Noninvasive measures of neuroinflammatory processes in humans could substantially aid diagnosis and therapeutic development for many disorders, including chronic pain. Several proton magnetic resonance spectroscopy (1H-MRS) metabolites have been linked with glial activity (ie, choline and myo-inositol) and found to be altered in chronic pain patients, but their role in the neuroinflammatory cascade is not well known. Our multimodal study evaluated resting functional magnetic resonance imaging connectivity and 1H-MRS metabolite concentration in insula cortex in 43 patients suffering from fibromyalgia, a chronic centralized pain disorder previously demonstrated to include a neuroinflammatory component, and 16 healthy controls. Patients demonstrated elevated choline (but not myo-inositol) in anterior insula (aIns) (P = 0.03), with greater choline levels linked with worse pain interference (r = 0.41, P = 0.01). In addition, reduced resting functional connectivity between aIns and putamen was associated with both pain interference (whole brain analysis, pcorrected < 0.01) and elevated aIns choline (r = −0.37, P = 0.03). In fact, aIns/putamen connectivity statistically mediated the link between aIns choline and pain interference (P < 0.01), highlighting the pathway by which neuroinflammation can impact clinical pain dysfunction. To further elucidate the molecular substrates of the effects observed, we investigated how putative neuroinflammatory 1H-MRS metabolites are linked with ex vivo tissue inflammatory markers in a nonhuman primate model of neuroinflammation. Results demonstrated that cortical choline levels were correlated with glial fibrillary acidic protein, a known marker for astrogliosis (Spearman r = 0.49, P = 0.03). Choline, a putative neuroinflammatory 1H-MRS-assessed metabolite elevated in fibromyalgia and associated with pain interference, may be linked with astrogliosis in these patients.
The therapeutic potential of transcutaneous auricular VNS (taVNS) is currently being explored for numerous clinical applications. However, optimized response for different clinical indications may depend on specific neuromodulation parameters, and systematic assessments of their influence are still needed to optimize this promising approach.
We proposed that stimulation frequency would have a significant effect on nucleus tractus solitarii (NTS) functional MRI (fMRI) response to respiratory-gated taVNS (RAVANS).
Brainstem fMRI response to auricular RAVANS (cymba conchae) was assessed for four different stimulation frequencies (2, 10, 25, 100 Hz). Sham (no current) stimulation was used to control for respiration effects on fMRI signal.
Our findings demonstrated that RAVANS delivered at 100 Hz evoked the strongest brainstem response, localized to a cluster in the left (ipsilateral) medulla and consistent with purported NTS. A co-localized, although weaker, response was found for 2 Hz RAVANS. Furthermore, RAVANS delivered at 100 Hz also evoked stronger fMRI responses for important monoamine neurotransmitter source nuclei (LC, noradrenergic; MR, DR, serotonergic) and pain/homeostatic regulation nuclei (i.e. PAG).
Our fMRI results support previous localization of taVNS afference to pontomedullary aspect of NTS in the human brainstem, and demonstrate the significant influence of the stimulation frequency on brainstem fMRI response.
The brainstem is known to be an important brain area for nociception and pain processing, and both relaying and coordinating signaling between the cerebrum, cerebellum, and spinal cord. Although preclinical models of pain have characterized the many roles that brainstem nuclei play in nociceptive processing, the degree to which these circuitries extend to humans is not as well known. Unfortunately, the brainstem is also a very challenging region to evaluate in humans with neuroimaging. The challenges for human brainstem imaging arise from the location of this elongated brain structure, proximity to cardiorespiratory noise sources, and the size of its constituent nuclei. These challenges can require dedicated approaches to brainstem imaging, which should be adopted when study hypotheses are focused on brainstem processing of nociception or modulation of pain perception. In fact, our review will highlight many pain neuroimaging studies that have reported some brainstem involvement in nociceptive processing and chronic pain pathology. However, we note that with recent advances in neuroimaging leading to improved spatial and temporal resolution, more studies are needed that take advantage of data collection and analysis methods focused on the challenges of brainstem neuroimaging.
