During that weekend in the hospital with M when they decided to do genetic testing and I discovered Dravet Syndrome, even as I was on an emotional roller coaster, I couldn't help but feel grateful for my science education and my ability to read and parse scientific papers. I'm certainly not an expert and there are plenty of things that are well beyond my understanding, but I can at least understand the process, discussions of significance, and what it means to be peer reviewed (or not). To me, knowledge is power, and even if I can't change anything about M's condition, at least I can read and try to understand everything about it I can get my hands on.
So it's extra nice to be surrounded by nerdy friends who also send me papers to read that they think might interest me. They do, in fact, interest me. Thank you, friends! (And, fellow nerds, perhaps you too can be offended that the stock cover image I chose for this post is listed as "molecule"?)
First up, a paper exploring the mechanism by which the ketogenic diet actually affects seizures in epileptic people. When the diet was originally designed 100 years ago, they didn't get why it worked, they just knew that it worked. These days, the more we understand about the gut microbiome and the myriad links it has to how our bodies function, the closer we get to understanding why diets can have such an impact on our health. This paper explores the effects of the ketogenic diet on two types of mice - one designed to be susceptible to electric impulses that induce seizures, and the others designed with a mutation similar to a human mutation where they spontaneously have seizures. In both cases, the presence of two very specific types of gut bacteria that are associated with being on a ketogenic diet was correlated with reduced seizure frequency, including in a control group fed a regular diet with those strains of bacteria transplanted in. And what's interesting is that the two types of bacteria *both* have to be there - just one or the other ("monocolonized") didn't work. An excerpt from the section about the electrically-induced seizure mice:
We next examined seizure susceptibility in mice with selective enrichment of KD [Ketogenic diet]-associated gut bacteria. Treatment with the KD alone elevated seizure thresholds by 24.5% from 19.4 ± 0.8 mA, in SPF CD [control diet] mice, to 24.2 ± 0.3 mA, in SPF KD mice, whereas Abx [antibiotic] treatment of KD-fed mice prevented this anti-seizure effect. Co-administration of A. muciniphila and Para-bacteroides restores seizure protection in Abx-treated mice fed the KD, raising thresholds by 36.0%, from 19.9 ± 0.3 mA, in Abx KD mice, to 27.0 ± 0.5 mA, in AkkPb KD mice. This protective effect is specific to A. muciniphila with P. merdae, as mice gavaged with A. muciniphila and P. distasonis exhibit no restoration of seizure protection. There is no significant increase in seizure threshold after enrichment of either A. muciniphila or Parabacteroides alone, indicating that both taxa are required for mediating the anti-seizure effects of the diet. There is also no effect of treatment with Bifidobacterium longum, as a negative control taxon that was enriched in CD-fed mice. Moreover, co-colonization of A. muciniphila and Parabacteroides in GF [raised germ-free] mice promotes seizure protection in response to the KD, when compared to GF, Parabac-teroides-monocolonized, or A. muciniphila-monocolonized mice, suggesting that A. muciniphila and Parabacteroides together raise seizure thresholds in the absence of other indigenous gut microbes.
This is useful because it provides an actual mechanism to understand better - the keto diet isn't equally effective in everyone with epilepsy, and it would be great to understand why - and potentially even ways to jumpstart or shortcut the process (fecal transplants anyone?).
The Gut Microbiota Mediates the Anti-Seizure Effects of the Ketogenic Diet (hint: turns out paper authors often love it when you ask for an electronic copy of their papers when you don't have a subscription to a journal. Just saying.)
Next one is the effect of Mozart's music on brain activity associated with seizures. The Mozart effect has been part of popular culture for a long time (it's why all my pre-standardized-test cram sessions had Mozart playing in the background), but this paper explores the specific effect it has on seizure frequency. It's not only Mozart music that can have this effect, nor is it all of Mozart's compositions that seem to work, and the paper starts digging into that a bit - there seem to be specific characteristics associated with some of his music that have the greatest impact. They primarily used a Sonata for Two Pianos (K.448). One excerpt:
To analyze the periodicity of music, Hughes et al. first converted musical notes into audio waveforms, i.e., acoustical pressure waves converted to voltage signals and digitized. A periodicity index was chosen to represent the degree of periodicity; this index was the ratio of the highest peak to the next highest (×10) (11). Hughes et al. found that the long-term periodicity of melodic line in the music of Mozart and two pieces of Bach’s were significantly more apparent and frequent when compared with the music of 55 other composers (such as Chopin, Mendelssohn) (11). This may account for the reduction of epileptiform discharges.
And this is really interesting too:
In our previous study, interictal discharges were reduced by an average of 24.1% in 81% of patients as patients listened to the Mozart K.448. However, when we used a digitally computerized string version of the same musical stimulus, the discharges showed slight increase by average 10.5% when listening to this music (3). A spectrogram analysis of the two versions, piano and string, was generated by a MATLAB program (Mathworks, Inc., MI, USA). To begin to describe the differences in the two versions, short-time Fourier transforms of the signals were computed. Although the two kinds of music had the same melody, spectrograms comparing the piano K.448 and string K.448 showed clear differences. The differences were particularly noteworthy at high frequencies. The string K.448 had much stronger high frequency harmonics.
So basically, it actually matters how a composition is played, and versions with lower harmonics appear to have more beneficial effects.
Why does this work? One theory the paper puts forth is that music increases dopamine levels in your brain, and some types of epilepsy are associated with impaired dopamine uptake, so the music might mitigate the negative effects. Another theory involves mirror neurons, which is kind of wild. A third theory is that it affects the parasympathetic nervous system that keeps all of your body's background activity functioning - in some epileptic people, that system doesn't work quite right, so perhaps the music is resetting it temporarily. But we don't know yet! These are the next steps for research in this area - exploring these different mechanisms to determine what it is the music is affecting, and finding ways to more reliably reproduce this effect.
Mozart’s music in children with epilepsy (full paper available online). The paper is from 2015, and this abstract of a 2018 paper indicates that no clear causal relationship has yet been determined, but that it's certainly a popular area of research. Obviously no music on its own is going to cure anyone's epilepsy but it's certainly no skin off our backs to have Alexa playing a sonata at dinner each night.
By the way, those of you who love to talk about how STEM can't leave out the arts - I think the Mozart study is a pretty prime example of a successful integration!
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