An Examination of Brain Network Organization and the Analgesic Mechanisms of a Non-Pharmacological Treatment in Chronic Centralized Pain

Chronic pain is a global public health challenge, affecting nearly one third of adults worldwide. Current treatments are inadequate, especially since some of the mainstay therapies (e.g. opioids, NSAIDs) are often ineffective and/or associated with significant toxicity. The solution to these problems requires an improved understanding of chronic pain pathology, particularly the role that the brain plays in causing or amplifying pain perception, and how analgesic intervention might target these brain-based mechanisms. This dissertation aims to identify brain network alterations in fibromyalgia (FM), a common and canonical chronic pain condition with presumed CNS pathology, and determine how non-invasive brain stimulation may target aberrant brain network connectivity to promote analgesia. Across a wide range of diverse neurological disorders, hubs (i.e. highly connected brain regions) appear to be disrupted and the character of this disruption can yield insights into the pathophysiology of these disorders. In Chapter 2, we describe the application of a brain network based approach to examine hub topology in FM patients compared to healthy volunteers. We identified significant disruptions in hub rank order in FM patients. In FM, but not controls, the anterior insula was a hub with significantly higher inter-modular connectivity and membership in the rich club (a functional backbone of connectivity formed by highly interconnected hubs). Among FM patients, rich club membership varied with the intensity of clinical pain: the posterior insula, primary somatosensory and motor cortices belonged to the rich club only in FM patients with the highest pain. Further, we found that the eigenvector centrality (a measure of how connected a brain region is to other highly connected regions) of the posterior insula positively correlated with clinical pain, and mediated the relationship between levels of glutamate + glutamine within this structure and the patient’s subjective clinical pain report. Together, these findings demonstrate an altered hub topology in FM and are the first to suggest that disruptions in the excitatory tone within the insula could alter the strength of the insula as a hub and subsequently lead to increased clinical pain. Transcranial direct current stimulation (tDCS) has emerged as an attractive noninvasive treatment for pain, given its ability to target specific cortical regions with relatively few side effects. Motor cortex (M1) tDCS relieves pain in FM, but the analgesic mechanism remains unknown. In Chapter 3, we measured changes in resting state functional connectivity after sham and real M1 tDCS in twelve FM patients and examined if these changes were related to subsequent analgesia. M1 tDCS (compared to sham) reduced pro-nociceptive functional connectivity, specifically between the motor and sensory nuclei of the thalamus and multiple cortical regions, including primary motor and somatosensory areas. Interestingly, decreased connectivity between the thalamus and posterior insula, M1 and somatosensory cortices correlated with reductions in clinical pain after both sham and active treatment. These results suggest that while there may be a placebo response common to both sham and real tDCS, repetitive M1 tDCS causes distinct changes in functional connectivity that last beyond the stimulation period and may produce analgesia by inhibiting pro-nociceptive thalamic connectivity. This research offers new insight into the neurobiology of chronic centralized pain conditions and contributes to the understanding of how non-invasive brain stimulation causes analgesia. This knowledge could lead to more informed stimulation sites and personalized treatment based on network connectivity in each individual patient.PHDNeuroscienceUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/143930/1/chelsmar_1.pd

Sistema modulatório descendente da dor na fibromialgia : preditores de disfunção e conectividade funcional por ressonância magnética funcional

