Somatotopic organization of brainstem analgesic circuitry.

The lateral periaqueductal gray (lPAG) evokes somatotopically appropriate defensive behaviors, including an analgesia that allows the animal to escape or fight unimpeded. Whether the lPAG and its descending targets are also able to drive somatotopically specific analgesic responses is not known. In this work, we performed ultrahigh-field functional magnetic resonance imaging of the lPAG in 93 participants during a placebo analgesia paradigm performed at different body locations. We found that analgesic responses are somatotopically organized in the lPAG and its descending outputs to the rostral ventromedial medulla. These data show that the PAG can regulate analgesic responses in a highly spatially localized manner and thus has the ability to mediate body site–selective control over pain. Editor's summary: The brain mechanisms underlying pain modulation remain to be fully elucidated. Crawford et al. used functional magnetic resonance imaging in humans to explore neural activity in the periaqueductal gray brain area, a key region involved in pain processing, and tested the organizational principle of placebo analgesia (see the Perspective by Moayedi and Atlas). The authors exposed participants to heat stimuli of varying intensities on the face, forearm, and leg with or without the application of a placebo analgesic cream and showed that placebo analgesic response was somatotopically (spatially) organized. The results provide insights into how the brain can enable precise and localized pain relief in order to optimize defensive responses. —Mattia Maroso INTRODUCTION: One of our most important survival features is the ability to detect danger and to confront or escape from it. Fight-or-flight behaviors can be instantly initiated by painful stimuli and are mediated by a specific area in the core of the brainstem, the periaqueductal gray matter (PAG). An important aspect of these behavioral reactions is the dampening of the initiating painful stimulus—i.e., analgesia—so that once fight-or-flight behaviors begin, they can be executed without the interference of pain. Experimental studies have shown that the PAG is somatotopically organized—one part receives pain inputs from the face and produces fight behaviors, whereas another part receives pain inputs from the body and produces flight behaviors. Whether the PAG is also organized in this manner with respect to analgesia is not known. If it is, it would be possible to activate specific parts of the PAG to produce pain relief in a restricted part of the head or body. One way to explore the organization of PAG analgesic responses is using a placebo analgesia paradigm. RATIONALE: By conducting a placebo analgesia conditioning paradigm using a falsely labeled and described cream, 93 pain-free participants believed that this cream could reduce the intensity of painful heat applied to either their face, arm, or leg. In reality, this "lidocaine" cream was a placebo, and the temperature of a thermode was surreptitiously lowered whenever placed onto this cream relative to a control Vaseline petroleum jelly site. During the collection of images of brainstem activity using a 7-T magnetic resonance imaging (MRI) scanner, both the placebo and control cream sites received identical temperatures, with a decrease in perceived pain intensity during the placebo cream site stimulation being a placebo analgesia response. We analyzed activity changes in the PAG and an area that the PAG contacts to inhibit pain, the rostral ventromedial medulla (RVM), during analgesia responses on the face, arm, and leg. Further, using the hidden application of a third cream to a separate body site, we explored whether analgesia was restricted to the area of stimulation or whether it was more widespread. RESULTS: Our findings show that analgesia evoked on the face, arm, and leg changes activity in a somatotopically organized fashion—i.e., face analgesia is toward the rostral (top) of the PAG and RVM, whereas arm and leg analgesia represented more caudally (lower). These somatotopically organized analgesic responses occurred on opposite sides of the PAG but at the same locations as pain activity changes, and the analgesia was restricted to the site where conditioning was applied. CONCLUSION: These data show that the PAG regulates analgesic responses in a highly spatially localized manner and has the ability to mediate body site–selective control over pain. The finding that both pain and analgesia evoked PAG activity changes in the same somatotopic fashion suggests that painful inputs to the PAG can not only evoke spatially appropriate behavioral responses, but that these responses are coupled to spatially appropriate analgesic responses. Somatotopic organization of analgesic brainstem circuitry.: Placebo analgesia induced on the face, arm, and leg evoked somatotopically organized activity changes within the lateral PAG and RVM revealed through 7-T functional MRI. This analgesic circuitry organization suggests that stimulating discrete brain circuits can produce pain relief in specific parts of the body or face and provides a platform for targeted analgesic treatment development. ipsi, ipsilateral; MNI, Montreal Neurological Institute; VAS, visual analog scale. [ABSTRACT FROM AUTHOR]