Publications

2016
Lee J, Lin RL, Garcia RG, Kim J, Kim H, Loggia ML, Mawla I, Wasan AD, Edwards RR, Rosen BR, Hadjikhani N, Napadow V. Reduced insula habituation associated with amplification of trigeminal brainstem input in migraine. Cephalalgia 2016;Abstract
BACKGROUND: Impaired sensory processing in migraine can reflect diminished habituation, increased activation, or even increased gain or amplification of activity from the primary synapse in the brainstem to higher cortical/subcortical brain regions. METHODS: We scanned 16 episodic migraine (interictal) and 16 healthy controls (cross-sectional study), and evaluated brain response to innocuous air-puff stimulation over the right forehead in the ophthalmic nerve (V1) trigeminal territory. We further evaluated habituation, and cortical/subcortical amplification relative to spinal trigeminal nucleus (Sp5) activation. RESULTS: Migraine subjects showed greater amplification from Sp5 to the posterior insula and hypothalamus. In addition, while controls showed habituation to repetitive sensory stimulation in all activated cortical regions (e.g. the bilateral posterior insula and secondary somatosensory cortices), for migraine subjects, habituation was not found in the posterior insula. Moreover, in migraine, the habituation slope was correlated with the amplification ratio in the posterior insula and secondary somatosensory cortex, i.e. greater amplification was associated with reduced habituation in these regions. CONCLUSIONS: These findings suggest that in episodic migraine, amplified information processing from spinal trigeminal relay nuclei is linked to an impaired habituation response. This phenomenon was localized in the posterior insula, highlighting the important role of this structure in mechanisms supporting altered sensory processing in episodic migraine.
jclee_cephalagia_2016.pdf
Sclocco R, Beissner F, Desbordes G, Polimeni JR, Wald LL, Kettner NW, Kim J, Garcia RG, Renvall V, Bianchi AM, Cerutti S, Napadow V, Barbieri R. Neuroimaging brainstem circuitry supporting cardiovagal response to pain: a combined heart rate variability/ultrahigh-field (7 T) functional magnetic resonance imaging study. Philos Trans A Math Phys Eng Sci 2016;374(2067)Abstract

Central autonomic control nuclei in the brainstem have been difficult to evaluate non-invasively in humans. We applied ultrahigh-field (7 T) functional magnetic resonance imaging (fMRI), and the improved spatial resolution it affords (1.2 mm isotropic), to evaluate putative brainstem nuclei that control and/or sense pain-evoked cardiovagal modulation (high-frequency heart rate variability (HF-HRV) instantaneously estimated through a point-process approach). The time-variant HF-HRV signal was used to guide the general linear model analysis of neuroimaging data. Sustained (6 min) pain stimulation reduced cardiovagal modulation, with the most prominent reduction evident in the first 2 min. Brainstem nuclei associated with pain-evoked HF-HRV reduction were previously implicated in both autonomic regulation and pain processing. Specifically, clusters consistent with the rostral ventromedial medulla, ventral nucleus reticularis (Rt)/nucleus ambiguus (NAmb) and pontine nuclei (Pn) were found when contrasting sustained pain versus rest. Analysis of the initial 2-min period identified Rt/NAmb and Pn, in addition to clusters consistent with the dorsal motor nucleus of the vagus/nucleus of the solitary tract and locus coeruleus. Combining high spatial resolution fMRI and high temporal resolution HF-HRV allowed for a non-invasive characterization of brainstem nuclei, suggesting that nociceptive afference induces pain-processing brainstem nuclei to function in concert with known premotor autonomic nuclei in order to affect the cardiovagal response to pain.

