Oxygen extraction fraction (OEF) values and applications in neurological diseases.

One of the goals of this systematic review is to provide a meta-analysis-derived mean OEF of healthy volunteers. Another aim of this study is to indicate the OEF ranges of various neurological pathologies. Potential clinical applications of OEF metrics are presented. Peer-reviewed studies reporting OEF metrics derived from computed tomography (CT)/positron emission tomography (PET) and/or magnetic resonance imaging (MRI) were considered. Databases utilized included MEDLINE, PubMed, EMBASE, Web of Science, and Google Scholar. The Newcastle-Ottawa scoring system was used for evaluating studies. R Studio was utilized for the meta-analysis calculations when appropriate. The GRADE framework was utilized to assess additional findings. Of 2267 potential studies, 165 met the inclusion criteria. The healthy volunteer meta-analysis included 339 subjects and found a mean OEF value of 38.87 (37.38, 40.36), with a prediction interval of 32.40-45.34. There were no statistical differences in OEF values derived from PET versus MRI. We provided a GRADE A certainty rating for the use of OEF metrics to predict stroke occurrence in patients with symptomatic carotid or cerebral vessel disease. We provided a GRADE B certainty rating for monitoring treatment response in Moyamoya disease. Use of OEF metrics in diagnosing and/or monitoring other conditions had a GRADE C certainty rating or less. OEF might have a role in diagnosing and monitoring patients with symptomatic carotid or cerebral vessel disease and Moyamoya disease. While we found insufficient evidence to support measuring OEF metrics in other patient populations, in many cases, further studies are warranted.

Quantitative Susceptibility Mapping for Staging Acute Cerebral Hemorrhages: Comparing the Conventional and Multiecho Complex Total Field Inversion magnetic resonance imaging MR Methods.

BACKGROUND: The perceived acuity of intracerebral hemorrhage (ICH) impacts the management of patients, both within emergent and outpatient/urgent settings. Morphology enabled dipole inversion (MEDI) quantitative susceptibility imaging (QSM) has improved characterization of ICH acuity, despite outstanding limitations in distinguishing blood products. PURPOSE/HYPOTHESIS: Using improved susceptibility quantification, novel postprocessing QSM method from multiecho complex total field inversion (mcTFI) may better discriminate between acute and subacute ICH, compared to MEDI. STUDY TYPE: Retrospective cohort study. SUBJECTS: A total of 121 subjects enrolled following positive computerized tomography (CT) findings for ICH. Subjects were grouped based on time between admission and MR imaging: hyperacute (<24 hours), acute (1-3 days), early subacute (3-7 days), and late subacute (7-18 days). FIELD STRENGTH/SEQUENCE: A multiecho gradient echo sequence at 3.0 T was paired with clinical noncontrast CT imaging. ASSESSMENT: A quantitative index (CTindex ) was derived based on relative intensities of blood on noncontrast CT. All images were co-registered, from which QSM parameters within the ICH area were assessed across groups, as well as the correlation with CTindex . STATISTICAL TESTS: Group differences were assessed using ANOVAs. Linear regressions between the CTindex , MEDI, and mcTFI measurements were used to assess their relationships. Statistical significance was set at P < 0.05. RESULTS: A total of 21 hyperacute, 72 acute, 21 early subacute, and 7 late-subacute patients were included in this analysis. Significant changes in blood susceptibility were found over time for the MEDI and mcTFI, although mcTFI better differentiated the hyperacute/acute from subacute stages. CTindex values within the ICH were more strongly correlated with mcTFI QSM (r = 0.727) than MEDI (r = 0.412) QSM. DATA CONCLUSION: McTFI susceptibility estimation demonstrated better correlation with ICH acuity as suggested by CT, providing an improved method to assess acuity of intracranial blood products in clinical settings to identify cases that may require acute intervention. LEVEL OF EVIDENCE: 4 TECHNICAL EFFICACY STAGE: 2.

The Pan-Cancer Landscape of Coamplification of the Tyrosine Kinases KIT, KDR, and PDGFRA.

