@article{pmid38015622c,

title = {[ 11 C]-PBR28 positron emission tomography signal as an imaging marker of joint inflammation in knee osteoarthritis},

author = {Angelica Sandström and Angel Torrado-Carvajal and Erin J Morrissey and Minhae Kim and Zeynab Alshelh and Yehui Zhu and Matthew D Li and Connie Y Chang and Mohamed Jarraya and Oluwaseun Akeju and Andrew Schrepf and Richard E Harris and Young-Min Kwon and Hany Bedair and Antonia F Chen and Nathaniel D Mercaldo and Norman Kettner and Vitaly Napadow and Nicola Toschi and Robert R Edwards and Marco L Loggia},

doi = {10.1097/j.pain.0000000000003114},

issn = {1872-6623},

year  = {2024},

date = {2024-05-01},

journal = {Pain},

volume = {165},

number = {5},

pages = {1121--1130},

abstract = {Although inflammation is known to play a role in knee osteoarthritis (KOA), inflammation-specific imaging is not routinely performed. In this article, we evaluate the role of joint inflammation, measured using [ 11 C]-PBR28, a radioligand for the inflammatory marker 18-kDa translocator protein (TSPO), in KOA. Twenty-one KOA patients and 11 healthy controls (HC) underwent positron emission tomography/magnetic resonance imaging (PET/MRI) knee imaging with the TSPO ligand [ 11 C]-PBR28. Standardized uptake values were extracted from regions-of-interest (ROIs) semiautomatically segmented from MRI data, and compared across groups (HC, KOA) and subgroups (unilateral/bilateral KOA symptoms), across knees (most vs least painful), and against clinical variables (eg, pain and Kellgren-Lawrence [KL] grades). Overall, KOA patients demonstrated elevated [ 11 C]-PBR28 binding across all knee ROIs, compared with HC (all P 's < 0.005). Specifically, PET signal was significantly elevated in both knees in patients with bilateral KOA symptoms (both P 's < 0.01), and in the symptomatic knee ( P < 0.05), but not the asymptomatic knee ( P = 0.95) of patients with unilateral KOA symptoms. Positron emission tomography signal was higher in the most vs least painful knee ( P < 0.001), and the difference in pain ratings across knees was proportional to the difference in PET signal ( r = 0.74, P < 0.001). Kellgren-Lawrence grades neither correlated with PET signal (left knee r = 0.32, P = 0.19; right knee r = 0.18, P = 0.45) nor pain ( r = 0.39, P = 0.07). The current results support further exploration of [ 11 C]-PBR28 PET signal as an imaging marker candidate for KOA and a link between joint inflammation and osteoarthritis-related pain severity.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38642615,

title = {Neuroinflammation in post-acute sequelae of COVID-19 (PASC) as assessed by [C]PBR28 PET correlates with vascular disease measures},

author = {Michael B VanElzakker and Hannah F Bues and Ludovica Brusaferri and Minhae Kim and Deena Saadi and Eva-Maria Ratai and Darin D Dougherty and Marco L Loggia},

doi = {10.1016/j.bbi.2024.04.015},

issn = {1090-2139},

year  = {2024},

date = {2024-04-01},

journal = {Brain Behav Immun},

abstract = {The COVID-19 pandemic caused by SARS-CoV-2 has triggered a consequential public health crisis of post-acute sequelae of COVID-19 (PASC), sometimes referred to as long COVID. The mechanisms of the heterogeneous persistent symptoms and signs that comprise PASC are under investigation, and several studies have pointed to the central nervous and vascular systems as being potential sites of dysfunction. In the current study, we recruited individuals with PASC with diverse symptoms, and examined the relationship between neuroinflammation and circulating markers of vascular dysfunction. We used [C]PBR28 PET neuroimaging, a marker of neuroinflammation, to compare 12 PASC individuals versus 43 normative healthy controls. We found significantly increased neuroinflammation in PASC versus controls across a wide swath of brain regions including midcingulate and anterior cingulate cortex, corpus callosum, thalamus, basal ganglia, and at the boundaries of ventricles. We also collected and analyzed peripheral blood plasma from the PASC individuals and found significant positive correlations between neuroinflammation and several circulating analytes related to vascular dysfunction. These results suggest that an interaction between neuroinflammation and vascular health may contribute to common symptoms of PASC.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38081435b,

title = {Neuroimmune activation and increased brain aging in chronic pain patients after the COVID-19 pandemic onset},

author = {Ludovica Brusaferri and Zeynab Alshelh and Jack H Schnieders and Angelica Sandström and Mehrbod Mohammadian and Erin J Morrissey and Minhae Kim and Courtney A Chane and Grace C Grmek and Jennifer P Murphy and Julia Bialobrzewski and Alexa DiPietro and Julie Klinke and Yi Zhang and Angel Torrado-Carvajal and Nathaniel Mercaldo and Oluwaseun Akeju and Ona Wu and Bruce R Rosen and Vitaly Napadow and Nouchine Hadjikhani and Marco L Loggia},

doi = {10.1016/j.bbi.2023.12.016},

issn = {1090-2139},

year  = {2024},

date = {2024-02-01},

journal = {Brain Behav Immun},

volume = {116},

pages = {259--266},

abstract = {The COVID-19 pandemic has exerted a global impact on both physical and mental health, and clinical populations have been disproportionally affected. To date, however, the mechanisms underlying the deleterious effects of the pandemic on pre-existing clinical conditions remain unclear. Here we investigated whether the onset of the pandemic was associated with an increase in brain/blood levels of inflammatory markers and MRI-estimated brain age in patients with chronic low back pain (cLBP), irrespective of their infection history. A retrospective cohort study was conducted on 56 adult participants with cLBP (28 'Pre-Pandemic', 28 'Pandemic') using integrated Positron Emission Tomography/ Magnetic Resonance Imaging (PET/MRI) and the radioligand [C]PBR28, which binds to the neuroinflammatory marker 18 kDa Translocator Protein (TSPO). Image data were collected between November 2017 and January 2020 ('Pre-Pandemic' cLBP) or between August 2020 and May 2022 ('Pandemic' cLBP). Compared to the Pre-Pandemic group, the Pandemic patients demonstrated widespread and statistically significant elevations in brain TSPO levels (P =.05, cluster corrected). PET signal elevations in the Pandemic group were also observed when 1) excluding 3 Pandemic subjects with a known history of COVID infection, or 2) using secondary outcome measures (volume of distribution -V- and V ratio - DVR) in a smaller subset of participants. Pandemic subjects also exhibited elevated serum levels of inflammatory markers (IL-16; P <.05) and estimated BA (P <.0001), which were positively correlated with [C]PBR28 SUVR (r's ≥ 0.35; P's < 0.05). The pain interference scores, which were elevated in the Pandemic group (P <.05), were negatively correlated with [C]PBR28 SUVR in the amygdala (r = -0.46; P<.05). This work suggests that the pandemic outbreak may have been accompanied by neuroinflammation and increased brain age in cLBP patients, as measured by multimodal imaging and serum testing. This study underscores the broad impact of the pandemic on human health, which extends beyond the morbidity solely mediated by the virus itself.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37727908,

title = {A Randomized Controlled Neuroimaging Trial of Cognitive Behavioral Therapy for Fibromyalgia Pain},

author = {Jeungchan Lee and Asimina Lazaridou and Myrella Paschali and Marco L Loggia and Michael P Berry and Dan-Mikael Ellingsen and Kylie Isenburg and Alessandra Anzolin and Arvina Grahl and Ajay D Wasan and Vitaly Napadow and Robert R Edwards},

doi = {10.1002/art.42672},

issn = {2326-5205},

year  = {2024},

date = {2024-01-01},

journal = {Arthritis Rheumatol},

volume = {76},

number = {1},

pages = {130--140},

abstract = {OBJECTIVE: Fibromyalgia (FM) is characterized by pervasive pain-related symptomatology and high levels of negative affect. Mind-body treatments such as cognitive behavioral therapy (CBT) appear to foster improvement in FM via reductions in pain-related catastrophizing, a set of negative, pain-amplifying cognitive and emotional processes. However, the neural underpinnings of CBT's catastrophizing-reducing effects remain uncertain. This randomized controlled mechanistic trial was designed to assess CBT's effects on pain catastrophizing and its underlying brain circuitry.nnMETHODS: Of 114 enrolled participants, 98 underwent a baseline neuroimaging assessment and were randomized to 8 weeks of individual CBT or a matched FM education control (EDU) condition.nnRESULTS: Compared with EDU, CBT produced larger decreases in pain catastrophizing post treatment (P < 0.05) and larger reductions in pain interference and symptom impact. Decreases in pain catastrophizing played a significant role in mediating those functional improvements in the CBT group. At baseline, brain functional connectivity between the ventral posterior cingulate cortex (vPCC), a key node of the default mode network (DMN), and somatomotor and salience network regions was increased during catastrophizing thoughts. Following CBT, vPCC connectivity to somatomotor and salience network areas was reduced.nnCONCLUSION: Our results suggest clinically important and CBT-specific associations between somatosensory/motor- and salience-processing brain regions and the DMN in chronic pain. These patterns of connectivity may contribute to individual differences (and treatment-related changes) in somatic self-awareness. CBT appears to provide clinical benefits at least partially by reducing pain-related catastrophizing and producing adaptive alterations in DMN functional connectivity.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37578456b,

title = {Thalamic neurometabolite alterations in chronic low back pain: a common phenomenon across musculoskeletal pain conditions?},

author = {Akila Weerasekera and Paulina C Knight and Zeynab Alshelh and Erin J Morrissey and Minhae Kim and Yi Zhang and Vitaly Napadow and Alessandra Anzolin and Angel Torrado-Carvajal and Robert R Edwards and Eva-Maria Ratai and Marco L Loggia},

doi = {10.1097/j.pain.0000000000003002},

issn = {1872-6623},

year  = {2024},

date = {2024-01-01},

journal = {Pain},

volume = {165},

number = {1},

pages = {126--134},

abstract = {Recently, we showed that patients with knee osteoarthritis (KOA) demonstrate alterations in the thalamic concentrations of several metabolites compared with healthy controls: higher myo-inositol (mIns), lower N-acetylaspartate (NAA), and lower choline (Cho). Here, we evaluated whether these metabolite alterations are specific to KOA or could also be observed in patients with a different musculoskeletal condition, such as chronic low back pain (cLBP). Thirty-six patients with cLBP and 20 healthy controls were scanned using 1 H-magnetic resonance spectroscopy (MRS) and a PRESS (Point RESolved Spectroscopy) sequence with voxel placement in the left thalamus. Compared with healthy controls, patients with cLBP demonstrated lower absolute concentrations of NAA ( P = 0.0005) and Cho ( P < 0.05) and higher absolute concentrations of mIns ( P = 0.01) when controlling for age, as predicted by our previous work in KOA. In contrast to our KOA study, mIns levels in this population did not significantly correlate with pain measures (eg, pain severity or duration). However, exploratory analyses revealed that NAA levels in patients were negatively correlated with the severity of sleep disturbance ( P < 0.01), which was higher in patients compared with healthy controls ( P < 0.001). Additionally, also in patients, both Cho and mIns levels were positively correlated with age ( P < 0.01 and P < 0.05, respectively). Altogether, these results suggest that thalamic metabolite changes may be common across etiologically different musculoskeletal chronic pain conditions, including cLBP and KOA, and may relate to symptoms often comorbid with chronic pain, such as sleep disturbance. The functional and clinical significance of these brain changes remains to be fully understood.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38289855,

title = {Characterization of cortico-meningeal translocator protein expression in multiple sclerosis},

author = {Elena Herranz and Constantina A Treaba and Valeria T Barletta and Ambica Mehndiratta and Russell Ouellette and Jacob A Sloane and Carolina Ionete and Suma Babu and Marina Mastantuono and Stefano Magon and Marco L Loggia and Meena M Makary and Jacob M Hooker and Ciprian Catana and Revere Kinkel and Richard Nicholas and Eric C Klawiter and Roberta Magliozzi and Caterina Mainero},

doi = {10.1093/brain/awae030},

issn = {1460-2156},

year  = {2024},

date = {2024-01-01},

journal = {Brain},

abstract = {Compartmentalized meningeal inflammation is thought to represent one of the key players in the pathogenesis of cortical demyelination in multiple sclerosis. Positron emission tomography targeting the 18 kDa mitochondrial Translocator Protein (TSPO) is a molecular-specific approach to quantify immune cell-mediated density in the cortico-meningeal tissue compartment in vivo. The aim of this study was to characterize cortical and meningeal TSPO expression in a heterogeneous cohort of multiple sclerosis cases using in vivo simultaneous MR-PET with 11C-PBR28, a second-generation TSPO radioligand, and ex vivo immunohistochemistry. Forty-nine multiple sclerosis patients (21 with secondary progressive and 28 with relapsing-remitting multiple sclerosis) with mixed or high affinity binding for 11C-PBR28 underwent 90-min 11C-PBR28 simultaneous MR-PET. Tracer binding was measured using 60-90 min normalized standardized uptake value ratio values sampled at mid-cortical depth and ∼3 mm above the pial surface. Data in multiple sclerosis patients were compared to 21 age-matched healthy controls. To characterize the nature of 11C-PBR28 PET uptake, the meningeal and cortical lesion cellular expression of TSPO was further described in post-mortem brain tissue from 20 cases with secondary progressive multiple sclerosis and five age-matched healthy donors. Relative to healthy controls, patients with multiple sclerosis exhibited abnormally increased TSPO signal in the cortex and meningeal tissue, diffusively in progressive disease and more localized in relapsing-remitting multiple sclerosis. In multiple sclerosis, increased meningeal TSPO levels were associated with increased Expanded Disability Status Scale scores (p = 0.007, by linear regression). Immunohistochemistry, validated using in-situ sequencing analysis, revealed increased TSPO expression in the meninges and adjacent subpial cortical lesions of post-mortem secondary progressive multiple sclerosis cases relative to control tissue. In these cases, increased TSPO expression was related to meningeal inflammation. Translocator Protein immunostaining was detected on meningeal major histocompatibility complex (MHC)-class II + macrophages and cortical activated MHC-class II + transmembrane protein (TMEM)119+ microglia. In vivo arterial blood data and neuropathology showed that endothelial binding did not significantly account for increased TSPO cortico-meningeal expression in multiple sclerosis. Our findings support the use of TSPO-PET in multiple sclerosis for imaging in vivo inflammation in the cortico-meningeal brain tissue compartment and provide in vivo evidence implicating meningeal inflammation in the pathogenesis of the disease.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37642641,

