Longitudinal Associations Between Blood Biomarkers and White Matter MRI in Sport-Related Concussion: A Study of the NCAA-DoD CARE Consortium.

BACKGROUND AND OBJECTIVES: To study longitudinal associations between blood-based neural biomarkers (including total tau, neurofilament light [NfL], glial fibrillary acidic protein [GFAP], and ubiquitin C-terminal hydrolase-L1) and white matter neuroimaging biomarkers in collegiate athletes with sport-related concussion (SRC) from 24 hours postinjury to 1 week after return to play. METHODS: We analyzed clinical and imaging data of concussed collegiate athletes in the Concussion Assessment, Research, and Education (CARE) Consortium. The CARE participants completed same-day clinical assessments, blood draws, and diffusion tensor imaging (DTI) at 3 time points: 24-48 hours postinjury, point of becoming asymptomatic, and 7 days after return to play. DTI probabilistic tractography was performed for each participant at each time point to render 27 participant-specific major white matter tracts. The microstructural organization of these tracts was characterized by 4 DTI metrics. Mixed-effects models with random intercepts were applied to test whether white matter microstructural abnormalities are associated with the blood-based biomarkers at the same time point. An interaction model was used to test whether the association varies across time points. A lagged model was used to test whether early blood-based biomarkers predict later microstructural changes. RESULTS: Data from 77 collegiate athletes were included in the following analyses. Among the 4 blood-based biomarkers, total tau had significant associations with the DTI metrics across the 3 time points. In particular, high tau level was associated with high radial diffusivity (RD) in the right corticospinal tract (ß = 0.25, SE = 0.07, p FDR-adjusted = 0.016) and superior thalamic radiation (ß = 0.21, SE = 0.07, p FDR-adjusted = 0.042). NfL and GFAP had time-dependent associations with the DTI metrics. NfL showed significant associations only at the asymptomatic time point (|ß|s > 0.12, SEs <0.09, psFDR-adjusted < 0.05) and GFAP showed a significant association only at 7 days after return to play (ßs > 0.14, SEs <0.06, psFDR-adjusted < 0.05). The p values for the associations of early tau and later RD were not significant after multiple comparison adjustment, but were less than 0.1 in 7 white matter tracts. DISCUSSION: This prospective study using data from the CARE Consortium demonstrated that in the early phase of SRC, white matter microstructural integrity detected by DTI neuroimaging was associated with elevated levels of blood-based biomarkers of traumatic brain injury. Total tau in the blood showed the strongest association with white matter microstructural changes.

Development of a Minipig Model of BINT From Blast Exposure Using a Repeatable Mobile Shock Expansion Tube.