sclocco_philtrans_2016.pdf
Maeda Y, Kettner N, Kim J, Kim H, Cina S, Malatesta C, Gerber J, McManus C, Libby A, Mezzacappa P, Mawla I, Morse LR, Audette J, Napadow V. Primary somatosensory/motor cortical thickness distinguishes paresthesia-dominant from pain-dominant carpal tunnel syndrome. Pain 2016;157(5):1085-93.Abstract

Paresthesia-dominant and pain-dominant subgroups have been noted in carpal tunnel syndrome (CTS), a peripheral neuropathic disorder characterized by altered primary somatosensory/motor (S1/M1) physiology. We aimed to investigate whether brain morphometry dissociates these subgroups. Subjects with CTS were evaluated with nerve conduction studies, whereas symptom severity ratings were used to allocate subjects into paresthesia-dominant (CTS-paresthesia), pain-dominant (CTS-pain), and pain/paresthesia nondominant (not included in further analysis) subgroups. Structural brain magnetic resonance imaging data were acquired at 3T using a multiecho MPRAGE T1-weighted pulse sequence, and gray matter cortical thickness was calculated across the entire brain using validated, automated methods. CTS-paresthesia subjects demonstrated reduced median sensory nerve conduction velocity (P = 0.05) compared with CTS-pain subjects. In addition, cortical thickness in precentral and postcentral gyri (S1/M1 hand area) contralateral to the more affected hand was significantly reduced in CTS-paresthesia subgroup compared with CTS-pain subgroup. Moreover, in CTS-paresthesia subjects, precentral cortical thickness was negatively correlated with paresthesia severity (r(34) = -0.40, P = 0.016) and positively correlated with median nerve sensory velocity (r(36) = 0.51, P = 0.001), but not with pain severity. Conversely, in CTS-pain subjects, contralesional S1 (r(9) = 0.62, P = 0.042) and M1 (r(9) = 0.61, P = 0.046) cortical thickness were correlated with pain severity, but not median nerve velocity or paresthesia severity. This double dissociation in somatotopically specific S1/M1 areas suggests a neuroanatomical substrate for symptom-based CTS subgroups. Such fine-grained subgrouping of CTS may lead to improved personalized therapeutic approaches, based on superior characterization of the linkage between peripheral and central neuroplasticity.

maeda_pain_2016.pdf
Macpherson H, Hammerschlag R, Coeytaux RR, Davis RT, Harris RE, Kong J-T, Langevin HM, Lao L, Milley RJ, Napadow V, Schnyer RN, Stener-Victorin E, Witt CM, Wayne PM. Unanticipated Insights into Biomedicine from the Study of Acupuncture. J Altern Complement Med 2016;Abstract
Research into acupuncture has had ripple effects beyond the field of acupuncture. This paper identifies five exemplars to illustrate that there is tangible evidence of the way insights gleaned from acupuncture research have informed biomedical research, practice, or policy. The first exemplar documents how early research into acupuncture analgesia has expanded into neuroimaging research, broadening physiologic understanding and treatment of chronic pain. The second describes how the acupuncture needle has become a tool to enhance biomedical knowledge of connective tissue. The third exemplar, which illustrates use of a modified acupuncture needle as a sham device, focuses on emergent understanding of placebo effects and, in turn, on insights into therapeutic encounters in treatments unrelated to acupuncture. The fourth exemplar documents that two medical devices now in widespread use were inspired by acupuncture: transcutaneous electrical nerve stimulators for pain control and antinausea wrist bands. The final exemplar describes how pragmatic clinical trial designs applied in acupuncture research have informed current general interest in comparative effectiveness research. In conclusion, these exemplars of unanticipated outcomes of acupuncture research comprise an additional rationale for continued support of basic and clinical research evaluating acupuncture and other under-researched therapies.