title = {Stroke-Related Visceral Alterations: A Voxel-Based Neuroanatomic Localization Study},

author = {Ethem Murat Arsava and Ken Chang and Ahmed Tawakol and Marco L Loggia and Joshua N Goldstein and James Brown and Kwang-Yeol Park and Aneesh B Singhal and Jayashree Kalpathy-Cramer and Alma Gregory Sorensen and Bruce R Rosen and Martin Allen Samuels and Hakan Ay},

doi = {10.1002/ana.26785},

issn = {1531-8249},

year  = {2023},

date = {2023-12-01},

journal = {Ann Neurol},

volume = {94},

number = {6},

pages = {1155--1163},

abstract = {OBJECTIVE: Functional and morphologic changes in extracranial organs can occur after acute brain injury. The neuroanatomic correlates of such changes are not fully known. Herein, we tested the hypothesis that brain infarcts are associated with cardiac and systemic abnormalities (CSAs) in a regionally specific manner.nnMETHODS: We generated voxelwise p value maps of brain infarcts for poststroke plasma cardiac troponin T (cTnT) elevation, QTc prolongation, in-hospital infection, and acute stress hyperglycemia (ASH) in 1,208 acute ischemic stroke patients prospectively recruited into the Heart-Brain Interactions Study. We examined the relationship between infarct location and CSAs using a permutation-based approach and identified clusters of contiguous voxels associated with p < 0.05.nnRESULTS: cTnT elevation not attributable to a known cardiac reason was detected in 5.5%, QTc prolongation in the absence of a known provoker in 21.2%, ASH in 33.9%, and poststroke infection in 13.6%. We identified significant, spatially segregated voxel clusters for each CSA. The clusters for troponin elevation and QTc prolongation mapped to the right hemisphere. There were 3 clusters for ASH, the largest of which was in the left hemisphere. We found 2 clusters for poststroke infection, one associated with pneumonia in the left and one with urinary tract infection in the right hemisphere. The relationship between infarct location and CSAs persisted after adjusting for infarct volume.nnINTERPRETATION: Our results show that there are discrete regions of brain infarcts associated with CSAs. This information could be used to bootstrap toward new markers for better differentiation between neurogenic and non-neurogenic mechanisms of poststroke CSAs. ANN NEUROL 2023;94:1155-1163.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38015622b,

title = {[11C]-PBR28 positron emission tomography signal as an imaging marker of joint inflammation in knee osteoarthritis},

author = {Angelica Sandström and Angel Torrado-Carvajal and Erin J Morrissey and Minhae Kim and Zeynab Alshelh and Yehui Zhu and Matthew D Li and Connie Y Chang and Mohamed Jarraya and Oluwaseun Akeju and Andrew Schrepf and Richard E Harris and Young-Min Kwon and Hany Bedair and Antonia F Chen and Nathaniel D Mercaldo and Norman Kettner and Vitaly Napadow and Nicola Toschi and Robert R Edwards and Marco L Loggia},

doi = {10.1097/j.pain.0000000000003114},

issn = {1872-6623},

year  = {2023},

date = {2023-11-01},

journal = {Pain},

abstract = {Although inflammation is known to play a role in knee osteoarthritis (KOA), inflammation-specific imaging is not routinely performed. In this article, we evaluate the role of joint inflammation, measured using [11C]-PBR28, a radioligand for the inflammatory marker 18-kDa translocator protein (TSPO), in KOA. Twenty-one KOA patients and 11 healthy controls (HC) underwent positron emission tomography/magnetic resonance imaging (PET/MRI) knee imaging with the TSPO ligand [11C]-PBR28. Standardized uptake values were extracted from regions-of-interest (ROIs) semiautomatically segmented from MRI data, and compared across groups (HC, KOA) and subgroups (unilateral/bilateral KOA symptoms), across knees (most vs least painful), and against clinical variables (eg, pain and Kellgren-Lawrence [KL] grades). Overall, KOA patients demonstrated elevated [11C]-PBR28 binding across all knee ROIs, compared with HC (all P's < 0.005). Specifically, PET signal was significantly elevated in both knees in patients with bilateral KOA symptoms (both P's < 0.01), and in the symptomatic knee (P < 0.05), but not the asymptomatic knee (P = 0.95) of patients with unilateral KOA symptoms. Positron emission tomography signal was higher in the most vs least painful knee (P < 0.001), and the difference in pain ratings across knees was proportional to the difference in PET signal (r = 0.74, P < 0.001). Kellgren-Lawrence grades neither correlated with PET signal (left knee r = 0.32, P = 0.19; right knee r = 0.18, P = 0.45) nor pain (r = 0.39, P = 0.07). The current results support further exploration of [11C]-PBR28 PET signal as an imaging marker candidate for KOA and a link between joint inflammation and osteoarthritis-related pain severity.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37905031,

title = {Neuroinflammation in post-acute sequelae of COVID-19 (PASC) as assessed by [¹¹C]PBR28 PET correlates with vascular disease measures},

author = {Michael B VanElzakker and Hannah F Bues and Ludovica Brusaferri and Minhae Kim and Deena Saadi and Eva-Maria Ratai and Darin D Dougherty and Marco L Loggia},

doi = {10.1101/2023.10.19.563117},

year  = {2023},

date = {2023-10-01},

urldate = {2023-10-01},

journal = {bioRxiv},

abstract = {The COVID-19 pandemic caused by SARS-CoV-2 has triggered a consequential public health crisis of post-acute sequelae of COVID-19 (PASC), sometimes referred to as long COVID. The mechanisms of the heterogeneous persistent symptoms and signs that comprise PASC are under investigation, and several studies have pointed to the central nervous and vascular systems as being potential sites of dysfunction. In the current study, we recruited individuals with PASC with diverse symptoms, and examined the relationship between neuroinflammation and circulating markers of vascular dysfunction. We used [  C]PBR28 PET neuroimaging, a marker of neuroinflammation, to compare 12 PASC individuals versus 43 normative healthy controls. We found significantly increased neuroinflammation in PASC versus controls across a wide swath of brain regions including midcingulate and anterior cingulate cortex, corpus callosum, thalamus, basal ganglia, and at the boundaries of ventricles. We also collected and analyzed peripheral blood plasma from the PASC individuals and found significant positive correlations between neuroinflammation and several circulating analytes related to vascular dysfunction. These results suggest that an interaction between neuroinflammation and vascular health may contribute to common symptoms of PASC.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36622041,

title = {The Back Pain Consortium (BACPAC) Research Program: Structure, Research Priorities, and Methods},

author = {Matthew C Mauck and Jeffrey Lotz and Matthew A Psioda and Timothy S Carey and Daniel J Clauw and Sharmila Majumdar and William S Marras and Nam Vo and Ayleen Aylward and Anna Hoffmeyer and Patricia Zheng and Anastasia Ivanova and Micah McCumber and Christiane Carson and Kevin J Anstrom and Anton E Bowden and Diane Dalton and Leslie Derr and Jonathan Dufour and Aaron J Fields and Julie Fritz and Afton L Hassett and Steven E Harte and Trisha F Hue and Roland Krug and Marco L Loggia and Prasath Mageswaran and Samuel A McLean and Ulrike H Mitchell and Conor O'Neill and Valentina Pedoia and David Adam Quirk and Daniel I Rhon and Viola Rieke and Lubdha Shah and Gwendolyn Sowa and Brennan Spiegel and Ajay D Wasan and Hsiao-Ying Monica Wey and Lisa LaVange},

doi = {10.1093/pm/pnac202},

issn = {1526-4637},

year  = {2023},

date = {2023-08-01},

journal = {Pain Med},

volume = {24},

number = {Suppl 1},

pages = {S3--S12},

abstract = {In 2019, the National Health Interview survey found that nearly 59% of adults reported pain some, most, or every day in the past 3 months, with 39% reporting back pain, making back pain the most prevalent source of pain, and a significant issue among adults. Often, identifying a direct, treatable cause for back pain is challenging, especially as it is often attributed to complex, multifaceted issues involving biological, psychological, and social components. Due to the difficulty in treating the true cause of chronic low back pain (cLBP), an over-reliance on opioid pain medications among cLBP patients has developed, which is associated with increased prevalence of opioid use disorder and increased risk of death. To combat the rise of opioid-related deaths, the National Institutes of Health (NIH) initiated the Helping to End Addiction Long-TermSM (HEAL) initiative, whose goal is to address the causes and treatment of opioid use disorder while also seeking to better understand, diagnose, and treat chronic pain. The NIH Back Pain Consortium (BACPAC) Research Program, a network of 14 funded entities, was launched as a part of the HEAL initiative to help address limitations surrounding the diagnosis and treatment of cLBP. This paper provides an overview of the BACPAC research program's goals and overall structure, and describes the harmonization efforts across the consortium, define its research agenda, and develop a collaborative project which utilizes the strengths of the network. The purpose of this paper is to serve as a blueprint for other consortia tasked with the advancement of pain related science.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36657520,

title = {Assessing the potential anti-neuroinflammatory effect of minocycline in chronic low back pain: Protocol for a randomized, double-blind, placebo-controlled trial},

author = {Erin J Morrissey and Zeynab Alshelh and Paulina C Knight and Atreyi Saha and Minhae Kim and Angel Torrado-Carvajal and Yi Zhang and Robert R Edwards and Chelsea Pike and Joseph J Locascio and Vitaly Napadow and Marco L Loggia},

doi = {10.1016/j.cct.2023.107087},

issn = {1559-2030},

year  = {2023},

date = {2023-03-01},

journal = {Contemp Clin Trials},

volume = {126},

pages = {107087},

abstract = {INTRODUCTION: Both preclinical studies, and more recent clinical imaging studies, suggest that glia-mediated neuroinflammation may be implicated in chronic pain, and therefore might be a potential treatment target. However, it is currently unknown whether modulating neuroinflammation effectively alleviates pain in humans. This trial tests the hypothesis that minocycline, an FDA-approved tetracycline antibiotic and effective glial cell inhibitor in animals, reduces neuroinflammation and may reduce pain symptoms in humans with chronic low back pain.nnMETHODS AND ANALYSIS: This study is a randomized, double-blind, placebo-controlled clinical trial. Subjects, aged 18-75, with a confirmed diagnosis of chronic (≥ six months) low back pain (cLBP) and a self-reported pain rating of at least four out of ten (for at least half of the days during an average week) are enrolled via written, informed consent. Eligible subjects are randomized to receive a 14-day course of either active drug (minocycline) or placebo. Before and after treatment, subjects are scanned with integrated Positron Emission Tomography/Magnetic Resonance Imaging (PET/MRI) using [C]PBR28, a second-generation radiotracer for the 18 kDa translocator protein (TSPO), which is highly expressed in glial cells and thus a putative marker of neuroinflammation. Pain levels are evaluated via daily surveys, collected seven days prior to the start of medication, and throughout the 14 days of treatment. General linear models will be used to assess pain levels and determine the treatment effect on brain (and spinal cord) TSPO signal.nnTRIAL REGISTRATION NUMBER: ClinicalTrials.gov (NCT03106740).},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35570655,

title = {Disruptions in Structural and Functional Connectivity Relate to Poststroke Fatigue},

author = {Judith D Schaechter and Minhae Kim and Baileigh G Hightower and Trevor Ragas and Marco L Loggia},

doi = {10.1089/brain.2022.0021},

issn = {2158-0022},

year  = {2023},

date = {2023-02-01},

journal = {Brain Connect},

volume = {13},

number = {1},

pages = {15--27},

abstract = { Poststroke fatigue (PSF) is a disabling condition with unclear etiology. The brain lesion is thought to be an important causal factor in PSF, although focal lesion characteristics such as size and location have not proven to be predictive. Given that the stroke lesion results not only in focal tissue death but also in widespread changes in brain networks that are structurally and functionally connected to damaged tissue, we hypothesized that PSF relates to disruptions in structural and functional connectivity.  Twelve patients who incurred an ischemic stroke in the middle cerebral artery (MCA) territory 1-3 years prior, and currently experiencing a range of fatigue severity, were enrolled. The patients underwent structural and resting-state functional magnetic resonance imaging (MRI). The structural MRI data were used to measure structural disconnection of gray matter resulting from lesion to white matter pathways. The functional MRI data were used to measure network functional connectivity.  The patients showed structural disconnection in varying cortical and subcortical regions. Fatigue severity correlated significantly with structural disconnection of several frontal cortex regions in the ipsilesional (IL) and contralesional hemispheres. Fatigue-related structural disconnection was most severe in the IL rostral middle frontal cortex. Greater structural disconnection of a subset of fatigue-related frontal cortex regions, including the IL rostral middle frontal cortex, trended toward correlating significantly with greater loss in functional connectivity. Among identified fatigue-related frontal cortex regions, only the IL rostral middle frontal cortex showed loss in functional connectivity correlating significantly with fatigue severity.  Our results provide evidence that loss in structural and functional connectivity of bihemispheric frontal cortex regions plays a role in PSF after MCA stroke, with connectivity disruptions of the IL rostral middle frontal cortex having a central role. Impact statement Poststroke fatigue (PSF) is a common disabling condition with unclear etiology. We hypothesized that PSF relates to disruptions in structural and functional connectivity secondary to the focal lesion. Using structural and resting-state functional connectivity magnetic resonance imaging (MRI) in patients with chronic middle cerebral artery (MCA) stroke, we found frontal cortex regions in the ipsilesional (IL) and contralesional hemispheres with greater structural disconnection correlating with greater fatigue. Among these fatigue-related cortices, the IL rostral middle frontal cortex showed loss in functional connectivity correlating with fatigue. These findings suggest that disruptions in structural and functional connectivity play a role in PSF after MCA stroke.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36472927,