INTRODUCTION: The Office of Naval Research (ONR) sponsored the Blast Load Assessment Sense and Test (BLAST) program to provide an approach to operationally relevant monitoring and analysis of blast exposure for optimization of service member performance and health. Of critical importance in this effort was the development of a standardized methodology for preclinical large animal studies that can reliably produce outcome measures that cannot be measured in human studies to support science-based guidelines. The primary advantage of this approach is that, because animal studies report physiological measures that correlate with human neuropathology, these data can be used to evaluate potential risks to service members by accounting for the anatomical and physiological differences between humans and large animal models. This article describes the methodology used to generate a comprehensive outcome measure dataset correlated with controlled blast exposure. METHODS AND MATERIALS: To quantify outcomes associated with a single exposure to blast, 23 age- and weight-matched Yucatan minipigs were exposed to a single blast event generated by a large-bore, compressed gas shock tube. The peak pressure ranged from 280 to 525 kPa. After a post-exposure 72-hour observation period, the physiological response was quantified using a comprehensive set of neurological outcome measures that included neuroimaging, histology, and behavioral measures. Responses of the blast-exposed animals were compared to the sham-treated cohort to identify statistically significant and physiologically relevant differences between the two groups. RESULTS: Following a single exposure, the minipigs were assessed for structural, behavioral, and cellular changes for 3 days after exposure. The following neurological changes were observed: Structural-Using Diffusion Tensor Imaging, a statistically significant decrement (P < .001) in Fractional Anisotropy across the entire volume of the brain was observed when comparing the exposed group to the sham group. This finding indicates that alterations in brain tissue following exposure are not focused at a single location but instead a diffuse brain volume that can only be observed through a systematic examination of the neurological tissue. Cellular-The histopathology results from several large white matter tract locations showed varied cellular responses from six different stains. Using standard statistical methods, results from stains such as Fluoro-Jade C and cluster of differentiation 68 in the hippocampus showed significantly higher levels of neurodegeneration and increased microglia/macrophage activation in blast-exposed subjects. However, other stains also indicated increased response, demonstrating the need for multivariate analysis with a larger dataset. Behavioral-The behavior changes observed were typically transient; the animals' behavior returned to near baseline levels after a relatively short recovery period. Despite behavioral recovery, the presence of active neurodegenerative and inflammatory responses remained. CONCLUSIONS: The results of this study demonstrate that (1) a shock tube provides an effective tool for generating repeatable exposures in large animals and (2) exposure to blast overpressure can be correlated using a combination of imaging, behavioral, and histological analyses. This research demonstrates the importance of using multiple physiological indicators to track blast-induced changes in minipigs. The methodology and findings from this effort were central to developing machine-learning models to inform the development of blast exposure guidelines.

Quantitative susceptibility mapping of basal ganglia iron is associated with cognitive and motor functions that distinguish spinocerebellar ataxia type 6 and type 3.

Background: In spinocerebellar ataxia type 3 (SCA3), volume loss has been reported in the basal ganglia, an iron-rich brain region, but iron content has not been examined. Recent studies have reported that patients with SCA6 have markedly decreased iron content in the cerebellar dentate, coupled with severe volume loss. Changing brain iron levels can disrupt cognitive and motor functions, yet this has not been examined in the SCAs, a disease in which iron-rich regions are affected. Methods: In the present study, we used quantitative susceptibility mapping (QSM) to measure tissue magnetic susceptibility (indicating iron concentration), structural volume, and normalized susceptibility mass (indicating iron content) in the cerebellar dentate and basal ganglia in people with SCA3 (n = 10) and SCA6 (n = 6) and healthy controls (n = 9). Data were acquired using a 7T Philips MRI scanner. Supplemental measures assessed motor, cognitive, and mood domains. Results: Putamen volume was lower in both SCA groups relative to controls, replicating prior findings. Dentate susceptibility mass and volume in SCA6 was lower than in SCA3 or controls, also replicating prior findings. The novel finding was that higher basal ganglia susceptibility mass in SCA6 correlated with lower cognitive performance and greater motor impairment, an association that was not observed in SCA3. Cerebellar dentate susceptibility mass, however, had the opposite relationship with cognition and motor function in SCA6, suggesting that, as dentate iron is depleted, it relocated to the basal ganglia, which contributed to cognitive and motor decline. By contrast, basal ganglia volume loss, rather than iron content, appeared to drive changes in motor function in SCA3. Conclusion: The associations of higher basal ganglia iron with lower motor and cognitive function in SCA6 but not in SCA3 suggest the potential for using brain iron deposition profiles beyond the cerebellar dentate to assess disease states within the cerebellar ataxias. Moreover, the role of the basal ganglia deserves greater attention as a contributor to pathologic and phenotypic changes associated with SCA.

Effects of White-Matter Tract Length in Sport-Related Concussion: A Tractography Study from the NCAA-DoD CARE Consortium.

