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To determine if history of mild traumatic brain injury (mTBI) is associated with advanced or accelerated brain aging among the United States (US) military Service Members and Veterans. Eight hundred and twenty-two participants (mean age = 40.4 years, 714 male/108 female) underwent MRI sessions at eight sites across the US. Two hundred and one participants completed a follow-up scan between five months and four years later. Predicted brain ages were calculated using T1-weighted MRIs and then compared with chronological ages to generate an Age Deviation Score for cross-sectional analyses and an Interval Deviation Score for longitudinal analyses. Participants also completed a neuropsychological battery, including measures of both cognitive functioning and psychological health. In cross-sectional analyses, males with a history of deployment-related mTBI showed advanced brain age compared to those without (t(884) = 2.1, p = .038), while this association was not significant in females. In follow-up analyses of the male participants, severity of posttraumatic stress disorder (PTSD), depression symptoms, and alcohol misuse were also associated with advanced brain age. History of deployment-related mTBI, severity of PTSD and depression symptoms, and alcohol misuse are associated with advanced brain aging in male US military Service Members and Veterans.

Radiotherapy for pediatric brain tumors is associated with reduced white matter structural integrity and neurocognitive decline. Superior cognitive outcomes have been reported following proton radiotherapy (PRT) compared to photon radiotherapy (XRT), presumably due to improved sparing of normal brain tissue. This exploratory study examined the relationship between white matter change and late cognitive effects in pediatric brain tumor survivors treated with XRT versus PRT. Pediatric brain tumor survivors treated with XRT (n = 10) or PRT (n = 12) underwent neuropsychological testing and diffusion weighted imaging >7 years post-radiotherapy. A healthy comparison group (n = 23) was also recruited. Participants completed age-appropriate measures of intellectual functioning, visual-motor integration, and motor coordination. Tractography was conducted using automated fiber quantification (AFQ). Fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD) were extracted from 12 tracts of interest. Overall, both white matter integrity (FA) and neuropsychological performance were lower in XRT patients while PRT patients were similar to healthy control participants with respect to both FA and cognitive functioning. These findings support improved long-term outcomes in PRT versus XRT. This exploratory study is the first to directly support for white matter integrity as a mechanism of cognitive sparing in PRT.

BACKGROUND The learning slope is typically represented as the raw difference between the final score and the score of the first learning trial. A new method for calculating the learning slope, the learning ratio (LR), was recently developed; it is typically represented as the number of items that are learned after the first trial divided by the number of items that are yet to be learned. OBJECTIVE To evaluate the convergent and criterion validity of the LR in order to understand its sensitivity to Alzheimer disease (AD) pathology. METHOD Fifty-six patients from a memory clinic underwent standard neuropsychological assessment and quantitative brain imaging. LR scores were calculated from the Hopkins Verbal Learning Test-Revised and the Brief Visuospatial Memory Test-Revised and were compared with both standard memory measures and total hippocampal volumes, as well as between individuals with AD and those with mild cognitive impairment. RESULTS Lower LR scores were consistently associated with poorer performances on standard memory measures and smaller total hippocampal volumes, generally more so than traditional learning slope scores. The LR scores of the AD group were smaller than those of the group with mild cognitive impairment. Furthermore, the aggregation of LR scores into a single metric was partially supported. CONCLUSION The LR is sensitive to AD pathology along the AD continuum. This result supports previous claims that the LR score can reflect learning capacity better than traditional learning calculations can by considering the amount of information that is learned at trial 1.

This study investigated patterns of cortical organization in adolescents who had sustained a traumatic brain injury (TBI) during early childhood to determine ways in which early head injury may alter typical brain development. Increased gyrification in other patient populations is associated with polymicrogyria and aberrant development, but this has not been investigated in TBI. Seventeen adolescents (mean age = 14.1 ± 2.4) who sustained a TBI between 1–8 years of age, and 17 demographically-matched typically developing children (TDC) underwent a high-resolution, T1-weighted 3-Tesla magnetic resonance imaging (MRI) at 6–15 years post-injury. Cortical white matter volume and organization was measured using FreeSurfer's Local Gyrification Index (LGI). Despite a lack of significant difference in white matter volume, participants with TBI demonstrated significantly increased LGI in several cortical regions that are among those latest to mature in normal development, including left parietal association areas, bilateral dorsolateral and medial frontal areas, and the right posterior temporal gyrus, relative to the TDC group. Additionally, there was no evidence of increased surface area in the regions that demonstrated increased LGI. Higher Vineland-II Socialization scores were associated with decreased LGI in right frontal and temporal regions. The present results suggest an altered pattern of expected development in cortical gyrification in the TBI group, with changes in late-developing frontal and parietal association areas. Such changes in brain structure may underlie cognitive and behavioral deficits associated with pediatric TBI. Alternatively, increased gyrification following TBI may represent a compensatory mechanism that allows for typical development of cortical surface area, despite reduced brain volume.

Studies of brain morphometry may illuminate the effects of pediatric mild traumatic brain injury (TBI; e.g., concussion). However, no published studies have examined cortical thickness in the early injury phases of pediatric mild TBI using an appropriate comparison group. The current study used an automated approach (i.e., FreeSurfer) to determine whether cortical thickness differed in children following a mild TBI or a mild orthopedic injury (OI), and to examine whether post-acute cortical thickness predicted post-acute and chronic post-concussive symptoms (PCS). Children ages 8.00-16.99 years with mild TBI (n = 136) or OI (n = 70) were recruited at emergency department visits to two children's hospitals, during which parents rated children's pre-injury symptoms retrospectively. Children completed a post-acute (3–24 days post-injury) assessment, which included a 3 Tesla MRI, and 3- and 6-month post-injury assessments. Parents and children rated PCS at each assessment. Cortical thickness was estimated using FreeSurfer. Linear mixed effects and multi-variable negative binomial regression models were used to test study aims, with false discovery rate (FDR) correction for multiple comparisons. Groups differed significantly on left parietal cortical thickness (TBI > OI) after FDR correction. Cortical thickness also varied by brain subregion and age, but not sex. Groups differed significantly on PCS post-acutely (TBI > OI), but not at 3 or 6 months. Right frontal thickness was positively related to post-acute PCS in both groups. Right cingulum thickness predicted chronic PCS in the OI group only. Results highlight the complexity of predicting outcomes of pediatric mild TBI from post-acute neuroimaging biomarkers.

