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The anatomical and functional architecture of the human brain is mainly determined by prenatal transcriptional processes. We describe an anatomically comprehensive atlas of the mid-gestational human brain, including de novo reference atlases, in situ hybridization, ultra-high-resolution magnetic resonance imaging (MRI) and microarray analysis on highly discrete laser-microdissected brain regions. In developing cerebral cortex, transcriptional differences are found between different proliferative and post-mitotic layers, wherein laminar signatures reflect cellular composition and developmental processes. Cytoarchitectural differences between human and mouse have molecular correlates, including species differences in gene expression in subplate, although surprisingly we find minimal differences between the inner and outer subventricular zones even though the outer zone is expanded in humans. Both germinal and post-mitotic cortical layers exhibit fronto-temporal gradients, with particular enrichment in the frontal lobe. Finally, many neurodevelopmental disorder and human-evolution-related genes show patterned expression, potentially underlying unique features of human cortical formation. These data provide a rich, freely-accessible resource for understanding human brain development. A spatially resolved transcriptional atlas of the mid-gestational developing human brain has been created using laser-capture microdissection and microarray technology, providing a comprehensive reference resource which also enables new hypotheses about the nature of human brain evolution and the origins of neurodevelopmental disorders. New whole-brain mapping resources With President Barack Obama's BRAIN (Brain Research through Advancing Innovative Neurotechnologies) initiative now entering year two, this issue of Nature presents two landmark papers that mobilize 'big science' resources to the cause. Hongkui Zeng and colleagues present the first brain-wide, mesoscale connectome for a mammalian species — the laboratory mouse — based on cell-type-specific tracing of axonal projections. The wiring diagram of a complete nervous system has long been available for a small roundworm, but neuronal connectivity data for larger animals has been patchy until now. The new three-dimensional Allen Mouse Brain Connectivity Atlas is a whole-brain connectivity matrix that will provide insights into how brain regions communicate. Much of the data generated in this project will be of relevance to investigations of neural networks in humans and should help to further our understanding of human brain connectivity and its involvement in brain disorders. In a separate report Ed Lein and colleagues present a transcriptional atlas of the mid-gestational human brain at high spatial resolution, based on laser microdissection and DNA microarray technology. The structure and function of the human brain is largely determined by prenatal transcriptional processes that initiate gene expression, but our understanding of the developing brain has been limited. The new data set reveals transcriptional signatures for developmental processes associated with the massive expansion of neocortex during human evolution, and suggests new cortical germinal zones or postmitotic neurons as sites of dynamic expression for many genes associated with neurological or psychiatric disorders.

We present an ultra-high resolution MRI dataset of an ex vivo human brain specimen. The brain specimen was donated by a 58-year-old woman who had no history of neurological disease and died of non-neurological causes. After fixation in 10% formalin, the specimen was imaged on a 7 Tesla MRI scanner at 100 µm isotropic resolution using a custom-built 31-channel receive array coil. Single-echo multi-flip Fast Low-Angle SHot (FLASH) data were acquired over 100 hours of scan time (25 hours per flip angle), allowing derivation of synthesized FLASH volumes. This dataset provides an unprecedented view of the three-dimensional neuroanatomy of the human brain. To optimize the utility of this resource, we warped the dataset into standard stereotactic space. We now distribute the dataset in both native space and stereotactic space to the academic community via multiple platforms. We envision that this dataset will have a broad range of investigational, educational, and clinical applications that will advance understanding of human brain anatomy in health and disease.

Corticogenesis is underpinned by a complex process of subcortical neuroproliferation, followed by highly orchestrated cellular migration. A greater appreciation of the processes involved in human fetal corticogenesis is vital to gaining an understanding of how developmental disturbances originating in gestation could establish a variety of complex neuropathology manifesting in childhood, or even in adult life. Magnetic resonance imaging modalities offer a unique insight into anatomical structure, and increasingly infer information regarding underlying microstructure in the human brain. In this study we applied a combination of high-resolution structural and diffusion-weighted magnetic resonance imaging to a unique cohort of three post-mortem fetal brain specimens, aged between 19 and 22 post-conceptual weeks. Specifically, we sought to assess patterns of diffusion coherence associated with subcortical neuroproliferative structures: the pallial ventricular/subventricular zone and subpallial ganglionic eminence. Two distinct three-dimensional patterns of diffusion coherence were evident: a clear radial pattern originating in ventricular/subventricular zone, and a tangentio-radial patterns originating in ganglionic eminence. These patterns appeared to regress in a caudo-rostral and lateral-ventral to medial-dorsal direction across the short period of fetal development under study. Our findings demonstrate for the first time distinct patterns of diffusion coherence associated with known anatomical proliferative structures. The radial pattern associated with dorsopallial ventricular/subventricular zone and the tangentio-radial pattern associated with subpallial ganglionic eminence are consistent with reports of radial–glial mediated neuronal migration pathways identified during human corticogenesis, supported by our prior studies of comparative fetal diffusion MRI and histology. The ability to assess such pathways in the fetal brain using MR imaging offers a unique insight into three-dimensional trajectories beyond those visualized using traditional histological techniques. Our results suggest that ex-vivo fetal MRI is a potentially useful modality in understanding normal human development and various disease processes whose etiology may originate in aberrant fetal neuronal migration. •We apply ex-vivo structural and diffusion MRI to study the human fetal brain.•We examine diffusion coherence associated with neuroproliferative structures.•A radial coherence pattern originated from ventricular/subventricular zone.•A tangentio-radial coherence pattern was associated with ganglionic eminence.•These patterns concur with histological descriptions of neuronal migration.