Sport-related concussion (SRC) is an important public health issue. White-matter alterations after SRC are widely studied by neuroimaging approaches, such as diffusion magnetic resonance imaging (MRI). Although the exact anatomical location of the alterations may differ, significant white-matter alterations are commonly observed in long fiber tracts, but are never proven. In the present study, we performed streamline tractography to characterize the association between tract length and white-matter microstructural alterations after SRC. Sixty-eight collegiate athletes diagnosed with acute concussion (24-48 h post-injury) and 64 matched contact-sport controls were included in this study. The athletes underwent diffusion tensor imaging (DTI) in 3.0 T MRI scanners across three study sites. DTI metrics were used for tract-based spatial statistics to map white-matter regions-of-interest (ROIs) with significant group differences. Whole-brain white-mater streamline tractography was performed to extract "affected" white-matter streamlines (i.e., streamlines passing through the identified ROIs). In the concussed athletes, streamline counts and DTI metrics of the affected white-matter fiber tracts were summarized and compared with unaffected white-matter tracts across tract length in the same participant. The affected white-matter tracts had a high streamline count at length of 80-100 mm and high length-adjusted affected ratio for streamline length longer than 80 mm. DTI mean diffusivity was higher in the affected streamlines longer than 100 mm with significant associations with the Brief Symptom Inventory score. Our findings suggest that long fibers in the brains of collegiate athletes are more vulnerable to acute SRC with higher mean diffusivity and a higher affected ratio compared with the whole distribution.

Neural Mechanisms of Facial Emotion Recognition in Autism: Distinct Roles for Anterior Cingulate and dlPFC.

OBJECTIVE: The present study sought to measure and internally validate neural markers of facial emotion recognition (FER) in adolescents and young adults with ASD to inform targeted intervention. METHOD: We utilized fMRI to measure patterns of brain activity among individuals with ASD (N = 21) and matched controls (CON; N = 20) 2 s prior to judgments about the identity of six distinct facial emotions (happy, sad, angry, surprised, fearful, disgust). RESULTS: Predictive modeling of fMRI data (support vector classification; SVC) identified mechanistic roles for brain regions that forecasted correct and incorrect identification of facial emotion as well as sources of errors over these decisions. BOLD signal activation in bilateral insula, anterior cingulate (ACC) and right dorsolateral prefrontal cortex (dlPFC) preceded accurate FER in both controls and ASD. Predictive modeling utilizing SVC confirmed the utility of ACC in forecasting correct decisions in controls but not ASD, and further indicated that a region within the right dlPFC was the source of a type 1 error signal in ASD (i.e. neural marker reflecting an impending correct judgment followed by an incorrect behavioral response) approximately two seconds prior to emotion judgments during fMRI. CONCLUSIONS: ACC forecasted correct decisions only among control participants. Right dlPFC was the source of a false-positive signal immediately prior to an error about the nature of a facial emotion in adolescents and young adults with ASD, potentially consistent with prior work indicating that dlPFC may play a role in attention to and regulation of emotional experience.

Future thinking to decrease real-world drinking in alcohol use disorder: Repairing reinforcer pathology in a randomized proof-of-concept trial.

Reinforcer Pathology theory proposes that expanding the temporal window of reinforcement (i.e., reducing delay discounting) using episodic future thinking (EFT) would decrease alcohol consumption. However, evidence of effectiveness in real-world settings is lacking. Using a randomized proof-of-concept field trial, the current study examined the effect of expanding the temporal window of reinforcement, using remotely delivered EFT, on decreasing real-world alcohol consumption among individuals with alcohol use disorder (AUD). Fifty-two individuals (9 females) aged 18-65 years who met the DSM-5 criteria for moderate or severe AUD and aimed to drink in moderation or abstain from drinking completed the study and were included in analysis. EFT significantly (p = .031) reduced alcohol consumption (mean change of consumption pre-post intervention = -2.18 drinks/day) compared to control episodic recent thinking (ERT; mean change of -0.52 drinks/day). Changes in discounting rates pre-post intervention significantly predicted changes in alcohol consumption (coef. = .424, 95% CI [.043-.813], p = .030) even after controlling for age, gender, race, income, education, marital status, and family history of addiction. Overall satisfaction across groups was rated as 3.92 on a 1 to 5-point scale, suggesting that the current remote approach is feasible and acceptable. The current findings were congruent with the theory, Reinforcer Pathology, that EFT expands the temporal window and decreases alcohol consumption, and the remote approach was considered feasible and acceptable. We believe the present study contributes new knowledge with tangible benefits for scientifically understanding and better defining novel interventions that may be clinically deployed to improve treatment outcomes. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Decoding the Brain's Surface to Track Deeper Activity.

