I’ve written a number of times over the years here about the placebo effect, and needless to note there’s still a lot more to be said. This new paper is stark evidence of that! It notes that there is evidence that (at least in mice) that the dopaminergic mesolimbic pathway is known to help modulate immune function, but is also involved in expectations of positive outcomes. This raises the possibility of a direct neural/biochemical linkage that might be behind some placebo effects, and the authors have had a chance to put that idea to the test.
The experimental design is quite something. They’re looking for increased activity in the ventral tegmenal area (VTA) as well as the bilaterial nucleus accumbens region of the brain, and this is determined by functional MRI imaging. But the volunteers in this trial got to watch the imaging, and got to practice strategies in increase that activity. This feedback could be any combination of “perceptual, affective, cognitive or meta-cognitive mental contents”, basically whatever did the job in the imaginative-positive-thoughts area, and each participant worked out whatever strategy was best to increase this dopaminergic mesolimbic activity.
There were two control groups: one of them used the fMRI feedback to learn to increase activity in some other brain region that had nothing to do with the mesolimbic pathways, and another group didn’t do the fMRI feedback practice at all. After the last training session/evaluation, all participants received a hepatitis B vaccine, and all were evaluated after 14 and 28 days to see what the antibody response was. A subset of patients were also evaluated after three months as well.
One potential complication was that even the people who weren’t specifically training up on the dopaminergic pathways might be getting some benefit there, because the entire training process is an anticipation/reward paradigm. Another variable is that some people simply don’t respond to the Hep B vaccine (there turned out to be seven of these, evenly distributed among the groups, and they were excluded from later analysis).
The results are quite interesting: the patients who learned to upregulate their VTA activity really did show enhanced response to the vaccine. They could be distinguished from the ones who did mostly upregulation of nucleus accumbens activity, and also from those who learned to upregulate activity in other brain regions not having to do with the dopaminergic/mesolimbic system. The people in the latter group who did show increased VTA activity anyway also showed better vaccine response, interestingly. The authors also tried to find other differences between the people who upregulated VTA, such as testing them for behavioral measures of response to incentives and approach/avoidance tendencies, but nothing really showed up by these measures. The authors:
“Altogether, our study demonstrates that upregulating the VTA with repeated fMRI-NF training is associated with a stronger post-vaccination immune response in humans. Considering the lack of evidence for alternative interpretations, our findings suggest a top-down brain-immune regulation mechanism, similar to that previously described in rodents”
The authors suggest that a follow-up study could concentrate more on specific VTA activation rather than other brain regions (in light of their results here), but also note that there are other physiological and psychological factors that they could have missed that could have affected the results. (One of these is the involvement of the VTA in wakefulness and the effects of sleep duration and habits on immune response). The effect of other immune challenges would also be very useful to check, and of course all of these would be better run on a larger scale to get even better statistical power.
But on the face of it, this does look like confirmation of an effect that already seems well-documented in rodents and now appears to extend to humans. It appears that our immune systems are to some degree cross-wired with our moods and specifically our expectations of rewards and positive outcomes. That at least is one physical, neurochemical connection between the world of thoughts and emotions and the (seemingly unrelated) world of B cells and antigen display. What others are out there?