Distinct neural signaling characteristics between fibromyalgia and provoked vestibulodynia revealed by means of functional magnetic resonance imaging in the brainstem and spinal cord.

Introduction: Fibromyalgia and provoked vestibulodynia are two chronic pain conditions that disproportionately affect women. The mechanisms underlying the pain in these conditions are still poorly understood, but there is speculation that both may be linked to altered central sensitization and autonomic regulation. Neuroimaging studies of these conditions focusing on the brainstem and spinal cord to explore changes in pain regulation and autonomic regulation are emerging, but none to date have directly compared pain and autonomic regulation in these conditions. This study compares groups of women with fibromyalgia and provoked vestibulodynia to healthy controls using a threat/safety paradigm with a predictable noxious heat stimulus. Methods: Functional magnetic resonance imaging data were acquired at 3 tesla in the cervical spinal cord and brainstem with previously established methods. Imaging data were analyzed with structural equation modeling and ANCOVA methods during: a period of noxious stimulation, and a period before the stimulation when participants were expecting the upcoming pain. Results: The results demonstrate several similarities and differences between brainstem/spinal cord connectivity related to autonomic and pain regulatory networks across the three groups in both time periods. Discussion: Based on the regions and connections involved in the differences, the altered pain processing in fibromyalgia appears to be related to changes in how autonomic and pain regulation networks are integrated, whereas altered pain processing in provoked vestibulodynia is linked in part to changes in arousal or salience networks as well as changes in affective components of pain regulation.

A Comparison of Functional Connectivity in the Human Brainstem and Spinal Cord Associated with Noxious and Innocuous Thermal Stimulation Identified by Means of Functional MRI.

The somatosensory system is multidimensional and processes important information for survival, including the experience of pain. The brainstem and spinal cord serve pivotal roles in both transmitting and modulating pain signals from the periphery; although, they are studied less frequently with neuroimaging when compared to the brain. In addition, imaging studies of pain often lack a sensory control condition, failing to differentiate the neural processes associated with pain versus innocuous sensations. The purpose of this study was to investigate neural connectivity between key regions involved in descending modulation of pain in response to a hot, noxious stimulus as compared to a warm, innocuous stimulus. This was achieved with functional magnetic resonance imaging (fMRI) of the brainstem and spinal cord in 20 healthy men and women. Functional connectivity was observed to vary between specific regions across painful and innocuous conditions. However, the same variations were not observed in the period of anticipation prior to the onset of stimulation. Specific connections varied with individual pain scores only during the noxious stimulation condition, indicating a significant role of individual differences in the experience of pain which are distinct from that of innocuous sensation. The results also illustrate significant differences in descending modulation before and during stimulation in both conditions. These findings contribute to a deeper understanding of the mechanisms underlying pain processing at the level of the brainstem and spinal cord, and how pain is modulated.

Proof-of-concept of a novel structural equation modelling approach for the analysis of functional magnetic resonance imaging data applied to investigate individual differences in human pain responses.

A novel network analysis method is demonstrated for applications with functional magnetic resonance imaging (fMRI) data. The method is based on structural equation modeling (SEM) plus modeling of physiological responses in order to explain blood oxygenation-level dependent (BOLD) responses across interconnected regions. The method, termed structural and physiological modeling (SAPM) aims to overcome a weakness of previous analysis methods by estimating both input and output signaling of every region of a network. The results also provide weighting factors (B) which describe the influence of each input signal to a region on its output signaling to another region. The SAPM method is demonstrated by applying it to fMRI data from the brainstem and spinal cord in 55 healthy participants undergoing repeated applications of a heat pain stimulation paradigm. Data are also analyzed using our established SEM method for comparison. The results with both methods indicate that individual differences in nociceptive processing are mediated by differences in descending regulation of spinal cord neurons under the influence of both the nucleus tractus solitarius and periaqueductal gray region. The SAPM results show that BOLD responses in the entire network can be explained during all periods of the stimulation paradigm based on two latent (unobserved) input signaling sources, and a model of the predicted BOLD responses to the heat stimulus. The results demonstrate the concept of our novel SAPM method and provide evidence for its validity. Additional studies are needed to further develop the method and its applications to investigations of complex neural processes across networks.