Neural activity can be readily and non-invasively recorded from the scalp using electromagnetic and optical signals, but unfortunately all scalp-based techniques have depth-dependent sensitivities. We hypothesize, though, that the cortex's connectivity with the rest of the brain could serve to construct proxy signals of deeper brain activity. For example, functional magnetic resonance imaging (fMRI)-derived models that link surface connectivity to deeper regions could subsequently extend the depth capabilities of other modalities. Thus, as a first step toward this goal, this study examines whether or not surface-limited support vector regression of resting-state fMRI can indeed track deeper regions and distributed networks in independent data. Our results demonstrate that depth-limited fMRI signals can in fact be calibrated to report ongoing activity of deeper brain structures. Although much future work remains to be done, the present study suggests that scalp recordings have the potential to ultimately overcome their intrinsic physical limitations by utilizing the multivariate information exchanged between the surface and the rest of the brain.

MRI brain templates of the male Yucatan minipig.

The pig is growing in popularity as an experimental animal because its gyrencephalic brain is similar to humans. Currently, however, there is a lack of appropriate brain templates to support functional and structural neuroimaging pipelines. The primary contribution of this work is an average volume from an iterative, non-linear registration of 70 five- to seven-month-old male Yucatan minipigs. In addition, several aspects of this study are unique, including the comparison of linear and non-linear template generation, the characterization of a large and homogeneous cohort, an analysis of effective resolution after averaging, and the evaluation of potential in-template bias as well as a comparison with a template from another minipig species using a "left-out" validation set. We found that within our highly homogeneous cohort, non-linear registration produced better templates, but only marginally so. Although our T1-weighted data were resolution limited, we preserved effective resolution across the multi-subject average, produced templates that have high gray-white matter contrast and demonstrate superior registration accuracy compared to an alternative minipig template.

The Cerebellum and Implicit Sequencing: Evidence from Cerebellar Ataxia.

The cerebellum recognizes sequences from prior experiences and uses this information to generate internal models that predict future outcomes in a feedforward manner [Front Hum Neurosci 8: 475, 2014; Cortex 47: 137-44, 2011; Cerebellum 7: 611-5, 2008; J Neurosci 26: 9107-16, 2006]. This process has been well documented in the motor domain, but the cerebellum's role in cognitive sequencing, within the context of implicit versus explicit processes, is not well characterized. In this study, we tested individuals with cerebellar ataxia and healthy controls to clarify the role of the cerebellum sequencing using variations on implicit versus explicit and motor versus cognitive demands across five experiments. Converging results across these studies suggest that cerebellar feedforward mechanisms may be necessary for sequencing in the implicit domain only. In the ataxia group, rhythmic tapping, rate of motor learning, and implicit sequence learning were impaired. However, for cognitive sequencing that could be accomplished using explicit strategies, the cerebellar group performed normally, as though they shifted to extra-cerebellar mechanisms to compensate. For example, when cognitive and motor functions relied on cerebellar function simultaneously, the ataxia group's motor function was unaffected, in contrast to that of controls whose motor performance declined as a function of cognitive load. These findings indicated that the cerebellum is not critical for all forms of sequencing per se. Instead, it plays a fundamental role for sequencing within the implicit domain, whether functions are motor or cognitive. Moreover, individuals with cerebellar ataxia are generally able to compensate for cognitive sequencing when explicit strategies are available in order to preserve resources for motor function.

