White Matter Alterations in Military Service Members With Remote Mild Traumatic Brain Injury.

Importance: Mild traumatic brain injury (mTBI) is the signature injury experienced by military service members and is associated with poor neuropsychiatric outcomes. Yet, there is a lack of reliable clinical tools for mTBI diagnosis and prognosis. Objective: To examine the white matter microstructure and neuropsychiatric outcomes of service members with a remote history of mTBI (ie, mTBI that occurred over 2 years ago) using diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI). Design, Setting, and Participants: This case-control study examined 98 male service members enrolled in a study at the National Intrepid Center of Excellence. Eligible participants were active duty status or able to enroll in the Defense Enrollment Eligibility Reporting system, ages 18 to 60 years, and had a remote history of mTBI; controls were matched by age. Exposures: Remote history of mTBI. Main Outcomes and Measures: White matter microstructure was assessed using a region-of-interest approach of skeletonized diffusion images, including DTI (fractional anisotropy, mean diffusivity, radial diffusivity and axial diffusivity) and NODDI (orientation dispersion index [ODI], isotropic volume fraction, intra-cellular volume fraction). Neuropsychiatric outcomes associated with posttraumatic stress disorder (PTSD) and postconcussion syndrome were assessed. Results: A total of 65 male patients with a remote history of mTBI (mean [SD] age, 40.5 [5.0] years) and 33 age-matched male controls (mean [SD] age, 38.9 [5.6] years) were included in analysis. Compared with the control cohort, the 65 service members with mTBI presented with significantly more severe PTSD-like symptoms (mean [SD] PTSD CheckList-Civilian [PCL-C] version scores: control, 19.0 [3.8] vs mTBI, 41.2 [11.6]; P < .001). DTI and NODDI metrics were altered in the mTBI group compared with the control, including intra-cellular volume fraction of the right cortico-spinal tract (ß = -0.029, Cohen d = 0.66; P < .001), ODI of the left posterior thalamic radiation (ß = -0.006, Cohen d = 0.55; P < .001), and ODI of the left uncinate fasciculus (ß = 0.013, Cohen d = 0.61; P < .001). In service members with mTBI, fractional anisotropy of the left uncinate fasciculus was associated with postconcussion syndrome (ß = 5.4 × 10-3; P = .003), isotropic volume fraction of the genu of the corpus callosum with PCL-C (ß = 4.3 × 10-4; P = .01), and ODI of the left fornix and stria terminalis with PCL-C avoidance scores (ß = 1.2 × 10-3; P = .02). Conclusions and Relevance: In this case-control study of military-related mTBI, the results suggest that advanced magnetic resonance imaging techniques using NODDI can reveal white matter microstructural alterations associated with neuropsychiatric symptoms in the chronic phase of mTBI. Diffusion trends observed throughout widespread white matter regions-of-interest may reflect mechanisms of neurodegeneration as well as postinjury tissue scarring and reorganization.

¹8F-fluorodeoxyglucose-positron emission tomography findings are not related to cognitive functioning in service members with remote history of mild traumatic brain injury.

OBJECTIVE: Determine whether glucose uptake as measured by 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging is associated with cognitive performance and cognitive deficits in active duty service members with a history of mild traumatic brain injury (mTBI). METHOD: 287 patients with a history of mTBI underwent FDG-PET scans at rest and neuropsychological testing at the National Intrepid Center of Excellence at Walter Reed National Military Medical Center. Glucose uptake in the bilateral frontal, parietal, occipital, and temporal lobes, and 58 cortical/cerebellar regions were correlated with seven neuropsychological composite scores, with and without relevant covariates. RESULTS: Perceptual reasoning correlated with bilateral hippocampi glucose uptake (rs = .141-.165, p < .03), processing speed was inversely related to glucose uptake in the left temporal lobe (r = -.134, p = .034), and working memory was related to glucose uptake in the left parietal, temporal, and occipital lobes (rs = .128-.140, p < .05); however, these findings did not survive correction for multiple comparisons. Partial correlations between cognition and the 56 cortical/cerebellar regions of interests were not significant after correction for multiple comparisons. Glucose uptake in the left hippocampus was inversely related to the likelihood of cognitive deficits (OR = .745, p = .041); however, this did not survive correction for multiple comparisons. CONCLUSIONS: After correction for multiple comparisons, there was no significant relationship between regional glucose uptake and neurocognitive performance or cognitive deficits. Glucose uptake as measured by FDG-PET is not indicative of cognitive performance in active duty service members with a remote history of mTBI. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Altered Metabolic Interrelationships in the Cortico-Limbic Circuitry in Military Service Members with Persistent Post-Traumatic Stress Disorder Symptoms Following Mild Traumatic Brain Injury.