Diffusion tensor MRI is sensitive to the coherent structure of brain tissue and is commonly used to study large-scale white matter structure. Diffusion in gray matter is more isotropic, however, several groups have observed coherent patterns of diffusion anisotropy within the cerebral cortical gray matter. We extend the study of cortical diffusion anisotropy by relating it to the local coordinate system of the folded cerebral cortex. We use 1mm and sub-millimeter isotropic resolution diffusion imaging to perform a laminar analysis of the principal diffusion orientation, fractional anisotropy, mean diffusivity and partial volume effects. Data from 6 in vivo human subjects, a fixed human brain specimen and an anesthetized macaque were examined. Large regions of cortex show a radial diffusion orientation. In vivo human and macaque data displayed a sharp transition from radial to tangential diffusion orientation at the border between primary motor and somatosensory cortex, and some evidence of tangential diffusion in secondary somatosensory cortex and primary auditory cortex. Ex vivo diffusion imaging in a human tissue sample showed some tangential diffusion orientation in S1 but mostly radial diffusion orientations in both M1 and S1. ► Measurement of diffusion anisotropy in the in vivo human cerebral cortex. ► Dominant diffusion orientation compared to the local cortical orientation. ► Analysis of cortical depth-dependent diffusion features and partial volume effects. ► Diffusion in the cortex is predominantly orthogonal to the cortical surface. ► Evidence of tangential diffusion in S1 and to a lesser extent S2 and A1.

The purpose of this study was to examine the efficacy of a new middle-school-classroom forgiveness curriculum in promoting forgiveness and reducing anger. The students in this study were 153 fourth through eighth graders in three regional parochial schools. The students were assigned to forgiveness education or control groups in the fall semester and reassigned to the opposite group in the spring semester. Before-and-after assessments of forgiveness and anger were collected in both the fall and spring semesters. The quantitative results showed that levels of forgiveness increased as expected in both semesters, but anger did not change in expected ways. The qualitative results showed that the children’s conceptualizations of the forgiveness process aligned closely with the core forgiveness curriculum content. The results suggest that meaningful work can be accomplished to promote forgiveness in the middle school classroom using this newly developed, efficient, and effective curriculum that can be implemented by teachers and staff.

Epidemiological studies suggest that a single moderate-to-severe traumatic brain injury (TBI) is associated with an increased risk of neurodegenerative disease, including Alzheimer's disease (AD) and Parkinson's disease (PD). Histopathological studies describe complex neurodegenerative pathologies in individuals exposed to single moderate-to-severe TBI or repetitive mild TBI, including chronic traumatic encephalopathy (CTE). However, the clinicopathological links between TBI and post-traumatic neurodegenerative diseases such as AD, PD, and CTE remain poorly understood. Here, we describe the methodology of the Late Effects of TBI (LETBI) study, whose goals are to characterize chronic post-traumatic neuropathology and to identify in vivo biomarkers of post-traumatic neurodegeneration. LETBI participants undergo extensive clinical evaluation using National Institutes of Health TBI Common Data Elements, proteomic and genomic analysis, structural and functional magnetic resonance imaging (MRI), and prospective consent for brain donation. Selected brain specimens undergo ultra-high resolution ex vivo MRI and histopathological evaluation including whole–mount analysis. Co-registration of ex vivo and in vivo MRI data enables identification of ex vivo lesions that were present during life. In vivo signatures of postmortem pathology are then correlated with cognitive and behavioral data to characterize the clinical phenotype(s) associated with pathological brain lesions. We illustrate the study methods and demonstrate proof of concept for this approach by reporting results from the first LETBI participant, who despite the presence of multiple in vivo and ex vivo pathoanatomic lesions had normal cognition and was functionally independent until her mid-80s. The LETBI project represents a multidisciplinary effort to characterize post-traumatic neuropathology and identify in vivo signatures of postmortem pathology in a prospective study.