As-Sanie S, Kim J, Schmidt-Wilcke T, Sundgren PC, Clauw DJ, Napadow V, Harris RE. Functional Connectivity Is Associated With Altered Brain Chemistry in Women With Endometriosis-Associated Chronic Pelvic Pain. J Pain 2016;17(1):1-13.Abstract
UNLABELLED: In contrast to women with relatively asymptomatic endometriosis, women with endometriosis-associated chronic pelvic pain (CPP) exhibit nonpelvic hyperalgesia and decreased gray matter volume in key neural pain processing regions. Although these findings suggest central pain amplification in endometriosis-associated CPP, the underlying changes in brain chemistry and function associated with central pain amplification remain unknown. We performed proton spectroscopy and seed-based resting functional connectivity magnetic resonance imaging to determine whether women with endometriosis display differences in insula excitatory neurotransmitter concentrations or intrinsic brain connectivity to other pain-related brain regions. Relative to age-matched pain-free controls, women with endometriosis-associated CPP displayed increased levels of combined glutamine-glutamate (Glx) within the anterior insula and greater anterior insula connectivity to the medial prefrontal cortex (mPFC). Increased connectivity between these regions was positively correlated with anterior insula Glx concentrations (r = .87), as well as clinical anxiety (r = .61, P = .02), depression (r = .60, P = .03), and pain intensity (r = .55, P = .05). There were no significant differences in insula metabolite levels or resting-state connectivity in endometriosis patients without CPP versus controls. We conclude that enhanced anterior insula glutamatergic neurotransmission and connectivity with the mPFC, key regions of the salience and default mode networks, may play a role in the pathophysiology of CPP independent of the presence of endometriosis. PERSPECTIVE: Similar to other chronic pain conditions, endometriosis-associated pelvic pain is associated with altered brain chemistry and function in pain processing regions. These findings support central pain amplification as a mechanism of chronic pelvic pain, and clinicians should consider the use of adjunctive therapies that target central pain dysfunction in these women.
2015
Sclocco R, Citi L, Garcia RG, Cerutti S, Bianchi AM, Kuo B, Napadow V, Barbieri R. Combining sudomotor nerve impulse estimation with fMRI to investigate the central sympathetic response to nausea. Conf Proc IEEE Eng Med Biol Soc 2015;2015:4683-6.Abstract

The skin conductance (SC) signal is one of the most important non-invasive indirect measures of autonomic outflow. Several mathematical models have been proposed in the literature to characterize specific SC features. In this work, we present a method for the estimation of central control of sudomotor nerve impulse (SMI) function using SC. The method is based on a differential formulation decomposed into two first order differential equations. We validate our estimation framework by applying it on an experimental protocol where eleven motion sickness-prone subjects were exposed to a nauseogenic visual stimulus while SC and fMRI signals were recorded. Our results show an expected significant increase in the mean amplitude of SMI peaks during the highest reported nausea, as well as a decreasing trend during recovery, which was not evident for skin conductance level. Importantly, SMI/fMRI analysis found a negative association between SMI and fMRI signal in orbitofrontal, dorsolateral prefrontal, and posterior insula cortices, consistent with previous studies correlating brain fMRI and microneurographic signals.

sclocco_embc_2015.pdf
Ay I, Napadow V, Ay H. Electrical stimulation of the vagus nerve dermatome in the external ear is protective in rat cerebral ischemia. Brain Stimul 2015;8(1):7-12.Abstract
BACKGROUND: Although cervical vagus nerve stimulation is effective for reducing infarct volume in rats, it is not feasible for acute human stroke as it requires surgical incision of the neck. We hypothesized that stimulation of the dermatome in the external ear innervated by the vagus nerve (auricular vagus nerve stimulation; aVNS) reduces infarct volume after transient focal ischemia in rats. METHODS: Animals were randomized to active aVNS or sham stimulation. For aVNS, electrical stimulation of the left cavum concha (1 h duration) using percutaneous needles was initiated 30 min after induction of ischemia. Behavioral and tissue outcome were measured 24 h after induction of ischemia. In a separate experimental dataset, c-Fos immunohistochemistry was performed to identify the brain regions activated after the stimulation. RESULTS: Stimulation of the left cavum concha resulted in bilateral c-Fos staining in the nuclei tractus solitarii and the loci coerulei in all animals. There was no c-Fos staining in any part of the brainstem in sham control animals. The mean infarct volume (SD) as calculated by indirect method was 44.20 ± 7.58% in controls and 31.65 ± 9.67% in treated animals (P < 0.0001). The effect of aVNS on tissue outcome was associated with better neurological scores at 24 h after ischemia (P < 0.0001). CONCLUSIONS: Electric stimulation of the vagus nerve dermatome in the external ear activates brainstem afferent vagal nuclei and reduces infarct volume in rats. This finding has potential to facilitate the development of treatments that leverage the brain's endogenous neuroprotective pathways at the setting of acute ischemic stroke.
