The question remains "downstream effect" caused by what?
My guess is dysfunctional brain cells. Which cells and why are they in that abnormal state? That's what we need researchers to focus on. If they study an endpoint (downstream effect), there's no guarantee that it will lead to the root cause, at least in less time/effort than it would take by looking directly for the root cause. I think the 'start downstream' approach is more likely to run into the 'we've found an abnormality, but there are thousands of possible causes for that' problem. Imagine that the abnormality is a slight difference in vagus nerve signals. We don't have enough data on vagus nerve function in normal healthy people vs unhealthy people to proceed past that point, without needing yet another mega-project to get that data, and that might lead to a similar 'lots of possibilities that we lack enough data on' situation only slightly further upstream.
If the question is: "why should we assume that the core dysfunction is in the brain rather than the body?", I offer two reasons:
1. People have tried lots of body-affecting treatments and not found any that reliably switch ME (and all its symptoms) off. The blood and tissue in the body has also been searched quite a lot--without finding a reliable marker, so maybe it's not there to be found. That argument is weaker for the brain cause, due to the BBB blocking many treatments and the difficulty of taking measurements. FWIW, both cuminaldehyde and T2 cross the BBB, and I assume prednisone does, and all three triggered temporary remissions.
2. Brain function is less well studied than the rest of the body, which means there's still lots of opportunity for the root cause of ME to hide. There have been quite a few new discoveries in brain function/structure in the last year; any of which can be considered 'virgin terrain' for looking for ME's core dysfunction.
