Investigating Descending Pain Regulation in Fibromyalgia and the Link to Altered Autonomic Regulation by Means of Functional MRI Data.

Fibromyalgia syndrome (FM) is a chronic pain condition that affects a significant portion of the population; yet, this condition is still poorly understood. Prior research has suggested that individuals with FM display a heightened sensitivity to pain and signs of autonomic dysfunction. Recent advances in functional MRI analysis methods to model blood-oxygenation-level-dependent (BOLD) responses across networks of regions, and structural and physiological modeling (SAPM) have shown the potential to provide more detailed information about altered neural activity than was previously possible. Therefore, this study aimed to apply novel analysis methods to investigate altered neural processes underlying pain sensitivity in FM in functional magnetic resonance imaging (fMRI) data from the brainstem and spinal cord. Prior fMRI studies have shown evidence of functional differences in fibromyalgia (FM) within brain regions associated with pain's motivational aspects, as well as differences in neural activity related to pain regulation, arousal, and autonomic homeostatic regulation within the brainstem and spinal cord regions. We, therefore, hypothesized that nociceptive processing is altered in FM compared to healthy controls (HCs) in the brainstem and spinal cord areas linked to autonomic function and descending pain regulation, including the parabrachial nuclei (PBN) and nucleus tractus solitarius (NTS). We expected that new details of this altered neural signaling would be revealed with SAPM. The results provide new evidence of altered neural signaling in FM related to arousal and autonomic homeostatic regulation. This further advances our understanding of the altered neural processing that occurs in women with FM.

Fibromyalgia is associated with hypersensitivity but not with abnormal pain modulation: evidence from QST trials and spinal fMRI.

Widespread pain and hyperalgesia are characteristics of chronic musculoskeletal pain conditions, including fibromyalgia syndrome (FM). Despite mixed evidence, there is increasing consensus that these characteristics depend on abnormal pain augmentation and dysfunctional pain inhibition. Our recent investigations of pain modulation with individually adjusted nociceptive stimuli have confirmed the mechanical and thermal hyperalgesia of FM patients but failed to detect abnormalities of pain summation or descending pain inhibition. Furthermore, our functional magnetic resonance imaging evaluations of spinal and brainstem pain processing during application of sensitivity-adjusted heat stimuli demonstrated similar temporal patterns of spinal cord activation in FM and HC participants. However, detailed modeling of brainstem activation showed that BOLD activity during "pain summation" was increased in FM subjects, suggesting differences in brain stem modulation of nociceptive stimuli compared to HC. Whereas these differences in brain stem activation are likely related to the hypersensitivity of FM patients, the overall central pain modulation of FM showed no significant abnormalities. These findings suggest that FM patients are hyperalgesic but modulate nociceptive input as effectively as HC.

Structural and Physiological Modeling (SAPM) for the Analysis of Functional MRI Data Applied to a Study of Human Nociceptive Processing.

A novel method has been developed for analyzing connectivity between regions based on functional magnetic resonance imaging (fMRI) data. This method, termed structural and physiological modeling (SAPM), combines information about blood oxygenation-level dependent (BOLD) responses, anatomy, and physiology to model coordinated signaling across networks of regions, including input and output signaling from each region and whether signaling is predominantly inhibitory or excitatory. The present study builds on a prior proof-of-concept demonstration of the SAPM method by providing evidence for the choice of network model and anatomical sub-regions, demonstrating the reproducibility of the results and identifying statistical thresholds needed to infer significance. The method is further validated by applying it to investigate human nociceptive processing in the brainstem and spinal cord and comparing the results to the known neuroanatomy, including anatomical regions and inhibitory and excitatory signaling. The results of this analysis demonstrate that it is possible to obtain reliable information about input and output signaling from anatomical regions and to identify whether this signaling has predominantly inhibitory or excitatory effects. SAPM provides much more detailed information about neuroanatomy than was previously possible based on fMRI data.

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.

Spinal cord neural activity of patients with fibromyalgia and healthy controls during temporal summation of pain: an fMRI study.

