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    Shock And Awe
    By Clayton Aldern | August 27th 2012 03:18 AM | 2 comments | Print | E-mail | Track Comments
    About Clayton

    Brown University '13. Neuro, disease-targeted research policy, science writing, em dashes, hungry. MSc Neuroscience at Oxford in the fall. Twitter...

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    Well this is objectively awesome. In a report published earlier last week in Science, Berényi et al. demonstrate that carefully controlled electrical stimulation of the rat skull can quickly and drastically diminish abnormal brain activity associated with epilepsy1.

    The experimental system is a seizure-stopper triggered by seizures: Implanted electrodes monitoring brain electrical activity alert a stimulator when irregular activity occurs, and the stimulator halts the episode via electrical pulses sent across the skull. All told, a rat spontaneously begins to have a seizure, the activity is immediately cut off, and our furry friend carries on with its fulfilling day of pellet-munching, wheel-running, and exploratory nose-poking.


    The study is great news for rodents, especially those prone to this variety of epileptic episodes. And luckily for us, a system like the one described here offers possible translation for needed human clinical applications.

    Epilepsy is tricky business. As one of the most common neurological disorders in the world, it affects approximately 50 million people2.

    And while it was the ancient Greek physician Hippocrates who first identified epilepsy as a disorder of the noggin (as opposed to the spirt or soul), it was not until the 19th century that a modern understanding of the disease began to emerge: Seizures are the result of uncontrolled and widespread electrical impulses in the brain3.

    That said, the disorder is treatable—most of the time. Traditional treatment for different varieties of epilepsy comes in the form of antiepileptic drugs like phenobarbital and valproic acid, daily pills or capsules that encourage inhibition of excess neural electrical activity. This is where the tricky business comes in: All drugs have side effects, epilepsy is a hugely variable spectrum of disorders, and many subsets of the disease are drug-resistant. Complexities like this motivate research for alternative therapies.

    A good way to study the elaborate brain dynamics at play in epilepsy is to use animal models. Enter epileptic rats. The authors of the Science study worked with a rodent model of generalized absence, or “petit mal”, seizures. Absence seizures are short, consciousness-impairing seizures characterized by “spike-wave” (SW) complexes across both hemispheres of the brain. The SW complexes are exactly what they sound like: perturbations in brain electrical activity that follow a quick spike, slow wave pattern. Imagine the upper half of a goldfish cracker. The pointy tail would be equivalent to the spike, while the broad, rounded body reflects the wave portion. A whole slew of lined-up goldfish—that is, the electrical trace of a petit mal seizure—generally lasts nine to twelve seconds in children, the group that absence seizures affect the most4. Quantitatively speaking, Berényi and colleagues were able to reduce the duration of SW episodes and the total amount of time spent in SW in a given experimental session by more than 60%. Plus, the system is clean: The group’s therapeutic level of stimulation did not affect rats’ arousal states when rats were sleeping, nor did it affect behavior during waking1.

    The researchers posit that the closed-loop feedback stimulation stops the seizures by exciting a rat’s cortex (the outermost few layers of the brain), which in turn recruits cells in a rat’s thalamus (a deeper, sensory relay center). While both areas are traditionally silent during the wave portion of SW episodes, thalamic activity—prodded by the experimenters’ stimulation—terminates the SW cycle1.

    The stimulation technique, called transcranial electrical stimulation (named after those pulses sent across the skull), or TES, is a promising new method for a couple reasons. First, it is not invasive: The stimulation plates are on the skull, not the brain. In a clinical application, a relatively simple implant like this would translate quite nicely. The researchers make a point of mentioning that the transcranial implants are “cosmetically acceptable.”

    While we may quibble about a solid definition of this phrase, a conservative theoretical benchmark is the electrodes are of at least Walmart beauty department quality. In a clinical setting, Walmart quality is leagues more appealing than transcranial magnetic stimulation (TMS), which is perhaps the equivalent to applying industrial plaster to one’s face as a substitute for cover-up. In TMS, large, heavy magnetic coils are required to deliver a stimulation. More striking than the noninvasiveness, however, is the manner in which the TES is initiated. Since it is a closed-loop system—that is, a circuit that responds to feedback as opposed to just chugging along blindly—the TES is triggered by seizure-like activity and otherwise stays quiet.