Early Influences of Microbiota on White Matter Development in Germ-Free Piglets.

Abnormalities in the prefrontal cortex (PFC), as well as the underlying white matter (WM) tracts, lie at the intersection of many neurodevelopmental disorders. The influence of microorganisms on brain development has recently been brought into the clinical and research spotlight as alterations in commensal microbiota are implicated in such disorders, including autism spectrum disorders, schizophrenia, depression, and anxiety via the gut-brain axis. In addition, gut dysbiosis is common in preterm birth patients who often display diffuse WM injury and delayed WM maturation in critical tracts including those within the PFC and corpus callosum. Microbial colonization of the gut aligns with ongoing postnatal processes of oligodendrogenesis and the peak of brain myelination in humans; however, the influence of microbiota on gyral WM development remains elusive. Here, we develop and validate a neonatal germ-free swine model to address these issues, as piglets share key similarities in WM volume, developmental trajectories, and distribution to humans. We find significant region-specific reductions, and sexually dimorphic trends, in WM volume, oligodendrogenesis, and mature oligodendrocyte numbers in germ-free piglets during a key postnatal epoch of myelination. Our findings indicate that microbiota plays a critical role in promoting WM development during early life when the brain is vulnerable to environmental insults that can result in an array of disabilities manifesting later in life.

Longitudinal white-matter abnormalities in sports-related concussion: A diffusion MRI study.

OBJECTIVE: To study longitudinal recovery trajectories of white matter after sports-related concussion (SRC) by performing diffusion tensor imaging (DTI) on collegiate athletes who sustained SRC. METHODS: Collegiate athletes (n = 219, 82 concussed athletes, 68 contact-sport controls, and 69 non-contact-sport controls) were included from the Concussion Assessment, Research and Education Consortium. The participants completed clinical assessments and DTI at 4 time points: 24 to 48 hours after injury, asymptomatic state, 7 days after return-to-play, and 6 months after injury. Tract-based spatial statistics was used to investigate group differences in DTI metrics and to identify white-matter areas with persistent abnormalities. Generalized linear mixed models were used to study longitudinal changes and associations between outcome measures and DTI metrics. Cox proportional hazards model was used to study effects of white-matter abnormalities on recovery time. RESULTS: In the white matter of concussed athletes, DTI-derived mean diffusivity was significantly higher than in the controls at 24 to 48 hours after injury and beyond the point when the concussed athletes became asymptomatic. While the extent of affected white matter decreased over time, part of the corpus callosum had persistent group differences across all the time points. Furthermore, greater elevation of mean diffusivity at acute concussion was associated with worse clinical outcome measures (i.e., Brief Symptom Inventory scores and symptom severity scores) and prolonged recovery time. No significant differences in DTI metrics were observed between the contact-sport and non-contact-sport controls. CONCLUSIONS: Changes in white matter were evident after SRC at 6 months after injury but were not observed in contact-sport exposure. Furthermore, the persistent white-matter abnormalities were associated with clinical outcomes and delayed recovery time.

Evaluating fMRI-Based Estimation of Eye Gaze During Naturalistic Viewing.

The collection of eye gaze information during functional magnetic resonance imaging (fMRI) is important for monitoring variations in attention and task compliance, particularly for naturalistic viewing paradigms (e.g., movies). However, the complexity and setup requirements of current in-scanner eye tracking solutions can preclude many researchers from accessing such information. Predictive eye estimation regression (PEER) is a previously developed support vector regression-based method for retrospectively estimating eye gaze from the fMRI signal in the eye's orbit using a 1.5-min calibration scan. Here, we provide confirmatory validation of the PEER method's ability to infer eye gaze on a TR-by-TR basis during movie viewing, using simultaneously acquired eye tracking data in five individuals (median angular deviation < 2°). Then, we examine variations in the predictive validity of PEER models across individuals in a subset of data (n = 448) from the Child Mind Institute Healthy Brain Network Biobank, identifying head motion as a primary determinant. Finally, we accurately classify which of the two movies is being watched based on the predicted eye gaze patterns (area under the curve = 0.90 ± 0.02) and map the neural correlates of eye movements derived from PEER. PEER is a freely available and easy-to-use tool for determining eye fixations during naturalistic viewing.

