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Age, genetics, and chromosomal sex have been identified as critical risk factors for late-onset Alzheimer's disease (LOAD). The predominant genetic risk factor for LOAD is the apolipoprotein E ε4 allele (APOE4), and the prevalence of LOAD is higher in females. However, the translational validity of APOE4 mouse models for AD-related cognitive impairment remains to be fully determined. The present study investigated the role of both sex and genotype on learning and memory in aged, humanized APOE knock-in mice. Aged (23.27 mo ± 1.21 mo; 39 male/37 female) APOE3/3, APOE3/4, and APOE4/4 mice performed a novel object recognition (NOR) assay. Task-related metrics were analyzed using two-way sex by genotype ANOVAs. Sex differences were more prominent relative to APOE genotype. Prior to NOR, female mice exhibited thigmotaxic center zone avoidance during the open field task relative to males, regardless of genotype. Within object familiarization and NOR tasks, females had greater object interaction and locomotion. Interestingly, only APOE4/4 females on average recognized the novel object. These results suggest that APOE4, although strongly related to LOAD pathogenesis, does not drive cognitive decline in the absence of other risk factors even in very aged mice. Chromosomal sex is a key driver of behavioral phenotypes and thus is a critical variable for translatability of interventions designed to preserve learning and memory in animal models of LOAD. Last, there was a very high degree of variability in behavioral performance across APOE genotypes. A cluster analysis of the behavioral data revealed a low-activity and a high-activity cluster. APOE4 carriers were overrepresented in the low-activity cluster, while male:female distributions did not differ. Collectively, the behavioral data indicate that chromosomal sex has the greatest impact on behavioral phenotype, and APOE4 carrier status may confer greater risk for cognitive decline in some animals.

Objective Identify the treatment effects of 6 weeks of daily 30-minute sessions of morning blue light therapy compared with placebo amber light therapy in the treatment of sleep disruption following mild traumatic brain injury. Design Placebo-controlled randomized trial. Participants Adults aged 18 to 45 years with a mild traumatic brain injury within the past 18 months (n = 35). Main outcome measures Epworth Sleepiness Scale, Pittsburgh Sleep Quality Index, Beck Depression Inventory II, Rivermead Post-concussion Symptom Questionnaire, Functional Outcomes of Sleep Questionnaire, and actigraphy-derived sleep measures. Results Following treatment, moderate to large improvements were observed with individuals in the blue light therapy group reporting lower Epworth Sleepiness Scale (Hedges' g = 0.882), Beck Depression Inventory II (g = 0.684), Rivermead Post-concussion Symptom Questionnaire chronic (g = 0.611), and somatic (g = 0.597) symptoms, and experiencing lower normalized wake after sleep onset (g = 0.667) than those in the amber light therapy group. In addition, individuals in the blue light therapy group experienced greater total sleep time (g = 0.529) and reported improved Functional Outcomes of Sleep Questionnaire scores (g = 0.929) than those in the amber light therapy group. Conclusion Daytime sleepiness, fatigue, and sleep disruption are common following a mild traumatic brain injury. These findings further substantiate blue light therapy as a promising nonpharmacological approach to improve these sleep-related complaints with the added benefit of improved postconcussion symptoms and depression severity.

Background: Emerging evidence suggests that post concussive symptoms, including mood changes, may be improved through morning blue-wavelength light therapy (BLT). However, the neurobiological mechanisms underlying these effects remain unknown. We hypothesize that BLT may influence the effective brain connectivity (EC) patterns within the default-mode network (DMN), particularly involving the medial prefrontal cortex (MPFC), which may contribute to improvements in mood. Methods: Resting-state functional MRI data were collected from 41 healthy-controls (HCs) and 28 individuals with mild traumatic brain injury (mTBI). Individuals with mTBI also underwent a diffusion-weighted imaging scan and were randomly assigned to complete either 6 weeks of daily morning BLT (N = 14) or amber light therapy (ALT; N = 14). Advanced spectral dynamic causal modeling (sDCM) and diffusion MRI connectometry were used to estimate EC patterns and structural connectivity strength within the DMN, respectively. Results: The sDCM analysis showed dominant connectivity pattern following mTBI (pre-treatment) within the hemisphere contralateral to the one observed for HCs. BLT, but not ALT, resulted in improved directional information flow (ie, EC) from the left lateral parietal cortex (LLPC) to MPFC within the DMN. The improvement in EC from LLPC to MPFC was accompanied by stronger structural connectivity between the 2 areas. For the BLT group, the observed improvements in function and structure were correlated (at a trend level) with changes in self-reported happiness. Conclusions: The current preliminary findings provide empirical evidence that morning short-wavelength light therapy could be used as a novel alternative rehabilitation technique for mTBI. Trial registry: The research protocols were registered in the ClinicalTrials.gov database (CT Identifiers NCT01747811 and NCT01721356).

