An Investigation of Functional Brain Organization in Chronic Centralized Pain

Abstract

Pain is a complex and subjective experience often associated with noxious stimulation. However, in the past several decades it has become clear that the central nervous system can augment or even cause pain in the absence of noxious input. For some individuals, the most common cause of pain is related to altered central nervous system function and collectively referred to as chronic overlapping pain conditions (COPCs). Together, these conditions are characterized by diffuse hyperalgesia (an elevated response to painful stimuli) and allodynia (perception of pain for non-noxious stimuli), in addition to sleep disturbances, fatigue, and mood disorders. Moreover, many chronic pain patients also have increased sensitivity to multiple sensory stimuli, that include light suggesting a global dysfunction in sensory processing. This dissertation aims to examine intrinsic network alterations in the central nervous system in fibromyalgia (FM), a prototypical chronic pain condition, and determine how aberrant visual processing may be associated with sensory hypersensitivity in chronic pain conditions. Neuroimaging has enhanced our understanding of the neural correlates of pain. Pain processing in the CNS normally occurs via ascending and descending nociceptive pathways that integrate in several brain regions to include the insular cortex. Resting state functional MRI has shown aberrant intrinsic functional connectivity among chronic pain patients between the insula and the Default Mode Network (DMN) an intrinsic network associated with self-referential thinking. To elucidate the complex nature of pain and general sensory processing in chronic pain, we examine the relationship between multiple brain regions simultaneously using graph theoretical analyses. Communities are a collection of nodes or brain regions that are more connected to each other than to other communities. In Chapter 2, we investigate the network organization of the brain through intrinsic functional communities generated from resting state functional MRI data of individuals with FM and healthy controls. Composition of community structure between two networks were assessed using normalized mutual information (NMI). We found that the global network community structure in chronic pain patients is less stable (more variable, lower within-group NMI). Subsequent analyses of node community assignment revealed the composition of the communities differed between chronic pain patients and controls at rest. Many individuals with chronic nociplastic pain conditions, such as fibromyalgia (FM), experience multimodal (i.e., tactile, visual, auditory, olfactory) sensory hypersensitivity. Moreover, the anterior insula plays a role in pain and conscious processing. In Chapter 3, we also measured brain network architecture with functional MRI during an aversive visual task (flashing checkerboard) in individuals with FM and healthy controls. We show that whole brain network community structure was more variable compared to that of HC during the visual stimulus (i.e., lower between-group NMI). As the anterior insula plays a role in pain, multisensory integration and gating conscious experience, we show the variability of insula community assignment during the visual stimulus was positively associated with clinical pain in FM. Together this dissertation research demonstrates that intrinsic network communities differ substantially between individuals with FM and healthy controls. These differences may represent a novel aspect of the pathophysiology of chronic nociplastic pain.