Trial Report Feasibility and tolerability of dual-target [rTMS] for treatment of [ME/CFS]: An open label pilot study, 2025, Corlier et al

[forestglip]

Feasibility and tolerability of dual-target repetitive transcranial magnetic stimulation (rTMS) for treatment of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): An open label pilot study

Juliana Corlier, Hrag Peltekian, Thomas E. Valles, Cole D. Matthews, Doan Ngo, Reza Tadayonnejad, Evan H. Einstein, Scott A. Wilke, Aaron Slan, Margaret G. Distler, Gil Hoftman, Adesewa E. Adelekun, Hanadi A. Oughli, Michael K. Leuchter, Hewa Artin, Ralph J. Koek, Nathaniel D. Ginder, David E. Krantz, Thomas Strouse, Andrew F. Leuchter
[Line breaks added]

Objective
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is characterized by extreme, persistent fatigue, pain, sleep disturbances, cognitive dysfunction, and mood dysregulation. Repetitive Transcranial Magnetic Stimulation (rTMS) has shown efficacy for improving these symptoms in patients with depression, fibromyalgia, and other conditions.

The goal of this pilot study was to evaluate whether a novel protocol involving dual-target rTMS to the left dorsolateral prefrontal cortex (DLPFC) and the primary motor cortex (M1) would demonstrate benefit in ME/CFS patients.

Methods
Fifteen female participants with ME/CFS were enrolled to receive 30 rTMS sessions administered sequentially to left DLPFC and M1. Electroencephalograms (EEG) were recorded to explore whether there were baseline EEG characteristics indicative of outcome.

The primary outcome measure was percent change in five symptom domains (fatigue, pain, mood, sleep, and cognition) from baseline to the end of treatment.

Results
No serious adverse effects were observed. The initial five subjects dropped out due to poor treatment tolerability, and the remaining 10 subjects completed a modified protocol adjusted to improve tolerability.

These 10 subjects completed all study procedures and demonstrated some improvement in all five symptom domains. EEG analysis showed that lower delta and theta, and higher alpha oscillatory power at baseline, were associated with better final outcomes in fatigue and sleep.

Conclusions
Dual-target rTMS at 80–100 % of resting motor threshold (MT) appears to be safe and tolerable, with short-term efficacy for treatment of primary ME/CFS symptoms. These findings support larger controlled studies of this treatment approach for ME/CFS.

Web | PDF | Transcranial Magnetic Stimulation

 

[Utsikt]

We learned that our initial treatment protocol was not feasible when the first five subjects dropped out due to the difficulty of commuting for five daily treatment sessions each week (3 subjects) or tolerating full stimulation intensity or iTBS stimulation (2 subjects). This subject attrition reflected the fact that patients with ME/CFS are a challenging population to enroll and retain in a clinical trial. They experience considerable fatigue even after minor exertion, such as traveling to a research site, parking, and walking to the clinic, and fatigue may not improve with rest. These patients also exhibit heightened pain sensitivity and frequently suffer from allodynia. The protocol therefore was modified to allow for fewer visits and flexible (lower) stimulation intensity (for further detail, see rTMS protocol section below).

I’m not sure the authors understand what PEM is based on this description.

We examined clinical symptoms at baseline and after 30 treatment sessions. Participants who attended all 30 sessions were considered treatment completers. The final outcome timepoint was session 30. The following five symptom domains were evaluated: 1) Fatigueusing the Fatigue Severity Scale (Learmonth et al., 2013); 2) Mood using the Inventory of Depressive Symptomatology – Self-Rated (IDS-SR), (Rush et al., 2000); 3) Pain using the Brief Pain Inventory-Short Form (Jumbo et al., 2021); 4) Sleep using the Patient-Reported Outcomes Measurement Information System (PROMIS Sleep) (Yu et al., 2012); 5) Subjective cognitive complaints using the Multidimensional Inventory of Subjective Cognitive Impairment (MISCI) (Kratz et al., 2015).

No objective outcomes related to functional capacity.

For symptoms of fatigue, pain, sleep, and cognitive complaints, for which the likelihood of benefit was unknown, we utilized a cutoff of 30 %. This value still exceeds the minimal clinically important difference for fibromyalgia (a closely related condition) of 14 % (Bennett et al., 2009, Farrar et al., 2000). For mood symptoms, which have been shown to be highly responsive to rTMS treatment, we utilized an even more stringent threshold for benefit of 50 % improvement. ‘Overall study responders’ were defined as patients who responded in at least 2 of 5 symptoms domains, expecting that each stimulation target would yield clinical improvement in at least one symptom domain. The criterion of at least two symptom domains made the study more rigorous than examining one single outcome.

The thresholds seems very arbitrary, but at least they didn’t just go for the «statistically significant».

