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  • 1
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    Online Resource
    An Interventional Response Phenotyping Study in Chronic Low Back Pain: Protocol for a Mechanistic Randomized Controlled Trial
    Oxford University Press (OUP) ; 2023
    In:  Pain Medicine Vol. 24, No. Supplement_1 ( 2023-08-04), p. S126-S138
    Details
    In: Pain Medicine, Oxford University Press (OUP), Vol. 24, No. Supplement_1 ( 2023-08-04), p. S126-S138
    Abstract: Evidence-based treatments for chronic low back pain (cLBP) typically work well in only a fraction of patients, and at present there is little guidance regarding what treatment should be used in which patients. Our central hypothesis is that an interventional response phenotyping study can identify individuals with different underlying mechanisms for their pain who thus respond differentially to evidence-based treatments for cLBP. Thus, we will conduct a randomized controlled Sequential, Multiple Assessment, Randomized Trial (SMART) design study in cLBP with the following three aims. Aim 1: Perform an interventional response phenotyping study in a cohort of cLBP patients (n = 400), who will receive a sequence of interventions known to be effective in cLBP. For 4 weeks, all cLBP participants will receive a web-based pain self-management program as part of a run-in period, then individuals who report no or minimal improvement will be randomized to: a) mindfulness-based stress reduction, b) physical therapy and exercise, c) acupressure self-management, and d) duloxetine. After 8 weeks, individuals who remain symptomatic will be re-randomized to a different treatment for an additional 8 weeks. Using those data, we will identify the subsets of participants that respond to each treatment. In Aim 2, we will show that currently available, clinically derived measures, can predict differential responsiveness to the treatments. In Aim 3, a subset of participants will receive deeper phenotyping (n = 160), to identify new experimental measures that predict differential responsiveness to the treatments, as well as to infer mechanisms of action. Deep phenotyping will include functional neuroimaging, quantitative sensory testing, measures of inflammation, and measures of autonomic tone.
    Type of Medium: Online Resource
    ISSN: 1526-2375 , 1526-4637
    URL: Article
    DOI: 10.1093/pm/pnad005
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
    detail.hit.zdb_id: 2023869-1
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  • 2
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    Risk Factors for the Development of Multisite Pain in Children
    Ovid Technologies (Wolters Kluwer Health) ; 2023
    In:  The Clinical Journal of Pain
    Details
    In: The Clinical Journal of Pain, Ovid Technologies (Wolters Kluwer Health)
    Abstract: Chronic pain has economic costs on par with cardiovascular disease, diabetes, and cancer. Despite this impact on the health care system and an increasing awareness of the relationship between pain and mortality, efforts to identify simple symptom-based risk factors for the development of pain, particularly in children, have fallen short. This is critically important as pain that manifests during childhood often persists into adulthood. To date no longitudinal studies have examined symptoms in pain-free children that presage a new, multisite manifestation of pain in the future. We hypothesized that female sex, sleep problems and heightened somatic complaints at baseline would be associated with the risk of developing new multisite pain one year later. Methods: Symptom assessments were completed by parents of youth (ages 9-10) enrolled in the Adolescent Brain Cognitive Development study. Multivariate logistic regression models focused on children who developed multisite pain one year later (n=331) and children who remained pain-free (n=3335) . Results: Female sex (OR=1.35; 95% CI=1.07, 1.71; P =0.01) , elevated non-painful somatic complaints (OR=1.17; 95% CI=1.06, 1.29; P 〈 0.01) , total sleep problems (OR=1.20; 95% CI=1.07, 1.34; P 〈 0.01) , and attentional issues (OR=1.22; 95% CI=1.10, 1.35; P 〈 0.001) at baseline were associated with new multisite pain one year later. Baseline negative affect was not associated with new multisite pain. Discussion: Identifying symptom-based risk factors for multisite pain in children is critical for early prevention. Somatic awareness, sleep and attention problems represent actionable targets for early detection, treatment, and possible prevention of multisite pain in youth.
