@article{pmid31151376,

title = {Diverse Role of Biological Plasticity in Low Back Pain and Its Impact on Sensorimotor Control of the Spine},

author = {Paul W Hodges and Mary F Barbe and Marco L Loggia and Jo Nijs and Laura S Stone},

doi = {10.2519/jospt.2019.8716},

issn = {1938-1344},

year  = {2019},

date = {2019-06-01},

journal = {J Orthop Sports Phys Ther},

volume = {49},

number = {6},

pages = {389--401},

abstract = {Pain is complex. It is no longer acceptable to consider pain solely as a peripheral phenomenon involving activation of nociceptive neurons. The contemporary understanding of pain involves consideration of different underlying pain mechanisms and an increasing awareness of plasticity in all of the biological systems. Of note, recent advances in technology and understanding have highlighted the critical importance of neuroimmune interactions, both in the peripheral and central nervous systems, and the interaction between the nervous system and body tissues in the development and maintenance of pain, including low back pain (LBP). Further, the biology of many tissues changes when challenged by pain and injury, as reported in a growing body of literature on the biology of muscle, fat, and connective tissue. These advances in understanding of the complexity of LBP have implications for our understanding of pain and its interaction with the motor system, and may change how we consider motor control in the rehabilitation of LBP. This commentary provides a state-of-the-art overview of plasticity of biology in LBP. The paper is divided into 4 parts that address (1) biology of pain mechanisms, (2) neuroimmune interaction in the central nervous system, (3) neuroimmune interaction in the periphery, and (4) brain and peripheral tissue interaction. Each section considers the implications for clinical management of LBP. .},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid31406952,

title = {Imaging Clinically Relevant Pain States Using Arterial Spin Labeling},

author = {Marco Luciano Loggia and Andrew Reilly Segerdahl and Matthew Alexander Howard and Irene Tracey},

doi = {10.1097/PR9.0000000000000750},

issn = {2471-2531},

year  = {2019},

date = {2019-05-01},

journal = {Pain Rep},

volume = {4},

number = {4},

abstract = {Arterial Spin Labeling (ASL) is a perfusion-based functional magnetic resonance imaging technique that uses water in arterial blood as a freely diffusible tracer to measure regional cerebral blood flow (rCBF) noninvasively. To date its application to the study of pain has been relatively limited. Yet, ASL possesses key features that make it uniquely positioned to study pain in certain paradigms. For instance, ASL is sensitive to very slowly fluctuating brain signals (in the order of minutes or longer). This characteristic makes ASL particularly suitable to the evaluation of brain mechanisms of tonic experimental, post-surgical and ongoing/or continuously varying pain in chronic or acute pain conditions (whereas BOLD fMRI is better suited to detect brain responses to short-lasting or phasic/evoked pain). Unlike positron emission tomography or other perfusion techniques, ASL allows the estimation of rCBF without requiring the administration of radioligands or contrast agents. Thus, ASL is well suited for within-subject longitudinal designs (e.g., to study evolution of pain states over time, or of treatment effects in clinical trials). ASL is also highly versatile, allowing for novel paradigms exploring a flexible array of pain states, plus it can be used to simultaneously estimate not only pain-related alterations in perfusion but also functional connectivity. In conclusion, ASL can be successfully applied in pain paradigms that would be either challenging or impossible to implement using other techniques. Particularly when used in concert with other neuroimaging techniques, ASL can be a powerful tool in the pain imager's toolbox.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid30918090,

title = {Imaging of neuroinflammation in migraine with aura: A [C]PBR28 PET/MRI study},

author = {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 Marco L Loggia and Nouchine Hadjikhani},

doi = {10.1212/WNL.0000000000007371},

issn = {1526-632X},

year  = {2019},

date = {2019-04-01},

journal = {Neurology},

volume = {92},

number = {17},

pages = {e2038--e2050},

abstract = {OBJECTIVE: To determine if migraine with aura is associated with neuroinflammation, which has been suggested by preclinical models of cortical spreading depression (CSD) as well as imaging of human pain conditions.nnMETHODS: Thirteen migraineurs with aura and 16 healthy controls received integrated PET/MRI brain scans with [C]PBR28, a radioligand that binds to the 18 kDa translocator protein, a marker of glial activation. Standardized uptake value ratio (SUVR) was compared between groups, and regressed against clinical variables, using region of interest and whole-brain voxelwise analyses.nnRESULTS: Compared to healthy controls, migraineurs demonstrated SUVR elevations in nociceptive processing areas (e.g., thalamus and primary/secondary somatosensory and insular cortices) as well as in areas previously shown to be involved in CSD generation (visual cortex). SUVR levels in frontoinsular cortex, primary/secondary somatosensory cortices, and basal ganglia were correlated with frequency of migraine attacks.nnCONCLUSIONS: These findings demonstrate that migraine with aura is associated with neuroimmune activation/neuroinflammation, and support a possible link between CSD and glial activation, previously observed in animals.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid30540621,

title = {Machine learning-based prediction of clinical pain using multimodal neuroimaging and autonomic metrics},

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

doi = {10.1097/j.pain.0000000000001417},

issn = {1872-6623},

year  = {2019},

date = {2019-03-01},

journal = {Pain},

volume = {160},

number = {3},

pages = {550--560},

abstract = {Although self-report pain ratings are the gold standard in clinical pain assessment, they are inherently subjective in nature and significantly influenced by multidimensional contextual variables. Although objective biomarkers for pain could substantially aid pain diagnosis and development of novel therapies, reliable markers for clinical pain have been elusive. In this study, individualized physical maneuvers were used to exacerbate clinical pain in patients with chronic low back pain (N = 53), thereby experimentally producing lower and higher pain states. Multivariate machine-learning models were then built from brain imaging (resting-state blood-oxygenation-level-dependent and arterial spin labeling functional imaging) and autonomic activity (heart rate variability) features to predict within-patient clinical pain intensity states (ie, lower vs higher pain) and were then applied to predict between-patient clinical pain ratings with independent training and testing data sets. Within-patient classification between lower and higher clinical pain intensity states showed best performance (accuracy = 92.45%, area under the curve = 0.97) when all 3 multimodal parameters were combined. Between-patient prediction of clinical pain intensity using independent training and testing data sets also demonstrated significant prediction across pain ratings using the combined model (Pearson's r = 0.63). Classification of increased pain was weighted by elevated cerebral blood flow in the thalamus, and prefrontal and posterior cingulate cortices, and increased primary somatosensory connectivity to frontoinsular cortex. Our machine-learning approach introduces a model with putative biomarkers for clinical pain and multiple clinical applications alongside self-report, from pain assessment in noncommunicative patients to identification of objective pain endophenotypes that can be used in future longitudinal research aimed at discovery of new approaches to combat chronic pain.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid30458059,

title = {A pilot trial of RNS60 in amyotrophic lateral sclerosis},

author = {Sabrina Paganoni and Mohamad J Alshikho and Sarah Luppino and James Chan and Lindsay Pothier and David Schoenfeld and Patricia L Andres and Suma Babu and Nicole R Zürcher and Marco L Loggia and Robert L Barry and Silvia Luotti and Giovanni Nardo and Maria Chiara Trolese and Serena Pantalone and Caterina Bendotti and Valentina Bonetto and Fabiola De Marchi and Bruce Rosen and Jacob Hooker and Merit Cudkowicz and Nazem Atassi},

doi = {10.1002/mus.26385},

issn = {1097-4598},

year  = {2019},

date = {2019-03-01},

journal = {Muscle Nerve},

volume = {59},

number = {3},

pages = {303--308},

abstract = {INTRODUCTION: RNS60 is a novel immune-modulatory agent that has shown neuroprotective effects in amytrophic lateral sclerosis (ALS) preclinical models. RNS60 is administered by weekly intravenous infusion and daily nebulization. The objective of this pilot open-label trial was to test the feasibility, safety, and tolerability of long-term RNS60 administration in ALS patients.nnMETHODS: The planned treatment duration was 23 weeks and the primary outcomes were safety and tolerability. Secondary outcomes included PBR28 positron emission tomography (PET) imaging and plasma biomarkers of inflammation.nnRESULTS: Sixteen participants with ALS received RNS60 and 13 (81%) completed 23 weeks of RNS60 treatment. There were no serious adverse events and no participants withdrew from the trial due to drug-related adverse events. There were no significant changes in the biomarkers.nnDISCUSSION: Long-term RNS60 administration was safe and well-tolerated. A large, multicenter, phase II trial of RNS60 is currently enrolling participants to test the effects of RNS60 on ALS biomarkers and disease progression. Muscle Nerve 59:303-308, 2019.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid29781581,

title = {Brain Correlates of Continuous Pain in Rheumatoid Arthritis as Measured by Pulsed Arterial Spin Labeling},

author = {Yvonne C Lee and Alexander Fine and Ekaterina Protsenko and Elena Massarotti and Robert R Edwards and Ishtiaq Mawla and Vitaly Napadow and Marco L Loggia},

doi = {10.1002/acr.23601},

issn = {2151-4658},

year  = {2019},

date = {2019-02-01},

journal = {Arthritis Care Res (Hoboken)},

volume = {71},

number = {2},

pages = {308--318},

abstract = {OBJECTIVE: Central nervous system pathways involving pain modulation shape the pain experience in patients with chronic pain. The aims of this study were to understand the mechanisms underlying pain in patients with rheumatoid arthritis (RA) and to identify brain signals that may serve as imaging markers for developing targeted treatments for RA-related pain.nnMETHODS: Patients with RA and matched control subjects underwent functional magnetic resonance imaging, using pulsed arterial spin labeling. The imaging conditions included 1) resting state, 2) low-intensity stimulus, and 3) high-intensity stimulus. Stimuli consisted of mechanical pressure applied to metacarpophalangeal (MCP) joints with an automated cuff inflator. The low-intensity stimulus was inflation to 30 mm Hg. The high-intensity stimulus was the amount of pressure required to achieve a pain intensity rating of 40 on a 100-point scale for each RA patient, with the same amount of pressure used in the matched control.nnRESULTS: Among RA patients, regional cerebral blood flow (rCBF) in the medial frontal cortex and dorsolateral prefrontal cortex increased during both low-pressure and high-pressure stimulation. No rCBF changes were observed in pain-free controls. Region-of-interest analyses in RA patients showed that baseline rCBF in the medial frontal cortex was negatively correlated with the pressure required for the high-intensity stimulus and positively correlated with pain induced by the low-intensity stimulus. Baseline rCBF was also marginally correlated with disease activity). Regional CBF during high pain was positively correlated with pain severity and pain interference.nnCONCLUSION: In response to clinically relevant joint pain evoked by pressure applied to the MCP joint, neural processing in the medial frontal cortex increases and is directly associated with clinical pain in patients with RA.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid30530989,

title = {PET neuroimaging reveals histone deacetylase dysregulation in schizophrenia},

author = {Tonya M Gilbert and Nicole R Zürcher and Christine J Wu and Anisha Bhanot and Baileigh G Hightower and Minhae Kim and Daniel S Albrecht and Hsiao-Ying Wey and Frederick A Schroeder and Anais Rodriguez-Thompson and Thomas M Morin and Kamber L Hart and Amelia M Pellegrini and Misha M Riley and Changning Wang and Steven M Stufflebeam and Stephen J Haggarty and Daphne J Holt and Marco L Loggia and Roy H Perlis and Hannah E Brown and Joshua L Roffman and Jacob M Hooker},