The perirhinal cortex (Brodmann's area 35) is a multimodal area that is important for normal memory function. Specifically, perirhinal cortex is involved in the detection of novel objects and manifests neurofibrillary tangles in Alzheimer's disease very early in disease progression. We scanned ex vivo brain hemispheres at standard resolution (1mm×1mm×1mm) to construct pial/white matter surfaces in FreeSurfer and scanned again at high resolution (120μm×120μm×120μm) to determine cortical architectural boundaries. After labeling perirhinal area 35 in the high resolution images, we mapped the high resolution labels to the surface models to localize area 35 in fourteen cases. We validated the area boundaries determined using histological Nissl staining. To test the accuracy of the probabilistic mapping, we measured the Hausdorff distance between the predicted and true labels and found that the median Hausdorff distance was 4.0mm for the left hemispheres (n=7) and 3.2mm for the right hemispheres (n=7) across subjects. To show the utility of perirhinal localization, we mapped our labels to a subset of the Alzheimer's Disease Neuroimaging Initiative dataset and found decreased cortical thickness measures in mild cognitive impairment and Alzheimer's disease compared to controls in the predicted perirhinal area 35. Our ex vivo probabilistic mapping of the perirhinal cortex provides histologically validated, automated and accurate labeling of architectonic regions in the medial temporal lobe, and facilitates the analysis of atrophic changes in a large dataset for earlier detection and diagnosis. ► Localized human perirhinal cortex using ex vivo MRI volumes ► Validated localization of perirhinal cortex with cytoarchitectural Nissl staining ► Mapped perirhinal labels from high resolution ex vivo to flattened spherical space ► Hausdorff distance measures were compared for right and left hemispheres. ► Cortical thickness showed differences between controls and Alzheimer's disease.

The phenological stage of maturity of grasses and supplementation program can impact forage utilization in grazing beef cattle. However, the potential interaction between harvest maturity of Eragrostis tef (teff) hay and energy supplement source was yet to be fully evaluated. Therefore, our objective was to determine the effects of harvest maturity of teff hay and supplemental energy sources on nutrient intake, apparent total-tract nutrient digestion, nitrogen (N) utilization, and ruminal fermentation characteristics in beef heifers. A split-plot design with teff hay harvest maturity as the whole plot and supplemental energy source as the subplot was administered in a three-period (21 d), three × three Latin square design. Six crossbred beef heifers (804 ± 53.6 kg of body weight; BW) were allocated to two harvest maturities (early- (EH]) or late-heading (LH)) and to two supplemental energy sources (no supplement (CON), or rolled corn grain or beet pulp pellet fed at 0.5% of BW). Data were analyzed using SAS. There was no harvest maturity × energy supplement interaction. Although harvest maturity had no impact on total dry matter intake (DMI), crude protein (CP) intake was greater (p < 0.01) for EH than LH heifers. Total intakes of dry (DM) and organic matter (OM) were also greater (p < 0.01) for supplemented than CON heifers, whereas acid detergent fiber (ADF) intake was greater for beet pulp heifers compared to heifers fed the CON diet and supplemental corn grain. Harvest maturity had no impact on ruminal pH. However, mean ruminal pH was lower (p = 0.04), duration pH < 6.2, and molar proportions of butyrate and branched-chain fatty acids were greater (p ≤ 0.049) for heifers fed corn grain compared to CON and beet pulp diets. Heifers fed EH hay had greater (p ≤ 0.02) apparent total-tract DM, OM, CP, NDF, and ADF digestibility than heifers fed LH hay. Although there was no supplemental energy effect on microbial nitrogen (N) flow, it was greater (p < 0.01) for EH than LH heifers. Apparent N retention, which did not differ, was negative across all diets. In summary, delaying the harvest of teff hay from the EH to LH stage of maturity compromised nutrient supply, which was not attenuated by feeding supplemental corn grain and beet pulp at 0.5% of diet DM. Because N retention was negative across harvest maturity, there might be a need to provide both energy and protein supplements to improve growth performance when feeding teff hay to beef cattle.

The impact of genetic and environmental factors on human brain structure is of great importance for understanding normative cognitive and brain aging as well as neuropsychiatric disorders. However, most studies of genetic and environmental influences on human brain structure have either focused on global measures or have had samples that were too small for reliable estimates. Using the classical twin design, we assessed genetic, shared environmental, and individual-specific environmental influences on individual differences in the size of 96 brain regions of interest (ROIs). Participants were 474 middle-aged male twins (202 pairs; 70 unpaired) in the Vietnam Era Twin Study of Aging (VETSA). They were 51–59 years old, and were similar to U.S. men in their age range in terms of sociodemographic and health characteristics. We measured thickness of cortical ROIs and volume of other ROIs. On average, genetic influences accounted for approximately 70% of the variance in the volume of global, subcortical, and ventricular ROIs and approximately 45% of the variance in the thickness of cortical ROIs. There was greater variability in the heritability of cortical ROIs (0.00–0.75) as compared with subcortical and ventricular ROIs (0.48–0.85). The results did not indicate lateralized heritability differences or greater genetic influences on the size of regions underlying higher cognitive functions. The findings provide key information for imaging genetic studies and other studies of brain phenotypes and endophenotypes. Longitudinal analysis will be needed to determine whether the degree of genetic and environmental influences changes for different ROIs from midlife to later life.