ay_brainstim_2015.pdf
Loggia ML, Chonde DB, Akeju O, Arabasz G, Catana C, Edwards RR, Hill E, Hsu S, Izquierdo-Garcia D, Ji R-R, Riley M, Wasan AD, Zürcher NR, Albrecht DS, Vangel MG, Rosen BR, Napadow V, Hooker JM. Evidence for brain glial activation in chronic pain patients. Brain 2015;138(Pt 3):604-15.Abstract
Although substantial evidence has established that microglia and astrocytes play a key role in the establishment and maintenance of persistent pain in animal models, the role of glial cells in human pain disorders remains unknown. Here, using the novel technology of integrated positron emission tomography-magnetic resonance imaging and the recently developed radioligand (11)C-PBR28, we show increased brain levels of the translocator protein (TSPO), a marker of glial activation, in patients with chronic low back pain. As the Ala147Thr polymorphism in the TSPO gene affects binding affinity for (11)C-PBR28, nine patient-control pairs were identified from a larger sample of subjects screened and genotyped, and compared in a matched-pairs design, in which each patient was matched to a TSPO polymorphism-, age- and sex-matched control subject (seven Ala/Ala and two Ala/Thr, five males and four females in each group; median age difference: 1 year; age range: 29-63 for patients and 28-65 for controls). Standardized uptake values normalized to whole brain were significantly higher in patients than controls in multiple brain regions, including thalamus and the putative somatosensory representations of the lumbar spine and leg. The thalamic levels of TSPO were negatively correlated with clinical pain and circulating levels of the proinflammatory citokine interleukin-6, suggesting that TSPO expression exerts pain-protective/anti-inflammatory effects in humans, as predicted by animal studies. Given the putative role of activated glia in the establishment and or maintenance of persistent pain, the present findings offer clinical implications that may serve to guide future studies of the pathophysiology and management of a variety of persistent pain conditions.
loggia_brain_2015.pdf
Desbordes G, Li A, Loggia ML, Kim J, Schalock PC, Lerner E, Tran TN, Ring J, Rosen BR, Kaptchuk TJ, Pfab F, Napadow V. Evoked itch perception is associated with changes in functional brain connectivity. Neuroimage Clin 2015;7:213-21.Abstract
Chronic itch, a highly debilitating condition, has received relatively little attention in the neuroimaging literature. Recent studies suggest that brain regions supporting itch in chronic itch patients encompass sensorimotor and salience networks, and corticostriatal circuits involved in motor preparation for scratching. However, how these different brain areas interact with one another in the context of itch is still unknown. We acquired BOLD fMRI scans in 14 atopic dermatitis patients to investigate resting-state functional connectivity before and after allergen-induced itch exacerbated the clinical itch perception in these patients. A seed-based analysis revealed decreased functional connectivity from baseline resting state to the evoked-itch state between several itch-related brain regions, particularly the insular and cingulate cortices and basal ganglia, where decreased connectivity was significantly correlated with increased levels of perceived itch. In contrast, evoked itch increased connectivity between key nodes of the frontoparietal control network (superior parietal lobule and dorsolateral prefrontal cortex), where higher increase in connectivity was correlated with a lesser increase in perceived itch, suggesting that greater interaction between nodes of this executive attention network serves to limit itch sensation via enhanced top-down regulation. Overall, our results provide the first evidence of itch-dependent changes in functional connectivity across multiple brain regions.
