: Blood pressure drugs linked with lower PTSD symptoms
*Paul Marvar, who worked with both David Harrison and Kerry Ressler at Emory, and is now at George Washington University
Related item on Marvar’s work: Immune cells required for stress-induced rise in blood pressure in animals
*Jeanie Park, kidney specialist who is here now! The grant is exploring the relationship between the sympathetic nervous system, regulation of blood pressure and PTSD.
2015Â TV interview with Park on her chronic kidney disease research
Those of us who are old enough to remember vinyl records will recall how a scratch can cause the same sounds to repeat many times. A similar type of genetic glitch causes neurodegenerative diseases such as Huntingtonâ€™s and several forms of spinocerebellar ataxia.
Huntingtonâ€™s and the spinocerebellar ataxias are known as â€œpolyglutamineâ€ diseases. In each, the affected gene has a stretch where the same three DNA letters are repeated several times — more than usual. As a result, the protein encoded by the affected gene has a patch, where only the building block glutamine can be found, disrupting that proteinâ€™s usual functions in the body.
Geneticist Xiao-Jiang Li and colleagues recently published a paper in Cell Reports that may explain why more aggressive juvenile-onset forms of polyglutamine diseases have different symptoms and pathology. Read more
These days, it sounds a bit old-fashioned to ask the question: â€œWhere is consciousness located in the brain?â€ 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 hadÂ not either.
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 â€“ around 35 times per second â€“ so it helps to think of the signal as an auditory tone. Lead author Beth Leeman-Markowski, director of EUHâ€™s Epilepsy Monitoring Unit at the time when the patient was evaluated, describes the signal as a â€œbuzz.â€
â€œThat buzz has something to do with maintenance of consciousness,â€ she says. Read more
Last week on Friday, Lab Land attended the annual Regenerative Engineering & Medicine center get-together to hear about progress in this exciting area.
During his talk, Tony Kim of Georgia Tech mentioned a topic that Rose Eveleth recently explored in The Atlantic: why arenâ€™t doctors using amazing â€œnanorobotsâ€ yet? Or as Kim put it, citing a recent review, â€œSo many papers and so few drugs.â€
[A summary: scaling up is difficult, testing pharmacokinetics, toxicity and efficacy is difficult, and so is satisfying the FDA.]
TheÂ talks Friday emerged from REM seed grants; manyÂ paired an Emory medical researcher with a Georgia Tech biomedical engineer. All of these projects take on challenges in delivering regenerative therapies: getting cells or engineered particles to the right place in the body.
For example, cardiologist W. Robert Taylor discussed the hurdles his team had encountered in scaling up his cells-in-capsules therapies for cardiovascular diseases to pigs, in collaboration with Luke Brewster. The pre-pig phase of this research is discussed in more detail here and here. Read more
A visitor might not realize this was a meeting devoted to people who experience excessive daytime sleepiness. The 2015 Hypersomnia Foundation Conference on Saturday was full of energy, with:
*more than 245 attendees, about twice as many people as last year’s conference
*medical experts from France, Wisconsin and Louisiana — in addition to Emory
*data from several recent clinical trials
*some signs of industry interest in hypersomnia
Hypersomnia is a sleep disorder in which individuals feel frequent or constant sleepiness and need to sleep for long portions of the day (more than 70 hours per week). It is distinct from other sleep disorders such as narcolepsy and sleep apnea, but its prevalence is still unclear. Conventional stimulants such as amphetamine or modafinil often can be used to treat the sleepiness, but some with hypersomnia find these drugs ineffective or hard to tolerate.
Previous research at Emory has shown that many individuals with hypersomnia have a substance in their spinal fluid that acts like a sleeping pill, enhancing the action of the neurotransmitter GABA. The identity of this mysterious substance is unknown, but Emory researchers report that they are close to identifying it. That could give hypersomnia a “molecular handle” similar to what narcolepsy has, with loss of hypocretin-producing neurons.
The terminology is still up in the air — keynote speaker Isabelle Arnulf from Paris said, “The term ‘idiopathic hypersomnia’ does not mean that you are an idiot.” Rather, she said, it means that even specialists can have trouble distinguishing hypersomnia from other sleep disorders, and “idiopathic” signifies that the detailed cause is still under investigation.
At what point did the human microbiome become such a hot topic?
When it was shown that babies born by Cesarean section are colonized with different bacteria than those born vaginally? With the cardiovascular studiesÂ of microbial byproducts of meatÂ digestion? With the advent of fecal transplant as a proposed treatment for Clostricium difficile infection?
The bacteria and other microbes that live within the human body are thought to influence not only digestive health, but metabolic and autoimmune diseases as well, possibly even psychiatric and neurodevelopmental disorders.Â The field is being propelled by next-generation sequencing technology, and Nature had to publish an editorial guarding against hype (a major theme: correlation is not causation).
At Emory, investigators from several departments are involved in microbiome-related work, and the number is expanding, and assembling a comprehensive list is becoming more difficult. Researchers interested in the topic are planning Emoryâ€™s first microbiome symposium in November, organized by Jennifer Mulle (readÂ herÂ intriguing review on autism spectrum disorders and the microbiome).
Microbial genomics expert Tim Read, infectious diseases specialist Colleen Kraft and intestinal pathologist Andrew Neish have formed an Emory microbiome interest group with a listserv and seminars.
Microbiome symposium sponsors:Â ACTSI, Hercules Exposome Center, Emory University School of Medicine, Omega Biotek, CFDE, Ubiome. Read more
From Emory Medicine, Spring 2013
A small clinical study of clarithromycin for the sleep disorder hypersomnia shows that the antibiotic can combat patients’ subjective experience of sleepiness, but it does not seem to improve reaction time measured in a video-game-type vigilance task.
The effects of clarithromycin in hypersomnia were first observed by Emory doctors when a pioneering patient (Anna Sumner, whose story is told in this Emory Medicine article) unexpectedly experienced sleeplessness when taking it for a respiratory infection.
The results of the study were published online by Annals of Neurology on June 10.
Lynn Marie Trotti, MD, David Rye, MD, PhD and colleagues from the Department of Neurology and Emory Sleep Center conducted the study, which involved 23 patients.
Advantages of clarithromycin:
- It’s inexpensive and widely available.
- It’s an option for people dealing with hypersomnia for whom other medications, such as modafinil, are not helpful or tolerable.
- It represents an alternative to flumazenil, the benzodiazepine antidote that has been shown to help some hypersomnia patients. Flumazenil used to be very scarce, and shortages occur (Hypersomnia Foundation/American Society of Health System Pharmacists).
Disadvantages of clarithromycin:
- It’s an antibiotic, so it probably changes intestinal bacteria.
- Chronic use could promote the growth of antibiotic-resistant bacteria.
- Most patients reported an altered sense of taste or smell. Some describe this as a metallic mouth sensation.