Marco Loggia

• PhD, Neurological Sciences
• Professor (Associate) at Harvard Medical School

Our group has shown that translocator protein (TSPO) levels, a putative marker of neuroinflammation, are increased in the brain and spinal cord of patients with chronic low back pain (cLBP). Whether neuroinflammation might be a therapeutic target for this condition is unknown. In this phase II double-blind, placebo-controlled, randomized clinical t...

Positron Emission Tomography (PET) of the 18 kDa translocator protein (TSPO) is critical for neuroinflammation studies but faces substantial methodological challenges. These include issues with arterial blood sampling for kinetic modeling, the absence of suitable reference regions, genetic polymorphisms affecting tracer affinity, altered blood-to-b...

Although the pathophysiology of migraine involves a complex ensemble of peripheral and central nervous system changes that remain incompletely understood, the activation and sensitization of the trigeminovascular system is believed to play a major role. However, non-invasive, in vivo neuroimaging studies investigating the underlying neural mechanis...

Although both central and peripheral inflammation have been observed consistently in depression, the relationship between the two remains obscure. Extra-axial immune cells may play a role in mediating the connection between central and peripheral immunity. This study investigates the potential roles of calvarial bone marrow and parameningeal spaces...

Despite hundreds of studies demonstrating the involvement of neuron-glia-immune interactions in the establishment and/or maintenance of persistent pain behaviors in animals, the role (or even occurrence) of so-called “neuroinflammation” in human pain has been an object of contention for decades. Here, I present the results of multiple positron emis...

Background Neuroinflammation, a pathophysiological process involved in numerous disorders, is typically imaged using [11C]PBR28 (or TSPO) PET. However, this technique is limited by high costs and ionizing radiation, restricting its widespread clinical use. MRI, a more accessible alternative, is commonly used for structural or functional imaging, bu...

Introduction Recent evidence suggests the blood-to-brain influx rate (K1) in TSPO PET imaging as a promising biomarker of blood–brain barrier (BBB) permeability alterations commonly associated with peripheral inflammation and heightened immune activity in the brain. However, standard compartmental modeling quantification is limited by the requireme...

Background Chronic pain involves communication between neural and immune systems. Recent data suggest localization of glial (brain immune cells) activation to the sensorimotor regions of the brain cortex (S1/M1) in chronic low back pain (LBP). As glia perform diverse functions that impact neural function, activation might contribute to sensorimotor...

Epigenetics has gained considerable interest as potential mediators of molecular alterations that could underlie the prolonged sensitization of nociceptors, neurons, and glia in response to various environmental stimuli. Histone acetylation and deacetylation, key processes in modulating chromatin, influence gene expression; elevated histone acetyla...

The COVID-19 pandemic caused by SARS-CoV-2 has triggered a consequential public health crisis of post-acute sequelae of COVID-19 (PASC), sometimes referred to as long COVID. The mechanisms of the heterogeneous persistent symptoms and signs that comprise PASC are under investigation, and several studies have pointed to the central nervous and vascul...

Although both central and peripheral inflammation have been consistently observed in depression, the relationship between the two remains obscure. Extra-axial immune cells may play a role in mediating the connection between central and peripheral immunity. This study investigates the potential roles of calvarial bone marrow and parameningeal spaces...

Compartmentalized meningeal inflammation is thought to represent one of the key players in the pathogenesis of cortical demyelination in multiple sclerosis. Positron emission tomography targeting the 18 kDa mitochondrial Translocator Protein (TSPO) is a molecular-specific approach to quantify immune cell-mediated density in the cortico-meningeal ti...

Although inflammation is known to play a role in knee osteoarthritis (KOA), inflammation-specific imaging is not routinely performed. In this article, we evaluate the role of joint inflammation, measured using [ ¹¹ C]-PBR28, a radioligand for the inflammatory marker 18-kDa translocator protein (TSPO), in KOA. Twenty-one KOA patients and 11 healthy...

Objective Fibromyalgia (FM) is characterized by pervasive pain‐related symptomatology and high levels of negative affect. Mind–body treatments such as cognitive behavioral therapy (CBT) appear to foster improvement in FM via reductions in pain‐related catastrophizing, a set of negative, pain‐amplifying cognitive and emotional processes. However, th...