Convergent validation of a verbal incidental learning (IL) task from the WAIS-IV using neuroimaging biomarkers is warranted to understand its sensitivity to Alzheimer's disease (AD) pathology. Fifty-five memory clinic patients aged 59 to 87 years received neuropsychological assessment, and measures of IL and quantitative brain imaging. Worse IL-Total Score and IL-Similarities performances were significantly associated with smaller hemispheric hippocampal volumes. IL measures were not significantly correlated with cerebral β-amyloid burden, though a trend was present and effect sizes were mild. These hippocampal volume results suggest that this IL task may be sensitive to AD pathology along the AD continuum.

Childhood traumatic brain injury (TBI) affects over 600 000 children per year in the United States. Following TBI, children are vulnerable to deficits in psychosocial adjustment and neurocognition, including social cognition, which persist long-term. They are also susceptible to direct and secondary damage to related brain networks. In this study, we examine whether brain morphometry of the mentalizing network (MN) and theory of mind (ToM; one component of social cognition) mediates the effects of TBI on adjustment. Children with severe TBI (n = 15, Mage = 10.32), complicated mild/moderate TBI (n = 30, Mage = 10.81) and orthopedic injury (OI; n = 42, Mage = 10.65) completed measures of ToM and executive function and underwent MRI; parents rated children’s psychosocial adjustment. Children with severe TBI demonstrated reduced right-hemisphere MN volume, and poorer ToM, vs children with OI. Ordinary least-squares path analysis indicated that right-hemisphere MN volume and ToM mediated the association between severe TBI and adjustment. Parallel analyses substituting the central executive network and executive function were not significant, suggesting some model specificity. Children at greatest risk of poor adjustment after TBI could be identified based in part on neuroimaging of social brain networks and assessment of social cognition and thereby more effectively allocate limited intervention resources.

Objective: While Spencer's verbal incidental learning (IL) task-from Vocabulary and Similarities subtests of the WAIS-has been validated relative to traditional memory measures and Alzheimer's disease (AD) pathology, the effectiveness of the particular scoring method used has not been assessed relative to alternative scoring weightings. The purpose of this study was to compare original and alternative scoring methods of this IL task by using an AD biomarker-benchmark to arrive at an optimal approach. Methods: Fifty-five memory-clinic patients aged 59-87 received neuropsychological assessment, measures of IL, and quantitative brain imaging. Partial correlation coefficients with total hippocampal volume-controlling for age, sex, and intracranial volume-were assessed across several IL scoring methods, and partial correlations with measures of memory were examined to evaluate convergent validity.Results: IL scoring methods maximizing the contribution of paired-associate-recall-performance were significantly correlated with both hippocampal volumes and traditional memory measures, whereas discrimination-emphasized scoring methods were not.Conclusions: IL scoring methods emphasizing memory paired-associate recall appeared to be preferable to those emphasizing memory discrimination. Administration of the IL- Similarities subtest alone, without IL- Vocabulary, may strike a balance between strength of relationships with both hippocampal volumes and standard memory measures, while also limiting administration time.

The learning slope is typically represented as the raw difference between the final score and the score of the first learning trial. A new method for calculating the learning slope, the learning ratio (LR), was recently developed; it is typically represented as the number of items that are learned after the first trial divided by the number of items that are yet to be learned.To evaluate the convergent and criterion validity of the LR in order to understand its sensitivity to Alzheimer disease (AD) pathology.Fifty-six patients from a memory clinic underwent standard neuropsychological assessment and quantitative brain imaging. LR scores were calculated from the Hopkins Verbal Learning Test-Revised and the Brief Visuospatial Memory Test-Revised and were compared with both standard memory measures and total hippocampal volumes, as well as between individuals with AD and those with mild cognitive impairment.Lower LR scores were consistently associated with poorer performances on standard memory measures and smaller total hippocampal volumes, generally more so than traditional learning slope scores. The LR scores of the AD group were smaller than those of the group with mild cognitive impairment. Furthermore, the aggregation of LR scores into a single metric was partially supported.The LR is sensitive to AD pathology along the AD continuum. This result supports previous claims that the LR score can reflect learning capacity better than traditional learning calculations can by considering the amount of information that is learned at trial 1.

Automated neuroimaging methods like FreeSurfer ( https://surfer.nmr.mgh.harvard.edu/ ) have revolutionized quantitative neuroimaging analyses. Such analyses provide a variety of metrics used for image quantification, including magnetic resonance imaging (MRI) volumetrics. With the release of FreeSurfer version 6.0, it is important to assess its comparability to the widely-used previous version 5.3. The current study used data from the initial 249 participants in the ongoing Chronic Effects of Neurotrauma Consortium (CENC) multicenter observational study to compare the volumetric output of versions 5.3 and 6.0 across various regions of interest (ROI). In the current investigation, the following ROIs were examined: total intracranial volume, total white matter volume, total ventricular volume, total gray matter volume, and right and left volumes for the thalamus, pallidum, putamen, caudate, amygdala and hippocampus. Absolute ROI volumes derived from FreeSurfer 6.0 differed significantly from those obtained using version 5.3. We also employed a clinically-based evaluation strategy to compare both versions in their prediction of age-mediated volume reductions (or ventricular increase) in the aforementioned structures. Statistical comparison involved both general linear modeling (GLM) and random forest (RF) methods, where cross-validation error was significantly higher using segmentations from FreeSurfer version 5.3 versus version 6.0 (GLM: t = 4.97, df = 99, p value = 2.706e-06; RF: t = 4.85, df = 99, p value = 4.424e-06). Additionally, the relative importance of ROIs used to predict age using RFs differed between FreeSurfer versions, indicating substantial differences in the two versions. However, from the perspective of correlational analyses, fitted regression lines and their slopes were similar between the two versions, regardless of version used. While absolute volumes are not interchangeable between version 5.3 and 6.0, ROI correlational analyses appear to yield similar results, suggesting the interchangeability of ROI volume for correlational studies.

