Impact of repeated blast exposure on active-duty United States Special Operations Forces.

United States (US) Special Operations Forces (SOF) are frequently exposed to explosive blasts in training and combat, but the effects of repeated blast exposure (RBE) on SOF brain health are incompletely understood. Furthermore, there is no diagnostic test to detect brain injury from RBE. As a result, SOF personnel may experience cognitive, physical, and psychological symptoms for which the cause is never identified, and they may return to training or combat during a period of brain vulnerability. In 30 active-duty US SOF, we assessed the relationship between cumulative blast exposure and cognitive performance, psychological health, physical symptoms, blood proteomics, and neuroimaging measures (Connectome structural and diffusion MRI, 7 Tesla functional MRI, [11C]PBR28 translocator protein [TSPO] positron emission tomography [PET]-MRI, and [18F]MK6240 tau PET-MRI), adjusting for age, combat exposure, and blunt head trauma. Higher blast exposure was associated with increased cortical thickness in the left rostral anterior cingulate cortex (rACC), a finding that remained significant after multiple comparison correction. In uncorrected analyses, higher blast exposure was associated with worse health-related quality of life, decreased functional connectivity in the executive control network, decreased TSPO signal in the right rACC, and increased cortical thickness in the right rACC, right insula, and right medial orbitofrontal cortex-nodes of the executive control, salience, and default mode networks. These observations suggest that the rACC may be susceptible to blast overpressure and that a multimodal, network-based diagnostic approach has the potential to detect brain injury associated with RBE in active-duty SOF.

PET-MRI Applications and Future Prospects in Psychiatry.

This article reviews the synergistic application of positron emission tomography-magnetic resonance imaging (PET-MRI) in neuroscience with relevance for psychiatry, particularly examining neurotransmission, epigenetics, and dynamic imaging methodologies. We begin by discussing the complementary insights that PET and MRI modalities provide into neuroreceptor systems, with a focus on dopamine, opioids, and serotonin receptors, and their implications for understanding and treating psychiatric disorders. We further highlight recent PET-MRI studies using a radioligand that enables the quantification of epigenetic enzymes, specifically histone deacetylases, in the brain in vivo. Imaging epigenetics is used to exemplify the impact the quantification of novel molecular targets may have, including new treatment approaches for psychiatric disorders. Finally, we discuss innovative designs involving functional PET using [18F]FDG (fPET-FDG), which provides detailed information regarding dynamic changes in glucose metabolism. Concurrent acquisitions of fPET-FDG and functional MRI provide a time-resolved approach to studying brain function, yielding simultaneous metabolic and hemodynamic information and thereby opening new avenues for psychiatric research. Collectively, the review underscores the potential of a multimodal PET-MRI approach to advance our understanding of brain structure and function in health and disease, which could improve clinical care based on objective neurobiological features and treatment response monitoring. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 1.

The pandemic brain: Neuroinflammation in non-infected individuals during the COVID-19 pandemic.

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

Extra-Axial Inflammatory Signal in Parameninges in Migraine with Visual Aura.

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

Developmental trajectories of neuroanatomical alterations associated with the 16p11.2 Copy Number Variations.

Most of human genome is present in two copies (maternal and paternal). However, segments of the genome can be deleted or duplicated, and many of these genomic variations (known as Copy Number Variants) are associated with psychiatric disorders. 16p11.2 copy number variants (breakpoint 4-5) confer high risk for neurodevelopmental disorders and are associated with structural brain alterations of large effect-size. Methods used in previous studies were unable to investigate the onset of these alterations and whether they evolve with age. In this study, we aim at characterizing age-related effects of 16p11.2 copy number variants by analyzing a group with a broad age range including younger individuals. A large normative developmental dataset was used to accurately adjust for effects of age. We normalized volumes of segmented brain regions as well as volumes of each voxel defined by tensor-based morphometry. Results show that the total intracranial volumes, the global gray and white matter volumes are respectively higher and lower in deletion and duplication carriers compared to control subjects at 4.5 years of age. These differences remain stable through childhood, adolescence and adulthood until 23 years of age (range: 0.5 to 1.0 Z-score). Voxel-based results are consistent with previous findings in 16p11.2 copy number variant carriers, including increased volume in the calcarine cortex and insula in deletions, compared to controls, with an inverse effect in duplication carriers (1.0 Z-score). All large effect-size voxel-based differences are present at 4.5 years and seem to remain stable until the age of 23. Our results highlight the stability of a neuroimaging endophenotype over 2 decades during which neurodevelopmental symptoms evolve at a rapid pace.

