Don't you tend to think that what is going on in the brain is effect, not cause? I'm skeptical of the claim by some that this is primarily a neurological disease and that the brain is driving symptoms. It seems much more plausible that what is going on in the brain is an effect of some system-wide immune and/or metabolic disturbance. Brain imaging is interesting but don't you agree it probably is not going to get at the core of this disease? Plus the fancy imaging studies that actually find big differences aren't widely available for clinical use.
I think there is an important difference between a cause of a disease and a core of a disease.
We have reasonably good evidence for ME being caused by a whole range of events and in many cases we think these events are long since gone by the time the illness is established. Understanding what at least some of these causes are may be very useful in order to understand mechanisms but I don't think they are the 'core' of the illness.
Most of us work on the model that all these different causal events can feed in to some common self-perpetuating process that can be identified by the core symptoms of ME. That is what I would call the core of ME. This is very like diabetes or rheumatoid arthritis. Many events can precipitate inadequate insulin production, which is the core of diabetes. Many initial B cell events can tip the immune system into an autoimmune cascade like RA. We manage these two diseases without anything much more than hypothesising what we think these initial events are. They do not matter because we are not in the business of preventing them happening and may never be.
My thinking about ME is very much led by my work on RA. When I got interested in RA we knew there were autoantibodies, which looked as if they might be causing things, at least on an ongoing basis in established disease. We also had symptoms and signs like pain and swelling. We had data on histology but in old fashioned language that did not tell us how to interpret in terms of antibodies causing inflammation causing symptoms. The critical work consisted of working out how the causal steps linked together in the target tissues of the joint and lung etc. We identified a very specific pathway and from that we could work back to explain why TNF inhibitors worked so well and why rituximab should also work well.
Multiple sclerosis may be an even closer analogy to ME. The causes of MS consist of a combination of genes and some random event in the immune system like in RA. The genes you are born with so you cannot do anything about them. The random event is long gone. You cannot even find any autoantibodies in the blood, although B cells in the blood are very likely causing all the problems of loss of mobility and thinking functions indirectly. Making sense of MS has depended again on piecing together how causal pathways mediate the core pathology, which in this case is central nervous system demyelination.
What I think I am saying is that we have primary causes and then intermediary events that are the effects of the primary causes but the direct causes of symptoms. Those intermediary events tend to be the defining core for illnesses.
The million dollar question is then whether the crucial intermediary events, that are not occurring in people with other illnesses, are in the brain or out in the muscles or blood vessels. I work on the basis that if you are pretty sure at least some of the events are in one place you go for that rather than going for places which might or might not be sites of core events. Brain fog, sensitivity to light and sound and sleep disturbance all seem to me to be things that must be arising in the brain. I suspect orthostatic hypotension is most likely to be controlled in the back of the brain in the hypothalamic/pituitary area. The same intermediary events, maybe involving mitochondria, might be going on both in brain and muscles, and that would be a neat way to explain everything in one go, but so far there is no compelling reason to say there must be things going wrong in muscle itself. If any significant metabolic change was happening in muscle it would have shown up on MR spectroscopy. David Jones is a muscle expert familiar with MR spectroscopy who has worked with Julia Newton. If there was really something abnormal in the metabolism there I think it would have been reported by now.
So those are my reasons for making sure people look at brain. I have not seen these applications as such and it may well be that Maureen Hanson's group includes brain studies and that James Baraniuk is involved either directly or indirectly. I would be surprised if not in a way because they are both well aware of each other's work and are both very open collaborative people.