Super simple version of my current thoughts on PEM. Glycogen phosphorylase (GF edit: this should be GP) changes glycogen to glucose for a quick source of energy. There is a form of GP in the brain that they don't know much about, except that if you don't have it you're probably dead. My hypothesis is that if a person has low GP in the brain and they use their brain for a lot of activity the brain says "Whoa! buddy, I don't have enough quick energy for this. I'm going to slow you down!" and the brain makes changes (that take a day or two to effect) that stop the person from being able to use their brain so much. The way they feel after the brain makes those changes is a crash. The changes wear off if the person doesn't use their brain too much for a while. More technical explanation below. Glycogen phosphorylase is pretty well known due to its role in helping to sustain activity in the muscles by rapidly supplying glucose during exercise, but the role of brain glycogen phosphorylase does not appear to have been explored yet. One thing that is known is that it doesn't have any loss of function mutations, which suggests that it is vital to life. Muscle GP mutations, on the other hand, are well known. Since GP changes glycogen to glucose for quick energy, it doesn't seem unreasonable to hypothesize that a deficiency could cause PEM. The hypothesis I am forming is that if a person has low brain GP their body would be likely to try to compensate through changes in genetic expression. These changes would be different in different individuals, and the symptoms would be different. I hypothesize that in people with CFS/ME the brain responds to brain activity that overreaches the ability of GP to supply the needs of the brain by instigating epigenetic changes to shut down the activity of the person, leaving them with greatly lessened ability to move and think. These epigenetic changes take a certain number of hours to effect, and the severity of the changes is in proportion to how far the activity has strained the GP needing parts of the brain. "In this review recent evidence has been brought forward highlighting what has been an emerging understanding in the field of brain energy metabolism: that brain glycogen is more than just a convenient way for the astrocyte to store energy for use in emergencies—it is in fact a dynamic molecule with versatile implications in normal brain function." I am planning to post in the general CFS/ME forum about how I think a person can become deficient in GP.