The cause for the increased sensitivity of patients with fibromyalgia (FM) to painful stimuli is unclear but sensitization of dorsal horn spinal cord neurons has been suggested. There, critical changes of sensory information occur which depend on the plasticity of second-order neurons and descending pain modulation, including facilitation and inhibition. This study used repetitive stimuli that produce temporal-summation-of-second-pain (TSSP) and central sensitization, relevant mechanisms for patients with chronic pain. We examined spinal cord neural activation during TSSP in patients with FM and healthy controls (HC) and used its functional connectivity with several brainstem nuclei to model the observed blood-oxygen-level-dependent (BOLD) time-course with pain ratings. Sixteen HC and 14 FM participants received repetitive heat stimuli to the hand at 0.4 Hz to achieve TSSP during functional imaging with a 3 T-Philips Achieva MRI scanner. Stimuli were adjusted to each individual's pain sensitivity to achieve maximal pain ratings of 50 ± 10 on a numerical pain scale (0-100). Using a 16-channel neurovascular coil, multiple image series were obtained from the cervical spinal cord to the brainstem using single-shot turbo-spin echo sequences. During repetitive, sensitivity-adjusted heat stimuli, pain ratings of all subjects increased as predicted, consistent with TSSP. HC and FM participants had similar temporal patterns of spinal activation: initial BOLD increase followed by deactivation. Structural equation modeling showed that the observed spinal activity during TSSP was associated with more BOLD activity across/within the brainstem in FM subjects than HC, suggesting differences in pain modulation.NEW & NOTEWORTHY "Windup" and its behavioral correlate "temporal-summation-of-second pain" (TSSP) represent spinal cord mechanisms of pain augmentation associated with central sensitization and chronic pain. Fibromyalgia (FM) is a chronic pain disorder, where abnormal TSSP has been demonstrated. We used fMRI to study spinal cord and brainstem activation during TSSP. We characterized the time course of spinal cord and brainstem BOLD activity during TSSP which showed abnormal brainstem activity in patients with FM, possibly due to deficient pain modulation.

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.

An Investigation of Descending Pain Modulation in Women With Provoked Vestibulodynia: Alterations of Brain Connectivity.

Provoked Vestibulodynia (PVD) is the most common vulvodynia subtype (idiopathic chronic vulvar pain). Functional magnetic resonance imaging (fMRI) studies indicate that women with PVD exhibit altered function in a number of pain modulatory regions in response to noxious stimulation, such as in the secondary somatosensory cortex, insula, dorsal midcingulate, posterior cingulate, and thalamus. However, previous neuroimaging studies of PVD have not examined periods of time before and after noxious stimulation or investigated functional connectivity among pain modulatory regions. Fourteen women with PVD and 14 matched Control participants underwent five fMRI runs with no painful stimuli interleaved randomly with five runs with calibrated, moderately painful heat stimuli applied to the thenar eminence. As recent findings indicate that pain processing begins before and continues after painful stimulation, 2-min periods were included in each run before and after the stimulus. Functional brain connectivity was assessed during both trials of Pain and No Pain stimulation for each group using structural equation modeling (SEM). Analyses of variance (ANOVAs) on connectivity values demonstrated significant main effects of study condition, and group, for connectivity among pain modulatory regions. Most of the differences between the Pain and No Pain conditions found only in the PVD group take place before (i.e., thalamus to INS, ACC to S1, thalamus to S1, and thalamus to S2) and after pain stimulation (i.e., INS to amygdala, PPC to S1, and thalamus to S2). Such differences were not observed in the Control group. These findings further support previous results indicating that women with PVD have altered pain processing compared to pain-free women.

An Investigation of Descending Pain Modulation in Women With Provoked Vestibulodynia (PVD): Alterations of Spinal Cord and Brainstem Connectivity.

