Tuesday, July 26, 2011

Exposing the Epipenomenon with TMS?

Nowadays it is proper for the neuroscientist to be slightly embarrassed and faintly apologetic about his or her fMRI researches. One should strike the same attitude about fMRI as one does about the British rock band Coldplay -- I know you like them, you know I like them, we all know we like Coldplay, but we're frankly a little bit ashamed about it. It is somehow tacky to like Coldplay.

There is a ready antidote for any researcher that wants to show everyone that he or she is not fooled by the easy listening schlock of fMRI, that he or she is a reluctant and skeptical user of that pretty little correlative toy. The ready antidote is transcranial magnetic stimulation -- TMS. TMS is tough. TMS is no-nonsense. TMS gets the job done -- and with no pictures. TMS tells you what is necessary, and it tells you about what is causal. And here's the kicker: TMS calls the bluff of fMRI, it holds fMRI to account, it cuts right through fMRI's bull. And TMS has nothing but contempt for Coldplay.

Here's how it often works with TMS. You've done a few fMRI studies and you keep showing that a region in the parietal lobe activates when subjects are engaged in a particular cognitive activity. It's not a one-off finding. You've used different paradigms and control conditions and this parietal area keeps popping up, it keeps stubbornly activating. You're a careful researcher. You've written the papers, you've presented the data at meetings, and your colleagues are impressed -- but not convinced. How do you know this region is "necessary" for the cognitive activity, they ask? How do you know it's not some sort of "epiphenomenon"? It's fMRI, after all.

At this point, you know what must be done. You know you have to zap your parietal area with TMS while subjects perform your paradigm. If you disrupt your parietal area with TMS and performance on the task suffers, then you've closed the loop. You've shown that your region is necessary, that it's causal, that it's for real, that it's not a stinking epiphenomenon. Case closed, The end.

That's the formula, that's the pattern, and that's how it usually unfolds. In other words, and somewhat paradoxically: TMS always has fMRI's back. TMS tells you what you thought you already knew. You never thought your parietal area was an "epiphenomenon", you thought it was doing something legitimately useful. Thanks for confirming for us what we already fervently believed, TMS!

But hang on. How come you never hear this story (this inferential pattern)?:

"After six fMRI studies implicating our parietal area in cognitive activity X, we performed a series of TMS studies designed to see whether our region was really necessary. The results showed no effect of TMS at the stimulation site during the critical task period, contrary to our expectations. We therefore conclude that activity in our parietal region is entirely epiphenomenal, and we begin our search anew for the neural basis of cognitive activity X".

Follow me here. If TMS is what we need to expose fMRI's empty and functionless epiphenomena for what they are -- technicolor gewgaws of no cognitive import -- then why are we never treated to hypothetical passages like the one quoted above? If we can't cite examples in the literature (perhaps such examples do exist, but I have just never come across them?), then it suggests that TMS, at least in the way it is being used, is not a really the no-nonsense tough guy we thought it was. Indeed, TMS is a rubber stamp for fMRI. You can can count on it never to expose an epiphenomenon. Don't worry, your epiphenomenon is safe with TMS.

Now, before you accuse me of being hard on TMS, let me say, I like TMS, I think it is a marvelous tool, I'm proud to call TMS a friend. But we need to consider why it rarely if ever exposes fMRI's ghoulish epiphenomena.

Reason #1. Exposing the epiphenomena involves proving the null. If zapping the parietal region has no effect on behavior, then the null hypothesis (e.g. epiphenomenon) is not rejected. The problem then is that conventional statistical inference is all about rejecting the null, and anything else is just a "negative finding". And negative findings are radically less likely to be published than positive ones. So, when it comes to exposing the epiphenomena, TMS has its hands tied. It couldn't expose an epiphenomenon even it wanted to -- it could only "fail to the reject the null hypothesis of an epiphenomenon". And who wants to do anything that sounds half as tedious as that?

Reason #2. One may speculate that fMRI epiphenomena (we're talking about replicable, reliable epiphenomena) are in point of fact pretty rare. In other words, if a region is reliably active during some cognitive paradigm, it's much more likely than not that the region is actually doing something functionally important, than that it is doing something useless and irrelevant to the task at hand. So when you zap the region with TMS, no surprise, performance tends to suffer.

