Spatiotemporal profile of atrophy in the first year following moderate-severe traumatic brain injury.

Traumatic brain injury (TBI) triggers progressive neurodegeneration resulting in brain atrophy that continues months-to-years following injury. However, a comprehensive characterization of the spatial and temporal evolution of TBI-related brain atrophy remains incomplete. Utilizing a sensitive and unbiased morphometry analysis pipeline optimized for detecting longitudinal changes, we analyzed a sample consisting of 37 individuals with moderate-severe TBI who had primarily high-velocity and high-impact injury mechanisms. They were scanned up to three times during the first year after injury (3 months, 6 months, and 12 months post-injury) and compared with 33 demographically matched controls who were scanned once. Individuals with TBI already showed cortical thinning in frontal and temporal regions and reduced volume in the bilateral thalami at 3 months post-injury. Longitudinally, only a subset of cortical regions in the parietal and occipital lobes showed continued atrophy from 3 to 12 months post-injury. Additionally, cortical white matter volume and nearly all deep gray matter structures exhibited progressive atrophy over this period. Finally, we found that disproportionate atrophy of cortex along sulci relative to gyri, an emerging morphometric marker of chronic TBI, was present as early as 3 month post-injury. In parallel, neurocognitive functioning largely recovered during this period despite this pervasive atrophy. Our findings demonstrate msTBI results in characteristic progressive neurodegeneration patterns that are divergent across regions and scale with the severity of injury. Future clinical research using atrophy during the first year of TBI as a biomarker of neurodegeneration should consider the spatiotemporal profile of atrophy described in this study.

Temporal dynamics of cerebral blood flow during the first year after moderate-severe traumatic brain injury: A longitudinal perfusion MRI study.

Traumatic brain injury (TBI) is associated with alterations in cerebral blood flow (CBF), which may underlie functional disability and precipitate TBI-induced neurodegeneration. Although it is known that chronic moderate-severe TBI (msTBI) causes decreases in CBF, the temporal dynamics during the early chronic phase of TBI remain unknown. Using arterial spin labeled (ASL) perfusion magnetic resonance imaging (MRI), we examined longitudinal CBF changes in 29 patients with msTBI at 3, 6, and 12 months post-injury in comparison to 35 demographically-matched healthy controls (HC). We investigated the difference between the two groups and the within-subject time effect in the TBI patients using whole-brain voxel-wise analysis. Mean CBF in gray matter (GM) was lower in the TBI group compared to HC at 6 and 12 months post-injury. Within the TBI group, we identified widespread regional decreases in CBF from 3 to 6 months post-injury. In contrast, there were no regions with decreasing CBF from 6 to 12 months post-injury, indicating stabilization of hypoperfusion. There was instead a small area of increase in CBF observed in the right precuneus. These CBF changes were not accompanied by cortical atrophy. The change in CBF was correlated with change in executive function from 3 to 6 months post-injury in TBI patients, suggesting functional relevance of CBF measures. Understanding the time course of TBI-induced hypoperfusion and its relationship with cognitive improvement could provide an optimal treatment window to benefit long-term outcome.

Dynamic contrast enhanced MRI for characterization of blood-brain-barrier dysfunction after traumatic brain injury.

BACKGROUND AND PURPOSE: Dysfunction of the blood-brain-barrier (BBB) is a recognized pathological consequence of traumatic brain injury (TBI) which may play an important role in chronic TBI pathophysiology. We hypothesized that BBB disruption can be detected with dynamic contrast-enhanced (DCE) MRI not only in association with focal traumatic lesions but also in normal-appearing brain tissue of TBI patients, reflecting microscopic microvascular injury. We further hypothesized that BBB integrity would improve but not completely normalize months after TBI. MATERIALS AND METHODS: DCE MRI was performed in 40 adult patients a median of 23 days after hospitalized TBI and in 21 healthy controls. DCE data was analyzed using Patlak and linear models, and derived metrics of BBB leakage including the volume transfer constant (Ktrans) and the normalized permeability index (NPI) were compared between groups. BBB metrics were compared with focal lesion distribution as well as with contemporaneous measures of symptomatology and cognitive function in TBI patients. Finally, BBB metrics were examined longitudinally among 18 TBI patients who returned for a second MRI a median of 204 days postinjury. RESULTS: TBI patients exhibited higher mean Ktrans (p = 0.0028) and proportion of suprathreshold NPI voxels (p = 0.001) relative to controls. Tissue-based analysis confirmed greatest TBI-related BBB disruption in association with focal lesions, however elevated Ktrans was also observed in perilesional (p = 0.011) and nonlesional (p = 0.044) regions. BBB disruption showed inverse correlation with quality of life (rho = -0.51, corrected p = 0.016). Among the subset of TBI patients who underwent a second MRI several months after the initial evaluation, metrics of BBB disruption did not differ significantly at the group level, though variable longitudinal changes were observed at the individual subject level. CONCLUSIONS: This pilot investigation suggests that TBI-related BBB disruption is detectable in the early post-injury period in association with focal and diffuse brain injury.