doi = {10.1172/JCI123743},

issn = {1558-8238},

year  = {2019},

date = {2019-01-01},

journal = {J Clin Invest},

volume = {129},

number = {1},

pages = {364--372},

abstract = {BACKGROUND: Patients with schizophrenia (SCZ) experience chronic cognitive deficits. Histone deacetylases (HDACs) are enzymes that regulate cognitive circuitry; however, the role of HDACs in cognitive disorders, including SCZ, remains unknown in humans. We previously determined that HDAC2 mRNA levels were lower in dorsolateral prefrontal cortex (DLPFC) tissue from donors with SCZ compared with controls. Here we investigated the relationship between in vivo HDAC expression and cognitive impairment in patients with SCZ and matched healthy controls using [11C]Martinostat positron emission tomography (PET).nnMETHODS: In a case-control study, relative [11C]Martinostat uptake was compared between 14 patients with SCZ or schizoaffective disorder (SCZ/SAD) and 17 controls using hypothesis-driven region-of-interest analysis and unbiased whole brain voxel-wise approaches. Clinical measures, including the MATRICS consensus cognitive battery, were administered.nnRESULTS: Relative HDAC expression was lower in the DLPFC of patients with SCZ/SAD compared with controls, and HDAC expression positively correlated with cognitive performance scores across groups. Patients with SCZ/SAD also showed lower relative HDAC expression in the dorsomedial prefrontal cortex and orbitofrontal gyrus, and higher relative HDAC expression in the cerebral white matter, pons, and cerebellum compared with controls.nnCONCLUSIONS: These findings provide in vivo evidence of HDAC dysregulation in patients with SCZ and suggest that altered HDAC expression may impact cognitive function in humans.nnFUNDING: National Institute of Mental Health (NIMH), Brain and Behavior Foundation, Massachusetts General Hospital (MGH), Athinoula A. Martinos Center for Biomedical Imaging, National Institute of Biomedical Imaging and Bioengineering (NIBIB), NIH Shared Instrumentation Grant Program.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid30223011,

title = {Brain glial activation in fibromyalgia - A multi-site positron emission tomography investigation},

author = {Daniel S Albrecht and Anton Forsberg and Angelica Sandström and Courtney Bergan and Diana Kadetoff and Ekaterina Protsenko and Jon Lampa and Yvonne C Lee and Caroline Olgart Höglund and Ciprian Catana and Simon Cervenka and Oluwaseun Akeju and Mats Lekander and George Cohen and Christer Halldin and Norman Taylor and Minhae Kim and Jacob M Hooker and Robert R Edwards and Vitaly Napadow and Eva Kosek and Marco L Loggia},

doi = {10.1016/j.bbi.2018.09.018},

issn = {1090-2139},

year  = {2019},

date = {2019-01-01},

journal = {Brain Behav Immun},

volume = {75},

pages = {72--83},

abstract = {Fibromyalgia (FM) is a poorly understood chronic condition characterized by widespread musculoskeletal pain, fatigue, and cognitive difficulties. While mounting evidence suggests a role for neuroinflammation, no study has directly provided evidence of brain glial activation in FM. In this study, we conducted a Positron Emission Tomography (PET) study using [C]PBR28, which binds to the translocator protein (TSPO), a protein upregulated in activated microglia and astrocytes. To enhance statistical power and generalizability, we combined datasets collected independently at two separate institutions (Massachusetts General Hospital [MGH] and Karolinska Institutet [KI]). In an attempt to disentangle the contributions of different glial cell types to FM, a smaller sample was scanned at KI with [C]--deprenyl-D PET, thought to primarily reflect astrocytic (but not microglial) signal. Thirty-one FM patients and 27 healthy controls (HC) were examined using [C]PBR28 PET. 11 FM patients and 11 HC were scanned using [C]--deprenyl-D PET. Standardized uptake values normalized by occipital cortex signal (SUVR) and distribution volume (V) were computed from the [C]PBR28 data. [C]--deprenyl-D was quantified using λ k. PET imaging metrics were compared across groups, and when differing across groups, against clinical variables. Compared to HC, FM patients demonstrated widespread cortical elevations, and no decreases, in [C]PBR28 V and SUVR, most pronounced in the medial and lateral walls of the frontal and parietal lobes. No regions showed significant group differences in [C]--deprenyl-D signal, including those demonstrating elevated [C]PBR28 signal in patients (p's ≥ 0.53, uncorrected). The elevations in [C]PBR28 V and SUVR were correlated both spatially (i.e., were observed in overlapping regions) and, in several areas, also in terms of magnitude. In exploratory, uncorrected analyses, higher subjective ratings of fatigue in FM patients were associated with higher [C]PBR28 SUVR in the anterior and posterior middle cingulate cortices (p's < 0.03). SUVR was not significantly associated with any other clinical variable. Our work provides the first in vivo evidence supporting a role for glial activation in FM pathophysiology. Given that the elevations in [C]PBR28 signal were not also accompanied by increased [C]--deprenyl-D signal, our data suggests that microglia, but not astrocytes, may be driving the TSPO elevation in these regions. Although [C]--deprenyl-D signal was not found to be increased in FM patients, larger studies are needed to further assess the role of possible astrocytic contributions in FM. Overall, our data support glial modulation as a potential therapeutic strategy for FM.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid30392530,

title = {Brain Mechanisms of Anticipated Painful Movements and Their Modulation by Manual Therapy in Chronic Low Back Pain},

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

doi = {10.1016/j.jpain.2018.05.012},

issn = {1528-8447},

year  = {2018},

date = {2018-11-01},

journal = {J Pain},

volume = {19},

number = {11},

pages = {1352--1365},

abstract = {Heightened anticipation and fear of movement-related pain has been linked to detrimental fear-avoidance behavior in chronic low back pain (cLBP). Spinal manipulative therapy (SMT) has been proposed to work partly by exposing patients to nonharmful but forceful mobilization of the painful joint, thereby disrupting the relationship among pain anticipation, fear, and movement. Here, we investigated the brain processes underpinning pain anticipation and fear of movement in cLBP, and their modulation by SMT, using functional magnetic resonance imaging. Fifteen cLBP patients and 16 healthy control (HC) subjects were scanned while observing and rating video clips depicting back-straining or neutral physical exercises, which they knew they would have to perform at the end of the visit. This task was repeated after a single session of spinal manipulation (cLBP and HC group) or mobilization (cLBP group only), in separate visits. Compared with HC subjects, cLBP patients reported higher expected pain and fear of performing the observed exercises. These ratings, along with clinical pain, were reduced by SMT. Moreover, cLBP, relative to HC subjects, demonstrated higher blood oxygen level-dependent signal in brain circuitry that has previously been implicated in salience, social cognition, and mentalizing, while observing back straining compared with neutral exercises. The engagement of this circuitry was reduced after SMT, and especially the spinal manipulation session, proportionally to the magnitude of SMT-induced reduction in anticipated pain and fear. This study sheds light on the brain processing of anticipated pain and fear of back-straining movement in cLBP, and suggests that SMT may reduce cognitive and affective-motivational aspects of fear-avoidance behavior, along with corresponding brain processes. PERSPECTIVE: This study of cLBP patients investigated how SMT affects clinical pain, expected pain, and fear of physical exercises. The results indicate that one of the mechanisms of SMT may be to reduce pain expectancy, fear of movement, and associated brain responses.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid29719953,

title = {Neuroinflammation in Huntington's Disease: New Insights with C-PBR28 PET/MRI},

author = {Cristina Lois and Iván González and David Izquierdo-García and Nicole R Zürcher and Paul Wilkens and Marco L Loggia and Jacob M Hooker and H Diana Rosas},

doi = {10.1021/acschemneuro.8b00072},

issn = {1948-7193},

year  = {2018},

date = {2018-11-01},

journal = {ACS Chem Neurosci},

volume = {9},

number = {11},

pages = {2563--2571},

abstract = {Huntington's disease is a devastating neurodegenerative genetic disorder that causes progressive motor dysfunction, emotional disturbances, and cognitive impairment. Unfortunately, there is no treatment to cure or slow the progression of the disease. Neuroinflammation is one hallmark of Huntington's disease, and modulation of neuroinflammation has been suggested as a potential target for therapeutic intervention. The relationship between neuroinflammation markers and the disease pathology is still poorly understood. To improve our understanding of neuroinflammation in Huntington's disease, we measured translocator protein (TSPO) expression using C-PBR28 and simultaneous PET/MRI. Standardized-uptake-value ratios, normalized by whole brain uptake, were calculated for data acquired 60-90 min after radiotracer administration. We identified distinct patterns of regional neuroinflammation (as defined by TSPO overexpression relative to a control group) in the basal ganglia of Huntington's disease patients. These patterns were observed at the individual level in all patients, with region of interest analysis confirming significant differences between patients and the control group in the putamen and the pallidum. Additionally, we observed further distinct regional and subregional signatures, which may provide insights into phenotypical variability. For example, in certain Huntington's disease patients, we observed in vivo elevation of the level of TSPO binding in subnuclei in the thalamus and brainstem that have been previously associated with visual function, motor function, and motor coordination. Our main result is an objective score, based solely on C-PBR28 measurements, that correlates well with measurements of brain atrophy. We conclude that PET/MR imaging using C-PBR28 provides a high signal-to-background ratio and has the potential to be used to assess Huntington's disease progression. Our results suggest C-PBR28 might prove useful in clinical trials evaluating therapies targeting neuroinflammation.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid29794615,

title = {Chronic pain and opioid receptor availability: disentangling the molecular contributions and the "chicken or the egg" dilemma},

author = {Marco L Loggia},

doi = {10.1097/j.pain.0000000000001283},

issn = {1872-6623},

year  = {2018},

date = {2018-09-01},

journal = {Pain},

volume = {159},

number = {9},

pages = {1679--1680},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid29579370,

title = {Encoding of Self-Referential Pain Catastrophizing in the Posterior Cingulate Cortex in Fibromyalgia},

author = {Jeungchan Lee and Ekaterina Protsenko and Asimina Lazaridou and Olivia Franceschelli and Dan-Mikael Ellingsen and Ishtiaq Mawla and Kylie Isenburg and Michael P Berry and Laura Galenkamp and Marco L Loggia and Ajay D Wasan and Robert R Edwards and Vitaly Napadow},

doi = {10.1002/art.40507},

issn = {2326-5205},

year  = {2018},

date = {2018-08-01},

journal = {Arthritis Rheumatol},

volume = {70},

number = {8},

pages = {1308--1318},

abstract = {OBJECTIVE: Pain catastrophizing is a common feature of chronic pain, including fibromyalgia (FM), and is strongly associated with amplified pain severity and disability. While previous neuroimaging studies have focused on evoked pain response modulation by catastrophizing, the brain mechanisms supporting pain catastrophizing itself are unknown. We designed a functional magnetic resonance imaging (fMRI)-based pain catastrophizing task whereby patients with chronic pain engaged in catastrophizing-related cognitions. We undertook this study to test our hypothesis that catastrophizing about clinical pain would be associated with amplified activation in nodes of the default mode network (DMN), which encode self-referential cognition and show altered functioning in chronic pain.nnMETHODS: During fMRI, 31 FM patients reflected on how catastrophizing (CAT) statements (drawn from the Pain Catastrophizing Scale) impact their typical FM pain experience. Response to CAT statements was compared to response to matched neutral (NEU) statements.nnRESULTS: During statement reflection, higher fMRI signal during CAT statements than during NEU statements was found in several DMN brain areas, including the ventral (posterior) and dorsal (anterior) posterior cingulate cortex (vPCC and dPCC, respectively). Patients' ratings of CAT statement applicability were correlated solely with activity in the vPCC, a main DMN hub supporting self-referential cognition (r = 0.38, P < 0.05). Clinical pain severity was correlated solely with activity in the dPCC, a PCC subregion associated with cognitive control and sensorimotor processing (r = 0.38, P < 0.05).nnCONCLUSION: These findings provide evidence that the PCC encodes pain catastrophizing in FM and suggest distinct roles for different PCC subregions. Understanding the brain circuitry encoding pain catastrophizing in FM will prove to be important in identifying and evaluating the success of interventions targeting negative affect in chronic pain management.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid29740862,

