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.

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.

Confirmation of resting-state BOLD fluctuations in the human brainstem and spinal cord after identification and removal of physiological noise.

PURPOSE: Resting-state functional MRI (rs-fMRI) has been used to investigate networks within the cortex, but its use in the brainstem (BS) and spinal cord (SC) has been limited. This region presents challenges for fMRI, partly because of sources of physiological noise. This study aims to quantify noise contributions to rs-fMRI, and to obtain evidence of resting-state blood oxygenation level-dependent (BOLD) fluctuations. METHODS: Resting-state-fMRI data were obtained from the BS/SC in 16 participants, at 3 Tesla, with T2 -weighted single-shot fast spin-echo imaging. The peripheral pulse, respiration, and expired CO2 were recorded continuously. Physiological noise was modeled from these recordings, movement parameters, and white matter regions. Model fits were then subtracted from the data. BOLD contributions were then investigated through connectivity. RESULTS: Bulk motion was the largest contributor to the signal variance (19% of the total), followed by cardiac-related motion (14%), nonspecific signal variations detected in white matter (10%), respiratory-related motion (2.6%), and end-tidal CO2 variations (0.7%). After noise was removed, significant left-right connectivity was detected in the SC dorsal horns and ventral horns. CONCLUSIONS: Resting-state BOLD fluctuations are demonstrated in the SC, as are the dominant noise contributions. These findings are an essential step toward establishing rs-fMRI in the BS/SC. Magn Reson Med 78:2149-2156, 2017. © 2017 International Society for Magnetic Resonance in Medicine.

FMRI of spinal and supra-spinal correlates of temporal pain summation in fibromyalgia patients.

Fibromyalgia syndrome (FM) is a debilitating chronic pain condition, which afflicts primarily females. Although the etiology of this illness is not completely understood, FM pain is thought to rely on enhanced pain sensitivity maintained by central mechanisms. One of these mechanisms is central pain amplification, which is characterized by altered temporal summation of second pain (TSSP). Here we use a TSSP paradigm and functional MRI (fMRI) of the spinal cord, brainstem, and brain to noninvasively examine the central nervous system contributions to TSSP in FM patients and normal controls (NC). Functional MRI of pain-free female adults (N = 15) and FM patients (N = 14) was conducted while brief, repetitive heat pain stimuli (0.33 Hz) were applied to the thenar eminence of the hand (C6 dermatome). The stimulus intensity was adjusted to each participant's heat pain sensitivity to achieve moderate pain. Data were analyzed by means of a General Linear Model and region-of-interest analyses. All participants demonstrated significant pain summation in the TSSP condition. FM subjects, however, required significantly lower stimulus intensities than NC to achieve similar TSSP. fMRI analyses of perceptually equal TSSP identified similar brain activity in NC and FM subjects; however, multiple areas in the brainstem (rostral ventromedial medulla and periaqueductal grey region) and spinal cord (dorsal horn) exhibited greater activity in NC subjects. Finally, increased after-sensations and enhanced dorsal horn activity was demonstrated in FM patients. In conclusion, the spinal and brainstem BOLD responses to TSSP are different between NC and FM patients, which may indicate alterations to descending pain control mechanisms suggesting contributions of these mechanisms to central sensitization and pain of FM patients.

fMRI Localization of Spinal Cord Processing Underlying Female Sexual Arousal.

Using functional magnetic resonance imaging, the authors aimed to determine the roles of the human spinal cord in mediating sexual responses in women. Functional magnetic resonance imaging of the entire lower thoracic, lumbar, and sacral spinal cord was performed using a sexual stimulation paradigm designed to elicit psychological and physical components of sexual arousal. Responses were measured in 9 healthy adult women during 3 consecutive conditions: (a) erotic audiovisual, (b) manual clitoral, and (c) audiovisual plus manual stimulation. Functional magnetic resonance imaging results in healthy subjects demonstrate that this method is sensitive for mapping sexual function in the spinal cord, and identify several key regions involved in human sexual response, including the intermediolateral cell column, the dorsal commissural nucleus, and the sacral parasympathetic nucleus. Using spinal functional magnetic resonance imaging, this study identified many of the spinal cord regions involved in female sexual responses. Results from audiovisual and manual clitoral stimulation correspond with previous data regarding lumbar and sacral neurologic changes during sexual arousal. This study provides the first characterization of neural activity in the human spinal cord underlying healthy female sexual responses and sets a foundation for future studies aimed at mapping changes that result from sexual dysfunction, spinal cord trauma or disease.

Neural correlates of temporal summation of second pain in the human brainstem and spinal cord.

