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.
Migraine pathophysiology includes altered brainstem excitability, and recent neuromodulatory approaches aimed at controlling migraine episodes have targeted key brainstem relay and modulatory nuclei. In this study, we evaluated the impact of respiratory-gated auricular vagal afferent nerve stimulation (RAVANS), a novel neuromodulatory intervention based on an existing transcutaneous vagus nerve stimulation approach, in the modulation of brainstem activity and connectivity in migraine patients. We applied 3T-functional magnetic resonance imaging with improved in-plane spatial resolution (2.62 × 2.62 mm) in episodic migraine (interictal) and age- and sex-matched healthy controls to evaluate brain response to RAVANS (gated to either inhalation or exhalation) and sham stimulation. We further investigated RAVANS modulation of tactile trigeminal sensory afference response in the brainstem using air-puff stimulation directed to the forehead during functional magnetic resonance imaging. Compared with sham and inhalatory-gated RAVANS (iRAVANS), exhalatory-gated RAVANS (eRAVANS) activated an ipsilateral pontomedullary region consistent with nucleus tractus solitarii (NTS). During eRAVANS, NTS connectivity was increased to anterior insula and anterior midcingulate cortex, compared with both sham and iRAVANS, in migraine patients. Increased connectivity was inversely correlated with relative time to the next migraine attack, suggesting clinical relevance to this change in connectivity. Poststimulation effects were also noted immediately after eRAVANS, as we found increased activation in putative pontine serotonergic (ie, nucleus raphe centralis) and noradrenergic (ie, locus coeruleus) nuclei in response to trigeminal sensory afference. Regulation of activity and connectivity of brainstem and cortical regions involved in serotonergic and noradrenergic regulation and pain modulation may constitute an underlying mechanism supporting beneficial clinical outcomes for eRAVANS applied for episodic migraine.
Objective.: Fibromyalgia is a chronic pain condition with few effective treatments. Many fibromyalgia patients seek acupuncture for analgesia; however, its efficacy is limited and not fully understood. This may be due to heterogeneous pathologies among participants in acupuncture clinical trials. We hypothesized that pressure pain tenderness would differentially classify treatment response to verum and sham acupuncture in fibromyalgia patients.
Design.: Baseline pressure pain sensitivity at the thumbnail at baseline was used in linear mixed models as a modifier of differential treatment response to sham versus verum acupuncture. Similarly, needle-induced sensation was also analyzed to determine its differential effect of treatment on clinical pain.
Methods and Patients.: A cohort of 114 fibromyalgia patients received baseline pressure pain testing and were randomized to either verum (N = 59) or sham (N = 55) acupuncture. Participants received treatments from once a week to three times a week, increasing in three-week blocks for a total of 18 treatments. Clinical pain was measured on a 101-point visual analog scale, and needle sensation was measured by questionnaire throughout the trial.
Results.: Participants who had higher pain pressure thresholds had greater reduction in clinical pain following verum acupuncture while participants who had lower pain pressure thresholds showed better analgesic response to sham acupuncture. Moreover, patients with lower pressure pain thresholds had exacerbated clinical pain following verum acupuncture. Similar relationships were observed for sensitivity to acupuncture needling.
Conclusions.: These findings suggest that acupuncture efficacy in fibromyalgia may be underestimated and a more personalized treatment for fibromyalgia may also be possible.
Fibromyalgia (FM) is a complex syndrome characterized by chronic widespread pain, hyperalgesia, and other disabling symptoms. Although the brain response to experimental pain in FM patients has been the object of intense investigation, the biological underpinnings of painful after-sensations (PAS), and their relation to negative affect have received little attention. In this cross-sectional cohort study, subjects with FM (n = 53) and healthy controls (n = 17) were assessed for PAS using exposure to a sustained, moderately painful cuff stimulus to the leg, individually calibrated to a target pain intensity of 40 of 100. Despite requiring lower cuff pressures to achieve the target pain level, FM patients reported more pronounced PAS 15 seconds after the end of cuff stimulation, which correlated positively with clinical pain scores. Functional magnetic resonance imaging revealed reduced deactivation of the medial temporal lobe (MTL; amygdala, hippocampus, parahippocampal gyrus) in FM patients, during pain stimulation, as well as in the ensuing poststimulation period, when PAS are experienced. Moreover, the functional magnetic resonance imaging signal measured during the poststimulation period in the MTL, as well as in the insular and anterior middle cingulate and medial prefrontal cortices, correlated with the severity of reported PAS by FM patients. These results suggest that the MTL plays a role in PAS in FM patients. PERSPECTIVE: PAS are more common and severe in FM, and are associated with clinical pain and catastrophizing. PAS severity is also associated with less MTL deactivation, suggesting that the MTL, a core node of the default mode network, may be important in the prolongation of pain sensation in FM.
