Slow blood-to-brain transport underlies enduring barrier dysfunction in American football players.

Repetitive mild traumatic brain injury in American football players has garnered increasing public attention following reports of chronic traumatic encephalopathy, a progressive tauopathy. While the mechanisms underlying repetitive mild traumatic brain injury-induced neurodegeneration are unknown and antemortem diagnostic tests are not available, neuropathology studies suggest a pathogenic role for microvascular injury, specifically blood-brain barrier dysfunction. Thus, our main objective was to demonstrate the effectiveness of a modified dynamic contrast-enhanced MRI approach we have developed to detect impairments in brain microvascular function. To this end, we scanned 42 adult male amateur American football players and a control group comprising 27 athletes practicing a non-contact sport and 26 non-athletes. MRI scans were also performed in 51 patients with brain pathologies involving the blood-brain barrier, namely malignant brain tumours, ischaemic stroke and haemorrhagic traumatic contusion. Based on data from prolonged scans, we generated maps that visualized the permeability value for each brain voxel. Our permeability maps revealed an increase in slow blood-to-brain transport in a subset of amateur American football players, but not in sex- and age-matched controls. The increase in permeability was region specific (white matter, midbrain peduncles, red nucleus, temporal cortex) and correlated with changes in white matter, which were confirmed by diffusion tensor imaging. Additionally, increased permeability persisted for months, as seen in players who were scanned both on- and off-season. Examination of patients with brain pathologies revealed that slow tracer accumulation characterizes areas surrounding the core of injury, which frequently shows fast blood-to-brain transport. Next, we verified our method in two rodent models: rats and mice subjected to repeated mild closed-head impact injury, and rats with vascular injury inflicted by photothrombosis. In both models, slow blood-to-brain transport was observed, which correlated with neuropathological changes. Lastly, computational simulations and direct imaging of the transport of Evans blue-albumin complex in brains of rats subjected to recurrent seizures or focal cerebrovascular injury suggest that increased cellular transport underlies the observed slow blood-to-brain transport. Taken together, our findings suggest dynamic contrast-enhanced-MRI can be used to diagnose specific microvascular pathology after traumatic brain injury and other brain pathologies.

Dissociative associative-memory deficit as a function of primacy and recency effects.

Studies designed to explore memory for single items versus paired items (i.e., associative memory) in young adults show inconsistent results. Some studies report a decrease in associative recognition and others report mild-to-moderate or even a null effect. The studies often do not take into account stimuli serial position (SSP) when analyzing the locus of associative accuracy. Studies testing SSP often target memory for items, while studies targeting associative memory decline as a function of SSP are lacking. The objective of the current study is to test the separate and joint effect of SSP (experiments 1 + 2) and presentation duration (experiment 2) on memory recognition for items versus associations. We hypothesized that greater associative decline (compared to the expected decline in memory for items with similar serial location) will be observed for the material located at the end of a learning list than the material located at the beginning of a learning list. The results of the two experiments converged and confirmed our hypotheses; the greatest associative deficit was observed for associative material located at the end of the learning list (experiments 1 + 2) and for material presented for short durations (experiment 2). The interaction between SSP and presentation duration did not reach significance; however, a direct estimation of the cumulative deficit of SSP and presentation duration confirmed our hypothesis regarding greater associative deficit for recently presented items for short durations. These results highlight the importance of the joint and separate, effect of SSP and presentation duration to the study of associative memory decline.

sec-Butyl-propylacetamide (SPD) and two of its stereoisomers rapidly terminate paraoxon-induced status epilepticus in rats.