desbordes_niclinical_2015.pdf
Kim J, Loggia ML, Cahalan CM, Harris RE, Beissner F, Garcia RG, Kim H, Barbieri R, Wasan AD, Edwards RR, Napadow V. The somatosensory link in fibromyalgia: functional connectivity of the primary somatosensory cortex is altered by sustained pain and is associated with clinical/autonomic dysfunction. Arthritis Rheumatol 2015;67(5):1395-405.Abstract
OBJECTIVE: Fibromyalgia (FM) is a chronic functional pain syndrome characterized by widespread pain, significant pain catastrophizing, sympathovagal dysfunction, and amplified temporal summation for evoked pain. While several studies have demonstrated altered resting brain connectivity in FM, studies have not specifically probed the somatosensory system and its role in both somatic and nonsomatic FM symptoms. Our objective was to evaluate resting primary somatosensory cortex (S1) connectivity and to explore how sustained, evoked deep tissue pain modulates this connectivity. METHODS: We acquired functional magnetic resonance imaging and electrocardiography data on FM patients and healthy controls during rest (the rest phase) and during sustained mechanical pressure-induced pain over the lower leg (the pain phase). Functional connectivity associated with different S1 subregions was calculated, while S1(leg) connectivity (representation of the leg in the primary somatosensory cortex) was contrasted between the rest phase and the pain phase and was correlated with clinically relevant measures in FM. RESULTS: During the rest phase, FM patients showed decreased connectivity between multiple ipsilateral and cross-hemispheric S1 subregions, which was correlated with clinical pain severity. Compared to the rest phase, the pain phase produced increased S1(leg) connectivity to the bilateral anterior insula in FM patients, but not in healthy controls. Moreover, in FM patients, sustained pain-altered S1(leg) connectivity to the anterior insula was correlated with clinical/behavioral pain measures and autonomic responses. CONCLUSION: Our study demonstrates that both somatic and nonsomatic dysfunction in FM, including clinical pain, pain catastrophizing, autonomic dysfunction, and amplified temporal summation, are closely linked with the degree to which evoked deep tissue pain alters S1 connectivity to salience/affective pain-processing regions. Additionally, diminished connectivity between S1 subregions during the rest phase in FM may result from ongoing widespread clinical pain.
kim_2015.pdf
Langevin HM, Schnyer R, Macpherson H, Davis R, Harris RE, Napadow V, Wayne PM, Milley RJ, Lao L, Stener-Victorin E, Kong J-T, Hammerschlag R. Manual and electrical needle stimulation in acupuncture research: pitfalls and challenges of heterogeneity. J Altern Complement Med 2015;21(3):113-28.Abstract
In the field of acupuncture research there is an implicit yet unexplored assumption that the evidence on manual and electrical stimulation techniques, derived from basic science studies, clinical trials, systematic reviews, and meta-analyses, is generally interchangeable. Such interchangeability would justify a bidirectional approach to acupuncture research, where basic science studies and clinical trials each inform the other. This article examines the validity of this fundamental assumption by critically reviewing the literature and comparing manual to electrical acupuncture in basic science studies, clinical trials, and meta-analyses. The evidence from this study does not support the assumption that these techniques are interchangeable. This article also identifies endemic methodologic limitations that have impaired progress in the field. For example, basic science studies have not matched the frequency and duration of manual needle stimulation to the frequency and duration of electrical stimulation. Further, most clinical trials purporting to compare the two types of stimulation have instead tested electroacupuncture as an adjunct to manual acupuncture. The current findings reveal fundamental gaps in the understanding of the mechanisms and relative effectiveness of manual versus electrical acupuncture. Finally, future research directions are suggested to better differentiate electrical from manual simulation, and implications for clinical practice are discussed.
langevin_jacm_2015.pdf
Nierhaus T, Pach D, Huang W, Long X, Napadow V, Roll S, Liang F, Pleger B, Villringer A, Witt CM. Differential cerebral response to somatosensory stimulation of an acupuncture point vs. two non-acupuncture points measured with EEG and fMRI. Front Hum Neurosci 2015;9:74.Abstract

Acupuncture can be regarded as a complex somatosensory stimulation. Here, we evaluate whether the point locations chosen for a somatosensory stimulation with acupuncture needles differently change the brain activity in healthy volunteers. We used EEG, event-related fMRI, and resting-state functional connectivity fMRI to assess neural responses to standardized needle stimulation of the acupuncture point ST36 (lower leg) and two control point locations (CP1 same dermatome, CP2 different dermatome). Cerebral responses were expected to differ for stimulation in two different dermatomes (CP2 different from ST36 and CP1), or stimulation at the acupuncture point vs. the control points. For EEG, mu rhythm power increased for ST36 compared to CP1 or CP2, but not when comparing the two control points. The fMRI analysis found more pronounced insula and S2 (secondary somatosensory cortex) activation, as well as precuneus deactivation during ST36 stimulation. The S2 seed-based functional connectivity analysis revealed increased connectivity to right precuneus for both comparisons, ST36 vs. CP1 and ST36 vs. CP2, however in different regions. Our results suggest that stimulation at acupuncture points may modulate somatosensory and saliency processing regions more readily than stimulation at non-acupuncture point locations. Also, our findings suggest potential modulation of pain perception due to acupuncture stimulation.