Connectomic assessment of injury burden and longitudinal structural network alterations in moderate-to-severe traumatic brain injury.

Traumatic brain injury (TBI) is a major public health problem. Caused by external mechanical forces, a major characteristic of TBI is the shearing of axons across the white matter, which causes structural connectivity disruptions between brain regions. This diffuse injury leads to cognitive deficits, frequently requiring rehabilitation. Heterogeneity is another characteristic of TBI as severity and cognitive sequelae of the disease have a wide variation across patients, posing a big challenge for treatment. Thus, measures assessing network-wide structural connectivity disruptions in TBI are necessary to quantify injury burden of individuals, which would help in achieving personalized treatment, patient monitoring, and rehabilitation planning. Despite TBI being a disconnectivity syndrome, connectomic assessment of structural disconnectivity has been relatively limited. In this study, we propose a novel connectomic measure that we call network normality score (NNS) to capture the integrity of structural connectivity in TBI patients by leveraging two major characteristics of the disease: diffuseness of axonal injury and heterogeneity of the disease. Over a longitudinal cohort of moderate-to-severe TBI patients, we demonstrate that structural network topology of patients is more heterogeneous and significantly different than that of healthy controls at 3 months postinjury, where dissimilarity further increases up to 12 months. We also show that NNS captures injury burden as quantified by posttraumatic amnesia and that alterations in the structural brain network is not related to cognitive recovery. Finally, we compare NNS to major graph theory measures used in TBI literature and demonstrate the superiority of NNS in characterizing the disease.

Arterial Spin Labeling Reveals Elevated Cerebral Blood Flow with Distinct Clusters of Hypo- and Hyperperfusion after Traumatic Brain Injury.

Imaging detection of brain perfusion alterations after traumatic brain injury (TBI) may provide prognostic insights. In this study, we used arterial spin labeling (ASL) to quantify cross-sectional and longitudinal changes in cerebral blood flow (CBF) after TBI and correlated changes with clinical outcome. We analyzed magnetic resonance imaging scans from adult participants with TBI requiring hospitalization in the acute (2 weeks post-injury, n = 33) and chronic (6 months post-injury, n = 16) phases, with 13 participants scanned longitudinally at both time points. We also analyzed 18 age- and sex-matched healthy controls. Whole-brain CBF maps were derived using a three-dimensional pseudo-continuous arterial spin label technique. Mean CBF across tissue-based regions (whole brain, gray matter, and white matter) was compared cross-sectionally and longitudinally. In addition, individual-level clusters of abnormal perfusion were identified using voxel-based z-score analysis of relative CBF maps, and number and volume of abnormally hypo- and hyperperfused clusters were assessed cross-sectionally and longitudinally. Finally, all CBF measures were correlated with clinical outcome measures. Mean global and gray matter CBF were significantly elevated in acute and chronic TBI participants compared to controls. Participants with better outcome at 6 months post-injury tended to have higher CBF in the acute phase compared to those with poorer outcome. Acute TBI participants had a significantly greater volume of hypo- and hyperperfused brain tissue compared to controls, with these regions partially normalizing by the chronic phase. Our findings demonstrate global elevation of CBF with focal hypo- and hyperperfusion in the early post-injury period and suggest a reparative role for acute elevation in CBF post-TBI.

Free Water Volume Fraction: An Imaging Biomarker to Characterize Moderate-to-Severe Traumatic Brain Injury.

Traumatic brain injury (TBI) is a major clinical and public health problem with few therapeutic interventions successfully translated to the clinic. Identifying imaging-based biomarkers characterizing injury severity and predicting long-term functional and cognitive outcomes in TBI patients is crucial for treatment. TBI results in white matter (WM) injuries, which can be detected using diffusion tensor imaging (DTI). Trauma-induced pathologies lead to accumulation of free water (FW) in brain tissue, and standard DTI is susceptible to the confounding effects of FW. In this study, we applied FW DTI to estimate free water volume fraction (FW-VF) in patients with moderate-to-severe TBI and demonstrated its association with injury severity and long-term outcomes. DTI scans and neuropsychological assessments were obtained longitudinally at 3, 6, and 12 months post-injury for 34 patients and once in 35 matched healthy controls. We observed significantly elevated FW-VF in 85 of 90 WM regions in patients compared to healthy controls (p < 0.05). We then presented a patient-specific summary score of WM regions derived using Mahalanobis distance. We observed that MVF at 3 months significantly predicted functional outcome (p = 0.008), executive function (p = 0.005), and processing speed (p = 0.01) measured at 12 months and was significantly correlated with injury severity (p < 0.001). Our findings are an important step toward implementing MVF as a biomarker for personalized therapy and rehabilitation planning for TBI patients.