The COVID-19 pandemic caused by SARS-CoV-2 has triggered a consequential public health crisis of post-acute sequelae of COVID-19 (PASC), sometimes referred to as long COVID. The mechanisms of the heterogeneous persistent symptoms and signs that comprise PASC are under investigation, and several studies have pointed to the central nervous and vascul...

Objective: Functional and morphologic changes in extracranial organs can occur after acute brain injury. The neuroanatomic correlates of such changes are not fully known. Herein, we tested the hypothesis that brain infarcts are associated with cardiac and systemic abnormalities (CSA) in a regionally-specific manner. Methods: We generated voxel-w...

Recently, we showed that patients with knee osteoarthritis (KOA) demonstrate alterations in the thalamic concentrations of several metabolites compared with healthy controls: higher myo-inositol (mIns), lower N-acetylaspartate (NAA), and lower choline (Cho). Here, we evaluated whether these metabolite alterations are specific to KOA or could also b...

Introduction: Both preclinical studies, and more recent clinical imaging studies, suggest that glia-mediated neuroinflammation may be implicated in chronic pain, and therefore might be a potential treatment target. However, it is currently unknown whether modulating neuroinflammation effectively alleviates pain in humans. This trial tests the hypo...

Voltage-gated sodium channels (Navs) play a crucial electrical signaling role in neurons. Nav-isoforms present in peripheral sensory neurons and dorsal root ganglia of the spinal cord are critically involved in pain perception and transmission. While these isoforms, particularly Nav1.7, are implicated in neuropathic pain disorders, changes in the f...

Objectives: Aromatase inhibitors (AIs), which potently inhibit estrogen biosynthesis, are a standard treatment for hormone sensitive early-stage breast cancer. AIs have been associated with substantial joint pain and muscle stiffness (aromatase inhibitor-associated musculoskeletal syndrome, AIMSS). However, the link between AIs and number of clini...

Introduction: Chronic pain is a debilitating medical problem that is difficult to treat. Neuroinflammatory pathways have emerged as a potential therapeutic target, as preclinical studies have demonstrated that glial cells and neuroglial interactions play a role in the establishment and maintenance of pain. Recently, we used positron emission tomog...

Amyotrophic lateral sclerosis (ALS) is a deadly neurodegenerative disorder affecting motor neurons in the spinal cord and brain. Studies have reported on atrophy within segments of the cervical cord, but we are not aware of previous investigations of the whole spinal cord. Herein we present our findings from a 3T MRI study involving 32 subjects (15...

The invasive measurement of the AIF for the full quantification of dynamic PET data limits its widespread use in clinical research studies. Current methods which estimate the AIF from imaging data are prone to large errors, even when based on NNs. This work aims to estimate the AIF from dynamic PET images using physically informed deep neural netwo...

Introduction Chronic pain is an extremely prevalent public health issue. However, the underlying mechanisms are poorly understood, thus limiting effective treatment options. Both preclinical studies, and more recent clinical imaging studies, suggest that glia-mediated neuroinflammation may be implicated in chronic pain, and therefore might be a pot...

Introduction: Poststroke fatigue (PSF) is a disabling condition with unclear etiology. The brain lesion is thought to be an important causal factor in PSF, though focal lesion characteristics such as size and location have not proven to be predictive. Given that the stroke lesion results not only in focal tissue death, but also widespread changes...

A previous study by our group showed that knee osteoarthritis (KOA) patients demonstrate alterations in the thalamic levels of several metabolites, as measured by 1H-magnetic resonance spectroscopy: i.e., higher myo-inositol (mIns), lower N-acetylaspartate (NAA) and lower Choline (Cho), when compared to healthy controls. We sought to replicate thes...

While the neural correlates of migraine have been widely studied, it remains unclear whether glial cells contribute to neuroinflammation in migraine. One marker of glial activation is the presence of elevated levels of 18 kDa translocator protein (TSPO), and earlier studies have shown that individuals suffering from migraine with aura (MWA) exhibit...