Objective/background Mild traumatic brain injuries (mTBI) are frequently associated with long-term, self-reported sleep disruption. Objective corroboration of these self-reports is sparse and limited by small sample sizes. The purpose of this study was to report on actigraphically-measured sleep outcomes in individuals with and without a history of recent mTBI in two U.S. cities (Boston, MA and Tucson, AZ). Patients/methods Fifty-eight individuals with a recent (within 18 months) mTBI and 35 individuals with no prior mTBI history were recruited for one of four studies across two sites. Participants completed a minimum of one week of actigraphy. Additionally, mTBI participants self-reported daytime sleepiness, sleep disruption, and functional sleep-related outcomes. Results In Boston, mTBI participants obtained less average sleep with shorter sleep onset latencies (SOL) than healthy individuals. In Tucson, mTBI participants had greater SOL and less night-to-night SOL variability compared to healthy individuals. Across mTBI participants, SOL was shorter and night-to-night SOL variability was greater in Boston than Tucson. Sleep efficiency (SE) variability was greater in Tucson than Boston across both groups. Only SOL variability was significantly associated with daytime sleepiness (r = 0.274) in the mTBI group after controlling for location. Conclusion Sleep quality, SOL and SE variability, are likely affected by mTBIs. Between-group differences in each site existed but went in opposite directions. These findings suggest the possibility of multiple, rather than a singular, profiles of sleep disruption following mTBI. Precision medicine models are warranted to determine whether multiple sleep disruption profiles do indeed exist following mTBI and the predisposing conditions that contribute to an individual's experience of sleep disruption.

Mild traumatic brain injury (mTBI) can alter the structure of the brain and result in a range of symptoms, including elevated aggression. Neurological damage associated with mTBI is traditionally viewed as transient, yet a growing number of studies suggest long-lasting psychological and neurological changes following mTBI. However, research examining the neural basis of emotion processing in the chronic stage of mTBI recovery remains sparse. In the current study, we utilized resting state functional MRI to explore the association between default mode network connectivity and aggression in 17 healthy controls and 17 adults at least 6 months post-mTBI. The association between within-network connectivity and aggression was examined using general linear models, controlling for the effects of depression. Increased connectivity between the right hippocampus and midcingulate cortex was associated with elevated aggression in adults with mTBI, but not in healthy controls. The results provide evidence for a link between intrinsic functional network disruptions and the manifestation of postconcussive symptoms within chronic stages of recovery following mTBI. These findings expand upon the current research, providing evidence for the use of resting state functional connectivity as a potential biomarker of postconcussive aggression in chronic mTBI.

Blue wavelength light has been used successfully as a treatment method for certain mood disorders, but, the underlying mechanisms behind the mood enhancing effects of light remain poorly understood. We investigated the effects of a single dose of 30 min of blue wavelength light (n = 17) vs. amber wavelength light (n = 12) exposure in a sample of healthy adults on subsequent resting-state functional and directed connectivity, and associations with changes in state affect. Individuals who received blue vs. amber wavelength light showed greater positive connectivity between the right amygdala and a region within the left dorsolateral prefrontal cortex (DLPFC). In addition, using granger causality, the findings showed that individuals who received blue wavelength light displayed greater bidirectional information flow between these two regions relative to amber light. Furthermore, the strength of amygdala-DLPFC functional connectivity was associated with greater decreases in negative mood for the blue, but not the amber light condition. Blue light exposure may positively influence mood by modulating greater information flow between the amygdala and the DLPFC, which may result in greater engagement of cognitive control strategies that are needed to perceive and regulate arousal and mood.

Exposure to light, particularly blue-wavelength light, has been shown to acutely increase brain activation, alertness, and some elementary aspects of cognitive performance such as working memory and emotional anticipation. Whether blue light exposure can have effects on brain activation and performance during more complex cognitive control tasks up to 30 min after light cessation is unknown. In a sample of 32 healthy adults, we examined the effects of a 30 min exposure to either blue (n = 16) or amber control (n = 16) light on subsequent brain activation and performance during the Multi-Source Interference Task (MSIT) measured a half-hour after light exposure. Performance on the MSIT did not differ between the blue and amber conditions. However, brain activation within the task positive network (TPN) to the interference condition was significantly lower in the blue relative to the amber condition, while no group differences were observed for suppression of the default mode network (DMN). These findings suggest that, compared to control, a single exposure to blue light was associated with enhanced neural efficiency, as demonstrated by reduced TPN activation to achieve the same level of performance. Blue light may be an effective method for optimizing neurocognitive performance under some conditions.

Introduction Stable, trait-like inter-individual resilience to sleep loss has been demonstrated for psychomotor vigilance, mood, subjective sleepiness, and some reasoning tasks, some of which have been associated with specific genetic or neurobiological markers. Resilience to executive control deficits induced by sleep deprivation (SD) has not been explored in terms of neurobiological markers. We, therefore, collected magnetic resonance imaging (MRI) scans of healthy individuals when well rested and correlated gray matter volume with resistance to inhibitory declines during 29 hours of SD. Methods Forty-five healthy individuals (22 female) ranging in age from 20 to 43 underwent structural MRI. Within 2-4 days after scanning, participants returned to the lab to undergo one night of SD, during which they completed a standard go/no-go task involving inhibitory processing every 4 hours. Scores were calculated as throughput (correct responses per working minute). The difference between performance in the evening (22:45) versus the performance the next morning (06:45) was calculated as an index of “inhibitory resilience.” Gray matter volume was regressed against the inhibitory resilience measure. Based on prior research, regions were constrained to the ventrolateral prefrontal cortex and ventromedial prefrontal cortex. Results Greater resilience against declines in inhibitory capacity during SD was predicted by 1) larger gray matter volume within the ventrolateral prefrontal cortex and 2) reduced volume within the ventromedial prefrontal cortex (p Conclusion The ability to sustain performance during an inhibitory go/no-go task during SD was predicted by greater gray matter volume within the ventrolateral prefrontal cortex, a region that has been previously associated with inhibitory capacity, and reduced volume within an area of the ventromedial prefrontal cortex, which is often related to the default mode network. Findings suggest that specific brain networks may confer task-specific resistance to SD. Support Defense Advanced Research Projects Agency, DARPA Young Faculty Award: DARPA-12-12-11-YFA-FP-029

