A startling new paper from Tehran claims Antidepressant effects of magnetic resonance imaging-based stimulation on major depressive disorder.
Yes, this study says that having an MRI scan has a powerful antidepressant effect.
They took 51 depressed patients, and gave them all either an MRI scan or a placebo sham scan. The sham was a "scan" in a decommissioned scanner. The magnet was off but they played recorded scannerish sounds to make it believable. Patients were blinded to group.
They found that people in the scanner group improved much more than those in the sham group over two weeks. Actually there were two different kinds of scans, T1 structural MRI and EPI functional MRI, but they were the same:
So is it true? I can't see any obvious flaws in the design. Assuming that the authors are right when they say that "patients could not distinguish the difference between the actual and sham MRI scan", i.e. assuming that the blind was truly blind, then the methodology was sound.
But let's look at the statistics. The paper is full of very impressive p values less than 0.001 but those turn out to all be referring to the changes within each group, and those changes are fairly meaningless. What matters is the differences in the groups and
Changes in BDI scores (between baseline and day 14) were significantly different among the three studied groups (F=5.48, p=0.007 overall) using ANOVA, and between the DWI group vs. Sham and T1 vs. Sham (p<0.05) using post hoc tests. Changes in HAMD24 scores (between baseline and day 14) were also compared among the 3 groups using ANOVA but the level of significance was slightly above the significance threshold (F=2.89, p=0.06).Which is rather less convincing. There was a close-to-significant group difference in the HAMD24, and a significant but only just effect on the BDI. Remember that there were only 17 people in each group.
I'm inclined to think that this is one of the 5% of experiments which will produce a nominally significant result even assuming everything goes to plan and there are no confounds. My suspicion is that everyone in the trial got better (they were all on antidepressants, plus there's the placebo effect and the effect of time) - except a small number of people who didn't improve. And by chance they were all in the sham group.
The reason I'm skeptical is that I just can't see a plausible mechanism. The authors suggest that MRI scans might stimulate the brain in a similar way to TMS and that this could have antidepressant effects.
But there's a lot of problems with this: 1) the evidence is questionable whether TMS even works for depression 2) the magnetic stimulation of the brain generated during MRI is much weaker than in the case of TMS and 3) if MRI really stimulated the brain like TMS, then, like TMS, it would have a risk of triggering seizures in people with epilepsy. But it doesn't.
Vaziri-Bozorg SM, et al (2011). Antidepressant effects of magnetic resonance imaging-based stimulation on major depressive disorder: a double-blind randomized clinical trial. Brain imaging and behavior PMID: 22069111
24 comments:
Reading the paper, the variance of the HAMD increased from pre- to post- in the sham group. As you noted, that's consistent with the 5 individuals in the sham group that "worsened", compared to only 1 or none that worsened in the treatment arms. But there was also a considerably larger number that "improved" in the non-sham groups, 15 in each versus only 9 in the sham group.
And that pattern of more worsening in the sham group is less obvious on the BDI score. I'm no expert on these inventories, so I don't have any idea why that difference between HAMD and BDI might arise. the BDI is a self-report, so perhaps small improvements in symptoms lead to more optimistic self-assessment?
I also noticed that the BDI was taken at days 3 and 14 post-treatment. At day 3 you can already see some improvement in the treated groups, but not much in the sham group. The effect seems linear.
Another possible confounder I can think of is the SSRI. They were all on the same drug at the same dose, but (and the authors state this clearly) the drug was clearly having an effect in all the groups (at least, we assume it's the drug!). I'd want to make sure that they all were on the drug for the same length of time before their scan, and possibly compare the groups for other pharmacokinetic-related parameters (such as BMI?)
Fascinating stuff, though.
So may e the man who was bold enough to order hius technician to look for a virus in AIDS will get a second Nobel prize if he lives long enough experimenting as he is now on magnetism traces of sort from homeopathic remedies.
Even Einstein best known dogma is put to the test of experimentation neuroskeptic...
This put relativity to your objection:
"The reason I'm skeptical is that I just can't see a plausible mechanism."
NB: You yourself exposed a British old psychiatrist who disgrace our profession defending in a tipîcal British arrogant and overagressive way his simplistic explanation of how psychiatric drugs work.
Plus:
The effect of digitals plant on the heart were known long before the receptors for their active component dicovered and even thexistence of chemical receptors for allopathic remedies and poisns alike.
Before Pasteur's discovery were accepted with that line of thinking you would have written that microbes do not exist.
Before Galileo mathematic findings were not susceptible to put to an early very hot death aboce a wwoden fire, you would have said that the sun turns around us and our earth.
The fact that this study contradict your beliefs and comprehension of the effect of magnetism or whatever on human psyche is a just a challenge to your intelligence and moral integrity as a researcher.