PURPOSE: Amplifications of receptor tyrosine kinases (RTKS) are therapeutic targets in multiple tumor types (e.g. HER2 in breast cancer), and amplification of the chromosome 4 segment harboring the three RTKs KIT, PDGFRA, and KDR (4q12amp) may be similarly targetable. The presence of 4q12amp has been sporadically reported in small tumor specific series but a large-scale analysis is lacking. We assess the pan-cancer landscape of 4q12amp and provide early clinical support for the feasibility of targeting this amplicon. EXPERIMENTAL DESIGN: Tumor specimens from 132,872 patients with advanced cancer were assayed with hybrid capture based comprehensive genomic profiling which assays 186-315 genes for all classes of genomic alterations, including amplifications. Baseline demographic data were abstracted, and presence of 4q12amp was defined as 6 or more copies of KIT/KDR/PDGFRA. Concurrent alterations and treatment outcomes with matched therapies were explored in a subset of cases. RESULTS: Overall 0.65% of cases harbored 4q12amp at a median copy number of 10 (range 6-344). Among cancers with >100 cases in this series, glioblastomas, angiosarcomas, and osteosarcomas were enriched for 4q12amp at 4.7%, 4.8%, and 6.4%, respectively (all p < 0.001), giving an overall sarcoma (n = 6,885) incidence of 1.9%. Among 99 pulmonary adenocarcinoma cases harboring 4q12amp, 50 (50%) lacked any other known driver of NSLCC. Four index cases plus a previously reported case on treatment with empirical TKIs monotherapy had stable disease on average exceeding 20 months. CONCLUSION: We define 4q12amp as a significant event across the pan-cancer landscape, comparable to known pan-cancer targets such as NTRK and microsatellite instability, with notable enrichment in several cancers such as osteosarcoma where standard treatment is limited. The responses to available TKIs observed in index cases strongly suggest 4q12amp is a druggable oncogenic target across cancers that warrants a focused drug development strategy. IMPLICATIONS FOR PRACTICE: Coamplification of the receptor tyrosine kinases (rtks) KIT/KDR/PDGFRA (4q12amp) is present broadly across cancers (0.65%), with enrichment in osteosarcoma and gliomas. Evidence for this amplicon having an oncogenic role is the mutual exclusivity of 4q12amp to other known drivers in 50% of pulmonary adenocarcinoma cases. Furthermore, preliminary clinical evidence for driver status comes from four index cases of patients empirically treated with commercially available tyrosine kinase inhibitors with activity against KIT/KDR/PDGFRA who had stable disease for 20 months on average. The sum of these lines of evidence suggests further clinical and preclinical investigation of 4q12amp is warranted as the possible basis for a pan-cancer drug development strategy.

Identifying cardiovascular risk factors that impact cerebrovascular reactivity: An ASL MRI study.

BACKGROUND: To maintain cerebral blood flow (CBF), cerebral blood vessels dilate and contract in response to blood supply through cerebrovascular reactivity (CR). PURPOSE: Cardiovascular (CV) disease is associated with increased stroke risk, but which risk factors specifically impact CR is unknown. STUDY TYPE: Prospective longitudinal. SUBJECTS: Fifty-three subjects undergoing carotid endarterectomy or stenting. FIELD STRENGTH/SEQUENCE: 3T, 3D pseudo-continuous arterial spin labeling (PCASL) ASL, and T1 3D fast spoiled gradient echo (FSPGR). ASSESSMENT: We evaluated group differences in CBF changes for multiple cardiovascular risk factors in patients undergoing carotid revascularization surgery. STATISTICAL TESTS: PRE (baseline), POST (48-hour postop), and 6MO (6 months postop) whole-brain CBF measurements, as 129 CBF maps from 53 subjects were modeled as within-subject analysis of variance (ANOVA). To identify CV risk factors associated with CBF change, the CBF change from PRE to POST, POST to 6MO, and PRE to 6MO were modeled as multiple linear regression with each CV risk factor as an independent variable. Statistical models were performed controlling for age on a voxel-by-voxel basis using SPM8. Significant clusters were reported if familywise error (FWE)-corrected cluster-level was P < 0.05, while the voxel-level significance threshold was set for P < 0.001. RESULTS: The entire group showed significant (cluster-level P < 0.001) CBF increase from PRE to POST, decrease from POST to 6MO, and no significant difference (all voxels with P > 0.001) from PRE to 6MO. Of multiple CV risk factors evaluated, only elevated systolic blood pressure (SBP, P = 0.001), chronic renal insufficiency (CRI, P = 0.026), and history of prior stroke (CVA, P < 0.001) predicted lower increases in CBF PRE to POST. Over POST to 6MO, obesity predicted lower (P > 0.001) and cholesterol greater CBF decrease (P > 0.001). DATA CONCLUSION: The CV risk factors of higher SBP, CRI, CVA, BMI, and cholesterol may indicate altered CR, and may warrant different stroke risk mitigation and special consideration for CBF change evaluation. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 5 J. Magn. Reson. Imaging 2020;51:734-747.