Fig. 1. Response rates by symptom domain for all study completers. A: Individual and group response rates. Each row represents one symptom core, each column represents one study participant. Green: Response; Grey: Non-response; The bottom row indicates overall responders (R) & Non-responder (NR), defined as response in any two symptom domains. Pie-charts summarize group response rates. B: Group average percent improvement for each symptom core (across responders and non-responders). C: Symptom improvement across treatment sessions. P-values represent repeated-measures ANOVA statistic for the factor “Treatment session”.

Can’t say I’m very impressed by these results. Moderate effects at best for everything except for mood, which seems to be the one that’s most susceptible to bias (link to questionnaire).

5. Limitations​

(…) The open label study design can have stronger placebo effects than randomized controlled studies. We have also not examined the durability of clinical benefit which should also be confirmed in a future large-scale study.

I’m not sure the authors understands that the issue with the combination of lack of blinding and subjective outcomes is that it results in too much bias. It appears like they believe that it can only make an effect appear bigger, and not create the appearance of an effect that isn’t there.

Overall, this seems like a complete waste of the time and health of the patients. They had to make 30 trips to the centre and the authors couldn’t even be bothered to do any objective outcomes or use longer follow up periods to make it worth their effort.

Given the lack of effective treatments for most symptoms of ME/CFS, this protocol could represent one of the few options to comprehensively address the full range of illness for this difficult-to-treat condition.

They call it comprehensive when they don’t even try to measure PEM..

 

[Utsikt]

Also, it’s completely ridiculous that they apparently expected pwME/CFS to make five trips a week for six weeks! No wonder everyone dropped out before they changed it.

 

[bobbler]

I’m not sure the authors understand what PEM is based on this description.

No objective outcomes related to functional capacity.

The thresholds seems very arbitrary, but at least they didn’t just go for the «statistically significant».
View attachment 28598

Can’t say I’m very impressed by these results. Moderate effects at best for everything except for mood, which seems to be the one that’s most susceptible to bias (link to questionnaire).

I’m not sure the authors understands that the issue with the combination of lack of blinding and subjective outcomes is that it results in too much bias. It appears like they believe that it can only make an effect appear bigger, and not create the appearance of an effect that isn’t there.

Overall, this seems like a complete waste of the time and health of the patients. They had to make 30 trips to the centre and the authors couldn’t even be bothered to do any objective outcomes or use longer follow up periods to make it worth their effort.

They call it comprehensive when they don’t even try to measure PEM..

Yeah talk about deceiving themselves that their machine they spent money on thinking they'd find some captive audience for it that it would work for, and the training they enthusiastically just soaked up would 'really help this lot'.

It's using the usual Krytpon Factor filter effect isn't it to just filter out the few in their group of 'fatigued people' who can make 30 sessions - ie excluding those who think 'well this is doing nothing other than exhausting me running back and forth', so after I've given 8 a try and it doesn't work then I think I'll nod and leave.

And then pretending the difference in fatigue levels of those who could make 30 commutes vs those who couldn't was 'down to the machine' instead of ... you know .. it being a filter in itself and just a way to cream off those least unwell.

And that's what their 'acceptability' ie miscontrued polite excuse so people don't get something bad on their notes actually is: it really doesn't work. SO what are the numbers and those graphs when they include the drop-outs.

Are they really so deluded that they think there is a bunch of seriously ill people who are finding this treatment miraculously useful to the point it makes the commute now not exhausting, and yet those same people think that benefit isn't worth said commute? Where is their logic? Or is the issue their warped perception of either the cohort or their treatment's usefulness/impact?


I don't think they even realising that they aren't studying ME/CFS but the usual 'I think I know what CFS is thanks very much ignorers version of 'something chronic fatiguey' that they assume is like when they are tired with a bit of what they assume is something linked to perception and puts all the things like cfs, fibro, mus in one pot together to make what they want to do as a job have some sort of big bucket audience'


I'm so frustrated by Nice doing analysis for the 2021 guideline and managing to point out this 'anything but ME/CFS' approach of the entire behavioural research area and all the 'professions' that call themselves experts and have been attracted to 'cfs/me'. ANd then not only do they not listen to the last few years as people tried to get them to see but stuck their fingers in their ears saying 'I think I know already' then just got worse in their assumptions and making things up in line with their own fiction of what they want it to be

I've also noticed that the only areas that seem to insist on doing 'acceptability' studies seem to be dodgy treatment areas based in pseudo-psychology, which sadly are often allowed to kid themselves isn't pseudo by calling it and sitting under departments claiming the term psych.

Don't they realise how weird they are to think that if they have a treatment that they could actually prove was effective or useful for an illness defined as the illness actually is and using normal, proper methods, then it stands as useful on its own basis - and is then down to informed consent and autonomy for those who want to make a living in it to be respectful and honest in telling people what it is they are pushing and so the person getting it done to them can make a full decision on whether it is worth it.

The way these people seem to react to these things like the commute stuff it feels/looks like the full message never really goes in of what people say, and I've met those who are stuck in this mode before and think it needs to be studied in itself as a phenomenon. I think it is linked to ability to have respect in some way too, given noone has insisted on training out the old guideline slurs and assumption that were trained into people with 'false belief' type rumours etc.

