I'm sure many of you have heard that autism is primarily due to sensory gating issues and overactivity of excitatory components in the brain. I suggest that some forms of CFS are similar, but instead of being an issue of a mutation in the GABA pathway, it is an mutation that affects other cells as well, namely immune cells, increasing excitability. I suggest this is the case because I have terrible fatigue and other symptoms that are totally prevented by phenibut, a VDCC blocker. My constipation, my fatigue, my pain, are all fixed. My acne is cleared by the next day. My ringworm fungus on my chest disappears within a day. My intelligence and ability to get things done improves drastically. Before you say that phenibut is also a gaba b agonist, that is true, but baclofen is much more selective for gaba b and it doesn't have nearly as profound effects for me. The primary effect of VDCC blockers would be a reduction in intracellular calcium and a reduction in postsynaptic neurotransmitter release. (calcium fuels the process that makes neurotransmitter carrying vesicles dissolve). I should also add that an increase in calcium concentration makes a neuron more positive and more likely to send an action potential. (ie increases sensitivity) I have compulsivity, pain, anxiety(only when I'm hyper aware of people looking at / waiting for me), etc. And my body gets high amounts of sensitization, for example my leg twitches at the spot where my cell phone vibrates and I hear the noise in my head at the same time. All point to high excitatory activity and sensitization going on. When I take phenibut, or when I'm sleep deprived(and have coffee), and I play video games, I feel like I'm not actually looking at anything, and most of the information is subliminal while my main brain is thinking about things like "what is most important to do right now, what is dangerous etc". My performance goes way up despite feeling like I'm zoned out. Also I can listen to music while playing games without getting severe brainfog/fatigue within 15 minutes. It feels like there is a huge filter keeping the "stuff not involving conscious thought" below the stuff that "needs conscious thought". Every day I can also feel normal for the first hour of the day, but then my cognition just disappears. This is separate from activity level or diet. Perhaps the conscious brain eventually gets overwhelmed. Memantine does nothing for me so I assume that my problem doesn't involve NMDA receptors. Piracetam effects AMPA receptors and does nothing so I assume that doesn't have any relation to my fatigue either. I need strong antioxidants to function such as vitamin C, and otherwise my symptoms are all much worse. Although I don't need antioxidants when I take phenibut. There are many receptors that effect both neurons and microglia. http://firstname.lastname@example.org (see table 1) From this article, I can see the candidates that could be the cause of my fatigue. They must increase intracellular calcium, and be in both neurons and microglia. The candidates are: mGluR1 and mGluR5a, Purinergic receptors: "Gi/Go-coupled P2Y (Y1, Y2, Y4 and Y12), P2X (X1, X4, and X7), P2Y8 and P2X6". And of course, VDCCs. The purinergic receptors are fairly new to me, this is interesting: https://en.wikipedia.org/wiki/Purinergic_receptor#Effects_on_chronic_pain Maybe the P2 receptors function in the same way for immune response, creating chronic immune responses and creating chronic states of heightened excitability of the immune system. Also VERY interesting, is that the P2Y receptors are activated by Uridine, and uridine supplementation for me gives extreme fatigue. Uridine is also found in beer. All in all, the mechanism I suggest is: Increased intracellular Ca+ in immune cells -> The cells are more sensitive to stimuli from pathogens/oxidation from exercise + the cells are more likely to trigger an inflammatory cascade. In addition, increased intracellular Ca+ in neurons -> disrupted sensory gating and sleep -> poor memory, fatigue, brain fog, poor focus. The cause of this mechanism of CFS could be genetic, or from gene expression changes due to viruses/the microbiome, or it could be self-perpetuating. Maybe a virus triggers these changes, so that the immune system is modulated in a certain way so that the virus is in a blind spot. For example, if the immune system is hyper sensitized to everything and has sensory gating issues, then it would get very confused and would be overwhelmed by information. Alright, that is all I got for now, too tired to write more.