Improving the robustness of pseudo-continuous arterial spin labeling to off-resonance and pulsatile flow velocity.

PURPOSE: To improve pseudo-continuous arterial spin labeling (PCASL) robustness to off-resonance and pulsatile blood flow velocity. METHODS: Bloch equations were solved to evaluate the effect of labeling parameters in a pulsatile flow model for a range of off-resonance. Experimental confirmation was achieved in volunteers using linear phase increase between labeling pulses to approximate off-resonance errors. We first assessed the location of the labeling plane in four volunteers. Next, we explored a range of parameters-including balanced and unbalanced gradients-in five more volunteers at an optimal labeling plane location. RESULTS: Simulations demonstrated that 1) high velocities are vulnerable to off-resonance, 2) unbalanced PCASL outperforms balanced PCASL, 3) increased B1 and low average gradient improve the labeling efficiency for high-velocity flow, and 4) a low ratio of selective to average gradient improves off-resonance robustness. A good agreement between theory and experiment was observed. CONCLUSION: The robustness of PCASL can be increased by selecting an unbalanced scheme with a low average gradient (0.5 mT/m), a low ratio (7×) of selective to average gradients, and the highest feasible B1 (1.8 µT). Placing the labeling plane above the carotid bifurcation and below the V3 segment, usually between the second and third vertebrae, yielded robust results. Magn Reson Med 78:1342-1351, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Volume of subclinical embolic infarct correlates to long-term cognitive changes after carotid revascularization.

OBJECTIVE: Carotid intervention is safe and effective in stroke prevention in appropriately selected patients. Despite minimal neurologic complications, procedure-related subclinical microemboli are common and their cognitive effects are largely unknown. In this prospective longitudinal study, we sought to determine long-term cognitive effects of embolic infarcts. METHODS: The study recruited 119 patients including 46% symptomatic patients who underwent carotid revascularization. Neuropsychological testing was administered preoperatively and at 1 month, 6 months, and 12 months postoperatively. Rey Auditory Verbal Learning Test (RAVLT) was the primary cognitive measure with parallel forms to avoid practice effect. All patients also received 3T brain magnetic resonance imaging with a diffusion-weighted imaging (DWI) sequence preoperatively and within 48 hours postoperatively to identify procedure-related new embolic lesions. Each DWI lesion was manually traced and input into a neuroimaging program to define volume. Embolic infarct volumes were correlated with cognitive measures. Regression models were used to identify relationships between infarct volumes and cognitive measures. RESULTS: A total of 587 DWI lesions were identified on 3T magnetic resonance imaging in 81.7% of carotid artery stenting (CAS) and 36.4% of carotid endarterectomy patients with a total volume of 29,327 mm3. Among them, 54 DWI lesions were found in carotid endarterectomy patients and 533 in the CAS patients. Four patients had transient postoperative neurologic symptoms and one had a stroke. CAS was an independent predictor of embolic infarction (odds ratio, 6.6 [2.1-20.4]; P < .01) and infarct volume (P = .004). Diabetes and contralateral carotid severe stenosis or occlusion had a trend of positive association with infarct volume, whereas systolic blood pressure ≥140 mm Hg had a negative association (P = .1, .09, and .1, respectively). There was a trend of improved RAVLT scores overall after carotid revascularization. Significantly higher infarct volumes were observed among those with RAVLT decline. Within the CAS cohort, infarct volume was negatively correlated with short- and long-term RAVLT changes (P < .05). CONCLUSIONS: Cognitive assessment of procedure-related subclinical microemboli is challenging. Volumes of embolic infarct correlate with long-term cognitive changes, suggesting that microembolization should be considered a surrogate measure for carotid disease management.

Brain structural connectivity distinguishes patients at risk for cognitive decline after carotid interventions.

