Efficacy of a wide range of things, from sleep & diet to supps & meds, may depend on timing
 
A study on epilepsy was published comparing gene expression in parts of the brain where seizures developed with adjacent healthy tissue (Li et al., 2017). It was in humans, so they couldn’t really have proper controls, because what healthy person would volunteer to have some of their brain chopped out?

They found the core circadian rhythm gene CLOCK was reduced in epileptogenic regions of the brain compared to healthy nearby tissue. It could be that this is just the way it is in healthy people, or that the seizure itself reduced CLOCK not vice versa. But the researchers followed-up with animal models lacking CLOCK in either inhibitory or excitatory neurons and showed mice lacking CLOCK in excitatory neurons had a lower seizure threshold and a more severe condition (suggests causation). They had worse seizures in the dark phase, similar to the findings in humans.


Bmal1 is CLOCK’s partner in crime. They also jack up REV-ERB, which ends up shuttin’ ‘em down in circadian fashion.

A semi-related study showed that a transporter which shuttles certain drugs out of the brain was under circadian control, and an anti-seizure drug was significantly more effective when administered when expression of that transporter was lowest (Zhang et al., 2017). If this means a lower dose can achieve the same efficacy, possibly with fewer side effects, I’m all for it.


There is an interesting interaction between brain-stuff (epilepsy in this case, but also cognition, memory, etc.), circadian rhythms (timing of seizures and LITERALLY EVERYTHING ELSE), and diet (keto, low GI, MAD, etc.). It has been speculated by some (myself included) to share some aspects with "brain fog" as well.


In lieu of full-disclosure: this post doesn’t have the answer… *I* don’t have the answer. I learned at a young age that the brain is extremely complicated.

For example, you could say “XYZ increases dopamine,” but there’s so much #fail in that statement, I wouldn’t even know where to begin. In which region? More specifically?

MORE SPECIFICALLY?

Which neurons? At certain times of day or all the time? Is it relative to timing of XYZ? What is the duration?


Coupled with the intricate complexities that we know of circadian rhythms, and we have a riddle wrapped in a mystery inside an enigma. And I stress "that we know" because I'm pretty sure this is one of the biggest example of unknown-unknowns ever.

Some of the intricate complexities -> LIGHT timing for circadian entrainment or just check out the image below:


Mediators? I don’t know! Depending on which specific aspects (and I’m guessing here): NAD+/NADH ratio, beta-hydroxybutyrate (directly/indirectly, HDAC, FFAR, etc.), the balance between excitatory and inhibitory signals, etc., etc.


Some prior musings on the topic:

Circadian Mismatch and Chronopharmacology (scroll down to part 2 for some actual examples of dose-timing for various drugs)

Ketosis: anti-brain fog. Neurotransmitters, dietary protein, and the gut microbiome

Ketone bodies as signaling metabolites

Fasting, circadian biology, and epigenetics

I don’t have the answers, but the blaring blue lit elephant in the room is circadian biology. It’s been linked to practically every single disease. Some of the mechanisms have been worked out in pre-clinical models, others we haven’t a clue.

The deeper I dive into this, the simpler my pan-health mantra has become: don’t eat like a child and CIRCADIAN RHYTHMS haha get some blue blockers :)

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