Integrated magnetic resonance imaging and [11 C]-PBR28 positron emission tomographic imaging in amyotrophic lateral sclerosis.

OBJECTIVE: To characterize [11 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 [11 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 [11 C]-PBR28 uptake in a larger cohort of patients with ALS and PLS. METHODS: Eighty-five participants including 53 with ALS, 11 with PLS, and 21 healthy controls underwent integrated [11 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). [11 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. [11 C]-PBR28 uptake and ALSFRS-R were compared longitudinally over 6 months in 10 ALS individuals. RESULTS: Whole brain voxelwise, surface-based, and region of interest analyses revealed increased [11 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 [11 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 [11 C]-PBR28 uptake over 6 months despite clinical progression. INTERPRETATION: Glial activation measured by in vivo [11 C]-PBR28 PET is increased in pathologically relevant regions in people with ALS and correlates with clinical measures. Ann Neurol 2018;83:1186-1197.

Pupillary Contagion in Autism.

Pupillary contagion is an involuntary change in the observer's pupil size in response to the pupil size of another person. This effect, presumed to be an important adaption for individuals living in groups, has been documented in both typical infants and adults. Here, for the first time, we report pupillary contagion in individuals with autism, a disorder of social communication. We found that, compared with a typical group ( n = 63), individuals with autism ( n = 54) exhibited comparable pupillary contagion when observing pictures of emotional faces, despite less spontaneous attention toward the eye region. Furthermore, the magnitude of the pupillary response in the autism group was negatively correlated with time spent fixating the eye region. The results suggest that even with less looking toward the eyes, individuals with autism respond to the affective and arousal levels transmitted from other individuals. These results are discussed in the context of an overarousal account of socioaffective-processing differences in autism.

Class I and II histone deacetylase expression is not altered in human amyotrophic lateral sclerosis: Neuropathological and positron emission tomography molecular neuroimaging evidence.

INTRODUCTION: There is an unmet need for mechanism-based biomarkers and effective disease modifying treatments in amyotrophic lateral sclerosis (ALS). Previous findings have provided evidence that histone deacetylases (HDAC) are altered in ALS, providing a rationale for testing HDAC inhibitors as a therapeutic option. METHODS: We measured class I and II HDAC protein and transcript levels together with acetylation levels of downstream substrates by using Western blotting in postmortem tissue of ALS and controls. [11 C]Martinostat, a novel HDAC positron emission tomography ligand, was also used to assess in vivo brain HDAC alterations in patients with ALS and healthy controls (HC). RESULTS: There was no significant difference in HDAC levels between patients with ALS and controls as measured by Western blotting and reverse-transcription quantitative polymerase chain reaction. Similarly, no differences were detected in [11 C]Martinostat-positron emission tomography uptake in ALS participants compared with HCs. DISCUSSION: These findings provide evidence that alterations in HDAC isoforms are not a dominant pathological feature at the bulk tissue level in ALS.

A pilot trial of RNS60 in amyotrophic lateral sclerosis.

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. METHODS: 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. RESULTS: 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. DISCUSSION: 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.

Effect of visual stimuli of pain on empathy brain network in people with and without Autism Spectrum Disorder.