OBJECTIVE: Organophosphates (OPs) are commonly used insecticides for agriculture and domestic purposes, but may also serve as nerve agents. Exposure to OPs result in overstimulation of the cholinergic system and lead to status epilepticus (SE), a life-threatening condition that is often resistant to treatment. SE is associated with significant neuronal damage, neurocognitive dysfunction, and the development of lifelong epilepsy. Therefore, rapid termination of SE and prevention of brain damage is of high interest. Here we tested the efficacy of sec-butyl-propylacetamide (SPD) and two of its individual stereoisomers, (2S,3S)-SPD and (2R,3R)-SPD, in discontinuing OP-induced seizures. SPD is a one carbon homolog of valnoctamide, a central nervous system (CNS)-active constitutional isomer of valproic acid (VPA) corresponding amide valpromide. METHODS: Rats were implanted with epidural telemetric electrodes to allow electrocorticography (ECoG) recording 24 h prior, during and 24 h after poisoning with the OP paraoxon (at a dose equivalent to 1.4 LD50 Median lethal dose). All rats were provided with antidotal treatment of atropine and toxogonin. Epileptic activity was measured using a novel automated system to evaluate the different effects of midazolam, SPD, and its individual stereoisomers in comparison to nontreated controls. RESULTS: Treatment with SPD or its individual stereoisomer (2S,3S)-SPD significantly shorten paraoxon-induced SE and reduced the duration of recorded pathologic activity after SE was terminated. (2S,3S)-SPD was superior to racemic-SPD in diminishing delayed pathologic epileptiform activity within the first 8 h after SE. SIGNIFICANCE: These results suggest SPD as an efficient drug for the rapid termination of SE and pathological epileptiform activity following OP poisoning, a strategy to reduce neuronal dysfunction and the risk for lifelong epilepsy.

Reduced corpus-callosum volume in posttraumatic stress disorder highlights the importance of interhemispheric connectivity for associative memory.

Memory deficits are a common complaint of patients with posttraumatic stress disorder (PTSD). Despite vivid trauma-related memory, previous studies report memory impairment for nontrauma-related stimuli when compared to controls, specifically in associative memory (Guez et al., 2011). Healthy individuals show hemispheric memory asymmetry with left-prefrontal lateralization of encoding and right-prefrontal lateralization of episodic retrieval, suggesting a role for interhemispheric communication in memory-related tasks (Gazzaniga, ; Ringo, Doty, Demeter, & Simard, ). Because brain magnetic resonance imaging (bMRI) studies in PTSD patients report volume changes in various regions, including white matter and corpus callosum (CC), we aimed to test the relationship between memory deficits and CC volume in PTSD patients. We probed for specific alterations in associative memory in PTSD and measured the volume of subportions within the CC employing bMRI. Our main finding was a reduction in CC white-matter volume in PTSD patients, as compared to controls, t(35) = -2.7, p = .010, that was correlated with lower associative performance (r = .76, p = .003). We propose that CC volume reduction is a substrate for the associative memory deficits found in PTSD.

Traumatic stress, active engagement and resilience in first responders and civilians in the outbreak of war.

Background: The outbreak of war in Israel on 7 October and the unique events of that day have presented unprecedented challenges to first responders (FRs), who are professionally trained to engage in providing assistance in such circumstances. Moreover, while research demonstrates the long-term psychological consequences of FRs, little is known regarding how FR's engagement in providing assistance relates to stress and resilience levels as events continue to unfold.Objective: The current study examined the relationship between traumatic stress symptoms (TSS) and resilience levels among FRs and controls during the first weeks of the Iron Swords war, while focusing on the moderating role of active engagement in providing assistance.Method: Data were collected during the first month of the Iron Swords war from 374 participants living in Southern Israel, of whom 77 (20.6%) were FRs. All participants filled out scales assessing TSS and resilience and provided relevant background information.Results: High TSS levels were associated with reduced resilience in FRs and non-FRs. Moreover, both the study group and active engagement were significant moderators for the TSS-resilience link, which was insignificant among FRs who provided assistance and for civilians who did not provide assistance. However, the TSS-resilience association remained significant for FRs who did not engage in providing assistance and for civilians who did.Conclusions: Our findings highlight the importance of examining the extent to which FRs act in line with their duties during times of adverse stress. Clinical interventions aimed towards FRs who did not engage in providing assistance are needed and should focus on the extent to which their moral values, beliefs and expectations are met, as these appear critical parameters in preserving resilience.

First responders report increased traumatic stress and reduced resilience.Active engagement moderated first responders' traumatic stress­resilience link.Findings are discussed in the context of potentially morally injurious events.

White-matter correlates of anxiety: The contribution of the corpus-callosum to the study of anxiety and stress-related disorders.