This investigation explored whether differences in cortical thickness could be detected in children who sustained a mild traumatic brain injury (mTBI) compared to those with orthopedic injury (OI) and whether cortical thickness related parental reporting of symptoms. To achieve this objective, FreeSurfer®-based cortical thickness measures were obtained in 330 children, 8 to 15 years of age, with either a history of mTBI or OI. Imaging was performed in all participants with the same 3 Tesla MRI scanner at six-months post-injury, where a parent-rated Post-Concussion Symptom Inventory (PCSI) was also obtained. Robust age-mediated reductions in cortical thickness were observed, but no consistent group-based differences between the mTBI and OI groups were observed. Also, the relation between mechanism of injury (i.e., sports-related, recreational, fall, motor vehicle accident or other) and cortical thickness was examined. Injuries associated with any type of abuse were excluded and children with OI could not have experienced a MVA. Mechanism of injury did not differentially relate to cortical thickness, although in the fall group, parental rating using the PCSI showed increased symptom reporting to be associated with reduced cortical thickness in the left interior frontal, temporal pole and lateral temporal lobe as well as in the right temporal pole. Results from these preliminary findings are discussed in terms of injury variables and developmental factors associated with mTBI in childhood.

Multisite and longitudinal neuroimaging studies are important in uncovering trajectories of recovery and neurodegeneration following traumatic brain injury (TBI) and concussion through the use of diffusion tensor imaging (DTI) and other imaging modalities. This study assessed differences in anisotropic diffusion measurement across four scanners using a human and a novel phantom developed in conjunction with the Chronic Effects of Neurotrauma Consortium.Human scans provided measurement within biological tissue, and the novel physical phantom provided measures of anisotropic intra-tubular diffusion to serve as a model for intra-axonal water diffusion. Intra- and inter-scanner measurement variances were compared, and the impact on effect size was calculated.Intra-scanner test-retest reliability estimates for fractional anisotropy (FA) demonstrated relative stability over testing intervals. The human tissue and phantom showed similar FA ranges, high linearity and large within-device effect sizes. However, inter-scanner measures of FA indicated substantial differences, some of which exceeded typical DTI effect sizes in mild TBI.The diffusion phantom may be used to better elucidate inter-scanner variability in DTI-based measurement and provides an opportunity to better calibrate results obtained from scanners used in multisite and longitudinal studies. Novel solutions are being evaluated to understand and potentially overcome these differences.

NeuroQuant® (NQ) and FreeSurfer (FS) are commonly used computer-automated programs for measuring MRI brain volume. Previously they were reported to have high intermethod reliabilities but often large intermethod effect size differences. We hypothesized that linear transformations could be used to reduce the large effect sizes. This study was an extension of our previously reported study. We performed NQ and FS brain volume measurements on 60 subjects (including normal controls, patients with traumatic brain injury, and patients with Alzheimer's disease). We used two statistical approaches in parallel to develop methods for transforming FS volumes into NQ volumes: traditional linear regression, and Bayesian linear regression. For both methods, we used regression analyses to develop linear transformations of the FS volumes to make them more similar to the NQ volumes. The FS-to-NQ transformations based on traditional linear regression resulted in effect sizes which were small to moderate. The transformations based on Bayesian linear regression resulted in all effect sizes being trivially small. To our knowledge, this is the first report describing a method for transforming FS to NQ data so as to achieve high reliability and low effect size differences. Machine learning methods like Bayesian regression may be more useful than traditional methods.

Investigate the relation of chronic pain interference to functional connectivity (FC) of brain regions and to cortical thickness in post-911 Veterans and Service Members (SMs) who sustained a mild traumatic brain injury (mTBI).This is an observational study with cross-sectional analyses. A sample of 65 enrollees completing initial evaluation at a single site of the Chronic Effects of Neurotrauma Consortium (CENC) reported pain interference ratings on the TBI QOL. Functional connectivity and cortical thickness were measured.Severity of pain interference was negatively related to FC of the default mode network (DMN), i.e., participants who reported more severe pain interference had less FC between mesial prefrontal cortex and posterior regions of the DMN including posterior cingulate cortex and precuneus. Cortical thickness of specific regions was positively related to severity of pain interference.The more that pain was perceived to interfere with daily life, the less the FC between regions in a network associated with self-referential thought and mind wandering. Although cortical thickness in specific brain regions was positively related to severity of pain interference, follow-up longitudinal data, control group data, and study of individual differences in this cohort will expand this initial report and replicate these findings.

Studies have shown that individuals with autism spectrum disorder (ASD) tend to perform significantly below typically developing individuals on standardized measures of attention, even when controlling for IQ. The current study sought to examine within ASD whether anatomical correlates of attention performance differed between those with average to above-average IQ (AIQ group) and those with low-average to borderline ability (LIQ group) as well as in comparison to typically developing controls (TDC). Using automated volumetric analyses, we examined regional volume of classic attention areas including the superior frontal gyrus, anterior cingulate cortex, and precuneus in ASD AIQ (n = 38) and LIQ (n = 18) individuals along with 30 TDC. Auditory attention performance was assessed using subtests of the Test of Memory and Learning (TOMAL) compared among the groups and then correlated with regional brain volumes. Analyses revealed group differences in attention. The three groups did not differ significantly on any auditory attention-related brain volumes; however, trends toward significant size-attention function interactions were observed. Negative correlations were found between the volume of the precuneus and auditory attention performance for the AIQ ASD group, indicating larger volume related to poorer performance. Implications for general attention functioning and dysfunctional neural connectivity in ASD are discussed.