The extent to which affective empathy is impaired in Autism Spectrum Disorder (ASD) remains unclear, as some-but not all-previous neuroimaging studies investigating empathy for pain in ASD have shown similar activation levels to those of neurotypicals individuals. These inconsistent results could be due to the use of different empathy-eliciting stimuli. While some studies used pictures of faces exhibiting a painful expression, others used pictures of limbs in painful situations. In this study, we used fMRI to compare activation in areas associated with empathy processing (empathy network) for these two types of stimuli in 31 participants (16 with ASD, 15 controls). We found a group difference in the inferior frontal gyrus (IFG) and the thalamus when participants viewed stimuli of limbs in painful situations, but not when they viewed face stimuli with a painful expression. Both groups of participants activated their empathy network more when viewing pictures of limbs in painful situations than when viewing pictures of faces with a painful expression; this increased activation for limbs versus faces was significantly enhanced in controls relative to ASD participants, especially in the secondary somatosensory cortex (SII). Our findings suggest that empathy defect of people with ASD is contingent upon the type of stimuli used, and may be related to the level of Mirror Neuron System involvement, as brain regions showing group differences (IFG, SII) underlie embodiment. We discuss the potential clinical implications of our findings in terms of developing interventions boosting the empathetic abilities of people with ASD.

Hypersensitivity to low intensity fearful faces in autism when fixation is constrained to the eyes.

Previous studies that showed decreased brain activation in people with autism spectrum disorder (ASD) viewing expressive faces did not control that participants looked in the eyes. This is problematic because ASD is characterized by abnormal attention to the eyes. Here, we collected fMRI data from 48 participants (27 ASD) viewing pictures of neutral faces and faces expressing anger, happiness, and fear at low and high intensity, with a fixation cross between the eyes. Group differences in whole brain activity were examined for expressive faces at high and low intensity versus neutral faces. Group differences in neural activity were also investigated in regions of interest within the social brain, including the amygdala and the ventromedial prefrontal cortex (vmPFC). In response to low intensity fearful faces, ASD participants showed increased activation in the social brain regions, and decreased functional coupling between the amygdala and the vmPFC. This oversensitivity to low intensity fear coupled with a lack of emotional regulation capacity could indicate an excitatory/inhibitory imbalance in their socio-affective processing system. This may result in social disengagement and avoidance of eye-contact to handle feelings of strong emotional reaction. Our results also demonstrate the importance of careful control of gaze when investigating emotional processing in ASD. Hum Brain Mapp 38:5943-5957, 2017. © 2017 Wiley Periodicals, Inc.

Evidence for brain glial activation in chronic pain patients.

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.

Dynamic functional imaging of brain glucose utilization using fPET-FDG.

Glucose is the principal source of energy for the brain and yet the dynamic response of glucose utilization to changes in brain activity is still not fully understood. Positron emission tomography (PET) allows quantitative measurement of glucose metabolism using 2-[(18)F]-fluorodeoxyglucose (FDG). However, FDG PET in its current form provides an integral (or average) of glucose consumption over tens of minutes and lacks the temporal information to capture physiological alterations associated with changes in brain activity induced by tasks or drug challenges. Traditionally, changes in glucose utilization are inferred by comparing two separate scans, which significantly limits the utility of the method. We report a novel method to track changes in FDG metabolism dynamically, with higher temporal resolution than exists to date and within a single session. Using a constant infusion of FDG, we demonstrate that our technique (termed fPET-FDG) can be used in an analysis pipeline similar to fMRI to define within-session differential metabolic responses. We use visual stimulation to demonstrate the feasibility of this method. This new method has a great potential to be used in research protocols and clinical settings since fPET-FDG imaging can be performed with most PET scanners and data acquisition and analysis are straightforward. fPET-FDG is a highly complementary technique to MRI and provides a rich new way to observe functional changes in brain metabolism.

In vivo translocator protein in females with autism spectrum disorder: a pilot study.