OBJECTIVES: Traumatic stress has been associated with increased risk for brain alterations and development of anxiety disorders. Studies conducted in posttraumatic patients have shown white-mater volume and diffusion alterations in the corpus-callosum. Decreased cognitive performance has been demonstrated in acute stress disorder and posttraumatic patients. However, whether cognitive alterations result from stress related neuropathology or reflect a predisposition is not known. In the current study, we examined in healthy controls, whether individual differences in anxiety are associated with those cognitive and brain alterations reported in stress related pathologies. METHODS: Twenty healthy volunteers were evaluated for anxiety using the state-trait inventory (STAI), and were tested for memory performance. Brain imaging was employed to extract volumetric and diffusion characteristics of the corpus-callosum. RESULTS: Significant correlations were found between trait anxiety and all three diffusion parameters (fractional-anisotropy, mean and radial-diffusivity). Associative-memory performance and corpus-callosum volume were also significantly correlated. CONCLUSION: We suggest that cognitive and brain alterations, as tested in the current work and reported in stress related pathologies, are present early and possibly persist throughout life. Our findings support the hypothesis that individual differences in trait anxiety predispose individuals towards negative cognitive outcomes and brain alterations, and potentially to stress related disorders.

Associative-memory deficit as a function of age and stimuli serial position.

Studies have shown associative-memory decline in aging. While the literature is inconclusive regarding the source of the deficit, some researchers argue that it is caused by impaired encoding and maintenance processes in working-memory (WM). Successful retrieval of a stimulus depends on its sequential presentation in the learning list: stimuli at the beginning or the end of the learning list benefit from higher retrieval probability. These effects are known as "primacy" and "recency" effects, respectively. In the case of the primacy-effect, stimuli at early list positions benefit from extensive rehearsal that results in enhanced consolidation and trace in long-term memory (LTM). In the case of the recency-effect, target stimuli at later serial positions are still maintained in WM and can therefore be effortlessly retrieved. Considering these effects could shed light on the involvement of WM in associative-binding. Both behavioral and neuroimaging researchers have studied associative-decline in aging. However, no work has explicitly tested age differences in memory for items versus associations as a function of stimuli serial position (SSP). In the current study, 22 younger and 22 older adults were recruited to participate in a study aimed to test the separate and joint effects of both SSP and aging on memory-recognition of items and associations. In the task used, retrieval was manipulated for SSP (beginning/middle/end of the list) and item/associations recognition modes. We hypothesized that greater associative-decline will be observed in older adults, specifically for recently presented material. The results showed that both groups presented a significant associative-deficit at the recency positions; this decrease was additive and did not correspond to the expected interaction effect. Further analysis showed that the source of associative-memory decline for stimuli at recency position in older adults resulted from an increase in false-alarm (FA) rates. These results support the involvement of WM-binding impairment in aging.

Victims of war-Psychoendocrine evidence for the impact of traumatic stress on psychological well-being of adolescents growing up during the Israeli-Palestinian conflict.

Violent conflicts are severe traumatic stressors with detrimental effects on physical and mental health, with children and adolescents being particularly at risk. For the hypothalamic-pituitary-adrenal (HPA) axis, characteristic patterns of dysregulation in trauma-exposed individuals have been shown. This study set out to investigate self-reported mental well-being in Palestinian adolescents growing up during the Israeli-Palestinian conflict. Hair cortisol concentrations (HCC) as a psychoendocrine marker for long-term HPA axis aberrations along with the potential protective factor sense of coherence (SoC; i.e., the global mindset to interpret the world and emerging stressors as comprehensible, manageable, and meaningful) were examined. Between 2014 and 2016, posttraumatic stress disorder (PTSD), depression, anxiety, HCC, and SoC were examined in 233 adolescents aged 11 to 16 from the West Bank. More than half of the participants reported trauma exposure, with 40% fulfilling the criteria of a preliminary PTSD diagnosis and a high prevalence of anxiety and depression. HCC was significantly elevated in the PTSD subgroup compared to the subgroup not exposed to any traumatic events (p = 0.046), with trauma-exposed individuals in between. HCC was further associated with typical sequelae of traumatic stress. Notably, SoC was inversely related to self-reported psychopathology, as well as to HCC in the trauma group. The results illustrate the situation of adolescents exposed to chronic traumatic stress and extend the literature on aberrant HPA axis functioning under such conditions. They also point out a central role of SoC, which may imply new strategies to aid individuals exposed to ongoing conflicts.

Victims of War: Dehydroepiandrosterone Concentrations in Hair and Their Associations with Trauma Sequelae in Palestinian Adolescents Living in the West Bank.

