Negative association between neurovascular coupling and cortical gray matter volume during the lifespan.

Recent studies have established the moment-to-moment turnover of the blood-oxygen-level-dependent signal (TBOLD) at resting state as a key measure of local cortical brain function. Here, we sought to extend that line of research by evaluating TBOLD in 70 cortical areas with respect to corresponding brain volume, age, and sex across the lifespan in 1,344 healthy participants including 633 from the Human Connectome Project (HCP)-Development cohort (294 males and 339 females, age range 8-21 yr) and 711 healthy participants from HCP-Aging cohort (316 males and 395 females, 36-90 yr old). In both groups, we found that 1) TBOLD increased with age, 2) volume decreased with age, and 3) TBOLD and volume were highly significantly negatively correlated, independent of age. The inverse association between TBOLD and volume was documented in nearly all 70 brain areas and for both sexes, with slightly stronger associations documented for males. The strong correspondence between TBOLD and volume across age and sex suggests a common influence such as chronic neuroinflammation contributing to reduced cortical volume and increased TBOLD across the lifespan.NEW & NOTEWORTHY We report a significant negative association between resting functional magnetic resonance imaging (fMRI) blood-oxygen-level-dependent (BOLD) signal turnover (TBOLD) and cortical gray matter volume across the lifespan, such that TBOLD increased whereas volume decreased. We attribute this association to a hypothesized chronic, low-grade neuroinflammation, probably induced by various neurotropic pathogens, including human herpes viruses known to be dormant in the brain in a latent state and reactivated by stress, fever, and various environmental exposures, such as ultraviolet light.

Changes of cortical gray matter volume during development: a Human Connectome Project study.

We assessed changes in gray matter volume of 35 cerebrocortical regions in a large sample of participants in the Human Connectome Project-Development (n = 649, 6-21 yr old, 299 males and 350 females). The same protocol for MRI data acquisition and processing was used for all brains. Volumes of individual areas were adjusted for estimated total intracranial volume and linearly regressed against age. We found changes of volume with age that were distinct among areas and consistent between sexes, as follows: 1) the overall cortical volume decreased significantly with age; 2) the volumes of 30/35 areas also decreased significantly with age; 3) the volumes of the hippocampal cortex (hippocampus, parahippocampal, and entorhinal) and that of pericalcarine cortex did not show significant age-related changes; and 4) the volume of the temporal pole increased significantly with age. The rates of volume reduction with age did not differ significantly between the two sexes, except for areas of the parietal lobe where males showed statistically significantly higher volume reduction with age than females. These results, obtained from a large sample of male and female participants, and acquired and processed in the same way, confirm previous findings, offer new insights into region-specific age-related changes in cortical brain volume, and are discussed in the context of the hypothesis that reduction in cortical volume may be partly due to a background, low-grade chronic neuroinflammation inflicted by common viruses residing latently in the brain, notably viruses of the human herpes family.NEW & NOTEWORTHY We report mixed effects of age on cortical gray matter volume during development in a large sample of 649 participants studied in an identical manner (6-21 yr old, 299 males, 350 females). Volumes of 30/35 cortical areas decreased with age, temporal pole increased, and pericalcarine and hippocampal cortex (hippocampus, parahippocampal, and entorhinal) did not change. These findings were very similar in both sexes and provide a solid base for assessing region-specific cortical changes during development.

Differential reduction of gray matter volume with age in 35 cortical areas in men (more) and women (less).

It is known that brain volume decreases with age. Here, we assessed the rate of this decrease in gray matter volume of 35 cortical regions in a large sample of healthy participants (n = 712, age range 36-90 yr) of the Human Connectome Project-Aging. We evaluated the difference in this rate between men (n = 316) and women (n = 396) and found that the volumes of cortical areas decreased by an average of 5.25%/decade, with the highest rate of decrease observed in the rostral anterior cingulate cortex (7.28%/decade). The rate of decrease was higher in men than in women in general and in 30/35 (85.7%) areas in particular, involving most prominently the cingulate lobe. These findings could serve as a normative reference for clinical conditions that manifest with abnormal brain atrophy.NEW & NOTEWORTHY This study showed an overall decrease of cortical gray matter with age but with different rates of volume reduction in different areas, with smaller decrease rates in women than in men. The highest volume reduction rate was observed for the rostral anterior cingulate cortex, an area linked to depression. These findings could serve as a normative reference for clinical conditions that manifest with abnormal brain atrophy.