Sex-based differences in the prevalence of autism spectrum disorder (ASD) are well-documented, with a male-to-female ratio of approximately 4:1. The clinical presentation of the core symptoms of ASD can also vary between sexes. Previously, positron emission tomography (PET) studies have identified alterations in the in vivo levels of translocator protein (TSPO)-a mitochondrial protein-in primarily or only male adults with ASD, with our group reporting lower TSPO relative to whole brain mean in males with ASD. However, whether in vivo TSPO levels are altered in females with ASD, specifically, is unknown. This is the first pilot study to measure in vivo TSPO in the brain in adult females with ASD using [11C]PBR28 PET-magnetic resonance imaging (MRI). Twelve adult females with ASD and 10 age- and TSPO genotype-matched controls (CON) completed one or two [11C]PBR28 PET-MRI scans. Females with ASD exhibited elevated [11C]PBR28 standardized uptake value ratio (SUVR) in the midcingulate cortex and splenium of the corpus callosum compared to CON. No brain area showed lower [11C]PBR28 SUVR in females with ASD compared to CON. Test-retest over several months showed stable [11C]PBR28 SUVR across time in both groups. Elevated regional [11C]PBR28 SUVR in females with ASD stand in stark contrast to our previous findings of lower regional [11C]PBR28 SUVR in males with ASD. Preliminary evidence of regionally elevated mitochondrial protein TSPO relative to whole brain mean in ASD females may reflect neuroimmuno-metabolic alterations specific to females with ASD.

Neuroimaging research in Williams syndrome: Beginning to bridge the gap with clinical care.

Williams syndrome (WS) is a genetic disorder affecting multiple organ systems. Cardinal features include cardiovascular disease, distinct facies, and a unique cognitive profile characterized by intellectual disability, hypersociability, and visuospatial weaknesses. Here, we synthesize neuroimaging research in WS with a focus on how the current literature and future work may be leveraged to improve health and quality of life in WS. More than 80 neuroimaging studies in WS have been conducted, the vast majority of which have focused on identifying morphometric brain differences. Aside from decreased volume of the parieto-occipital region and increased cerebellar volume, morphometric findings have been variable across studies. fMRI studies investigating the visuospatial deficit have identified dorsal stream dysfunction and abnormal activation of the hippocampal formation. Minimal work has been done using PET or MRS. Future approaches that conduct neuroimaging in tandem with clinical phenotyping, utilize novel imaging techniques to visualize brain vasculature or provide biochemical and molecular information, and include more homogenous age groups across the lifespan, have significant potential to advance clinical care.

Striatal dopamine in anhedonia: A simultaneous [11C]raclopride positron emission tomography and functional magnetic resonance imaging investigation.

BACKGROUND: Anhedonia is hypothesized to be associated with blunted mesocorticolimbic dopamine (DA) functioning in samples with major depressive disorder. The purpose of this study was to examine linkages between striatal DA, reward circuitry functioning, anhedonia, and, in an exploratory fashion, self-reported stress, in a transdiagnostic anhedonic sample. METHODS: Participants with (n = 25) and without (n = 12) clinically impairing anhedonia completed a reward-processing task during simultaneous positron emission tomography and magnetic resonance (PET-MR) imaging with [11C]raclopride, a DA D2/D3 receptor antagonist that selectively binds to striatal DA receptors. RESULTS: Relative to controls, the anhedonia group exhibited decreased task-related DA release in the left putamen, caudate, and nucleus accumbens and right putamen and pallidum. There were no group differences in task-related brain activation (fMRI) during reward processing after correcting for multiple comparisons. General functional connectivity (GFC) findings revealed blunted fMRI connectivity between PET-derived striatal seeds and target regions in the anhedonia group. Associations were identified between anhedonia severity and the magnitude of task-related DA release to rewards in the left putamen, but not mesocorticolimbic GFC. CONCLUSIONS: Results provide evidence for reduced striatal DA functioning during reward processing and blunted mesocorticolimbic network functional connectivity in a transdiagnostic sample with clinically significant anhedonia.

Optimizing Brain Health of United States Special Operations Forces.