Due to its anti-glucocorticoid properties, the steroid hormone dehydroepiandrosterone (DHEA) might play a role for coping with traumatic stress and posttraumatic stress disorder (PTSD). The majority of studies report elevated DHEA secretion and decreased cortisol/DHEA ratio associated with traumatic stress, however, contrasting results have also been published. One reason for this heterogeneity might be that in past studies, DHEA has been measured in plasma or saliva samples reflecting acute hormone levels. In comparison, the current study assessed the hair levels of DHEA and cortisol as long-term markers along with self-reported data on psychopathology and coping in 92 female adolescents aged 11⁻16 from the West Bank affected by the Israeli⁻Palestinian conflict. Results showed that trauma-exposed individuals had significantly higher DHEA levels (p = 0.013) and lower cortisol/DHEA ratios (p = 0.036) than participants from the non-trauma group. Furthermore, DHEA and cortisol/DHEA ratio emerged as associated with trauma load and timing, but not with coping. By applying the novel method of DHEA analysis from hair samples, this study adds to the growing literature on the interplay of DHEA, cortisol, traumatic stress and coping, and provides valuable starting points for further research.

Paroxysmal slow cortical activity in Alzheimer's disease and epilepsy is associated with blood-brain barrier dysfunction.

A growing body of evidence shows that epileptic activity is frequent but often undiagnosed in patients with Alzheimer's disease (AD) and has major therapeutic implications. Here, we analyzed electroencephalogram (EEG) data from patients with AD and found an EEG signature of transient slowing of the cortical network that we termed paroxysmal slow wave events (PSWEs). The occurrence per minute of the PSWEs was correlated with level of cognitive impairment. Interictal (between seizures) PSWEs were also found in patients with epilepsy, localized to cortical regions displaying blood-brain barrier (BBB) dysfunction, and in three rodent models with BBB pathology: aged mice, young 5x familial AD model, and status epilepticus-induced epilepsy in young rats. To investigate the potential causative role of BBB dysfunction in network modifications underlying PSWEs, we infused the serum protein albumin directly into the cerebral ventricles of naïve young rats. Infusion of albumin, but not artificial cerebrospinal fluid control, resulted in high incidence of PSWEs. Our results identify PSWEs as an EEG manifestation of nonconvulsive seizures in patients with AD and suggest BBB pathology as an underlying mechanism and as a promising therapeutic target.

Blood-brain barrier dysfunction in aging induces hyperactivation of TGFß signaling and chronic yet reversible neural dysfunction.

Aging involves a decline in neural function that contributes to cognitive impairment and disease. However, the mechanisms underlying the transition from a young-and-healthy to aged-and-dysfunctional brain are not well understood. Here, we report breakdown of the vascular blood-brain barrier (BBB) in aging humans and rodents, which begins as early as middle age and progresses to the end of the life span. Gain-of-function and loss-of-function manipulations show that this BBB dysfunction triggers hyperactivation of transforming growth factor-ß (TGFß) signaling in astrocytes, which is necessary and sufficient to cause neural dysfunction and age-related pathology in rodents. Specifically, infusion of the serum protein albumin into the young rodent brain (mimicking BBB leakiness) induced astrocytic TGFß signaling and an aged brain phenotype including aberrant electrocorticographic activity, vulnerability to seizures, and cognitive impairment. Furthermore, conditional genetic knockdown of astrocytic TGFß receptors or pharmacological inhibition of TGFß signaling reversed these symptomatic outcomes in aged mice. Last, we found that this same signaling pathway is activated in aging human subjects with BBB dysfunction. Our study identifies dysfunction in the neurovascular unit as one of the earliest triggers of neurological aging and demonstrates that the aging brain may retain considerable latent capacity, which can be revitalized by therapeutic inhibition of TGFß signaling.

The Effect of Trier Social Stress Test (TSST) on Item and Associative Recognition of Words and Pictures in Healthy Participants.