Peripheral measures of autonomic nervous system (ANS) activity at rest have been extensively employed as putative biomarkers of autonomic cardiac control. However, a comprehensive characterization of the brain-based central autonomic network (CAN) sustaining cardiovascular oscillations at rest is missing, limiting the interpretability of these ANS measures as biomarkers of cardiac control. We evaluated combined cardiac and fMRI data from 34 healthy subjects from the Human Connectome Project to detect brain areas functionally linked to cardiovagal modulation at rest. Specifically, we combined voxel-wise fMRI analysis with instantaneous heartbeat and spectral estimates obtained from inhomogeneous linear point-process models. We found exclusively negative associations between cardiac parasympathetic activity at rest and a widespread network including bilateral anterior insulae, right dorsal middle and left posterior insula, right parietal operculum, bilateral medial dorsal and ventrolateral posterior thalamic nuclei, anterior and posterior mid-cingulate cortex, medial frontal gyrus/pre-supplementary motor area. Conversely, we found only positive associations between instantaneous heart rate and brain activity in areas including frontopolar cortex, dorsomedial prefrontal cortex, anterior, middle and posterior cingulate cortices, superior frontal gyrus, and precuneus. Taken together, our data suggests a much wider involvement of diverse brain areas in the CAN at rest than previously thought, which could reflect a differential (both spatially and directionally) CAN activation according to the underlying task. Our insight into CAN activity at rest also allows the investigation of its impairment in clinical populations in which task-based fMRI is difficult to obtain (e.g., comatose patients or infants).
While several studies have found that chronic pain is characterized by increased cross-network connectivitybetween salience, sensorimotor, and default mode (DMN) networks, a large sample-size investigation allowing a more reliable evaluation of somatotopic specificity and subgroup analyses with linkage to clinical pain intensity has been lacking. We enrolled healthy adults and a large cohort of patients (N=181) suffering from chronic low back pain (cLBP). To specifically link brain connectivity with clinical pain intensity, patients were scanned at baseline and after performing physical maneuvers that exacerbated pain. Compared to healthy adults, cLBP patients demonstrated increased connectivity between the functionally-localized back representation in primary somatosensory cortex (S1back) and both salience and DMN networks. Pain exacerbation maneuvers increased S1back connectivity to salience network regions, but decreased connectivity to DMN, with greater pain intensity increase associated with greater shifts in these connectivity patterns. Furthermore, only in cLBP patients reporting high pain catastrophizing, DMN connectivity was increased to a cardinal node of the salience network, anterior insula cortex, which was correlated with increased post-maneuver pain in this cLBP subgroup. Hence, increased information transfer between salience processing regions, particularly anterior insula, and DMN may be strongly influenced by pain catastrophizing. Increased information transfer between salience network and S1 likely plays an important role in shifting nociceptive afference away from self-referential processing, re-allocating attentional focus and affective coding of nociceptive afference from specific body areas. These results demonstrate S1 somatotopic specificity for cross-network connectivity in encoding clinical back pain, and moderating influence of catastrophizing for DMN/insula connectivity.
Background Brainstem-focused mechanisms supporting transcutaneous auricular VNS (taVNS) effects are not well understood, particularly in humans. We employed ultrahigh field (7T) fMRI and evaluated the influence of respiratory phase for optimal targeting, applying our respiratory-gated auricular vagal afferent nerve stimulation (RAVANS) technique. Hypothesis We proposed that targeting of nucleus tractus solitarii (NTS) and cardiovagal modulation in response to taVNS stimuli would be enhanced when stimulation is delivered during a more receptive state, i.e. exhalation. Methods Brainstem fMRI response to auricular taVNS (cymba conchae) was assessed for stimulation delivered during exhalation (eRAVANS) or inhalation (iRAVANS), while exhalation-gated stimulation over the greater auricular nerve (GANctrl, i.e. earlobe) was included as control. Furthermore, we evaluated cardiovagal response to stimulation by calculating instantaneous HF-HRV from cardiac data recorded during fMRI. Results Our findings demonstrated that eRAVANS evoked fMRI signal increase in ipsilateral pontomedullary junction in a cluster including purported NTS. Brainstem response to GANctrl localized a partially-overlapping cluster, more ventrolateral, consistent with spinal trigeminal nucleus. A region-of-interest analysis also found eRAVANS activation in monoaminergic source nuclei including locus coeruleus (LC, noradrenergic) and both dorsal and median raphe (serotonergic) nuclei. Response to eRAVANS was significantly greater than iRAVANS for all nuclei, and greater than GANctrl in LC and raphe nuclei. Furthermore, eRAVANS, but not iRAVANS, enhanced cardiovagal modulation, confirming enhanced eRAVANS response on both central and peripheral neurophysiological levels. Conclusion 7T fMRI localized brainstem response to taVNS, linked such response with autonomic outflow, and demonstrated that taVNS applied during exhalation enhanced NTS targeting.