Evidence for Integration of Cognitive, Affective, and Autonomic Influences During the Experience of Acute Pain in Healthy Human Volunteers.

Our psychological state greatly influences our perception of sensations and pain, both external and visceral, and is expected to contribute to individual pain sensitivity as well as chronic pain conditions. This investigation sought to examine the integration of cognitive and emotional communication across brainstem regions involved in pain modulation by comparing data from previous functional MRI studies of affective modulation of pain. Data were included from previous studies of music analgesia (Music), mood modulation of pain (Mood), and individual differences in pain (ID), totaling 43 healthy women and 8 healthy men. The Music and Mood studies were combined into an affective modulation group consisting of runs with music and positive-valenced emotional images plus concurrent presentation of pain, and a control group of runs with no-music, and neutral-valenced images with concurrent presentation of pain. The ID group was used as an independent control. Ratings of pain intensity were collected for each run and were analyzed in relation to the functional data. Differences in functional connectivity were identified across conditions in relation to emotional, autonomic, and pain processing in periods before, during and after periods of noxious stimulation. These differences may help to explain healthy pain processes and the cognitive and emotional appraisal of predictable noxious stimuli, in support of the Fields' Decision Hypothesis. This study provides a baseline for current and future investigation of expanded neural networks, particularly within higher limbic and cortical structures. The results obtained by combining data across studies with different methods of pain modulation provide further evidence of the neural signaling underlying the complex nature of pain.

Music to My Senses: Functional Magnetic Resonance Imaging Evidence of Music Analgesia Across Connectivity Networks Spanning the Brain and Brainstem.

Pain is often viewed and studied as an isolated perception. However, cognition, emotion, salience effects, and autonomic and sensory input are all integrated to create a comprehensive experience. Music-induced analgesia has been used for thousands of years, with moderate behavioural effects on pain perception, yet the neural mechanisms remain ambiguous. The purpose of this study was to investigate the effects of music analgesia through individual ratings of pain, and changes in connectivity across a network of regions spanning the brain and brainstem that are involved in limbic, paralimbic, autonomic, cognitive, and sensory domains. This is the first study of its kind to assess the effects of music analgesia using complex network analyses in the human brain and brainstem. Functional MRI data were collected from 20 healthy men and women with concurrent presentation of noxious stimulation and music, in addition to control runs without music. Ratings of peak pain intensity and unpleasantness were collected for each run and were analysed in relation to the functional data. We found that music alters connectivity across these neural networks between regions such as the insula, thalamus, hypothalamus, amygdala and hippocampus (among others), and is impacted by individual pain sensitivity. While these differences are important for how we understand pain and analgesia, it is essential to note that these effects are variable across participants and provide moderate pain relief at best. Therefore, a therapeutic strategy involving music should use it as an adjunct to pain management in combination with healthy lifestyle changes and/or pharmaceutical intervention.

Altered Pain in the Brainstem and Spinal Cord of Fibromyalgia Patients During the Anticipation and Experience of Experimental Pain.

Chronic pain associated with fibromyalgia (FM) affects a large portion of the population but the underlying mechanisms leading to this altered pain are still poorly understood. Evidence suggests that FM involves altered neural processes in the central nervous system and neuroimaging methods such as functional magnetic resonance imaging (fMRI) are used to reveal these underlying alterations. While many fMRI studies of FM have been conducted in the brain, recent evidence shows that the changes in pain processing in FM may be linked to autonomic and homeostatic dysregulation, thus requiring further investigation in the brainstem and spinal cord. Functional magnetic resonance imaging data from 15 women with FM and 15 healthy controls were obtained in the cervical spinal cord and brainstem at 3 tesla using previously established methods. In order to investigate differences in pain processing in these groups, participants underwent trials in which they anticipated and received a predictable painful stimulus, randomly interleaved with trials with no stimulus. Differences in functional connectivity between the groups were investigated by means of structural equation modeling. The results demonstrate significant differences in brainstem/spinal cord network connectivity between the FM and control groups which also correlated with individual differences in pain responses. The regions involved in these differences in connectivity included the LC, hypothalamus, PAG, and PBN, which are known to be associated with autonomic homeostatic regulation, including fight or flight responses. This study extends our understanding of altered neural processes associated with FM and the important link between sensory and autonomic regulation systems in this disorder.