title = {Integrated magnetic resonance imaging and [ C]-PBR28 positron emission tomographic imaging in amyotrophic lateral sclerosis},

author = {Mohamad J Alshikho and Nicole R Zürcher and Marco L Loggia and Paul Cernasov and Beverly Reynolds and Olivia Pijanowski and Daniel B Chonde and David Izquierdo Garcia and Caterina Mainero and Ciprian Catana and James Chan and Suma Babu and Sabrina Paganoni and Jacob M Hooker and Nazem Atassi},

doi = {10.1002/ana.25251},

issn = {1531-8249},

year  = {2018},

date = {2018-06-01},

journal = {Ann Neurol},

volume = {83},

number = {6},

pages = {1186--1197},

abstract = {OBJECTIVE: To characterize [ C]-PBR28 brain uptake using positron emission tomography (PET) in people with amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS). We have previously shown increased [ C]-PBR28 uptake in the precentral gyrus in a small group of ALS patients. Herein, we confirm our initial finding, study the longitudinal changes, and characterize the gray versus white matter distribution of [ C]-PBR28 uptake in a larger cohort of patients with ALS and PLS.nnMETHODS: Eighty-five participants including 53 with ALS, 11 with PLS, and 21 healthy controls underwent integrated [ C]-PBR28 PET-magnetic resonance brain imaging. Patients were clinically assessed using the Upper Motor Neuron Burden (UMNB) and the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R). [ C]-PBR28 uptake was quantified as standardized uptake value ratio (SUVR) and compared between groups. Cortical thickness and fractional anisotropy were compared between groups and correlated with SUVR and the clinical data. [ C]-PBR28 uptake and ALSFRS-R were compared longitudinally over 6 months in 10 ALS individuals.nnRESULTS: Whole brain voxelwise, surface-based, and region of interest analyses revealed increased [ C]-PBR28 uptake in the precentral and paracentral gyri in ALS, and in the subcortical white matter for the same regions in PLS, compared to controls. The increase in [ C]-PBR28 uptake colocalized and correlated with cortical thinning, reduced fractional anisotropy, and increased mean diffusivity, and correlated with higher UMNB score. No significant changes were detected in [ C]-PBR28 uptake over 6 months despite clinical progression.nnINTERPRETATION: Glial activation measured by in vivo [ C]-PBR28 PET is increased in pathologically relevant regions in people with ALS and correlates with clinical measures. Ann Neurol 2018;83:1186-1197.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid29708334,

title = {Correction to In Vivo Imaging of Human Neuroinflammation},

author = {Daniel S Albrecht and Cristina Granziera and Jacob M Hooker and Marco L Loggia},

doi = {10.1021/acschemneuro.8b00188},

issn = {1948-7193},

year  = {2018},

date = {2018-06-01},

journal = {ACS Chem Neurosci},

volume = {9},

number = {6},

pages = {1515},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid29419657,

title = {Neuroinflammation of the spinal cord and nerve roots in chronic radicular pain patients},

author = {Daniel S Albrecht and Shihab U Ahmed and Norman W Kettner and Ronald J H Borra and Julien Cohen-Adad and Hao Deng and Timothy T Houle and Arissa Opalacz and Sarah A Roth and Marcos F Vidal Melo and Lucy Chen and Jianren Mao and Jacob M Hooker and Marco L Loggia and Yi Zhang},

doi = {10.1097/j.pain.0000000000001171},

issn = {1872-6623},

year  = {2018},

date = {2018-05-01},

journal = {Pain},

volume = {159},

number = {5},

pages = {968--977},

abstract = {Numerous preclinical studies support the role of spinal neuroimmune activation in the pathogenesis of chronic pain, and targeting glia (eg, microglia/astrocyte)- or macrophage-mediated neuroinflammatory responses effectively prevents or reverses the establishment of persistent nocifensive behaviors in laboratory animals. However, thus far, the translation of those findings into novel treatments for clinical use has been hindered by the scarcity of data supporting the role of neuroinflammation in human pain. Here, we show that patients suffering from a common chronic pain disorder (lumbar radiculopathy), compared with healthy volunteers, exhibit elevated levels of the neuroinflammation marker 18 kDa translocator protein, in both the neuroforamina (containing dorsal root ganglion and nerve roots) and spinal cord. These elevations demonstrated a pattern of spatial specificity correlating with the patients' clinical presentation, as they were observed in the neuroforamen ipsilateral to the symptomatic leg (compared with both contralateral neuroforamen in the same patients as well as to healthy controls) and in the most caudal spinal cord segments, which are known to process sensory information from the lumbosacral nerve roots affected in these patients (compared with more superior segments). Furthermore, the neuroforaminal translocator protein signal was associated with responses to fluoroscopy-guided epidural steroid injections, supporting its role as an imaging marker of neuroinflammation, and highlighting the clinical significance of these observations. These results implicate immunoactivation at multiple levels of the nervous system as a potentially important and clinically relevant mechanism in human radicular pain, and suggest that therapies targeting immune cell activation may be beneficial for chronic pain patients.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid29678977,

title = {Minimizing ICU Neurological Dysfunction with Dexmedetomidine-induced Sleep (MINDDS): protocol for a randomised, double-blind, parallel-arm, placebo-controlled trial},

author = {Kenneth T Shelton and Jason Qu and Federico Bilotta and Emery N Brown and Gaston Cudemus and David A D'Alessandro and Hao Deng and Alan DiBiasio and Jacob A Gitlin and Eunice Y Hahm and Lauren E Hobbs and Timothy T Houle and Reine Ibala and Marco L Loggia and Kara J Pavone and Shahzad Shaefi and George Tolis and M Brandon Westover and Oluwaseun Akeju},

doi = {10.1136/bmjopen-2017-020316},

issn = {2044-6055},

year  = {2018},

date = {2018-04-01},

journal = {BMJ Open},

volume = {8},

number = {4},

pages = {e020316},

abstract = {INTRODUCTION: Delirium, which is prevalent in postcardiac surgical patients, is an acute brain dysfunction characterised by disturbances in attention, awareness and cognition not explained by a pre-existing neurocognitive disorder. The pathophysiology of delirium remains poorly understood. However, basic science and clinical studies suggest that sleep disturbance may be a modifiable risk factor for the development of delirium. Dexmedetomidine is a α-2A adrenergic receptor agonist medication that patterns the activity of various arousal nuclei similar to sleep. A single night-time loading dose of dexmedetomidine promotes non-rapid eye movement sleep stages N2 and N3 sleep. This trial hypothesises dexmedetomidine-induced sleep as pre-emptive therapy for postoperative delirium.nnMETHODS AND ANALYSIS: The MINDDS (Minimizing ICU Neurological Dysfunction with Dexmedetomidine-induced Sleep) trial is a 370-patient block-randomised, placebo-controlled, double-blinded, single-site, parallel-arm superiority trial. Patients over 60 years old, undergoing cardiac surgery with planned cardiopulmonary bypass, will be randomised to receive a sleep-inducing dose of dexmedetomidine or placebo. The primary outcome is the incidence of delirium on postoperative day 1, assessed with the Confusion Assessment Method by staff blinded to the treatment assignment. To ensure that the study is appropriately powered for the primary outcome measure, patients will be recruited and randomised into the study until 370 patients receive the study intervention on postoperative day 0. Secondary outcomes will be evaluated by in-person assessments and medical record review for in-hospital end points, and by telephone interview for 30-day, 90-day and 180-day end points. All trial outcomes will be evaluated using an intention-to-treat analysis plan. Hypothesis testing will be performed using a two-sided significance level (type I error) of α=0.05. Sensitivity analyses using the actual treatment received will be performed and compared with the intention-to-treat analysis results. Additional sensitivity analyses will assess the potential impact of missing data due to loss of follow-up.nnETHICS AND DISSEMINATION: The Partners Human Research Committee approved the MINDDS trial. Recruitment began in March 2017. Dissemination plans include presentations at scientific conferences, scientific publications and popular media.nnTRIAL REGISTRATION NUMBER: NCT02856594.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid28983743,

title = {PET Imaging of Human Brown Adipose Tissue with the TSPO Tracer [C]PBR28},

author = {Chongzhao Ran and Daniel S Albrecht and Miriam A Bredella and Jing Yang and Jian Yang and Steven H Liang and Aaron M Cypess and Marco L Loggia and Nazem Atassi and Anna Moore},

doi = {10.1007/s11307-017-1129-z},

issn = {1860-2002},

year  = {2018},

date = {2018-04-01},

journal = {Mol Imaging Biol},

volume = {20},

number = {2},

pages = {188--193},

abstract = {PURPOSE: Brown adipose tissue (BAT) in adult humans has been recently rediscovered and intensively investigated as a new potential therapeutic target for obesity and type 2 diabetes (T2D). However, reliable assessment of BAT mass in vivo represents a considerable challenge. The purpose of this investigation is to demonstrate for the first time that human BAT depots can be imaged with a translocator protein (TSPO)-specific positron emission tomography (PET) tracer [C]PBR28 under thermoneutral conditions.nnPROCEDURES: In this retrospective analysis, we analyzed the images of three healthy volunteers who underwent PET/magnetic resonance (MR) imaging after injection of 14 m Ci of [C]PBR28 at room temperature. Thirty-minute static PET images were reconstructed from the data obtained 60-90 min after the injection of the tracer.nnRESULTS: [C]PBR28 uptake in the neck/supraclavicular regions was identified, which was parallel to the known distribution pattern of human BAT depots. These areas co-localized with the areas of hyperintensity and corresponded to fat on T1-weighted MR images. Standardized uptake value (SUV) was used to quantify [C]PBR28 signal in BAT depots. The average (± SD) SUV and SUV for BAT depots was 2.13 (± 0.33) and 3.19 (± 0.34), respectively, while the average SUV for muscle and subcutaneous adipose tissue was 0.79 (± 0.1) and 0.18 (± 0.04), respectively.nnCONCLUSIONS: In this brief article, we provide the first evidence suggesting that [C]PBR28, a widely available TSPO-specific PET tracer, can be used for imaging human BAT mass under thermoneutral conditions.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid30112276,

title = {Integrated imaging of [C]-PBR28 PET, MR diffusion and magnetic resonance spectroscopy H-MRS in amyotrophic lateral sclerosis},

author = {Eva-Maria Ratai and Mohamad J Alshikho and Nicole R Zürcher and Marco L Loggia and Catherine L Cebulla and Paul Cernasov and Beverly Reynolds and Jennifer Fish and Raghav Seth and Suma Babu and Sabrina Paganoni and Jacob M Hooker and Nazem Atassi},