nierhaus_frontiershn_2015.pdf
Kim H, Kim J, Loggia ML, Cahalan C, Garcia RG, Vangel MG, Wasan AD, Edwards RR, Napadow V. Fibromyalgia is characterized by altered frontal and cerebellar structural covariance brain networks. Neuroimage Clin 2015;7:667-77.Abstract
Altered brain morphometry has been widely acknowledged in chronic pain, and recent studies have implicated altered network dynamics, as opposed to properties of individual brain regions, in supporting persistent pain. Structural covariance analysis determines the inter-regional association in morphological metrics, such as gray matter volume, and such structural associations may be altered in chronic pain. In this study, voxel-based morphometry structural covariance networks were compared between fibromyalgia patients (N = 42) and age- and sex-matched pain-free adults (N = 63). We investigated network topology using spectral partitioning, which can delineate local network submodules with consistent structural covariance. We also explored white matter connectivity between regions comprising these submodules and evaluated the association between probabilistic white matter tractography and pain-relevant clinical metrics. Our structural covariance network analysis noted more connections within the cerebellum for fibromyalgia patients, and more connections in the frontal lobe for healthy controls. For fibromyalgia patients, spectral partitioning identified a distinct submodule with cerebellar connections to medial prefrontal and temporal and right inferior parietal lobes, whose gray matter volume was associated with the severity of depression in these patients. Volume for a submodule encompassing lateral orbitofrontal, inferior frontal, postcentral, lateral temporal, and insular cortices was correlated with evoked pain sensitivity. Additionally, the number of white matter fibers between specific submodule regions was also associated with measures of evoked pain sensitivity and clinical pain interference. Hence, altered gray and white matter morphometry in cerebellar and frontal cortical regions may contribute to, or result from, pain-relevant dysfunction in chronic pain patients.
kim_niclinical_2015.pdf
Beissner F, Brünner F, Fink M, Meissner K, Kaptchuk TJ, Napadow V. Placebo-induced somatic sensations: a multi-modal study of three different placebo interventions. PLoS One 2015;10(4):e0124808.Abstract
Somatic sensations induced by placebos are a frequent phenomenon whose etiology and clinical relevance remains unknown. In this study, we have evaluated the quantitative, qualitative, spatial, and temporal characteristics of placebo-induced somatic sensations in response to three different placebo interventions: (1) placebo irritant solution, (2) placebo laser stimulation, and (3) imagined laser stimulation. The quality and intensity of evoked sensations were assessed using the McGill pain questionnaire and visual analogue scales (VAS), while subjects' sensation drawings processed by a geographic information system (GIS) were used to measure their spatial characteristics. We found that all three interventions are capable of producing robust sensations most frequently described as "tingling" and "warm" that can reach consider-able spatial extent (≤ 205 mm²) and intensity (≤ 80/100 VAS). Sensations from placebo stimulation were often referred to areas remote from the stimulation site and exhibit considerable similarity with referred pain. Interestingly, there was considerable similarity of qualitative features as well as spatial patterns across subjects and placebos. However, placebo laser stimulation elicited significantly stronger and more widespread sensations than placebo irritant solution. Finally, novelty seeking, a character trait assessed by the Temperament and Character Inventory and associated with basal dopaminergic activity, was less pronounced in subjects susceptible to report placebo-induced sensations. Our study has shown that placebo-induced sensations are frequent and can reach considerable intensity and extent. As multiple somatosensory subsystems are involved despite the lack of peripheral stimulus, we propose a central etiology for this phenomenon.