Although there are several techniques to analyze diffusion-weighted imaging, any technique must be sufficiently sensitive to detect clinical abnormalities. This is especially critical in disorders like mild traumatic brain injury (mTBI), where pathology is likely to be subtle. mTBI represents a major public health concern, especially for youth under 15 years of age. However, the developmental period from birth to 18 years is also a time of tremendous brain changes. Therefore, it is important to establish the degree of age- and sex-related differences. Participants were children aged 8–15 years with mTBI or mild orthopedic injuries (OI). Imaging was obtained within 10 days of injury. We performed tract-based spatial statistics (TBSS), deterministic tractography using AFQ (Automated Fiber Quantification), and probabilistic tractography using TRACULA (TRActs Constrained by UnderLying Anatomy) to evaluate whether any method provided improved sensitivity at identifying group, developmental, and/or sex-related differences. Although, there were no group differences from any of the three analyses, many of the tracts, but not all, revealed increases of fractional anisotropy (FA) and decreases of axial, radial, and mean diffusivity (AD, RD, and MD, respectively) with age. TBSS analyses resulted in age-related changes across all white matter tracts. AFQ and TRACULA revealed age-related changes within the corpus callosum, cingulum cingulate, corticospinal tract, inferior and superior longitudinal fasciculus, and uncinate fasciculus. The results are in many ways consistent across all three methods. However, results from the tractography methods provided improved sensitivity and better tract-specific results for identifying developmental and sex-related differences within the brain.

Introduction: Mild traumatic brain injury (TBI) is a global public health concern that affects millions of children annually. Mild TBI tends to result in subtle and diffuse alterations in brain tissue, which challenges accurate clinical detection and prognostication. Diffusion tensor imaging (DTI) holds promise as a diagnostic and prognostic tool, but little research has examined DTI in post-acute mild TBI. The current study compared post-acute white matter microstructure in children with mild TBI versus those with mild orthopedic injury (OI), and examined whether post-acute DTI metrics can predict post-acute and chronic post-concussive symptoms (PCS). Materials and methods: Children aged 8–16.99 years with mild TBI (n = 132) or OI (n = 69) were recruited at emergency department visits to two children's hospitals, during which parents rated children's pre-injury symptoms retrospectively. Children completed a post-acute (

Objectives The chronic effects of neurotrauma consortium (CENC) observational study is a multisite investigation designed to examine the long-term longitudinal effects of mild traumatic brain injury (mTBI). All participants in this initial CENC cohort had a history of deployment in Operation Enduring Freedom (Afghanistan), Operation Iraqi Freedom (Iraq), and/or their follow-on conflicts (Operation Freedom's Sentinel). All participants undergo extensive medical, neuropsychological, and neuroimaging assessments and either meet criteria for any lifetime mTBI or not. These assessments are integrated into six CENC core studies-Biorepository, Biostatistics, Data and Study Management, Neuroimaging, and Neuropathology. Methods The current study outlines the quantitative neuroimaging methods managed by the Neuroimaging Core using FreeSurfer automated software for image quantification. Results At this writing, 319 participants from the CENC observational study have completed all baseline assessments including the imaging protocol and tertiary data quality assurance procedures. Conclusions/discussion The preliminary findings of this initial cohort are reported to describe how the Neuroimaging Core manages neuroimaging quantification for CENC studies.

White matter hyperintensities (WMHs) are foci of abnormal signal intensity in white matter regions seen with magnetic resonance imaging (MRI). WMHs are associated with normal ageing and have shown prognostic value in neurological conditions such as traumatic brain injury (TBI). The impracticality of manually quantifying these lesions limits their clinical utility and motivates the utilization of machine learning techniques for automated segmentation workflows.This study develops a concatenated random forest framework with image features for segmenting WMHs in a TBI cohort. The framework is built upon the Advanced Normalization Tools (ANTs) and ANTsR toolkits. MR (3D FLAIR, T2- and T1-weighted) images from 24 service members and veterans scanned in the Chronic Effects of Neurotrauma Consortium's (CENC) observational study were acquired. Manual annotations were employed for both training and evaluation using a leave-one-out strategy. Performance measures include sensitivity, positive predictive value, [Formula: see text] score and relative volume difference.Final average results were: sensitivity = 0.68 ± 0.38, positive predictive value = 0.51 ± 0.40, [Formula: see text] = 0.52 ± 0.36, relative volume difference = 43 ± 26%. In addition, three lesion size ranges are selected to illustrate the variation in performance with lesion size.Paired with correlative outcome data, supervised learning methods may allow for identification of imaging features predictive of diagnosis and prognosis in individual TBI patients.

An important component of the multicentre Chronic Effects of Neurotrauma Consortium (CENC) project is the development of improved quantitative magnetic resonance imaging (MRI) methods, including volumetric analysis. Although many studies routinely employ quality assurance (QA) procedures including MR and human phantoms to promote accuracy and monitor site differences, few studies perform rigorous direct comparisons of these data nor report findings that enable inference regarding site-to-site comparability. These gaps in evaluating cross-site differences are concerning, especially given the well-established differences that can occur between data acquired on scanners with different manufacturer, hardware or software.This study reports findings on (1) a series of studies utilizing two MR phantoms to interrogate machine-based variability using data collected on the same magnet, (2) a human phantom repeatedly imaged on the same scanner to investigate within-subject, within-site variability and (3) a human phantom imaged on three different scanners to examine within subject, between-site variability.Although variability is relatively minimal for the phantom scanned on the same magnet, significantly more variability is introduced in a human subject, particularly when regions are relatively small or multiple sites used.Vigilance when combining data from different sites is suggested and that future efforts address these issues.

In a sample of children with traumatic brain injury, this magnetic resonance imaging (MRI)–based investigation examined whether presence of a focal lesion uniquely influenced cortical thickness in any brain region. Specifically, the study explored the relation of cortical thickness to injury severity as measured by Glasgow Coma Scale score and length of stay, along with presence of encephalomalacia, focal white matter lesions or presence of hemosiderin deposition as a marker of shear injury. For comparison, a group of children without head injury but with orthopedic injury of similar age and sex were also examined. Both traumatic brain injury and orthopedic injury children had normally reduced cortical thickness with age, assumed to reflect neuronal pruning. However, the reductions observed within the traumatic brain injury sample were similar to those in the orthopedic injury group, suggesting that in this sample traumatic brain injury, per se, did not uniquely alter cortical thickness in any brain region at the group level. Injury severity in terms of Glasgow Coma Scale or longer length of stay was associated with greater reductions in frontal and occipitoparietal cortical thickness. However, presence of focal lesions were not related to unique changes in cortical thickness despite having a prominent distribution of lesions within frontotemporal regions among children with traumatic brain injury. Because focal lesions were highly heterogeneous, their association with cortical thickness and development appeared to be idiosyncratic, and not associated with group level effects.

