Thursday, August 6, 2015

Try & Try Again: Sam Vogelstein & CBD

Fred Vogelstein wrote about his son's epilepsy in a fine 2010 New York Times Magazine article. That piece,  "Epilepsy's Big Fat Miracle," focused on the high-fat ketogenic diet; Fred's son Sam, who was nine years old at the time, had once been buffeted by hundreds of  absence seizures a day. Medications weren't helping. The ketogenic diet, described by Vogelstein as a "desperate" treatment, seemed to work. He was only having about six seizures a day. Sam was finally "a happy, healthy, and independent kid," Fred wrote. Hence the Big Fat Miracle;  Sam's life was back on track.

In the July 2015 issue of WIRED, though, Sam and Fred are back on the therapy trail in a piece titled "One Man's Desperate Quest to Cure His Son's Epilepsy--With Weed."  Between the two features, Sam's seizures returned again. With a vengeance. This time, having tried everything else, they head off to London, in 2012,  to try another desperate treatment: this one is an extract of the marijuana plant known as cannabidiol, or CBD. The compelling piece is largely about the hoops the Vogelsteins have to go through to try the compound at all.

"It had taken four months of phone calls, emails, and meetings with doctors and pharmaceutical company executives on two continents to get permission to try this drug," writes Fred. "Sam wasn’t joining an ongoing clinical trial. The company made the pills just for him" By the time the Vogelstein's win approval from the DEA to import CBD into the US, they have spent more than $120,000 of their own money on the effort. Their expense and efforts seem to have paid off. Both for Sam, whose seizures are again under control, and for many others who still suffer from medication-resistant epilepsy in the US. Sam's story seems to have helped pave the way for several sizable studies of CBD in major US research centers. A CBD-based drug made by the British company GW Pharmaceuticals may be on the shelves less than three years from now.

Friday, February 27, 2015

Plastic Brains and Exercise

Adults have always envied kids' ability to learn new things quickly. And the dream of reopening the brain's natural plasticity later in life is an old one, too. An excellent piece by Rebecca Boyle, out today in my new favorite online magazine, Aeon, looks at research on the use of both the seizure drug valproate and the dementia drug donepezil to stimulate that plastic neural magic where language, music, and bike riding can be effortlessly added to one's repertoire. The research is promising, but hardly unequivocal. And as far as I can tell, the effectiveness of these drugs has not been rigorously compared to much more accessible techniquest of boosting plasticity. The most important and obvious is exercise. Among its other neuro-salutary benefits, exercise causes the release of Brain Derived Neurotrophic Factor (BDNF), a stimulant to the creation of new neurons and the maintenance of old ones. 

But does exercise reopen the window of neuroplasticity?  That might be the wrong way to frame the question. One of the last couple of decades' big neurological insights, as Boyle's piece recounts, is that the window stays open, or at least openable, our whole lives. "Your brain can always change, whatever your age," says UCSF's Michael Merzenich, a seminal researcher of brain plasticity. "And there are things you can do to make it change faster," he says. 

As far as my review of the science can tell, nothing works better than exercise to keep the brain's plasticity window open...or to pry it open once again. So for now, while you wait for a learning pill to take before dulcimer class, Rebecca, try walking to your lesson. 

Wednesday, January 21, 2015

Black Mirror's Memory-Enhancing BMI

The grain: contact lenses attached to a
processor/transmitter/memory chip
 implanted just behind the ear. 
Seen Black Mirror, the smart, fun, creepy British TV drama on Netflix? It's a kind of an update of The Twilight Zone. Each episode has a different situation, set, and cast, but all deal with the alternately progressive and sinister effects of IT on our near futures. The third episode, “The Entire History of You,” considers the effect of a device, called a “grain” (as in brain the size of a rice grain)  that combines Google Glass-like contact lenses and a processor/transmitter implanted behind the ear. Just about everyone's got one—you’d have to be a Luddite not to!--and people are constantly replaying their experiences, either for each other on ubiquitous TV screens or privately on the inside of their own lenses. The device is perfectly plausible. 

The episode follows a married couple struggling over the wife's relationship with an old beau. The husband's suspicions, which seem obsessive, controlling, and self-fulfilling at first, are eventually validated by "re-dos," the playing back of experiences captured by the wife's video implants. On one hand, the grain helps the couple face the truth of the betrayal. And facing the truth is good. Right?  Well, yes. On the other hand, the obsessive re-experiencing of the past leaves no room for a tolerable present, let alone a viable future. They're marriage is doomed. The accumulated weight of their past sinks it like a stone. And they're not alone; it's hard to imagine anyone getting over themselves in such a continuously-recorded and replayed world. 