Background: Fibromyalgia is a chronic pain state that includes widespread musculoskeletal pain, fatigue, psychiatric symptoms, cognitive and sleep disturbances, and multiple somatic symptoms. Current therapies are often insufficient or come with significant risks, and while there is an increasing demand for non-pharmacologic and especially non-opioid pain management such as that offered through complementary and alternative medicine therapies, there is currently insufficient evidence to recommend these therapies. Percutaneous electrical neural stimulation (PENS) is an evidence-based treatment option for pain conditions that involves electrical current stimulation through needles inserted into the skin. Percutaneous electrical neural field stimulation (PENFS) of the auricle is similar to PENS, but instead of targeting a single neurovascular bundle, PENFS stimulates the entire ear, covering all auricular branches of the cranial nerves, including the vagus nerve. The neural mechanisms of PENFS for fibromyalgia symptom relief are unknown. Objective: We hypothesize that PENFS treatment will decrease functional brain connectivity between the default mode network (DMN) and right posterior insula in fibromyalgia patients. We expect that the decrease in functional connectivity between the DMN and insula will correlate with patient-reported analgesic improvements as indicated by the Defense and Veterans Pain Rating Scale (DVPRS) and will be anti-correlated with patient-reported analgesic medication consumption. Exploratory analyses will be performed for further hypothesis generation. Methods: A total of 20 adults from the Atlanta Veterans Affairs Medical Center diagnosed with fibromyalgia will be randomized into 2 groups: 10 subjects to a control (standard therapy) group and 10 subjects to a PENFS treatment group. The pragmatic, standard therapy group will include pharmacologic treatments such as anticonvulsants, non-steroidal anti-inflammatory drugs, topical agents and physical therapy individualized to patient comorbidities and preferences, prescribed by a pain management practitioner. The PENFS group will include the above therapies in addition to the PENFS treatments. The PENFS subject group will have the Neuro-Stim System placed on the ear for 5 days then removed and replaced once per week for 4 weeks. The primary outcome will be resting functional magnetic resonance imaging connectivity between DMN and insula, which will also be correlated with pain relief and functional improvements. This connectivity will be analyzed utilizing functional connectivity magnetic resonance imaging (fcMRI) and will be compared with patient-reported analgesic improvements as indicated by the DVPRS and patient-reported analgesic medication consumption. Pain and function will be further evaluated using Patient-Reported Outcomes Measurement Information System measures and measures describing a person's functional status from Activity and Participation section of the International Classification of Functioning Disability and Health. Results: This trial has been funded by the Veterans Health Administration Program Office. This study attained approval by the Emory University/Veterans Affairs (VA) institutional review board and VA Research & Development committee. Institutional review board expedited approval was granted on 2/7/17 (IRB00092224). The study start date is 6/1/17 and estimated completion date is 5/31/20. The recruitment started in June 2017. Conclusions: This is a feasibility study that is meant to demonstrate the practicality of using fcMRI to study the neural correlates of PENFS outcomes and provide information regarding power calculations in order to design and execute a larger randomized controlled clinical trial to determine the efficacy of PENFS for improving pain and function. Trial Registration: ClinicalTrials.gov NCT03008837; https://clinicaltrials.gov/ct2/show/NCT03008837 (Archived by WebCite at http://www.webcitation.org/6wrY3NmaQ).
Expectation can significantly modulate pain and treatment effects. This study aims to investigate if boosting patients' expectancy can enhance the treatment of knee osteoarthritis (KOA), and its underlying brain mechanism.
Seventy-four KOA patients were recruited and randomized to three groups: boosted acupuncture (with a manipulation to enhance expectation), standard acupuncture, or treatment as usual (TAU). Each patient underwent six treatments before being debriefed, and four additional treatments after being debriefed. The fMRI scans were applied during the first and sixth treatment sessions.