While brain connectivity analyses have been demonstrated to identify ill patients for a number of diseases, their ability to predict cognitive impairment after brain injury is not well established. Traditional post brain injury models, such as stroke, are limited for this evaluation because pre-injury brain connectivity patterns are infrequently available. Patients with severe carotid stenosis, in contrast, often undergo non-emergent revascularization surgery, allowing the collection of pre and post-operative imaging, may experience brain insult due to perioperative thrombotic/embolic infarcts or hypoperfusion, and can suffer post-operative cognitive decline. We hypothesized that a distributed function such as memory would be more resilient in patients with brains demonstrating higher degrees of modularity. To test this hypothesis, we analyzed preoperative structural connectivity graphs (using T1 and DWI MRI) for 34 patients that underwent carotid intervention, and evaluated differences in graph metrics using the Brain Connectivity Toolbox. We found that patients with lower binary component number, binary community number and weighted community number prior to surgery were at greater risk for developing cognitive decline. These findings highlight the promise of brain connectivity analyses to predict cognitive decline following brain injury and serve as a clinical decision support tool. Hum Brain Mapp 37:2185-2194, 2016. © 2016 Wiley Periodicals, Inc.

Microembolization is associated with transient cognitive decline in patients undergoing carotid interventions.

OBJECTIVE: Carotid interventions are important in helping to reduce the risk of stroke for patients with high-grade carotid artery stenosis; however, subclinical cerebral microemboli can occur during these procedures. Associations have been found between the incidence of microemboli and postoperative decline in memory. We therefore sought to determine whether this decline persisted long-term and to assess changes in other cognitive domains. METHODS: Patients were prospectively recruited under an Institutional Review Board-approved protocol at a single academic center. Neuropsychological testing was administered preoperatively and at 1-month and 6-month intervals postoperatively. Cognitive domains that were evaluated included verbal memory, visual memory, psychomotor speed, dexterity, and executive function. Diffusion-weighted magnetic resonance imaging sequencing was performed preoperatively and ≤48 hours postoperatively to identify procedure-related microemboli. Univariate and multivariate regression models were used to identify relationships among microembolization, demographics, and cognition. RESULTS: Included were 80 male patients with an average age of 69 years. Forty patients underwent carotid artery stenting and 40 underwent carotid endarterectomy. Comorbidities included diabetes in 45%, coronary artery disease in 50%, and prior neurologic symptoms in 41%. New postoperative microemboli were found in 45 patients (56%). Microembolization was significantly more common in the carotid artery stenting cohort (P < .005). Univariate analysis demonstrated that patients with procedurally related embolization showed decline 1 month postoperatively in verbal memory and Trail Making A measures. Multivariate analysis demonstrated that procedurally related embolization (odds ratio [OR], 2.8; P = .04) and preoperative symptomatic stenosis (OR, 3.2; P = .026) were independent predictors of decline for the Rey Auditory Verbal Learning Test Short Delay measure at 1 month. At 6 months, no significant relationship was found between emboli and decline on Rey Auditory Verbal Learning Test Short Delay, but age (OR, 1.1, P = .005) and chronic obstructive pulmonary disease (OR, 7.1, P = .018) were significantly associated with decline at 6 months after the intervention. CONCLUSIONS: Microembolization that is associated with carotid artery intervention predicts short-term cognitive decline. However, some of these cognitive deficits persist at 6 months after the intervention, and further investigation is warranted to determine individual patient risk factors that may affect recovery.

mcTFI QSM MRI ABC/2 intracranial hemorrhage to noncontrast head CT volume measurement equivalence.