Migraine is a highly prevalent chronic pain disorder that is characterized by sensitization and dysregulation of the central autonomic nervous system. Interoception is the sensing of signals originating from within the body, and is altered in chronic pain conditions including episodic migraine. The relationship between brain mechanisms of interocep...

Objective Expectancies have a well-documented influence on the experience of pain, responses to treatment, and post-surgical outcomes. In individuals with osteoarthritis, several studies have shown that expectations predict increased pain and disability after total knee replacement surgery. Despite the growing recognition of the importance of expec...

Background The establishment of test–retest reliability and reproducibility (TRR) is an important part of validating any research tool, including functional magnetic resonance imaging (fMRI). The primary objective of this study is to investigate the reliability of pseudo-Continuous Arterial Spin Labeling (pCASL) and Blood Oxygen Level Dependent (BO...

Objective Abnormal central pain processing is a leading cause of pain in fibromyalgia (FM) and is perceptually characterized with the psychophysical measure of temporal summation of pain (TSP). TSP is the perception of increasingly greater pain in response to repetitive or tonic noxious stimuli. Previous neuroimaging studies have used static (i.e.,...

Background and Objectives The presence of HIV in the CNS has been related to chronic immune activation and cognitive dysfunction. The aim of this work was to investigate (1) the presence of neuroinflammation in aviremic people with HIV (PWH) on therapy and in nontreated aviremic PWH (elite controllers [ECs]) using a translocator protein 18 kDa radi...

While COVID-19 research has seen an explosion in the literature, the impact of pandemic-related societal and lifestyle disruptions on brain health among the uninfected remains underexplored. However, a global increase in the prevalence of fatigue, brain fog, depression and other “sickness behavior”-like symptoms implicates a possible dysregulation...

Objective Chronic pain can have detrimental effects on quality of life and a profound impact on one’s identity. The Pictorial Representation of Illness- and Self-Measure (PRISM), is a visual tool designed to measure the self-illness separation (SIS) that represents the degree of schema-enmeshment (i.e., the degree to which the self-schema and the i...

About a third of all United States veterans who served in the 1991 Gulf War (GW) report a range of chronic health symptoms including fatigue, neurocognitive symptoms, and musculoskeletal pain. There is growing evidence supporting the detrimental effects of maladaptive neuroimmune reactions in this multi-symptom illness. Indeed, recent studies using...

Background The impact of COVID-19 on human health extends beyond the morbidity and death toll directly caused by the SARS-CoV-2 virus. In fact, accumulating evidence indicates a global increase in the incidence of fatigue, brain fog and depression, including among non-infected, since the pandemic onset. Motivated by previous evidence linking those...

Osteoarthritis (OA) and major depression (MD) are two debilitating disorders that frequently co-occur and affect millions of the elderly each year. Despite the greater symptom severity, poorer clinical outcomes, and increased mortality of the comorbid conditions, we have a limited understanding of their etiologic relationships. In this study, we co...

We recently showed that patients with different chronic pain conditions (such as chronic low back pain, fibromyalgia, migraine, and Gulf War Illness) demonstrated elevated brain and/or spinal cord levels of the glial marker 18 kDa translocator protein, which suggests that neuroinflammation might be a pervasive phenomenon observable across multiple...

Neuroinflammation occurs in response to acute ischemic stroke, and has been speculated to underlie secondary poststroke pathologies, such as depression, that often develop over time poststroke. However, no study has examined whether neuroinflammation is present in chronic stroke patients (e.g. ≥ 1 year poststroke). This study tested whether neuroin...

Aims Gulf War Illness (GWI), a chronic debilitating disorder characterized by fatigue, joint pain, cognitive, gastrointestinal, respiratory, and skin problems, is currently diagnosed by self-reported symptoms. The Boston Biorepository, Recruitment, and Integrative Network (BBRAIN) is the collaborative effort of expert Gulf War Illness (GWI) researc...

The positron emission tomography (PET) radiotracer [ ¹¹ C]PBR28 has been increasingly used to image the translocator protein (TSPO) as a marker of neuroinflammation in a variety of brain disorders. Interrelatedly, similar clinical populations can also exhibit altered brain perfusion, as has been shown using arterial spin labelling in magnetic reson...

