Research with Mice May Explain How the Placebo Effect Works
The placebo effect is the best-known effect in medicine: We get better from an illness in part because we think we will. That’s not “just imagination”; it is proven by the best double-blind randomized clinical trials. When testing a new medication, researchers must subtract the placebo effect from their overall results in order to assess the medication’s true efficacy.
But how the placebo effect works in humans is something of a mystery. For example, it works even when patients know it’s a fake. And it may be getting stronger as researchers learn to manipulate it more effectively
Unexpected Results
A recent development from an experiment on mice sheds a bit of light. A group of researchers at the University of North Carolina, Chapel Hill, found circuits in the brain that unexpectedly play an role:
… researchers at the UNC School of Medicine — with colleagues from Stanford, the Howard Hughes Medical Institute and the Allen Institute for Brain Science — found a pain control pathway in the brain.
The researchers then showed that certain neurons and synapses along this pathway are highly activated when mice expect pain relief, with the mice experiencing pain relief even when no medication is involved.
MARK DEREWICZ, “BRAIN CIRCUITS OFFER PLACEBO EFFECT PAIN RELIEF,” UCCCH RESEARCH, JULY 31, 2024
How did the researchers know what the mice were expecting? As Adam Kovac explains at Gizmodo,
In their study, published this week in the journal Nature, the scientists trained mice by placing them in two connected chambers for a week. For the first few days, the floors of both chambers were pleasantly warm. Then, the floor of one chamber was made painfully hot, but the mice were able to seek shelter from the pain by scampering to the second chamber. Finally, on the last day, the floors of both chambers were made painfully hot. The mice, having been conditioned to expect relief upon reaching the second chamber, experienced some pain relief by virtue of the placebo effect. Upon reaching the second chamber, and despite it being just as hot as the first chamber, the mice displayed fewer behaviors associated with being hurt, such as jumping and paw licking.
ADAM KOVAC, “HOW PLACEBOS TRICK THE BRAIN INTO REDUCING PAIN,” GIZMODO, JULY 23, 2024
Not Nice to Mice
This sounds like cruelty to animals, yet something of value was learned. The mice had been injected with a virus that caused brain areas that experienced a change to light up. These were areas the researchers had not expected to be involved in pain control.
As they put it in their Abstract,
Here, we show that analgesia from the expectation of pain relief is mediated by rostral anterior cingulate cortex (rACC) neurons that project to the pontine nucleus (rACC→Pn), a pre-cerebellar nucleus with no established function in pain. We created a behavioral assay that generates placebo-like anticipatory pain relief in mice. In vivo calcium imaging of neural activity and electrophysiological recordings in brain slices showed that expectations of pain relief boost the activity of rACC→Pn neurons and potentiate neurotransmission in this pathway.
CHEN, C., NIEHAUS, J.K., DINC, F. ET AL. NEURAL CIRCUIT BASIS OF PLACEBO PAIN RELIEF.NATURE (2024). AN ACCELERATED PREVIEW OF THE PAPER IS OPEN ACCESS
Of course, with humans, things are likely to be more complex than with mice. The mice had to be placed in a very simple painful situation in order to trigger a placebo effect. With humans, it is often just a matter of communicating orally that “This [sugar pill] works!” But identifying new brain circuits that are changed by the expectation alone — the neural correlates of expectation — may help produce more effective pain control for both human and animals.
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