beissner_plos1_2015.pdf
Loggia ML, Berna C, Kim J, Cahalan CM, Martel M-O, Gollub RL, Wasan AD, Napadow V, Edwards RR. The lateral prefrontal cortex mediates the hyperalgesic effects of negative cognitions in chronic pain patients. J Pain 2015;16(8):692-9.Abstract
UNLABELLED: Although high levels of negative affect and cognitions have been associated with greater pain sensitivity in chronic pain conditions, the neural mechanisms mediating the hyperalgesic effect of psychological factors in patients with pain disorders are largely unknown. In this cross-sectional study, we hypothesized that 1) catastrophizing modulates brain responses to pain anticipation and 2) anticipatory brain activity mediates the hyperalgesic effect of different levels of catastrophizing in fibromyalgia (FM) patients. Using functional magnetic resonance imaging, we scanned the brains of 31 FM patients exposed to visual cues anticipating the onset of moderately intense deep-tissue pain stimuli. Our results indicated the existence of a negative association between catastrophizing and pain-anticipatory brain activity, including in the right lateral prefrontal cortex. A bootstrapped mediation analysis revealed that pain-anticipatory activity in the lateral prefrontal cortex mediates the association between catastrophizing and pain sensitivity. These findings highlight the role of the lateral prefrontal cortex in the pathophysiology of FM-related hyperalgesia and suggest that deficits in the recruitment of pain-inhibitory brain circuitry during pain-anticipatory periods may play an important contributory role in the association between various degrees of widespread hyperalgesia in FM and levels of catastrophizing, a well-validated measure of negative cognitions and psychological distress. PERSPECTIVE: This article highlights the presence of alterations in pain-anticipatory brain activity in FM. These findings provide the rationale for the development of psychological or neurofeedback-based techniques aimed at modifying patients' negative affect and cognitions toward pain.
loggia_jpain_2015.pdf
Napadow V, Li A, Loggia ML, Kim J, Mawla I, Desbordes G, Schalock PC, Lerner EA, Tran TN, Ring J, Rosen BR, Kaptchuk TJ, Pfab F. The imagined itch: brain circuitry supporting nocebo-induced itch in atopic dermatitis patients. Allergy 2015;70(11):1485-92.Abstract
BACKGROUND: Psychological factors are known to significantly modulate itch in patients suffering from chronic itch. Itch is also highly susceptible to both placebo and nocebo (negative placebo) effects. Brain activity likely supports nocebo-induced itch, but is currently unknown. METHODS: We collected functional MRI (fMRI) data from atopic dermatitis (AD) patients, in a within-subject design, and contrast brain response to nocebo saline understood to be allergen vs open-label saline control. Exploratory analyses compared results to real allergen itch response and placebo responsiveness, evaluated in the same patients. RESULTS: Nocebo saline produced greater itch than open saline control (P < 0.01). Compared to open saline, nocebo saline demonstrated greater fMRI response in caudate, dorsolateral prefrontal cortex (dlPFC), and intraparietal sulcus (iPS) - brain regions important for cognitive executive and motivational processing. Exploratory analyses found that subjects with greater dlPFC and caudate activation to nocebo-induced itch also demonstrated greater dlPFC and caudate activation, respectively, for real allergen itch. Subjects reporting greater nocebo-induced itch also demonstrated greater placebo reduction of allergen-evoked itch, suggesting increased generalized modulation of itch perception. CONCLUSIONS: Our study demonstrates the capacity of nocebo saline to mimic both the sensory and neural effects of real allergens and provides an insight to the brain mechanisms supporting nocebo-induced itch in AD, thus aiding our understanding of the role that expectations and other psychological factors play in modulating itch perception in chronic itch patients.