The most common subtype of vulvodynia (idiopathic chronic vulvar pain) is provoked vestibulodynia (PVD). Previous imaging studies have shown that women with vulvodynia exhibit increased neural activity in pain-related brain regions (e.g., the secondary somatosensory cortex, insula, dorsal midcingulate, posterior cingulate, and thalamus). However, despite the recognized role of the spinal cord/brainstem in pain modulation, no previous neuroimaging studies of vulvodynia have examined the spinal cord/brainstem. Sixteen women with PVD and sixteen matched Control women underwent a spinal cord/brainstem functional magnetic resonance imaging (fMRI) session consisting of five runs with no painful thermal stimuli (No Pain), interleaved randomly with five runs with calibrated, moderately painful heat stimulation (Pain). Functional connectivity was also assessed in periods before, during, and after, pain stimulation to investigate dynamic variations in pain processing throughout the stimulation paradigm. Functional connectivity in the brainstem and spinal cord for each group was examined using structural equation modeling (SEM) for both Pain and No Pain conditions. Significant connectivity differences during stimulation were identified between PVD and Control groups within pain modulatory regions. Comparisons of Pain and No Pain conditions identified a larger number of connections in the Control group than in the PVD group, both before and during stimulation. The results suggest that women with PVD exhibit altered pain processing and indicate an insufficient response of the pain modulation system. This study is the first to examine the spinal cord/brainstem functional connectivity in women with PVD, and it demonstrates altered connectivity related to pain modulation in the spinal cord/brainstem.

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.

Unique brain regions involved in positive versus negative emotional modulation of pain.

Background and aims Research has shown that negative emotions increase perceived pain whereas positive emotions reduce pain. Here we aim to investigate the neural mechanisms underlying this phenomenon. Methods While undergoing functional magnetic resonance imaging of the brain, 20 healthy adult females were presented with negative, neutral, and positive emotion-evoking visual stimuli in combination with the presentation of a noxious thermal stimulus to the hand. Participants rated the intensity and unpleasantness of the noxious thermal stimulus during each of the valence conditions. General linear model analyses were performed on the imaging data for each valence condition and specific contrasts were run. Results Significant differences were detected for the emotional modulation of pain (EMP) between the positive and negative conditions. Unique to the positive condition, there was increased activity in the inferior parietal, parahippocampal/perirhinal, precuneus/superior parietal, and the prefrontal cortices. Unique to the negative condition, there was increased activity in anterior and posterior cingulate and angular gyrus. Conclusions Positive and negative EMP appear to involve different brain regions. Implications Although there is some overlap in the brain regions involved in the positive and negative EMP, brain regions unique to each condition are identified and, moreover, the regions identified are involved in internal and external focus, respectively, pointing to a potential mechanism underlying this phenomenon.

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.

Investigation of Resting-State BOLD Networks in the Human Brainstem and Spinal Cord.

Resting-state functional magnetic resonance imaging (rs-fMRI) has been used to investigate networks within the cortex and has also provided some insight into the networks present in the brainstem (BS) and spinal cord (SC). The purpose of this study was to investigate resting-state blood oxygenation-level dependent (BOLD) fluctuations in the BS/SC and to identify resting-state networks (RSNs) across these regions. Resting-state BOLD fMRI data were obtained from the entire BS and cervical SC in 16 healthy participants, at 3 T, with T2-weighted single-shot fast spin-echo imaging. Data were spatially normalized and processed to remove physiological noise. Cluster-cluster functional connectivity was investigated across the entire 3D region by means of temporal correlations, and structural equation modeling (SEM) was used to investigate RSNs. Extensive connectivity was observed within and across BS and SC regions, with connections spanning up to 120 mm, although shorter connections were more prevalent. SEM results revealed extensive brainstem-cord connectivity that included specific anatomical regions within the brainstem. The results indicate the presence of a complex resting-state network which is highly interconnected in the spinal cord. Known anatomical connections between cortical and BS regions support the conclusion that the observed resting-state BOLD fluctuations in the BS/SC may be related to autonomic regulation. Future studies are required to further investigate these resting-state BOLD networks.

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.