The placebo effect unlocked: How the brain tricks itself into pain relief through a newly discovered pain pathway

Good news! Are we finally understanding the placebo effect better! What opportunities beckon to treat pain in the future?

"... Publishing in Nature, researchers ... discovered a pain control pathway that links the cingulate cortex in the front of the brain, through the pons region of the brainstem, to cerebellum in the back of the brain. ...
then showed that certain neurons and synapses along this pathway are highly activated when mice expect pain relief and experience pain relief, even when there is no medication involved. ..."

"... They found that the large, branch-like Purkinje cells in the cerebellum replicated the activity seen in the initial area of neuronal excitement, in the ACC [anterior cingulate cortex]. It confirmed that the cerebellum had a key part to play in pain messaging. ..."

From the abstract:

"Placebo effects are striking demonstrations of mind-body interactions. During pain perception, in the absence of any treatment, an expectation of pain relief can reduce the experience of pain, a phenomenon known as placebo analgesia. However, despite the strength of placebo effects and their impact on everyday human experience and failure of clinical trials for new therapeutics, the neural circuit basis of placebo effects has remained elusive. 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. Transcriptomic studies of Pn neurons revealed an abundance of opioid receptors, further suggesting a role in pain modulation. Inhibition of the rACC→Pn pathway disrupted placebo analgesia and decreased pain thresholds, whereas activation elicited analgesia in the absence of placebo conditioning. Finally, Purkinje cells exhibited activity patterns resembling those of rACC→Pn neurons during pain relief expectation, providing cellular-level evidence of a role for the cerebellum in cognitive pain modulation. These findings open the possibility of targeting this prefrontal cortico-ponto-cerebellar pathway with drugs or neurostimulation to treat pain."

The placebo effect unlocked: How the brain tricks itself into pain relief In a fascinating discovery, scientists have pinpointed what happens in our brains when we're expecting pain relief but are given a placebo, unknowingly, instead. It not only confirms 'the placebo effect,' but offers clues into how powerful the mind is in mitigating physiological functions such as pain.

Scientists Discover Brain Circuits for Placebo Effect Pain Relief (original news release) ... research published in Nature reveals a new pain control pathway from the cortex to the cerebellum crucial to placebo analgesia – when the expectation of pain relief leads to pain alleviation without a therapeutic intervention, such as with a drug.

Neural circuit basis of placebo pain relief (no public access)

Along the 'placebo pathway', the cells in yellow in the pons (left) receive input from the green cells in the cingulate cortex (rACC, right), with subdivisions Cg1 and Cg2