Practicing prospection promotes patience: Repeated episodic future thinking cumulatively reduces delay discounting.

BACKGROUND: Delay discounting, or the preference for smaller, sooner over larger, later rewards, has been associated with alcohol use disorder and problem drinking. Episodic future thinking has been suggested as an intervention to address steep delay discounting. In the present study, we examined the effect of up to six consecutive sessions of episodic future thinking. METHODS: Repeated, within-subject data were collected from current and recent problem drinkers (n = 50) over six sessions. Linear mixed-effect models were used to estimate effects of repeated sessions and manipulations. Participants completed episodic future thinking interviews at up to six sessions, in which they generated personalized future events. Participants also engaged with cues of scarcity. At each session, participants completed three delay discounting tasks under: a no-cue baseline condition, a future cue condition, and a scarcity cue condition. RESULTS: Delay discounting in the no cue condition did not change over time. Discounting rates were reduced in the future cue condition, and these effects grew larger with repeated sessions. In the scarcity condition, discounting rates were slightly higher, with no effect of repeated sessions. CONCLUSIONS: Episodic future thinking reduced delay discounting rate while future cues were presented, and these effects grew larger with repeated sessions. This suggests that repeated episodic future thinking may cumulatively potentiate repair of excessive preference for immediate reward.

Reinforcer pathology: Common neural substrates for delay discounting and snack purchasing in prediabetics.

Reinforcer pathology theory stipulates that individuals with both (a) high preference for smaller, immediate over larger, delayed rewards; and (b) high demand for unhealthy commodities are uniquely susceptible to poor health outcomes. Specifically, two behavioral economic tasks (delay discounting, assessing preference for smaller, immediate or larger, delayed rewards; and purchasing, assessing purchases of commodities over changes in price) have been independently associated with conditions such as overweight/obesity and problem substance use. In the present study, we examined possible shared neural regions involved in the processes of delay discounting and demand for snack foods in a prediabetic sample. Fifty-four participants completed both of these tasks. Conjunction between delay discounting and purchasing task results indicates substantial common neural substrates recruited during these two tasks, consistent with interpretations of executive control, interoception, and attention, in the prefrontal cortex, insula, and frontoparietal cortex (superior/middle frontal cortex and superior/inferior parietal lobules), respectively. Collectively, these results suggest possible neural substrates in which the two behavioral risk factors of reinforcer pathology may interact during real-world decision-making in prediabetes.

Early childhood investment impacts social decision-making four decades later.

Early childhood educational investment produces positive effects on cognitive and non-cognitive skills, health, and socio-economic success. However, the effects of such interventions on social decision-making later in life are unknown. We recalled participants from one of the oldest randomized controlled studies of early childhood investment-the Abecedarian Project (ABC)-to participate in well-validated interactive economic games that probe social norm enforcement and planning. We show that in a repeated-play ultimatum game, ABC participants who received high-quality early interventions strongly reject unequal division of money across players (disadvantageous or advantageous) even at significant cost to themselves. Using a multi-round trust game and computational modeling of social exchange, we show that the same intervention participants also plan further into the future. These findings suggest that high quality early childhood investment can result in long-term changes in social decision-making and promote social norm enforcement in order to reap future benefits.

Working Memory Training Improves Alcohol Users' Episodic Future Thinking: A Rate-Dependent Analysis.

