Tuesday, December 9, 2014

In the Blogs: Has a Harvard Neurologist Discovered the Cure for Insomnia?

By John Cloud

The night before I met Patrick Fuller, a 39-year-old neurologist at Harvard Medical School who just discovered an area in the brain that could unlock the mysteries of sleep, I stayed in a hotel that offered a bedside remedy called “Dream Water.” About the size of a 5-Hour Energy drink, it was fortified with melatonin (a hormone often used as a sleep aid) and, more important, gamma-hydroxybutyrate, or GABA, the neurochemical that makes us sleep. While GABA’s importance has been understood for decades, doctors and drugmakers have only been able to make use of it in relatively crude ways. The existence of a product like Dream Water is a testament to the fact that we are a nation still struggling desperately to get its Zs.

For me, waking up at 2 a.m. and never falling back asleep is pretty normal. I can’t remember the last time I woke up feeling well-rested. In that respect, I'm far from alone. According to the Centers for Disease Control, approximately 30 million Americans 16 years and older have endured at least 30 consecutive days of “insufficient rest.” In the South, the nation's tiredest region, one in five people has a sleep disorder. 

The next morning, I woke up at 4:45 a.m. Not the 7:30 I’d been shooting for, but not too bad by my standards. As I prepared for the day, I was curious whether Fuller would give me hope that I’ll rest better in the years ahead.

Since the 1970s, millions of studies around the globe have focused on human sleep. During the same period, pharmaceutical companies have created myriad products to address insomnia, including plenty of blockbusters. Americans spend billions of dollars every year on sleep drugs, but a well-understood and regrettable secret of the pharma industry is that none is very good. We can knock you out, but you may not feel right for a day or so. We can softly sedate you, but you may spring wide awake four hours later. The best-known drugs in the category -- including barbiturates, benzodiazepines, and z-class hypnotics like Ambien and Lunesta -- work by manipulating the behavior of GABA in the upper part of the brain. But many neurologists have long suspected that there is probably a better way to induce deep sleep.

The research Fuller and his team published in the journal Nature Neuroscience in October could be the solution. It's possible that the cure to insomnia lies in the tiny region they recently discovered in the brain stem -- the part of the brain that, among other things, helps controls the basic functions of our hearts and lungs. They even named this new neurological nook: the parafacial zone.  

Fuller has neatly cropped salt-and-pepper hair and the air of a man who knows what shirt he will wear in the morning. He was disarmingly polite when I arrived, even though, clumsily, I had shown up on the wrong floor. (Clearly, the man was at ease dealing with sleep-deprived people.) We were meeting at a gleaming new medical research center in Boston, an 18-story, 700,000-square-foot scientist's dream, that houses facilities for Harvard, Dana-Farber Cancer Institute, and Children's Hospital of Boston. 

In his quest to solve the neurological mysteries of sleep, Fuller went all the way back to scientific research from the 1950s. Even then, many believed there must be a localized center of neurons, probably in the lower part of the brain, that played a central role in deep sleep. Although the upper-brain structures crucial to “slow-wave sleep” -- the dreamless kind of slumber that is thought to consolidate memories, encourage the immune system, and provide a sense of wakefulness in the morning — had been known for years, they account for only about half of the deep sleep we get. Modern pharmaceuticals let us push around all the GABA we want up there in the cerebral cortex, but with very different results for different people. Why?

"What people forget," Fuller told me, "is that almost the entire brain stem is wake-promoting." 

Fuller and his team at Harvard (and the University at Buffalo) spent more than three years searching for the hypothetical little node of brain-stem neurons in the brain stem that might counteract that effect. One of their methods was to introduce a virus into various areas of the mouse brains. (He showed me a refrigerated mouse brain encased in solution; it looked precisely like a tiny sculpture of a human brain. In fact, the two organs are remarkably similar, and brain studies in mice tend to carry over well to humans.)

Among his investigators is a French scientist, Christelle Anaclet, whose job was to watch videos of mice sleeping for hours on end, stopping every ten seconds to see whether a note was required. One day in 2011, she happened to notice that mice who had been infected with the harmless virus in a largely unexplored lower-brain area adjacent to the facial nerve (which partly controls your face) were staying awake far longer than those who hadn’t been infected in the same area. So Fuller, a straightforward man, dubbed it the “parafacial zone.”

More important, the team also found that they could induce deep sleep by tinkering with the same region: They could turn it on like a switch any time of day by using a virus that instructed those lower-brain cells to gush GABA. The animals fell into a slumber despite the fact that they were not given any drugs, and the process caused no harm to cells.

Fuller’s research couldn’t come at a more important time for people who have serious sleep problems. For a while, Ambien seemed like the answer. But when so-called z-class drugs move gobs of GABA around the prefrontal cortex in order to convince you that you’re asleep, upper-brain urges for food and sex also get activated. In many users, this results in disturbing patterns of behavior. By 2010, doctors had begun to write fewer prescriptions for Ambien and its siblings. Just last year, the Federal Drug Administration issued an unusual recommendation saying that women should take half the prescribed dosage.

By contrast, targeting the parafacial zone offers the possibility of a treatment that turns you out like a light in a matter of seconds without creating a secondary set of problems.

Too good to be true? Possibly. But now that we know about the parafacial zone, we should be able to engineer drugs that initiate a GABA response in the brain stem. It will take years to identify something unique about the receptors those cells express or the transmitters they release. According to Fuller, if this proves too difficult, there are other options. One is a more mechanical process already well understood in patients with Parkinson’s: deep brain stimulation, which implants a thin wire into the brain. Another would be to use electromagnetic induction, which is noninvasive and painless.

If all this sounds like it’s going to take 40 years, it won’t. Let’s call it five to ten. Thanks to Fuller and his team, we know that sleep can be controlled with the precision and minimal harm of other brain-stem procedures -- similar to, say, those that help modify reflexes like blinking too often. My husband sometimes says, “Just fall asleep!” I desperately wish I could. I'll be dreaming of the day it's actually as easy as it sounds.

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