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Traumatic brain injury (TBI) remains one of the most prevalent forms of morbidity among Veterans and Service Members, particularly for those engaged in the conflicts in Iraq and Afghanistan. Neuroimaging has been considered a potentially useful diagnostic and prognostic tool across the spectrum of TBI generally, but may have particular importance in military populations where the diagnosis of mild TBI is particularly challenging, given the frequent lack of documentation on the nature of the injuries and mixed etiologies, and highly comorbid with other disorders such as posttraumatic stress disorder, depression, and substance misuse. Imaging has also been employed in attempts to understand better the potential late effects of trauma and to evaluate the effects of promising therapeutic interventions. This review surveys the use of structural and functional neuroimaging techniques utilized in military studies published to date, including the utilization of quantitative fluid attenuated inversion recovery (FLAIR), susceptibility weighted imaging (SWI), volumetric analysis, diffusion tensor imaging (DTI), magnetization transfer imaging (MTI), positron emission tomography (PET), magnetoencephalography (MEG), task-based and resting state functional MRI (fMRI), arterial spin labeling (ASL), and magnetic resonance spectroscopy (MRS). The importance of quality assurance testing in current and future research is also highlighted. Current challenges and limitations of each technique are outlined, and future directions are discussed.

Manuscript describing study assessing neural correlates of self-reference processing in children (7-12 years of age) at familial high risk for psychosis. ; This work was supported by the National Institute of Mental Health (R21 MH 092840) and the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement No. 749201.

Post-print version of 2018 Molecular Psychiatry paper entitled 'Functional connectome organization predicts conversion to psychosis in clinical high-risk youth from the SHARP program'. Archived after 6-month embargo period, in compliance with Publisher copyright policies & self-archiving (SHERPA / RoMEO). Archive is intended to ensure Green Open Access, in compliance with funding requirements from European Union's Horizon 2020 research and innovation programme.

Manuscript describing study assessing a combined clinical and resting-state fMRI outcome prediction model in a large sample of adolescents and young adults at Clinical High Risk (CHR) for psychosis from the Shanghai At Risk for Psychosis (SHARP) program. ; This work was supported by the United States National Institute of Mental Health (R21 MH 093294, R01 MH 101052, R01 MH 111448, R01 MH 108574, and R01 MH 64023), the Ministry of Science and Technology of China (2016 YFC 1306803), the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement No 749201 (to GC), and VA Merit Awards from the US Department of Veterans Affairs (to MES and RWM).

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease confirmed at post-mortem. Those at highest risk are professional athletes who participate in contact sports and military personnel who are exposed to repetitive blast events. All neuropathologically-confirmed CTE cases, to date, have had a history of repetitive head impacts. This suggests that repetitive head impacts may be necessary for the initiation of the pathogenetic cascade that, in some cases, leads to CTE. Importantly, while all CTE appears to result from repetitive brain trauma, not all repetitive brain trauma results in CTE. Magnetic resonance imaging has great potential for understanding better the underlying mechanisms of repetitive brain trauma. In this review we provide an overview of advanced imaging techniques currently used to investigate brain anomalies. We also provide an overview of neuroimaging findings in those exposed to repetitive head impacts in the acute/subacute and chronic phase of injury and in more neurodegenerative phases of injury, as well as in military personnel exposed to repetitive head impacts. Finally, we discuss future directions for research that will likely lead to a better understanding of the underlying mechanisms separating those who recover from repetitive brain trauma versus those who go on to develop CTE.

Mild Traumatic brain injury (mTBI) is a signature wound in military personnel, and repetitive mTBI has been linked to age‐related neurogenerative disorders that affect white matter (WM) in the brain. However, findings of injury to specific WM tracts have been variable and inconsistent. This may be due to the heterogeneity of mechanisms, etiology, and comorbid disorders related to mTBI. Non‐negative matrix factorization (NMF) is a data‐driven approach that detects covarying patterns (components) within high‐dimensional data. We applied NMF to diffusion imaging data from military Veterans with and without a self‐reported TBI history. NMF identified 12 independent components derived from fractional anisotropy (FA) in a large dataset (n = 1,475) gathered through the ENIGMA (Enhancing Neuroimaging Genetics through Meta‐Analysis) Military Brain Injury working group. Regressions were used to examine TBI‐ and mTBI‐related associations in NMF‐derived components while adjusting for age, sex, post‐traumatic stress disorder, depression, and data acquisition site/scanner. We found significantly stronger age‐dependent effects of lower FA in Veterans with TBI than Veterans without in four components (q < 0.05), which are spatially unconstrained by traditionally defined WM tracts. One component, occupying the most peripheral location, exhibited significantly stronger age‐dependent differences in Veterans with mTBI. We found NMF to be powerful and effective in detecting covarying patterns of FA associated with mTBI by applying standard parametric regression modeling. Our results highlight patterns of WM alteration that are differentially affected by TBI and mTBI in younger compared to older military Veterans.