Changes of gray matter volumes of subcortical regions across the lifespan: a Human Connectome Project study.

We assessed changes in gray matter volume (GMV) of nine subcortical regions (accumbens, amygdala, brainstem, caudate, cerebellar cortex, pallidum, putamen, thalamus, and ventral diencephalon) across the lifespan in a large sample of participants in the Human Connectome Project (n = 2,458, 5-90 yr old, 1,113 males and 1,345 females). 3T MRI data were acquired using a harmonized protocol and were processed in an identical way for all brains. GMVs of individual regions were adjusted for estimated total intracranial volume and regressed against age. We found highly statistically significant changes in GMV with age (P < 0.001) that were distinct among areas and mostly consistent between sexes, as follows. 1) The GMVs of accumbens, caudate, putamen, and cerebellum decreased with age in a linear fashion. The rate of decrease was steeper in males than in females for all regions. 2) The GMVs of the amygdala, pallidum, thalamus, ventral diencephalon, and brainstem changed with age in a quadratic fashion, i.e., increasing first and decreasing afterward. The estimated age at the peak (vertex) of the parabola was 51.8 yr for the brainstem and 28.0-37.9 yr for the other regions. The peak occurred earlier in males than in females, by an average of 8 yr, with the exception of the brainstem, where the age at the peak was very similar in both sexes. These results confirm previous findings and offer new insights into region-specific age-related changes in subcortical brain GMVs.NEW & NOTEWORTHY We report mixed effects of age on subcortical grey matter volume (GMV) during lifespan (n = 2458, 5-90 yr old, 1113 male, 1345 female). Striatal and cerebellar GMVs decreased linearly with age, more steeply in males. In contrast, GMVs of the amygdala, pallidum, thalamus, ventral diencephalon, and brainstem changed in a quadratic fashion, increasing first and decreasing afterward, with males peaking earlier than females in all regions but the brainstem where they peaked at nearly the same time.

The dynamic shaping of local cortical circuitry by sex and age, and its relation to pattern comparison processing speed.

Previous resting-state functional magnetic resonance imaging (fMRI) studies have shown that the strength of local neural interactions decreases with distance. Here, we extend that line of research to evaluate effects of sex and age on local cortical circuitry in six cortical areas (superior frontal, precentral, postcentral, superior parietal, inferior parietal, and lateral occipital) using data acquired from 1,054 healthy young adults who participated in the Human Connectome Project. We confirmed previous findings that the strength of zero-lag correlations between prewhitened, resting-state, blood level oxygenation-dependent (BOLD) fMRI time series decreased with distance locally and documented that the rate of decrease with distance (spatial steepness) 1) was progressively lower from anterior to posterior areas, 2) was greater in women, especially in anterior areas, 3) increased with age, particularly for women, 4) was significantly correlated with percent inhibition, and 5) was positively and highly significantly correlated with pattern comparison processing speed (PCPS). A hierarchical tree clustering analysis of this dependence of PCPS on spatial steepness revealed a differential organization in processing that information between the two hemispheres, namely, a more independent vs. a more integrative processing in the left and right hemispheres, respectively. These findings document sex and age differences in dynamic local cortical interactions and provide evidence that spatial sharpening of these interactions may underlie cognitive processing speed differently organized in the two hemispheres.NEW & NOTEWORTHY Sex and age significantly affect shaping of local cortical interactions that are more limited in women and older brains. The net result is an increase in local spatial steepness of interactions, leading to a reduction of overlap among local ensembles and, hence, a more efficient information processing and an increase in the number of independent local cortical "processors." Remarkably, cognitive processing speed was positively associated with local spatial steepness, in keeping with the reasoning earlier.

Heritability of brain neurovascular coupling.