Background Fibromyalgia is a centralized multidimensional chronic pain syndrome, but its pathophysiology is not fully understood. Methods We applied 3D magnetic resonance spectroscopic imaging (MRSI), covering multiple cortical and subcortical brain regions, to investigate the association between neuro-metabolite (e.g., combined glutamate and glut...

Mechanisms of neuroimmune and mitochondrial dysfunction have been repeatedly implicated in autism spectrum disorder (ASD). To examine these mechanisms in ASD individuals, we measured the in vivo expression of the 18 kDa translocator protein (TSPO), an activated glial marker expressed on mitochondrial membranes. Participants underwent scanning on a...

Aromatase Inhibitor-associated MusculoSkeletal Syndrome (AIMSS), reported by 36-87% of women with breast cancer undergoing AI therapy, may reduce quality of life and medication adherence. The objective of this analysis was to compare clinical pain and generalized pain sensitivity between breast cancer patients who did or did not receive AI therapy....

We recently showed elevated levels of the 18kDa translocator protein (TSPO), a marker of neuroinflammation, in chronic low back pain patients (cLBP) compared to healthy controls(Loggia et al., 2015). Here, we test whether TSPO signal 1) can further subtype cLBP patients based on their clinical presentation, and 2) is associated with functional conn...

Fibromyalgia is a multidimensional chronic pain syndrome. It is thought to result mainly from central nervous system dysfunction, but its working mechanism is not fully understood. In this study, we applied multi-slice magnetic resonance spectroscopy imaging (MRSI) to investigate the relationship between brain metabolite (e.g., combined glutamate a...

Negative affect (NA) is a significant cause of disability for chronic pain patients. While little is known about the mechanism underlying pain-comorbid NA, previous studies have implicated neuroinflammation in the pathophysiology of both depression and chronic pain. Here, we tested the hypothesis that NA in pain patients is linked to elevations in...

The weak association between disability levels and "peripheral" (i.e., knee) findings suggests that central nervous system alterations may contribute to the pathophysiology of knee osteoarthritis (KOA). Here, we evaluated brain metabolite alterations in KOA patients, before and after total knee arthroplasty (TKA), using 1H-magnetic resonance spectr...

Chronic low back pain (cLBP) has been associated with changes in brain plasticity. Non-pharmacological therapies such as Manual Therapy (MT) have shown promise for relieving cLBP. However, translational neuroimaging research is needed to understand potential central mechanisms supporting MT. We investigated the effect of MT on resting-state salienc...

Using positron emission tomography, we recently demonstrated elevated brain levels of the 18kDa translocator protein (TSPO), a glial activation marker, in chronic low back pain (cLBP) patients, compared to healthy controls (HC). Here, we first sought to replicate the original findings in an independent cohort (15 cLBP, 37.8±12.5 y/o; 18 HC, 48.2±12...

Issues with model fitting (i.e. suboptimal standard deviation, linewidth/full-width-at-half-maximum, and/or signal-to-noise ratio) in multi-voxel MRI spectroscopy, or chemical shift imaging (CSI) can result in the significant loss of usable voxels. A potential solution to minimize this problem is to estimate the value of unusable voxels by utilizin...

Major surgery is associated with a systemic inflammatory cascade that is thought, in some cases, to contribute to transient and/or sustained cognitive decline, possibly through neuroinflammatory mechanisms. However, the relationship between surgery, peripheral and central nervous system inflammation, and post-operative cognitive outcomes remains un...

Objective While much brain research on fibromyalgia (FM) focuses on the study of hyperresponsiveness to painful stimuli, some studies suggest that the increased pain‐related brain activity often reported in FM studies may be partially explained by stronger responses to salient aspects of the stimulation rather than, or in addition to, the stimulati...

Prior studies have shown that patients suffering from chronic Low Back Pain (cLBP) have impaired somatosensory processing including reduced tactile acuity, i.e. reduced ability to resolve fine spatial details with the perception of touch. The central mechanism(s) underlying reduced tactile acuity are unknown but may include changes in specific brai...