United States Special Operations Forces (SOF) personnel are frequently exposed to explosive blasts in training and combat. However, the effects of repeated blast exposure on the human brain are incompletely understood. Moreover, there is currently no diagnostic test to detect repeated blast brain injury (rBBI). In this "Human Performance Optimization" article, we discuss how the development and implementation of a reliable diagnostic test for rBBI has the potential to promote SOF brain health, combat readiness, and quality of life.

A 7 tesla FMRI study of amygdala responses to fearful faces.

The amygdalae are involved in the perception of emotions such as happiness, anger and fear. Because of their proximity to the sinuses, the image signal intensity in T2* weighted fMRI data is often affected by signal loss due to through-slice dephasing, especially at high field strength. In this study, the feasibility of fMRI in the amygdalae at 7 Tesla was investigated. A paradigm based on the presentation of fearful faces was used for stimulation. Previously, opposite effects have been found for presentation of averted and direct gaze fearful faces. Here, we show that (1) sufficiently high temporal SNR values are reached in the amygdalae for detection of small BOLD signal changes and (2) that the BOLD signal in the amygdalae for presentation of a direct or averted gaze in a fearful face depends on stimulus duration.

Epigenetics of Autism Spectrum Disorder: Histone Deacetylases.

The etiology of autism spectrum disorder (ASD) remains unknown, but gene-environment interactions, mediated through epigenetic mechanisms, are thought to be a key contributing factor. Prenatal environmental factors have been shown to be associated with both increased risk of ASD and altered histone deacetylases (HDACs) or acetylation levels. The relationship between epigenetic changes and gene expression in ASD suggests that alterations in histone acetylation, which lead to changes in gene transcription, may play a key role in ASD. Alterations in the acetylome have been demonstrated for several genes in ASD, including genes involved in synaptic function, neuronal excitability, and immune responses, which are mechanisms previously implicated in ASD. We review preclinical and clinical studies that investigated HDACs and autism-associated behaviors and discuss risk genes for ASD that code for proteins associated with HDACs. HDACs are also implicated in neurodevelopmental disorders with a known genetic etiology, such as 15q11-q13 duplication and Phelan-McDermid syndrome, which share clinical features and diagnostic comorbidities (e.g., epilepsy, anxiety, and intellectual disability) with ASD. Furthermore, we highlight factors that affect the behavioral phenotype of acetylome changes, including sensitive developmental periods and brain region specificity in the context of epigenetic programming.

Long-Term Effects of Repeated Blast Exposure in United States Special Operations Forces Personnel: A Pilot Study Protocol.

Emerging evidence suggests that repeated blast exposure (RBE) is associated with brain injury in military personnel. United States (U.S.) Special Operations Forces (SOF) personnel experience high rates of blast exposure during training and combat, but the effects of low-level RBE on brain structure and function in SOF have not been comprehensively characterized. Further, the pathophysiological link between RBE-related brain injuries and cognitive, behavioral, and physical symptoms has not been fully elucidated. We present a protocol for an observational pilot study, Long-Term Effects of Repeated Blast Exposure in U.S. SOF Personnel (ReBlast). In this exploratory study, 30 active-duty SOF personnel with RBE will participate in a comprehensive evaluation of: 1) brain network structure and function using Connectome magnetic resonance imaging (MRI) and 7 Tesla MRI; 2) neuroinflammation and tau deposition using positron emission tomography; 3) blood proteomics and metabolomics; 4) behavioral and physical symptoms using self-report measures; and 5) cognition using a battery of conventional and digitized assessments designed to detect subtle deficits in otherwise high-performing individuals. We will identify clinical, neuroimaging, and blood-based phenotypes that are associated with level of RBE, as measured by the Generalized Blast Exposure Value. Candidate biomarkers of RBE-related brain injury will inform the design of a subsequent study that will test a diagnostic assessment battery for detecting RBE-related brain injury. Ultimately, we anticipate that the ReBlast study will facilitate the development of interventions to optimize the brain health, quality of life, and battle readiness of U.S. SOF personnel.