Introduction Sleep disruptions, including the increase of daytime sleepiness, are reported in roughly 70% of all individuals who have suffered a mild traumatic brain injury (mTBI). Prior research using magnetic resonance imaging (MRI) has identified associations between functional brain changes and daytime sleepiness following mTBI. In the present study, we aimed to identify whether structural differences in cortical thickness are associated with increased daytime sleepiness in adults with mTBI. Methods A total of 58 adults between 18 and 45 years of age (M=23.58±5.31) participated in the study, including 19 healthy controls and 39 individuals with a documented mTBI. Individuals with mTBI were further divided based on time-since-injury into a sub-acute (n=22) or chronic (n=17) group. Daytime sleepiness was assessed using the Epworth Sleepiness Scale (ESS) and cortical thickness was measured using high-resolution T1-weighted structural MRI. Whole-brain vertex-wise estimations of cortical thickness were calculated using FreeSurfer (v.6.0) and entered into a GLM to identify between-group differences in cortical thickness and the association with ESS. Results Significant differences in cortical thickness were found between the two mTBI groups (cluster-forming threshold p Conclusion More daytime sleepiness was associated with reduced inferior parietal cortical thickness in those 2 to 12-weeks post-injury, an association not observed in those 6 to 12-months post-injury or healthy controls. The inferior parietal lobule is part of the frontoparietal attention network and has been associated with vulnerability to sleep loss. Our findings suggest structural damage to the attention network following mTBI may be one factor affecting daytime sleepiness in mTBI. These findings may reflect a potential biomarker of sleep disturbances in mTBI. Support USAMRMC grant (W81XWH-12–0386).

Introduction Long-term sleep disruption, fatigue, and depression are common after mild traumatic brain injuries (mTBIs). Efficacious treatments for these disturbances in the context of mTBIs are lacking. Morning blue light therapy (BLT) effectively treats sleep disruption and improves mood. This study evaluated the treatment effects of morning BLT on post-mTBI daytime sleepiness, depression, and post-concussion symptoms. Methods 62 individuals (Boston: n=31; age: 23.11±7.20y; 17 females; days post-injury: 236.00±121.40; Tucson: n=31; age: 26.35±8.08y; 20 females; days post-injury: 272.94±167.69) received either BLT (n=30) or placebo amber light therapy (ALT; n=32). All participants completed the Epworth Sleepiness Scale (ESS), Pittsburgh Sleep Quality Index (PSQI), Beck Depression Inventory (BDI), and Rivermead Post-concussion Symptom Questionnaire (RPQ3 and RPQ13 subscales) pre- and post-treatment. Treatment consisted of direct exposure to either blue or amber light (30 minutes each morning), delivered via tabletop light-box, over six weeks. Baseline and post-treatment values were compared to a non-mTBI, non-treated control sample (Tucson: n=32, age: 23.94±5.41y; 19 females). Results Baseline scores were higher in both mTBI light groups (BLT, ALT, respectively) than controls for the ESS (Cohen’s d=0.83, 0.83), PSQI (d=1.45, 1.71), BDI (d=1.46, 1.62), RPQ3 (d=1.72, 1.62) and RPQ13 (d=1.86, d=1.76). BLT resulted in lower within-group ESS (d=-0.58), BDI (d=-0.50), PSQI (d=-0.57), and RPQ13 (d=-0.45, p=0.005) scores. No improvements were seen following ALT. Minimal ESS score differences between the BLT and controls were observed after treatment (d=0.25). Conclusion Daily morning BLT resulted in moderate improvements in post-mTBI daytime sleepiness, sleep quality, depression, and post-concussion symptoms. These improvements may contribute to enhanced academic and job performance, post-mTBI quality of life, and general recovery. Future work is needed to clarify optimal dosage and precision medicine factors indentifying those most likely to benefit from morning BLT. Support This research was supported by multiple grants from the US Army Medical Research and Materiel Command (USAMRMC) to Dr. William D. S. Killgore, including W81XWH-11-1-0056 and W81XWH-14-1-0571.