    Type of Medium: Online Resource
    ISSN: 1536-5409
    URL: Article
    DOI: 10.1097/AJP.0000000000001148
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2023
    detail.hit.zdb_id: 1497640-7
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  • 3
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    Neurophysiologic Complexity in Children Increases with Developmental Age and Is Reduced by General Anesthesia
    Ovid Technologies (Wolters Kluwer Health) ; 2021
    In:  Anesthesiology Vol. 135, No. 5 ( 2021-11-01), p. 813-828
    Details
    In: Anesthesiology, Ovid Technologies (Wolters Kluwer Health), Vol. 135, No. 5 ( 2021-11-01), p. 813-828
    Abstract: Neurophysiologic complexity in the cortex has been shown to reflect changes in the level of consciousness in adults but remains incompletely understood in the developing brain. This study aimed to address changes in cortical complexity related to age and anesthetic state transitions. This study tested the hypotheses that cortical complexity would (1) increase with developmental age and (2) decrease during general anesthesia. Methods This was a single-center, prospective, cross-sectional study of healthy (American Society of Anesthesiologists physical status I or II) children (n = 50) of age 8 to 16 undergoing surgery with general anesthesia at Michigan Medicine. This age range was chosen because it reflects a period of substantial brain network maturation. Whole scalp (16-channel), wireless electroencephalographic data were collected from the preoperative period through the recovery of consciousness. Cortical complexity was measured using the Lempel–Ziv algorithm and analyzed during the baseline, premedication, maintenance of general anesthesia, and clinical recovery periods. The effect of spectral power on Lempel–Ziv complexity was analyzed by comparing the original complexity value with those of surrogate time series generated through phase randomization that preserves power spectrum. Results Baseline spatiotemporal Lempel–Ziv complexity increased with age (yr; slope [95% CI], 0.010 [0.004, 0.016] ; P & lt; 0.001); when normalized to account for spectral power, there was no significant age effect on cortical complexity (0.001 [–0.004, 0.005]; P = 0.737). General anesthesia was associated with a significant decrease in spatiotemporal complexity (median [25th, 75th] ; baseline, 0.660 [0.620, 0.690] vs. maintenance, 0.459 [0.402, 0.527] ; P & lt; 0.001), and spatiotemporal complexity exceeded baseline levels during postoperative recovery (0.704 [0.642, 0.745]; P = 0.009). When normalized, there was a similar reduction in complexity during general anesthesia (baseline, 0.913 [0.887, 0.923] vs. maintenance 0.851 [0.823, 0.877]; P & lt; 0.001), but complexity remained significantly reduced during recovery (0.873 [0.840, 0.902], P & lt; 0.001). Conclusions Cortical complexity increased with developmental age and decreased during general anesthesia. This association remained significant when controlling for spectral changes during anesthetic-induced perturbations in consciousness but not with developmental age. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New
    Type of Medium: Online Resource
    ISSN: 0003-3022 , 1528-1175
    URL: Article
    DOI: 10.1097/ALN.0000000000003929
    RVK:
    XA 22600
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2021
    detail.hit.zdb_id: 2016092-6
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  • 4
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    Constrained Functional Connectivity Dynamics in Pediatric Surgical Patients Undergoing General Anesthesia
    Ovid Technologies (Wolters Kluwer Health) ; 2022
    In:  Anesthesiology Vol. 137, No. 1 ( 2022-07-01), p. 28-40
    Details
    In: Anesthesiology, Ovid Technologies (Wolters Kluwer Health), Vol. 137, No. 1 ( 2022-07-01), p. 28-40
    Abstract: Functional connectivity in cortical networks is thought to be important for consciousness and can be disrupted during the anesthetized state. Recent work in adults has revealed dynamic connectivity patterns during stable general anesthesia, but whether similar connectivity state transitions occur in the developing brain remains undetermined. The hypothesis was that anesthetic-induced unconsciousness is associated with disruption of functional connectivity in the developing brain and that, as in adults, there are dynamic shifts in connectivity patterns during the stable maintenance phase of general anesthesia. Methods This was a preplanned analysis of a previously reported single-center, prospective, cross-sectional