The moment-to-moment variation of neurovascular coupling in the brain was determined by computing the moment-to-moment turnover of the blood-oxygen-level-dependent signal (TBOLD) at resting state. Here we show that 1) TBOLD is heritable, 2) its heritability estimates are highly correlated between left and right hemispheres, and 3) the degree of its heritability is determined, in part, by the anatomical proximity of the brain areas involved. We also show that the regional distribution of TBOLD in the cortex is significantly associated with that of the vesicular acetylcholine transporter. These findings establish that TBOLD as a key heritable measure of local cortical brain function captured by neurovascular coupling.NEW & NOTEWORTHY Here we show that the sample-to-sample turnover of the resting state fMRI blood-oxygen-level-dependent turnover (TBOLD) is heritable, the left and right hemisphere TBOLD heritabilities are highly correlated, and TBOLD heritability varies among cortical areas. Moreover, we documented that TBOLD is associated with the regional cortical distribution of the vesicular acetylcholine transporter.

The brain landscape of the two-hit model of posttraumatic stress disorder.

The neurophysiological mechanisms underlying the development of posttraumatic stress disorder (PTSD) are poorly understood. Here we test a proposal that PTSD symptoms reflect fixed, highly correlated neural networks resulting from massive engagement of sensory inputs and the sequential involvement of those projections to limbic areas. Three-tesla functional magnetic resonance imaging (fMRI) data were acquired at rest in 15 veterans diagnosed with PTSD and 21 healthy control veterans from which zero-lag cross correlations between 50 brain areas (N = 1,225 pairs) were computed and analyzed. The brain areas were assigned to tiers based on the neurocircuitry of successively converging sensory pathways proposed by Jones and Powell (Jones EG, Powell TP. Brain 93: 793-820, 1970). The primary analyses assessed normalized proportional differences in cross correlation strength within and across tiers in veterans with PTSD and control veterans. Compared with control veterans, cross correlation strength was higher in veterans with PTSD, within and across tiers of areas involved in processing sensory inputs, and systematically increased from sensory processing areas to limbic areas. The functional relevance of this hypercorrelation was further documented by the finding that the severity of self-reported PTSD symptomatology was positively associated with higher neural correlations.NEW & NOTEWORTHY The neurophysiological mechanisms underlying the development of PTSD are poorly understood. Here we document that massive engagement of sensory modalities during trauma exposure leads to fixed, hypercorrelated frontal, parietal, temporal, and limbic networks, reflecting the successive integration of salient sensory inputs along the framework of Jones and Powell.

BOLD turnover in task-free state: variation among brain areas and effects of age and human leukocyte antigen (HLA) DRB1*13.

Blood oxygen level dependent (BOLD) signal in functional magnetic resonance imaging (fMRI) is frequently used as a proxy for underlying neural activity. Although this is a plausible assumption for experiments where a task is performed, it may not hold to the same degree for conditions of fMRI recording in a task-free, "resting" state where neural synaptic events are weak and, hence, neurovascular coupling and endothelial vascular factors become more prominent (Hillman Annu Rev Neurosci 37:161-181, 2014, 10.1146/annurev-neuro-071013-014111). Here we investigated the magnitude of change of BOLD in consecutive samples over the acquisition time period (turnover of BOLD, "TBOLD") by first-order differencing of single-voxel BOLD time series acquired in 70 areas of the cerebral cortex of 57 cognitively healthy women in a task-free resting state. More specifically, we evaluated (a) the variation of TBOLD among different cortical areas, (b) its dependence on age, and (c) its dependence on the presence (or absence) of the neuroprotective Human Leukocyte Antigen (HLA) gene DRB1*13 (DRB1*13:02 and DRB1*13:01). We found that TBOLD (a) varied substantially by 2.2 × among cortical areas, being highest in parahippocampal and entorhinal areas and lowest in parietal-occipital areas, (b) was significantly reduced in DRB1*13 carriers across cortical areas (from ~ 15% reduction in orbitofrontal cortex to 2% reduction in cuneus), and (c) increased with age in noncarriers of DRB1*13 but decreased with age in DRB1*13 carriers. These findings document significant dependencies of TBOLD on cortical area location, HLA DRB1*13 and age.