title = {Radiocaine: An Imaging Marker of Neuropathic Injury},

author = {Nicole D Bartolo and Sarah E Reid and Hema S Krishnan and Azra Haseki and Muthukrishnan Renganathan and Tally M Largent-Milnes and Braxton A Norwood and Marco L Loggia and Jacob M Hooker},

doi = {10.1021/acschemneuro.2c00717},

issn = {1948-7193},

year  = {2022},

date = {2022-12-01},

journal = {ACS Chem Neurosci},

volume = {13},

number = {24},

pages = {3661--3667},

abstract = {Voltage-gated sodium channels (Nas) play a crucial electrical signaling role in neurons. Na-isoforms present in peripheral sensory neurons and dorsal root ganglia of the spinal cord are critically involved in pain perception and transmission. While these isoforms, particularly Na1.7, are implicated in neuropathic pain disorders, changes in the functional state and expression levels of these channels have not been extensively studied in vivo. Radiocaine, a fluorine-18 radiotracer based on the local anesthetic lidocaine, a non-selective Na blocker, has previously been used for cardiac Na1.5 imaging using positron-emission tomography (PET). In the present study, we used Radiocaine to visualize changes in neuronal Na expression after neuropathic injury. In rats that underwent unilateral spinal nerve ligation, PET/MR imaging demonstrated significantly higher uptake of Radiocaine into the injured sciatic nerve, as compared to the uninjured sciatic nerve, for up to 32 days post-surgery. Radiocaine, due to its high translational potential, may serve as a novel diagnostic tool for neuropathic pain conditions using PET imaging.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36136765,

title = {Increased Clinical Pain Locations and Pain Sensitivity in Women After Breast Cancer Surgery: Influence of Aromatase Inhibitor Therapy},

author = {Yehui Zhu and Marco L Loggia and Robert R Edwards and Kelsey M Flowers and Dennis W Muñoz-Vergara and Ann H Partridge and Kristin L Schreiber},

doi = {10.1097/AJP.0000000000001073},

issn = {1536-5409},

year  = {2022},

date = {2022-12-01},

journal = {Clin J Pain},

volume = {38},

number = {12},

pages = {721--729},

abstract = {OBJECTIVES: Aromatase inhibitors (AIs), which potently inhibit estrogen biosynthesis, are a standard treatment for hormone sensitive early-stage breast cancer. AIs have been associated with substantial joint pain and muscle stiffness (aromatase inhibitor-associated musculoskeletal syndrome). However, the link between AIs and number of clinical pain locations and pain sensitivity are less well understood. The aim of this study was to compare longitudinal changes in clinical pain and quantitative pain sensitivity between women who did or did not receive AI therapy.nnMETHODS: Women with early-stage breast cancer were prospectively enrolled and assessed for clinical pain in surgical and nonsurgical body areas using the Brief Pain Inventory and Breast Cancer Pain Questionnaire, and for pain sensitivity using quantitative sensory testing preoperatively and at 1 year postoperatively. Pain outcomes between participants who did and did not begin adjuvant AI therapy were compared using Wilcoxon Signed-Ranks and generalized estimating equation linear regression analyses.nnRESULTS: Clinical pain and pain sensitivity were comparable between AI (n=49) and no-AI (n=106) groups preoperatively. After adjusting for body mass index, AI therapy was associated with a greater increase in the number of painful nonsurgical body sites (significant time by treatment interaction, P =0.024). Pain location was most frequent in knees (28%), lower back (26%), and ankles/feet (17%). Quantitative sensory testing revealed a significant decrease in pain sensitivity (increased pressure pain threshold) in the no-AI group over time, but not in the AI group.nnCONCLUSIONS: AI therapy was associated with increased diffuse joint-related pain and greater post-treatment pain sensitivity, potentially implicating central sensitization as a contributing pain mechanism of aromatase inhibitor-associated musculoskeletal syndrome worthy of future investigation.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36123113,

title = {Study protocol for a phase II, double-blind, randomised controlled trial of cannabidiol (CBD) compared with placebo for reduction of brain neuroinflammation in adults with chronic low back pain},

author = {Chelsea K Pike and Minhae Kim and Kristina Schnitzer and Nathaniel Mercaldo and Robert Edwards and Vitaly Napadow and Yi Zhang and Erin Janas Morrissey and Zeynab Alshelh and A Eden Evins and Marco L Loggia and Jodi M Gilman},

doi = {10.1136/bmjopen-2022-063613},

issn = {2044-6055},

year  = {2022},

date = {2022-09-01},

journal = {BMJ Open},

volume = {12},

number = {9},

pages = {e063613},

abstract = {INTRODUCTION: Chronic pain is a debilitating medical problem that is difficult to treat. Neuroinflammatory pathways have emerged as a potential therapeutic target, as preclinical studies have demonstrated that glial cells and neuroglial interactions play a role in the establishment and maintenance of pain. Recently, we used positron emission tomography (PET) to demonstrate increased levels of 18 kDa translocator protein (TSPO) binding, a marker of glial activation, in patients with chronic low back pain (cLBP). Cannabidiol (CBD) is a glial inhibitor in animal models, but studies have not assessed whether CBD reduces neuroinflammation in humans. The principal aim of this trial is to evaluate whether CBD, compared with placebo, affects neuroinflammation, as measured by TSPO levels.nnMETHODS AND ANALYSIS: This is a double-blind, randomised, placebo-controlled, phase II clinical trial. Eighty adults (aged 18-75) with cLBP for >6 months will be randomised to either an FDA-approved CBD medication (Epidiolex) or matching placebo for 4 weeks using a dose-escalation design. All participants will undergo integrated PET/MRI at baseline and after 4 weeks of treatment to evaluate neuroinflammation using [C]PBR28, a second-generation radioligand for TSPO. Our primary hypothesis is that participants randomised to CBD will demonstrate larger reductions in thalamic [C]PBR28 signal compared with those receiving placebo. We will also assess the effect of CBD on (1) [C]PBR28 signal from limbic regions, which our prior work has linked to depressive symptoms and (2) striatal activation in response to a reward task. Additionally, we will evaluate self-report measures of cLBP intensity and bothersomeness, depression and quality of life at baseline and 4 weeks.nnETHICS AND DISSEMINATION: This protocol is approved by the Massachusetts General Brigham Human Research Committee (protocol number: 2021P002617) and FDA (IND number: 143861) and registered with ClinicalTrials.gov. Results will be published in peer-reviewed journals and presented at conferences.nnTRIAL REGISTRATION NUMBER: NCT05066308; ClinicalTrials.gov.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35482515,

title = {The Influence of Expectancies on Pain and Function Over Time After Total Knee Arthroplasty},

author = {Junie S Carriere and Marc Olivier Martel and Marco L Loggia and Claudia M Campbell and Michael T Smith and Jennifer A Haythornthwaite and Robert R Edwards},

doi = {10.1093/pm/pnac067},

issn = {1526-4637},

year  = {2022},

date = {2022-09-01},

journal = {Pain Med},

volume = {23},

number = {10},

pages = {1767--1776},

abstract = {OBJECTIVE: Expectancies have a well-documented influence on the experience of pain, responses to treatment, and postsurgical outcomes. In individuals with osteoarthritis, several studies have shown that expectations predict increased pain and disability after total knee replacement surgery. Despite the growing recognition of the importance of expectancies in clinical settings, few studies have examined the influence of expectancies throughout postsurgical recovery trajectories. The objective of the present study was to examine the role of presurgical expectancies on pain and function at 6-week, 6-month, and 1-year follow-ups after total knee arthroplasty.nnDESIGN AND PARTICIPANTS: Data were collected from patients scheduled for total knee arthroplasty 1 week before surgery and then at 6 weeks, 6 months, and 1 year after surgery. Correlational and multivariable regression analyses examined the influence of expectancies on patients' perceptions of pain reduction and functional improvement at each time point. Analyses controlled for age, sex, body mass index, presurgical pain intensity and function, pain catastrophizing, anxiety, and depression.nnRESULTS: Results revealed that expectancies significantly predicted pain reduction and functional improvement at 1-year follow-up. However, expectancies did not predict outcomes at the 6-week and 6-month follow-ups. Catastrophizing and depressive symptoms emerged as short-term predictors of postsurgical functional limitations at 6-week and 6-month follow-ups, respectively.nnCONCLUSIONS: The results suggest that targeting high levels of catastrophizing and depressive symptoms could optimize short-term recovery after total knee arthroplasty. However, the results demonstrate that targeting presurgical negative expectancies could prevent prolonged recovery trajectories, characterized by pain and loss of function up to 1 year after total knee arthroplasty.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34561394,

title = {Transcriptional and cellular signatures of cortical morphometric remodelling in chronic pain},

author = {Daniel Martins and Ottavia Dipasquale and Mattia Veronese and Federico Turkheimer and Marco L Loggia and Stephen McMahon and Matthew A Howard and Steven C R Williams},

doi = {10.1097/j.pain.0000000000002480},

issn = {1872-6623},

year  = {2022},

date = {2022-06-01},

journal = {Pain},

volume = {163},

number = {6},

pages = {e759--e773},

abstract = {Chronic pain is a highly debilitating and difficult to treat condition, which affects the structure of the brain. Although the development of chronic pain is moderately heritable, how disease-related alterations at the microscopic genetic architecture drive macroscopic brain abnormalities is currently largely unknown. Here, we examined alterations in morphometric similarity (MS) and applied an integrative imaging transcriptomics approach to identify transcriptional and cellular correlates of these MS changes, in 3 independent small cohorts of patients with distinct chronic pain syndromes (knee osteoarthritis, low back pain, and fibromyalgia) and age-matched and sex-matched pain-free controls. We uncover a novel pattern of cortical MS remodelling involving mostly small-to-medium MS increases in the insula and limbic cortex (none of these changes survived stringent false discovery rate correction for the number of regions tested). This pattern of changes is different from that observed in patients with major depression and cuts across the boundaries of specific pain syndromes. By leveraging transcriptomic data from Allen Human Brain Atlas, we show that cortical MS remodelling in chronic pain spatially correlates with the brain-wide expression of genes related to pain and broadly involved in the glial immune response and neuronal plasticity. Our findings bridge levels to connect genes, cell classes, and biological pathways to in vivo imaging correlates of chronic pain. Although correlational, our data suggest that cortical remodelling in chronic pain might be shaped by multiple elements of the cellular architecture of the brain and identifies several pathways that could be prioritized in future genetic association or drug development studies.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35181440,

title = {The pandemic brain: Neuroinflammation in non-infected individuals during the COVID-19 pandemic},

author = {Ludovica Brusaferri and Zeynab Alshelh and Daniel Martins and Minhae Kim and Akila Weerasekera and Hope Housman and Erin J Morrissey and Paulina C Knight and Kelly A Castro-Blanco and Daniel S Albrecht and Chieh-En Tseng and Nicole R Zürcher and Eva-Maria Ratai and Oluwaseun Akeju and Meena M Makary and Ciprian Catana and Nathaniel D Mercaldo and Nouchine Hadjikhani and Mattia Veronese and Federico Turkheimer and Bruce R Rosen and Jacob M Hooker and Marco L Loggia},

doi = {10.1016/j.bbi.2022.02.018},

issn = {1090-2139},

year  = {2022},

date = {2022-05-01},

journal = {Brain Behav Immun},

volume = {102},

pages = {89--97},

abstract = {While COVID-19 research has seen an explosion in the literature, the impact of pandemic-related societal and lifestyle disruptions on brain health among the uninfected remains underexplored. However, a global increase in the prevalence of fatigue, brain fog, depression and other "sickness behavior"-like symptoms implicates a possible dysregulation in neuroimmune mechanisms even among those never infected by the virus. We compared fifty-seven 'Pre-Pandemic' and fifteen 'Pandemic' datasets from individuals originally enrolled as control subjects for various completed, or ongoing, research studies available in our records, with a confirmed negative test for SARS-CoV-2 antibodies. We used a combination of multimodal molecular brain imaging (simultaneous positron emission tomography / magnetic resonance spectroscopy), behavioral measurements, imaging transcriptomics and serum testing to uncover links between pandemic-related stressors and neuroinflammation. Healthy individuals examined after the enforcement of 2020 lockdown/stay-at-home measures demonstrated elevated brain levels of two independent neuroinflammatory markers (the 18 kDa translocator protein, TSPO, and myoinositol) compared to pre-lockdown subjects. The serum levels of two inflammatory markers (interleukin-16 and monocyte chemoattractant protein-1) were also elevated, although these effects did not reach statistical significance after correcting for multiple comparisons. Subjects endorsing higher symptom burden showed higher TSPO signal in the hippocampus (mood alteration, mental fatigue), intraparietal sulcus and precuneus (physical fatigue), compared to those reporting little/no symptoms. Post-lockdown TSPO signal changes were spatially aligned with the constitutive expression of several genes involved in immune/neuroimmune functions. This work implicates neuroimmune activation as a possible mechanism underlying the non-virally-mediated symptoms experienced by many during the COVID-19 pandemic. Future studies will be needed to corroborate and further interpret these preliminary findings.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35366813,