study of healthy (American Society of Anesthesiologists status I or II) children aged 8 to 16 yr undergoing surgery with general anesthesia (n = 50) at Michigan Medicine. Whole-scalp (16-channel), wireless electroencephalographic data were collected from the preoperative period through the recovery of consciousness. Functional connectivity was measured using a weighted phase lag index, and discrete connectivity states were classified using cluster analysis. Results Changes in functional connectivity were associated with anesthetic state transitions across multiple regions and frequency bands. An increase in prefrontal–frontal alpha (median [25th, 75th]; baseline, 0.070 [0.049, 0.101] vs. maintenance 0.474 [0.286, 0.606]; P & lt; 0.001) and theta connectivity (0.038 [0.029, 0.048] vs. 0.399 [0.254, 0.488] ; P & lt; 0.001), and decrease in parietal–occipital alpha connectivity (0.171 [0.145, 0.243] vs. 0.089 [0.055, 0.132] ; P & lt; 0.001) were among those with the greatest effect size. Contrary to the hypothesis, connectivity patterns during the maintenance phase of general anesthesia were dominated by stable theta and alpha prefrontal–frontal and alpha frontal–parietal connectivity and exhibited high between-cluster similarity (r = 0.75 to 0.87). Conclusions Changes in functional connectivity are associated with anesthetic state transitions but, unlike in adults, connectivity patterns are constrained during general anesthesia in late childhood and early adolescence. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New
    Type of Medium: Online Resource
    ISSN: 0003-3022 , 1528-1175
    URL: Article
    DOI: 10.1097/ALN.0000000000004221
    RVK:
    XA 22600
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
    detail.hit.zdb_id: 2016092-6
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  • 5
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    Targeting network hubs with noninvasive brain stimulation in patients with fibromyalgia
    Ovid Technologies (Wolters Kluwer Health) ; 2020
    In:  Pain Vol. 161, No. 1 ( 2020-01), p. 43-46
    Details
    In: Pain, Ovid Technologies (Wolters Kluwer Health), Vol. 161, No. 1 ( 2020-01), p. 43-46
    Type of Medium: Online Resource
    ISSN: 0304-3959 , 1872-6623
    URL: Article
    DOI: 10.1097/j.pain.0000000000001696
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2020
    detail.hit.zdb_id: 1494115-6
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  • 6
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    Functional and neurochemical disruptions of brain hub topology in chronic pain
    Ovid Technologies (Wolters Kluwer Health) ; 2019
    In:  Pain Vol. 160, No. 4 ( 2019-04), p. 973-983
    Details
    In: Pain, Ovid Technologies (Wolters Kluwer Health), Vol. 160, No. 4 ( 2019-04), p. 973-983
    Abstract: A critical component of brain network architecture is a robust hub structure, wherein hub regions facilitate efficient information integration by occupying highly connected and functionally central roles in the network. Across a wide range of neurological disorders, hub brain regions seem to be disrupted, and the character of this disruption can yield insights into the pathophysiology of these disorders. We applied a brain network–based approach to examine hub topology in fibromyalgia, a chronic pain condition with prominent central nervous system involvement. Resting state functional magnetic resonance imaging data from 40 fibromyalgia patients and 46 healthy volunteers, and a small validation cohort of 11 fibromyalgia patients, were analyzed using graph theoretical techniques to model connections between 264 brain regions. In fibromyalgia, the anterior insulae functioned as hubs and were members of the rich club, a highly interconnected nexus of hubs. In fibromyalgia, rich-club membership varied with the intensity of clinical pain: the posterior insula, primary somatosensory, and motor cortices belonged to the rich club only in patients with the highest pain intensity. Furthermore, the eigenvector centrality (a measure of how connected a region is to other highly connected regions) of the posterior insula positively correlated with clinical pain and mediated the relationship between glutamate + glutamine (assessed by proton magnetic resonance spectroscopy) within this structure and the patient's clinical pain report. Together, these findings reveal altered hub topology in fibromyalgia and demonstrate, for the first time to our knowledge, a neurochemical basis for altered hub strength and its relationship to the perception of pain.