Unfortunatly it is one that the ben Goldacre ere not equipped for with all respects paid to a bright psychiatrist and reseacher. Still that Ben Goldacre is too arrogantly minded and I bet that he is not open and curious enough to merit a Nobel prize in the future as long as he lives. Can't help it
To venture in the physicist kingdom when I am incompetent (one of my sons is a ENS Ulm alumni and the gentle young man find it difficult to bear with incompetent people demonstrating anything with the support of misanderstanding pysics)
Provided the study is replicated by different teams of courseit Jim Al-Khalili, professor of physics (Surrey universty) told that if the Opera team physicists results about neutrons behaving in a way that contradict Eistein and followers he would eat his boxer short on TV.
The Opera team replicated their findings.
Of course it is not enough
-and there are not many teams with the needed infrastructures.
And under an Italian mountain (we call big stone in an Italian typical self-itonic way) that the receiving end of the neutrons is.
Italians are crooks but also less arrogant than anglo-saxons- you can't have it all can you?- Fernando Ferroni, président of the INFN responsable of the Opera detector, is talking with every needed restraint to the journalist.
This remained me that in Paris but in Italian diplomatic territory I was privileged to hear a very well known italian physicist- not F Ferroni saying that he was convinced ot the homepathic remedies physical activities-actually Pr Montagnier was invited to at that Conference.
Really very interesting paper, unfortunately the only way I can see forward is to rerun the experiment, since as you say, even the authors can't suggest a realistic mechanism...on the other hand, it does (assuming it isn't replicated) wonderfully demonstrate the perils of using p-values to inform treatment choices!
Off topic: On Monday Baroness Susan Greenfield is coming to speak at the Cambridge Neurological Society, who seem to be fawning over her...any ideas for choice questions to put the pressure on? The talk title is 'what is consciousness? How does it happen?'
Actually, I believe the effect, just not the interpretation. The results show us that being in a scanner environment is sufficient to cause a Placebo effect. Now my interpretation: the more "scientific" or "better" the scanner environment, the higher the Placebo effect. For example, wearning a white coat also increases the Placebo effect.
Subjects weren't asked about how realistic/scientific they thought the scanning was, but everyone who has been in a real scanner knows that it is quite different to a mock scanner.
would be wonderful if neuroscientists knew how to feel their feelings, feel their brainwaves .. so much research would go faster, and much would never be done
Anonymous18 November 2011 10:46
2 suggestions of line of questions:
1) Do you not think Baroness that we scientists have to lead the way in educating the lay people about the difficulties and cost to verify hypotheses and the differences between the two?
In those times of financial difficulties should not we the best scientists in the world be careful in not making the lay people believing that our hypothesis are scentically demonstrated findings without the need to do the research?
2) What worries me is that reading what you dare to tell the press wearing the bright armor of a british successful female British scientist the academic foreign communauties will think of us as arrogant bastards?
The choice depend really of the proportion of British in the audience.
NB: I love Cambridge be it only because Dr Davidson from the engeneering department wrote to whom it may concern a few years ago that my son Samuel Fulli-Lemaire an ENS physic student who spend 8month as a graduate under his supervision- was part of the 5% of the brightest of Cambridge students and would have a great future in research in physics if he chose so (the young man is doing a PhD in International law).
Anonymous 18 November 2011 10:46
I tried my little bit in answering to your cry for help for I dislike the dangerous woman public attitude -I do not know the person- not because I like what you wrote. I hated it.
1)You can also try "science sans conscience n'est que ruine de l'âme" Rabelais writer and physician century XVI."Science without conscience is only ruin of the soul". Do you not think baroness that even the best scientist in the world like yourself have to be careful not to manipulate lay people and deprive without scientific bases young people of theit right to play videogames without guilt until you have science to prove it harmful and for whom?
2) I didn't like your unscientifically dangerous and biased:
"since as you say, even the authors can't suggest a realistic mechanism...on the other hand, it does (assuming it isn't replicated) wonderfully demonstrate the perils of using p-values to inform treatment choices!
No sir, research in medecine is not fundamental research in mathematics and you need to be humbler in front of the results.
The human bodies ( minds included ) and souls are so complicated that you have to fairly - I wrote fairly- assess the methodology and then wait calmly for replications for any results whether they please your ideologies and beliefs or not.
If not you are closer to people teaching that the earth is flat or that Jesus drived a dinosaur that you think.
Martin 18 November 2011 11:14
If you do not trust NS writing why do you not check the original paper before making a fool of yourself?
NS post:
The sham was a "scan" in a decommissioned scanner. The magnet was off but they played recorded scannerish sounds to make it believable. Patients were blinded to group.