Introduction Blue wavelength light is an effective treatment for delayed sleep phase syndrome, seasonal affective disorder and bipolar depression. The role of blue light in regulating melatonin production has been extensively studied, but other potential neurophysiological effects remain poorly understood. Some studies have suggested that daily blue light exposure may modulate functional brain responses within the amygdala and prefrontal cortex (PFC), potentially explaining blue light’s antidepressant effect. In this study we investigated the effects of a single 30-minute session of blue light exposure on functional resting state connectivity between the amygdala and PFC. Methods Twenty-nine healthy 18–32 year olds were randomly assigned to either receive 30 minutes of blue (n=17) or non-blue (amber) light (n=12) exposure followed by a 7-minute resting state scan. Pre- and post light exposure, participants completed the Positive and Negative Affect Scale, as a measure of state affect. Results Individuals who received blue versus amber light showed greater positive connectivity between the right amygdala and the left dorsolateral prefrontal cortex (DLPFC) (x=-24, y=46, z=18, k=90, volume p-FDR corrected, p Conclusion Blue light exposure appears to facilitate greater information flow between the amygdala and the DLPFC at rest, potentially enhancing cognitive processes that regulate arousal and mood. As blue light exposure has been shown to enhance attention and learning, using blue light exposure during practice of emotional regulation strategies, such as reappraisal, may further increase the beneficial effects of blue light on mood. In order to use blue light exposure in a more targeted manner for sleep and mood disorders, further research into the underlying neurophysiological mechanisms is needed. Support This research was supported by a USAMRAA grant to WDSK (W81XWH-14-1-0571) as well as by an Arizona Health Education Centers (AHEC) Research Grant to AA.

Introduction The hippocampus is well known for its role in sleep and memory consolidation in adolescents, and has been shown to demonstrate neural plasticity and neuronal regeneration. However, the relationship between sleep and hippocampal gray matter volume in healthy adults remains to be fully characterized. We hypothesized that total sleep time (TST), as measured by actigraphy, would correlate positively with gray matter volume (GMV) in the hippocampus, a key memory region of the brain. Methods Forty-five healthy normal sleeping adults between 20–45 years of age wore an actigraph for seven days to quantify habitual sleep duration and underwent magnetic resonance imaging during the actigraphy period. Voxel based morphometry in SPM12 was used to estimate GMV at the whole brain level. A region-of-interest mask was used to constrain data analysis to the left and right hippocampi. Results Habitual sleep duration per night correlated positively with gray matter volume within part of the left hippocampus (x=-36,y=-20,z=-18; k=32, pFWE-corr=0.093), controlling for age, sex, total intracranial volume, intelligence scores and mood. No correlation was found between TST and hippocampal GMV in the right hippocampus. Conclusion Longer sleep time was associated with greater gray matter volume in the left hippocampus. This finding is consistent with what has been observed in healthy children and extend these findings to healthy normal sleeping adults. While TST and GMV are correlated, the causal association cannot be established here. Further research may explore the effects of sleep extension on GMV and how these volume differences associate with various aspects of cognition, particularly memory. It should be noted that this study only included healthy adults with sleep durations between 6–9 hours per night. Future studies would benefit from including adults with a greater variance in their sleep patterns to better understand the relationship between sleep and hippocampal volume, and its potential effects on memory performance. Support Defense Advanced Research Projects Agency Young Faculty Award: DARPA-12-12-11-YFA11-FP-029

Suicidal ideation (SUI) can occur in the absence of concomitant psychiatric diagnoses, and even normal levels can be problematic among individuals experiencing excess stress or lack of social support. The objective of this study was to investigate the neuroanatomical basis of SUI in non-clinical human populations who are within the normal limits of SUI, after accounting for elevated stress and perceived lack of social support. Neuroanatomical data were collected from 55 healthy individuals (mean age 30.9 ± 8.1 years, 27 females) whose depression severity levels were below the Diagnostic and Statistical Manual of Mental Disorders criteria. Measures of SUI, aggression, stress, non-support, and treatment rejection were collected from the treatment-consideration scales (TCS) of the Personality Assessment Inventory (PAI). Correlations between standardized SUI scores and three brain morphometry measures, including vertex wise cortical thickness (CT), cortical surface area (CSA), and cortical volume (CV), were estimated for each participant, controlling for age, sex, intracranial volume, and the remaining TCS measures. We observed a significant negative association between scores on SUI and both CSA and CV (cluster-forming threshold of p < 0.005, clusterwise threshold of p < 0.05, FDR corrected for multiple comparisons) within the left rostral middle frontal gyrus. Our findings suggest that greater CSA and CV within the dorsolateral prefrontal cortex are associated with reduced SUI in a non-clinical population with mild levels of stress and perceived lack of social support. Because the dorsolateral prefrontal cortex has been broadly linked to cognitive reappraisal, self-critical thoughts, and emotional regulation, greater CSA and CV within these regions may lead to better mental health by protecting healthy individuals from engaging in SUI during periods of stress and perceived insufficient social support. As our data consisted of only healthy individuals with non-clinical levels of SUI, further investigation will be necessary to explore the neural basis of SUI in populations who may be at greater risk of future suicidal behavior

Objective/Background Poor quality and inadequate sleep are associated with impaired cognitive, motor, and behavioral components of sport performance and increased injury risk. While prior work identifies sports-related concussions as predisposing factors for poor sleep, the role of sleep as a sports-related concussion risk factor is unknown. The purpose of this study was to quantify the effect of poor sleep quality and insomnia symptoms on future sports-related concussion risk. Patients/Methods In this study, 190 NCAA Division-1 athletes completed a survey battery, including the Insomnia Severity Index (ISI) and National Health and Nutrition Examination Survey (NHANES) Sleep module. Univariate risk ratios for future sports-related concussions were computed with ISI and NHANES sleepiness scores as independent predictors. An additional multiple logistic regression model including sport, sports-related concussion history, and significant univariate predictors jointly assessed the odds of sustaining a concussion. Results Clinically moderate-to-severe insomnia severity (RR = 3.13, 95% CI: 1.320–7.424, p = 0.015) and excessive daytime sleepiness two or more times per month (RR = 2.856, 95% CI: 0.681–11.977, p = 0.037) increased concussion risk. These variables remained significant and comparable in magnitude in a multivariate model adjusted for sport participation. Conclusion Insomnia and daytime sleepiness are independently associated with increased sports-related concussion risk. More completely identifying bidirectional relationships between concussions and sleep requires further research. Clinicians and athletes should be cognizant of this relationship and take proactive measures – including assessing and treating sleep-disordered breathing, limiting insomnia risk factors, improving sleep hygiene, and developing daytime sleepiness management strategies – to reduce sports-related concussion risk and support overall athletic performance.

