Resolving the Brainstem Contributions to Attentional Analgesia.

Previous human imaging studies manipulating attention or expectancy have identified the periaqueductal gray (PAG) as a key brainstem structure implicated in endogenous analgesia. However, animal studies indicate that PAG analgesia is mediated largely via caudal brainstem structures, such as the rostral ventromedial medulla (RVM) and locus coeruleus (LC). To identify their involvement in endogenous analgesia, we used brainstem optimized, whole-brain imaging to record responses to concurrent thermal stimulation (left forearm) and visual attention tasks of titrated difficulty in 20 healthy subjects. The PAG, LC, and RVM were anatomically discriminated using a probabilistic atlas. Pain ratings disclosed the anticipated analgesic interaction between task difficulty and pain intensity ( p < 0.001). Main effects of noxious thermal stimulation were observed across several brain regions, including operculoinsular, primary somatosensory, and cingulate cortices, whereas hard task difficulty was represented in anterior insular, parietal, and prefrontal cortices. Permutation testing within the brainstem nuclei revealed the following: main effects of task in dorsal PAG and right LC; and main effect of temperature in RVM and a task × temperature interaction in right LC. Intrasubject regression revealed a distributed network of supratentorial brain regions and the RVM whose activity was linearly related to pain intensity. Intersubject analgesia scores correlated to activity within a distinct region of the RVM alone. These results identify distinct roles for a brainstem triumvirate in attentional analgesia: with the PAG activated by attentional load; specific RVM regions showing pronociceptive and antinociceptive processes (in line with previous animal studies); and the LC showing lateralized activity during conflicting attentional demands. SIGNIFICANCE STATEMENT Attention modulates pain intensity, and human studies have identified roles for a network of forebrain structures plus the periaqueductal gray (PAG). Animal data indicate that the PAG acts via caudal brainstem structures to control nociception. We investigated this issue within an attentional analgesia paradigm with brainstem-optimized fMRI and analysis using a probabilistic brainstem atlas. We find pain intensity encoding in several forebrain structures, including the insula and attentional activation of the PAG. Discrete regions of the rostral ventromedial medulla bidirectionally influence pain perception, and locus coeruleus activity mirrors the interaction between attention and nociception. This approach has enabled the resolution of contributions from a hub of key brainstem structures to endogenous analgesia.