We found significantly decreased knee pain in the boosted acupuncture group compared to the standard acupuncture or TAU groups after both six and ten treatments. Resting state functional connectivity (rsFC) analyses using the nucleus accumbens (NAc) as the seed showed rsFC increases between the NAc and the medial prefrontal cortex (MPFC)/rostral anterior cingulate cortex (rACC) and dorsolateral prefrontal cortex in the boosted group as compared to the standard acupuncture group after multiple treatments. Expectancy scores after the first treatment were significantly associated with increased NAc-rACC/MPFC rsFC and decreased knee pain following treatment.
Our study provides a novel method and mechanism for boosting the treatment of pain in patients with KOA. Our findings may shed light on enhancing outcomes of pharmacological and integrative medicines in clinical settings.
The objective of this study was to examine the association between facets of trait mindfulness, pain catastrophizing, and pain severity in a sample of patients with fibromyalgia. Patients with fibromyalgia completed validated baseline and diary assessments of clinical pain, mindfulness, and pain catastrophizing. Multilevel modeling analyses indicated that the daily association between catastrophizing and pain intensity was moderated by certain mindfulness facets. Our findings suggest that various aspects of mindfulness may interact differently with pain and catastrophizing, which may have implications for the design and testing of interventions targeting mindfulness and catastrophizing in fibromyalgia patients.
Heightened anticipation and fear of movement-related pain has been linked to detrimental fear-avoidance behavior in chronic low back pain (cLBP). Spinal manipulative therapy (SMT) has been proposed to work partly by exposing patients to nonharmful but forceful mobilization of the painful joint, thereby disrupting the relationship among pain anticipation, fear, and movement. Here, we investigated the brain processes underpinning pain anticipation and fear of movement in cLBP, and their modulation by SMT, using functional magnetic resonance imaging. Fifteen cLBP patients and 16 healthy control (HC) subjects were scanned while observing and rating video clips depicting back-straining or neutral physical exercises, which they knew they would have to perform at the end of the visit. This task was repeated after a single session of spinal manipulation (cLBP and HC group) or mobilization (cLBP group only), in separate visits. Compared with HC subjects, cLBP patients reported higher expected pain and fear of performing the observed exercises. These ratings, along with clinical pain, were reduced by SMT. Moreover, cLBP, relative to HC subjects, demonstrated higher blood oxygen level–dependent signal in brain circuitry that has previously been implicated in salience, social cognition, and mentalizing, while observing back straining compared with neutral exercises. The engagement of this circuitry was reduced after SMT, and especially the spinal manipulation session, proportionally to the magnitude of SMT-induced reduction in anticipated pain and fear. This study sheds light on the brain processing of anticipated pain and fear of back-straining movement in cLBP, and suggests that SMT may reduce cognitive and affective-motivational aspects of fear-avoidance behavior, along with corresponding brain processes. Perspective This study of cLBP patients investigated how SMT affects clinical pain, expected pain, and fear of physical exercises. The results indicate that one of the mechanisms of SMT may be to reduce pain expectancy, fear of movement, and associated brain responses.
Abstract Objective Central nervous system pathways involving pain modulation shape the pain experience in patients with chronic pain. Our objectives were to understand the mechanisms underlying pain in rheumatoid arthritis (RA) and identify brain signals that may serve as imaging markers for developing targeted treatments for RA pain. Methods Subjects with RA and matched controls underwent functional magnetic resonance imaging, using pulsed arterial spin labeling (pASL). The imaging conditions included: 1) resting state, 2) low intensity stimulus and 3) high intensity stimulus. Stimuli consisted of mechanical pressure applied to metacarpophalangeal (MCP) joints with an automated cuff inflator. The low intensity stimulus was 30 mmHg. The high intensity stimulus was the amount of pressure required to achieve 40/100 pain intensity for each RA patient, with the same amount of pressure given to the matched control. Results Among RA patients, regional cerebral blood flow (rCBF) in medial frontal cortex (MFC) and dorsolateral prefrontal cortex increased during both low and high pressure stimuli. No rCBF changes were noted for pain-free controls. In region of interest analyses among RA patients, baseline rCBF in MFC was negatively correlated with pressure required for the high intensity stimulus (p<0.01) and positively correlated with pain induced by the low intensity stimulus (p<0.05). Baseline rCBF also marginally correlated with disease activity (p=0.05). rCBF during high pain was positively correlated with pain severity and interference (p's<0.05). Conclusion In response to clinically-relevant joint pain evoked by MCP pressure, neural processing in MFC increases and is directly associated with clinical pain in RA. This article is protected by copyright. All rights reserved.