BACKGROUND/OBJECTIVES: Intracranial hemorrhage (ICH) volume assessment is an important part of patient management and is routinely obtained by non-contrast head CT (NCHCT) using the validated ABC/2 measurement method. Because conventional MRI imaging sequences demonstrate variability in ICH appearance, volumetric analyses for MRI bleed volume in a standardized manner using ABC/2 is not possible. The recently introduced multiecho-complex total field inversion quantitative susceptibility mapping (mcTFI QSM) MRI technique, which maps brain tissue susceptibility to both depict brain tissue structures and quantify tissue susceptibility, may provide a viable alternative. In this study we evaluated mcTFI QSM ABC/2 ICH volume assessment relative to NCHCT. METHODS: Patients with ICH who had undergone NCHCT and MRI brain scans within 48 h were recruited for this retrospective study. The ABC/2 method was applied to estimate the bleed volume for both NCHCT and MRI by a CAQ-certified neuroradiologist with 10 years of experience and a trained laboratory assistant. Results were analyzed via Bland-Altman (B-A) and linear regression. RESULTS: 54 patients (27 females) who had undergone NCHCT and MRI within 48 h (<24 h., n = 31, 24-48 h, n = 10) were enrolled. mcTFI QSM ICH volume measurement method showed a positive correlation (99.5%) compared to NCHCT. B-A plot comparing ABC/2 ICH volume on NCHCT and mcTFI MRI done for patients within 24 h demonstrates a bias of -0.09%. CONCLUSIONS: ICH volume calculation using ABC/2 on mcTFI QSM showed a high correlation with NCHCT measurement. These results suggest mcTFI QSM is a promising MRI method for ABC/2 for bleed volume measurement.

Quantitative susceptibility mapping improves cerebral microbleed detection relative to susceptibility-weighted images.

BACKGROUND AND PURPOSE: Cerebral microbleed (CMB) detection impacts disease diagnosis and management. Susceptibility-weighted imaging (SWI) MRI depictions of CMBs are used with phase images (SWIP) to distinguish blood from calcification, via qualitative intensity evaluation (bright/dark). However, the intensities depicted for a single lesion can vary within and across consecutive SWIP image planes, impairing the classification of findings as a CMB. We hypothesize that quantitative susceptibility mapping (QSM) MRI, which maps tissue susceptibility, demonstrates less in- and through-plane intensity variation, improving the clinician's ability to categorize a finding as a CMB. METHODS: Forty-eight patients with acute intracranial hemorrhage who received multi-echo gradient echo MRI used to generate both SWI/SWIP and morphology-enabled dipole inversion QSM images were enrolled. Five hundred and sixty lesions were visually classified as having homogeneous or heterogeneous in-plane and through-plane intensity by a neuroradiologist and two diagnostic radiology residents using published rating criteria. When available, brain CT scans were analyzed for calcification or acute hemorrhage. Relative risk (RR) ratios and confidence intervals (CIs) were calculated using a generalized linear model with log link and binary error. RESULTS: QSM showed unambiguous lesion signal intensity three times more frequently than SWIP (RR = 0.3235, 95% CI 0.2386-0.4386, p<.0001). The probability of QSM depicting homogeneous lesion intensity was three times greater than SWIP for small (RR = 0.3172, 95% CI 0.2382-0.4225, p<.0001), large (RR = 0.3431, 95% CI 0.2045-0.5758, p<.0001), lobar (RR = 0.3215, 95% CI 0.2151-0.4805, p<.0001), cerebellar (RR = 0.3215, 95% CI 0.2151-0.4805, p<.0001), brainstem (RR = 0.3100, 95% CI 0.1192-0.8061, p = .0163), and basal ganglia (RR = 0.3380, 95% CI 0.1980-0.5769, p<.0001) lesions. CONCLUSIONS: QSM more consistently demonstrates interpretable lesion intensity compared to SWIP as used for distinguishing CMBs from calcification.

Antiplatelet medications and intracranial hemorrhage in patients with primary brain tumors.

BACKGROUND: Spontaneous intracranial hemorrhage (ICH) is a frequent and severe consequence of primary brain tumors. The safety of antiplatelet medications in this patient population is undefined. OBJECTIVE: The primary objective was to determine whether antiplatelet medications are associated with an increased risk of ICH in patients with primary brain tumors. PATIENTS/METHODS: We performed a matched, retrospective cohort study of patients with the diagnosis of primary brain tumor treated at our institution between 2010 and 2021. Radiographic images of all potential ICH events underwent blinded review. The primary end point of the study was the cumulative incidence of ICH at 1 year after tumor diagnosis. RESULTS AND CONCLUSIONS: A total of 387 patients with primary brain tumors were included in the study population (130 exposed to antiplatelet agents, 257 not exposed). The most common malignancy was glioblastoma (n = 256, 66.1%). Among the intervention cohort, 119 patients received aspirin monotherapy. The cumulative incidence of any ICH at 1 year was 11.0% (95% CI, 5.3-16.6) in those receiving antiplatelet medications and 13.0% (95% CI, 8.5-17.6) in those not receiving antiplatelet medications (Gray test, p = 0.6). The cumulative incidence of major ICH was similar between the cohorts (3.3% in antiplatelet cohort vs 2.9% in control cohort, p = 1.0). This study did not identify an increased incidence of ICH in patients with primary brain tumors exposed to antiplatelet medications.