 

[Jaybee00]

Umm my primary care doctor bought one of these brain zapper machines for like $300,000. Last time I visited his office he was so excited to show off the zapper that he barely paid any attention to anything I said. He wanted a couple thousand dollars for like six zapping sessions. I passed.

 

[hotblack]

Interesting to see that Solve ME/CFS were involved. I wonder how much input they had on the design?

An organisation which exists to promote TMS was also involved in funding the article (but not the research it seems). This from the Acknowledgments

This pilot study was funded the Iris Cantor UCLA Women’s Health Center in collaboration with the Solve ME/CFS Initiative. Juliana Corlier has received NIMH funding, grant # K01MH123887.
Andrew Leuchter has received NIMH funding, grant # R01MH135293.
The funding for this article was provided by a generous donation from the Neil S. Hirsch Foundation through the Foundation for the Advancement of Clinical TMS.

 

[arnoble]

What do we think of the "Fatigue Severity Scale"? It seemingly was constucted by some doctors in 1989 to track/diagnose MS and SLE. To equally weight 9 questions like "1. My motivation is lower when I am fatigued. 2. Exercise brings on my fatigue. 3. I am easily fatigued. " seems not very responsive, and ignores PEM entirely.

 

[Mij]

I had a lot of difficulty describing delayed PEM on Leonard Jason's questionnaires. Every question asked how to describe 'fatigue' 10 different ways.

I didn't finish filling it out because it gave me PEM.

 

[bobbler]

What do we think of the "Fatigue Severity Scale"? It seemingly was constucted by some doctors in 1989 to track/diagnose MS and SLE. To equally weight 9 questions like "1. My motivation is lower when I am fatigued. 2. Exercise brings on my fatigue. 3. I am easily fatigued. " seems not very responsive, and ignores PEM entirely.

Important discussion to raise - I hope I’ll come back to this in next few days and take a look as we need measures and it’s not quite there yet

I’ll add for now that it’s doubly tricky because there are a few concepts going on

Like if we are having to do lots then often there is that trying to calculate something ‘relative’ to how exhausted we would expect to be from ‘having done that’ vs ‘how exhausted we are’ but then even that is relative to a frame of reference which could be compared to last week or before ill or because me/cfs is a moving feast then even six months ago .

And is probably impacted by how we feel in ourselves at the time so a good vs bad nights sleep is enough to nudge the dial just enough on some of these measures and methods vs what they count as ‘change’ or significant that it’s an issue too.

I know it’s broken record to then note that those who finish one of these trials are also likely to have adapted their commitments/chores/routine they had ‘before’ to ‘fit in’ the load associated with participating as we can’t magic energy. And that makes said calculations even more ‘wicked’ on top of the ambiguity and lack of clarity in questions of precisely what they are measuring.

The causal ness though of some of the phrases in some of these scales does astound me sometimes until I then think maybe they are deliberately simplified for what might be good reasons it strikes someone like me who experienced every type of exhaustion + situation and cumulating ‘hang-over’ that presents in so many different ways I can now separate from each other as quite ‘observer-based’ ie written by someone who just thinks it’s what they see rather than getting the difference between not being able to remember a 6 digit code that day or saying words in wrong order vs not being able to wake to me are very different things but simmered down to ‘fog’ and then there is the physical stuff where you can feel your body straining vs it not because you are resting but are you ‘more fatigued’ in one than the other is influenced by momentum and distraction and includes both long term build up and what you’ve done today.

I’m intrigued that this scale is used for other conditions like MS because I’d bet their fatigue isn’t described perfectly either and/but I’d be intrigued to get insight from experienced pwMS to compare and understand that and be sure I’ve got that right. And see where /which bits are similar and which bits differ etc.

So the ‘feel’ stuff is important in some things and not done well eg those stuck in rolling PEM early in illness but I struggle to see how it can be asked without those contextual bits being accounted for - or how they can be without creating something that becomes a bit beautiful mind other than changing questions to eg tasks or thought experiments eg like ‘if you had rested this morning could you shower/add up/trust yourself to reply to work emails’ would still be as influenced by if you’ve had ten coffees or the burglar alarm went off all night two days ago . And we could hope huge sample sizes could even it out but only if there wasn’t some attendance issue that causes drop-outs and these things causing adaptations most will have to do (family being nicer because you are trying something perhaps common)

Then when I stand back and think how disabled pwme are and how we shouldn’t be putting up with that being ‘something to just get on with’

And it makes me think the issue for some of these is just how gaslighting the whole thing is because the measure for this could have in itself just been ‘vote with their feet’

If it helped people enough to be worthwhile and change their exhaustion then there would have been a point where drop-outs stopped (people were getting more tired in hope of it working and then suddenly at 8 sessions they started feeling benefit and were less exhausted than they would have expected to be after 10 days of the commute) vs a point where drop-outs started (as PEM kicked in and exhaustion from attending 8 sessions accumulated) . Albeit there are a few more complications in that equation too