doi = {10.1016/j.nicl.2018.08.007},

issn = {2213-1582},

year  = {2018},

date = {2018-01-01},

journal = {Neuroimage Clin},

volume = {20},

pages = {357--364},

abstract = {OBJECTIVE: To determine the relationship between brain tissue metabolites measured by  magnetic resonance spectroscopy (H-MRS), and glial activation assessed with [C]-PBR28 uptake in people with amyotrophic lateral sclerosis (ALS).nnMETHODS: Forty ALS participants were evaluated clinically using the revised ALS functional rating scale (ALSFRS-R) and upper motor neuron burden (UMNB). All participants underwent simultaneous brain [C]-PBR28 PET and MR imaging including diffusion tensor imaging to acquire fractional anisotropy (FA). [C]-PBR28 uptake was measured as standardized uptake values normalized by whole brain mean (SUVR). H-MRS metabolite ratios (myo-inositol/creatine, mI/Cr; -acetylaspartate/creatine, NAA/Cr) were measured within the precentral gyri and brain stem (regions known to be involved in ALS pathophysiology), and precuneus (which served as a control region). Whole brain voxel-wise correlation analyses were employed to identify brain regions exhibiting an association between metabolites within the VOIs and [C]-PBR28 uptake.nnRESULTS: In the precentral gyri, [C]-PBR28 uptake correlated positively with mI/Cr and negatively with NAA/Cr. The same correlations were not statistically significant in the brain stem, or in the control precuneus region. Whole brain voxel-wise correlation analyses between the estimated brain metabolites within the VOIs and SUVR were highly correlated in the precentral gyri. Decreased FA values in the precentral gyri were correlated with reduced NAA/Cr and elevated mI/Cr. Higher UMNB was correlated with increased [C]-PBR28 uptake and mI/Cr, and decreased NAA/Cr. ALSFRS-R total score correlated positively with NAA/Cr and negatively with mI/Cr.nnCONCLUSION: Integrated PET-MR and H-MRS imaging demonstrates associations between markers for neuronal integrity and neuroinflammation and may provide valuable insights into disease mechanisms in ALS.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid29159046,

title = {Imaging of glia activation in people with primary lateral sclerosis},

author = {Sabrina Paganoni and Mohamad J Alshikho and Nicole R Zürcher and Paul Cernasov and Suma Babu and Marco L Loggia and James Chan and Daniel B Chonde and David Izquierdo Garcia and Ciprian Catana and Caterina Mainero and Bruce R Rosen and Merit E Cudkowicz and Jacob M Hooker and Nazem Atassi},

doi = {10.1016/j.nicl.2017.10.024},

issn = {2213-1582},

year  = {2018},

date = {2018-01-01},

journal = {Neuroimage Clin},

volume = {17},

pages = {347--353},

abstract = {BACKGROUND: Glia activation is thought to contribute to neuronal damage in several neurodegenerative diseases based on preclinical and human - studies, but its role in primary lateral sclerosis (PLS) is unknown.nnOBJECTIVES: To localize and measure glia activation in people with PLS compared to healthy controls (HC).nnMETHODS: Ten participants with PLS and ten age-matched HCs underwent simultaneous magnetic resonance (MR) and proton emission tomography (PET). The radiotracer [C]-PBR28 was used to obtain PET-based measures of 18 kDa translocator protein (TSPO) expression, a marker of activated glial cells. MR techniques included a structural sequence to measure cortical thickness and diffusion tensor imaging (DTI) to assess white matter integrity.nnRESULTS: PET data showed increased [C]-PBR28 uptake in anatomically-relevant motor regions which co-localized with areas of regional gray matter atrophy and decreased subcortical fractional anisotropy.nnCONCLUSIONS: This study supports a link between glia activation and neuronal degeneration in PLS, and suggests that these disease mechanisms can be measured  in PLS. Future studies are needed to determine the longitudinal changes of these imaging measures and to clarify if MR-PET with [C]-PBR28 can be used as a biomarker for drug development in the context of clinical trials for PLS.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid28818984,

title = {Pseudoreference Regions for Glial Imaging with C-PBR28: Investigation in 2 Clinical Cohorts},

author = {Daniel S Albrecht and Marc D Normandin and Sergey Shcherbinin and Dustin W Wooten and Adam J Schwarz and Nicole R Zürcher and Vanessa N Barth and Nicolas J Guehl and Oluwaseun Akeju and Nazem Atassi and Mattia Veronese and Federico Turkheimer and Jacob M Hooker and Marco L Loggia},

doi = {10.2967/jnumed.116.178335},

issn = {1535-5667},

year  = {2018},

date = {2018-01-01},

journal = {J Nucl Med},

volume = {59},

number = {1},

pages = {107--114},

abstract = {The translocator protein (TSPO) is a commonly used imaging target to investigate neuroinflammation. Although TSPO imaging demonstrates great promise, its signal exhibits substantial interindividual variability, which needs to be accounted for to uncover group effects that are truly reflective of neuroimmune activation. Recent evidence suggests that relative metrics computed using pseudoreference approaches can minimize within-group variability and increase sensitivity to detect physiologically meaningful group differences. Here, we evaluated various ratio approaches for TSPO imaging and compared them with standard kinetic modeling techniques, analyzing 2 different disease cohorts. Patients with chronic low back pain (cLBP) or amyotrophic lateral sclerosis (ALS) and matching healthy controls received C-PBR28 PET scans. The occipital cortex, cerebellum and whole brain were first evaluated as candidate pseudoreference regions by testing for the absence of group differences in SUV and distribution volume () estimated with an arterial input function. The SUV from target regions (cLBP study, thalamus; ALS study, precentral gyrus) was normalized with the SUV from candidate pseudoreference regions (i.e., occipital cortex, cerebellum, and whole brain) to obtain SUVR, SUVR, and SUVR The sensitivity to detect group differences in target regions was compared using various SUVR approaches, as well as distribution volume ratio (DVR) estimated with (blDVR) or without arterial input function (refDVR), and  Additional voxelwise SUVR group analyses were performed. We observed no significant group differences in pseudoreference  or SUV, excepting whole-brain , which was higher in cLBP patients than controls. Target  elevations in patients ( = 0.028 and 0.051 in cLBP and ALS, respectively) were similarly detected by SUVR and SUVR, and by refDVR and blDVR (less reliably by SUVR). In voxelwise analyses, SUVR, but not SUVR, identified regional group differences initially observed with SUVR, and in additional areas suspected to be affected in the pathology examined. All ratio metrics were highly cross-correlated, but generally were not associated with  Although important caveats need to be considered when using relative metrics, ratio analyses appear to be similarly sensitive to detect pathology-related group differences in C-PBR28 signal as classic kinetic modeling techniques. The occipital cortex may be a suitable pseudoreference region, at least for the populations evaluated, pending further validation in larger cohorts.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid27521844,

title = {Reduced insula habituation associated with amplification of trigeminal brainstem input in migraine},

author = {Jeungchan Lee and Richard L Lin and Ronald G Garcia and Jieun Kim and Hyungjun Kim and Marco L Loggia and Ishtiaq Mawla and Ajay D Wasan and Robert R Edwards and Bruce R Rosen and Nouchine Hadjikhani and Vitaly Napadow},

doi = {10.1177/0333102416665223},

issn = {1468-2982},

year  = {2017},

date = {2017-10-01},

journal = {Cephalalgia},

volume = {37},

number = {11},

pages = {1026--1038},

abstract = {Background Impaired sensory processing in migraine can reflect diminished habituation, increased activation, or even increased gain or amplification of activity from the primary synapse in the brainstem to higher cortical/subcortical brain regions. Methods We scanned 16 episodic migraine (interictal) and 16 healthy controls (cross-sectional study), and evaluated brain response to innocuous air-puff stimulation over the right forehead in the ophthalmic nerve (V) trigeminal territory. We further evaluated habituation, and cortical/subcortical amplification relative to spinal trigeminal nucleus (Sp5) activation. Results Migraine subjects showed greater amplification from Sp5 to the posterior insula and hypothalamus. In addition, while controls showed habituation to repetitive sensory stimulation in all activated cortical regions (e.g. the bilateral posterior insula and secondary somatosensory cortices), for migraine subjects, habituation was not found in the posterior insula. Moreover, in migraine, the habituation slope was correlated with the amplification ratio in the posterior insula and secondary somatosensory cortex, i.e. greater amplification was associated with reduced habituation in these regions. Conclusions These findings suggest that in episodic migraine, amplified information processing from spinal trigeminal relay nuclei is linked to an impaired habituation response. This phenomenon was localized in the posterior insula, highlighting the important role of this structure in mechanisms supporting altered sensory processing in episodic migraine.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid28685641,

title = {Sleep disturbances and severe stress as glial activators: key targets for treating central sensitization in chronic pain patients?},

author = {Jo Nijs and Marco L Loggia and Andrea Polli and Maarten Moens and Eva Huysmans and Lisa Goudman and Mira Meeus and Luc Vanderweeën and Kelly Ickmans and Daniel Clauw},

doi = {10.1080/14728222.2017.1353603},

issn = {1744-7631},

year  = {2017},

date = {2017-08-01},

journal = {Expert Opin Ther Targets},

volume = {21},

number = {8},

pages = {817--826},

abstract = {The mechanism of sensitization of the central nervous system partly explains the chronic pain experience in many patients, but the etiological mechanisms of this central nervous system dysfunction are poorly understood. Recently, an increasing number of studies suggest that aberrant glial activation takes part in the establishment and/or maintenance of central sensitization. Areas covered: This review focused on preclinical work and mostly on the neurobiochemistry studied in animals, with limited human studies available. Glial overactivation results in a low-grade neuroinflammatory state, characterized by high levels of BDNF, IL-1β, TNF-α, which in turn increases the excitability of the central nervous system neurons through mechanisms like long-term potentiation and increased synaptic efficiency. Aberrant glial activity in chronic pain might have been triggered by severe stress exposure, and/or sleeping disturbances, each of which are established initiating factors for chronic pain development. Expert opinion: Potential treatment avenues include several pharmacological options for diminishing glial activity, as well as conservative interventions like sleep management, stress management and exercise therapy. Pharmacological options include propentofylline, minocycline, β -adrenergic receptor antagonists, and cannabidiol. Before translating these findings from basic science to clinical settings, more human studies exploring the outlined mechanisms in chronic pain patients are needed.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid28626012,

title = {Pharmacological Modulation of Noradrenergic Arousal Circuitry Disrupts Functional Connectivity of the Locus Ceruleus in Humans},

author = {Andrew H Song and Aaron Kucyi and Vitaly Napadow and Emery N Brown and Marco L Loggia and Oluwaseun Akeju},

doi = {10.1523/JNEUROSCI.0446-17.2017},

issn = {1529-2401},

year  = {2017},

date = {2017-07-01},

journal = {J Neurosci},

volume = {37},

number = {29},

pages = {6938--6945},

abstract = {State-dependent activity of locus ceruleus (LC) neurons has long suggested a role for noradrenergic modulation of arousal. However,  insights into noradrenergic arousal circuitry have been constrained by the fundamental inaccessibility of the human brain for invasive studies. Functional magnetic resonance imaging (fMRI) studies performed during site-specific pharmacological manipulations of arousal levels may be used to study brain arousal circuitry. Dexmedetomidine is an anesthetic that alters the level of arousal by selectively targeting α2 adrenergic receptors on LC neurons, resulting in reduced firing rate and norepinephrine release. Thus, we hypothesized that dexmedetomidine-induced altered arousal would manifest with reduced functional connectivity between the LC and key brain regions involved in the regulation of arousal. To test this hypothesis, we acquired resting-state fMRI data in right-handed healthy volunteers 18-36 years of age ( = 15, 6 males) at baseline, during dexmedetomidine-induced altered arousal, and recovery states. As previously reported, seed-based resting-state fMRI analyses revealed that the LC was functionally connected to a broad network of regions including the reticular formation, basal ganglia, thalamus, posterior cingulate cortex (PCC), precuneus, and cerebellum. Functional connectivity of the LC to only a subset of these regions (PCC, thalamus, and caudate nucleus) covaried with the level of arousal. Functional connectivity of the PCC to the ventral tegmental area/pontine reticular formation and thalamus, in addition to the LC, also covaried with the level of arousal. We propose a framework in which the LC, PCC, thalamus, and basal ganglia comprise a functional arousal circuitry. Electrophysiological studies of locus ceruleus (LC) neurons have long suggested a role for noradrenergic mechanisms in mediating arousal. However, the fundamental inaccessibility of the human brain for invasive studies has limited a precise understanding of putative brain regions that integrate with the LC to regulate arousal. Our results suggest that the PCC, thalamus, and basal ganglia are key components of a LC-noradrenergic arousal circuit.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid28300650,