title = {Comparison of test-retest reliability of BOLD and pCASL fMRI in a two-center study},

author = {James W Ibinson and Andrea G Gillman and Vince Schmidthorst and Conrad Li and Vitaly Napadow and Marco L Loggia and Ajay D Wasan},

doi = {10.1186/s12880-022-00791-9},

issn = {1471-2342},

year  = {2022},

date = {2022-04-01},

journal = {BMC Med Imaging},

volume = {22},

number = {1},

pages = {62},

abstract = {BACKGROUND: The establishment of test-retest reliability and reproducibility (TRR) is an important part of validating any research tool, including functional magnetic resonance imaging (fMRI). The primary objective of this study is to investigate the reliability of pseudo-Continuous Arterial Spin Labeling (pCASL) and Blood Oxygen Level Dependent (BOLD) fMRI data acquired across two different scanners in a sample of healthy adults. While single site/single scanner studies have shown acceptable repeatability, TRR of both in a practical multisite study occurring in two facilities spread out across the country with weeks to months between scans is critically needed.nnMETHODS: Ten subjects were imaged with similar 3 T MRI scanners at the University of Pittsburgh and Massachusetts General Hospital. Finger-tapping and Resting-state data were acquired for both techniques. Analysis of the resting state data for functional connectivity was performed with the Functional Connectivity Toolbox, while analysis of the finger tapping data was accomplished with FSL. pCASL Blood flow data was generated using AST Toolbox. Activated areas and networks were identified via pre-defined atlases and dual-regression techniques. Analysis for TRR was conducted by comparing pCASL and BOLD images in terms of Intraclass correlation coefficients, Dice Similarity Coefficients, and repeated measures ANOVA.nnRESULTS: Both BOLD and pCASL scans showed strong activation and correlation between the two locations for the finger tapping tasks. Functional connectivity analyses identified elements of the default mode network in all resting scans at both locations. Multivariate repeated measures ANOVA showed significant variability between subjects, but no significant variability for location. Global CBF was very similar between the two scanning locations, and repeated measures ANOVA showed no significant differences between the two scanning locations.nnCONCLUSIONS: The results of this study show that when similar scanner hardware and software is coupled with identical data analysis protocols, consistent and reproducible functional brain images can be acquired across sites. The variability seen in the activation maps is greater for pCASL versus BOLD images, as expected, however groups maps are remarkably similar despite the low number of subjects. This demonstrates that multi-site fMRI studies of task-based and resting state brain activity is feasible.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34725971,

title = {Dynamic Functional Brain Connectivity Underlying Temporal Summation of Pain in Fibromyalgia},

author = {Joshua C Cheng and Alessandra Anzolin and Michael Berry and Hamed Honari and Myrella Paschali and Asimina Lazaridou and Jeungchan Lee and Dan-Mikael Ellingsen and Marco L Loggia and Arvina Grahl and Martin A Lindquist and Robert R Edwards and Vitaly Napadow},

doi = {10.1002/art.42013},

issn = {2326-5205},

year  = {2022},

date = {2022-04-01},

journal = {Arthritis Rheumatol},

volume = {74},

number = {4},

pages = {700--710},

abstract = {OBJECTIVE: Abnormal central pain processing is a leading cause of pain in fibromyalgia (FM) and is perceptually characterized with the psychophysical measure of temporal summation of pain (TSP). TSP is the perception of increasingly greater pain in response to repetitive or tonic noxious stimuli. Previous neuroimaging studies have used static (i.e., summary) measures to examine the functional magnetic resonance imaging (fMRI) correlates of TSP in FM. However, functional brain activity rapidly and dynamically reorganizes over time, and, similarly, TSP is a temporally evolving process. This study was undertaken to demonstrate how a complete understanding of the neural circuitry supporting TSP in FM thus requires a dynamic measure that evolves over time.nnMETHODS: We utilized novel methods for analyzing dynamic functional brain connectivity in patients with FM in order to examine how TSP-associated fluctuations are linked to the dynamic functional reconfiguration of the brain. In 84 FM patients and age- and sex-matched healthy controls, we collected high-temporal-resolution fMRI data during a resting state and during a state in which sustained cuff pressure pain was applied to the leg.nnRESULTS: FM patients experienced greater TSP than healthy controls (mean ± SD TSP score 17.93 ± 19.24 in FM patients versus 9.47 ± 14.06 in healthy controls; P = 0.028), but TSP scores varied substantially between patients. In the brain, the presence versus absence of TSP in patients with FM was marked by more sustained enmeshment between sensorimotor and salience networks during the pain period. Furthermore, dynamic enmeshment was noted solely in FM patients with high TSP, as interactions with all other brain networks were dampened during the pain period.nnCONCLUSION: This study elucidates the dynamic brain processes underlying facilitated central pain processing in FM. Our findings will enable future investigation of dynamic symptoms in FM.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34528069,

title = {Neuroimmune signatures in chronic low back pain subtypes},

author = {Zeynab Alshelh and Ludovica Brusaferri and Atreyi Saha and Erin Morrissey and Paulina Knight and Minhae Kim and Yi Zhang and Jacob M Hooker and Daniel Albrecht and Angel Torrado-Carvajal and Michael S Placzek and Oluwaseun Akeju and Julie Price and Robert R Edwards and Jeungchan Lee and Roberta Sclocco and Ciprian Catana and Vitaly Napadow and Marco L Loggia},

doi = {10.1093/brain/awab336},

issn = {1460-2156},

year  = {2022},

date = {2022-04-01},

journal = {Brain},

volume = {145},

number = {3},

pages = {1098--1110},

abstract = {We recently showed that patients with different chronic pain conditions (such as chronic low back pain, fibromyalgia, migraine and Gulf War illness) demonstrated elevated brain and/or spinal cord levels of the glial marker 18-kDa translocator protein (TSPO), which suggests that neuroinflammation might be a pervasive phenomenon observable across multiple aetiologically heterogeneous pain disorders. Interestingly, the spatial distribution of this neuroinflammatory signal appears to exhibit a degree of disease specificity (e.g. with respect to the involvement of the primary somatosensory cortex), suggesting that different pain conditions may exhibit distinct 'neuroinflammatory signatures'. To explore this hypothesis further, we tested whether neuroinflammatory signal can characterize putative aetiological subtypes of chronic low back pain patients based on clinical presentation. Specifically, we explored neuroinflammation in patients whose chronic low back pain either did or did not radiate to the leg (i.e. 'radicular' versus 'axial' back pain). Fifty-four patients with chronic low back pain, 26 with axial back pain [43.7 ± 16.6 years old (mean ± SD)] and 28 with radicular back pain (48.3 ± 13.2 years old), underwent PET/MRI with 11C-PBR28, a second-generation radioligand for TSPO. 11C-PBR28 signal was quantified using standardized uptake values ratio (validated against volume of distribution ratio; n = 23). Functional MRI data were collected simultaneously to the 11C-PBR28 data (i) to functionally localize the primary somatosensory cortex back and leg subregions; and (ii) to perform functional connectivity analyses (in order to investigate possible neurophysiological correlations of the neuroinflammatory signal). PET and functional MRI measures were compared across groups, cross-correlated with one another and with the severity of 'fibromyalgianess' (i.e. the degree of pain centralization, or 'nociplastic pain'). Furthermore, statistical mediation models were used to explore possible causal relationships between these three variables. For the primary somatosensory cortex representation of back/leg, 11C-PBR28 PET signal and functional connectivity to the thalamus were: (i) higher in radicular compared to axial back pain patients; (ii) positively correlated with each other; (iii) positively correlated with fibromyalgianess scores, across groups; and finally (iv) fibromyalgianess mediated the association between 11C-PBR28 PET signal and primary somatosensory cortex-thalamus connectivity across groups. Our findings support the existence of 'neuroinflammatory signatures' that are accompanied by neurophysiological changes and correlate with clinical presentation (in particular, with the degree of nociplastic pain) in chronic pain patients. These signatures may contribute to the subtyping of distinct pain syndromes and also provide information about interindividual variability in neuroimmune brain signals, within diagnostic groups, that could eventually serve as targets for mechanism-based precision medicine approaches.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35140142,

title = {Multimodal Investigation of Neuroinflammation in Aviremic Patients With HIV on Antiretroviral Therapy and HIV Elite Controllers},

author = {Hasan Sari and Riccardo Galbusera and Guillaume Bonnier and Yang Lin and Zeynab Alshelh and Angel Torrado-Carvajal and Shibani S Mukerji and Eva M Ratai and Rajesh T Gandhi and Jacqueline T Chu and Oluwaseun Akeju and Vwaire Orhurhu and Andrew N Salvatore and Janet Sherman and Douglas S Kwon and Bruce Walker and Bruce Rosen and Julie C Price and Lauren E Pollak and Marco L Loggia and Cristina Granziera},

doi = {10.1212/NXI.0000000000001144},

issn = {2332-7812},

year  = {2022},

date = {2022-03-01},

journal = {Neurol Neuroimmunol Neuroinflamm},

volume = {9},

number = {2},

abstract = {BACKGROUND AND OBJECTIVES: The presence of HIV in the CNS has been related to chronic immune activation and cognitive dysfunction. The aim of this work was to investigate (1) the presence of neuroinflammation in aviremic people with HIV (PWH) on therapy and in nontreated aviremic PWH (elite controllers [ECs]) using a translocator protein 18 kDa radioligand; (2) the relationship between neuroinflammation and cognitive function in aviremic PWH; and (3) the relationship between [C]-PBR28 signal and quantitative MRI (qMRI) measures of brain tissue integrity such as T1 and T2 relaxation times (rts).nnMETHODS: [C]-PBR28 (standard uptake value ratio, SUVR) images were generated in 36 participants (14 PWH, 6 ECs, and 16 healthy controls) using a statistically defined pseudoreference region. Group comparisons of [C]-PBR28 SUVR were performed using region of interest-based and voxelwise analyses. The relationship between inflammation, qMRI measures, and cognitive function was studied.nnRESULTS: In region of interest analyses, ECs exhibited significantly lower [C]-PBR28 signal in the thalamus, putamen, superior temporal gyrus, prefrontal cortex, and cerebellum compared with the PWH. In voxelwise analyses, differences were observed in the thalamus, precuneus cortex, inferior temporal gyrus, occipital cortex, cerebellum, and white matter (WM). [C]-PBR28 signal in the WM and superior temporal gyrus was related to processing speed and selective attention in PWH. In a subset of PWH (n = 12), [C]-PBR28 signal in the thalamus and WM regions was related to a decrease in T2 rt and to an increase in T1 rt suggesting a colocalization of increased glial metabolism, decrease in microstructural integrity, and iron accumulation.nnDISCUSSION: This study casts a new light onto the role of neuroinflammation and related microstructural alterations of HIV infection in the CNS and shows that ECs suppress neuroinflammation more effectively than PWH on therapy.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36137496,

title = {Selective atrophy of the cervical enlargement in whole spinal cord MRI of amyotrophic lateral sclerosis},

author = {Robert L Barry and Angel Torrado-Carvajal and John E Kirsch and Grae E Arabasz and Daniel S Albrecht and Zeynab Alshelh and Olivia Pijanowski and Austin J Lewis and Mackenzie Keegan and Beverly Reynolds and Paulina C Knight and Erin J Morrissey and Marco L Loggia and Nazem Atassi and Jacob M Hooker and Suma Babu},

doi = {10.1016/j.nicl.2022.103199},

issn = {2213-1582},

year  = {2022},

date = {2022-01-01},

journal = {Neuroimage Clin},

volume = {36},

pages = {103199},

abstract = {Amyotrophic lateral sclerosis (ALS) is a deadly neurodegenerative disorder affecting motor neurons in the spinal cord and brain. Studies have reported on atrophy within segments of the cervical cord, but we are not aware of previous investigations of the whole spinal cord. Herein we present our findings from a 3T MRI study involving 32 subjects (15 ALS participants and 17 healthy controls) characterizing cross-sectional area along the entire cord. We report atrophy of the cervical enlargement in ALS participants, but no evidence of atrophy of the thoracolumbar enlargement. These results suggest that MR-based analyses of the cervical cord may be sufficient for in vivo investigations of spinal cord atrophy in ALS, and that atrophy of the cervical enlargement (C4-C7) is a potential imaging marker for quantifying lower motor neuron degradation.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36118965,

title = {The art of pain: A quantitative color analysis of the self-portraits of Frida Kahlo},

author = {Federico E Turkheimer and Jingyi Liu and Erik D Fagerholm and Paola Dazzan and Marco L Loggia and Eric Bettelheim},

doi = {10.3389/fnhum.2022.1000656},

issn = {1662-5161},

year  = {2022},

date = {2022-01-01},

journal = {Front Hum Neurosci},

volume = {16},

pages = {1000656},

abstract = {Frida Kahlo (1907-1954) was a Mexican artist who is remembered for her self-portraits, pain and passion, and bold, vibrant colors. This work aims to use her life story and her artistic production in a longitudinal study to examine with quantitative tools the effects of physical and emotional pain (rage) on artistic expression. Kahlo suffered from polio as a child, was involved in a bus accident as a teenager where she suffered multiple fractures of her spine and had 30 operations throughout her lifetime. She also had a tempestuous relationship with her painter husband, Diego Rivera. Her physical and personal troubles however became the texture of her vivid visual vocabulary-usually expressed through the depiction of Mexican and indigenous culture or the female experience and form. We applied color analysis to a series of Frida's self-portraits and revealed a very strong association of physical pain and emotional rage with low wavelength colors (red and yellow), indicating that the expression of her ailments was, consciously or not, achieved by increasing the perceived luminance of the canvas. Further quantitative analysis that used the fractal dimension identified "The broken column" as the portrait with higher compositional complexity, which matches previous critical acclaim of this portrait as the climax of her art. These results confirm the ability of color analysis to extract emotional and cognitive features from artistic work. We suggest that these tools could be used as markers to support artistic and creative interventions in mental health.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34693367,