Introduction: Comorbid mild traumatic brain injury (mTBI) and post-traumatic stress disorder (PTSD) are common in military service members. The aim of this study is to investigate brain metabolic interrelationships in service members with and without persistent PTSD symptoms after mTBI by using 18F-fluorodeoxyglucose (FDG) positron emission tomography. Methods: Service members (n = 408) diagnosed with mTBI were studied retrospectively. Principal component analysis was applied to identify latent metabolic systems, and the associations between metabolic latent systems and self-report measures of post-concussive and PTSD symptoms were evaluated. Participants were divided into two groups based on DSM-IV-TR (Diagnostic and Statistical Manual of Mental Disorders, fourth edition-Text Revision) criteria for PTSD, and structural equation modeling was performed to test a priori hypotheses on metabolic interrelationships among the brain regions in the cortico-limbic circuitry responsible for top-down control and bottom-up emotional processing. The differences in metabolic interrelationships between age-matched PTSD-absent (n = 204) and PTSD-present (n = 204) groups were evaluated. Results: FDG uptake in the temporo-limbic system was positively correlated with post-concussive and hyperarousal symptoms. For the bottom-up emotional processing, the insula and amygdala-hippocampal complex in the PTSD-present group had stronger metabolic interrelationships with the bilateral rostral anterior cingulate, left lingual, right lateral occipital, and left superior temporal cortices, but a weaker relationship with the right precuneus cortex, compared with the PTSD-absent group. For the top-down control, the PTSD-present group had decreased metabolic engagements of the dorsolateral prefrontal cortex on the amygdala. Discussion: Our results suggest altered metabolic interrelationships in the cortico-limbic circuitry in mTBI subjects with persistent PTSD symptoms, which may underlie the pathophysiological mechanisms of comorbid mTBI and PTSD. Impact statement This is the first 18F-fluorodeoxyglucose positron emission tomography study to investigate brain metabolic interrelationships in service members with persistent post-traumatic stress disorder (PTSD) symptoms after mild traumatic brain injury (mTBI). We identified that the temporo-limbic metabolic system was associated with post-concussive and hyperarousal symptoms. Further, brain metabolic interrelationships in the cortico-limbic circuitry were altered in mTBI subjects with significant PTSD symptoms compared with those without them.

Assessment of Brain Venous Structure in Military Traumatic Brain Injury Patients using Susceptibility Weighted Imaging and Quantitative Susceptibility Mapping.

Brain venous volume above the lateral ventricle in military patients with traumatic brain injury (TBI) was assessed using two segmentation approaches on susceptibility weighted images (SWI) and quantitative susceptibility maps (QSM). This retrospective study included a total of 147 subjects: 14 patients with severe TBI; 38 patients with moderate TBI, 58 patients with mild TBI (28 with blast-related injuries and 30 with non-blast-related injuries), and 37 control subjects without history of TBI. Using the multiscale vessel enhancement filter on SWI images, patients with severe TBI demonstrated significantly higher segmented venous volumes compared with controls. Using a threshold approach on QSM images, TBI patients with different severities all demonstrated increased segmented volumes compared with control subjects: in the whole brain (severe, p = 0.001; moderate, p = 0.008; mild, p = 0.042, compared with controls), in the left hemisphere (severe, p = 0.01; moderate, p = 0.038, compared with controls), in the right hemisphere (severe, p = 0.001; moderate, p = 0.013; mild, p = 0.027, compared with controls). While segmented volumes on SWI appear to overlay directly on the visualized venous structures, the QSM-derived segments also encompass some perivascular and deep white matter areas. This might represent the damage in the perivascular regions associated with iron deposition or astroglial scarring.

Corrigendum: Potential role of the glycolytic oscillator in acute hypoxia in tumors (2015 Phys. Med. Biol. 60 9215).

