Cortical and Brainstem Circuits Responsible for Pain Modulatory Responses in Healthy Humans

Abstract

The human ability to regulate our own pain is governed by specific sites and circuits within the brain which can powerfully inhibit or enhance nociception. Placebo analgesia and nocebo hyperalgesia are the modulatory phenomena which leverage these circuits in the presence of a pharmacologically inert treatment to cause perceived changes in pain. The principal aim of this thesis was to utilize recent advancements in high field human brain imaging to assess the responsibility of descending pain-modulatory circuits within the brainstem, as well as the cortical connections which recruit these circuits in the generation of placebo analgesia and nocebo hyperalgesia.

Chapter 2 establishes the brainstem’s role in both phenomena. We utilized a response conditioning model and a brainstem-specific imaging pipeline to reveal how activation within discrete nuclei altered depending on the intensity of placebo and nocebo responses. Building on this work, Chapter 3 presents a dual network model of the human cortical sites which regulate brainstem output in the context of placebo analgesia. Relative to chapter 2, this work included a larger sample size, a higher placebo response rate, and analyses sensitive to how cortical connections to the brainstem change across time. Chapter 4 bridges function and biochemistry, circumventing limitations in functional magnetic resonance imaging by incorporating proton magnetic resonance spectroscopy (1H-MRS) to investigate how metabolite concentrations within the dorsolateral prefrontal cortex (dlPFC) - a primary node in the cortical pain system - play a role in the generation of placebo analgesia. I conclude by discussing the clinical and experimental implications of our three studies, with a focus on how further interrogation of the circuits revealed could aid and assist in the development of new approaches that treat chronic pain, by leveraging the neural mechanisms of placebo analgesia and nocebo hyperalgesia.