title = {Association of the tissue microstructural diffusivity and translocator protein PET in Gulf War Illness},

author = {Chia-Hsin Cheng and Zeynab Alshelh and Yi Guan and Kimberly Sullivan and Marco L Loggia and Bang-Bon Koo},

doi = {10.1016/j.bbih.2021.100364},

issn = {2666-3546},

year  = {2021},

date = {2021-12-01},

journal = {Brain Behav Immun Health},

volume = {18},

pages = {100364},

abstract = {About a third of all United States veterans who served in the 1991 Gulf War (GW) report a range of chronic health symptoms including fatigue, neurocognitive symptoms, and musculoskeletal pain. There is growing evidence supporting the detrimental effects of maladaptive neuroimmune reactions in this multi-symptom illness. Indeed, recent studies using positron emission tomography (PET) using the radioligand [C]PBR28, which binds the neuroinflammation marker 18 ​kDa translocator protein (TSPO), and diffusion magnetic resonance imaging (dMRI) have independently identified the anterior cingulate (ACC) and midcingulate cortices (MCC) as key regions for differentiating GWI veterans from healthy controls (HC). Here, we used integrated (i.e., simultaneous) PET/MRI imaging techniques, paired with dMRI processing methods (neurite density imaging, NDI, and free-water diffusion tensor model to single-shell high-order dMRI), to directly evaluate the relationship between ACC and MCC microstructural tissue parameters, TSPO signal and clinical parameters in the same cohorts of 10 GWI veterans and 19 ​HCs. Within the regions evaluated, TSPO signal elevations were associated with restricted diffusivity in the extracellular compartment, while clinical measures were best explained by neurite density and cellular structure complexity measures. Our study is the first to provide evidence of a relationship between PET and dMRI modalities in GWI and suggests that microstructural changes in the ACC and MCC are correlated to mood symptoms and cognitive performances in GWI veterans.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34589819,

title = {A pilot [C]PBR28 PET/MRI study of neuroinflammation and neurodegeneration in chronic stroke patients},

author = {Judith D Schaechter and Baileigh G Hightower and Minhae Kim and Marco L Loggia},

doi = {10.1016/j.bbih.2021.100336},

issn = {2666-3546},

year  = {2021},

date = {2021-11-01},

journal = {Brain Behav Immun Health},

volume = {17},

pages = {100336},

abstract = {Neuroinflammation occurs in response to acute ischemic stroke, and has been speculated to underlie secondary poststroke pathologies, such as depression, that often develop over time poststroke. However, no study has examined whether neuroinflammation is present in chronic stroke patients (e.g., ​≥ ​1 year poststroke). This study tested whether neuroinflammation is present in chronic stroke patients, and is associated with neurodegeneration, using [C]PBR28 PET and diffusion MRI. Eight patients with middle cerebral artery (MCA) ischemic stroke incurred 1-3 years prior and 16 healthy controls underwent [C]PBR28 PET to measure glial activation and diffusion MRI to measure microstructural integrity by mean diffusivity (MD) and fractional anisotropy (FA) using an integrated PET/MRI scanner. Group differences in [C]PBR28 binding, MD and FA were analyzed voxelwise across the whole brain excluding the infarct zone defined as voxels containing the infarct in any patient. Compared to controls, patients showed elevations in [C]PBR28 binding in several brain regions outside the infarct zone, including regions with presumed direct neuroanatomical connections to the infarct (e.g., ipsilesional internal capsule and thalamus) and those without known direct connections (e.g., contralesional thalamus and cingulate gyrus). Patients also showed widespread elevations in MD, with a subset of these regions having reduced FA. In patients, MD was more elevated in regions with co-localized elevations in [C]PBR28 binding than in contralateral regions without elevations in [C]PBR28 binding. This pilot study supports the presence of extensive glial activation along with widespread loss in microstructural integrity in non-infarcted tissue in a cohort of patients with chronic MCA stroke. The loss in microstructural integrity was greater in regions with co-localized glial activation. It is possible that stroke risk factors (e.g., hypertension) contributed to these tissue changes in patients.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34453948,

title = {Boston biorepository, recruitment and integrative network (BBRAIN): A resource for the Gulf War Illness scientific community},

author = {D Keating and C G Zundel and M Abreu and M Krengel and K Aenlle and M D Nichols and R Toomey and L L Chao and J Golier and L Abdullah and E Quinn and T Heeren and J R Groh and B B Koo and R Killiany and M L Loggia and J Younger and J Baraniuk and P Janulewicz and J Ajama and M Quay and P W Baas and L Qiang and L Conboy and E Kokkotou and J P O'Callaghan and L Steele and N Klimas and K Sullivan},

doi = {10.1016/j.lfs.2021.119903},

issn = {1879-0631},

year  = {2021},

date = {2021-11-01},

journal = {Life Sci},

volume = {284},

pages = {119903},

abstract = {AIMS: Gulf War Illness (GWI), a chronic debilitating disorder characterized by fatigue, joint pain, cognitive, gastrointestinal, respiratory, and skin problems, is currently diagnosed by self-reported symptoms. The Boston Biorepository, Recruitment, and Integrative Network (BBRAIN) is the collaborative effort of expert Gulf War Illness (GWI) researchers who are creating objective diagnostic and pathobiological markers and recommend common data elements for GWI research.nnMAIN METHODS: BBRAIN is recruiting 300 GWI cases and 200 GW veteran controls for the prospective study. Key data and biological samples from prior GWI studies are being merged and combined into retrospective datasets. They will be made available for data mining by the BBRAIN network and the GWI research community. Prospective questionnaire data include general health and chronic symptoms, demographics, measures of pain, fatigue, medical conditions, deployment and exposure histories. Available repository biospecimens include blood, plasma, serum, saliva, stool, urine, human induced pluripotent stem cells and cerebrospinal fluid.nnKEY FINDINGS: To date, multiple datasets have been merged and combined from 15 participating study sites. These data and samples have been collated and an online request form for repository requests as well as recommended common data elements have been created. Data and biospecimen sample requests are reviewed by the BBRAIN steering committee members for approval as they are received.nnSIGNIFICANCE: The BBRAIN repository network serves as a much needed resource for GWI researchers to utilize for identification and validation of objective diagnostic and pathobiological markers of the illness.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34159823,

title = {[C]PBR28 radiotracer kinetics are not driven by alterations in cerebral blood flow},

author = {Christin Y Sander and Stefano Bovo and Angel Torrado-Carvajal and Daniel Albrecht and Hongping Deng and Vitaly Napadow and Julie C Price and Jacob M Hooker and Marco L Loggia},

doi = {10.1177/0271678X211023387},

issn = {1559-7016},

year  = {2021},

date = {2021-11-01},

journal = {J Cereb Blood Flow Metab},

volume = {41},

number = {11},

pages = {3069--3084},

abstract = {The positron emission tomography (PET) radiotracer [C]PBR28 has been increasingly used to image the translocator protein (TSPO) as a marker of neuroinflammation in a variety of brain disorders. Interrelatedly, similar clinical populations can also exhibit altered brain perfusion, as has been shown using arterial spin labelling in magnetic resonance imaging (MRI) studies. Hence, an unsolved debate has revolved around whether changes in perfusion could alter delivery, uptake, or washout of the radiotracer [C]PBR28, and thereby influence outcome measures that affect interpretation of TSPO upregulation. In this simultaneous PET/MRI study, we demonstrate that [C]PBR28 signal elevations in chronic low back pain patients are not accompanied, in the same regions, by increases in cerebral blood flow (CBF) compared to healthy controls, and that areas of marginal hypoperfusion are not accompanied by decreases in [C]PBR28 signal. In non-human primates, we show that hypercapnia-induced increases in CBF during radiotracer delivery or washout do not alter [C]PBR28 outcome measures. The combined results from two methodologically distinct experiments provide support from human data and direct experimental evidence from non-human primates that changes in CBF do not influence outcome measures reported by [C]PBR28 PET imaging studies and corresponding interpretations of the biological meaning of TSPO upregulation.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34641855,

title = {The "self" in pain: high levels of schema-enmeshment worsen fibromyalgia impact},

author = {Myrella Paschali and Asimina Lazaridou and Eric S Vilsmark and Jeungchan Lee and Michael Berry and Arvina Grahl and Alessandra Anzolin and Marco Loggia and Vitaly Napadow and Robert R Edwards},

doi = {10.1186/s12891-021-04740-5},

issn = {1471-2474},

year  = {2021},

date = {2021-10-01},

journal = {BMC Musculoskelet Disord},

volume = {22},

number = {1},

pages = {871},

abstract = {OBJECTIVE: Chronic pain can have detrimental effects on quality of life and a profound impact on one's identity. The Pictorial Representation of Illness- and Self-Measure (PRISM), is a visual tool designed to measure the self-illness separation (SIS) that represents the degree of schema-enmeshment (i.e., the degree to which the self-schema and the illness-schema come to overlap). Our aim was to investigate the relationship between schema-enmeshment and pain-related outcomes in patients with fibromyalgia.nnMETHODS: In this cross-sectional study, 114 patients with fibromyalgia completed self-report assessments of pain catastrophizing, pain severity and interference, impact of symptoms, anxiety, and depression. SIS was assessed using an iPad version of PRISM. Mediation analyses evaluated the mediating role of schema-enmeshment on the association between pain catastrophizing and fibromyalgia impact.nnRESULTS: A higher degree of schema-enmeshment was associated with greater pain catastrophizing, pain severity and interference, impact of symptoms, and depression. Moreover, a mediation analysis revealed that schema-enmeshment significantly mediated the association between pain catastrophizing and fibromyalgia impact (p < 0.001).nnCONCLUSIONS: Our results indicate that schema-enmeshment is associated with greater intrusiveness of chronic pain on everyday life, thereby posing significant limitations on the emotional and physical well-being of fibromyalgia patients. Schema-enmeshment also appears to partly account for the deleterious effect of pain catastrophizing on disease impact. The PRISM is a simple tool that may uniquely capture the extent to which chronic pain and illness infiltrates and affects one's self-concept.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34102707,

title = {3D magnetic resonance spectroscopic imaging reveals links between brain metabolites and multidimensional pain features in fibromyalgia},

author = {Jeungchan Lee and Ovidiu C Andronesi and Angel Torrado-Carvajal and Eva-Maria Ratai and Marco L Loggia and Akila Weerasekera and Michael P Berry and Dan-Mikael Ellingsen and Laura Isaro and Asimina Lazaridou and Myrella Paschali and Arvina Grahl and Ajay D Wasan and Robert R Edwards and Vitaly Napadow},

doi = {10.1002/ejp.1820},

issn = {1532-2149},

year  = {2021},

date = {2021-10-01},

journal = {Eur J Pain},

volume = {25},

number = {9},

pages = {2050--2064},

abstract = {BACKGROUND: Fibromyalgia is a centralized multidimensional chronic pain syndrome, but its pathophysiology is not fully understood.nnMETHODS: We applied 3D magnetic resonance spectroscopic imaging (MRSI), covering multiple cortical and subcortical brain regions, to investigate the association between neuro-metabolite (e.g. combined glutamate and glutamine, Glx; myo-inositol, mIno; and combined (total) N-acetylaspartate and N-acetylaspartylglutamate, tNAA) levels and multidimensional clinical/behavioural variables (e.g. pain catastrophizing, clinical pain severity and evoked pain sensitivity) in women with fibromyalgia (N = 87).nnRESULTS: Pain catastrophizing scores were positively correlated with Glx and tNAA levels in insular cortex, and negatively correlated with mIno levels in posterior cingulate cortex (PCC). Clinical pain severity was positively correlated with Glx levels in insula and PCC, and with tNAA levels in anterior midcingulate cortex (aMCC), but negatively correlated with mIno levels in aMCC and thalamus. Evoked pain sensitivity was negatively correlated with levels of tNAA in insular cortex, MCC, PCC and thalamus.nnCONCLUSIONS: These findings support single voxel placement targeting nociceptive processing areas in prior  H-MRS studies, but also highlight other areas not as commonly targeted, such as PCC, as important for chronic pain pathophysiology. Identifying target brain regions linked to multidimensional symptoms of fibromyalgia (e.g. negative cognitive/affective response to pain, clinical pain, evoked pain sensitivity) may aid the development of neuromodulatory and individualized therapies. Furthermore, efficient multi-region sampling with 3D MRSI could reduce the burden of lengthy scan time for clinical research applications of molecular brain-based mechanisms supporting multidimensional aspects of fibromyalgia.nnSIGNIFICANCE: This large N study linked brain metabolites and pain features in fibromyalgia patients, with a better spatial resolution and brain coverage, to understand a molecular mechanism underlying pain catastrophizing and other aspects of pain transmission. Metabolite levels in self-referential cognitive processing area as well as pain-processing regions were associated with pain outcomes. These results could help the understanding of its pathophysiology and treatment strategies for clinicians.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid33470749,

title = {Thalamic neurometabolite alterations in patients with knee osteoarthritis before and after total knee replacement},

author = {Akila Weerasekera and Erin Morrissey and Minhae Kim and Atreyi Saha and Yang Lin and Zeynab Alshelh and Angel Torrado-Carvajal and Daniel Albrecht and Oluwaseun Akeju and Young-Min Kwon and Hany Bedair and Antonia F Chen and Vitaly Napadow and Kristin Schreiber and Eva-Maria Ratai and Robert R Edwards and Marco L Loggia},