Reason #3. Scientific orientation. Due to reason #1, you have to try pretty hard to expose an epiphenomenon with TMS. You have to be gunning for it. You're probably going to have to use unconventional Bayesian statistics to prove the null. How many researchers have undertaken a TMS study with the a priori hypothesis that the region that they were stimulating is only epiphenomenally involved in the cognitive activity required to perform the task at hand? Not many, I'd venture to say.

To sum up, I think TMS is a wonderful tool, and there is some first rate TMS research going on. The future is bright for TMS. But is it an fMRI "epiphenomenon-killer"? It doesn't seem to be. This is because killing an epiphenomenon requires proving the null; because epiphenomena maybe aren't that prevalent or at any rate clear-cut to begin with; and because if you really want to be an epiphenomenon hunter, you have to want it in earnest. You're gonna have to get all Bayesian if at the end of the day you want to be standing triumphantly atop a giant epiphenomenal carcass, with your TMS spear stuck deep in its epiphenomenal guts.


13 comments:

  1. Hi Brad,

    Just thought I'd give an example or 2 of TMS exposing epiphenomenonal activation.

    Ventral occipitotemporal cortex (vOT)  is a region that is robustly activated by visual recognition tasks according to dozens of PET and fMRI studies so is a good candidate for testing for a causal relation between activation and reading ability.  Indeed, when we TMS'd (vOT) during a visual lexical decision task we found that response times to words are significantly slowed and we replicated this in three different experiments, using both repetitive TMS and double pulses (see link below). In contrast, TMS had no effect on pseudowords despite the fact that if anything,  pseudowords produce greater vOT activation than words.  Again, we've replicated that finding twice (and in a third, as yet unpublished paper) and we know of two other labs who have also seen this (once with double pulse TMS and once with 1 Hz stimulation). So despite the fact that vOT is consistently activated by words and pseudowords in imaging studies, the area is not necessary for pseudoword reading  - i.e. the activation reported there is epiphenomenal.

    In addition, we also found that although lateral occipital complex (LOC) is robustly activated by words and pseudowords, TMS to the area does not disrupt responses.

    Thus while it may well be the case that TMS studies generally find  that fMRI/PET activation is not epiphenomenal (I guess it would be fairly surprising if lots of brain activity was causally unrelated to the task), it is certainly not always the case.

    http://www.mitpressjournals.org/doi/abs/10.1162/jocn.2009.21207

    Keith

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  2. Interesting post. Re 1) I suspect people would be reluctant to publish results showing that the blobs that they'd identified in previous fMRI studies were epiphenomena! But if there was a controversy over whether a certain area was causal or not, you'd expect that people on both sides of the debate would be trying to use TMS to show that the other side's blobs weren't causal.

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  3. It may be worth noting that despite this selection bias, some groups have published null-TMS effects in the context of their own fMRI activations. So in addition to the ones Keith mentioned, Brad Postle's group has shown consistent activation in DLPFC and superior parietal lobes for memory-guided responses but in a recent TMS study, they found that rTMS only had a behavioural effect when applied to DLPFC and not to SPL. If I recall correctly, the argued that the SPL activity seen in the imaging studies was indeed epi-phenomenal.

    Anyway, I agree with Brad's original post that even though TMS offers the opportunity to expose the epi-phenomenal, this rarely happens in practice. Partly this is a function of all the reasons mentioned and it also reflects the relative paucity of TMS labs in the US (thanks, FDA!). Presumably now that TMS is becoming increasingly available, a great number of studies will begin to distinguish between causal and epi-phenomenal activations.

    Hamidi M, Tononi G, Postle BR. (2009) Evaluating the role of prefrontal and parietal cortices in memory-guided response with repetitive transcranial magnetic stimulation. Neuropsychologia. 2009 Jan;47(2):295-302.