Microstructural neuropathology occurs in the corpus callosum (CC) after repetitive sports concussion in boxers and can be dose-dependent. However, the specificity and relation of CC changes to boxing exposure extent and post-career psychiatric and neuropsychological outcomes are largely unknown. Using deterministic diffusion tensor imaging (DTI) techniques, boxers and demographically-matched, noncontact sport athletes were compared to address literature gaps. Ten boxers and 9 comparison athletes between 26 and 59 years old (M = 44.63, SD = 9.24) completed neuropsychological testing and MRI. Quantitative DTI metrics were estimated for CC subregions. Group×Region interaction effects were observed on fractional anisotropy (FA; η2p ≥ .21). Follow-up indicated large effects of group (η2p ≥ .26) on splenium FA (boxers comparisons), but not radial diffusivity (RD). The group of boxers had moderately elevated number of psychiatric symptoms and reduced neuropsychological scores relative to the comparison group. In boxers, years sparring, professional bouts, and knockout history correlated strongly (r > |.40|) with DTI metrics and fine motor dexterity. In the comparison group, splenium FA correlated positively with psychiatric symptoms. In the boxer group, neuropsychological scores correlated with DTI metrics in all CC subregions. Results suggested relative vulnerability of the splenium and, to a lesser extent, the genu to chronic, repetitive head injury from boxing. Dose-dependent associations of professional boxing history extent with DTI white matter structure indices as well as fine motor dexterity were supported. Results indicated that symptoms of depression and executive dysfunction may provide the strongest indicators of global CC disruption from boxing.

The authors have presented a case of a 14-year-old male who suffered a severe traumatic brain injury. His narrative is derived from follow-up over an interval from 1-week postinjury through 24-year postinjury by virtue of participation in a prospective longitudinal follow-up study. This chapter summarizes his postinjury course from age 14 to 22 years previously published and extends the description of his course to 38 years of age. In contrast to the famous case of Phineas Gage who came to represent the classical poor outcome after traumatic brain injury, we have named him Phineas Re-enGage to emphasize his sustained positive quality of life changes in multiple domains of function that occurred after 11 years of severe postinjury psychiatric, socio-emotional, and occupational dysfunction. The chapter discusses biopsychosocial aspects of outcome of pediatric traumatic brain injury.

The relationship between brain development and clinical heterogeneity in autism (ASD) is unknown. This study examines the Social Responsiveness Scale (SRS) in relation to the longitudinal development of cortical thickness. Participants (N = 91 ASD, N = 56 TDC; 3–39 years at first scan) were scanned up to three times over a 7-year period. Mixed-effects models examined cortical thickness in relation to SRS score. ASD participants with higher SRS scores showed regionally increased age-related cortical thinning. Regional thickness differences and reduced age-related cortical thinning were found in predominantly right lateralized regions in ASD with decreasing SRS scores over time. Our findings emphasize the importance of examining clinical phenotypes in brain-based studies of ASD.

Traumatic brain injury (TBI) is a significant cause of morbidity in military Veterans and Service Members. While most individuals recover fully from mild injuries within weeks, some continue to experience symptoms including headaches, disrupted sleep, and other cognitive, behavioral or physical symptoms. Diffusion magnetic resonance imaging (dMRI) shows promise in identifying areas of structural disruption and predicting outcomes. Although some studies suggest widespread structural disruption after brain injury, dMRI studies of military brain injury have yielded mixed results so far, perhaps due to the subtlety of mild injury, individual differences in injury location, severity and mechanism, and co-morbidity with other disorders such as post-traumatic stress disorder (PTSD), depression, and substance abuse. We present preliminary dMRI results from the ENIGMA (Enhancing NeuroImaging Genetics through Meta-Analysis) military brain injury working group. We found higher fractional anisotropy (FA) in participants with a history of TBI. Understanding the injury and recovery process, along with factors that influence these, will lead to improved diagnosis and treatment.

PURPOSE To examine intermethod reliabilities and differences between FreeSurfer and the FDA-cleared congener, NeuroQuant®, both fully automated methods for structural brain MRI measurements. MATERIALS AND METHODS MRI scans from 20 normal control subjects, 20 Alzheimer's disease patients, and 20 mild traumatically brain-injured patients were analyzed with NeuroQuant® and with FreeSurfer. Intermethod reliability was evaluated. RESULTS Pairwise correlation coefficients, intraclass correlation coefficients, and effect size differences were computed. NeuroQuant® versus FreeSurfer measures showed excellent to good intermethod reliability for the 21 regions evaluated (r: .63 to .99/ICC: .62 to .99/ES: –.33 to 2.08) except for the pallidum (r/ICC/ES = .31/.29/–2.2) and cerebellar white matter (r/ICC/ES = .31/.31/.08). Volumes reported by NeuroQuant were generally larger than those reported by FreeSurfer with the whole brain parenchyma volume reported by NeuroQuant 6.50% larger than the volume reported by FreeSurfer. There was no systematic difference in results between the 3 subgroups. CONCLUSION NeuroQuant® and FreeSurfer showed good to excellent intermethod reliability in volumetric measurements for all brain regions examined with the only exceptions being the pallidum and cerebellar white matter. This finding was robust for normal individuals, patients with Alzheimer's disease, and patients with mild traumatic brain injury.

Studies have shown that individuals with autism spectrum disorder (ASD) tend to perform significantly below typical developing individuals on standardized measures of memory, even when not significantly different on measures of IQ. The current study sought to examine within ASD whether anatomical correlates of memory performance differed between those with average-to-above-average IQ (AIQ group) and those with low-average to borderline ability (LIQ group) as well as in relations to typically developing comparisons (TDC). Using automated volumetric analyses, we examined regional volume of classic memory areas including the hippocampus, parahippocampal gyrus, entorhinal cortex, and amygdala in an all-male sample AIQ (n = 38) and LIQ (n = 18) individuals with ASD along with 30 typically developing comparisons (TDC). Memory performance was assessed using the Test of Memory and Learning (TOMAL) compared among the groups and then correlated with regional brain volumes. Analyses revealed group differences on almost all facets of memory and learning as assessed by the various subtests of the TOMAL. The three groups did not differ on any region of interest (ROI) memory-related brain volumes. However, significant size-memory function interactions were observed. Negative correlations were found between the volume of the amygdala and composite, verbal, and delayed memory indices for the LIQ ASD group, indicating larger volume related to poorer performance. Implications for general memory functioning and dysfunctional neural connectivity in ASD are discussed.

