A Multimodal Examination of Functional Brain and Neurochemical Mechanisms Underlying Nociplastic Pain

Abstract

Chronic pain affects well-being, causes suffering, and is a major burden to society. Unfortunately, pain management in the U.S. remains poor, primarily due to a lack of understanding of neurobiological mechanisms underlying pain. Research over the past few decades has shown that maladaptive central nervous system processing may contribute to the development or maintenance of a particular type of chronic pain called nociplastic pain. The prototypical nociplastic pain condition is fibromyalgia, which is characterized by widespread body pain, fatigue, sleep problems, and heightened sensory sensitivity. Understanding the central nervous system in nociplastic pain, therefore, has great potential to develop biomarkers for diagnosis and prognosis, while generating mechanistically informed treatment options. Therefore, this dissertation aims to understand neurochemical and functional brain processes involved in pain augmentation (i.e., hyperalgesia) and how non-pharmacologic pain relief (i.e., analgesia) may alter such aberrant neurobiological processes in nociplastic pain.

Nociplastic pain has been characterized by augmented cross-network functional communication between the brain’s sensorimotor, default mode, and attentional (salience/ventral and dorsal) networks. However, the underlying mechanisms of these aberrant communication patterns are unknown. In chapter 2, I sought to understand large-scale topographic patterns at instantaneous timepoints, known as co-activation patterns (CAPs). I found that a sustained pressure pain challenge temporally modulated the occurrence of CAPs. Using proton magnetic resonance spectroscopy, I found that greater basal excitatory neurotransmitter levels within the anterior insula orchestrated higher cross-network connectivity between the insula and the default mode network via lower occurrence of a CAP encompassing the attentional networks during sustained pain. Moreover, I found that hyperalgesia in nociplastic pain was mediated via increased occurrence of a CAP encompassing the sensorimotor network during sustained pain.

Acupuncture is a complex multi-component treatment with demonstrated promise, however, clinical trials have shown mixed results, possibly due to heterogeneous methodology and lack of understanding of the underlying mechanism of action. In chapter 3, I sought to understand the specific contribution of somatosensory afference to improvements in clinical pain, and the specific brain circuits involved. In this trial, nociplastic pain patients were randomized to receive electroacupuncture (with somatosensory afference) or mock laser acupuncture (no somatosensory afference). Patients in the electroacupuncture arm experienced a greater reduction in pain severity compared to the mock laser. Patients receiving electroacupuncture also displayed increased resting functional connectivity between the primary somatosensory cortical representation of the leg and the anterior insula, which was associated with reductions in pain severity and increases in inhibitory neurotransmitter levels in the anterior insula, following therapy. Post-therapy increases in anterior insula inhibitory neurotransmitter levels mediated the relationship between increases in primary somatosensory to anterior insula connectivity and clinical pain reduction.

Taken together, the studies presented in this dissertation elucidate the role of local neurochemistry, functional circuits, and large-scale spatiotemporal networks in shaping hyperalgesia and analgesia in nociplastic pain. The knowledge from this dissertation could be implemented into rigorous biomarker development and mechanism-based treatment design for individual nociplastic pain patients.