A fibromialgia (FM) é uma síndrome que se caracteriza por dor musculoesquelética generalizada, fadiga, sono não reparador, alterações cognitivas, sintomas depressivos e neurovegetativos, cujo processo neurobiológico é múltiplo e complexo. Apesar de ser de grande relevância ao indivíduo e à sociedade, esta patologia com frequência não recebe a atenção necessária pelos órgãos que definem as prioridades da assistência na saúde. A prevalência populacional, segundo os critérios da Sociedade Americana de Reumatologia, chega a 5,4%, e os gastos decorrentes de atendimento, impostos e aposentadoria precoce por incapacidade são estimados em mais de 29 bilhões de dólares ao ano nos EUA. A falha das terapêuticas farmacológicas convencionais ocorre em cerca de 50% dos pacientes. Postula-se que essas taxas elevadas de insucesso se devam em parte à falta de conhecimento sobre os mecanismos fisiopatológicos. O mecanismo que permeia o conjunto de sintomas que constituem a FM é a síndrome de sensibilização central (SSC). O conjunto de sintomas inclui o sofrimento psíquico, distúrbios do sono, fadiga, dor, alodínia e hiperalgesia. Esta condição tem como mecanismo fisiopatológico o funcionamento prejudicado de neurônios e circuitos em vias nociceptivas, com aumento do campo receptivo, da eficácia sináptica da excitabilidade e redução da inibição. Outro componente fundamental na SSC é a disfunção do sistema modulatório descendente da dor (SMDD), que pode ser avaliado através do teste de modulação condicionada da dor (conditioned pain modulation test [CPM-test]). Neste teste, os participantes podem ser classificados como respondedores ou não respondedores, sendo que neste último grupo há uma perda da capacidade de inibição do SMDD. Estudos de neuroimagem em pacientes com dor crônica demonstram alterações funcionais corticais e de suas conexões com estruturas subcorticais que constituem a neuromatriz da dor. Entre as técnicas de neuroimagem, merece destaque o estudo com ressonância magnética funcional (fMRI) em estado de repouso (do inglês, resting-state [fMRI ou rs-fMRI]), para avaliar a conectividade funcional intrínseca (CFI). Com a finalidade de compreender fatores clínicos, laboratoriais e de neuroimagem que poderiam discriminar a disfunção do SMDD, foram desenvolvidos dois estudos. No primeiro estudo, buscamos identificar se um conjunto de sintomas da FM e os biomarcadores de neuroplasticidade poderiam constituir um índice composto de gravidade, bem como se esse teria poder discriminatório para identificar respondedores e não respondedores ao teste de CPM. Nesse estudo transversal foram incluídas 117 mulheres com FM (n = 60) não respondedoras e (n = 57) respondedoras, com idade entre 30 e 65 anos. A avaliação do SMDD pelo teste de CPM foi feita pelas mudanças nos escores da escala numérica de dor, usando-se um protocolo padronizado. A análise de regressão logística multivariada hierárquica foi usada para construir um índice ajustado ao escore de propensão para identificar não respondedores em comparação com respondedores ao teste de CPM. As seguintes variáveis foram mantidas nos modelos: uso de analgésico quatro ou mais vezes por semana, limiar de dor ao calor (heat pain threshold, HPT), má qualidade do sono, catastrofização da dor, níveis séricos de fator neurotrófico derivado do cérebro (BDNF), número de diagnósticos psiquiátricos e impacto dos sintomas da FM na qualidade da vida. A receiver operating characteristic curve (ROC) mostrou que os não respondedores podem ser discriminados dos respondedores por um índice composto pelos sintomas da FM combinados a marcadores de neuroplasticidade (área sob a curva [AUC] = 0,83; sensibilidade = 100%; especificidade = 98%). O segundo estudo avaliou padrões de CFI entre as redes cerebrais de processamento da dor e o SMDD, através da rs-fMRI em pacientes com FM. Além disso, investigamos se o padrão de conectividade entre o córtex somatossensorial primário (do inglês, primary somatosensory córtex [PSC ou S1]) e a substância cinzenta periaquedutal (do inglês, periaqueductal gray matter [PAG]) está relacionado aos sintomas clínicos, em pacientes respondedoras e não respondedoras ao CPMtest. Nesse estudo, foram incluídas 33 mulheres com FM, classificadas como não respondedoras (n = 13) e respondedores (n = 20) ao teste de CPM. Na análise em que comparamos respondedoras e não respondedoras com um modelo linear generalizado, identificamos que não respondedoras apresentaram diminuição da CFI entre o PSC e a PAG (χ2 =10,41; DF = 1; p < 0,001). A CFI S1-PAG no hemisfério cerebral esquerdo foi positivamente correlacionada aos níveis de sintomas de sensibilização central e negativamente correlacionada à qualidade do sono e aos escores de dor. A análise com ROC mostrou que a CFI entre o S1-PAG oferece sensibilidade e especificidade de 85% ou mais (AUC 0,78; IC 95% 0,63-0,94) para discriminar respondedoras de não respondedoras ao CPM-test. Os achados desses estudos mostram que os sintomas cardinais da FM e marcadores de neuroplasticidade predizem a disfunção do SMDD, assim como os padrões de CFI em estado de repouso no S1-PAG podem ser potenciais marcadores para predizer a resposta à