At the time of publication, our group had performed short tandem repeat (STR) testing on the SCC22B cell line and believed that had been correctly identified. As part of a recent comprehensive process to confirm the identity of cell lines in use in our lab, we repeated STR testing on all cell lines. These results were compared to the ExPASy Cellosaurus database (http://web.expasy.org/cellosaurus/). One cell line used in this manuscript was a near perfect match for T24 (CVCL_0554), a bladder carcinoma cell line commonly found as a cellular contaminant. Although we are unable to test the exact cells used in this manuscript, we believe that the cells labeled as SCC22B are most likely to actually be T24. The authors believe that neither the results nor the conclusions have been significantly changed on the basis of the specific cell line utilized.

Volumetric Versus Unidimensional Measures of Metastatic Colorectal Cancer in Assessing Disease Response.

INTRODUCTION: The purpose of this study was to compare unidimensional (1D/linear) and volumetric (3D) measures of metastatic colorectal cancer (mCRC) at computed tomography (CT) for predicting clinical outcome. PATIENTS AND METHODS: Analysis of CT images in 105 patients (mean age, 59 years; range, 25-81 years; 45 women, 60 men) receiving treatment for mCRC was performed. Both unidimensional and volumetric measures were obtained on index lesions at 3 time points (baseline/midpoint/post-therapy; mean interval, 4.1 months; median, 3.7 months) by 3 readers using a semi-automated technique. Measurements were summed and compared using best overall response across the 3 time points. Patient response was categorized based on Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 thresholds for unidimensional and volume measures (CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease). Survival data was correlated (mean follow-up, 19.9 ± 17.1 months; median, 14.7 months). Intra/interobserver variability and reproducibility of 1D and 3D measures was assessed. Cox survival and Kaplan-Meier models were constructed and compared. RESULTS: Cox models and Kaplan-Meier curves for unidimensional versus volumetric assessment were very similar in appearance. Both 1D and 3D measurements effectively separated PD from the SD/PR groups, but neither separated SD from PR well. Volumetric measures showed comparable intra/interobserver variability on Bland-Altman analysis to unidimensional measures across readers using a semi-automated measurement technique. Metastatic site (lung, liver, node, other) did not seem to impact measurement reproducibility. CONCLUSIONS: Although CT volumetric assessment of metastatic colorectal cancer is fairly reproducible by reader and site using a semi-automated technique, the ability to stratify progressive disease from other disease response categories in terms of survival was similar to unidimensional measurement.

Monitoring Ischemic Cerebral Injury in Spontaneously Hypertensive Rats by Diffusion Tensor Imaging.

AIM: We have applied diffusion tensor imaging (DTI) to interrogate microstructural changes in white matter integrity in a widely used middle cerebral artery occlusion (MCAO) model of cerebral ischemia. MATERIAL AND METHODS: We performed ex vivo DTI 35 days after 60 minutes transient focal ischemia in male spontaneously hypertensive rats and generated fractional anisotropy (FA), mean, axial and radial diffusivity maps. Regions of interest corresponding to external capsule (EC), corpus callosum (CC) and internal capsule (IC) were compared among sham and stroked rats. We compared tractographic projections of white matter fiber patterns and examined white matter integrity by Luxol fast blue histological analysis. We also determined infarct lesion volumes at 24 hours post-ischemia by T2-weighted magnetic resonance imaging (MRI) or at 35 days by histological staining with cresyl violet. RESULTS: We found alterations in EC and IC, but not CC, as represented by decreased FA and increased mean, axial and radial diffusivities. The size of the ischemic lesion detected subacutely by T2-weighted MRI or at 35 days by histological staining correlated with the decline in FA in the affected structures. Tractography revealed disruption of fiber trajectories through the EC and reorientation of fibers within the caudate/putamen of rats subjected to MCAO. Similarly, loss of white matter integrity in the EC and increased white matter density in the caudate/putamen along the infarct border zone was evidenced by Luxol fast blue staining. CONCLUSION: Diffusion tensor imaging therefore allows for monitoring of white matter injury and reorganization in hypertensive rats.

Potential role of the glycolytic oscillator in acute hypoxia in tumors.