Evers AWM, Colloca L, Blease C, Annoni M, Atlas LY, Bnedetti F, Bingel U, Büchel C, Carvalho C, Colagiuri B, Crum AJ, Enck P, Gaab J, Geers AL, Howick J, Jensen KB, Kirsch I, Meissner K, Napadow V, Peerdeman KJ, Raz A, Rief W, Vase L, Wager TD, Wampold BE, Weimer K, Wiech KA, Kaptchuk TJ, Klinger RB, Kelley JM. Implications of Placebo and Nocebo Effects for Clinical Practice: Expert Consensus. Psychotherapy and Psychosomatics 2018;87:204-210.Abstract
Background: Placebo and nocebo effects occur in clinical or laboratory medical contexts after administration of an inert treatment or as part of active treatments and are due to psychobiological mechanisms such as expectancies of the patient. Placebo and nocebo studies have evolved from predominantly methodological research into a far-reaching interdisciplinary field that is unravelling the neurobiological, behavioural and clinical underpinnings of these phenomena in a broad variety of medical conditions. As a consequence, there is an increasing demand from health professionals to develop expert recommendations about evidence-based and ethical use of placebo and nocebo effects for clinical practice. Methods: A survey and interdisciplinary expert meeting by invitation was organized as part of the 1st Society for Interdisciplinary Placebo Studies (SIPS) conference in 2017. Twenty-nine internationally recognized placebo researchers participated. Results: There was consensus that maximizing placebo effects and minimizing nocebo effects should lead to better treatment outcomes with fewer side effects. Experts particularly agreed on the importance of informing patients about placebo and nocebo effects and training health professionals in patient-clinician communication to maximize placebo and minimize nocebo effects. Conclusions: The current paper forms a first step towards developing evidence-based and ethical recommendations about the implications of placebo and nocebo research for medical practice, based on the current state of evidence and the consensus of experts. Future research might focus on how to implement these recommendations, including how to optimize conditions for educating patients about placebo and nocebo effects and providing training for the implementation in clinical practice.
Objective Pain catastrophizing is a common feature of chronic pain, including fibromyalgia (FM), and is strongly associated with amplified pain severity and disability. While previous neuroimaging studies have focused on evoked pain response modulation by catastrophizing, the brain mechanisms supporting pain catastrophizing itself are unknown. We designed a functional magnetic resonance imaging (fMRI)–based pain catastrophizing task whereby patients with chronic pain engaged in catastrophizing-related cognitions. We undertook this study to test our hypothesis that catastrophizing about clinical pain would be associated with amplified activation in nodes of the default mode network (DMN), which encode self-referential cognition and show altered functioning in chronic pain. Methods During fMRI, 31 FM patients reflected on how catastrophizing (CAT) statements (drawn from the Pain Catastrophizing Scale) impact their typical FM pain experience. Response to CAT statements was compared to response to matched neutral (NEU) statements. Results During statement reflection, higher fMRI signal during CAT statements than during NEU statements was found in several DMN brain areas, including the ventral (posterior) and dorsal (anterior) posterior cingulate cortex (vPCC and dPCC, respectively). Patients’ ratings of CAT statement applicability were correlated solely with activity in the vPCC, a main DMN hub supporting self-referential cognition (r = 0.38, P < 0.05). Clinical pain severity was correlated solely with activity in the dPCC, a PCC subregion associated with cognitive control and sensorimotor processing (r = 0.38, P < 0.05). Conclusion These findings provide evidence that the PCC encodes pain catastrophizing in FM and suggest distinct roles for different PCC subregions. Understanding the brain circuitry encoding pain catastrophizing in FM will prove to be important in identifying and evaluating the success of interventions targeting negative affect in chronic pain management.