Functional cortical associations and their intraclass correlations and heritability as revealed by the fMRI Human Connectome Project.

We report on the functional connectivity (FC), its intraclass correlation (ICC), and heritability among 70 areas of the human cerebral cortex. FC was estimated as the Pearson correlation between averaged prewhitened Blood Oxygenation Level-Dependent time series of cortical areas in 988 young adult participants in the Human Connectome Project. Pairs of areas were assigned to three groups, namely homotopic (same area in the two hemispheres), ipsilateral (both areas in the same hemisphere), and heterotopic (nonhomotopic areas in different hemispheres). ICC for each pair of areas was computed for six genetic groups, namely monozygotic (MZ) twins, dizygotic (DZ) twins, singleton siblings of MZ twins (MZsb), singleton siblings of DZ twins (DZsb), non-twin siblings (SB), and unrelated individuals (UNR). With respect to FC, we found the following. (a) Homotopic FC was stronger than ipsilateral and heterotopic FC; (b) average FCs of left and right cortical areas were highly and positively correlated; and (c) FC varied in a systematic fashion along the anterior-posterior and inferior-superior dimensions, such that it increased from anterior to posterior and from inferior to superior. With respect to ICC, we found the following. (a) Homotopic ICC was significantly higher than ipsilateral and heterotopic ICC, but the latter two did not differ significantly from each other; (b) ICC was highest for MZ twins; (c) ICC of DZ twins was significantly lower than that of the MZ twins and higher than that of the three sibling groups (MZsb, DZsb, SB); and (d) ICC was close to zero for UNR. Finally, with respect to heritability, it was highest for homotopic areas, followed by ipsilateral, and heterotopic; however, it did not differ statistically significantly from each other.

Effects of sex and age on presumed inhibitory interactions in 6 areas of the human cerebral cortex as revealed by the fMRI Human Connectome Project.

Cortical inhibition is theorized to reflect an underlying property of human brain function, sharpening tuning and shaping connectivity. Although age and sex effects on large-scale resting-state brain connectivity have been well documented, effects on local cortical inhibition have received relatively limited attention. Here, we evaluated age and sex effects on presumed local inhibitory interactions in 6 lateral cortical areas using resting-state functional magnetic resonance imaging (fMRI) data acquired from 1054 young adults who participated in the Human Connectome Project. For each area, all possible pairwise crosscorrelations between prewhitened blood oxygenation level-dependent (BOLD) time series were calculated, and the highest value (CCmax) was retained to determine the mean and percentage of negative and positive CCmax. Here, we focused on the percentage of negative CCmax which we referred to as presumed "percent inhibition". The results documented regional differences in percent inhibition as well as age and sex effects, such that women's brains were characterized by significantly higher percent inhibition than men overall and in 4 of the 6 cortical areas, and the percent inhibition increased significantly with age in all 6 areas for women but in only one area for men. The findings from this young adult sample are presumed to reflect ongoing maturational processes involving local network connectivity that may be shaped by sex differences in brain structure, function, and neurochemistry.

Human Connectome Project: heritability of brain volumes in young healthy adults.

Here we report on the heritability and Intraclass Correlation Coefficients (ICCs) of brain volumes in 1,103 young healthy adults with mean age 29.2 years. Among them are: 153 monozygotic (MZ) twin pairs and 86 dizygotic (DZ) twin pairs, 133 non-twin siblings of MZ twins, 76 non-twin siblings of DZ twins, 335 siblings, and 81 unrelated individuals. ICCs were calculated between pairs of the following genetic groups: (1) MZ twins; (2) DZ twins; (3) MZ twins-their singleton siblings; (4) DZ twins-their singleton siblings; (5) siblings (SB); and (6) unrelated individuals (NR). We studied 4 brain groups: global, lobar, subcortical, and cortical brain regions. For each of 4 brain groups we found the same order of ICCs ranging from the highest values for MZ twins, statistically significantly smaller for the DZ twins and 3 sibling groups, and practically zero for NR. The DZ twins and 3 sibling groups were not different. No hemispheric difference was found in any genetic group. Among brain groups, the highest heritability was for the global regions, followed by lobar and subcortical groups. Only the cortical brain group heritability was statistically lower than other brain groups. We found less genetic control on the left hemisphere than on the right but no significant difference between hemispheres, and no hemispheric lateralization of heritability for any of the brain groups. These findings document substantial and systematic heritability of global and regional brain volumes.