How fMRI Analysis Using Structural Equation Modeling Techniques Can Improve Our Understanding of Pain Processing in Fibromyalgia.

PURPOSE: The purpose of this study was to investigate the utility of data-driven analyses of functional magnetic resonance imaging (fMRI) data, by means of structural equation modeling, for the investigation of pain processing in fibromyalgia (FM). PATIENTS AND METHODS: Datasets from two separate pain fMRI studies involving healthy controls (HC) and participants with FM were re-analyzed using both a conventional model-driven approach and a data-driven approach, and the results from these analyses were compared. The first dataset contained 15 women with FM and 15 women as healthy controls. The second dataset contained 15 women with FM and 11 women as healthy controls. RESULTS: Consistent with previous studies, the model-driven analyses did not identify differences in pain processing between the HC and FM study groups in both datasets. On the other hand, the data-driven analyses identified significant group differences in both datasets. CONCLUSION: Data-driven analyses can enhance our understanding of pain processing in healthy controls and in clinical populations by identifying activity associated with pain processing specific to the clinical groups that conventional model-driven analyses may miss.

A comparison of the effectiveness of functional MRI analysis methods for pain research: The new normal.

Studies of the neural basis of human pain processing present many challenges because of the subjective and variable nature of pain, and the inaccessibility of the central nervous system. Neuroimaging methods, such as functional magnetic resonance imaging (fMRI), have provided the ability to investigate these neural processes, and yet commonly used analysis methods may not be optimally adapted for studies of pain. Here we present a comparison of model-driven and data-driven analysis methods, specifically for the study of human pain processing. Methods are tested using data from healthy control participants in two previous studies, with separate data sets spanning the brain, and the brainstem and spinal cord. Data are analyzed by fitting time-series responses to predicted BOLD responses in order to identify significantly responding regions (model-driven), as well as with connectivity analyses (data-driven) based on temporal correlations between responses in spatially separated regions, and with connectivity analyses based on structural equation modeling, allowing for multiple source regions to explain the signal variations in each target region. The results are assessed in terms of the amount of signal variance that can be explained in each region, and in terms of the regions and connections that are identified as having BOLD responses of interest. The characteristics of BOLD responses in identified regions are also investigated. The results demonstrate that data-driven approaches are more effective than model-driven approaches for fMRI studies of pain.

Coordinated Human Brainstem and Spinal Cord Networks during the Expectation of Pain Have Elements Unique from Resting-State Effects.

Functional magnetic resonance imaging (fMRI) research on the human brainstem (BS) and spinal cord (SC) has identified extensive BS/SC resting-state networks (RSNs) by showing spontaneous coordinated blood oxygenation-level dependent (BOLD) signal fluctuations in the absence of a stimulus. Studies have shown that these networks can be influenced by participants' level of arousal or attention (e.g., watching a video), and linked network function to autonomic homeostatic regulation. Here we explore how the cognitive state of expecting pain can influence connectivity in these networks. Data from two studies (a predictable pain stimulus study, and a resting-state study) were compared to show the effects of expecting pain on BS/SC networks, and how networks differed from networks associated with the resting-state. In each study, BOLD fMRI data were obtained from the cervical SC and brainstem in healthy participants at 3 tesla using a T2-weighted single-shot fast spin-echo imaging method. Functional connectivity was investigated within the entire 3D volume by means of structural equation modeling (SEM) and analyses of covariance (ANCOVA). Results showed extensive connectivity within/across BS and SC regions during the expectation of pain, and ANCOVA analyses showed that connectivity in specific components of these networks varied with individual pain sensitivity. Comparing these results to RSN fluctuations revealed commonalities in coordination between BS and SC regions, and specific BS-BS connectivity fluctuations unique to the expectation of pain. Based on the regions involved, these results provide evidence of brainstem regulation specific to the expectation of pain.