Tumor acute hypoxia has a dynamic component that is also, at least partially, coherent. Using blood oxygen level dependent magnetic resonance imaging, we observed coherent oscillations in hemoglobin saturation dynamics in cell line xenograft models of head and neck squamous cell carcinoma. We posit a well-established biochemical nonlinear oscillatory mechanism called the glycolytic oscillator as a potential cause of the coherent oscillations in tumors. These data suggest that metabolic changes within individual tumor cells may affect the local tumor microenvironment including oxygen availability and therefore radiosensitivity. These individual cells can synchronize the oscillations in patches of similar intermediate glucose levels. These alterations have potentially important implications for radiation therapy and are a potential target for optimizing the cancer response to radiation.

CT textural analysis of hepatic metastatic colorectal cancer: pre-treatment tumor heterogeneity correlates with pathology and clinical outcomes.

PURPOSE: The purpose of the study was to determine if CT texture features of untreated hepatic metastatic colorectal cancer (CRC) relate to pathologic features and clinical outcomes. METHODS: Tumor texture analysis was performed on single hepatic metastatic lesions on pre-treatment contrast-enhanced CT scans in 77 pts (mean age 58, 34F/43M) using a novel tool. Measures of heterogeneity, including entropy, kurtosis, skewness, mean, mean positive pixels (MPP), and standard deviation (SD) of pixel distribution histogram were derived with filter values corresponding to fine (spatial scaling factor (ssf) 2), medium (ssf 3, 4), and coarse textures (ssf 5, 6). Texture parameters were correlated with tumor grade, baseline serum CEA, and KRAS mutation status. Overall survival was also correlated using Cox proportional hazards models. Single-slice 2D vs. whole-tumor volumetric 3D texture analysis was compared in a subcohort of 20 patients. RESULTS: Entropy, MPP, and SD at medium filtration levels were significantly associated with tumor grade (MPP ssf 3 P = 0.002, SD ssf 3 P = 0.004, entropy ssf 4 P = 0.007). Skewness was negatively associated KRAS mutation (P = 0.02). Entropy at coarse filtration levels was associated with survival (Hazard ratio (HR) for death 0.65, 95% CI 0.44-0.95, P = 0.03). Texture results for 2D and 3D analysis were similar. CONCLUSIONS: CT texture features, particularly entropy, MPP, and SD, are significantly associated with tumor grade in untreated CRC liver metastases. Tumor entropy at coarse filters correlates with overall survival. Single-slice 2D texture analysis appears to be adequate.

Low-echo sphere phantoms and methods for assessing imaging performance of medical ultrasound scanners.

Tissue-mimicking phantoms and software for quantifying the ability of human observers to detect small low-echo spheres as a function of depth have been developed. Detectability is related to the imager's ability to delineate the boundary of a 3-D object such as a spiculated tumor. The phantoms accommodate a broad range of transducer shapes and sizes. Three phantoms are described: one with 2-mm-diameter spheres (for higher frequencies), one with 3.2-mm-diameter spheres (for lower frequencies) and one with 4-mm-diameter spheres (for lower frequencies). The spheres are randomly distributed in each phantom. The attenuation coefficients of spheres and surroundings are nearly identical; thus, compromising shadowing or enhancement distal to spheres does not occur. Reproducibility results are given for pairs of independent data sets involving eight different combinations of scanner, transducer and console settings. The following comparison results are also reported: (i) only the selected frequency differs; (ii) transducers and scan parameters are nearly the same but manufacturers differ; (iii) ordinary B-scanning, spatial compounding and tissue harmonic imaging are addressed. The phantoms and software promise to be valuable tools for scanning system and setup comparisons and for acceptance testing.

TrkB receptor agonist 7, 8 dihydroxyflavone triggers profound gender- dependent neuroprotection in mice after perinatal hypoxia and ischemia.