BACKGROUND: Episodic thinking, whether past or future, uses similar neural machinery, and individuals with alcohol dependence have clear challenges with both. Moreover, alcohol-dependent individuals' narrowed temporal window likely gives rise to greater valuation of immediate rewards. We aimed to strengthen working memory (WM) in alcohol-dependent individuals and measure performance on near-transfer (novel WM) and far-transfer delay discounting (DD) tasks, including episodic future thinking (EFT) performance. Importantly, heterogeneous intervention responses could obscure a treatment effect due to individuals' baseline differences. Therefore, we considered WM, DD, and EFT DD scores using rate-dependent analyses. METHODS: A total of 50 alcohol-dependent individuals received either 20 active (Trained) or sham (Control) WM training sessions using the Cogmed adaptive WM training program. Participants completed a near-transfer novel WM task and far-transfer DD and EFT DD tasks before and after training. RESULTS: Active WM training improved performance on the near-transfer task. As determined by Oldham's correlation [rmean(x,y),y-x], initially low near-transfer task scores improved more than initially high scores (i.e., rate dependence) in the Trained group only. Moreover, Trained group individuals with the highest rates of EFT DD at baseline rate-dependently decreased following training, whereas WM training had no effect on DD alone. CONCLUSIONS: These data support the notion that WM training improves near-transfer task performance and may enhance the effects of EFT DD in a subset of alcohol-dependent individuals trapped within the narrowest temporal window. Rate-dependent changes highlight that we should attend to baseline performance to better identify individuals who would most benefit from an intervention.

Acute White-Matter Abnormalities in Sports-Related Concussion: A Diffusion Tensor Imaging Study from the NCAA-DoD CARE Consortium.

Sports-related concussion (SRC) is an important public health issue. Although standardized assessment tools are useful in the clinical management of acute concussion, the underlying pathophysiology of SRC and the time course of physiological recovery after injury remain unclear. In this study, we used diffusion tensor imaging (DTI) to detect white matter alterations in football players within 48 h after SRC. As part of the NCAA-DoD CARE Consortium study of SRC, 30 American football players diagnosed with acute concussion and 28 matched controls received clinical assessments and underwent advanced magnetic resonance imaging scans. To avoid selection bias and partial volume effects, whole-brain skeletonized white matter was examined by tract-based spatial statistics to investigate between-group differences in DTI metrics and their associations with clinical outcome measures. Mean diffusivity was significantly higher in brain white matter of concussed athletes, particularly in frontal and subfrontal long white matter tracts. In the concussed group, axial diffusivity was significantly correlated with the Brief Symptom Inventory and there was a similar trend with the symptom severity score of the Sport Concussion Assessment Tool. In addition, concussed athletes with higher fractional anisotropy performed better on the cognitive component of the Standardized Assessment of Concussion. Overall, the results of this study are consistent with the hypothesis that SRC is associated with changes in white matter tracts shortly after injury, and these differences are correlated clinically with acute symptoms and functional impairments.

Stability of MRI metrics in the advanced research core of the NCAA-DoD concussion assessment, research and education (CARE) consortium.

The NCAA-DoD Concussion Assessment, Research, and Education (CARE) consortium is performing a large-scale, comprehensive study of sport related concussions in college student-athletes and military service academy cadets. The CARE "Advanced Research Core" (ARC), is focused on executing a cutting-edge investigative protocol on a subset of the overall CARE athlete population. Here, we present the details of the CARE ARC MRI acquisition and processing protocol along with preliminary analyzes of within-subject, between-site, and between-subject stability across a variety of MRI biomarkers. Two experimental datasets were utilized for this analysis. First, two "human phantom" subjects were imaged multiple times at each of the four CARE ARC imaging sites, which utilize equipment from two imaging vendors. Additionally, a control cohort of healthy athletes participating in non-contact sports were enrolled in the study at each CARE ARC site and imaged at four time points. Multiple morphological image contrasts were acquired in each MRI exam; along with quantitative diffusion, functional, perfusion, and relaxometry imaging metrics. As expected, the imaging markers were found to have varying levels of stability throughout the brain. Importantly, between-subject variance was generally found to be greater than within-subject and between-site variance. These results lend support to the expectation that cross-site and cross-vendor advanced quantitative MRI metrics can be utilized to improve analytic power in assessing sensitive neurological variations; such as those effects hypothesized to occur in sports-related-concussion. This stability analysis provides a crucial foundation for further work utilizing this expansive dataset, which will ultimately be freely available through the Federal Interagency Traumatic Brain Injury Research Informatics System.

