Figure 1. (Left):The cingulate cortex (colored areas) lies in the medial wall of each hemisphere, adjacent to the corpus callosum (white). Brodmann divided this area into a precingulate (pink), now called the anterior cingulate cortex (ACC) and a postcingulate (blue) now called the posterior cingulate cortex (PCC). 1 (Right): The ACC is further subdivided into two major sections. The three most common approaches to naming are illustrated. 1-3 The dorsal posterior section (outlined in gold) has been called caudal or dorsal ACC. In Vogt's system it is considered a separate area, the middle cingulate cortex (MCC). The ventral anterior section (outlined in yellow) has been called rostral or ventral ACC. In Vogt's system, it is considered ACC. These major sections are commonly further divided, as illustrated. Figure 2. (Left):Von Economo (spindle) neurons are found in humans and great apes, but not other nonhuman primates, nor in most mammals. 4,5 In humans, they are found in the insula and cingulate cortex (yellow area on MRI). These are large projection neurons, with an average volume more than four times that of pyramidal neurons. The apical and basal dendrites are also quite different from pyramidal neurons, both longer and less branched. It has been suggested that the larger size may indicate faster conduction times and more extensive connections. (Right): A pyramidal neuron is illustrated for comparison. Figure 3. Parcellation of cingulate cortex based on patterns of structural connectivity (estimated from diffusion tensor imaging) support the presence of multiple functional regions. Approximations of the areas of cingulate cortex with the strongest connections to specific cortical and subcortical regions are color-coded onto midline sagittal MR images. 6 The resultant parcellation is illustrated on the cover. Cover and

Large-scale multi-ethnic cohorts offer unprecedented opportunities to elucidate the genetic factors influencing complex traits related to health and disease among minority populations. At the same time, the genetic diversity in these cohorts presents new challenges for analysis and interpretation. We consider the utility of race and/or ethnicity categories in genome-wide association studies (GWASs) of multi-ethnic cohorts. We demonstrate that race/ethnicity information enhances the ability to understand population-specific genetic architecture. To address the practical issue that self-identified racial/ethnic information may be incomplete, we propose a machine learning algorithm that produces a surrogate variable, termed HARE. We use height as a model trait to demonstrate the utility of HARE and ethnicity-specific GWASs.

FIGURE 1 AND COVER. Recent studies have begun to explore how the underlying neurobiology of posttraumatic stress disorder (PTSD) may be affected by the nature of the index trauma. The results of a meta-analysis that grouped task-activated (trauma reminders) functional MRI (fMRI) studies by PTSD index trauma are color-coded by trauma type (blue, sexual/physical abuse; pink, combat-related) (1). Of note, although areas of greater activation were predominately in the right hemisphere for both groups, there was little or no overlap. One study has compared resting-state regional cerebral metabolic rate between veterans with PTSD grouped by whether the index trauma was danger-and/or fear-based (i.e., life threat to self or other) or nondanger-based (i.e., witnessing violence, traumatic loss, moral injury by self or other). Regions of interest (ROIs) (yellow circles) were areas previously reported to be activated by fear stimuli (bilateral amygdalae, right rostral anterior cingulate cortex) or by traumatic script imagery (right dorsal anterior cingulate cortex, left posterior cingulate cortex, left precuneus). Danger-and/or fear-based traumas were associated with higher metabolism in the amygdala (red fill), whereas nondanger-based traumas were associated with higher metabolism in the precuneus (green fill). As noted by the authors, heightened metabolism in the precuneus for nondanger-based traumas may relate to its role in self-referential processing (2). Moral injury often co-occurs with PTSD. Moral injuries that are index traumas for PTSD are more strongly associated with emotions that developed after the event than emotions experienced during the event, suggesting that the underlying neurobiology may differ (3). An fMRI study of military veterans has explored relationships between resting-state activity (amplitude of low frequency fluctuation [ALFF]) and symptoms of PTSD (Clinician Administered PTSD Scale [CAPS]) and moral injury (Moral Injury Events Scale [MIES]) (4). CAPS score was not significantly correlated with average ALFF in any ROI. Both subscales of the MIES (transgressions, betrayals) correlated with left inferior parietal lobule ROI activity (purple circle) but in opposite directions (Cover). As discussed by the authors, these results indicate that the neural correlates of PTSD and moral injury differ at least in part (4).

clinicaltrials.gov Identifier: NCT01421342.

Objective Use Diffusion Tensor Imaging (DTI) to investigate white matter alterations associated with blast exposure with or without acute symptoms of traumatic brain injury (TBI). Participants Forty-five veterans of the recent military conflicts included twenty-three exposed to primary blast without TBI symptoms, six having primary blast mild TBI, and sixteen unexposed to blast. Design Cross-sectional case control study. Main Measures Neuropsychological testing and DTI metrics that quantified the number of voxel clusters with altered fractional anisotropy (FA) radial diffusivity (RD), and axial diffusivity (AD), regardless of their spatial location. Results Significantly lower FA and higher RD was observed in veterans exposed to primary blast with and without mild TBI relative to blast unexposed veterans. Voxel clusters of lower FA were spatially dispersed and heterogeneous across affected individuals. Conclusion These results suggest that lack of clear TBI symptoms following primary blast exposure may not accurately reflect the extent of brain injury. If confirmed, our findings would argue for supplementing the established approach of making diagnoses based purely on clinical history and observable acute symptoms with novel neuroimaging-based diagnostic criteria that “look below the surface” for pathology.

In this proof-of-concept study, we demonstrated application of the PheWAS using large EHR biobanks to inform drug effects. The findings of an association of the IL6R SNP with reduced risk for aortic aneurysms correspond with the newest indication for IL6R blockade, giant cell arteritis, of which a major complication is aortic aneurysm.

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The United States (US) Department of Veterans Affairs (VA) Mid-Atlantic Mental Illness Research, Education, and Clinical Center (MIRECC) Post-Deployment Mental Health (PDMH) multi-site study examines post-deployment mental health in US military Afghanistan/Iraq-era veterans. The study includes the comprehensive behavioral health characterization of over 3600 study participants and the genetic, metabolomic, neurocognitive, and neuroimaging data for many of the participants. The study design also incorporates an infrastructure for a data repository to re-contact participants for follow-up studies. The overwhelming majority (94%) of participants consented to be re-contacted for future studies, and our recently completed feasibility study indicates that 73-83% of these participants could be reached successfully for enrollment into longitudinal follow-up investigations. Longitudinal concurrent cohort follow-up studies will be conducted (5-10+ years post-baseline) to examine predictors of illness chronicity, resilience, recovery, functional outcome, and other variables, and will include neuroimaging, genetic/epigenetic, serum biomarker, and neurocognitive studies, among others. To date, the PDMH study has generated more than 35 publications from the baseline data and the repository has been leveraged in over 20 publications from follow-up studies drawing from this cohort. Limitations that may affect data collection for a longitudinal follow-up study are also presented.