doi = {10.1097/j.pain.0000000000002198},

issn = {1872-6623},

year  = {2021},

date = {2021-07-01},

journal = {Pain},

volume = {162},

number = {7},

pages = {2014--2023},

abstract = {The weak association between disability levels and "peripheral" (ie, knee) findings suggests that central nervous system alterations may contribute to the pathophysiology of knee osteoarthritis (KOA). Here, we evaluated brain metabolite alterations in patients with KOA, before and after total knee arthroplasty (TKA), using 1H-magnetic resonance spectroscopy (MRS). Thirty-four presurgical patients with KOA and 13 healthy controls were scanned using a PRESS sequence (TE = 30 ms, TR = 1.7 seconds, voxel size = 15 × 15 × 15 mm). In addition, 13 patients were rescanned 4.1 ± 1.6 (mean ± SD) weeks post-TKA. When using creatine (Cr)-normalized levels, presurgical KOA patients demonstrated lower N-acetylaspartate (NAA) (P < 0.001), higher myoinositol (mIns) (P < 0.001), and lower Choline (Cho) (P < 0.05) than healthy controls. The mIns levels were positively correlated with pain severity scores (r = 0.37, P < 0.05). These effects reached statistical significance also using water-referenced concentrations, except for the Cho group differences (P ≥ 0.067). Post-TKA patients demonstrated an increase in NAA (P < 0.01), which returned to the levels of healthy controls (P > 0.05), irrespective of metric. In addition, patients demonstrated postsurgical increases in Cr-normalized (P < 0.001), but not water-referenced mIns, which were proportional to the NAA/Cr increases (r = 0.61, P < 0.05). Because mIns is commonly regarded as a glial marker, our results are suggestive of a possible dual role for neuroinflammation in KOA pain and post-TKA recovery. Moreover, the apparent postsurgical normalization of NAA, a putative marker of neuronal integrity, might implicate mitochondrial dysfunction, rather than neurodegenerative processes, as a plausible pathophysiological mechanism in KOA. More broadly, our results add to a growing body of literature suggesting that some pain-related brain alterations can be reversed after peripheral surgical treatment.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid33321196,

title = {Increased Salience Network Connectivity Following Manual Therapy is Associated with Reduced Pain in Chronic Low Back Pain Patients},

author = {Kylie Isenburg and Ishtiaq Mawla and Marco L Loggia and Dan-Mikael Ellingsen and Ekaterina Protsenko and Matthew H Kowalski and David Swensen and Deanna O'Dwyer-Swensen and Robert R Edwards and Vitaly Napadow and Norman Kettner},

doi = {10.1016/j.jpain.2020.11.007},

issn = {1528-8447},

year  = {2021},

date = {2021-05-01},

journal = {J Pain},

volume = {22},

number = {5},

pages = {545--555},

abstract = {Chronic low back pain (cLBP) has been associated with changes in brain plasticity. Nonpharmacological therapies such as Manual Therapy (MT) have shown promise for relieving cLBP. However, translational neuroimaging research is needed to understand potential central mechanisms supporting MT. We investigated the effect of MT on resting-state salience network (SLN) connectivity, and whether this was associated with changes in clinical pain. Fifteen cLBP patients, and 16 matched healthy controls (HC) were scanned with resting functional Magnetic Resonance Imaging (fMRI), before and immediately after a MT intervention (cross-over design with two separate visits, pseudorandomized, grades V 'Manipulation' and III 'Mobilization' of the Maitland Joint Mobilization Grading Scale). Patients rated clinical pain (0-100) pre- and post-therapy. SLN connectivity was assessed using dual regression probabilistic independent component analysis. Both manipulation (Pre: 39.43 ± 16.5, Post: 28.43 ± 16.5) and mobilization (Pre: 38.83 ± 17.7, Post: 31.76 ± 19.4) reduced clinical back pain (P < .05). Manipulation (but not mobilization) significantly increased SLN connectivity to thalamus and primary motor cortex. Additionally, a voxelwise regression indicated that greater MT-induced increase in SLN connectivity to the lateral prefrontal cortex was associated with greater clinical back pain reduction immediately after intervention, for both manipulation (r = -0.8) and mobilization (r = -0.54). Our results suggest that MT is successful in reducing clinical low back pain by both spinal manipulation and spinal mobilization. Furthermore, this reduction post-manipulation occurs via modulation of SLN connectivity to sensorimotor, affective, and cognitive processing regions. PERSPECTIVE: MT both reduces clinical low back pain and modulates brain activity important for the processing of pain. This modulation was shown by increased functional brain connectivity between the salience network and brain regions involved in cognitive, affective, and sensorimotor processing of pain.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32076115,

title = {[C]PBR28 MR-PET imaging reveals lower regional brain expression of translocator protein (TSPO) in young adult males with autism spectrum disorder},

author = {N R Zürcher and M L Loggia and J E Mullett and C Tseng and A Bhanot and L Richey and B G Hightower and C Wu and A J Parmar and R I Butterfield and J M Dubois and D B Chonde and D Izquierdo-Garcia and H Y Wey and C Catana and N Hadjikhani and C J McDougle and J M Hooker},

doi = {10.1038/s41380-020-0682-z},

issn = {1476-5578},

year  = {2021},

date = {2021-05-01},

journal = {Mol Psychiatry},

volume = {26},

number = {5},

pages = {1659--1669},

abstract = {Mechanisms of neuroimmune and mitochondrial dysfunction have been repeatedly implicated in autism spectrum disorder (ASD). To examine these mechanisms in ASD individuals, we measured the in vivo expression of the 18 kDa translocator protein (TSPO), an activated glial marker expressed on mitochondrial membranes. Participants underwent scanning on a simultaneous magnetic resonance-positron emission tomography (MR-PET) scanner with the second-generation TSPO radiotracer [C]PBR28. By comparing TSPO in 15 young adult males with ASD with 18 age- and sex-matched controls, we showed that individuals with ASD exhibited lower regional TSPO expression in several brain regions, including the bilateral insular cortex, bilateral precuneus/posterior cingulate cortex, and bilateral temporal, angular, and supramarginal gyri, which have previously been implicated in autism in functional MR imaging studies. No brain region exhibited higher regional TSPO expression in the ASD group compared with the control group. A subset of participants underwent a second MR-PET scan after a median interscan interval of 3.6 months, and we determined that TSPO expression over this period of time was stable and replicable. Furthermore, voxelwise analysis confirmed lower regional TSPO expression in ASD at this later time point. Lower TSPO expression in ASD could reflect abnormalities in neuroimmune processes or mitochondrial dysfunction.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid33065737,

title = {Thalamic neuroinflammation as a reproducible and discriminating signature for chronic low back pain},

author = {Angel Torrado-Carvajal and Nicola Toschi and Daniel S Albrecht and Ken Chang and Oluwaseun Akeju and Minhae Kim and Robert R Edwards and Yi Zhang and Jacob M Hooker and Andrea Duggento and Jayashree Kalpathy-Cramer and Vitaly Napadow and Marco L Loggia},

doi = {10.1097/j.pain.0000000000002108},

issn = {1872-6623},

year  = {2021},

date = {2021-04-01},

journal = {Pain},

volume = {162},

number = {4},

pages = {1241--1249},

abstract = {Using positron emission tomography, we recently demonstrated elevated brain levels of the 18 kDa translocator protein (TSPO), a glial activation marker, in chronic low back pain (cLBP) patients, compared to healthy controls (HCs). Here, we first sought to replicate the original findings in an independent cohort (15 cLBP, 37.8 ± 12.5 y/o; 18 HC, 48.2 ± 12.8 y/o). We then trained random forest machine learning algorithms based on TSPO imaging features combining discovery and replication cohorts (totaling 25 cLBP, 42.4 ± 13.2 y/o; 27 HC, 48.9 ± 12.6 y/o), to explore whether image features other than the mean contain meaningful information that might contribute to the discrimination of cLBP patients and HC. Feature importance was ranked using SHapley Additive exPlanations values, and the classification performance (in terms of area under the curve values) of classifiers containing only the mean, other features, or all features was compared using the DeLong test. Both region-of-interest and voxelwise analyses replicated the original observation of thalamic TSPO signal elevations in cLBP patients compared to HC (P < 0.05). The random forest-based analyses revealed that although the mean is a discriminating feature, other features demonstrate similar level of importance, including the maximum, kurtosis, and entropy. Our observations suggest that thalamic neuroinflammatory signal is a reproducible and discriminating feature for cLBP, further supporting a role for glial activation in human cLBP, and the exploration of neuroinflammation as a therapeutic target for chronic pain. This work further shows that TSPO signal contains a richness of information that the simple mean might fail to capture completely.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid31138890,

title = {The neuroinflammatory component of negative affect in patients with chronic pain},

author = {D S Albrecht and M Kim and O Akeju and A Torrado-Carvajal and R R Edwards and Y Zhang and C Bergan and E Protsenko and A Kucyi and A D Wasan and J M Hooker and V Napadow and M L Loggia},

doi = {10.1038/s41380-019-0433-1},

issn = {1476-5578},

year  = {2021},

date = {2021-03-01},

journal = {Mol Psychiatry},

volume = {26},

number = {3},

pages = {864--874},

abstract = {Negative affect (NA) is a significant cause of disability for chronic pain patients. While little is known about the mechanism underlying pain-comorbid NA, previous studies have implicated neuroinflammation in the pathophysiology of both depression and chronic pain. Here, we tested the hypothesis that NA in pain patients is linked to elevations in the brain levels of the glial marker 18 kDa translocator protein (TSPO), and changes in functional connectivity. 25 cLBP patients (42.4 ± 13 years old; 13F, 12M) with chronic low back pain (cLBP) and 27 healthy control subjects (48.9 ± 13 years old; 14F, 13M) received an integrated (i.e., simultaneous) positron emission tomography (PET)/magnetic resonance imaging (MRI) brain scan with the second-generation TSPO ligand [C]PBR28. The relationship between [C]PBR28 signal and NA was assessed first with regression analyses against Beck Depression Inventory (BDI) scores in patients, and then by comparing cLBP patients with little-to-no, or mild-to-moderate depression against healthy controls. Further, the relationship between PET signal, BDI and frontolimbic functional connectivity was evaluated in patients with mediation models. PET signal was positively associated with BDI scores in patients, and significantly elevated in patients with mild-to-moderate (but not low) depression compared with controls, in anterior middle and pregenual anterior cingulate cortices (aMCC, pgACC). In the pgACC, PET signal was also associated with this region's functional connectivity to the dorsolateral PFC (pgACC-dlPFC), and mediated of the association between pgACC-dlPFC connectivity and BDI. These observations support a role for glial activation in pain-comorbid NA, identifying in neuroinflammation a potential therapeutic target for this condition.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid33239404,

title = {The Neuroimmunology of Chronic Pain: From Rodents to Humans},

author = {Peter M Grace and Vivianne L Tawfik and Camilla I Svensson and Michael D Burton and Marco L Loggia and Mark R Hutchinson},

doi = {10.1523/JNEUROSCI.1650-20.2020},

issn = {1529-2401},

year  = {2021},

date = {2021-02-01},

journal = {J Neurosci},

volume = {41},

number = {5},

pages = {855--865},

abstract = {Chronic pain, encompassing conditions, such as low back pain, arthritis, persistent post-surgical pain, fibromyalgia, and neuropathic pain disorders, is highly prevalent but remains poorly treated. The vast majority of therapeutics are directed solely at neurons, despite the fact that signaling between immune cells, glia, and neurons is now recognized as indispensable for the initiation and maintenance of chronic pain. This review highlights recent advances in understanding fundamental neuroimmune signaling mechanisms and novel therapeutic targets in rodent models of chronic pain. We further discuss new technological developments to study, diagnose, and quantify neuroimmune contributions to chronic pain in patient populations.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34603368,

title = {Cross-Disorder Genomics Data Analysis Elucidates a Shared Genetic Basis Between Major Depression and Osteoarthritis Pain},

author = {Sophie Barowsky and Jae-Yoon Jung and Nicholas Nesbit and Micah Silberstein and Maurizio Fava and Marco L Loggia and Jordan W Smoller and Phil H Lee},

doi = {10.3389/fgene.2021.687687},

issn = {1664-8021},

year  = {2021},

date = {2021-01-01},

journal = {Front Genet},

volume = {12},

pages = {687687},

abstract = {Osteoarthritis (OA) and major depression (MD) are two debilitating disorders that frequently co-occur and affect millions of the elderly each year. Despite the greater symptom severity, poorer clinical outcomes, and increased mortality of the comorbid conditions, we have a limited understanding of their etiologic relationships. In this study, we conducted the first cross-disorder investigations of OA and MD, using genome-wide association data representing over 247K cases and 475K controls. Along with significant positive genome-wide genetic correlations (  = 0.299 ± 0.026,  = 9.10 × 10), Mendelian randomization (MR) analysis identified a bidirectional causal effect between OA and MD (β   = 0.09, SE = 0.02, -score -value < 1.02 × 10; β   = 0.19, SE = 0.026,  < 2.67 × 10), indicating genetic variants affecting OA risk are, in part, shared with those influencing MD risk. Cross-disorder meta-analysis of OA and MD identified 56 genomic risk loci (  ≤ 5 × 10), which show heightened expression of the associated genes in the brain and pituitary. Gene-set enrichment analysis highlighted "" genes (GO:0007638;   = 2.45 × 10) as potential biological mechanisms that simultaneously increase susceptibility to these mental and physical health conditions. Taken together, these findings show that OA and MD share common genetic risk mechanisms, one of which centers on the neural response to the sensation of mechanical stimulus. Further investigation is warranted to elaborate the etiologic mechanisms of the pleiotropic risk genes, as well as to develop early intervention and integrative clinical care of these serious conditions that disproportionally affect the aging population.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid33122208,