    Type of Medium: Online Resource
    ISSN: 0304-3959 , 1872-6623
    URL: Article
    DOI: 10.1097/j.pain.0000000000001480
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2019
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  • 7
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    Large-scale momentary brain co-activation patterns are associated with hyperalgesia and mediate focal neurochemistry and cross-network functional connectivity in fibromyalgia
    Ovid Technologies (Wolters Kluwer Health) ; 2023
    In:  Pain ( 2023-9-26)
    Details
    In: Pain, Ovid Technologies (Wolters Kluwer Health), ( 2023-9-26)
    Abstract: Fibromyalgia has been characterized by augmented cross-network functional communication between the brain's sensorimotor, default mode, and attentional (salience/ventral and dorsal) networks. However, the underlying mechanisms of these aberrant communication patterns are unknown. In this study, we sought to understand large-scale topographic patterns at instantaneous timepoints, known as co-activation patterns (CAPs). We found that a sustained pressure pain challenge temporally modulated the occurrence of CAPs. Using proton magnetic resonance spectroscopy, we found that greater basal excitatory over inhibitory neurotransmitter levels within the anterior insula orchestrated higher cross-network connectivity between the anterior insula and the default mode network through lower occurrence of a CAP encompassing the attentional networks during sustained pain. Moreover, we found that hyperalgesia in fibromyalgia was mediated through increased occurrence of a CAP encompassing the sensorimotor network during sustained pain. In conclusion, this study elucidates the role of momentary large-scale topographic brain patterns in shaping noxious information in patients with fibromyalgia, while laying the groundwork for using precise spatiotemporal dynamics of the brain for the potential development of therapeutics.
    Type of Medium: Online Resource
    ISSN: 0304-3959 , 1872-6623
    URL: Article
    DOI: 10.1097/j.pain.0000000000002973
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2023
    detail.hit.zdb_id: 1494115-6
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  • 8
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    A multi-modal MRI study of the central response to inflammation in rheumatoid arthritis
    Springer Science and Business Media LLC ; 2018
    In:  Nature Communications Vol. 9, No. 1 ( 2018-06-08)
    Details
    In: Nature Communications, Springer Science and Business Media LLC, Vol. 9, No. 1 ( 2018-06-08)
    Abstract: It is unknown how chronic inflammation impacts the brain. Here, we examined whether higher levels of peripheral inflammation were associated with brain connectivity and structure in 54 rheumatoid arthritis patients using functional and structural MRI. We show that higher levels of inflammation are associated with more positive connections between the inferior parietal lobule (IPL), medial prefrontal cortex, and multiple brain networks, as well as reduced IPL grey matter, and that these patterns of connectivity predicted fatigue, pain and cognitive dysfunction. At a second scan 6 months later, some of the same patterns of connectivity were again associated with higher peripheral inflammation. A graph theoretical analysis of whole-brain functional connectivity revealed a pattern of connections spanning 49 regions, including the IPL and medial frontal cortex, that are associated with peripheral inflammation. These regions may play a critical role in transducing peripheral inflammatory signals to the central changes seen in rheumatoid arthritis.
    Type of Medium: Online Resource
    ISSN: 2041-1723
    URL: Article
    DOI: 10.1038/s41467-018-04648-0
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2018
    detail.hit.zdb_id: 2553671-0
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  • 9
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    Greater Somatosensory Afference With Acupuncture Increases Primary Somatosensory Connectivity and Alleviates Fibromyalgia Pain via Insular γ‐Aminobutyric Acid: A Randomized Neuroimaging Trial
    Wiley ; 2021
    In:  Arthritis & Rheumatology Vol. 73, No. 7 ( 2021-07), p. 1318-1328
    Details
    In: Arthritis & Rheumatology, Wiley, Vol. 73, No. 7 ( 2021-07), p. 1318-1328