Temporal summation of second pain (TSSP) occurs when painful stimuli are presented repetitively (≥ 0.33 Hz) and results from a C-fibre evoked enhancement (or "wind-up") of the dorsal horn neurons. Based on electrophysiological studies in intact animals, windup is considered a purely central phenomenon. With advancements in functional MRI (fMRI), we can now probe the central mechanisms of this pain response in humans. The aim of this study is to characterize the fMRI responses in the healthy human brainstem and spinal cord that correspond to TSSP. Functional MRI of healthy female adults (N = 15) was conducted while brief, repetitive heat pain stimuli were applied to the right thenar eminence (C6 dermatome), and TSSP (0.33 Hz) and control (0.17 Hz) heat pain paradigms were employed. The stimulus intensity was adjusted to each participant's heat pain sensitivity. Data were analyzed by means of a general linear model, and region-of-interest analyses. As predicted, participants demonstrated significant behavioural summation of pain in the TSSP condition. FMRI results identified enhanced activity in the spinal cord dorsal horn at C6 in response to the TSSP condition. Additionally, multiple areas of the brainstem (RVM and PAG) showed greater responses with the TSSP condition. These results suggest that, in humans, increased pain perception in the TSSP condition is reflected by greater responses in the dorsal horn and in regions known to play a role in the descending modulation of pain, which may modulate the spinal cord response.

Spinal cord response to stepwise and block presentation of thermal stimuli: a functional MRI study.

PURPOSE: To examine the characteristics of the spinal cord and brainstem blood oxygenation level-dependent (BOLD) responses to peripheral stimulation in which the temperature is raised in a stepwise fashion, in order to enhance receptor responses, compared to a block design. MATERIALS AND METHODS: Functional magnetic resonance imaging (fMRI) studies of the spinal cord and brainstem were carried out in 14 healthy volunteers at 3T. Thermal sensory stimuli were applied to the right hand in a block-design paradigm, and in a stepwise paradigm to the same peak temperature. Data were analyzed by means of a general linear model, region of interest analyses, and by structural equation modeling. RESULTS: Results demonstrated BOLD responses in a number of consistent regions between the two paradigms as well as significant differences (P < .001) in the locations and magnitudes of some responses. Specifically, the BOLD response in the dorsal horn was significantly higher in the stepwise compared to the block condition (P < .001). However, more significant connections (T >2) between regions were observed in the block condition. CONCLUSION: Results from this study demonstrate the means to design thermal sensory paradigms to probe components of sensory processing in the brainstem and spinal cord.

Spinal and supraspinal processing of thermal stimuli: an fMRI study.

PURPOSE: To assess and characterize responses to innocuous/noxious thermal stimuli and heat allodynia using functional spinal magnetic resonance imaging (spinal fMRI). MATERIALS AND METHODS: Spinal/supraspinal activation patterns of 16 healthy subjects were investigated by applying painful and nonpainful heat stimuli to dermatome C6 baseline and after sensitization with the heat/capsaicin model using fMRI (3T, single-shot TSE, TR 9000 msec, TE 38 msec, FOV 288 × 144 × 20 mm, matrix 192 × 96, voxel size 1 × 1 × 2 mm). RESULTS: Increased activity was observed in ipsi- and contralateral ventral and dorsal spinal horn during noxious heat and heat allodynia. During noxious heat, but not during heat allodynia, activations were visible in the periaqueductal gray, ipsilateral cuneiform nucleus, and ipsilateral dorsolateral pontine tegmentum (DLPT). However, during heat allodynia activations were observed in bilateral ruber nuclei, contralateral DLPT, and rostral ventromedial medulla oblongata (RVM). Activations in contralateral subnucleus reticularis dorsalis (SRD) were visible during both noxious heat and heat allodynia (T >2.5, P < 0.01 for all of the above). After sensitization, activations in RVM and SRD correlated with activations in the ipsilateral dorsal horn of the spinal cord (R = 0.52-0.98, P < 0.05). CONCLUSION: Spinal fMRI successfully demonstrates increased spinal activity and secondary changes in activation of supraspinal centers involved in pain modulation caused by peripheral nociceptor sensitization. J. Magn. Reson. Imaging 2015;41:1046-1055. © 2014 Wiley Periodicals, Inc.

Developmental improvements in voluntary control of behavior: effect of preparation in the fronto-parietal network?

The ability to prepare for an action improves the speed and accuracy of its performance. While many studies indicate that behavior performance continues to improve throughout childhood and adolescence, it remains unclear whether or how preparatory processes change with development. Here, we used a rapid event-related fMRI design in three age groups (8-12, 13-17, 18-25years) who were instructed to execute either a prosaccade (look toward peripheral target) or an antisaccade (look away from target) task. We compared brain activity within the core fronto-parietal network involved in saccade control at two epochs of saccade generation: saccade preparation related to task instruction versus saccade execution related to target appearance. The inclusion of catch trials containing only task instruction and no target or saccade response allowed us to isolate saccade preparation from saccade execution. Five regions of interest were selected: the frontal, supplementary, parietal eye fields which are consistently recruited during saccade generation, and two regions involved in top down executive control: the dorsolateral prefrontal and anterior cingulate cortices. Our results showed strong evidence that developmental improvements in saccade performance were related to better saccade preparation rather than saccade execution. These developmental differences were mostly attributable to children who showed reduced fronto-parietal activity during prosaccade and antisaccade preparation, along with longer saccade reaction times and more incorrect responses, compared to adolescents and adults. The dorsolateral prefrontal cortex was engaged similarly across age groups, suggesting a general role in maintaining task instructions through the whole experiment. Overall, these findings suggest that developmental improvements in behavioral control are supported by improvements in effectively presetting goal-appropriate brain systems.