An adaptive, individualized fMRI delay discounting procedure to increase flexibility and optimize scanner time.

Research on the rate at which people discount the value of future rewards has become increasingly prevalent as discount rate has been shown to be associated with many unhealthy patterns of behavior such as drug abuse, gambling, and overeating. fMRI research points to a fronto-parietal-limbic pathway that is active during decisions between smaller amounts of money now and larger amounts available after a delay. Researchers in this area have used different variants of delay discounting tasks and reported various contrasts between choice trials of different types from these tasks. For instance, researchers have compared 1) choices of delayed monetary amounts to choices of the immediate monetary amounts, 2) 'hard' choices made near one's point of indifference to 'easy' choices that require little thought, and 3) trials where an immediate choice is available versus trials where one is unavailable, regardless of actual eventual choice. These differences in procedure and analysis make comparison of results across studies difficult. In the present experiment, we designed a delay discounting task with the intended capability of being able to construct contrasts of all three comparisons listed above while optimizing scanning time to reduce costs and avoid participant fatigue. This was accomplished with an algorithm that customized the choice trials presented to each participant with the goal of equalizing choice trials of each type. We compared this task, which we refer to here as the individualized discounting task (IDT), to two other delay discounting tasks previously reported in the literature (McClure et al., 2004; Amlung et al., 2014) in 18 participants. Results show that the IDT can examine each of the three contrasts mentioned above, while yielding a similar degree of activation as the reference tasks. This suggests that this new task could be used in delay discounting fMRI studies to allow researchers to more easily compare their results to a majority of previous research while minimizing scanning duration.

Detecting Chronic Post-Traumatic Osteomyelitis of Mouse Tibia via an IL-13Rα2 Targeted Metallofullerene Magnetic Resonance Imaging Probe.

Differential diagnosis of chronic post-traumatic osteomyelitis (CPO) from aseptic inflammation remains challenging, since both pathological processes share similar clinical symptoms. Here we utilized a novel targeted metallofullerene nanoparticle based magnetic resonance imaging (MRI) probe IL-13-TAMRA-Gd3N@C80(OH)30(CH2CH2COOH)20 to detect CPO in mouse tibia via overexpressed IL-13Rα2 receptors. The functionalized metallofullerene was characterized by X-ray photoelectron spectroscopy. Upon lipopolysaccharide (LPS) stimulation, macrophage Raw 264.7 cells showed elevated IL-13Rα2 expression via immunofluorescence staining and increased MRI probe binding via built-in TAMRA fluorescence imaging. Trauma was induced in both tibia of mice and bacteria soaked suture was inserted into the right tibia to initiate infection. During the acute phase (1.5 weeks), luminol-bioluminescence imaging revealed much higher myeloperoxidase activity in the infected tibia compared to the sham. In the chronic phase (4 weeks), X-ray radiography illustrated bone deformation in the infected tibia compared to the sham. With T1 weighted sequences, the probe clearly exhibited hyperintensity in the infection foci at both acute and chronic phases, which was not observed in the sham tibia. Histological analysis revealed severe bone structural destruction and massive inflammatory cell infiltration in the infected tibia. Immunohistochemistry confirmed abundant expression of IL-13Rα2 in the infection site. In summary, we developed a noninvasive imaging approach to detect and differentiate CPO from aseptic inflammation using a new IL-13Rα2 targeted metallofullerene MRI probe. In addition, for the first time, IL-13Rα2 was investigated as a unique biomarker in the context of osteomyelitis. Our data established a foundation for the translational application of this MRI probe in the clinical differentiation of CPO.