Psychological stress, induced by the Trier Social Stress Test (TSST), has repeatedly been shown to alter memory performance. Although factors influencing memory performance such as stimulus nature (verbal/pictorial) and emotional valence have been extensively studied, results whether stress impairs or improves memory are still inconsistent. This study aimed at exploring the effect of TSST on item versus associative memory for neutral, verbal, and pictorial stimuli. 48 healthy subjects were recruited, 24 participants were randomly assigned to the TSST group and the remaining 24 participants were assigned to the control group. Stress reactivity was measured by psychological (subjective state anxiety ratings) and physiological (Galvanic skin response recording) measurements. Subjects performed an item-association memory task for both stimulus types (words, pictures) simultaneously, before, and after the stress/non-stress manipulation. The results showed that memory recognition for pictorial stimuli was higher than for verbal stimuli. Memory for both words and pictures was impaired following TSST; while the source for this impairment was specific to associative recognition in pictures, a more general deficit was observed for verbal material, as expressed in decreased recognition for both items and associations following TSST. Response latency analysis indicated that the TSST manipulation decreased response time but at the cost of memory accuracy. We conclude that stress does not uniformly affect memory; rather it interacts with the task's cognitive load and stimulus type. Applying the current study results to patients diagnosed with disorders associated with traumatic stress, our findings in healthy subjects under acute stress provide further support for our assertion that patients' impaired memory originates in poor recollection processing following depletion of attentional resources.

Breakdown of Inter-Hemispheric Connectivity Is Associated with Posttraumatic Symptomatology and Memory Impairment.

Altered brain anatomy in specific gray-matter regions has been shown in patients with posttraumatic stress disorder (PTSD). Recently, white-matter tracts have become a focus of research in PTSD. The corpus callosum (CC) is the principal white-matter fiber bundle, crucial in relaying sensory, motor and cognitive information between hemispheres. Alterations in CC fibers have been reported in PTSD and might be assumed to underlie substantial behavioral and cognitive sequelae; however most diffusion tensor imaging (DTI) studies in adult-onset PTSD failed to address the clinical correlates between imaging and PTSD symptoms severity, behavioral manifestation and cognitive functions. In the current study we examined (a) to what extent microstructural integrity of the CC is associated with memory performance and (b) whether imaging and cognitive parameters are associated with PTSD symptom severity. DTI data were obtained and fractional anisotropy (FA) values were computed for 16 patients and 14 controls. PTSD symptom severity was assessed by employing the clinician administered PTSD scale (CAPS) and memory was tested using a task probing item and associative memory for words and pictures. Significant correlations were found between PTSD symptoms severity, memory accuracy and reaction-time to CC FA values in the PTSD group. This study demonstrates meaningful clinical and cognitive correlates of microstructural connectivity. These results have implications for diagnostic tools and future studies aimed at identifying individuals at risk for PTSD.

Negative Emotional Arousal Impairs Associative Memory Performance for Emotionally Neutral Content in Healthy Participants.

The effect of emotional arousal on memory presents a complex pattern with previous studies reporting conflicting results of both improved and reduced memory performance following arousal manipulations. In this study we further tested the effect of negative emotional arousal (NEA) on individual-item recognition and associative recognition of neutral stimuli in healthy participants, and hypothesized that NEA will particularly impair associative memory performance. The current study consists of two experiments; in both, participants studied a list of word-pairs and were then tested for items (items recognition test), and for associations (associative recognition test). In the first experiment, the arousal manipulation was induced by flashing emotionally-negative or neutral pictures between study-pairs while in the second experiment arousal was induced by presenting emotionally-negative or neutral pictures between lists. The results of the two experiments converged and supported an associative memory deficit observed under NEA conditions. We suggest that NEA is associated with an altered ability to bind one stimulus to another as a result of impaired recollection, resulting in poorer associative memory performance. The current study findings may contribute to the understanding of the mechanism underlying memory impairments reported in disorders associated with traumatic stress.

Altered processing of visual emotional stimuli in posttraumatic stress disorder: an event-related potential study.

Patients with posttraumatic stress disorder (PTSD) display abnormal emotional processing and bias towards emotional content. Most neurophysiological studies in PTSD found higher amplitudes of event-related potentials (ERPs) in response to trauma-related visual content. Here we aimed to characterize brain electrical activity in PTSD subjects in response to non-trauma-related emotion-laden pictures (positive, neutral and negative). A combined behavioral-ERP study was conducted in 14 severe PTSD patients and 14 controls. Response time in PTSD patients was slower compared with that in controls, irrespective to emotional valence. In both PTSD and controls, response time to negative pictures was slower compared with that to neutral or positive pictures. Upon ranking, both control and PTSD subjects similarly discriminated between pictures with different emotional valences. ERP analysis revealed three distinctive components (at ~300, ~600 and ~1000 ms post-stimulus onset) for emotional valence in control subjects. In contrast, PTSD patients displayed a similar brain response across all emotional categories, resembling the response of controls to negative stimuli. We interpret these findings as a brain-circuit response tendency towards negative overgeneralization in PTSD.