Behavioral-genetic associations in the Human Connectome Project.

The Human Connectome Project (HCP) provides a rich dataset of quantitative and domain-specific behavioral measures from twins and extensive family structures. This makes the dataset a unique and a valuable resource to investigate heritability and determine individual differences. Using a set of measures of behavioral domains (motor, emotion, personality, sensory, and cognition), we estimated the intraclass correlations (ICCs) and heritability of 56 behavioral measures for 4 genetically identified groups of participants: monozygotic (MZ) twins, dizygotic (DZ) twins, non-twin siblings (SB), and unrelated individuals (NR). The ICCs range varied among behavioral domains but systematically so among the four genetic groups. We found the same rank order of ICCs, from the highest values for MZ twins, statistically significantly smaller for the DZ twins and sibling group (compared to MZ), and close to zero for NR. The mean heritability values of the five behavioral domains were: cognition h2 = 0.405, emotion h2 = 0.316, motor h2 = 0.138, personality h2 = 0.444, and sensory h2 = 0.193. These domains share overlapping brain networks. The heritability of motor domain was significantly smaller than cognitive, personality, and emotion domains. These findings provide new insight into the effect of genetics on the various diverse behavioral measures.

Invariant and heritable local cortical organization as revealed by fMRI.

Neural interactions in local cortical networks critically depend on the distance between interacting elements: the shorter the distance, the stronger the interactions. Here we quantified these interactions in six cortical areas of 854 individuals, including monozygotic and dizygotic twins, nontwin siblings, and nonrelated individuals. We found that the strength of zero-lag correlation between prewhitened, resting-state, blood level oxygenation-dependent functional magnetic resonance imaging time series decreased with distance as a power law. The rate of decrease, b, varied among individuals by ~1.9×, was highly correlated between hemispheres, but differed among areas (by ~1.2×) in a systematic fashion, becoming progressively less steep from frontal to occipital areas. With respect to twin status, b was significantly correlated between monozygotic twins, less so between dizygotic twins or nontwin siblings, and not at all in nonrelated individuals. These results quantify the lawful, distance-related cortical interactions and demonstrate, for the first time, the heritability of their power law. NEW & NOTEWORTHY Local cortical circuitry involves orderly neuronal interactions. A key feature of these interactions is that they are stronger the closer the interacting neurons. Here we quantified this crucial dependence of neural interactions on distance with functional magnetic resonance imaging and found that the strength of interactions decreases with distance as a power law that is very similar in all cortical lobes and heritable. These findings identify an invariant and heritable property of local cortical organization.

Subcortical brain atrophy in Gulf War Illness.

Gulf War Illness (GWI) is a multisystem disorder that has affected a substantial number of veterans who served in the 1990-1991 Gulf War. The brain is prominently affected, as manifested by the presence of neurological, cognitive and mood symptoms. Although brain dysfunction in GWI has been well documented (EBioMedicine 12:127-32, 2016), abnormalities in brain structure have been debated. Here we report a substantial (~10%) subcortical brain atrophy in GWI comprising mainly the brainstem, cerebellum and thalamus, and, to a lesser extent, basal ganglia, amygdala and diencephalon. The highest atrophy was observed in the brainstem, followed by left cerebellum and right thalamus, then by right cerebellum and left thalamus. These findings indicate graded atrophy of regions anatomically connected through the brainstem via the crossed superior cerebellar peduncle (left cerebellum â†’ right thalamus, right cerebellum â†’ left thalamus). This distribution of atrophy, together with the observed systematic reduction in volume of other subcortical areas (basal ganglia, amygdala and diencephalon), resemble the distribution of atrophy seen in toxic encephalopathy (Am J Neuroradiol 13:747-760, 1992) caused by a variety of substances, including organic solvents. Given the potential exposure of Gulf War veterans to "a wide range of biological and chemical agents including sand, smoke from oil-well fires, paints, solvents, insecticides, petroleum fuels and their combustion products, organophosphate nerve agents, pyridostigmine bromide, …" (Institute of Medicine National Research Council. Gulf War and Health: Volume 1. Depleted uranium, pyridostigmine bromide, sarin, and vaccines. National Academies Press, Washington DC, 2000), it is reasonable to suppose that such exposures, alone or in combination, could underlie the subcortical atrophy observed.