NeuroQuant

Heightened auditory sensitivity and atypical auditory processing are common in autism. Functional studies suggest abnormal neural response and hemispheric activation to auditory stimuli, yet the neurodevelopment underlying atypical auditory function in autism is unknown. In this study, we model longitudinal volumetric growth of Heschl's gyrus gray matter and white matter during childhood and adolescence in 40 individuals with autism and 17 typically developing participants. Up to three time points of magnetic resonance imaging data, collected on average every 2.5 years, were examined from individuals 3-12 years of age at the time of their first scan. Consistent with previous cross-sectional studies, no group differences were found in Heschl's gyrus gray matter volume or asymmetry. However, reduced longitudinal gray matter volumetric growth was found in the right Heschl's gyrus in autism. Reduced longitudinal white matter growth in the left hemisphere was found in the right-handed autism participants. Atypical Heschl's gyrus white matter volumetric growth was found bilaterally in the autism individuals with a history of delayed onset of spoken language. Heightened auditory sensitivity, obtained from the Sensory Profile, was associated with reduced volumetric gray matter growth in the right hemisphere. Our longitudinal analyses revealed dynamic gray and white matter changes in Heschl's gyrus throughout childhood and adolescence in both typical development and autism.

Despite repeated findings of abnormal corpus callosum structure in autism, the developmental trajectories of corpus callosum growth in the disorder have not yet been reported. In this study, we examined corpus callosum size from a developmental perspective across a 30-year age range in a large cross-sectional sample of individuals with autism compared to a typically developing sample. Midsagittal corpus callosum area and the 7 Witelson subregions were examined in 68 males with autism (mean age 14.1 years; range 3–36 years) and 47 males with typical development (mean age 15.3 years; range 4–29 years). Controlling for total brain volume, increased variability in total corpus callosum area was found in autism. In autism, increased midsagittal areas were associated with reduced severity of autism behaviors, higher intelligence, and faster speed of processing (p=0.003, p=0.011, p=0.013, respectively). A trend toward group differences in isthmus development was found (p=0.029, uncorrected). These results suggest that individuals with autism benefit functionally from increased corpus callosum area. Our cross-sectional examination also shows potential maturational abnormalities in autism, a finding that should be examined further with longitudinal datasets.

This study examined peer relationships in children with traumatic brain injury (TBI) relative to children with orthopedic injuries (OI), and explored whether differences in peer relationships correlated with white matter volumes. Classroom procedures were used to elicit peer perceptions of social behavior, acceptance, and friendships for eighty-seven 8- to 13-year-old children, 15 with severe TBI, 40 with complicated mild/moderate TBI, and 32 with OI. Magnetic resonance imaging (MRI) and voxel-based morphometry (VBM) were used to investigate volumetric correlates of peer relationship measures. Children with severe TBI were rated higher in rejection-victimization than children with OI, and were less likely than children with OI to have a mutual friendship in their classroom (47% vs. 88%). Children with TBI without a mutual friend were rated lower than those with a mutual friend on sociability-popularity and prosocial behavior and higher on rejection-victimization, and had lower peer acceptance ratings. Mutual friendship ratings were related to white matter volumes in several posterior brain regions, but not to overall brain atrophy. Severe TBI in children is associated with detrimental peer relationships that are related to focal volumetric reductions in white matter within regions of the brain involved in social information-processing. (JINS, 2013, 19, 1–10)

Common neuroimaging findings in mild traumatic brain injury (mTBI), including sport-related concussion (SRC), are reviewed based on computed tomography and magnetic resonance imaging (MRI). Common abnormalities radiologically identified on the day of injury, typically a computed tomographic scan, are in the form of contusions, small subarachnoid or intraparenchymal hemorrhages as well as subdural and epidural collections, edema, and skull fractures. Common follow-up neuroimaging findings with MRI include white matter hyperintensities, hypointense signal abnormalities that reflect prior hemorrhage, focal encephalomalacia, presence of atrophy and/or dilated Virchow-Robins perivascular space. The MRI findings from a large pediatric mTBI study show low frequency of positive MRI findings at 6 months postinjury. The review concludes with an examination of some of the advanced MRI-based image analysis methods that can be performed in the patient who has sustained an mTBI.

This investigation had two main objectives: 1) to assess the comparability of volumes determined by operator-controlled image quantification with automated image analysis in evaluating atrophic brain changes related to traumatic brain injury (TBI) in children, and 2) to assess the extent of diffuse structural changes throughout the brain as determined by reduced volume of a brain structure or region of interest (ROI). Operator-controlled methods used ANALYZE software for segmentation and tracing routines of pre-defined brain structures and ROIs. For automated image analyses, the open-access FreeSurfer program was used. Sixteen children with moderate-to-severe TBI were compared to individually matched, typically developing control children and the volumes of 18 brain structures and/or ROIs were compared between the two methods. Both methods detected atrophic changes but differed in the magnitude of the atrophic effect with the best agreement in subcortical structures. The volumes of all brain structures/ROIs were smaller in the TBI group regardless of method used; overall effect size differences were minimal for caudate and putamen but moderate to large for all other measures. This is reflective of the diffuse nature of TBI and its widespread impact on structural brain integrity, indicating that both FreeSurfer and operator-controlled methods can reliably assess cross-sectional volumetric changes in pediatric TBI.