Comparing Coordinated Networks Across the Brainstem and Spinal Cord in the Resting State and Altered Cognitive State.

Resting-state (RS) functional magnetic resonance imaging (fMRI) has been used to investigate networks of activity within the brain, as well as the brainstem (BS) and spinal cord (SC). While previous research has shown coordinated resting state networks (RSNs) in the BS/SC, their function is still unclear. The aim of this study was to investigate the function of RSNs across these regions, by examining how these networks change when participants are experiencing different cognitive states (RS, listening to an audio presentation, or watching a video). RS blood oxygenation-level dependent fMRI data were obtained from the human cervical SC and BS in 20 healthy participants (14 women, 6 men), at 3 tesla, with T2-weighted single-shot fast spin-echo imaging. Functional connectivity was investigated within the entire three-dimensional region by means of temporal correlations between anatomical regions and by structural equation modeling (SEM). Both correlational analyses and SEM showed extensive connectivity within and across BS and SC regions, and 37% to 40% of significant connections were consistent across study conditions. However, significant differences in connectivity between specific regions of the BS and SC were also identified which depended on the study conditions. The results indicate that connectivity across the RS SC/BS is influenced by a person's cognitive/emotional state. The known anatomical functions of the regions involved support the conclusion that this RS network may play a role in the integration of homeostatic autonomic functions.

Ten Key Insights into the Use of Spinal Cord fMRI.

A comprehensive review of the literature-to-date on functional magnetic resonance imaging (fMRI) of the spinal cord is presented. Spinal fMRI has been shown, over more than two decades of work, to be a reliable tool for detecting neural activity. We discuss 10 key points regarding the history, development, methods, and applications of spinal fMRI. Animal models have served a key purpose for the development of spinal fMRI protocols and for experimental spinal cord injury studies. Applications of spinal fMRI span from animal models across healthy and patient populations in humans using both task-based and resting-state paradigms. The literature also demonstrates clear trends in study design and acquisition methods, as the majority of studies follow a task-based, block design paradigm, and utilize variations of single-shot fast spin-echo imaging methods. We, therefore, discuss the similarities and differences of these to resting-state fMRI and gradient-echo EPI protocols. Although it is newly emerging, complex connectivity and network analysis is not only possible, but has also been shown to be reliable and reproducible in the spinal cord for both task-based and resting-state studies. Despite the technical challenges associated with spinal fMRI, this review identifies reliable solutions that have been developed to overcome these challenges.

Pain processing in the human brainstem and spinal cord before, during, and after the application of noxious heat stimuli.

Descending regulation of spinal cord responses to nociceptive signaling has a strong influence on pain perception. Previous studies using functional magnetic resonance imaging (fMRI) have indicated that in addition to reactive responses to nociceptive signals, there is a continuous component to regulation, and that it may vary with differences in pain sensitivity. We hypothesize that this continuous regulation component occurs routinely in fMRI studies before noxious stimulation, as well as during, and after stimulation. This hypothesis was tested by analyzing data from 59 healthy participants in 4 previous fMRI studies in our laboratory using noxious heat stimuli. Analyses included structural equation modeling to identify coordinated blood oxygenation-level-dependent (BOLD) signal variations between regions (ie, connectivity) and Bayesian regression of BOLD time-series responses in relation to pain ratings and stimulus temperatures. The results demonstrate the periaqueductal gray-rostral ventromedial medulla-spinal cord descending modulation pathway, influenced by input from the hypothalamus, parabrachial nucleus, and nucleus tractus solitarius. Connectivity between specific regions is observed to vary in relation to pain sensitivity. The results support the conclusion that homeostatic autonomic control influences the net descending pain regulation, and therefore influences pain sensitivity. The results describe the overall properties of pain processing (specifically pain elicited by heat) in the healthy human brainstem and spinal cord, and mechanisms for variation across individuals. This understanding is expected to be important for studies of how pain processing is altered in chronic pain conditions.