OBJECTIVE: To develop evidence-informed, expert consensus research diagnostic criteria for traumatic encephalopathy syndrome (TES), the clinical disorder associated with neuropathologically diagnosed chronic traumatic encephalopathy (CTE). METHODS: A panel of 20 expert clinician-scientists in neurology, neuropsychology, psychiatry, neurosurgery, and physical medicine and rehabilitation, from 11 academic institutions, participated in a modified Delphi procedure to achieve consensus, initiated at the First National Institute of Neurological Disorders and Stroke Consensus Workshop to Define the Diagnostic Criteria for TES April, 2019. Before consensus, panelists reviewed evidence from all published cases of CTE with neuropathologic confirmation, and they examined the predictive validity data on clinical features in relation to CTE pathology from a large clinicopathologic study (n = 298). RESULTS: Consensus was achieved in 4 rounds of the Delphi procedure. Diagnosis of TES requires (1) substantial exposure to repetitive head impacts (RHIs) from contact sports, military service, or other causes; (2) core clinical features of cognitive impairment (in episodic memory and/or executive functioning) and/or neurobehavioral dysregulation; (3) a progressive course; and (4) that the clinical features are not fully accounted for by any other neurologic, psychiatric, or medical conditions. For those meeting criteria for TES, functional dependence is graded on 5 levels, ranging from independent to severe dementia. A provisional level of certainty for CTE pathology is determined based on specific RHI exposure thresholds, core clinical features, functional status, and additional supportive features, including delayed onset, motor signs, and psychiatric features. CONCLUSIONS: New consensus diagnostic criteria for TES were developed with a primary goal of facilitating future CTE research. These criteria will be revised as updated clinical and pathologic information and in vivo biomarkers become available.

OBJECTIVE: To develop evidence-informed, expert consensus research diagnostic criteria for traumatic encephalopathy syndrome (TES), the clinical disorder associated with neuropathologically diagnosed chronic traumatic encephalopathy (CTE). METHODS: A panel of 20 expert clinician-scientists in neurology, neuropsychology, psychiatry, neurosurgery, and physical medicine and rehabilitation, from 11 academic institutions, participated in a modified Delphi procedure to achieve consensus, initiated at the First National Institute of Neurological Disorders and Stroke Consensus Workshop to Define the Diagnostic Criteria for TES, April, 2019. Before consensus, panelists reviewed evidence from all published cases of CTE with neuropathologic confirmation, and they examined the predictive validity data on clinical features in relation to CTE pathology from a large clinicopathologic study (n = 298). RESULTS: Consensus was achieved in 4 rounds of the Delphi procedure. Diagnosis of TES requires (1) substantial exposure to repetitive head impacts (RHIs) from contact sports, military service, or other causes; (2) core clinical features of cognitive impairment (in episodic memory and/or executive functioning) and/or neurobehavioral dysregulation; (3) a progressive course; and (4) that the clinical features are not fully accounted for by any other neurologic, psychiatric, or medical conditions. For those meeting criteria for TES, functional dependence is graded on 5 levels, ranging from independent to severe dementia. A provisional level of certainty for CTE pathology is determined based on specific RHI exposure thresholds, core clinical features, functional status, and additional supportive features, including delayed onset, motor signs, and psychiatric features. CONCLUSIONS: New consensus diagnostic criteria for TES were developed with a primary goal of facilitating future CTE research. These criteria will be revised as updated clinical and pathologic information and in vivo biomarkers become available.

Traumatic brain injury (TBI) is common among military personnel and the civilian population and is often followed by a heterogeneous array of clinical, cognitive, behavioral, mood, and neuroimaging changes. Unlike many neurological disorders that have a characteristic abnormal central neurologic area(s) of abnormality pathognomonic to the disorder, a sufficient head impact may cause focal, multifocal, diffuse or combination of injury to the brain. This inconsistent presentation makes it difficult to establish or validate biological and imaging markers that could help improve diagnostic and prognostic accuracy in this patient population. The purpose of this manuscript is to describe both the challenges and opportunities when conducting military-relevant TBI research and introduce the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Military Brain Injury working group. ENIGMA is a worldwide consortium focused on improving replicability and analytical power through data sharing and collaboration. In this paper, we discuss challenges affecting efforts to aggregate data in this patient group. In addition, we highlight how "big data" approaches might be used to understand better the role that each of these variables might play in the imaging and functional phenotypes of TBI in Service member and Veteran populations, and how data may be used to examine important military specific issues such as return to duty, the late effects of combat-related injury, and alteration of the natural aging processes.