Besides, i never had to submit to the procedure myself but cli_nets an,d friends had never reported it to be a nice experience.
First people are usually very anxious of a bad result that will make them rush to check their will is up to date and suffer after that uncommonly painful medical procedures.
Then some are claustrophobic of sort and suffer great pain on that account.
A young bright aspie I advise to accept to participate to a trial in Lyon told me that he got a headhache and the noise was difficult to bear.
But of course if you think that a doctor in a white coat is not more pleasant and human than that kind of useful machinery...
@ivana Fulli, my fundamental belief is that extraordinary claims require extraordinary evidence.
1) Although groundbreaking discoveries are made and are necessary for scientific progress, they are not the norm. To use this specific example MRI has been used in countless patients, and as noted is at a signicantly lower magnetic field strength compared to TMS. It is not inconceivable that it is having some kind of effect, but given the small sample size I would be cautious before recommending fMRI as a new antidepressant therapy. My personal suspicion is that this will prove to be the ~1/20 trials predicted by the p value of 0.06 to provide an anomalous positive result. Of course it is a fascinating paper and I am quite interested to see if my suspicions are borne out.
2) Scientific research is, in theory at least, blind to fame. It should not matter what a person has done when they present new papers. Equally when they make unfounded assertions based on inaccessible, unpublished data, from a position of authority, their opinion is not necessarily valid. This is my concern with Baroness Greenfield's assertions about the neurological effects of electronic entertainment etc. This is in addition to the fact that she does this in broadsheet supplements, using examples (such as brain remodelling with electronic stimuli-any stimulus remodels the brain's architecture slightly, its how we react and learn) which will concern a lay person, whilst not adequately explaining her scientific concerns. It is for this reason I was asking for advice as to how to broach the subject after the talk.
3) I actually find it quite hard to follow your lines of reasoning between the typos and references to 16th century philosophers, so I apologise if I have got the wrong end of your argument!
Dear Ivana,
Thanks for your reply.
Here's the original citation from the paper:
"The participants of the [...] third group (sham or control group) experienced sham MR scans in which they were placed in a condition similar to actual MRI [...]."
and
"In this group, patients received sounds recorded either from T1 or DWI sequence sessions with similar duration and quality via the machine speaker."
And - of course - the study title says it's double blind.
Here' my point in other words. There's something problematic with double blind studies: Are experimental and Placebo conditions comparable? If you ask a person whether he/she was in the experimental or Placebo group, there are studies indicating these subjects can tell. One contributing factor is that the side effects are normally stronger in the experimental condition than the Nocebo effect, and the Placebo pill doesn't control for that difference. That means a better Placebo pill would control for everything that is different apart from the actual effect you are interested in).
This study is a nice example where this reasoning could apply. Maybe the Placebo effect was in a real magnet just larger. Reading the study, I believe so more and more. Everyone who has been in the scanner knows that playing sounds via the Intercom is nothing compared to receiving e.g. a DWI scan where your whole body may vibrate or an EPI.
Now of course you could argue that this doesn't disprove that there actually *was* an effect, but maybe we should let Occam's razor speak - and the wealth of studies investigating the effects of MRI on tissue, hardly ever showing anything at magnetic field strengths of 1.5T.
Martin: I agree, but the devil is in the details.
If the subjects had had a real MRI scan before, they'd have a chance of knowing it was fake. You're right that the shaking might tip them off, also I don't know how realistic these recorded sounds were.
But what if they'd never had one? It would be a lot harder to tell.
Also, the radiographer(s) "doing" the sham scans will have known it was a sham. Were they good actors?
This effect has been reported anekdotally at my imaging center, and also in a paper on bipolar depression, see
Am J Psychiatry. 2004 Jan;161(1):93-8.
Low-field magnetic stimulation in bipolar depression using an MRI-based stimulator.
But I am skeptical about the double blindness of the study, the MRI operators would surely have known if they were operating a mock scanner, and thereby possibly communicated that nonverbally to the subjects.
Exactly. Couldn't have been double blind.
Concerning the difference: Anyone who has had an MRI before should probably be excluded anyway. I'm just saying that faking an MRI is not such a good idea if you don't use a real mockup scanner where everything is identical (these are pretty expensive, though).
If you don't have such a scanner: Why not change the field of view to a region outside of the brain (can be done by using a head coil and a body coil and then just imaging the body in the control condition). This is like TMSing the center of the brain rather than using sham TMS. Not sure if it's possible to use both coils together, haven't done that.
Interesting paper about effects of lack of blinding in an antidepressant trial. I'll just list the conclusion: "Patient beliefs regarding treatment may have a stronger association with clinical outcome than the actual medication received, and the strength of this association may depend upon the particular combination of treatment guessed and treatment received".
