Prepare to be weirded out a bit. We’re going to talk about the placebo effect again – actually, we’re going to talk about its evil twin, the nocebo effect. In the same way that a placebo is an inactive/nonexistent agent that people think is doing them good, a nocebo is one that people believe is doing them harm. For example, in every double-blinding trial of a new drug, there will be people who drop out of the study because of side effects. But when these patients are unblinded, some of them will turn out not to have been taking the drug. You can see this in the figures at the end of the trial, when the major side effects are reported, and it’s then mentioned whether these were significantly different than the control group. Classic nocebo symptoms are headache, tiredness, digestive/stomach problems, and hard-to-localize pain, but there are others. To complicate matters, any of these can also be a real side effect of a real drug as well.

It’s already known that the placebo effect is stronger when people believe that they’re taking a more expensive treatment. This is exactly the same effect, you’d have to think, as the tendency to rate an unknown wine as more enjoyable when it’s presented with a higher price tag (and if you think that wine merchants – and restaurants – are unaware of that latter effect, you need to adjust your priors, as the Bayesians say). So you have to wonder if the nocebo effect also strengthens as a result of perceived price, and this new paper says that it does.

The authors (from Hamburg, Colorado, and Cambridge) have developed an NMR imaging technique that lets them monitor the cortex, brainstem, and spinal cord simultaneously, which covers a lot of the pain-sensing machinery. They then took a skin cream with no pharmaceutical activity at all and packaged it two different ways – one batch went into a cheaper-looking box with generic orange printing, and the other went into a fancier-looking blue box. Preliminary studies showed that people (not in the later study) estimated that the former definitely cost less than the latter, and in the actual study, they reinforced that by references to a “cheap” and an “expensive” cream for the two test groups. Each group also had a control skin cream, but in reality, all three of them were the same.

The subjects were told that they were testing a cream that was prescribed for dermatitis, but which had been reported to make people more sensitive to heat pain sensation, and that the purpose of the study was to follow up on reports that the two creams produced different levels of this effect (but not in which direction). They then applied the “cheap” or the “expensive” cream to a patch on the patients’ arms, along with another patch of the “control” cream, and then used a heat-generating skin testing device to establish each patient’s scale of pain sensation (low, medium, and high). The patients were then told that they would receive that same amount of heat on each patch of skin, test and control, but in reality they got more heat on the “test” patch, to reinforce the idea that the creams could produce heat sensitivity. In the next phase of the experiment, on a later day, the same test-and-control patch method was used, and the patients went into the NMR scanner. The heat-sensation scale was checked again while no imaging data was collected, then they went in for imaging and (supposedly) comparisons between the skin patches. In reality, they were getting exactly the same medium level of heat in each case.

And sure enough, the people who thought that they were getting the expensive cream showed significantly more pain sensation in the “treated” patches than the people who thought that they were getting the cheap stuff. (The belief is that people tend to associate the expensive one with newer, more advanced, and more potent drugs, while the cheaper substance are older and generic). The fMRI data were quite interesting. They identified a number of regions of activity, which corresponded well with previous imaging studies on pain sensation. The periaqueductal gray (PAG) showed a significant difference in the “expensive” cream treated patients as compared to the “cheap” stuff. Some regions in the frontal cortex and amygdala also showed differences. It turns out that the regions involved in the nocebo effect are quite similar to the ones involved in the placebo effect in earlier studies, suggesting that the same mechanisms are at work, in the end. The PAG, for example, is activated whether people think their pain is getting worse or getting better under the influence of a nonexistent treatment. The rostral anterior cingulate cortex shows a similar pattern – it’s involved in a continuum of activity whether there’s a perceived positive or perceived negative effect going on. And the level of that activation apparently correlates with the perceived expectation of strength or value, so if you’re looking for where in the frontal cortex this gets calibrated, that’s a strong candidate.

I’m reminded of studies of consumer preference. When I was doing my post-doc in Germany, I noticed that (at least in that era) that a surprising number (at least to me) of German shampoos were clear, or at most lightly colored while still transparent. That seemed to be marketing to a preference for purity – this clear, pure substance is just what you need to achieve cleanliness. That was as opposed to the many opaque, opalescent shampoos on the market in the US, which seemed to be holding out the promise of “Yeah, there’s something in there, this is some distinctive and powerful stuff”. Perhaps that also had to do with promises of cleaning power versus other effects on the hair, allegedly “feeding” it, adding “body”, and so on. I don’t expect to see any fMRI studies of shampoo any time soon, but if an easier technique develops to monitor brain activity, I wouldn’t rule it out, either.

That’s because this sort of study is still only the beginning. Neuroscience, as many have predicted (with varying levels of anticipation and fear) is going to continue to mess with our expectations and beliefs about consciousness, decision-making, and free will, and the better the tools we come up with to study and understand brain activity, the more thoroughly, I predict, will we be, well. . .unnerved.