Background: Sleep loss contributes to obesity through a variety of mechanisms, including neuroendocrine functioning, increased hunger, and increased food intake. Additionally, sleep loss alters functional activation within brain regions associated with reward and behavioral control. However, it remains unknown whether individual differences in baseline neural functioning can predict eating behaviors during total sleep deprivation (TSD). We used functional magnetic resonance imaging (fMRI) to test the hypothesis that individuals with increased baseline responsiveness within reward regions are more vulnerable to TSD-induced overeating. Methods: N=45 subjects completed several fMRI scans during a single pre-TSD session that included performance on the Multi-Source Interference Task (MSIT) and the n-back task. Subjects returned to the laboratory for an overnight TSD session, during which they were given ad libitum access to 10,900 kcal of food. Leftover food and packaging were collected every 6 hours (00:00, 06:00, 12:00) to measure total food consumption. Subjects reported sleepiness every hour and performed a food rating task every 3 hours. Results: Functional activation within the ventral striatum during the MSIT and n-back was positively correlated with total caloric and carbohydrate intake during the final 6 hours (06:00–12:00) of TSD. Activation within the middle and superior temporal gyri during the MSIT also correlated with total carbohydrates consumed. Food consumption was not correlated with subjective sleepiness, hunger, or food desire. Conclusions: Individual differences in neural activity of reward processing areas (i.e., nucleus accumbens) prior to sleep deprivation is associated with an individual’s propensity to overeat during subsequent sleep deprivation. This suggests that individual differences within reward processing pathways are potential key factors in sleep loss related overeating. Sleep loss and obesity are tightly linked. Both phenomena have been associated with increased neural activation in regions associated with reward, inhibitory control, and disrupted dopamine signaling. Elevated baseline reward sensitivity in the ventral striatum appears to be further compounded by sleep deprivation induced dysfunction in the reward neurocircuitry, increasing the likelihood of overeating. Our findings suggest that large individual differences in baseline responsiveness of hedonic reward pathways may modulate the association between sleep loss and obesity.

To successfully navigate the social world, individuals must be able to employ appropriate social cognitive processes to guide behaviors. This includes the ability to perceive and comprehend the behaviors and social dispositions of oneself and that of others, and place these perceptions into the context of one’s own interpersonal norms before a behavior can be enacted. Due to its complexity, social functioning is mediated by a number of factors, including sleep quantity and quality. Our society is currently facing a sleep loss epidemic, and unfortunately such frequent and cumulative sleep loss can have drastic consequences on an individual’s social functioning. Sleep loss impairs decision-making, self-regulation, and emotional processing - all of which impact social cognitive processes. This chapter provides a concise overview of the available literature assessing sleep loss in the context of social cognition and judgment. Sleep loss has been shown to unmask biases, prejudices, and ethical behavior. In addition, sleep loss significantly impacts social decision-making and prosocial behaviors such as trust, bargaining, altruism, and general team dynamics. Research efforts in these areas should utilize naturalistic testing paradigms and sleep schedules to gain a more comprehensive understanding of the intricate relationship between sleep and social cognition.

Context: The long-term effects of concussion on brain function during cognitive tasks are not fully understood and neuroimaging findings are equivocal. Some images show hyperactivation of prefrontal brain regions in previously concussed individuals relative to controls, suggesting increased cognitive resource allocation. Others show prefrontal hypoactivation and hyperactivation in other regions as a presumed compensatory mechanism. Given the relationship between sympathetic arousal and neural activation, physiologic measures of arousal, such as electrodermal activity, may provide additional insight into the brain's functional changes in those with a history of concussion. Objective: To quantify differences in electrodermal activity during a commonly used standardized neurocognitive assessment between individuals with or without a history of concussion. Design: Descriptive laboratory study. Setting: Research laboratory. Patients or Other Participants: Seven asymptomatic individuals with a self-reported history of physician-diagnosed, sport-related concussion (number of previous concussions = 1.43 ± 0.53; time since most recent concussion = 0.75 to 6 years, median = 3 years) and 10 individuals without a history of concussion participated in this study. Main Outcome Measure(s): All participants wore bilateral wrist electrodermal activity sensors during the Standardized Assessment of Concussion. We measured normalized phasic (reactive) electrodermal activity during each test element (orientation, immediate recall, concentration, delayed recall). Results: A significant group-by-test element interaction was present (P = .003). Individuals with a history of concussion had greater phasic activity during delayed recall (P < .001). Delayed-recall phasic activity was greater in both groups relative to the other elements. Conclusions: Delayed recall resulted in greater physiologic arousal in previously concussed individuals relative to healthy control participants, supporting previous neuroimaging findings of increased prefrontal cortex activity during memory tasks after concussion. Given similar task performance and arousal patterns across the test, our results suggest that previously concussed individuals incur additional cognitive demands in a short-delay recall task.