In this study, we investigated the effects of a bioactive high-affinity TrkB receptor agonist 7,8- dihydroxyflavone (7,8 DHF) on neonatal brain injury in female and male mice after hypoxia ischemia (HI). HI was induced by exposure of postnatal day 9 (P9) mice to 10% O2 for 50 minutes at 37°C after unilateral ligation of the left common carotid artery. Animals were randomly assigned to HI-vehicle control group [phosphate buffered saline (PBS), intraperitoneally (i.p.)] or HI + 7,8 DHF-treated groups (5 mg/kg in PBS, i.p at 10 min, 24 h, or with subsequent daily injections up to 7 days after HI). The HI-vehicle control mice exhibited neuronal degeneration in the ipsilateral hippocampus and cortex with increased Fluoro-Jade C positive staining and loss of microtubule associated protein 2 expression. In contrast, the 7,8 DHF-treated mice showed less hippocampal neurodegeneration and astrogliosis, with more profound effects in female than in male mice. Moreover, 7,8 DHF-treated mice improved motor learning and spatial learning at P30-60 compared to the HI-vehicle control mice. Diffusion tensor imaging of ex vivo brain tissues at P90 after HI revealed less reduction of fractional anisotropy values in the ipsilateral corpus callosum of 7,8 DHF-treated brains, which was accompanied with better preserved myelin basic protein expression and CA1 hippocampal structure. Taken together, these findings strongly suggest that TrkB agonist 7,8 DHF is protective against HI-mediated hippocampal neuronal death, white matter injury, and improves neurological function, with a more profound response in female than in male mice.

Chronic neurological deficits in mice after perinatal hypoxia and ischemia correlate with hemispheric tissue loss and white matter injury detected by MRI.

We investigated the effects of perinatal hypoxia-ischemia (HI) on brain injury and neurological functional outcome at postnatal day (P)30 through P90. HI was induced by exposing P9 mice to 8% O(2) for 55 min using the Vannucci HI model. Following HI, mice were treated with either vehicle control or Na(+)/H(+) exchanger isoform 1 (NHE1) inhibitor HOE 642. The animals were examined by the accelerating rotarod test at P30 and the Morris water maze (MWM) test at P60. T(2)-weighted MRI was conducted at P90. Diffusion tensor imaging (DTI) was subsequently performed in ex vivo brains, followed by immunohistochemical staining for changes in myelin basic protein (MBP) and neurofilament protein expression in the corpus callosum (CC). Animals at P30 after HI showed deficits in motor and spatial learning. T(2) MRI detected a wide spectrum of brain injury in these animals. A positive linear correlation was observed between learning deficits and the degree of tissue loss in the ipsilateral hemisphere and hippocampus. Additionally, CC DTI fractional anisotropy (FA) values correlated with MBP expression. Both FA and MBP values correlated with performance on the MWM test. HOE 642-treated mice exhibited improved spatial learning and memory, and less white matter injury in the CC. These findings suggest that HI-induced cerebral atrophy and CC injury contribute to the development of deficits in learning and memory, and that inhibition of NHE1 is neuroprotective in part by reducing white matter injury. T(2)-weighted MRI and DTI are useful indicators of functional outcome after perinatal HI.

Cleft lip and palate results from Hedgehog signaling antagonism in the mouse: Phenotypic characterization and clinical implications.

BACKGROUND: The Hedgehog (Hh) pathway provides inductive signals critical for developmental patterning of the brain and face. In humans and in animal models interference with this pathway yields birth defects, among the most well-studied of which fall within the holoprosencephaly (HPE) spectrum. METHODS: Timed-pregnant C57Bl/6J mice were treated with the natural Hh signaling antagonist cyclopamine by subcutaneous infusion from gestational day (GD) 8.25 to 9.5, or with a potent cyclopamine analog, AZ75, administered by oral gavage at GD 8.5. Subsequent embryonic morphogenesis and fetal central nervous system (CNS) phenotype were respectively investigated by scanning electron microscopy and high resolution magnetic resonance imaging (MRI). RESULTS: In utero Hh signaling antagonist exposure induced a spectrum of craniofacial and brain malformations. Cyclopamine exposure caused lateral cleft lip and palate (CLP) defects attributable to embryonic deficiency of midline and lower medial nasal prominence tissue. The CLP phenotype was accompanied by olfactory bulb hypoplasia and anterior pituitary aplasia, but otherwise grossly normal brain morphology. AZ75 exposure caused alobar and semilobar HPE with associated median facial deficiencies. An intermediate phenotype of median CLP was produced infrequently by both drug administration regimens. CONCLUSIONS: The results of this study suggest that interference with Hh signaling should be considered in the CLP differential and highlight the occurrence of CNS defects that are expected to be present in a cohort of patients having CLP. This work also illustrates the utility of fetal MRI-based analyses and establishes a novel mouse model for teratogen-induced CLP.