    Electrical stimulation to treat disease is not a new concept, as clinicians have employed a technique called deep brain stimulation to treat Parkinsonian symptoms and major depression for years. Yet deep brain stimulation runs continuously, and while the constant activation is a necessary component in the control of motor deficiencies present in Parkinson’s Disease, side-effects related to continuous stimulation of the brain could be avoided if the stimulation was delivered sparingly. Seizures recur sporadically, so a closed-loop system that responds to their onset is ideal. This is precisely what Berényi et al. have delivered. In an elegant display of mathematical acrobatics, the raw electrical signal is filtered, above-threshold activity is detected and relayed to the TES system, and a few volts of electricity are passed across the skull to quickly quell the seizure.

    Of course, we are far off from a clinical application in humans, but the described setup is a pretty good start. The “closed-loop” aspect of the system is enough to get most scientists’ mouths watering, as the term hints at a high degree of efficiency. The cosmetic acceptability of intracranial plates paired with ultralight electrical circuits is absolutely attractive as far as a practical solution goes. But there is a bit of an unsolved problem. Berényi et al.’s system hinges on implanted electrodes’ ability to recognize seizure-like activity and relay these triggers to the TES electrodes. In other words, the only reason the researchers can turn on the therapeutic stimulation is that they have electrodes sitting in the brain.

    This, of course, is a tad invasive (read: holes drilled through the skull). While previous studies have shown that certain types of epileptic seizures could possibly be circumvented by using deep-implanted recording and cortical stimulation devices in humans, it remains to be demonstrated that a noninvasive (i.e. skin- or skull-implanted) signal is strong or accurate enough to be a reliable trigger for TES5.

    And so academia pushes ever onward—but once the aforementioned problems are addressed, a clinically viable solution would start to sound pretty realistic. It could be the end of many drug-resistant epilepsies as we know them. Stimulating, no?

    References

    [1] Berényi A, Belluscio M, Mao D, and Buzsáki G. Closed-loop control of epilepsy by transcranial electrical stimulation. Science 10 August 2012: 337 (6095), 735-737.

    [2] World Health Organization. Annual Report 2003: Global Campaign Against Epilepsy: Out of the Shadows. 2003. Global Campaign Against Epilepsy: Annual Reports.

    [3] World Health Organization. Epilepsy, the disorder. 2005. World Health Organization Epilepsy Atlas: 15-28.

    [4] Hughes J. Absence seizures: A review of recent reports with new concepts. Epilepsy&Behavior August 2009: 14 (4), 404-412.

    [5] Morrell M. Responsive cortical stimulation for the treatment of medically intractable partial epilepsy. Neurology 27 September 2011: 77 (13), 1295-1304.

    Comments

    Gerhard Adam
    With respect to drug treatments, how does this square with any research that relates marijuana usage to controlling seizures?  I've heard much anecdotal information, but haven't seen anything specific regarding the science of such.

    It certainly seems plausible as a potential treatment, at least in some cases, but I'm continuously amazed at the fact that social pressures would override legitimate scientific inquiry on the subject.

    Mundus vult decipi
    compatibilism
    I looked into this a bit, and a couple reviews published last year (here and here) highlight the majority of basic and clinical research conducted in reference to treating epilepsy with marijuana/cannabinoids. There's not a whole lot of convincing work out there, but you're right—in some cases, there's a demonstrable positive effect. However, it's important to note that most of the research comes from indirect (i.e. basic endocannabinoid molecular signaling mechanisms, etc.) research as opposed to actual clinical trials.

    While the legal and social pressures are certainly significant, what truly hinders cannabinoid-epilepsy research is what we already know: Some studies demonstrated a pro-convulsive—i.e not anti-convulsive—effect of marijuana interventions in animal studies, and the massively dense chemical interactions induced by marijuana exposure complicate data sets tremendously.