Textural kinetics: a novel dynamic contrast-enhanced (DCE)-MRI feature for breast lesion classification.

Dynamic contrast-enhanced (DCE)-magnetic resonance imaging (MRI) of the breast has emerged as an adjunct imaging tool to conventional X-ray mammography due to its high detection sensitivity. Despite the increasing use of breast DCE-MRI, specificity in distinguishing malignant from benign breast lesions is low, and interobserver variability in lesion classification is high. The novel contribution of this paper is in the definition of a new DCE-MRI descriptor that we call textural kinetics, which attempts to capture spatiotemporal changes in breast lesion texture in order to distinguish malignant from benign lesions. We qualitatively and quantitatively demonstrated on 41 breast DCE-MRI studies that textural kinetic features outperform signal intensity kinetics and lesion morphology features in distinguishing benign from malignant lesions. A probabilistic boosting tree (PBT) classifier in conjunction with textural kinetic descriptors yielded an accuracy of 90%, sensitivity of 95%, specificity of 82%, and an area under the curve (AUC) of 0.92. Graph embedding, used for qualitative visualization of a low-dimensional representation of the data, showed the best separation between benign and malignant lesions when using textural kinetic features. The PBT classifier results and trends were also corroborated via a support vector machine classifier which showed that textural kinetic features outperformed the morphological, static texture, and signal intensity kinetics descriptors. When textural kinetic attributes were combined with morphologic descriptors, the resulting PBT classifier yielded 89% accuracy, 99% sensitivity, 76% specificity, and an AUC of 0.91.

Cortical Thickness and Diffusion Properties in the Injured Brain: The Influence of Chronic Health Complaints.

INTRODUCTION: Cortical thickness and diffusion properties can be served as an indicator of aging and other brain changes such as those related to brain injury. It can additionally provide another platform by which we can characterize the injury and its associated symptoms, especially in the chronic condition. METHODS: We examined the changes in cortical thickness and diffusion properties in white matter tracts in 51 patients with and without traumatic brain injury (TBI) and/or self-report chronic symptoms. RESULTS: Significant cortical thinning was observed in the frontal lobe and temporal lobe for TBI patients with chronic symptoms, but not for TBI patients without chronic symptoms, compared with control group. Significant reduction in fractional anisotropy occurred on average across left and right major fiber tracts for TBI patients with chronic symptoms. No mean diffusivity changes were found in any individual white matter tract for TBI patients with or without chronic symptoms. CONCLUSIONS: Traumatic brain injury patients with chronic symptoms have more significant cortical thinning or degeneration of diffusion properties than the mild to severe TBI patients without chronic symptoms. This finding suggests that symptom reporting should be assessed in line with objective measures in clinical practice.

Automated fiber tract reconstruction for surgery planning: Extensive validation in language-related white matter tracts.

Diffusion MRI and tractography hold great potential for surgery planning, especially to preserve eloquent white matter during resections. However, fiber tract reconstruction requires an expert with detailed understanding of neuroanatomy. Several automated approaches have been proposed, using different strategies to reconstruct the white matter tracts in a supervised fashion. However, validation is often limited to comparison with manual delineation by overlap-based measures, which is limited in characterizing morphological and topological differences. In this work, we set up a fully automated pipeline based on anatomical criteria that does not require manual intervention, taking advantage of atlas-based criteria and advanced acquisition protocols available on clinical-grade MRI scanners. Then, we extensively validated it on epilepsy patients with specific focus on language-related bundles. The validation procedure encompasses different approaches, including simple overlap with manual segmentations from two experts, feasibility ratings from external multiple clinical raters and relation with task-based functional MRI. Overall, our results demonstrate good quantitative agreement between automated and manual segmentation, in most cases better performances of the proposed method in qualitative terms, and meaningful relationships with task-based fMRI. In addition, we observed significant differences between experts in terms of both manual segmentation and external ratings. These results offer important insights on how different levels of validation complement each other, supporting the idea that overlap-based measures, although quantitative, do not offer a full perspective on the similarities and differences between automated and manual methods.