Neural mechanisms underlying the exploration of small city maps using magnetoencephalography.

The neural mechanisms underlying spatial cognition in the context of exploring realistic city maps are unknown. We conducted a novel brain imaging study to address the question of whether and how features of special importance for map exploration are encoded in the brain to make a spatial decision. Subjects explored by eyes small city maps exemplifying five different street network types in order to locate a hypothetical City Hall, while neural activity was recorded continuously by 248 magnetoencephalography (MEG) sensors at high temporal resolution. Monitoring subjects' eye positions, we locally characterized the maps by computing three spatial parameters of the areas that were explored. We computed the number of street intersections, the total street length, and the regularity index in the circular areas of 6 degrees of visual angle radius centered on instantaneous eye positions. We tested the hypothesis that neural activity during exploration is associated with the spatial parameters and modulated by street network type. All time series were rendered stationary and nonautocorrelated by applying an autoregressive integrated moving average model and taking the residuals. We then assessed the associations between the prewhitened time-varying MEG time series from 248 sensors and the prewhitened spatial parameters time series, for each street network type, using multiple linear regression analyses. In accord with our hypothesis, ongoing neural activity was strongly associated with the spatial parameters through localized and distributed networks, and neural processing of these parameters depended on the type of street network. Overall, processing of the spatial parameters seems to predominantly involve right frontal and prefrontal areas, but not for all street network layouts. These results are in line with findings from a series of previous studies showing that frontal and prefrontal areas are involved in the processing of spatial information and decision making. Modulation of neural processing of the spatial parameters by street network type suggests that some street network layouts may contain other types of spatial information that subjects use to explore maps and make spatial decisions.

Diagnosis of posttraumatic stress disorder (PTSD) based on correlations of prewhitened fMRI data: outcomes and areas involved.

Successful diagnosis of PTSD has been achieved using neural correlations from prewhitened magnetoencephalographic (MEG) time series (Georgopoulos et al. in J Neural Eng 7:16011, 2010. doi:10.1088/1741-2560/7/1/016011; James et al. 2015). Here, we show that highly successful classification of PTSD and control subjects can be obtained using neural correlations from prewhitened resting-state fMRI data. All but one PTSD (14/15; sensitivity = 93.3 %) and all but one control (20/21; specificity = 95.2 %) subjects were correctly classified using 15 out of 2701 possible correlations between 74 brain areas. In contrast, correlations of the same but non-prewhitened data yielded chance-level classifications. We conclude that, if properly processed, fMRI has the prospect of aiding significantly in PTSD diagnosis. Twenty-five brain areas were most prominently involved in correct subject classification, including areas from all cortical lobes and the left pallidum.

Exploring small city maps.

The exploration of city maps has exploded recently due to the wide availability, increasing use of, and reliance on small positioning and navigational devices for personal use. In this study, subjects explored small, 3-mile diameter circular maps exemplifying five different types of street networks common in the United States, in order to locate a hypothetical city hall. Chosen locations indicated that subjects are able to identify more accessible sites. Monitoring eye position revealed that women explored maps faster, using more widely dispersed but more narrowly focused gaze clusters than men. The type of street network influenced the time spent by the eyes in a locale and differentially affected the size of gaze clusters between women and men, underscoring the complex interactions of gender-specific strategies with street network types.

A voxel-by-voxel parametric fMRI study of motor mental rotation: hemispheric specialization and gender differences in neural processing efficiency.

