Somatotopic organization of the human periaqueductal gray revealed in pain and placebo analgesia

Abstract

Pain is a critical and fundamental homeostatic state that results in the execution of defensive behaviours, one of which is a profound placebo analgesia. Early discoveries on the midbrain periaqueductal gray (PAG) found that its electrical stimulation would evoke analgesia in experimental animals. Subsequent seminal studies led to thorough investigations on the anatomical, behavioural and physiological mechanisms that govern PAG function. Functional and tract-tracing studies revealed a somatotopic organisation of noxious afferent inputs/outputs and defensive behaviours of the PAG from the primary afferent synapse of the medulla and spinal cord. The principal aim of this thesis was to utilize recent advancements in ultra-high field imaging to assess the functional organisation of the human PAG during noxious stimulation and analgesic processing across different body sites, to find whether a somatotopy exists in humans as in animals.

Chapter 2 establishes a somatotopic organisation in the human PAG. We uncovered a rostro-caudal pattern of activation depending on whether pain was induced on the face or body. Building on this work, Chapter 3 utilized a response conditioning model in the context of placebo analgesia to observe if this same rostro-caudal pattern of activity was preserved in the PAG. Chapter 4 bridges the cortex, subcortex and brainstem to reveal if a consistent pattern exists in key regions involved in top-down control of pain modulation across the same body sites. This thesis concludes by discussing the behavioural, clinical and experimental implications of our three studies, with a focus on how the delineation of spatially separate face-body circuits within the PAG may be phyletically preserved across species. In addition, we propose how further interrogation of these circuits could aid and assist in the development of new approaches that treat chronic pain, by leveraging the neural mechanisms of a somatotopic organisation within the human PAG.