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  4. Hi, nice post. I just want to point out that there is a published opinion piece on exactly this issue:

    Neurosci Biobehav Rev. 2011 Jan;35(3):871-7. Epub 2010 Oct 16.
    Null results in TMS: from absence of evidence to evidence of absence.
    de Graaf TA, Sack AT.

    could be of interest

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  5. Keith,

    Sorry for the long delay in responding to your comment. I did have a chance to look over your paper and it stirred so many thoughts that it seemed to require a blog post of its own (perhaps forthcoming ....)

    In short, I think you've wounded an epiphenomenon, which is in fact quite an achievement. There are, however, questions which I may expand on more fully later. Here are a few.

    1. You show that TMS of vOT causes a slowing of RTs for low frequency words, but not high frequency or pseudowords. This leads to the conclusion that vOT activity is epiphenomenal for the latter two cases but necessary for the first case. In your paper you take a stab (I realize a tentative one) at an explanation that argues that BOLD activity in vOT for pseudowords reflects a failure of word recognition (pg. 747). TMS does not have an effect on the area because it fails to disrupt the failure!

    But why doesn't it? It seems like it really ought to. In fact, if "failure" is a kind of signal of non-wordness, than TMSing the region that provides the failure signal should play havoc with lexical decision.

    2. I would very much like to see a dissociation. Is there a ventral occipital region that when stimulated with TMS does slow pseudoword rejection? I have not reviewed the literature, perhaps this has been demonstrated.

    3. It will be important to pinpoint how TMS is affecting the RT distribution across conditions. For instance, you used median RTs for all analyses and this may have prevented you from detecting TMS effects on the skewness of the RT distribution. An Ex-Gaussian or diffusion model type analysis would allow you to attribute TMS effects to different parameters of a distribution, for instance in the case of the diffusion model, the drift rate, the response boundary and non-decision time. See Ratcliff, 2004 Psychological Review. You will need many trials for this, but perhaps you can pool data across studies.

    See also Palmer, EM. "What are the shapes of response time distributions in visual search?", 2011

    thanks for the comment!

    Brad

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  6. @Neuroskeptic,

    " I suspect people would be reluctant to publish results showing that the blobs that they'd identified in previous fMRI studies were epiphenomena!"

    You're probably right. Has no one the courage to "kill their darlings" in cognitive neuroscience?

    "Sit down before fact like a little child" -- Thomas Henry Huxley.

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  7. @Joe,

    thanks for the comment. Yes, Postle hasn't been afraid to gun for an epiphenomenon.

    Also, the paucity of TMS labs probably does indeed have them "outgunned" when it comes to directly competing with fMRI.

    We may also need TMS specialists, researchers who are not also fMRI enthusiasts and therefore have no "pet regions" to protect.

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  9. Just thought I'd chime in on the pseudoword effect in vOT. One widely held assumption in recognition literature is that participants use an internal temporal criterion for making 'not recognised' responses. This is because recognition tasks involve matching some perceptual evidence to a memory representation. If this cannot be achieved within some arbitrarily set temporal criterion, then a 'non-word' response is made. So you would not expect TMS to effect 'non-word' responses because this judgement isn't really based on any kind of perceptual processing. Assuming that TMS would have an effect on pseudoword judgements is odd since it suggests that we have a separate memory store of all possible pseudowords!

    From my own face recognition studies it seems to me that people use the stimulus offset as the signal to make a 'not reconised judgement'. I've played around with a few different stimulus durations and it seems like presenting faces longer doesn't really change correct recognition reaction times, but can push back the correct 'not recognised' reaction times.

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  10. kiisudankan: "Ventral occipitotemporal cortex (vOT) is a region that is robustly activated by visual recognition tasks according to dozens of PET and fMRI studies"

    Hmm.

    "We found that increased left lateralization for words relative to pictures was the consequence of reduced activation in right vOT rather than increased activation in left vOT."

    http://www.ncbi.nlm.nih.gov/pubmed/21994390

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  11. fMRI has come under intense scrutiny in autism research. You can follow the reasons and my own tongue in cheek comments on fMRI at:

    http://sfari.org/news-and-opinion/news/2012/movement-during-brain-scans-may-lead-to-spurious-patterns

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