Which brings me to my new favorite subject. Namely, the neurological mechanisms of controlled forgetting. Without ignoring we’d be lost in a phantasmagorical avalanche of data overload. And without forgetting, we’d be unable zero in on the present. Maybe it is exactly our loose grasp on the past that keeps us attentive to the present and invested in the future. UC Santa Cruz experimental psychologist and memory expert Benjamin Storm says, “the goal of memory is to serve our future behaviors so that we behave more adaptively, not to give us the truth about the past.”

In fact, according to a new cadre of neuroscientists, forgetting the details of the past is one of our brain's major accomplishments.  Whereas neuroscientists once assumed forgetting was just memory’s failure, it turns out forgetting has its own mechanisms, rules, and triggers. It is a lot of neurological work to forget properly and well. 

More on the importance of forgetting soon. Meanwhile, watch “The Entire History of You.” 

Thursday, January 8, 2015

Epilepsy Research Highlights of 2014

was an important year for epilepsy research. A review in the January 2015 issue of Nature Neuroscience cites four milestones, each emphasizing a positive trend toward increasing reliance on research collaborations and data sharing. The piece starts with the International League Against Epilepsy’s (ILAE's) long-awaited update of the definition of the word “epilepsy” itself. In 2013, a person with epilepsy was stuck with a lifelong diagnosis, whether they continued to have seizures or not. Under the new definition, people may officially shed the diagnosis once they have been both seizure free for ten years and off seizure meds for the last five of those. People who have outgrown childhood epilepsy syndromes also now may consider their epilepsy “resolved.” Of course, this doesn't change the fact that both of those groups are more likely to have recurring seizures than the population at large, but it does reflect a growing international consensus that an epilepsy diagnosis may outgrow its helpfulness after years of medicine-free seizure freedom. Epilepsy has also been upgraded (or downgraded, I suppose, depending how you look at it)  from a “disorder” to a “disease,” a taxonomic shift better reflecting the gravity of the diagnosis.

The Nature piece also cites a study that resolves an old debate about the dangers of extended fever-related seizures (febrile status epilepticus). Such seizures can, and often do--the study shows--cause significant damage to hippocampi. And that that damage can evolve into hippocampal sclerosis, which can cause temporal lobe seizures later on. In other words, extended febrile seizures are serious business.

The third study Nature cites is a genetic meta-analysis drawing on more than 8,000 epilepsy patients and about 26,000 controls. The study included 12 large genotype-phenotype genetic databases from three continents to locate genetic markers for common epilepsies. It found two key risk locations for all epilepsies. The work suggests that even though epilepsy is a wildly diverse disorder--I mean disease--a wide range of common seizure types seem to have some common genetic roots.

Fourth, the Nature piece refers to research showing that while heritable genetic mutations have received the bulk of study from researchers, somatic genetic mutation--those that occur after an individual is formed, and are not heritable--may be a fairly common cause of brain malformations associated with epilepsy. These mutations are found in only a small percentage of the body’s cells and so don’t usually show up in the standard genetic analyses. The upshot, somatic mutations will be a promising area of genetic study in coming years.

Finally, the review cites a large multi-center study of the effects of anti-epileptic drugs (AEDs) on the children of breastfeeding mothers who take them. The conclusion: go ahead and breastfeed your baby and continue to take your meds. “Breastfed children displayed higher IQ and enhanced verbal abilities compared with non-breastfed children,” the study concludes, whether the mother is taking AEDs or not.

What Nature didn’t describe in its review was the blossoming of research on 1) implantable devices, 2) the effective control of epilepsy through dietary treatments, and 3) the study of cannabidiol (CBD), an extract of the marijuana plant. All three are areas of quick research growth and of high excitement at the annual American Epilepsy Society meeting in Seattle a month ago. 

At that meeting, awards were also given for new and vastly improved algorithms developed for seizure recognition and prediction. In time, these algorithms, and others like them, will enable to implantable devices to shut down mounting seizure activity before it achieves critical mass. Like the milestones outlined in the Nature piece, this one was largely the product of data sharing and international collaboration. It is an excellent trend! 

Wednesday, October 8, 2014

Location! Location! Location!