    Abstract: Acupuncture is a complex multicomponent treatment that has shown promise in the treatment of fibromyalgia (FM). However, clinical trials have shown mixed results, possibly due to heterogeneous methodology and lack of understanding of the underlying mechanism of action. The present study was undertaken to understand the specific contribution of somatosensory afference to improvements in clinical pain, and the specific brain circuits involved. Methods Seventy‐six patients with FM were randomized to receive either electroacupuncture (EA), with somatosensory afference, or mock laser acupuncture (ML), with no somatosensory afference, twice a week over 8 treatments. Patients with FM in each treatment group were assessed for pain severity levels, measured using Brief Pain Inventory (BPI) scores, and for levels of functional brain network connectivity, assessed using resting state functional magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy in the right anterior insula, before and after treatment. Results Fibromyalgia patients who received EA therapy experienced a greater reduction in pain severity, as measured by the BPI, compared to patients who received ML therapy (mean difference in BPI from pre‐ to posttreatment was −1.14 in the EA group versus −0.46 in the ML group; P for group × time interaction = 0.036). Participants receiving EA treatment, as compared to ML treatment, also exhibited resting functional connectivity between the primary somatosensory cortical representation of the leg (S1 leg ; i.e. primary somatosensory subregion activated by EA) and the anterior insula. Increased S1 leg –anterior insula connectivity was associated with both reduced levels of pain severity as measured by the BPI ( r = −0.44, P = 0.01) and increased levels of γ‐aminobutyric acid (GABA+) in the anterior insula ( r = 0.48, P = 0.046) following EA therapy. Moreover, increased levels of GABA+ in the anterior insula were associated with reduced levels of pain severity as measured by the BPI ( r = −0.59, P = 0.01). Finally, post–EA treatment changes in levels of GABA+ in the anterior insula mediated the relationship between changes in S1 leg –anterior insula connectivity and pain severity on the BPI (bootstrap confidence interval −0.533, −0.037). Conclusion The somatosensory component of acupuncture modulates primary somatosensory functional connectivity associated with insular neurochemistry to reduce pain severity in FM.
    Type of Medium: Online Resource
    ISSN: 2326-5191 , 2326-5205
    URL: Issue
    URL: Article
    DOI: 10.1002/art.v73.7
    DOI: 10.1002/art.41620
    RVK:
    XA 10000
    RVK:
    XA 30325
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 2754614-7
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  • 10
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    Association of Inflammation With Pronociceptive Brain Connections in Rheumatoid Arthritis Patients With Concomitant Fibromyalgia
    Wiley ; 2020
    In:  Arthritis & Rheumatology Vol. 72, No. 1 ( 2020-01), p. 41-46
    Details
    In: Arthritis & Rheumatology, Wiley, Vol. 72, No. 1 ( 2020-01), p. 41-46
    Abstract: Rheumatoid arthritis (RA) patients with concomitant fibromyalgia (FM) exhibit alterations in brain connectivity synonymous with central sensitization. This study was undertaken to investigate how peripheral inflammation, the principal nociceptive stimulus in RA, interacts with brain connectivity in RA patients with FM. Methods RA patients with concomitant FM and those without FM (FM+ and FM−, respectively; n = 27 per group) underwent functional connectivity magnetic resonance imaging. Seed‐to–whole‐brain functional connectivity analyses were conducted using seeds from the left mid/posterior insula and left inferior parietal lobule (IPL), which are regions that have been previously linked to FM symptoms and inflammation, respectively. The association between functional connectivity and erythrocyte sedimentation rate (ESR) was assessed in each group separately, followed by post hoc analyses to test for interaction effects. Cluster‐level, family‐wise error (FWE) rates were considered significant if the P value was less than 0.05. Results The group of RA patients with FM and those without FM did not differ by age, sex, or ESR ( P 〉 0.2). In FM+ RA patients, increased functional connectivity of the insula–left IPL, left IPL–dorsal anterior cingulate, and left IPL–medial prefrontal cortex regions correlated with higher levels of ESR (all FWE‐corrected P 〈 0.05). Post hoc interaction analyses largely confirmed the relationship between ESR and connectivity changes as FM scores increased. Conclusion We report the first neurobiologic evidence that FM in RA may be linked to peripheral inflammation via pronociceptive patterns of brain connectivity. In patients with such “bottom‐up” pain centralization, concomitant symptoms may partially respond to antiinflammatory treatments.
    Type of Medium: Online Resource
    ISSN: 2326-5191 , 2326-5205
    URL: Issue
    URL: Article
    DOI: 10.1002/art.v72.1
    DOI: 10.1002/art.41069
    RVK:
    XA 10000
    RVK:
    XA 30325
    Language: English
    Publisher: Wiley
    Publication Date: 2020
    detail.hit.zdb_id: 2754614-7
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