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.

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.

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.

Impaired executive function signals in motor brain regions in Parkinson's disease.

Recent evidence has shown that patients with Parkinson's disease (PD) often display deficits in executive functions, such as planning for future behavior, and these deficits may stem from pathologies in prefrontal cortex and basal ganglia circuits that are critical to executive control. Using the antisaccade task (look away from a visual stimulus), we show that when the preparatory 'readiness' to perform a given action is dissociated from the actual execution of that action, PD patients off and on dopamine medication display behavioral impairments and reduced cortical brain activation that cannot be explained by a pathology related to dysfunction in movement execution. Rather, they show that the appropriate task set signals were not in place in motor regions prior to execution, resulting in impairments in the control of subsequent voluntary movement. This is the first fMRI study of antisaccade deficits in Parkinson's disease, and importantly, the findings point to a critical role of the basal ganglia in translating signals related to rule representation (executive) into those governing voluntary motor behavior.

Somatotopic arrangement of thermal sensory regions in the healthy human spinal cord determined by means of spinal cord functional MRI.

Previous functional MRI studies of normal sensory function in the human spinal cord, including right-to-left symmetry of activity, have been influenced by order effects between repeated studies. In this study, we apply thermal sensory stimulation to four dermatomes within each functional MRI time-series acquisition. Each of the four dermatomes receives a unique stimulation paradigm, such that the four paradigms form a linearly independent set, enabling detection of each individual stimulus response. Functional MRI data are shown spanning the cervical spinal cord and brainstem in 10 healthy volunteers. Results of general linear model analysis demonstrate consistent patterns of activity within the spinal cord segments corresponding to each dermatome, and a high degree of symmetry between right-side and left-side stimulation. Connectivity analyses also demonstrate consistent areas of activity and connectivity between spinal cord and brainstem regions corresponding to known anatomy. However, right-side and left-side responses are not at precisely the same rostral-caudal positions, but are offset by several millimeters, with left-side responses consistently more caudal than right-side responses. The results confirm that distinct responses to multiple interleaved sensory stimuli can be distinguished, enabling studies of sensory responses within the spinal cord without the confounding effects of comparing sequential studies.

Diffusion tensor imaging in the human spinal cord: development, limitations, and clinical applications.

Diffusion tensor imaging (DTI) is currently the only non-invasive in vivo assessment of white matter tract integrity. Capitalizing on the diffusion properties of water within an axon, DTI enables the visualization of tissue structure at a microscopic scale. Furthermore, measurements of anisotropy and diffusivity enable the detection of subtle details of the effects of injury that cannot be detected using conventional magnetic resonance techniques. Recently, DTI has been applied to the spinal cord, and results have demonstrated it to be a valuable tool for assessing the extent of white matter damage in numerous spinal cord-related conditions including multiple sclerosis, spinal cord injury, amyotrophic lateral sclerosis, myelitis, and spinal cord tumors. The purpose of this review is to discuss the technical limitations of the imaging method within the spinal cord, review possible solutions, and highlight the current uses and the potential clinical application of this technique.

Neural correlates of sexual arousal in the spinal cords of able-bodied men: a spinal fMRI investigation.

The purpose of this study was to determine whether spinal cord functional magnetic resonance imaging could be used to map neural activity throughout the lower thoracic, lumbar, and sacral spinal cord regions during sexual arousal in healthy men. The authors found that viewing erotic films and genital self-stimulation elicited predominantly increased signal, indicative of amplified neuronal input to the dorsal and ventral horns and in the autonomic preganglionic nuclei of the lower thoracic, lumbar, and sacral spinal cord. In addition, linear regression analyses revealed a number of robust correlations (|R| ≥ 0.7) between signal intensity changes in these spinal cord regions and self-reported ratings of mental and physical sexual arousal. Taken together, these results demonstrate that spinal cord functional magnetic resonance imaging is an effective and sensitive technique for mapping the neural correlates of sexual arousal in the spinal cords of able-bodied men. Most important, the results from this study indicate that spinal cord functional magnetic resonance imaging may have important applications as a clinical tool for assessing and mapping the changes that occur in the spinal cords of men suffering from sexual dysfunction as a result of spinal cord trauma.

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.

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.