Where are you? And how do you know? The answers find their most fundamental satisfaction through a mechanism in the temporal lobe discovered and explored by the three winners of this year's Nobel Prize for Physiology or Medicine. On Monday, the Nobel committee announced that John O'Keefe, May-Britt Moser, and Edvard Moser will share this year's prize for explaining the brain's global positioning system, a network of cells in the temporal lobe. In 1971, O'Keefe, now a professor of cognitive neuroscience at the University College London, first described what he called "place cells," neurons that identify specific places where a rat has been; the same neurons consistently activate whenever the rat walks by that location. Thirty four years later, the Mosers, who are a married couple and both professors at the Norwegian University of Science and Technology in Trondheim, discovered "grid cells." These neurons form clusters of triangular grids into which the place cells register their locations relative to each other.  Together, these two systems allow rats, humans, non-human primates, and probably most other brainy creatures, to determine their position in space, to store location information, and to navigate.

Last year, the first human grid cells were directly identified via electrodes temporarily implanted in the temporal lobes of epilepsy patients. The implants were put in place to study the patients' brains in preparation for surgery aimed at quelling their seizures. That work was done by Joshua Jacobs at Drexel University and appeared in  Nature Neuroscience.

The same area of the brain occupied by the grid cell navigation system is often hit by early Alzheimer's disease. Easily getting lost is a common early symptom of Alzheimer's.

James Gorman's good profile of the Mosers--who are both brilliant and adorable--was published in the Times last April.

Friday, August 22, 2014

New Study Shows Autism May Be Caused by Inadequate Synaptic Pruning? How About Epilepsy?

An infant's brain is chock full of connections. The average one has many times more synapses per neuron than the typical adult's. It is with the pruning of those extra neurons that networks enabling specific functions emerge. A story in today's New York Times describes research, published Thursday in the journal Neuron,  suggesting that the brains of autistic children are failing to prune away synapses as aggressively as they should.

David Sulzer, at Columbia University Medical Center, analyzed tissue from the brains of 20 children who had died between the ages of 2 and 20. Ten of those children had autism. The other ten did not. Both groups had about the same number of synaptic connections when they were very young. By the time the non-autistic children turned 19, they had 41 percent fewer synapses than when they were infants. The children with autism had only 16 percent fewer synapses.

Sulzer and colleagues found the same trends in rat models. Administering a drug used to prevent organ transplant rejection, to rats caused their brains to restore normal levels of synaptic pruning.

From the Columbia University press release:

"Although the drug, rapamycin, has side effects that may preclude its use in people with autism, “the fact that we can see changes in behavior suggests that autism may still be treatable after a child is diagnosed, if we can find a better drug,” said the study’s senior investigator, David Sulzer, PhD, professor of neurobiology in the Departments of Psychiatry, Neurology, and Pharmacology at CUMC."

More than a third of kids with autism also have epilepsy, and it is thought that reduced synaptic pruning, and the neural over-excitation it may cause, could also play a key role in some forms of epilepsy. See my story about epilepsy and autism in Epilepsy USA. I'll investigate this further from the epilepsy researcher's point of view and report back soon.

Wednesday, May 28, 2014

CNEP Wins $26M from DARPA for Neural Implants

UCSF neurosurgeon Edward
Chang developing read/write
neural implants to treat neuro-
psychiatric illness. (Photo by
Eric Millette) 
NPR's Morning Edition yesterday featured a good story about the work of Eddie Chang, the brilliant neurosurgeon/scientist at UCSF, and his cohorts at CNEP. These guys--whom I've written about  for Discover, San Francisco Magazine, and Berkeley Engineer--are on fire. The NPR piece reported on CNEP's part of a five-year $70-million DARPA project using brain implants to identify, study, and reform errant neural circuitry behind depression, PTSD, and addiction. The UCSF/Berkeley CNEP team is getting about $26 million of the funding to work on both the implants and the algorithms needed to 1) read and make sense of the brain's activity and 2) know when and how to apply subtle electrical impulses to lead the brain to "unlearn dysfunction" in areas causing psychiatric symptoms. It would be an entirely new way of treating mental  illness...unless you count electroconvulsive therapy (ECT), which also used electrical stimulation to interrupt pathological symptoms. Let's hope the new approach is a little more nuanced in its application and effects. Whether the implant approach will even work at all is unclear, but in just trying to find out the CNEP group will surely make huge strides toward directly linking brains and computers. 

I don't question DARPA's interest in helping millions of vets and others to overcome disabling and agonizing mental illness, but nor do I doubt the military research organization's incentive to develop brain-machine interfaces for a host of other purposes, too. More to come on this soon. 

Listen to NPR's Morning Edition story, Military Plans to Test Brain Implants to Fight Mental Disorders, by Jon Hamilton. Here's a link to DARPA's announcement. And a UC Berkeley release about the project.