Two nights of recovery sleep restores hippocampal connectivity but not episodic memory after total sleep deprivation.

Sleep deprivation significantly impairs a range of cognitive and brain function, particularly episodic memory and the underlying hippocampal function. However, it remains controversial whether one or two nights of recovery sleep following sleep deprivation fully restores brain and cognitive function. In this study, we used functional magnetic resonance imaging (fMRI) and examined the effects of two consecutive nights (20-hour time-in-bed) of recovery sleep on resting-state hippocampal connectivity and episodic memory deficits following one night of total sleep deprivation (TSD) in 39 healthy adults in a controlled in-laboratory protocol. TSD significantly reduced memory performance in a scene recognition task, impaired hippocampal connectivity to multiple prefrontal and default mode network regions, and disrupted the relationships between memory performance and hippocampal connectivity. Following TSD, two nights of recovery sleep restored hippocampal connectivity to baseline levels, but did not fully restore memory performance nor its associations with hippocampal connectivity. These findings suggest that more than two nights of recovery sleep are needed to fully restore memory function and hippocampal-memory associations after one night of total sleep loss.

Relationship of Cerebral Blood Flow to Cognitive Function and Recovery in Early Chronic Traumatic Brain Injury.

Traumatic brain injury (TBI) is a leading cause of morbidity worldwide, for which biomarkers are needed to better understand the underlying pathophysiology. Microvascular injury represents a subset of pathological mechanisms contributing to cognitive dysfunction after TBI, which may also impair subsequent neural repair thereby inhibiting cognitive recovery. Magnetic resonance imaging (MRI)-based measurement of cerebral blood flow (CBF) by arterial spin labeling (ASL) provides an appealing means of assessing microvascular disruption in TBI; however, the relationship between CBF alterations in the early chronic post-TBI setting and cognitive dysfunction as well as subsequent cognitive recovery remain poorly understood. Structural MRI and ASL were performed in 42 TBI subjects 3 months post-injury and 35 matched healthy controls. Neuropsychological testing was performed in each subject, as well as in a subset of TBI patients (n = 33) at 6 and/or 12 months post-injury. TBI and control subject CBF data were compared between groups in a voxel-wise fashion while controlling for the effects of structural atrophy. A region-of-interest approach was then used to compare CBF to clinical and neuropsychological measures within the TBI group in a cross-sectional fashion, as well as to the degree of subsequent cognitive recovery among subjects with follow-up testing. At 3 months post-injury, the TBI group demonstrated lower performance in each cognitive domain (p < 0.05), as well as widespread reductions in gray matter CBF independent of structural atrophy (p < 0.05). Within the TBI group, CBF was moderately correlated with injury severity (r = -0.43; p = 0.009) and executive function (r = 0.43; p = 0.01). In the longitudinal analysis, there was a positive correlation between initial CBF and processing speed recovery (r = 0.43; p = 0.015) independent of age, education level, and initial test score. Early chronic TBI is associated with widespread gray matter CBF deficits, which are correlated with injury severity and cognitive dysfunction. CBF may predict subsequent recovery in some cognitive domains.

Test-retest reliability of brain responses to risk-taking during the balloon analogue risk task.

The Balloon Analogue Risk Task (BART) provides a reliable and ecologically valid model for the assessment of individual risk-taking propensity and is frequently used in neuroimaging and developmental research. Although the test-retest reliability of risk-taking behavior during the BART is well established, the reliability of brain activation patterns in response to risk-taking during the BART remains elusive. In this study, we used functional magnetic resonance imaging (fMRI) and evaluated the test-retest reliability of brain responses in 34 healthy adults during a modified BART by calculating the intraclass correlation coefficients (ICC) and Dice's similarity coefficients (DSC). Analyses revealed that risk-induced brain activation patterns showed good test-retest reliability (median ICC â€‹= â€‹0.62) and moderate to high spatial consistency, while brain activation patterns associated with win or loss outcomes only had poor to fair reliability (median ICC â€‹= â€‹0.33 for win and 0.42 for loss). These findings have important implications for future utility of the BART in fMRI to examine brain responses to risk-taking and decision-making.

Neuroimaging Findings in US Government Personnel With Possible Exposure to Directional Phenomena in Havana, Cuba.