Are any antidepressant trials truly double blind? If not, how do we know that current medications are really effective and that the drug/placebo difference is not just due to lack of blinding?
This study just needs a bigger N and better controls.
Anonymous 18 November 201
With Blogger you read first the signature and I suggest you stop reading what I write since I belong to the minority who either use an original pseudo or use their name.I wish you did te same.
Still if somebody could tell me how to stop the little window "leave your comment" to underline everything I write in red it will improve my typos.Not my command of English though.
@ivana Fulli, my fundamental belief is that extraordinary claims require extraordinary evidence.
My fundamental belief is that extraordinary claims require a rigorous but fair treatment
provided the results are not the result of fraud.
because what we lack most in neurosciences and clinical psychiatry are very bright and new ideas.
I still admire greatly Pr Gelder but biological psychiatry has let the patients down and open an avenue for Big Pharma marketing strategies.
Martin 18 November 2011 15:13
Many thanks to you indeed sweet Martin
I cannot afford to look over the paywall of the Brain Imagination and Behavior or whatever is called that Journal of yours.
In Finland health authorities have expressed concern about the huge amount of money clinicians would have to paid in subscrition to medical scientific journal to keep their knownledge in shape.
Art
Crooks wait for the results and manipulate it until they find something to publish.
I was privileged to benefit from a little teaching of stats at Paris VI University in my youth and was told that.
1)Can't you read that the Harvard )guys had found a ludicrious way to attack a plant remedy -not on his homeopathic form - to please their masters?
http://projects.propublica.org/docdollars/
I was told also by great mathematicians and human beings:
Great discoveries do not need help from stats.
By the way, I do not know why Pr Henri Laborit and my old maste P Pierre Deniker didn't get a Nobel prize of medecine for antipsychotic drugs discovery.
Do not despise antipsyhotics until you met a young man suffering hallucinations of painful rotting of his bones (the bones having been dead before the rest of his body delusion) happy to have gain 30 kgs of weight among other side effects because the pain from the roting bones was unbearable.
In my youth I was blessed with excellent teaching thanks to my father Enzo Fulli. A barrister (and former communist mayor for decades who did not enrich himself) who sent me to Paris to escape the far left teaching I was receiving at La Sapienza University.
My father thought I was the brightest of his children (with two boys) and might have a bright political career ahead of me.How wrong could he be that old left feminist of sort!
And that far left beautiful boys might jeopardize it because I went to university two years in advance and I was only 17 when I became interested in students protests.
I always wanted to be a doctor and not a politician anyway but can't blame my father since it was hard for me when my sons gave up physic and engineering.
2) Or do you belong to the gestapo against free scientific thinking driven only by personal ambition and ego with anger to spare like I bet Anonymous 18 November 2011 10:46 pay allegeance to?
Dear Art
you also wrote:
"Are any antidepressant trials truly double blind?"
Easier to design double blind studies when you test one antidepressant of the same family of side effects against another.
But: You want to know if the side effects and direct and hiden monetary cost of the pill are worth it do you not?
Answer: testing against placebo.
No ethic problem like say in a placebo group controlled study of a new antibiotic treatment of syphilis on the long term.
Because so many people stop to take their antidepressants in the real life and thoses studies with placebo group suggest that antidepressants are not very superior to placebo.
And
Big Pharma runs the show so far in antidepressant published trials.
Americans elected a president who did some laws against the worst sins of Big pharma: marketing out of so called proven effect and indications.
Henceford trials well designed are needed.
I was in a trial for depression and part of the protocol was a brain MRI. I still remember how great I felt after the MRI. I was totally relaxed and happy. Didn't last long but I would not say no to another.
Anonymous 21 November 2011 05:19
Is it impolite to ask you to ask you:
How you felt before it and about it?
Where you in particular afraid that a canbcer or something abnormal might be diagnosed?
(I would not ask such a closed question in a clinical setting but we are discussing as friends)
If this study has been e published have you read it or will you it is to to be published in future?
What would you think about designing a study for other voluteers with professonals to help them with your experience ?
A number of studies point to magnetic fields(esp pulsed fields) having potential for depression treatment. There is something very puzzling going on here because other studies find benefits for dementias and Parkinson's.
http://www.medicalnewstoday.com/releases/237965.php
John
The Nobel Laureat who was bold enough to order his technicians to look for a virus in a new worrying acquired immunity deficit illness because he was convinced it must be viral has been registering and studying the magnetic effect of homeopathic remedies.
Did you ever do a search on older/other studies. I remember there were similar results out of Harvard I believe, a few years ago.
Skeptics should always double check their own assumptions ;)
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