Carpal tunnel syndrome is the most common entrapment neuropathy, affecting the median nerve at the wrist. Acupuncture is a minimally-invasive and conservative therapeutic option, and while rooted in a complex practice ritual, acupuncture overlaps significantly with many conventional peripherally-focused neuromodulatory therapies. However, the neurophysiological mechanisms by which acupuncture impacts accepted subjective/psychological and objective/physiological outcomes are not well understood. Eligible patients (n = 80, 65 female, age: 49.3 ± 8.6 years) were enrolled and randomized into three intervention arms: (i) verum electro-acupuncture 'local' to the more affected hand; (ii) verum electro-acupuncture at 'distal' body sites, near the ankle contralesional to the more affected hand; and (iii) local sham electro-acupuncture using non-penetrating placebo needles. Acupuncture therapy was provided for 16 sessions over 8 weeks. Boston Carpal Tunnel Syndrome Questionnaire assessed pain and paraesthesia symptoms at baseline, following therapy and at 3-month follow-up. Nerve conduction studies assessing median nerve sensory latency and brain imaging data were acquired at baseline and following therapy. Functional magnetic resonance imaging assessed somatotopy in the primary somatosensory cortex using vibrotactile stimulation over three digits (2, 3 and 5). While all three acupuncture interventions reduced symptom severity, verum (local and distal) acupuncture was superior to sham in producing improvements in neurophysiological outcomes, both local to the wrist (i.e. median sensory nerve conduction latency) and in the brain (i.e. digit 2/3 cortical separation distance). Moreover, greater improvement in second/third interdigit cortical separation distance following verum acupuncture predicted sustained improvements in symptom severity at 3-month follow-up. We further explored potential differential mechanisms of local versus distal acupuncture using diffusion tensor imaging of white matter microstructure adjacent to the primary somatosensory cortex. Compared to healthy adults (n = 34, 28 female, 49.7 ± 9.9 years old), patients with carpal tunnel syndrome demonstrated increased fractional anisotropy in several regions and, for these regions we found that improvement in median nerve latency was associated with reduction of fractional anisotropy near (i) contralesional hand area following verum, but not sham, acupuncture; (ii) ipsilesional hand area following local, but not distal or sham, acupuncture; and (iii) ipsilesional leg area following distal, but not local or sham, acupuncture. As these primary somatosensory cortex subregions are distinctly targeted by local versus distal acupuncture electrostimulation, acupuncture at local versus distal sites may improve median nerve function at the wrist by somatotopically distinct neuroplasticity in the primary somatosensory cortex following therapy. Our study further suggests that improvements in primary somatosensory cortex somatotopy can predict long-term clinical outcomes for carpal tunnel syndrome.
The human brainstem plays a central role in connecting the cerebrum, the cerebellum and the spinal cord to one another, hosting relay nuclei for afferent and efferent signaling, and providing source nuclei for several neuromodulatory systems that impact central nervous system function. While the investigation of the brainstem with functional or structural magnetic resonance imaging has been hampered for years due to this brain structure's physiological and anatomical characteristics, the field has seen significant advances in recent years thanks to the broader adoption of ultrahigh-field (UHF) MRI scanning. In the present review, we focus on the advantages offered by UHF in the context of brainstem imaging, as well as the challenges posed by the investigation of this complex brain structure in terms of data acquisition and analysis. We also illustrate how UHF MRI can shed new light on the neuroanatomy and neurophysiology underlying different brainstem-based circuitries, such as the central autonomic network and neurotransmitter/neuromodulator systems, discuss existing and foreseeable clinical applications to better understand diseases such as chronic pain and Parkinson's disease, and explore promising future directions for further improvements in brainstem imaging using UHF MRI techniques.