title = {Painful After-Sensations in Fibromyalgia are Linked to Catastrophizing and Differences in Brain Response in the Medial Temporal Lobe},

author = {Kristin L Schreiber and Marco L Loggia and Jieun Kim and Christine M Cahalan and Vitaly Napadow and Robert R Edwards},

doi = {10.1016/j.jpain.2017.02.437},

issn = {1528-8447},

year  = {2017},

date = {2017-07-01},

journal = {J Pain},

volume = {18},

number = {7},

pages = {855--867},

abstract = {Fibromyalgia (FM) is a complex syndrome characterized by chronic widespread pain, hyperalgesia, and other disabling symptoms. Although the brain response to experimental pain in FM patients has been the object of intense investigation, the biological underpinnings of painful after-sensations (PAS), and their relation to negative affect have received little attention. In this cross-sectional cohort study, subjects with FM (n = 53) and healthy controls (n = 17) were assessed for PAS using exposure to a sustained, moderately painful cuff stimulus to the leg, individually calibrated to a target pain intensity of 40 of 100. Despite requiring lower cuff pressures to achieve the target pain level, FM patients reported more pronounced PAS 15 seconds after the end of cuff stimulation, which correlated positively with clinical pain scores. Functional magnetic resonance imaging revealed reduced deactivation of the medial temporal lobe (MTL; amygdala, hippocampus, parahippocampal gyrus) in FM patients, during pain stimulation, as well as in the ensuing poststimulation period, when PAS are experienced. Moreover, the functional magnetic resonance imaging signal measured during the poststimulation period in the MTL, as well as in the insular and anterior middle cingulate and medial prefrontal cortices, correlated with the severity of reported PAS by FM patients. These results suggest that the MTL plays a role in PAS in FM patients.nnPERSPECTIVE: PAS are more common and severe in FM, and are associated with clinical pain and catastrophizing. PAS severity is also associated with less MTL deactivation, suggesting that the MTL, a core node of the default mode network, may be important in the prolongation of pain sensation in FM.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid28092321,

title = {Dexmedetomidine Disrupts the Local and Global Efficiencies of Large-scale Brain Networks},

author = {Javeria A Hashmi and Marco L Loggia and Sheraz Khan and Lei Gao and Jieun Kim and Vitaly Napadow and Emery N Brown and Oluwaseun Akeju},

doi = {10.1097/ALN.0000000000001509},

issn = {1528-1175},

year  = {2017},

date = {2017-03-01},

journal = {Anesthesiology},

volume = {126},

number = {3},

pages = {419--430},

abstract = {BACKGROUND: A clear understanding of the neural basis of consciousness is fundamental to research in clinical and basic neuroscience disciplines and anesthesia. Recently, decreased efficiency of information integration was suggested as a core network feature of propofol-induced unconsciousness. However, it is unclear whether this finding can be generalized to dexmedetomidine, which has a different molecular target.nnMETHODS: Dexmedetomidine was administered as a 1-μg/kg bolus over 10 min, followed by a 0.7-μg · kg · h infusion to healthy human volunteers (age range, 18 to 36 yr; n = 15). Resting-state functional magnetic resonance imaging data were acquired during baseline, dexmedetomidine-induced altered arousal, and recovery states. Zero-lag correlations between resting-state functional magnetic resonance imaging signals extracted from 131 brain parcellations were used to construct weighted brain networks. Network efficiency, degree distribution, and node strength were computed using graph analysis. Parcellated brain regions were also mapped to known resting-state networks to study functional connectivity changes.nnRESULTS: Dexmedetomidine significantly reduced the local and global efficiencies of graph theory-derived networks. Dexmedetomidine also reduced the average brain connectivity strength without impairing the degree distribution. Functional connectivity within and between all resting-state networks was modulated by dexmedetomidine.nnCONCLUSIONS: Dexmedetomidine is associated with a significant drop in the capacity for efficient information transmission at both the local and global levels. These changes result from reductions in the strength of connectivity and also manifest as reduced within and between resting-state network connectivity. These findings strengthen the hypothesis that conscious processing relies on an efficient system of information transfer in the brain.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid27518491,

title = {Effects of Cognitive-Behavioral Therapy (CBT) on Brain Connectivity Supporting Catastrophizing in Fibromyalgia},

author = {Asimina Lazaridou and Jieun Kim and Christine M Cahalan and Marco L Loggia and Olivia Franceschelli and Chantal Berna and Peter Schur and Vitaly Napadow and Robert R Edwards},

doi = {10.1097/AJP.0000000000000422},

issn = {1536-5409},

year  = {2017},

date = {2017-03-01},

journal = {Clin J Pain},

volume = {33},

number = {3},

pages = {215--221},

abstract = {OBJECTIVE(S): Fibromyalgia (FM) is a chronic, common pain disorder characterized by hyperalgesia. A key mechanism by which cognitive-behavioral therapy (CBT) fosters improvement in pain outcomes is via reductions in hyperalgesia and pain-related catastrophizing, a dysfunctional set of cognitive-emotional processes. However, the neural underpinnings of these CBT effects are unclear. Our aim was to assess CBT's effects on the brain circuitry underlying hyperalgesia in FM patients, and to explore the role of treatment-associated reduction in catastrophizing as a contributor to normalization of pain-relevant brain circuitry and clinical improvement.nnMETHODS: In total, 16 high-catastrophizing FM patients were enrolled in the study and randomized to 4 weeks of individual treatment with either CBT or a Fibromyalgia Education (control) condition. Resting state functional magnetic resonance imaging scans evaluated functional connectivity between key pain-processing brain regions at baseline and posttreatment. Clinical outcomes were assessed at baseline, posttreatment, and 6-month follow-up.nnRESULTS: Catastrophizing correlated with increased resting state functional connectivity between S1 and anterior insula. The CBT group showed larger reductions (compared with the education group) in catastrophizing at posttreatment (P<0.05), and CBT produced significant reductions in both pain and catastrophizing at the 6-month follow-up (P<0.05). Patients in the CBT group also showed reduced resting state connectivity between S1 and anterior/medial insula at posttreatment; these reductions in resting state connectivity were associated with concurrent treatment-related reductions in catastrophizing.nnDISCUSSION: The results add to the growing support for the clinically important associations between S1-insula connectivity, clinical pain, and catastrophizing, and suggest that CBT may, in part via reductions in catastrophizing, help to normalize pain-related brain responses in FM.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid27837005,

title = {Glial activation colocalizes with structural abnormalities in amyotrophic lateral sclerosis},

author = {Mohamad J Alshikho and Nicole R Zürcher and Marco L Loggia and Paul Cernasov and Daniel B Chonde and David Izquierdo Garcia and Julia E Yasek and Oluwaseun Akeju and Ciprian Catana and Bruce R Rosen and Merit E Cudkowicz and Jacob M Hooker and Nazem Atassi},

doi = {10.1212/WNL.0000000000003427},

issn = {1526-632X},

year  = {2016},

date = {2016-12-01},

journal = {Neurology},

volume = {87},

number = {24},

pages = {2554--2561},

abstract = {OBJECTIVE: In this cross-sectional study, we aimed to evaluate brain structural abnormalities in relation to glial activation in the same cohort of participants.nnMETHODS: Ten individuals with amyotrophic lateral sclerosis (ALS) and 10 matched healthy controls underwent brain imaging using integrated MR/PET and the radioligand [C]-PBR28. Diagnosis history and clinical assessments including Upper Motor Neuron Burden Scale (UMNB) were obtained from patients with ALS. Diffusion tensor imaging (DTI) analyses including tract-based spatial statistics and tractography were applied. DTI metrics including fractional anisotropy (FA) and diffusivities (mean, axial, and radial) were measured in regions of interest. Cortical thickness was assessed using surface-based analysis. The locations of structural changes, measured by DTI and the areas of cortical thinning, were compared to regional glial activation measured by relative [C]-PBR28 uptake.nnRESULTS: In this cohort of individuals with ALS, reduced FA and cortical thinning colocalized with regions demonstrating higher radioligand binding. [C]-PBR28 binding in the left motor cortex was correlated with FA (r = -0.68, p < 0.05) and cortical thickness (r = -0.75, p < 0.05). UMNB was correlated with glial activation (r = +0.75, p < 0.05), FA (r = -0.77, p < 0.05), and cortical thickness (r = -0.75, p < 0.05) in the motor cortex.nnCONCLUSIONS: Increased uptake of the glial marker [C]-PBR28 colocalizes with changes in FA and cortical thinning. This suggests a link between disease mechanisms (gliosis and inflammation) and structural changes (cortical thinning and white and gray matter changes). In this multimodal neuroimaging work, we provide an in vivo model to investigate the pathogenesis of ALS.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid27686563,

title = {Neuroinflammatory component of gray matter pathology in multiple sclerosis},

author = {Elena Herranz and Costanza Giannì and Céline Louapre and Constantina A Treaba and Sindhuja T Govindarajan and Russell Ouellette and Marco L Loggia and Jacob A Sloane and Nancy Madigan and David Izquierdo-Garcia and Noreen Ward and Gabriel Mangeat and Tobias Granberg and Eric C Klawiter and Ciprian Catana and Jacob M Hooker and Norman Taylor and Carolina Ionete and Revere P Kinkel and Caterina Mainero},

doi = {10.1002/ana.24791},

issn = {1531-8249},

year  = {2016},

date = {2016-11-01},

journal = {Ann Neurol},

volume = {80},

number = {5},

pages = {776--790},

abstract = {OBJECTIVE: In multiple sclerosis (MS), using simultaneous magnetic resonance-positron emission tomography (MR-PET) imaging with  C-PBR28, we quantified expression of the 18kDa translocator protein (TSPO), a marker of activated microglia/macrophages, in cortex, cortical lesions, deep gray matter (GM), white matter (WM) lesions, and normal-appearing WM (NAWM) to investigate the in vivo pathological and clinical relevance of neuroinflammation.nnMETHODS: Fifteen secondary-progressive MS (SPMS) patients, 12 relapsing-remitting MS (RRMS) patients, and 14 matched healthy controls underwent  C-PBR28 MR-PET. MS subjects underwent 7T T2*-weighted imaging for cortical lesion segmentation, and neurological and cognitive evaluation.  C-PBR28 binding was measured using normalized 60- to 90-minute standardized uptake values and volume of distribution ratios.nnRESULTS: Relative to controls, MS subjects exhibited abnormally high  C-PBR28 binding across the brain, the greatest increases being in cortex and cortical lesions, thalamus, hippocampus, and NAWM. MS WM lesions showed relatively modest TSPO increases. With the exception of cortical lesions, where TSPO expression was similar,  C-PBR28 uptake across the brain was greater in SPMS than in RRMS. In MS, increased  C-PBR28 binding in cortex, deep GM, and NAWM correlated with neurological disability and impaired cognitive performance; cortical thinning correlated with increased thalamic TSPO levels.nnINTERPRETATION: In MS, neuroinflammation is present in the cortex, cortical lesions, deep GM, and NAWM, is closely linked to poor clinical outcome, and is at least partly linked to neurodegeneration. Distinct inflammatory-mediated factors may underlie accumulation of cortical and WM lesions. Quantification of TSPO levels in MS could prove to be a sensitive tool for evaluating in vivo the inflammatory component of GM pathology, particularly in cortical lesions. Ann Neurol 2016;80:776-790.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid26985861,