title = {Brain MR Spectroscopic Findings in 3 Consecutive Patients with COVID-19: Preliminary Observations},

author = {O Rapalino and A Weerasekera and S J Moum and K Eikermann-Haerter and B L Edlow and D Fischer and A Torrado-Carvajal and M L Loggia and S S Mukerji and P W Schaefer and R G Gonzalez and M H Lev and E-M Ratai},

doi = {10.3174/ajnr.A6877},

issn = {1936-959X},

year  = {2021},

date = {2021-01-01},

journal = {AJNR Am J Neuroradiol},

volume = {42},

number = {1},

pages = {37--41},

abstract = {Brain multivoxel MR spectroscopic imaging was performed in 3 consecutive patients with coronavirus disease 2019 (COVID-19). These included 1 patient with COVID-19-associated necrotizing leukoencephalopathy, another patient who had a recent pulseless electrical activity cardiac arrest with subtle white matter changes, and a patient without frank encephalopathy or a recent severe hypoxic episode. The MR spectroscopic imaging findings were compared with those of 2 patients with white matter pathology not related to Severe Acute Respiratory Syndrome coronavirus 2 infection and a healthy control subject. The NAA reduction, choline elevation, and glutamate/glutamine elevation found in the patient with COVID-19-associated necrotizing leukoencephalopathy and, to a lesser degree, the patient with COVID-19 postcardiac arrest, follow a similar pattern as seen with the patient with delayed posthypoxic leukoencephalopathy. Lactate elevation was most pronounced in the patient with COVID-19 necrotizing leukoencephalopathy.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32632531,

title = {Inpainting as a Technique for Estimation of Missing Voxels in Brain Imaging},

author = {Angel Torrado-Carvajal and Daniel S Albrecht and Jeungchan Lee and Ovidiu C Andronesi and Eva-Maria Ratai and Vitaly Napadow and Marco L Loggia},

doi = {10.1007/s10439-020-02556-3},

issn = {1573-9686},

year  = {2021},

date = {2021-01-01},

journal = {Ann Biomed Eng},

volume = {49},

number = {1},

pages = {345--353},

abstract = {Issues with model fitting (i.e. suboptimal standard deviation, linewidth/full-width-at-half-maximum, and/or signal-to-noise ratio) in multi-voxel MRI spectroscopy, or chemical shift imaging (CSI) can result in the significant loss of usable voxels. A potential solution to minimize this problem is to estimate the value of unusable voxels by utilizing information from reliable voxels in the same image. We assessed an image restoration method called inpainting as a tool to restore unusable voxels, and compared it with traditional interpolation methods (nearest neighbor, trilinear interpolation and tricubic interpolation). In order to evaluate the performance across varying image contrasts and spatial resolutions, we applied the same techniques to a T1-weighted MRI brain dataset, and N-acetylaspartate (NAA) spectroscopy maps from a CSI dataset. For all image types, inpainting exhibited superior performance (lower normalized root-mean-square errors, NRMSE) compared to all other methods considered (p's < 0.001). Inpainting maintained an average NRMSE of less than 5% even with 50% missing voxels, whereas the other techniques demonstrated up to three times that value, depending on the nature of the image. For CSI maps, inpainting maintained its superiority whether the previously unusable voxels were randomly distributed, or located in regions most commonly affected by voxel loss in real-world data. Inpainting is a promising approach for recovering unusable or missing voxels in voxel-wise analyses, particularly in imaging modalities characterized by low SNR such as CSI. We hypothesize that this technique may also be applicable for datasets from other imaging modalities, such as positron emission tomography, or dynamic susceptibility contrast MRI.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32169920,

title = {Moving Toward Multicenter Therapeutic Trials in Amyotrophic Lateral Sclerosis: Feasibility of Data Pooling Using Different Translocator Protein PET Radioligands},

author = {Donatienne Van Weehaeghe and Suma Babu and Joke De Vocht and Nicole R Zürcher and Sheena Chew and Chieh-En J Tseng and Marco L Loggia and Michel Koole and Ahmadreza Rezaei and Georg Schramm and Philip Van Damme and Jacob M Hooker and Koen Van Laere and Nazem Atassi},

doi = {10.2967/jnumed.119.241059},

issn = {1535-5667},

year  = {2020},

date = {2020-11-01},

journal = {J Nucl Med},

volume = {61},

number = {11},

pages = {1621--1627},

abstract = {Neuroinflammation has been implicated in amyotrophic lateral sclerosis (ALS) and can be visualized using translocator protein (TSPO) radioligands. To become a reliable pharmacodynamic biomarker for ALS multicenter trials, TSPO radioligands have some challenges to overcome. We aimed to investigate whether multicenter data pooling of different TSPO tracers (C-PBR28 and F-DPA714) is feasible, after validation of an established C-PBR28 PET pseudo reference analysis technique for F-DPA714.  Seven ALS patients from Belgium (58.9 ± 6.7 y old, 5 men and 2 women), 8 healthy volunteers from Belgium (52.1 ± 15.2 y old, 3 men and 5 women), 7 ALS patients from the United States (53.4 ± 9.8 y old, 5 men and 2 women), and 7 healthy volunteers from the United States (54.6 ± 9.6 y old, 4 men and 3 women) from a previously published study underwent dynamic F-DPA714 (Leuven, Belgium) or C-PBR28 (Boston, Massachusetts) PET/MRI. For F-DPA714, maps of total volume of distribution (V) were compared with SUV ratio (SUVR) images from 40 to 60 min after injection (SUVR) calculated using the pseudo reference regions cerebellum, occipital cortex, and whole brain (WB) without ventricles. For C-PBR28, SUVR images from 60 to 90 min after injection using the WB without ventricles were calculated.  In line with previous studies, increased F-DPA714 uptake (17.0% ± 5.6%) in primary motor cortices was observed in ALS subjects, as measured by both V and SUVR approaches. The highest sensitivity was found for SUVR calculated using the WB without ventricles (average cluster, 21.6% ± 0.1%). F-DPA714 V ratio was highly correlated with the SUVR ( > 0.8,  < 0.001). A similar pattern of increased uptake (average cluster, 20.5% ± 0.5%) in the primary motor cortices was observed in ALS subjects for C-PBR28 SUVR calculated using the WB without ventricles. Analysis of the F-DPA714 and C-PBR28 data together resulted in a more extensive pattern of significantly increased glial activation bilaterally in the primary motor cortices.  The same pseudo reference region analysis technique for C-PBR28 PET can be extended toward F-DPA714 PET. Therefore, in ALS, standardized analysis across these 2 tracers enables pooling of TSPO PET data across multiple centers and increases the power of TSPO as a biomarker for future therapeutic trials.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid31368404,

title = {Profiles of cortical inflammation in multiple sclerosis by C-PBR28 MR-PET and 7 Tesla imaging},

author = {Elena Herranz and Céline Louapre and Constantina Andrada Treaba and Sindhuja T Govindarajan and Russell Ouellette and Gabriel Mangeat and Marco L Loggia and Julien Cohen-Adad and Eric C Klawiter and Jacob A Sloane and Caterina Mainero},

doi = {10.1177/1352458519867320},

issn = {1477-0970},

year  = {2020},

date = {2020-10-01},

journal = {Mult Scler},

volume = {26},

number = {12},

pages = {1497--1509},

abstract = {BACKGROUND: Neuroinflammation with microglia activation is thought to be closely related to cortical multiple sclerosis (MS) lesion pathogenesis.nnOBJECTIVE: Using C-PBR28 and 7 Tesla (7T) imaging, we assessed in 9 relapsing-remitting multiple sclerosis (RRMS) and 10 secondary progressive multiple sclerosis (SPMS) patients the following: (1) microglia activation in lesioned and normal-appearing cortex, (2) cortical lesion inflammatory profiles, and (3) the relationship between neuroinflammation and cortical integrity.nnMETHODS: Mean C-PBR28 uptake was measured in focal cortical lesions, cortical areas with 7T quantitative T* (q-T*) abnormalities, and normal-appearing cortex. The relative difference in cortical C-PBR28 uptake between patients and 14 controls was used to classify cortical lesions as either active or inactive. Disease burden was investigated according to cortical lesion inflammatory profiles. The relation between q-T* and C-PBR28 uptake along the cortex was assessed.nnRESULTS: C-PBR28 uptake was abnormally high in cortical lesions in RRMS and SPMS; in SPMS, tracer uptake was significantly increased also in normal-appearing cortex. C-PBR28 uptake and q-T* correlated positively in many cortical areas, negatively in some regions. Patients with high cortical lesion inflammation had worse clinical outcome and higher intracortical lesion burden than patients with low inflammation.nnCONCLUSION: C-PBR28 and 7T imaging reveal distinct profiles of cortical inflammation in MS, which are related to disease burden.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32380138,

title = {Reduced tactile acuity in chronic low back pain is linked with structural neuroplasticity in primary somatosensory cortex and is modulated by acupuncture therapy},

author = {Hyungjun Kim and Ishtiaq Mawla and Jeungchan Lee and Jessica Gerber and Kathryn Walker and Jieun Kim and Ana Ortiz and Suk-Tak Chan and Marco L Loggia and Ajay D Wasan and Robert R Edwards and Jian Kong and Ted J Kaptchuk and Randy L Gollub and Bruce R Rosen and Vitaly Napadow},

doi = {10.1016/j.neuroimage.2020.116899},

issn = {1095-9572},

year  = {2020},

date = {2020-08-01},

journal = {Neuroimage},

volume = {217},

pages = {116899},

abstract = {Prior studies have shown that patients suffering from chronic Low Back Pain (cLBP) have impaired somatosensory processing including reduced tactile acuity, i.e. reduced ability to resolve fine spatial details with the perception of touch. The central mechanism(s) underlying reduced tactile acuity are unknown but may include changes in specific brain circuitries (e.g. neuroplasticity in the primary somatosensory cortex, S1). Furthermore, little is known about the linkage between changes in tactile acuity and the amelioration of cLBP by somatically-directed therapeutic interventions, such as acupuncture. In this longitudinal neuroimaging study, we evaluated healthy control adults (HC, N ​= ​50) and a large sample of cLBP patients (N ​= ​102) with structural brain imaging (T1-weighted MRI for Voxel-Based Morphometry, VBM; Diffusion Tensor Imaging, DTI) and tactile acuity testing using two-point discrimination threshold (2PDT) over the lower back (site of pain) and finger (control) locations. Patients were evaluated at baseline and following a 4-week course of acupuncture, with patients randomized to either verum acupuncture, two different forms of sham acupuncture (designed with or without somatosensory afference), or no-intervention usual care control. At baseline, cLBP patients demonstrated reduced acuity (greater 2PDT, P ​= ​0.01) over the low back, but not finger (P ​= ​0.29) locations compared to HC, suggesting that chronic pain affects tactile acuity specifically at body regions encoding the experience of clinical pain. At baseline, Gray Matter Volume (GMV) was elevated and Fractional Anisotropy (FA) was reduced, respectively, in the S1-back region of cLBP patients compared to controls (P ​< ​0.05). GMV in cLBP correlated with greater 2PDT-back scores (ρ ​= ​0.27, P ​= ​0.02). Following verum acupuncture, tactile acuity over the back was improved (reduced 2PDT) and greater improvements were associated with reduced S1-back GMV (ρ ​= ​0.52, P ​= ​0.03) and increased S1-back adjacent white matter FA (ρ ​= ​-0.56, P ​= ​0.01). These associations were not seen for non-verum control interventions. Thus, S1 neuroplasticity in cLBP is linked with deficits in tactile acuity and, following acupuncture therapy, may represent early mechanistic changes in somatosensory processing that track with improved tactile acuity.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32027960,

title = {In-vivo imaging of neuroinflammation in veterans with Gulf War illness},

author = {Zeynab Alshelh and Daniel S Albrecht and Courtney Bergan and Oluwaseun Akeju and Daniel J Clauw and Lisa Conboy and Robert R Edwards and Minhae Kim and Yvonne C Lee and Ekaterina Protsenko and Vitaly Napadow and Kimberly Sullivan and Marco L Loggia},

doi = {10.1016/j.bbi.2020.01.020},

issn = {1090-2139},

year  = {2020},

date = {2020-07-01},

journal = {Brain Behav Immun},

volume = {87},

pages = {498--507},

abstract = {Gulf War Illness (GWI) is a chronic disorder affecting approximately 30% of the veterans who served in the 1991 Gulf War. It is characterised by a constellation of symptoms including musculoskeletal pain, cognitive problems and fatigue. The cause of GWI is not definitively known but exposure to neurotoxicants, the prophylactic use of pyridostigmine bromide (PB) pills, and/or stressors during deployment have all been suspected to play some pathogenic role. Recent animal models of GWI have suggested that neuroinflammatory mechanisms may be implicated, including a dysregulated activation of microglia and astrocytes. However, neuroinflammation has not previously been directly observed in veterans with GWI. To measure GWI-related neuroinflammation in GW veterans, we conducted a Positron Emission Tomography (PET) study using [C]PBR28, which binds to the 18 kDa translocator protein (TSPO), a protein upregulated in activated microglia/macrophages and astrocytes. Veterans with GWI (n = 15) and healthy controls (HC, n = 33, including a subgroup of healthy GW veterans, HC, n = 8), were examined using integrated [C]PBR28 PET/MRI. Standardized uptake values normalized by occipital cortex signal (SUVR) were compared across groups and against clinical variables and circulating inflammatory cytokines (TNF-α, IL-6 and IL-1β). SUVR were validated against volume of distribution ratio (n = 13). Whether compared to the whole HC group, or only the HC subgroup, veterans with GWI demonstrated widespread cortical elevations in [C]PBR28 PET signal, in areas including precuneus, prefrontal, primary motor and somatosensory cortices. There were no significant group differences in the plasma levels of the inflammatory cytokines evaluated. There were also no significant correlations between [C]PBR28 PET signal and clinical variables or circulating inflammatory cytokines. Our study provides the first direct evidence of brain upregulation of the neuroinflammatory marker TSPO in veterans with GWI and supports the exploration of neuroinflammation as a therapeutic target for this disorder.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32017421,