Background Cortical spreading depression (CSD) underlies the neurobiology of migraine with aura (MWA). Animal studies reveal networks of microvessels linking brain‐meninges‐bone marrow. CSD activates the trigeminovascular system, evoking a meningeal inflammatory response. Accordingly, this study examines the upregulation of an inflammatory marker i...

Rationale: Neuroinflammation has been implicated in Amyotrophic Lateral Sclerosis (ALS) and can be visualized using translocator protein (TSPO) radioligands. To become a reliable pharmacodynamic biomarker for ALS multicenter trials, some challenges have to be overcome. We aimed to investigate whether multicenter data pooling of different TSPO trac...

Issues with model fitting (i.e. suboptimal standard deviation, linewidth/full-width-at-half-maximum, and/or signal-to-noise ratio) in multi-voxel MRI spectroscopy, or chemical shift imaging (CSI), can result in the significant loss of usable voxels. A potential solution to minimize this problem is to estimate the value of unusable voxels by utilizi...

Gulf War Illness (GWI) is a chronic disorder affecting approximately 30% of the veterans who served in the 1991 Gulf War. It is characterised by a constellation of symptoms including musculoskeletal pain, cognitive problems and fatigue. The cause of GWI is not definitively known but exposure to neurotoxicants, the prophylactic use of pyridostigmine...

Background: Chronic pain and mood disorders share common neuroanatomical substrates involving disruption of the reward system. Although increase in negative affect (NA) and decrease in positive affect (PA) are well-known factors complicating the clinical presentation of chronic pain patients, our understanding of the mechanisms underlying the inte...

Non-invasive measures of neuroinflammatory processes in humans could substantially aid diagnosis and therapeutic development for many disorders, including chronic pain. Several proton Magnetic Resonance Spectroscopy (H-MRS) metabolites have been linked with glial activity (i.e. choline and myo-inositol) and found to be altered in chronic pain patie...

Background: Neuroinflammation with microglia activation is thought to be closely related to cortical multiple sclerosis (MS) lesion pathogenesis. Objective: Using 11C-PBR28 and 7 Tesla (7T) imaging, we assessed in 9 relapsing–remitting multiple sclerosis (RRMS) and 10 secondary progressive multiple sclerosis (SPMS) patients the following: (1) micro...

Background Neuroinflammation with microglia activation is thought to be closely related to cortical multiple sclerosis (MS) lesion pathogenesis. Objective Using ¹¹C-PBR28 and 7 Tesla (7T) imaging, we assessed in 9 relapsing–remitting multiple sclerosis (RRMS) and 10 secondary progressive multiple sclerosis (SPMS) patients the following: (1) microg...

Background Activated microglia, which can be detected in vivo by ¹¹C-PBR28 positron emission tomography (PET), represent a main component of MS pathology in the brain. Their role in the cerebellum is still unexplored, although cerebellar involvement in MS is frequent and accounts for disability progression. Objectives We aimed at characterizing ce...

Chronic low back pain (cLBP) has been associated with maladaptive brain plasticity, and non-pharmacological therapies such as Spinal Manipulative Therapy (SMT) have shown promise in reducing pain and modifying intrinsic brain physiology. However, more translational research is needed using clinical models. We investigated functional salience networ...

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. Methods: Thirteen migraineurs with aura and 16 healthy controls received integrated PET/MRI brain scans with [11C]PBR28, a radioliga...

While several studies have found that chronic pain is characterized by increased cross-network connectivity between salience, sensorimotor, and default mode (DMN) networks, a large sample-size investigation allowing a more reliable evaluation of somatotopic specificity and subgroup analyses with linkage to clinical pain intensity has been lacking....

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‐rel...

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 (D...

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...

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) stu...

Objective To determine the relationship between brain tissue metabolites measured by in vivo magnetic resonance spectroscopy (¹H-MRS), and glial activation assessed with [¹¹C]-PBR28 uptake in people with amyotrophic lateral sclerosis (ALS). Methods Forty ALS participants were evaluated clinically using the revised ALS functional rating scale (ALSF...

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 anticip...

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 down the progression of the disease. Neuroinflammation is one hallmark of Huntington’s disease and modulation of neuroinflammation...

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 s...