title = {In Vivo Imaging of Human Neuroinflammation},

author = {Daniel S Albrecht and Cristina Granziera and Jacob M Hooker and Marco L Loggia},

doi = {10.1021/acschemneuro.6b00056},

issn = {1948-7193},

year  = {2016},

date = {2016-04-01},

journal = {ACS Chem Neurosci},

volume = {7},

number = {4},

pages = {470--483},

abstract = {Neuroinflammation is implicated in the pathophysiology of a growing number of human disorders, including multiple sclerosis, chronic pain, traumatic brain injury, and amyotrophic lateral sclerosis. As a result, interest in the development of novel methods to investigate neuroinflammatory processes, for the purpose of diagnosis, development of new therapies, and treatment monitoring, has surged over the past 15 years. Neuroimaging offers a wide array of non- or minimally invasive techniques to characterize neuroinflammatory processes. The intent of this Review is to provide brief descriptions of currently available neuroimaging methods to image neuroinflammation in the human central nervous system (CNS) in vivo. Specifically, because of the relatively widespread accessibility of equipment for nuclear imaging (positron emission tomography [PET]; single photon emission computed tomography [SPECT]) and magnetic resonance imaging (MRI), we will focus on strategies utilizing these technologies. We first provide a working definition of "neuroinflammation" and then discuss available neuroimaging methods to study human neuroinflammatory processes. Specifically, we will focus on neuroimaging methods that target (1) the activation of CNS immunocompetent cells (e.g. imaging of glial activation with TSPO tracer [(11)C]PBR28), (2) compromised BBB (e.g. identification of MS lesions with gadolinium-enhanced MRI), (3) CNS-infiltration of circulating immune cells (e.g. tracking monocyte infiltration into brain parenchyma with iron oxide nanoparticles and MRI), and (4) pathological consequences of neuroinflammation (e.g. imaging apoptosis with [(99m)Tc]Annexin V or iron accumulation with T2* relaxometry). This Review provides an overview of state-of-the-art techniques for imaging human neuroinflammation which have potential to impact patient care in the foreseeable future.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid26061382,

title = {Optimizing and Interpreting Insular Functional Connectivity Maps Obtained During Acute Experimental Pain: The Effects of Global Signal and Task Paradigm Regression},

author = {James W Ibinson and Keith M Vogt and Kevin B Taylor and Shiv B Dua and Christopher J Becker and Marco Loggia and Ajay D Wasan},

doi = {10.1089/brain.2015.0354},

issn = {2158-0022},

year  = {2015},

date = {2015-12-01},

journal = {Brain Connect},

volume = {5},

number = {10},

pages = {649--657},

abstract = {The insula is uniquely located between the temporal and parietal cortices, making it anatomically well-positioned to act as an integrating center between the sensory and affective domains for the processing of painful stimulation. This can be studied through resting-state functional connectivity (fcMRI) imaging; however, the lack of a clear methodology for the analysis of fcMRI complicates the interpretation of these data during acute pain. Detected connectivity changes may reflect actual alterations in low-frequency synchronous neuronal activity related to pain, may be due to changes in global cerebral blood flow or the superimposed task-induced neuronal activity. The primary goal of this study was to investigate the effects of global signal regression (GSR) and task paradigm regression (TPR) on the changes in functional connectivity of the left (contralateral) insula in healthy subjects at rest and during acute painful electric nerve stimulation of the right hand. The use of GSR reduced the size and statistical significance of connectivity clusters and created negative correlation coefficients for some connectivity clusters. TPR with cyclic stimulation gave task versus rest connectivity differences similar to those with a constant task, suggesting that analysis which includes TPR is more accurately reflective of low-frequency neuronal activity. Both GSR and TPR have been inconsistently applied to fcMRI analysis. Based on these results, investigators need to consider the impact GSR and TPR have on connectivity during task performance when attempting to synthesize the literature.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid26280659,

title = {The imagined itch: brain circuitry supporting nocebo-induced itch in atopic dermatitis patients},

author = {V Napadow and A Li and M L Loggia and J Kim and I Mawla and G Desbordes and P C Schalock and E A Lerner and T N Tran and J Ring and B R Rosen and T J Kaptchuk and F Pfab},

doi = {10.1111/all.12727},

issn = {1398-9995},

year  = {2015},

date = {2015-11-01},

journal = {Allergy},

volume = {70},

number = {11},

pages = {1485--1492},

abstract = {BACKGROUND: Psychological factors are known to significantly modulate itch in patients suffering from chronic itch. Itch is also highly susceptible to both placebo and nocebo (negative placebo) effects. Brain activity likely supports nocebo-induced itch, but is currently unknown.nnMETHODS: We collected functional MRI (fMRI) data from atopic dermatitis (AD) patients, in a within-subject design, and contrast brain response to nocebo saline understood to be allergen vs open-label saline control. Exploratory analyses compared results to real allergen itch response and placebo responsiveness, evaluated in the same patients.nnRESULTS: Nocebo saline produced greater itch than open saline control (P < 0.01). Compared to open saline, nocebo saline demonstrated greater fMRI response in caudate, dorsolateral prefrontal cortex (dlPFC), and intraparietal sulcus (iPS) - brain regions important for cognitive executive and motivational processing. Exploratory analyses found that subjects with greater dlPFC and caudate activation to nocebo-induced itch also demonstrated greater dlPFC and caudate activation, respectively, for real allergen itch. Subjects reporting greater nocebo-induced itch also demonstrated greater placebo reduction of allergen-evoked itch, suggesting increased generalized modulation of itch perception.nnCONCLUSIONS: Our study demonstrates the capacity of nocebo saline to mimic both the sensory and neural effects of real allergens and provides an insight to the brain mechanisms supporting nocebo-induced itch in AD, thus aiding our understanding of the role that expectations and other psychological factors play in modulating itch perception in chronic itch patients.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid25937162,

title = {The lateral prefrontal cortex mediates the hyperalgesic effects of negative cognitions in chronic pain patients},

author = {Marco L Loggia and Chantal Berna and Jieun Kim and Christine M Cahalan and Marc-Olivier Martel and Randy L Gollub and Ajay D Wasan and Vitaly Napadow and Robert R Edwards},

doi = {10.1016/j.jpain.2015.04.003},

issn = {1528-8447},

year  = {2015},

date = {2015-08-01},

journal = {J Pain},

volume = {16},

number = {8},

pages = {692--699},

abstract = {Although high levels of negative affect and cognitions have been associated with greater pain sensitivity in chronic pain conditions, the neural mechanisms mediating the hyperalgesic effect of psychological factors in patients with pain disorders are largely unknown. In this cross-sectional study, we hypothesized that 1) catastrophizing modulates brain responses to pain anticipation and 2) anticipatory brain activity mediates the hyperalgesic effect of different levels of catastrophizing in fibromyalgia (FM) patients. Using functional magnetic resonance imaging, we scanned the brains of 31 FM patients exposed to visual cues anticipating the onset of moderately intense deep-tissue pain stimuli. Our results indicated the existence of a negative association between catastrophizing and pain-anticipatory brain activity, including in the right lateral prefrontal cortex. A bootstrapped mediation analysis revealed that pain-anticipatory activity in the lateral prefrontal cortex mediates the association between catastrophizing and pain sensitivity. These findings highlight the role of the lateral prefrontal cortex in the pathophysiology of FM-related hyperalgesia and suggest that deficits in the recruitment of pain-inhibitory brain circuitry during pain-anticipatory periods may play an important contributory role in the association between various degrees of widespread hyperalgesia in FM and levels of catastrophizing, a well-validated measure of negative cognitions and psychological distress.nnPERSPECTIVE: This article highlights the presence of alterations in pain-anticipatory brain activity in FM. These findings provide the rationale for the development of psychological or neurofeedback-based techniques aimed at modifying patients' negative affect and cognitions toward pain.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid25622796,

title = {The somatosensory link in fibromyalgia: functional connectivity of the primary somatosensory cortex is altered by sustained pain and is associated with clinical/autonomic dysfunction},

author = {Jieun Kim and Marco L Loggia and Christine M Cahalan and Richard E Harris and Florian Beissner and Ronald G Garcia and Hyungjun Kim and Ajay D Wasan and Robert R Edwards and Vitaly Napadow},

doi = {10.1002/art.39043},

issn = {2326-5205},

year  = {2015},

date = {2015-05-01},

journal = {Arthritis Rheumatol},

volume = {67},

number = {5},

pages = {1395--1405},

abstract = {OBJECTIVE: Fibromyalgia (FM) is a chronic functional pain syndrome characterized by widespread pain, significant pain catastrophizing, sympathovagal dysfunction, and amplified temporal summation for evoked pain. While several studies have demonstrated altered resting brain connectivity in FM, studies have not specifically probed the somatosensory system and its role in both somatic and nonsomatic FM symptoms. Our objective was to evaluate resting primary somatosensory cortex (S1) connectivity and to explore how sustained, evoked deep tissue pain modulates this connectivity.nnMETHODS: We acquired functional magnetic resonance imaging and electrocardiography data on FM patients and healthy controls during rest (the rest phase) and during sustained mechanical pressure-induced pain over the lower leg (the pain phase). Functional connectivity associated with different S1 subregions was calculated, while S1(leg) connectivity (representation of the leg in the primary somatosensory cortex) was contrasted between the rest phase and the pain phase and was correlated with clinically relevant measures in FM.nnRESULTS: During the rest phase, FM patients showed decreased connectivity between multiple ipsilateral and cross-hemispheric S1 subregions, which was correlated with clinical pain severity. Compared to the rest phase, the pain phase produced increased S1(leg) connectivity to the bilateral anterior insula in FM patients, but not in healthy controls. Moreover, in FM patients, sustained pain-altered S1(leg) connectivity to the anterior insula was correlated with clinical/behavioral pain measures and autonomic responses.nnCONCLUSION: Our study demonstrates that both somatic and nonsomatic dysfunction in FM, including clinical pain, pain catastrophizing, autonomic dysfunction, and amplified temporal summation, are closely linked with the degree to which evoked deep tissue pain alters S1 connectivity to salience/affective pain-processing regions. Additionally, diminished connectivity between S1 subregions during the rest phase in FM may result from ongoing widespread clinical pain.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid25582579,

title = {Evidence for brain glial activation in chronic pain patients},

author = {Marco L Loggia and Daniel B Chonde and Oluwaseun Akeju and Grae Arabasz and Ciprian Catana and Robert R Edwards and Elena Hill and Shirley Hsu and David Izquierdo-Garcia and Ru-Rong Ji and Misha Riley and Ajay D Wasan and Nicole R Zürcher and Daniel S Albrecht and Mark G Vangel and Bruce R Rosen and Vitaly Napadow and Jacob M Hooker},

