Brain Area Activation May Reproducibly Predict Placebo Pain Effect Via fMRI: an fMRI Study Done RIght

One of my criticisms in past years of fMRI has been the lack of reproducibility of most published fMRI studies. The excessive type I statistical errors (false positives) in the fMRI literature may reflect the fact that the statistical N in such studies usually is linked to the number of voxels on the fMRI software used in such studies (often tens of thousands) rather than the number of subjects studied (generally less than 20, sometimes less than 5). Similar concerns come up with EEG analysis, where the N may reflect thousands of individual voltage measures over time in a few subjects, whereas the proper N should be the number of persons studied, often less than 10.

The study below, published in Plos One Biology, may have accomplished a rare confirmation of their hypothesis, one that might, if done consistently, remove most of the remaining type I errors from fMRI studies yet to be published: they looked at one group of placebo responders, got their data on which part of the brain changed with placebo pain relief, and then verified that area on another subject pool.

If a separate group of researchers verify the same area as correlated with placebo pain relief, this would be very strong evidence that the placebo response in pain correlates with activation of the right midfrontal gyrus. This is an area previously linked to executive function. What does executive function have to do with pain? That is unclear. According to Japee et al at the NIH, "The right middle frontal gyrus (MFG) has been proposed to be a site of convergence of the dorsal and ventral attention networks, by serving as a circuit-breaker to interrupt ongoing endogenous attentional processes in the dorsal network and reorient attention to an exogenous stimulus." So, perhaps this part of the brain can under some circumstances prevent us from paying attention to our pains.

Note that although the brain region (the right mid-frontal cortex) involved in placebo pain response seems to have been confirmed on the second study, the effects of duloxetine being different in the different study subjects would have to be verified in a third, still not done study.

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ABSTRACT

Brain Connectivity Predicts Placebo Response across Chronic Pain Clinical Trials

Pascal T├ętreault, Ali Mansour, Etienne Vachon-Presseau, Thomas J. Schnitzer, A. Vania Apkarian , Marwan N. Baliki

Published: October 27, 2016http://dx.doi.org/10.1371/journal.pbio.1002570

Placebo response in the clinical trial setting is poorly understood and alleged to be driven by statistical confounds, and its biological underpinnings are questioned. Here we identified and validated that clinical placebo response is predictable from resting-state functional magnetic-resonance-imaging (fMRI) brain connectivity. This also led to discovering a brain region predicting active drug response and demonstrating the adverse effect of active drug interfering with placebo analgesia. Chronic knee osteoarthritis (OA) pain patients (n = 56) underwent pretreatment brain scans in two clinical trials. Study 1 (n = 17) was a 2-wk single-blinded placebo pill trial. Study 2 (n = 39) was a 3-mo double-blinded randomized trial comparing placebo pill to duloxetine. Study 3, which was conducted in additional knee OA pain patients (n = 42), was observational. fMRI-derived brain connectivity maps in study 1 were contrasted between placebo responders and nonresponders and compared to healthy controls (n = 20). Study 2 validated the primary biomarker and identified a brain region predicting drug response. In both studies, approximately half of the participants exhibited analgesia with placebo treatment. In study 1, right midfrontal gyrus connectivity best identified placebo responders. In study 2, the same measure identified placebo responders (95% correct) and predicted the magnitude of placebo’s effectiveness. By subtracting away linearly modeled placebo analgesia from duloxetine response, we uncovered in 6/19 participants a tendency of duloxetine enhancing predicted placebo response, while in another 6/19, we uncovered a tendency for duloxetine to diminish it. Moreover, the approach led to discovering that right parahippocampus gyrus connectivity predicts drug analgesia after correcting for modeled placebo-related analgesia. Our evidence is consistent with clinical placebo response having biological underpinnings and shows that the method can also reveal that active treatment in some patients diminishes modeled placebo-related analgesia.

Trial Registration ClinicalTrials.gov NCT02903238

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