Differences between men and women in brain size, cognitive performance and lateralization of brain activation have been perennial and controversial issues. Here we show that in a motor mental rotation task where women and men performed equally well, the slope of the functional magnetic resonance imaging (fMRI) blood oxygenation level dependent (BOLD) signal per degree of mental rotation was overall 2.4x higher in men than in women. This was attributed to the much more inefficient engagement (i.e. higher slopes) of the right hemisphere by men (mainly the frontal lobe). These findings indicate that women process information much more efficiently than men, which could offset smaller brain size.

A Two-Hit Model of The Biological Origin of Posttraumatic Stress Disorder (PTSD).

Posttraumatic stress disorder (PTSD) is a debilitating disorder that can develop following exposure to a traumatic event. Although the cause of PTSD is known, the brain mechanisms of its development remain unknown, especially why it arises in some people but not in others. Most of the research on PTSD has dealt with psychological and brain mechanisms underlying its symptomatology, including intrusive memories, fear and avoidance (see ref.1 for a broad coverage of PTSD research)1. Here we focus, instead, on the origin of PTSD, namely on the neural mechanisms underlying its development. Specifically, we propose a two-hit model for PTSD development, with the following components. (a) The 1st hit is a neuroimmune challenge, as a preexisting condition, and the 2nd hit is intense glutamatergic neurotransmission, induced by the traumatic event; (b) the key molecule that mediates the effects of these two hits is intercellular adhesion molecule 5 (ICAM-5) which was found to be differentially expressed in PTSD2. ICAM-5 is activated by neuroimmune challenge3,4 and glutamatergic neurotransmission5,6, it further enhances glutamatergic transmission6, and exerts a potent effect on synapse formation and neural plasticity, in addition to immunoregulatory functions3,4,7; and (c) with respect to the neural network(s) involved, the brain areas most involved are medial temporal cortical areas, and interconnected cortical and subcortical areas8-10. We hypothesize that the net result of intense glutamatergic transmission in those areas induced by a traumatic event in the presence of ongoing neuroimmune challenge leads to increased levels of ICAM-5 which further enhances glutamatergic transmission and thus leads to a state of a neural network with highly correlated neural interactions, as has been observed in functional neuroimaging studies8-10. We assume that such a "locked-in" network underlies the intrusive re-experiencing in PTSD and maintains associated symptomatology, such as fear and avoidance.

Protective Effect of Human Leukocyte Antigen (HLA) Allele DRB1*13:02 on Age-Related Brain Gray Matter Volume Reduction in Healthy Women.

BACKGROUND: Reduction of brain volume (brain atrophy) during healthy brain aging is well documented and dependent on genetic, lifestyle and environmental factors. Here we investigated the possible dependence of brain gray matter volume reduction in the absence of the Human Leukocyte Antigen (HLA) allele DRB1*13:02 which prevents brain atrophy in Gulf War Illness (James et al., 2017). METHODS: Seventy-one cognitively healthy women (32-69years old) underwent a structural Magnetic Resonance Imaging (sMRI) scan to measure the volumes of total gray matter, cerebrocortical gray matter, and subcortical gray matter. Participants were assigned to two groups, depending on whether they lacked the DRB1*13:02 allele (No DRB1*13:02 group, N=60) or carried the DRB1*13:02 allele (N=11). We assessed the change of brain gray matter volume with age in each group by performing a linear regression where the brain volume (adjusted for total intracranial volume) was the dependent variable and age was the independent variable. FINDINGS: In the No DRB1*13:02 group, the volumes of total gray matter, cerebrocortical gray matter, and subcortical gray matter were reduced highly significantly. In contrast, none of these volumes showed a statistically significant reduction with age in the DRB1*13:02 group. INTERPRETATION: These findings document the protective effect of DRB1*13:02 on age-dependent reduction of brain gray matter in healthy individuals. Since the role of this allele is to connect to matching epitopes of external antigens for the subsequent production of antibodies and elimination of the offending antigen, we hypothesize that its protective effect may be due to the successful elimination of such antigens to which we are exposed during the lifespan, antigens that otherwise would persist causing gradual brain atrophy. In addition, we consider a possible beneficial role of DRB1*13:02 attributed to its binding to cathepsin S, a known harmful substance in brain aging (Wendt et al., 2008). Of course, other factors covarying with the presence of DRB1*13:02 could be involved.