Post-traumatic seizures affect 12-35% of children after traumatic brain injury (TBI) and are associated with worse cognitive and functional outcome, even after adjustment for severity of injury. Unfortunately, experimental models of pediatric post-traumatic epilepsy are lacking, and pathogenesis remains poorly understood. We have applied a standard model of TBI in immature rats to determine the effect of TBI on electroconvulsive seizure thresholds later in life. Male rats underwent controlled cortical impact to left parietal cortex on post-natal day (PND) 16-18. Hindbrain, forebrain, and limbic seizure thresholds were assessed, respectively, by tonic hindlimb extension (THE), minimal clonic, and partial psychomotor seizure responses during adolescence (PND 34-40) and at maturity (PND 60-63). Post-traumatic seizure thresholds were compared to those obtained in age- and litter-matched sham craniotomy and naive controls. TBI during immaturity had no clear effect on THE seizure thresholds. In contrast, TBI lowered minimal clonic seizure thresholds at maturity (p

Complicated mild traumatic brain injury (mTBI) or cmTBI is based on the presence of visibly identifiable brain pathology on the day-of-injury computed tomography (CT) scan. In a paediatric sample the relation of DOI CT to late MRI findings and neuropsychological outcome was examined.MRI (12 months) was obtained in paediatric cmTBI patients and a sample of orthopaedically injured (OI) children. Those children with positive imaging findings (MRI+) were quantitatively compared to those without (MRI-) or with the OI sample. Groups were also compared in neurocognitive outcome from WASI sub-tests and the WISC-IV Processing Speed Index (PSI), along with the Test of Everyday Attention for Children (TEA-Ch) and a parent-rated behavioural functioning measure (ABAS-II).Despite the MRI+ group having significantly more DOI CT findings than the MRI- group, no quantitative differences were found. WASI Vocabulary and Matrix Reasoning scores were significantly lower, but not PSI, TEA-Ch or ABAS-II scores. MRI+ and MRI- groups did not differ on these measures.Heterogeneity in the occurrence of MRI-identified focal pathology was not associated with uniform changes in quantitative analyses of brain structure in cmTBI. Increased number of DOI CT abnormalities was associated with lowered neuropsychological performance.

The natural history of brain growth in autism spectrum disorders remains unclear. Cross-sectional studies have identified regional abnormalities in brain volume and cortical thickness in autism, although substantial discrepancies have been reported. Preliminary longitudinal studies using two time points and small samples have identified specific regional differences in cortical thickness in the disorder. To clarify age-related trajectories of cortical development, we examined longitudinal changes in cortical thickness within a large mixed cross-sectional and longitudinal sample of autistic subjects and age- and gender-matched typically developing controls. Three hundred and forty-five magnetic resonance imaging scans were examined from 97 males with autism (mean age = 16.8 years; range 3–36 years) and 60 males with typical development (mean age = 18 years; range 4–39 years), with an average interscan interval of 2.6 years. FreeSurfer image analysis software was used to parcellate the cortex into 34 regions of interest per hemisphere and to calculate mean cortical thickness for each region. Longitudinal linear mixed effects models were used to further characterize these findings and identify regions with between-group differences in longitudinal age-related trajectories. Using mean age at time of first scan as a reference (15 years), differences were observed in bilateral inferior frontal gyrus, pars opercularis and pars triangularis, right caudal middle frontal and left rostral middle frontal regions, and left frontal pole. However, group differences in cortical thickness varied by developmental stage, and were influenced by IQ. Differences in age-related trajectories emerged in bilateral parietal and occipital regions (postcentral gyrus, cuneus, lingual gyrus, pericalcarine cortex), left frontal regions (pars opercularis, rostral middle frontal and frontal pole), left supramarginal gyrus, and right transverse temporal gyrus, superior parietal lobule, and paracentral, lateral orbitofrontal, and lateral occipital regions. We suggest that abnormal cortical development in autism spectrum disorders undergoes three distinct phases: accelerated expansion in early childhood, accelerated thinning in later childhood and adolescence, and decelerated thinning in early adulthood. Moreover, cortical thickness abnormalities in autism spectrum disorders are region-specific, vary with age, and may remain dynamic well into adulthood.

To examine intermethod reliabilities and differences between FreeSurfer and the FDA-cleared congener, NeuroQuant, both fully automated methods for structural brain MRI measurements.MRI scans from 20 normal control subjects, 20 Alzheimer's disease patients, and 20 mild traumatically brain-injured patients were analyzed with NeuroQuant and with FreeSurfer. Intermethod reliability was evaluated.Pairwise correlation coefficients, intraclass correlation coefficients, and effect size differences were computed. NeuroQuant versus FreeSurfer measures showed excellent to good intermethod reliability for the 21 regions evaluated (r: .63 to .99/ICC: .62 to .99/ES: -.33 to 2.08) except for the pallidum (r/ICC/ES = .31/.29/-2.2) and cerebellar white matter (r/ICC/ES = .31/.31/.08). Volumes reported by NeuroQuant were generally larger than those reported by FreeSurfer with the whole brain parenchyma volume reported by NeuroQuant 6.50% larger than the volume reported by FreeSurfer. There was no systematic difference in results between the 3 subgroups.NeuroQuant and FreeSurfer showed good to excellent intermethod reliability in volumetric measurements for all brain regions examined with the only exceptions being the pallidum and cerebellar white matter. This finding was robust for normal individuals, patients with Alzheimer's disease, and patients with mild traumatic brain injury.

Magnetic Resonance (MR) imaging allows volumetric quantification of a variety of neuroanatomical structures using two dimensional (2D) images as well as three-dimensional (3D) reconstruction of the brain and any of its constituent parts. Three-dimensional analysis permits integration of the neuroanatomical changes which occur in pathologic states, with the cognitive and behavioral changes elucidated through neuropsychological assessment. This paper describes uniform methods for 3D neuroanatomical isolation of the neocortex, ventricular system, and hippocampus in both normal and pathologic states. The 3D methods are described in detail using two different software programs, ANALYZE and IMAGE. Three-dimensional neuroanatomical reconstructions were carried out on a patient who sustained a very severe traumatic brain injury. The 3D image analysis in the patient with traumatic brain injury, revealed structural changes in frontal and temporal cortex, ventricular dilation, and hippocampal atropy. The neuropsychological impairments in this patient, were consistent with the observed neuroanatomical changes revealed on 3D image reconstruction. This technology permits precise determinations of the extent and severity of the neuroanatomical changes which follow neurological injury disease.