Introduction Light exposure has powerful effects on the circadian timing of sleep and wake, primarily through the regulation of the secretion of melatonin. However, it is becoming clear that light has additional alerting effects beyond its primary effect on the circadian system. Exposure to light, particularly blue-wavelength light, has been shown to acutely increase brain activation, alertness, and some elementary aspects of cognitive performance such as working memory and emotional anticipation during the day. Whether blue light exposure can have longer-lasting effects on brain activation and performance during more complex cognitive control tasks up to 30-minutes after light cessation is unknown. Methods In a sample of 30 healthy adults, we examined the effects of a single 30-minute exposure to either blue (n=14) or amber placebo (n=16) light on subsequent brain activation and performance during the Multi-Source Interference Task (MSIT) measured a half-hour after light cessation using functional magnetic resonance imaging. Mean activation in all regions showing increased task-related activation (i.e., Task Positive Network; TPN) and regions showing decreased activation (i.e., Default Mode Network; DMN) at p Results Performance metrics for the MSIT, including accuracy, response time, and cognitive throughput, did not differ between the blue and amber conditions, suggesting that performance was sustained equally between light conditions. However, brain activation within the TPN to the interference condition of the MSIT was significantly lower (p=.024) in the blue relative to the amber condition, with no group differences observed for suppression of the DMN. Conclusion Compared to amber, a single exposure to blue light was associated with enhanced neural efficiency a half-hour later as demonstrated by reduced TPN activation to achieve the same level of cognitive performance. Blue light may be an effective method for optimizing neurocognitive performance under some conditions. Support US Army Medical Research and Materiel Command: W81XWH-14-1-0571

Introduction Daytime sleepiness is among the most frequent self-reported complaints by individuals who have sustained a mild traumatic brain injury (mTBI). Previous research demonstrates reduced vigilance and processing speed following mTBI. It has yet to be determined, however, if sustaining a mTBI alone, or the combination of daytime sleepiness and brain injury more greatly impacts cognitive function. The goal of this preliminary analysis was to determine the association between vigilance, daytime sleepiness, and mTBI. Methods A total of 137 adults (Mage = 24.89±7.2; 83 females) participated in the study, including 33 healthy controls (HCs) and 104 individuals with a documented mTBI within the preceding 12 months. Daytime sleepiness was assessed using the Epworth Sleepiness Scale (ESS), while daytime vigilance was measured using the Psychomotor Vigilance Task (PVT). To assess the effect of mTBI and daytime sleepiness on vigilance, we fit a Poisson regression to the number of lapses on the PVT, with group and ESS scores as predictors. Results ESS scores were significantly higher (p Conclusion Daytime sleepiness was negatively associated with sustained vigilance for all participants. However, the magnitude of this association was roughly twice as high in individuals who had sustained a mTBI in the previous year. These findings provide evidence of a significant compounding effect of daytime sleepiness and brain injury on sustained vigilant attention. Clinical evaluation of mTBI would benefit from routine assessment of daytime sleepiness. Support USAMRMC grant (W81XWH-12–0386).

Introduction Inter-individual differences in resistance to cognitive effects of sleep loss are well established and extend from basic vigilance capacities to more nuanced emotional processing. Neurobiological markers related to gray matter volumetric differences associated with resilience to sleep deprivation (SD) have yet to be explored. We collected anatomical magnetic resonance imaging on well-rested healthy adults and correlated gray matter volume (GMV) with the number of lapses on a psychomotor vigilance test (PVT) subsequently occurring over 29-hours of SD. Methods 45 individuals (23 males; mean age: 25.36 ± 5.62y) completed a baseline neuroimaging session while well-rested and returned 2-4 days later to complete 29h of SD. The PVT was administered at one-hour intervals across SD. High-resolution T1 structural scans were used for a volume-based morphometric analysis (CAT12). Images were segmented and normalized following automated procedures and smoothed at 8 mm FWHM. Regions of interest were constrained to the anterior cingulate and ventral frontal areas of the cortex. GM volume was correlated with the total number of lapses across all PVT administrations, after controlling for age, sex, and total intracranial volume. Results Total number of lapses positively correlated with GMV in two clusters comprised of areas in the anterior cingulate cortex (FWE corrected, p = 0.046), as well as the opercular and triangular parts of the inferior frontal gyrus (FWE corrected, p = 0.006). Conclusion Susceptibility to attentional lapses was predicted by greater gray matter volume in the ventrolateral prefrontal and anterior cingulate cortices. Current findings support that individual differences in attentional resiliency during SD may be, in part, due to differences in gray matter volume within cortical areas previously shown to be functionally affected by sleep loss. Support DARPA (12-12-11-YFA11-FP-029)