BACKGROUND: A clear understanding of the neural basis of consciousness is fundamental to research in clinical and basic neuroscience disciplines and anesthesia. Recently, decreased efficiency of information integration was suggested as a core network feature of propofol-induced unconsciousness. However, it is unclear whether this finding can be generalized to dexmedetomidine, which has a different molecular target.
METHODS: Dexmedetomidine was administered as a 1-μg/kg bolus over 10 min, followed by a 0.7-μg · kg · h infusion to healthy human volunteers (age range, 18 to 36 yr; n = 15). Resting-state functional magnetic resonance imaging data were acquired during baseline, dexmedetomidine-induced altered arousal, and recovery states. Zero-lag correlations between resting-state functional magnetic resonance imaging signals extracted from 131 brain parcellations were used to construct weighted brain networks. Network efficiency, degree distribution, and node strength were computed using graph analysis. Parcellated brain regions were also mapped to known resting-state networks to study functional connectivity changes.
RESULTS: Dexmedetomidine significantly reduced the local and global efficiencies of graph theory-derived networks. Dexmedetomidine also reduced the average brain connectivity strength without impairing the degree distribution. Functional connectivity within and between all resting-state networks was modulated by dexmedetomidine.
CONCLUSIONS: Dexmedetomidine is associated with a significant drop in the capacity for efficient information transmission at both the local and global levels. These changes result from reductions in the strength of connectivity and also manifest as reduced within and between resting-state network connectivity. These findings strengthen the hypothesis that conscious processing relies on an efficient system of information transfer in the brain.
The brain networks supporting nausea not yet understood. We previously found that while visual stimulation activated primary (V1) and extrastriate visual cortices (MT+/V5, coding for visual motion), increasing nausea was associated with increasing sustained activation in several brain areas, with significant co-activation for anterior insula (aIns) and mid-cingulate (MCC) cortices. Here, we hypothesized that motion sickness also alters functional connectivity between visual motion and previously identified nausea-processing brain regions. Subjects prone to motion sickness and controls completed a motion sickness provocation task during fMRI/ECG acquisition. We studied changes in connectivity between visual processing areas activated by the stimulus (MT+/V5, V1), right aIns and MCC when comparing rest (BASELINE) to peak nausea state (NAUSEA). Compared to BASELINE, NAUSEA reduced connectivity between right and left V1 and increased connectivity between right MT+/V5 and aIns and between left MT+/V5 and MCC. Additionally, the change in MT+/V5 to insula connectivity was significantly associated with a change in sympathovagal balance, assessed by heart rate variability analysis. No state-related connectivity changes were noted for the control group. Increased connectivity between a visual motion processing region and nausea/salience brain regions may reflect increased transfer of visual/vestibular mismatch information to brain regions supporting nausea perception and autonomic processing. We conclude that vection-induced nausea increases connectivity between nausea-processing regions and those activated by the nauseogenic stimulus. This enhanced low-frequency coupling may support continual, slowly evolving nausea perception and shifts toward sympathetic dominance. Disengaging this coupling may be a target for biobehavioral interventions aimed at reducing motion sickness severity.
Cyclic Vomiting Syndrome (CVS) has been linked to episodic migraine, yet little is known about the precise brain-based mechanisms underpinning CVS, and whether these associated conditions share similar pathophysiology. We investigated the functional integrity of salience (SLN) and sensorimotor (SMN) intrinsic connectivity networks in CVS, migraine and healthy controls using brain functional Magnetic Resonance Imaging. CVS, relative to both migraine and controls, showed increased SLN connectivity to middle/posterior insula, a key brain region for nausea and viscerosensory processing. In contrast, this same region showed diminished SMN connectivity in both CVS and migraine. These results highlight both unique and potentially shared pathophysiology between these conditions, and suggest a potential target for therapeutics in future studies.