Magnetic resonance imaging (MRI) provides a method to identify and quantify abnormalities resulting from traumatic brain injury (TBI). MRI abnormalities in children with TBI have not been fully characterized according to the frequency, location, and quantitative measurement of a range of pathologies critical for studies of neuropsychological outcome. Here, we report MRI findings from a large, multicenter study of childhood TBI, the Social Outcomes of Brain Injury in Kids (SOBIK) study, which compared qualitative and quantitative neuroimaging findings in 72 children with complicated mild-to-severe TBI to 52 children with orthopedic injury (OI).Qualitative analyses of MRI scans coded white matter hyperintensities (WMHs), hemosiderin deposits reflecting prior hemorrhagic lesions, regions of encephalomalacia and/or atrophy, and corpus callosum atrophy and traumatic shear lesions. Two automated quantitative analyses were conducted: (a) FreeSurfer methods computed volumes for total brain, white matter (WM), gray matter (GM), corpus callosum, ventricles, amygdala, hippocampus, basal ganglia, and thalamus along with a ventricle-to-brain ratio (VBR); and (b) voxel-based morphometry (VBM) to identify WM, GM, and cerebrospinal fluid. We also examined performance on the Processing Speed Index (PSI) from the Wechsler Intelligence Scale for Children, Fourth Edition, in relation to the above-mentioned neuroimaging variables.WMHs, hemosiderin deposits, and focal areas of encephalomalacia or atrophy were common in children with TBI, were related to injury severity, and were mostly observed within a frontotemporal distribution. Quantitative analyses showed volumetric changes related to injury severity, especially ventricular enlargement and reduced corpus callosum volume. VBM demonstrated similar findings, but, in addition, GM reductions in the inferior frontal, basal forebrain region, especially in the severe TBI group. The complicated mild TBI group showed few differences from the OI group. PSI was significantly associated with global atrophy, as measured by VBR.MRI findings after childhood TBI are diverse and particularly influenced by injury severity, and they involve common features, group heterogeneity, and individual variability.

There has been limited examination of the effect of brain pathology on subsequent function. The current study examined the relationships between regional variation in grey matter volume, age and cognitive impairment using a semi-automated image analysis tool. This study included 69 individuals with mild-to-severe TBI, 41 of whom also completed neuropsychological tests of attention, working memory, processing speed, memory and executive functions. A widespread reduction in grey matter volume was associated with increasing age. Regional volumes that were affected also related to the severity of injury, whereby the most severe TBI participants displayed the most significant pathology. Poorer retention of newly learned material was associated with reduced cortical volume in frontal, parietal, and occipital brain regions. In addition, poorer working memory and executive control performance was found for individuals with lower cortical volume in temporal, parietal, and occipital regions. These findings are largely in line with previous literature, which suggests that frontal, temporal, and parietal regions are integral for the encoding of memories into long-term storage, memory retrieval, and working memory. The present study suggests that automated image analysis methods may be used to explore the relationships between regional variation in grey matter volume and cognitive function following TBI.

We studied three forms of dyadic communication involving theory of mind (ToM) in 82 children with traumatic brain injury (TBI) and 61 children with orthopedic injury (OI): Cognitive (concerned with false belief), Affective (concerned with expressing socially deceptive facial expressions), and Conative (concerned with influencing another's thoughts or feelings). We analyzed the pattern of brain lesions in the TBI group and conducted voxel-based morphometry for all participants in five large-scale functional brain networks, and related lesion and volumetric data to ToM outcomes. Children with TBI exhibited difficulty with Cognitive, Affective, and Conative ToM. The perturbation threshold for Cognitive ToM is higher than that for Affective and Conative ToM, in that Severe TBI disturbs Cognitive ToM but even Mild–Moderate TBI disrupt Affective and Conative ToM. Childhood TBI was associated with damage to all five large-scale brain networks. Lesions in the Mirror Neuron Empathy network predicted lower Conative ToM involving ironic criticism and empathic praise. Conative ToM was significantly and positively related to the package of Default Mode, Central Executive, and Mirror Neuron Empathy networks and, more specifically, to two hubs of the Default Mode Network, the posterior cingulate/retrosplenial cortex and the hippocampal formation, including entorhinal cortex and parahippocampal cortex.

This study compared the ventricle-to-brain ratio (VBR) of the day-of-injury (DOI) computerized tomogram (CT) in traumatic brain-injured (TBI) patients with post-injury (2 months or greater) magnetic resonance (MR) VBRs in the same patients and in medical control subjects. The DOI VBR did not differ significantly from the medical controls, but both (DOI and medical control VBR) differed significantly from post-injury VBR. Additionally, a case study is presented wherein MR imaging studies were obtained prior to TBI so that a direct comparison of pre-injury to DOI to post-injury changes could be made. In this case the pre-injury and DOI VBRs were within approximately 9% of each other. In contrast, the post-injury VBR demonstrated over a 100% increase in comparison to either the pre-injury or DOI scan. This case and another case are illustrated using three-dimensional image analysis to represent ventricular change over time. These cases, along with the similarity of the DOI VBR with the medical controls, suggests that the DOI VBR can be utilized as an estimate or index of pre-injury ventricle/brain morphology. This will permit the use of DOI CT data for within-subject designs in TBI research that examines the course of degenerative changes over time.

A detailed case study is presented in which pre-injury CT scan findings are compared and contrasted with post-injury CT and MR results in a case of traumatic brain injury (TBI). The day-of-injury scan represented an adequate estimate of pre-injury morphological status based on cross-sectional area measurements of the ventricular system. By comparing pre-injury CT measurements with those obtained on the day of injury, 2 days post-injury and 16 months post-injury via assessing cross-sectional area of select ventricular regions (e.g. anterior and temporal horns, body and third ventricle) it was demonstrated that the TBI induced over a 50% ventricular expansion. Such ventricular expansions are felt to provide some index into diffuse axonal injury which may provide a means of eventually quantifying the degree of structural damage secondary to TBI. This analysis also demonstrated that there were no significant differences between selected cross-sectional ventricular areas in the 15 day and 16 month post-injury MR scans. This finding suggests that the degenerative effects of TBI have a rapid onset and are becoming readily apparent by 15 days post-injury. Thus, early imaging may provide a good index of long-term morphological outcome in TBI.