Introduction Daytime sleepiness has been associated with some neuroimaging metrics, including altered functional connectivity within the default mode network and decreased gray matter volume (GMV) of the medial prefrontal cortex. Most prior studies, however, have focused on patients with sleep disorders or other pathologies. Here we examined the association between GMV and self-reported daytime sleepiness among a healthy group of young adults who reported no sleep-related problems. Methods Forty-five healthy adults (22 female; Mean Age=25.4, SD=5.6), who self-reported no history of sleep-related disorders or major medical conditions, completed the Epworth Sleepiness Scale (ESS), the Repeatable Battery for Neuropsychological Status (RBANS) and underwent high-resolution structural neuroimaging at 3T. Gray matter volumes were processed using standard procedures in SPM12. After controlling for age, sex, and intracranial volume, GMV was regressed against ESS scores. Results Greater ESS was associated with larger GMV within a cluster of voxels in the right middle temporal gyrus (MNI coordinates: 57, -9, -22; k=1344 voxels, p=.003, FWE cluster corrected). After controlling for ESS scores, larger GMV in this region was associated with poorer delayed memory performance (r=-.345, p=.022) and total neurocognitive performance on the RBANS (r=-.303, p=.046). Conclusion Greater daytime sleepiness in healthy normal sleepers was associated with greater GMV within a region of the right middle temporal gyrus. Greater volume of this region was also associated with poorer neuropsychological performance. Decreased GMV of this same region has previously been reported in patients with obstructive sleep apnea and insomnia, suggesting that it may be particularly sensitive to sleep disruption or may play a role in the etiology of sleep disorders, even among young individuals who deny any history of sleep-related dysfunction. Longitudinal work should focus on the potential of this region as a biomarker of vulnerability to sleep problems. Support

Introduction Light exposure, particularly blue wavelength light, has consistent positive effects on daytime sleepiness following mild traumatic brain injuries (mTBIs). While self-perceived improvements in daytime sleepiness are well-documented, the neurobiological underpinnings are not well understood. The purpose of this study was to localize changes in functional connectivity after daily morning blue light therapy (BLT) and to associate these changes with improvements in post-mTBI daytime sleepiness. Methods 29 individuals with a history of mTBI were randomized to receive either BLT (n=13) or placebo amber light (ALT; n=16). All participants self-reported daytime sleepiness (Epworth Sleepiness Scale (ESS); lower is better) and underwent resting-state functional magnetic resonance imaging at pre- and post-treatment. Whole-brain functional connectivity (FC) was estimated as the correlations between 400 cortical regions of interest (ROIs) assigned to 7 resting-state networks. A two-sample T-test for post-treatment ROI-to-ROI FC identified target connections (FDR corrected p Results Lower FC after BLT in 4 ROI-to-ROI connections linking the default mode and visual networks was associated with lower ESS scores. Higher FC after BLT in 9 ROI-to-ROI connections linking attention, cognitive control, and visual networks was also associated with lower ESS scores. Conclusion BLT resulted in decreased self-reported daytime sleepiness, which was associated with decoupling of the default mode and visual networks as well as increased connectivity between and within attention and cognitive control networks, suggesting potentially improved attention to relevant stimuli and cognitive processes and less internal mentation. These associations may contribute to improved alertness, attention, and cognitive performance following a mTBI. Further work is needed to identify the optimal timing and dosage of BLT to maximize these outcomes. Support This study was funded by an award to Dr. Killgore from the US Army Medical Research and Materiel Command (USAMRMC; award number: W81XWH-14-1-0571).

Mild traumatic brain injury (mTBI) remains the most commonly reported head injury in the United States, and is associated with a wide range of post-concussive symptoms including physical, cognitive and affective impairments. Elevated aggression has been documented in mTBI; however, the neural mechanisms associated with aggression at the chronic stage of recovery remain poorly understood. In the present study, we investigated the association between white matter integrity and aggression in mTBI using diffusion tensor imaging (DTI). Twenty-six age-matched adults participated in the study, including 16 healthy controls (HCs) and 10 individuals in the chronic stage of recovery (either 6-months or 12 months post-mTBI). Psychological measures of aggression included the Buss-Perry Aggression Questionnaire and the Personality Assessment Inventory (PAI). Axonal pathways implicated in affective processing were studied, including the corpus callosum, anterior thalamic radiation, cingulum and uncinate fasciculus, and measures of white matter integrity included fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD) and axial diffusivity (AD). We found that adults with mTBI in the chronic stage of recovery had higher levels aggression. Individuals with mTBI also had greater RD in the corpus callosum compared to HCs, indicating reduced fiber integrity. Furthermore, we observed a significant association between reduced white matter integrity in the corpus callosum and greater aggression. Our findings provide additional evidence for underlying neuroanatomical mechanisms of aggression, although future research will be necessary to characterize the specific relationship between aggression and the white matter pathways we identified.