doi = {10.1093/brain/awu377},

issn = {1460-2156},

year  = {2015},

date = {2015-03-01},

journal = {Brain},

volume = {138},

number = {Pt 3},

pages = {604--615},

abstract = {Although substantial evidence has established that microglia and astrocytes play a key role in the establishment and maintenance of persistent pain in animal models, the role of glial cells in human pain disorders remains unknown. Here, using the novel technology of integrated positron emission tomography-magnetic resonance imaging and the recently developed radioligand (11)C-PBR28, we show increased brain levels of the translocator protein (TSPO), a marker of glial activation, in patients with chronic low back pain. As the Ala147Thr polymorphism in the TSPO gene affects binding affinity for (11)C-PBR28, nine patient-control pairs were identified from a larger sample of subjects screened and genotyped, and compared in a matched-pairs design, in which each patient was matched to a TSPO polymorphism-, age- and sex-matched control subject (seven Ala/Ala and two Ala/Thr, five males and four females in each group; median age difference: 1 year; age range: 29-63 for patients and 28-65 for controls). Standardized uptake values normalized to whole brain were significantly higher in patients than controls in multiple brain regions, including thalamus and the putative somatosensory representations of the lumbar spine and leg. The thalamic levels of TSPO were negatively correlated with clinical pain and circulating levels of the proinflammatory citokine interleukin-6, suggesting that TSPO expression exerts pain-protective/anti-inflammatory effects in humans, as predicted by animal studies. Given the putative role of activated glia in the establishment and or maintenance of persistent pain, the present findings offer clinical implications that may serve to guide future studies of the pathophysiology and management of a variety of persistent pain conditions.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid26366304,

title = {Neural Plasticity in Common Forms of Chronic Headaches},

author = {Tzu-Hsien Lai and Ekaterina Protsenko and Yu-Chen Cheng and Marco L Loggia and Gianluca Coppola and Wei-Ta Chen},

doi = {10.1155/2015/205985},

issn = {1687-5443},

year  = {2015},

date = {2015-01-01},

journal = {Neural Plast},

volume = {2015},

pages = {205985},

abstract = {Headaches are universal experiences and among the most common disorders. While headache may be physiological in the acute setting, it can become a pathological and persistent condition. The mechanisms underlying the transition from episodic to chronic pain have been the subject of intense study. Using physiological and imaging methods, researchers have identified a number of different forms of neural plasticity associated with migraine and other headaches, including peripheral and central sensitization, and alterations in the endogenous mechanisms of pain modulation. While these changes have been proposed to contribute to headache and pain chronification, some findings are likely the results of repetitive noxious stimulation, such as atrophy of brain areas involved in pain perception and modulation. In this review, we provide a narrative overview of recent advances on the neuroimaging, electrophysiological and genetic aspects of neural plasticity associated with the most common forms of chronic headaches, including migraine, cluster headache, tension-type headache, and medication overuse headache.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid25844321,

title = {Fibromyalgia is characterized by altered frontal and cerebellar structural covariance brain networks},

author = {Hyungjun Kim and Jieun Kim and Marco L Loggia and Christine Cahalan and Ronald G Garcia and Mark G Vangel and Ajay D Wasan and Robert R Edwards and Vitaly Napadow},

doi = {10.1016/j.nicl.2015.02.022},

issn = {2213-1582},

year  = {2015},

date = {2015-01-01},

journal = {Neuroimage Clin},

volume = {7},

pages = {667--677},

abstract = {Altered brain morphometry has been widely acknowledged in chronic pain, and recent studies have implicated altered network dynamics, as opposed to properties of individual brain regions, in supporting persistent pain. Structural covariance analysis determines the inter-regional association in morphological metrics, such as gray matter volume, and such structural associations may be altered in chronic pain. In this study, voxel-based morphometry structural covariance networks were compared between fibromyalgia patients (N = 42) and age- and sex-matched pain-free adults (N = 63). We investigated network topology using spectral partitioning, which can delineate local network submodules with consistent structural covariance. We also explored white matter connectivity between regions comprising these submodules and evaluated the association between probabilistic white matter tractography and pain-relevant clinical metrics. Our structural covariance network analysis noted more connections within the cerebellum for fibromyalgia patients, and more connections in the frontal lobe for healthy controls. For fibromyalgia patients, spectral partitioning identified a distinct submodule with cerebellar connections to medial prefrontal and temporal and right inferior parietal lobes, whose gray matter volume was associated with the severity of depression in these patients. Volume for a submodule encompassing lateral orbitofrontal, inferior frontal, postcentral, lateral temporal, and insular cortices was correlated with evoked pain sensitivity. Additionally, the number of white matter fibers between specific submodule regions was also associated with measures of evoked pain sensitivity and clinical pain interference. Hence, altered gray and white matter morphometry in cerebellar and frontal cortical regions may contribute to, or result from, pain-relevant dysfunction in chronic pain patients.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid25685708,

title = {Increased in vivo glial activation in patients with amyotrophic lateral sclerosis: assessed with [(11)C]-PBR28},

author = {Nicole R Zürcher and Marco L Loggia and Robert Lawson and Daniel B Chonde and David Izquierdo-Garcia and Julia E Yasek and Oluwaseun Akeju and Ciprian Catana and Bruce R Rosen and Merit E Cudkowicz and Jacob M Hooker and Nazem Atassi},

doi = {10.1016/j.nicl.2015.01.009},

issn = {2213-1582},

year  = {2015},

date = {2015-01-01},

journal = {Neuroimage Clin},

volume = {7},

pages = {409--414},

abstract = {Evidence from human post mortem, in vivo and animal model studies implicates the neuroimmune system and activated microglia in the pathology of amyotrophic lateral sclerosis. The study aim was to further evaluate in vivo neuroinflammation in individuals with amyotrophic lateral sclerosis using [(11)C]-PBR28 positron emission tomography. Ten patients with amyotrophic lateral sclerosis (seven males, three females, 38-68 years) and ten age- and [(11)C]-PBR28 binding affinity-matched healthy volunteers (six males, four females, 33-65 years) completed a positron emission tomography scan. Standardized uptake values were calculated from 60 to 90 min post-injection and normalized to whole brain mean. Voxel-wise analysis showed increased binding in the motor cortices and corticospinal tracts in patients with amyotrophic lateral sclerosis compared to healthy controls (p FWE < 0.05). Region of interest analysis revealed increased [(11)C]-PBR28 binding in the precentral gyrus in patients (normalized standardized uptake value = 1.15) compared to controls (1.03, p < 0.05). In patients those values were positively correlated with upper motor neuron burden scores (r = 0.69, p < 0.05), and negatively correlated with the amyotrophic lateral sclerosis functional rating scale (r = -0.66, p < 0.05). Increased in vivo glial activation in motor cortices, that correlates with phenotype, complements previous histopathological reports. Further studies will determine the role of [(11)C]-PBR28 as a marker of treatments that target neuroinflammation.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid25610783,

title = {Evoked itch perception is associated with changes in functional brain connectivity},

author = {Gaëlle Desbordes and Ang Li and Marco L Loggia and Jieun Kim and Peter C Schalock and Ethan Lerner and Thanh N Tran and Johannes Ring and Bruce R Rosen and Ted J Kaptchuk and Florian Pfab and Vitaly Napadow},

doi = {10.1016/j.nicl.2014.12.002},

issn = {2213-1582},

year  = {2015},

date = {2015-01-01},

journal = {Neuroimage Clin},

volume = {7},

pages = {213--221},

abstract = {Chronic itch, a highly debilitating condition, has received relatively little attention in the neuroimaging literature. Recent studies suggest that brain regions supporting itch in chronic itch patients encompass sensorimotor and salience networks, and corticostriatal circuits involved in motor preparation for scratching. However, how these different brain areas interact with one another in the context of itch is still unknown. We acquired BOLD fMRI scans in 14 atopic dermatitis patients to investigate resting-state functional connectivity before and after allergen-induced itch exacerbated the clinical itch perception in these patients. A seed-based analysis revealed decreased functional connectivity from baseline resting state to the evoked-itch state between several itch-related brain regions, particularly the insular and cingulate cortices and basal ganglia, where decreased connectivity was significantly correlated with increased levels of perceived itch. In contrast, evoked itch increased connectivity between key nodes of the frontoparietal control network (superior parietal lobule and dorsolateral prefrontal cortex), where higher increase in connectivity was correlated with a lesser increase in perceived itch, suggesting that greater interaction between nodes of this executive attention network serves to limit itch sensation via enhanced top-down regulation. Overall, our results provide the first evidence of itch-dependent changes in functional connectivity across multiple brain regions.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid25432022,

title = {Disruption of thalamic functional connectivity is a neural correlate of dexmedetomidine-induced unconsciousness},

author = {Oluwaseun Akeju and Marco L Loggia and Ciprian Catana and Kara J Pavone and Rafael Vazquez and James Rhee and Violeta Contreras Ramirez and Daniel B Chonde and David Izquierdo-Garcia and Grae Arabasz and Shirley Hsu and Kathleen Habeeb and Jacob M Hooker and Vitaly Napadow and Emery N Brown and Patrick L Purdon},

doi = {10.7554/eLife.04499},

issn = {2050-084X},

year  = {2014},

date = {2014-11-01},

journal = {Elife},

volume = {3},

pages = {e04499},

abstract = {Understanding the neural basis of consciousness is fundamental to neuroscience research. Disruptions in cortico-cortical connectivity have been suggested as a primary mechanism of unconsciousness. By using a novel combination of positron emission tomography and functional magnetic resonance imaging, we studied anesthesia-induced unconsciousness and recovery using the α₂-agonist dexmedetomidine. During unconsciousness, cerebral metabolic rate of glucose and cerebral blood flow were preferentially decreased in the thalamus, the Default Mode Network (DMN), and the bilateral Frontoparietal Networks (FPNs). Cortico-cortical functional connectivity within the DMN and FPNs was preserved. However, DMN thalamo-cortical functional connectivity was disrupted. Recovery from this state was associated with sustained reduction in cerebral blood flow and restored DMN thalamo-cortical functional connectivity. We report that loss of thalamo-cortical functional connectivity is sufficient to produce unconsciousness.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid24135900,

title = {Phenotype matters: the absence of a positive association between cortical thinning and chronic low back pain when controlling for salient clinical variables},

author = {Andrew J Dolman and Marco L Loggia and Robert R Edwards and Randy L Gollub and Jian Kong and Vitaly Napadow and Ajay D Wasan},

doi = {10.1097/AJP.0000000000000043},

issn = {1536-5409},

year  = {2014},

date = {2014-10-01},

journal = {Clin J Pain},

volume = {30},

number = {10},

pages = {839--845},

abstract = {AIMS/OBJECTIVES/BACKGROUND: Studies have associated chronic low back pain (cLBP) with grey matter thinning. But these studies have not controlled for important clinical variables (such as a comorbid affective disorder, pain medication, age, or pain phenotype), which may reduce or eliminate these associations.nnMETHODS: We conducted cortical thickness and voxel-based morphometry (VBM) analyses in 14 cLBP patients with a discogenic component to their pain, not taking opioids or benzodiazepines, and not depressed or anxious. They were age and gender matched to 14 pain-free controls (PFCs). An ROI-driven analysis (regions of interest) was conducted, using 18 clusters from a previous arterial spin labeling study demonstrating greater regional cerebral blood flow (rCBF) in these cLBP subjects than the PFCs. Cortical thickness and VBM-based gray matter volume measurements were obtained from a structural MRI scan and group contrasts were calculated.nnRESULTS: Multivariate analysis of variance showed a trend toward cortical thickening in the right paracentral lobule in cLBP subjects (F1,17=3.667, P<0.067), and significant thickening in the right rostral middle frontal gyrus (F1,17=6.880, P<0.014). These clusters were non-significant after including age as a covariate (P<0.891; P<0.279). A whole-brain cortical thickness and VBM analysis also did not identify significant clusters of thinning or thickening. Exploratory analyses identified group differences for correlations between age and cortical thickness of the right rostral middle frontal gyrus (cLBP: R=-0.03, P=0.9; PFCs: R=-0.81, P<0.001), that is, PFCs demonstrated age-related thinning while cLBP patients did not.nnCONCLUSIONS: Our pilot results suggest that controlling for affect, age, and concurrent medications may reduce or eliminate some of the previously reported structural brain alterations in cLBP.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid23222890,