napadow_allergy_2015.pdf
2014
Napadow V, Harris RE. What has functional connectivity and chemical neuroimaging in fibromyalgia taught us about the mechanisms and management of 'centralized' pain?. Arthritis Res Ther 2014;16(5):425.Abstract
Research suggests that fibromyalgia is a central, widespread pain syndrome supported by a generalized disturbance in central nervous system pain processing. Over the past decades, multiple lines of research have identified the locus for many functional, chronic pain disorders to the central nervous system, and the brain. In recent years, brain neuroimaging techniques have heralded a revolution in our understanding of chronic pain, as they have allowed researchers to non-invasively (or minimally invasively) evaluate human patients suffering from various pain disorders. While many neuroimaging techniques have been developed, growing interest in two specific imaging modalities has led to significant contributions to chronic pain research. For instance, resting functional connectivity magnetic resonance imaging (fcMRI) is a recent adaptation of fMRI that examines intrinsic brain connectivity - defined as synchronous oscillations of the fMRI signal that occurs in the resting basal state. Proton magnetic resonance spectroscopy (1H-MRS) is a non-invasive magnetic resonance imaging technique that can quantify the concentration of multiple metabolites within the human brain. This review will outline recent applications of the complementary imaging techniques - fcMRI and 1H-MRS - to improve our understanding of fibromyalgia pathophysiology and how pharmacological and non-pharmacological therapies contribute to analgesia in these patients. A better understanding of the brain in chronic pain, with specific linkage as to which neural processes relate to spontaneous pain perception and hyperalgesia, will greatly improve our ability to develop novel therapeutics. Neuroimaging will play a growing role in the translational research approaches needed to make this a reality.
napadow_arthritisrt_2014.pdf
Pfab F, Schalock PC, Napadow V, Athanasiadis GI, Huss-Marp J, Ring J. Acupuncture for allergic disease therapy--the current state of evidence. Expert Rev Clin Immunol 2014;10(7):831-41.Abstract
This review summarizes current evidence for acupuncture treatment of allergies. Several randomized controlled trials have demonstrated a specific effect of acupuncture for allergic rhinitis; while a few studies have shown positive effects for atopic dermatitis, asthma and itch. Specifically for allergic rhinitis and asthma, acupuncture may be cost-effective in terms of money spent per quality-of-life gained. Acupuncture plays an increasingly important role as an evidence-based therapy for allergy relief and can be recommended as adjunct therapy for allergic rhinitis. Future randomized controlled trials need to further explore acupuncture efficacy for the treatment of itch, atopic dermatitis and asthma. More experimental research is also needed to investigate mechanisms of action underlying acupuncture for allergy relief.
Loggia ML, Edwards RR, Harris RE, Napadow V. Reply: To PMID 24449585. Arthritis Rheumatol 2014;66(6):1684-5.
Ichesco E, Schmidt-Wilcke T, Bhavsar R, Clauw DJ, Peltier SJ, Kim J, Napadow V, Hampson JP, Kairys AE, Williams DA, Harris RE. Altered resting state connectivity of the insular cortex in individuals with fibromyalgia. J Pain 2014;15(8):815-826.e1.Abstract
UNLABELLED: The insular cortex (IC) and cingulate cortex (CC) are critically involved in pain perception. Previously we demonstrated that fibromyalgia (FM) patients have greater connectivity between the insula and default mode network at rest, and that changes in the degree of this connectivity were associated with changes in the intensity of ongoing clinical pain. In this study we more thoroughly evaluated the degree of resting-state connectivity to multiple regions of the IC in individuals with FM and healthy controls. We also investigated the relationship between connectivity, experimental pain, and current clinical chronic pain. Functional connectivity was assessed using resting-state functional magnetic resonance imaging in 18 FM patients and 18 age- and sex-matched healthy controls using predefined seed regions in the anterior, middle, and posterior IC. FM patients exhibited greater connectivity between 1) right mid IC and right mid/posterior CC and right mid IC, 2) right posterior IC and left CC, and 3) right anterior IC and left superior temporal gyrus. Healthy controls displayed greater connectivity between left anterior IC and bilateral medial frontal gyrus/anterior cingulate cortex; and left posterior IC and right superior frontal gyrus. Within the FM group, greater connectivity between the IC and CC was associated with decreased pressure-pain thresholds. PERSPECTIVE: These data provide further support for altered resting-state connectivity between the IC and other brain regions known to participate in pain perception/modulation, which may play a pathogenic role in conditions such as FM. We speculate that altered IC connectivity is associated with the experience of chronic pain in individuals with FM.
ichesco_jpain_2014-2.pdf

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