Increased Myo-Inositol in Primary Motor Cortex of Contact Sports Athletes without a History of Concussion.

The objective of the study was to determine whether repetitive hits to the head at a subclinical level are associated with structural and functional brain abnormalities and whether these effects are influenced by high levels of fitness associated with intense physical activity. Seventy-two college students were recruited: 24 nonathletic, 24 athletes practicing a varsity contact sport, and 24 athletes practicing a varsity noncontact sport. They were recruited for a neuropsychological evaluation and a magnetic resonance imaging session that included magnetic resonance spectroscopy of primary motor cortex (M1) and prefrontal cortex and susceptibility-weighted imaging. There was no evidence for reduced cognitive performance or presence of micro bleeds in contact sports athletes. Abnormalities in contact sports athletes were found for myo-inositol concentration (mIns) in M1, where levels were significantly higher compared with noncontact sports athletes (p = 0.016) and nonathletes (p = 0.029). In prefrontal cortex, glutamate + glutamine (Glx) was significantly reduced in contact sports athletes compared with noncontact sports athletes (p = 0.016), and a similar reduction was observed for gamma-aminobutyric acid (GABA) levels (p = 0.005). Varsity contact sports are associated with area-specific alterations in mIns concentration in the primary motor cortex. In the prefrontal cortex, high levels of fitness could modulate the effects of head impact exposure on prefrontal metabolite concentration. Indeed, although athletes in contact and noncontact sports show different neurometabolic profiles, they do not differ from sedentary controls.

Integration of neural and epigenetic contributions to posttraumatic stress symptoms: The role of hippocampal volume and glucocorticoid receptor gene methylation.

Many Veterans exposed to physical and psychological trauma experience symptoms of posttraumatic stress disorder (PTSD). As the etiology of PTSD symptoms is complex, a better understanding of the underlying biological mechanisms may improve preventative care and treatment for PTSD. Recent findings from the fields of neuroimaging and epigenetics offer important insights into the potential brain structures and biochemical pathways of modified gene expression associated with PTSD. We combined neuroimaging and epigenetic measures to assess current PTSD symptoms by measuring overall hippocampal volume and methylation of the glucocorticoid receptor (GR) gene (promoter region). Multiple regression analyses indicated that the hippocampal volume/GR methylation interaction was a predictor of PTSD symptoms. Our findings suggest that neuroimaging and epigenetic measures contribute interactively to PTSD symptoms. Incorporation of these metrics may aid in the identification and treatment of PTSD patients.

Convergence Analysis of Micro-Lesions (CAML): An approach to mapping of diffuse lesions from carotid revascularization.

Carotid revascularization (endarterectomy, stenting) prevents stroke; however, procedure-related embolization is common and results in small brain lesions easily identified by diffusion weighted magnetic resonance imaging (DWI). A crucial barrier to understanding the clinical significance of these lesions has been the lack of a statistical approach to identify vulnerable brain areas. The problem is that the lesions are small, numerous, and non-overlapping. Here we address this problem with a new method, the Convergence Analysis of Micro-Lesions (CAML) technique, an extension of the Anatomic Likelihood Analysis (ALE). The method combines manual lesion tracing, constraints based on known lesion patterns, and convergence analysis to represent regions vulnerable to lesions as probabilistic brain atlases. Two studies were conducted over the course of 12 years in an active, vascular surgery clinic. An analysis in an initial group of 126 patients at 1.5 T MRI was cross-validated in a second group of 80 patients at 3T MRI. In CAML, lesions were manually defined and center points identified. Brains were aligned according to side of surgery since this factor powerfully determines lesion distribution. A convergence based analysis, was performed on each of these groups. Results indicated the most consistent region of vulnerability was in motor and premotor cortex regions. Smaller regions common to both groups included the dorsolateral prefrontal cortex and medial parietal regions. Vulnerability of motor cortex is consistent with previous work showing changes in hand dexterity associated with these procedures. The consistency of CAML also demonstrates the feasibility of this new approach to characterize small, diffuse, non-overlapping lesions in patients with multifocal pathologies.