tarefa da CPM. Esses dados podem auxiliar na identificação de perfis para o planejamento individualizado do tratamento de pacientes com fibromialgia.Fibromyalgia (FM) is a syndrome characterized by generalized musculoskeletal pain, fatigue, non-repairing sleep, cognitive, and neurovegetative changes, with multiple and complex neurobiological processes. Despite being a significant disease, it often does not receive attention from the organs that define health care policies. The population prevalence, according to the criteria of the American Society of Rheumatology, reaches 5.4%, and the expenses arising from care, taxes and disability anticipation are estimated at more than 29 billion dollars per year in the US. Failure of pharmacological therapies occurs in about 50% of patients. These high failure rates are postulated partly due to a lack of knowledge about the pathophysiological mechanisms. The mechanism that permeates the set of symptoms that configure FM is the central sensitization syndrome (CSS), which is characterized by distress, sleep disturbances, fatigue, pain, allodynia, and hyperalgesia. This condition has as pathophysiological mechanism the impaired nociceptive functioning of neurons and circuits, increasing the receptive field and reduction of excitation mechanisms. Another critical factor in CCS is the dysfunction of the descending pain modulatory system (DPMS), which can be assessed using the conditioned pain modulation test (CPM test). This test can classify participants as responders and nonresponders, where in this last group, t mechanism of pain inhibition is dysfunctional. Neuroimaging studies have shown there are changes in the brain connectivity in FM patients, mainly among the pain neuromatrix and in the DPMS. Among the neuroimaging techniques, the functional magnetic resonance imaging (fMRI) in resting-state (rs-fMRI) stands out in assessing intrinsic connectivity (IFC). In order to understand clinical, laboratory and neuroimaging factors that could discriminate SMDD dysfunction, two studies were developed. In the first study, we sought to identify whether a set of FM symptoms and neuroplasticity biomarkers could constitute a composite severity index and whether it would have discriminatory power to identify responders and non-responders to the CPM test. In this crosssectional study, 117 women with FM (n = 60) non-responders and (n = 57) responders, aged between 30 and 65 years, were included. Assessment of DPMS by the CPM test was assessed by changes in Numerical Pain Scale (NPS-10) scores using a standardized protocol. Hierarchical multivariate logistic regression analysis was used to construct a propensity scoreadjusted index to identify non-responders compared with CPM test responders. The models maintained the following variables: analgesic use four or more times a week, heat pain threshold (HPT), poor sleep quality, pain catastrophizing, serum BDNF levels, number of psychiatric diagnoses and the impact of FM symptoms on quality of life. The receiver operating characteristic curve (ROC) showed that non-responders could be distinguished from responders by an index composed of FM symptoms combined with neuroplasticity markers (area under the curve (AUC) = 0.83, sensitivity = 100% and specificity). = 98%). The second study evaluated IFC patterns between brain pain processing networks and DPMS using rs-fMRI in FM patients. In addition, we investigated whether the connectivity pattern between the primary somatosensory cortex and the periaqueductal gray is related to clinical symptoms in CPM-test responders or non-responders. In this study, 33 women with FM were classified as nonresponders (n=13) or responders (n=20) to the CPM test. In the analysis that compared responders and non-responders with a generalized linear model (GLM), we identified that nonresponders showed a decrease in IFC between the PSC and the PAG [(χ2 =10.41, DF = 1 p < 0.001)]. IFC S1-PAG in the left cerebral hemisphere was positively correlated with levels of central sensitization symptoms and negatively correlated with sleep quality and pain scores. ROC analysis showed that the IFC between S1-PAG offers sensitivity and specificity of 85% or greater [AUC 0.78, 95% confidence interval (CI), 0.63-0.94] to discriminate responders from non-responders. Respondents to the CPM test. Findings from these studies show that cardinal symptoms of FM and neuroplasticity markers predict DPMS dysfunction and resting-state IFC patterns in S1-PAG may be potential markers for predicting CPM task response. These data can help identify profiles for individualized treatment planning for patients with fibromyalgia