title = {The brain circuitry mediating antipruritic effects of acupuncture},

author = {Vitaly Napadow and Ang Li and Marco L Loggia and Jieun Kim and Peter C Schalock and Ethan Lerner and Thanh-Nga Tran and Johannes Ring and Bruce R Rosen and Ted J Kaptchuk and Florian Pfab},

doi = {10.1093/cercor/bhs363},

issn = {1460-2199},

year  = {2014},

date = {2014-04-01},

journal = {Cereb Cortex},

volume = {24},

number = {4},

pages = {873--882},

abstract = {Itch is an aversive sensory experience and while systemic therapies, such as acupuncture, have shown promise in alleviating itch in patients suffering from chronic itch, their antipruritic mechanisms are unknown. As several lines of evidence implicate brain-focused mechanisms, we applied functional magnetic resonance imaging and our validated temperature-modulation itch model to evaluate the underlying brain circuitry supporting allergen-induced itch reduction in atopic dermatitis patients by acupuncture, antihistamine, and respective placebo treatments. Brain response to allergen itch demonstrated phase dependency. During an increasing itch phase, activation was localized in anterior insula and striatum, regions associated with salience/interoception and motivation processing. Once itch reached peak plateau, robust activation was noted in prefrontal cognitive and premotor areas. Acupuncture reduced itch and itch-evoked activation in the insula, putamen, and premotor and prefrontal cortical areas. Neither itch sensation nor itch-evoked brain response was altered following antihistamine or placebo acupuncture. Greater itch reduction following acupuncture was associated with greater reduction in putamen response, a region implicated in motivation and habitual behavior underlying the urge to scratch, specifically implicating this region in acupuncture's antipruritic effects. Understanding brain circuitry underlying itch reduction following acupuncture and related neuromodulatory therapies will significantly impact the development and applicability of novel therapies to reduce an itch.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid24816735,

title = {Amygdala perfusion is predicted by its functional connectivity with the ventromedial prefrontal cortex and negative affect},

author = {Garth Coombs and Marco L Loggia and Douglas N Greve and Daphne J Holt},

doi = {10.1371/journal.pone.0097466},

issn = {1932-6203},

year  = {2014},

date = {2014-01-01},

journal = {PLoS One},

volume = {9},

number = {5},

pages = {e97466},

abstract = {BACKGROUND: Previous studies have shown that the activity of the amygdala is elevated in people experiencing clinical and subclinical levels of anxiety and depression (negative affect). It has been proposed that a reduction in inhibitory input to the amygdala from the prefrontal cortex and resultant over-activity of the amygdala underlies this association. Prior studies have found relationships between negative affect and 1) amygdala over-activity and 2) reduced amygdala-prefrontal connectivity. However, it is not known whether elevated amygdala activity is associated with decreased amygdala-prefrontal connectivity during negative affect states.nnMETHODS: Here we used resting-state arterial spin labeling (ASL) and blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) in combination to test this model, measuring the activity (regional cerebral blood flow, rCBF) and functional connectivity (correlated fluctuations in the BOLD signal) of one subregion of the amygdala with strong connections with the prefrontal cortex, the basolateral nucleus (BLA), and subsyndromal anxiety levels in 38 healthy subjects.nnRESULTS: BLA rCBF was strongly correlated with anxiety levels. Moreover, both BLA rCBF and anxiety were inversely correlated with the strength of the functional coupling of the BLA with the caudal ventromedial prefrontal cortex. Lastly, BLA perfusion was found to be a mediator of the relationship between BLA-prefrontal connectivity and anxiety.nnCONCLUSIONS: These results show that both perfusion of the BLA and a measure of its functional coupling with the prefrontal cortex directly index anxiety levels in healthy subjects, and that low BLA-prefrontal connectivity may lead to increased BLA activity and resulting anxiety. Thus, these data provide key evidence for an often-cited circuitry model of negative affect, using a novel, multi-modal imaging approach.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid24449585,

title = {Disrupted brain circuitry for pain-related reward/punishment in fibromyalgia},

author = {Marco L Loggia and Chantal Berna and Jieun Kim and Christine M Cahalan and Randy L Gollub and Ajay D Wasan and Richard E Harris and Robert R Edwards and Vitaly Napadow},

doi = {10.1002/art.38191},

issn = {2326-5205},

year  = {2014},

date = {2014-01-01},

journal = {Arthritis Rheumatol},

volume = {66},

number = {1},

pages = {203--212},

abstract = {OBJECTIVE: While patients with fibromyalgia (FM) are known to exhibit hyperalgesia, the central mechanisms contributing to this altered pain processing are not fully understood. This study was undertaken to investigate potential dysregulation of the neural circuitry underlying cognitive and hedonic aspects of the subjective experience of pain, such as anticipation of pain and anticipation of pain relief.nnMETHODS: Thirty-one FM patients and 14 controls underwent functional magnetic resonance imaging, while receiving cuff pressure pain stimuli on the leg calibrated to elicit a pain rating of ~50 on a 100-point scale. During the scan, subjects also received visual cues informing them of the impending onset of pain (pain anticipation) and the impending offset of pain (relief anticipation).nnRESULTS: Patients exhibited less robust activation during both anticipation of pain and anticipation of relief within regions of the brain commonly thought to be involved in sensory, affective, cognitive, and pain-modulatory processes. In healthy controls, direct searches and region-of-interest analyses of the ventral tegmental area revealed a pattern of activity compatible with the encoding of punishment signals: activation during anticipation of pain and pain stimulation, but deactivation during anticipation of pain relief. In FM patients, however, activity in the ventral tegmental area during periods of pain and periods of anticipation (of both pain and relief) was dramatically reduced or abolished.nnCONCLUSION: FM patients exhibit disrupted brain responses to reward/punishment. The ventral tegmental area is a source of reward-linked dopaminergic/γ-aminobutyric acid-releasing (GABAergic) neurotransmission in the brain, and our observations are compatible with reports of altered dopaminergic/GABAergic neurotransmission in FM. Reduced reward/punishment signaling in FM may be related to the augmented central processing of pain and reduced efficacy of opioid treatments in these patients.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid23965184,

title = {S1 is associated with chronic low back pain: a functional and structural MRI study},

author = {Jian Kong and Rosa B Spaeth and Hsiao-Ying Wey and Alexandra Cheetham and Amanda H Cook and Karin Jensen and Ying Tan and Hesheng Liu and Danhong Wang and Marco L Loggia and Vitaly Napadow and Jordan W Smoller and Ajay D Wasan and Randy L Gollub},

doi = {10.1186/1744-8069-9-43},

issn = {1744-8069},

year  = {2013},

date = {2013-08-01},

journal = {Mol Pain},

volume = {9},

pages = {43},

abstract = {A fundamental characteristic of neural circuits is the capacity for plasticity in response to experience. Neural plasticity is associated with the development of chronic pain disorders. In this study, we investigated 1) brain resting state functional connectivity (FC) differences between patients with chronic low back pain (cLBP) and matched healthy controls (HC); 2) FC differences within the cLBP patients as they experienced different levels of endogenous low back pain evoked by exercise maneuvers, and 3) morphometric differences between cLBP patients and matched HC. We found the dynamic character of FC in the primary somatosensory cortex (S1) in cLBP patients, i.e., S1 FC decreased when the patients experienced low intensity LBP as compared with matched healthy controls, and FC at S1 increased when cLBP patients experienced high intensity LBP as compared with the low intensity condition. In addition, we also found increased cortical thickness in the bilateral S1 somatotopically associated with the lower back in cLBP patients as compared to healthy controls. Our results provide evidence of structural plasticity co-localized with areas exhibiting FC changes in S1 in cLBP patients.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid23718988,

title = {Sustained deep-tissue pain alters functional brain connectivity},

author = {Jieun Kim and Marco L Loggia and Robert R Edwards and Ajay D Wasan and Randy L Gollub and Vitaly Napadow},

doi = {10.1016/j.pain.2013.04.016},

issn = {1872-6623},

year  = {2013},

date = {2013-08-01},

journal = {Pain},

volume = {154},

number = {8},

pages = {1343--1351},

abstract = {Recent functional brain connectivity studies have contributed to our understanding of the neurocircuitry supporting pain perception. However, evoked-pain connectivity studies have employed cutaneous and/or brief stimuli, which induce sensations that differ appreciably from the clinical pain experience. Sustained myofascial pain evoked by pressure cuff affords an excellent opportunity to evaluate functional connectivity change to more clinically relevant sustained deep-tissue pain. Connectivity in specific networks known to be modulated by evoked pain (sensorimotor, salience, dorsal attention, frontoparietal control, and default mode networks: SMN, SLN, DAN, FCN, and DMN) was evaluated with functional-connectivity magnetic resonance imaging, both at rest and during a sustained (6-minute) pain state in healthy adults. We found that pain was stable, with no significant changes of subjects' pain ratings over the stimulation period. Sustained pain reduced connectivity between the SMN and the contralateral leg primary sensorimotor (S1/M1) representation. Such SMN-S1/M1 connectivity decreases were also accompanied by and correlated with increased SLN-S1/M1 connectivity, suggesting recruitment of activated S1/M1 from SMN to SLN. Sustained pain also increased DAN connectivity to pain processing regions such as mid-cingulate cortex, posterior insula, and putamen. Moreover, greater connectivity during pain between contralateral S1/M1 and posterior insula, thalamus, putamen, and amygdala was associated with lower cuff pressures needed to reach the targeted pain sensation. These results demonstrate that sustained pain disrupts resting S1/M1 connectivity by shifting it to a network known to process stimulus salience. Furthermore, increased connectivity between S1/M1 and both sensory and affective processing areas may be an important contribution to interindividual differences in pain sensitivity.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid23111164,

title = {Default mode network connectivity encodes clinical pain: an arterial spin labeling study},

author = {Marco L Loggia and Jieun Kim and Randy L Gollub and Mark G Vangel and Irving Kirsch and Jian Kong and Ajay D Wasan and Vitaly Napadow},

doi = {10.1016/j.pain.2012.07.029},

issn = {1872-6623},

year  = {2013},

date = {2013-01-01},

journal = {Pain},

volume = {154},

number = {1},

pages = {24--33},

abstract = {Neuroimaging studies have suggested the presence of alterations in the anatomo-functional properties of the brain of patients with chronic pain. However, investigation of the brain circuitry supporting the perception of clinical pain presents significant challenges, particularly when using traditional neuroimaging approaches. While potential neuroimaging markers for clinical pain have included resting brain connectivity, these cross-sectional studies have not examined sensitivity to within-subject exacerbation of pain. We used the dual regression probabilistic Independent Component Analysis approach to investigate resting-state connectivity on arterial spin labeling data. Brain connectivity was compared between patients with chronic low back pain (cLBP) and healthy controls, before and after the performance of maneuvers aimed at exacerbating clinical pain levels in the patients. Our analyses identified multiple resting state networks, including the default mode network (DMN). At baseline, patients demonstrated stronger DMN connectivity to the pregenual anterior cingulate cortex (pgACC), left inferior parietal lobule, and right insula (rINS). Patients' baseline clinical pain correlated positively with connectivity strength between the DMN and right insula (DMN-rINS). The performance of calibrated physical maneuvers induced changes in pain, which were paralleled by changes in DMN-rINS connectivity. Maneuvers also disrupted the DMN-pgACC connectivity, which at baseline was anticorrelated with pain. Finally, baseline DMN connectivity predicted maneuver-induced changes in both pain and DMN-rINS connectivity. Our results support the use of arterial spin labeling to evaluate clinical pain, and the use of resting DMN connectivity as a potential neuroimaging biomarker for chronic pain perception.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}