OBJECTIVE(S): Fibromyalgia (FM) is a chronic, common pain disorder characterized by hyperalgesia. A key mechanism by which cognitive-behavioral therapy (CBT) fosters improvement in pain outcomes is via reductions in hyperalgesia and pain-related catastrophizing, a dysfunctional set of cognitive-emotional processes. However, the neural underpinnings of these CBT effects are unclear. Our aim was to assess CBT's effects on the brain circuitry underlying hyperalgesia in FM patients, and to explore the role of treatment-associated reduction in catastrophizing as a contributor to normalization of pain-relevant brain circuitry and clinical improvement.
METHODS: In total, 16 high-catastrophizing FM patients were enrolled in the study and randomized to 4 weeks of individual treatment with either CBT or a Fibromyalgia Education (control) condition. Resting state functional magnetic resonance imaging scans evaluated functional connectivity between key pain-processing brain regions at baseline and posttreatment. Clinical outcomes were assessed at baseline, posttreatment, and 6-month follow-up.
RESULTS: Catastrophizing correlated with increased resting state functional connectivity between S1 and anterior insula. The CBT group showed larger reductions (compared with the education group) in catastrophizing at posttreatment (P<0.05), and CBT produced significant reductions in both pain and catastrophizing at the 6-month follow-up (P<0.05). Patients in the CBT group also showed reduced resting state connectivity between S1 and anterior/medial insula at posttreatment; these reductions in resting state connectivity were associated with concurrent treatment-related reductions in catastrophizing.
DISCUSSION: The results add to the growing support for the clinically important associations between S1-insula connectivity, clinical pain, and catastrophizing, and suggest that CBT may, in part via reductions in catastrophizing, help to normalize pain-related brain responses in FM.
Acupuncture can have instant and sustained effects, however, its mechanisms of action are still unclear. Here, we investigated the sustained effect of acupuncture by evaluating centrality changes in resting-state functional magnetic resonance imaging after manually stimulating the acupuncture point ST36 at the lower leg or two control point locations (CP1 same dermatome, CP2 different dermatome). Data from a previously published experiment evaluating instant BOLD effects and S2-seed-based resting state connectivity was re-analyzed using eigenvector centrality mapping and degree centrality mapping. These data-driven methods might add new insights into sustained acupuncture effects on both global and local inter-region connectivity (centrality) by evaluating the summary of connections of every voxel. We found higher centrality in parahippocampal gyrus and middle temporal gyrus after ST36 stimulation in comparison to the two control points. These regions are positively correlated to major hubs of the default mode network, which might be the primary network affected by chronic pain. The stronger integration of both regions within the whole-brain connectome after stimulation of ST36 might be a potential contributor to pain modulation by acupuncture. These findings highlight centrality mapping as a valuable analysis for future imaging studies investigating clinically relevant outcomes associated with physiological response to acupuncture stimulation.
CLINICAL TRIAL REGISTRATION: NCT01079689, ClinicalTrials.gov.
OBJECTIVE: Pregabalin (PGB) is an α2 δ calcium-channel subunit ligand that has previously been shown to reduce chronic pain in multiple conditions. Preclinical studies indicate that PGB may down-regulate brain glutamate release while also inhibiting astrocyte induction of glutamatergic synapse formation, and recent clinical findings support the notion that PGB modulates glutamatergic activity and functional brain connectivity in order to produce analgesia. The present study was undertaken to examine concurrent changes in brain gray matter volume (GMV) or evoked-pain connectivity in humans receiving PGB.
METHODS: Sixteen female fibromyalgia patients participated in a randomized double-blind 2-period crossover study of PGB versus placebo. Before and after each period, patients underwent high-resolution structural and evoked pressure-pain functional brain imaging. GMV was analyzed using voxel-based morphometry, and functional connectivity during evoked pressure-pain was assessed.
RESULTS: PGB administration significantly reduced GMV within the posterior insula bilaterally, whereas there were no significant changes in insular GMV following placebo treatment. GMV reductions in the medial frontal gyrus were also observed when comparing PGB versus placebo treatment, and were associated with reduced clinical pain. These reductions in insular GMV were associated with concomitant reductions in connectivity to the default mode network, which was also associated with reduced clinical pain.
CONCLUSION: Short-term PGB treatment altered brain structure and evoked-pain connectivity, and these decreases were associated with reduced clinical pain. We speculate that these fairly rapid changes in GMV may be related to brain neuroplasticity. It is unknown whether these effects are generalizable to other chronic pain states.