title = {Aberrant Salience? Brain Hyperactivation in Response to Pain Onset and Offset in Fibromyalgia},

author = {Catherine S Hubbard and Asimina Lazaridou and Christine M Cahalan and Jieun Kim and Robert R Edwards and Vitaly Napadow and Marco L Loggia},

doi = {10.1002/art.41220},

issn = {2326-5205},

year  = {2020},

date = {2020-07-01},

journal = {Arthritis Rheumatol},

volume = {72},

number = {7},

pages = {1203--1213},

abstract = {OBJECTIVE: While much brain research on fibromyalgia (FM) focuses on the study of hyperresponsiveness to painful stimuli, some studies suggest that the increased pain-related brain activity often reported in FM studies may be partially explained by stronger responses to salient aspects of the stimulation rather than, or in addition to, the stimulation's painfulness. Therefore, this study was undertaken to test our hypothesis that FM patients would demonstrate elevated brain responses to both pain onset and offset-2 salient sensory events of opposing valences.nnMETHODS: Thirty-eight FM patients (mean ± SD age 46.1 ± 13.4 years; 33 women) and 15 healthy controls (mean ± SD age 45.5 ± 12.4; 10 women) received a moderately painful pressure stimulus to the leg during blood oxygen level-dependent (BOLD) functional magnetic resonance imaging. Stimulus onset and offset transients were analyzed using a general linear model as stick functions.nnRESULTS: During pain onset, higher BOLD signal response was observed in FM patients compared to healthy controls in dorsolateral and ventrolateral prefrontal cortices (DLPFC and VLPFC, respectively), orbitofrontal cortex (OFC), frontal pole, and precentral gyrus (PrCG). During pain offset, higher and more widespread BOLD signal response was demonstrated in FM patients compared to controls in frontal regions significantly hyperactivated in response to onset. In FM patients, some of these responses were positively correlated with pain unpleasantness ratings (VLPFC, onset; r = 0.35, P = 0.03), pain catastrophizing scores (DLPFC, offset; r = 0.33, P = 0.04), or negatively correlated with stimulus intensity (OFC, offset; r = -0.35, P = 0.03) (PrCG, offset; r = -0.39, P = 0.02).nnCONCLUSION: Our results suggest that the increased sensitivity exhibited by FM patients in response to the onset and offset of painful stimuli may reflect a more generalized hypersensitivity to salient sensory events, and that brain hyperactivation may be a mechanism potentially involved in the generalized hypervigilance to salient stimuli in FM.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid31990749,

title = {Magnetic resonance imaging of neuroinflammation in chronic pain: a role for astrogliosis?},

author = {Changjin Jung and Eric Ichesco and Eva-Maria Ratai and Ramon Gilberto Gonzalez and Tricia Burdo and Marco L Loggia and Richard E Harris and Vitaly Napadow},

doi = {10.1097/j.pain.0000000000001815},

issn = {1872-6623},

year  = {2020},

date = {2020-07-01},

journal = {Pain},

volume = {161},

number = {7},

pages = {1555--1564},

abstract = {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 (H-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 H-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 H-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 H-MRS-assessed metabolite elevated in fibromyalgia and associated with pain interference, may be linked with astrogliosis in these patients.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32239542,

title = {Extra-Axial Inflammatory Signal in Parameninges in Migraine with Visual Aura},

author = {Nouchine Hadjikhani and Daniel S Albrecht and Caterina Mainero and Eri Ichijo and Noreen Ward and Cristina Granziera and Nicole R Zürcher and Oluwaseun Akeju and Guillaume Bonnier and Julie Price and Jacob M Hooker and Vitaly Napadow and Matthias Nahrendorf and Marco L Loggia and Michael A Moskowitz},

doi = {10.1002/ana.25731},

issn = {1531-8249},

year  = {2020},

date = {2020-06-01},

journal = {Ann Neurol},

volume = {87},

number = {6},

pages = {939--949},

abstract = {OBJECTIVE: Cortical spreading depression (CSD) underlies the neurobiology of migraine with aura (MWA). Animal studies reveal networks of microvessels linking brain-meninges-bone marrow. CSD activates the trigeminovascular system, evoking a meningeal inflammatory response. Accordingly, this study examines the upregulation of an inflammatory marker in extra-axial tissues in migraine with visual aura.nnMETHODS: We used simultaneously acquired  C-PBR28 positron emission tomography/magnetic resonance imaging data of 18kDa translocator protein (an inflammatory marker) in MWA patients (n = 11) who experienced headaches and visual aura in the preceding month. We measured mean tracer uptake (standardized uptake value ratio [SUVR]) in 4 regions of interest comprising the meninges plus the adjacent overlying skull bone (parameningeal tissues [PMT]). These data were compared to healthy controls and patients with pain (chronic low back pain).nnRESULTS: MWA had significantly higher mean SUVR in PMT overlying occipital cortex than both other groups, although not in the PMT overlying 3 other cortical areas. A positive correlation was also found between the number of visual auras and tracer uptake in occipital PMT.nnINTERPRETATION: A strong persistent extra-axial inflammatory signal was found in meninges and calvarial bone overlying the occipital lobe in migraine with visual auras. Our findings are reminiscent of CSD-induced meningeal inflammation and provide the first imaging evidence implicating inflammation in the pathophysiology of migraine meningeal symptoms. We suspect that this inflammatory focus results from a signal that migrates from underlying brain and if so, may implicate newly discovered bridging vessels that crosstalk between brain and skull marrow, a finding of potential relevance to migraine and other neuroinflammatory brain disorders. ANN NEUROL 2020;87:939-949.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32068162,

title = {Striatal hypofunction as a neural correlate of mood alterations in chronic pain patients},

author = {Minhae Kim and Ishtiaq Mawla and Daniel S Albrecht and Roee Admon and Angel Torrado-Carvajal and Courtney Bergan and Ekaterina Protsenko and Poornima Kumar and Robert R Edwards and Atreyi Saha and Vitaly Napadow and Diego A Pizzagalli and Marco L Loggia},

doi = {10.1016/j.neuroimage.2020.116656},

issn = {1095-9572},

year  = {2020},

date = {2020-05-01},

journal = {Neuroimage},

volume = {211},

pages = {116656},

abstract = {BACKGROUND: Chronic pain and mood disorders share common neuroanatomical substrates involving disruption of the reward system. Although increase in negative affect (NA) and decrease in positive affect (PA) are well-known factors complicating the clinical presentation of chronic pain patients, our understanding of the mechanisms underlying the interaction between pain and PA/NA remains limited. Here, we used a validated task probing behavioral and neural responses to monetary rewards and losses in conjunction with functional magnetic resonance imaging (fMRI) to test the hypothesis that dysfunction of the striatum, a key mesolimbic structure involved in the encoding of motivational salience, relates to mood alterations comorbid with chronic pain.nnMETHODS: Twenty-eight chronic musculoskeletal pain patients (chronic low back pain, n=15; fibromyalgia, n=13) and 18 healthy controls underwent fMRI while performing the Monetary Incentive Delay (MID) task. Behavioral and neural responses were compared across groups and correlated against measures of depression (Beck Depression Inventory) and hedonic capacity (Snaith-Hamilton Pleasure Scale).nnRESULTS: Compared to controls, patients demonstrated higher anhedonia and depression scores, and a dampening of striatal activation and incentive-related behavioral facilitation (reduction in reaction times) during reward and loss trials of the MID task (ps ​< ​0.05). In all participants, lower activation of the right striatum during reward trials was correlated with lower incentive-related behavioral facilitation and higher anhedonia scores (ps ​< ​0.05). Finally, among patients, lower bilateral striatal activation during loss trials was correlated with higher depression scores (ps ​< ​0.05).nnCONCLUSIONS: In chronic pain, PA reduction and NA increase are accompanied by striatal hypofunction as measured by the MID task.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid30973800,

title = {Evidence of diffuse cerebellar neuroinflammation in multiple sclerosis by C-PBR28 MR-PET},

author = {Valeria T Barletta and Elena Herranz and Costantina A Treaba and Russell Ouellette and Ambica Mehndiratta and Marco L Loggia and Eric C Klawiter and Carolina Ionete and Sloane A Jacob and Caterina Mainero},

doi = {10.1177/1352458519843048},

issn = {1477-0970},

year  = {2020},

date = {2020-05-01},

journal = {Mult Scler},

volume = {26},

number = {6},

pages = {668--678},

abstract = {BACKGROUND: Activated microglia, which can be detected in vivo by C-PBR28 positron emission tomography (PET), represent a main component of MS pathology in the brain. Their role in the cerebellum is still unexplored, although cerebellar involvement in MS is frequent and accounts for disability progression.nnOBJECTIVES: We aimed at characterizing cerebellar neuroinflammation in MS patients compared to healthy subjects by combining C-PBR28 MRI-Positron Emission Tomography (MR-PET) with 7 Tesla (T) MRI and assessing its relationship with brain neuroinflammation and clinical outcome measures.nnMETHODS: Twenty-eight MS patients and 16 healthy controls underwent C-PBR28 MR-PET to measure microglia activation in normal appearing cerebellum and lesions segmented from 7 T scans. Patients were evaluated using the Expanded Disability Status Scale and Symbol Digit Modalities Test. C-PBR28 binding was assessed in regions of interest using 60-90 minutes standardized uptake values normalized by a pseudo-reference region in the brain normal appearing white matter. Multilinear regression was used to compare tracer uptake in MS and healthy controls and assess correlations with clinical scores.nnRESULTS: In all cerebellar regions examined, MS patients showed abnormally increased tracer uptake, which correlated with cognitive and neurological disability.nnCONCLUSION: Neuroinflammation is widespread in the cerebellum of patients with MS and related to neurological disability and cognitive impairment.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32712451,

title = {The Role of Inflammation after Surgery for Elders (RISE) study: Examination of [C]PBR28 binding and exploration of its link to post-operative delirium},

author = {Yuta Katsumi and Annie M Racine and Angel Torrado-Carvajal and Marco L Loggia and Jacob M Hooker and Douglas N Greve and Baileigh G Hightower and Ciprian Catana and Michele Cavallari and Steven E Arnold and Tamara G Fong and Sarinnapha M Vasunilashorn and Edward R Marcantonio and Eva M Schmitt and Guoquan Xu and Towia A Libermann and Lisa Feldman Barrett and Sharon K Inouye and Bradford C Dickerson and Alexandra Touroutoglou and Jessica A Collins and },

doi = {10.1016/j.nicl.2020.102346},

issn = {2213-1582},

year  = {2020},

date = {2020-01-01},

journal = {Neuroimage Clin},

volume = {27},

pages = {102346},

abstract = {Major surgery is associated with a systemic inflammatory cascade that is thought, in some cases, to contribute to transient and/or sustained cognitive decline, possibly through neuroinflammatory mechanisms. However, the relationship between surgery, peripheral and central nervous system inflammation, and post-operative cognitive outcomes remains unclear in humans, primarily owing to limitations of in vivo biomarkers of neuroinflammation which vary in sensitivity, specificity, validity, and reliability. In the present study, [C]PBR28 positron emission tomography, cerebrospinal fluid (CSF), and blood plasma biomarkers of inflammation were assessed pre-operatively and 1-month post-operatively in a cohort of patients (N = 36; 30 females; ≥70 years old) undergoing major orthopedic surgery under spinal anesthesia. Delirium incidence and severity were evaluated daily during hospitalization. Whole-brain voxel-wise and regions-of-interest analyses were performed to determine the magnitude and spatial extent of changes in [C]PBR28 uptake following surgery. Results demonstrated that, compared with pre-operative baseline, [C]PBR28 binding in the brain was globally downregulated at 1 month following major orthopedic surgery, possibly suggesting downregulation of the immune system of the brain. No significant relationship was identified between post-operative delirium and [C]PBR28 binding, possibly due to a small number (n = 6) of delirium cases in the sample. Additionally, no significant relationships were identified between [C]PBR28 binding and CSF/plasma biomarkers of inflammation. Collectively, these results contribute to the literature by demonstrating in a sizeable sample the effect of major surgery on neuroimmune activation and preliminary evidence identifying no apparent associations between [C]PBR28 binding and fluid inflammatory markers or post-operative delirium.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid30839429,

title = {Somatotopically specific primary somatosensory connectivity to salience and default mode networks encodes clinical pain},

author = {Jieun Kim and Ishtiaq Mawla and Jian Kong and Jeungchan Lee and Jessica Gerber and Ana Ortiz and Hyungjun Kim and Suk-Tak Chan and Marco L Loggia and Ajay D Wasan and Robert R Edwards and Randy L Gollub and Bruce R Rosen and Vitaly Napadow},

doi = {10.1097/j.pain.0000000000001541},

issn = {1872-6623},

year  = {2019},

date = {2019-07-01},

journal = {Pain},

volume = {160},

number = {7},

pages = {1594--1605},

abstract = {Although several studies have found that chronic pain is characterized by increased cross-network connectivity between salience network, sensorimotor network, and default mode network (DMN), a large sample-size investigation allowing for 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 with healthy adults, patients with cLBP demonstrated increased connectivity between the functionally localized back representation in the primary somatosensory cortex (S1back) and both salience network and DMN. 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 patients with cLBP reporting high pain catastrophizing, DMN connectivity was increased to a cardinal node of the salience network, anterior insula cortex, which was correlated with increased postmaneuver 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 the salience network and S1 likely plays an important role in shifting nociceptive afference away from self-referential processing, reallocating 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.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}