IMPORTANCE: United States government personnel experienced potential exposures to uncharacterized directional phenomena while serving in Havana, Cuba, from late 2016 through May 2018. The underlying neuroanatomical findings have not been described. OBJECTIVE: To examine potential differences in brain tissue volume, microstructure, and functional connectivity in government personnel compared with individuals not exposed to directional phenomena. DESIGN, SETTING, AND PARTICIPANTS: Forty government personnel (patients) who were potentially exposed and experienced neurological symptoms underwent evaluation at a US academic medical center from August 21, 2017, to June 8, 2018, including advanced structural and functional magnetic resonance imaging analytics. Findings were compared with imaging findings of 48 demographically similar healthy controls. EXPOSURES: Potential exposure to uncharacterized directional phenomena of unknown etiology, manifesting as pressure, vibration, or sound. MAIN OUTCOMES AND MEASURES: Potential imaging-based differences between patients and controls with regard to (1) white matter and gray matter total and regional brain volumes, (2) cerebellar tissue microstructure metrics (eg, mean diffusivity), and (3) functional connectivity in the visuospatial, auditory, and executive control subnetworks. RESULTS: Imaging studies were completed for 40 patients (mean age, 40.4 years; 23 [57.5%] men; imaging performed a median of 188 [range, 4-403] days after initial exposure) and 48 controls (mean age, 37.6 years; 33 [68.8%] men). Mean whole brain white matter volume was significantly smaller in patients compared with controls (patients: 542.22 cm3; controls: 569.61 cm3; difference, -27.39 [95% CI, -37.93 to -16.84] cm3; P < .001), with no significant difference in the whole brain gray matter volume (patients: 698.55 cm3; controls: 691.83 cm3; difference, 6.72 [95% CI, -4.83 to 18.27] cm3; P = .25). Among patients compared with controls, there were significantly greater ventral diencephalon and cerebellar gray matter volumes and significantly smaller frontal, occipital, and parietal lobe white matter volumes; significantly lower mean diffusivity in the inferior vermis of the cerebellum (patients: 7.71 × 10-4 mm2/s; controls: 8.98 × 10-4 mm2/s; difference, -1.27 × 10-4 [95% CI, -1.93 × 10-4 to -6.17 × 10-5] mm2/s; P < .001); and significantly lower mean functional connectivity in the auditory subnetwork (patients: 0.45; controls: 0.61; difference, -0.16 [95% CI, -0.26 to -0.05]; P = .003) and visuospatial subnetwork (patients: 0.30; controls: 0.40; difference, -0.10 [95% CI, -0.16 to -0.04]; P = .002) but not in the executive control subnetwork (patients: 0.24; controls: 0.25; difference: -0.016 [95% CI, -0.04 to 0.01]; P = .23). CONCLUSIONS AND RELEVANCE: Among US government personnel in Havana, Cuba, with potential exposure to directional phenomena, compared with healthy controls, advanced brain magnetic resonance imaging revealed significant differences in whole brain white matter volume, regional gray and white matter volumes, cerebellar tissue microstructural integrity, and functional connectivity in the auditory and visuospatial subnetworks but not in the executive control subnetwork. The clinical importance of these differences is uncertain and may require further study.

Myelin water imaging of moderate to severe diffuse traumatic brain injury.

Traumatic axonal injury (TAI), a signature injury of traumatic brain injury (TBI), is increasingly known to involve myelin damage. The objective of this study was to demonstrate the clinical relevance of myelin water imaging (MWI) by first quantifying changes in myelin water after TAI and then correlating those changes with measures of injury severity and neurocognitive performance. Scanning was performed at 3 months post-injury in 22 adults with moderate to severe diffuse TBI and 30 demographically matched healthy controls using direct visualization of short transverse component (ViSTa) MWI. Fractional anisotropy (FA) and radial diffusivity (RD) were also obtained using diffusion tensor imaging. Duration of post-traumatic amnesia (PTA) and cognitive processing speed measured by the Processing Speed Index (PSI) from Wechsler Adult Intelligence Scale-IV, were assessed. A between-group comparison using Tract-Based Spatial Statistics revealed that there was a widespread reduction of apparent myelin water fraction (aMWF) in TBI, consistent with neuropathology involving TAI. The group difference map of aMWF yielded topography that was different from FA and RD. Importantly, aMWF demonstrated significant associations with PTA (r = -0.564, p = .006) and PSI (r = 0.452, p = .035). In conclusion, reduced myelin water, quantified by ViSTa MWI, is prevalent in moderate-to-severe diffuse TBI and could serve as a potential biomarker for injury severity and prediction of clinical outcomes.