Background: Mild traumatic brain injuries (mTBIs) are a significant social, sport, and military health issue. In spite of advances in the clinical management of these injuries, the underlying pathophysiology is not well-understood. There is a critical need to advance objective biomarkers, allowing the identification and tracking of the long-term evolution of changes resulting from mTBI. Diffusion-weighted imaging (DWI) allows for the assessment of white-matter properties in the brain and shows promise as a suitable biomarker of mTBI pathophysiology. Methods: 34 individuals within a year of an mTBI (age: 24.4 ± 7.4) and 18 individuals with no history of mTBI (age: 23.2 ± 3.4) participated in this study. Participants completed self-report measures related to functional outcomes, psychological health, post-injury symptoms, and sleep, and underwent a neuroimaging session that included DWI. Whole-brain white matter was skeletonized using tract-based spatial statistics (TBSS) and compared between groups as well as correlated within-group with the self-report measures. Results: There were no statistically significant anatomical differences between the two groups. After controlling for time since injury, fractional anisotropy (FA) demonstrated a negative correlation with sleep quality scores (higher FA was associated with better sleep quality) and increasing depressive symptoms in the mTBI participants. Conversely, mean (MD) and radial diffusivity (RD) demonstrated positive correlations with sleep quality scores (higher RD was associated with worse sleep quality) and increasing depressive symptoms. These correlations were observed bilaterally in the internal capsule (anterior and posterior limbs), corona radiata (anterior and superior), fornix, and superior fronto-occipital fasciculi. Conclusion: The results of this study indicate that the clinical presentation of mTBI, particularly with respect to depression and sleep, is associated with reduced white-matter integrity in multiple areas of the brain, even after controlling for time since injury. These areas are generally associated not only with sleep and emotion regulation but also cognition. Consequently, the onset of depression and sleep dysfunction as well as cognitive impairments following mTBI may be closely related to each other and to white-matter integrity throughout the brain.

Previous research has reported that younger adults make fewer cognitive errors on an auditory vigilance task while in chest-deep water compared with on land. The purpose of this study was to extend this previous work to include older adults and to examine the effect of environment (water vs land) on linear and nonlinear measures of postural control under single- and dual-task conditions.Twenty-one older adult participants (age = 71.6 ± 8.34 years) performed a cognitive (auditory vigilance) and motor (standing balance) task separately and simultaneously on land and in chest-deep water. Listening errors (n = count) from the auditory vigilance test and sample entropy (SampEn), center of pressure area, and velocity for the balance test served as dependent measures. Environment (land vs water) and task (single vs dual) comparisons were made with a Wilcoxon matched-pair test.Listening errors were 111% greater during land than during water environments (single-task = 4.0 ± 3.5 vs 1.9 ± 1.7; P = .03). Conversely, SampEn values were 100% greater during water than during land environments (single-task = 0.04 ± 0.01 vs 0.02 ± 0.01; P.001). Center of pressure area and velocity followed a similar trend to SampEn with respect to environment differences, and none of the measures were different between single- and dual-task conditions (P.05).The findings of this study expand current support for the potential use of partial aquatic immersion as a viable method for challenging both cognitive and motor abilities in older adults.

Objectives Previous work suggests that sleep restriction (SR) reduces cognitive control and may increase negative implicit biases. Here we investigated whether SR might influence decision making on a social-evaluative task where individuals had to make judgments of threat based on facial photographs. Furthermore, we investigated the effect of changes in negative implicit biases as a result of sleep restriction on this decision-making task. Design Fourteen healthy adults underwent two 3-week counterbalanced in-laboratory stays (chronic SR and control sleep [CS] conditions). Participants completed the Arab Muslim Names implicit association test (a measure of implicit bias/attitudes toward Arab Muslims) and the Karolinska Airport Task (a measure of explicit decision making). The Karolinska Airport Task requires participants to judge the potential dangerousness of individuals based on facial photographs. Results After SR, participants were more likely to deem individuals with less positive and more negative facial features as dangerous than after CS. In addition, after SR, those participants showing higher negative implicit bias toward Arab Muslims tended to consider as more dangerous individuals with more quintessentially untrustworthy facial features (r = 0.76, P = .007), whereas this relationship was nonsignificant after CS (r = 0.33, P = .28). Conclusions These findings show not only that SR may increase implicit biases against a particular minority group but that SR also modifies how individuals make explicit decisions about another's trustworthiness based on facial features. These findings may have important implications for many occupations where workers who are routinely restricted of sleep are also responsible for making judgments about other people's trustworthiness (eg, police, security, military personnel).

Considerable work in recent years has examined the relationship between cortical thickness (CT) and general intelligence (IQ) in healthy individuals. It is not known whether specific IQ variables (i.e., perceptual reasoning [PIQ], verbal comprehension IQ [VIQ], and full-scale IQ [FSIQ]) are associated with multiple cortical measures (i.e., CT, cortical volume (CV), cortical surface area (CSA) and cortical gyrification (CG)) within the same individuals. Here we examined the association between these neuroimaging metrics and IQ in 56 healthy adults. At a cluster-forming threshold (CFT) of p 0.05, we observed significant positive relationships between CT and all three IQ variables in regions within the posterior frontal and superior parietal lobes. Regions within the temporal and posterior frontal lobes exhibited positive relationships between CV and two IQ variables (PIQ and FSIQ) and regions within the inferior parietal lobe exhibited positive relationships between CV and PIQ. Additionally, CV was positively associated with VIQ in the left insula and with FSIQ within the inferior frontal gyrus. At a more stringent CFT (p 0.01), the CT-PIQ, CT-VIQ, CT-FSIQ, and CV-PIQ relationships remained significant within the posterior frontal lobe, as did the CV-PIQ relationship within the temporal and inferior parietal lobes. We did not observe statistically significant relationships between IQ and either CSA or CG. Our findings suggest that the neural basis of IQ extends beyond previously observed relationships with fronto-parietal regions. We also conclude that CT and CV may be more useful metrics than CSA or CG in the study of intellectual abilities.