Multimodal MRI reveals brainstem connections that sustain wakefulness in human consciousness.

Consciousness is composed of arousal (i.e., wakefulness) and awareness. Substantial progress has been made in mapping the cortical networks that underlie awareness in the human brain, but knowledge about the subcortical networks that sustain arousal in humans is incomplete. Here, we aimed to map the connectivity of a proposed subcortical arousal network that sustains wakefulness in the human brain, analogous to the cortical default mode network (DMN) that has been shown to contribute to awareness. We integrated data from ex vivo diffusion magnetic resonance imaging (MRI) of three human brains, obtained at autopsy from neurologically normal individuals, with immunohistochemical staining of subcortical brain sections. We identified nodes of the proposed default ascending arousal network (dAAN) in the brainstem, hypothalamus, thalamus, and basal forebrain. Deterministic and probabilistic tractography analyses of the ex vivo diffusion MRI data revealed projection, association, and commissural pathways linking dAAN nodes with one another and with DMN nodes. Complementary analyses of in vivo 7-tesla resting-state functional MRI data from the Human Connectome Project identified the dopaminergic ventral tegmental area in the midbrain as a widely connected hub node at the nexus of the subcortical arousal and cortical awareness networks. Our network-based autopsy methods and connectivity data provide a putative neuroanatomic architecture for the integration of arousal and awareness in human consciousness.

The Effects of Harvest Maturity of Eragrostis tef 'Moxie' Hay and Supplemental Energy Source on Forage Utilization in Beef Heifers.

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.

Sustaining wakefulness: Brainstem connectivity in human consciousness.

Consciousness is comprised of arousal (i.e., wakefulness) and awareness. Substantial progress has been made in mapping the cortical networks that modulate awareness in the human brain, but knowledge about the subcortical networks that sustain arousal is lacking. We integrated data from ex vivo diffusion MRI, immunohistochemistry, and in vivo 7 Tesla functional MRI to map the connectivity of a subcortical arousal network that we postulate sustains wakefulness in the resting, conscious human brain, analogous to the cortical default mode network (DMN) that is believed to sustain self-awareness. We identified nodes of the proposed default ascending arousal network (dAAN) in the brainstem, hypothalamus, thalamus, and basal forebrain by correlating ex vivo diffusion MRI with immunohistochemistry in three human brain specimens from neurologically normal individuals scanned at 600-750 µm resolution. We performed deterministic and probabilistic tractography analyses of the diffusion MRI data to map dAAN intra-network connections and dAAN-DMN internetwork connections. Using a newly developed network-based autopsy of the human brain that integrates ex vivo MRI and histopathology, we identified projection, association, and commissural pathways linking dAAN nodes with one another and with cortical DMN nodes, providing a structural architecture for the integration of arousal and awareness in human consciousness. We release the ex vivo diffusion MRI data, corresponding immunohistochemistry data, network-based autopsy methods, and a new brainstem dAAN atlas to support efforts to map the connectivity of human consciousness.

Robust joint registration of multiple stains and MRI for multimodal 3D histology reconstruction: Application to the Allen human brain atlas.

Joint registration of a stack of 2D histological sections to recover 3D structure ("3D histology reconstruction") finds application in areas such as atlas building and validation of in vivo imaging. Straightforward pairwise registration of neighbouring sections yields smooth reconstructions but has well-known problems such as "banana effect" (straightening of curved structures) and "z-shift" (drift). While these problems can be alleviated with an external, linearly aligned reference (e.g., Magnetic Resonance (MR) images), registration is often inaccurate due to contrast differences and the strong nonlinear distortion of the tissue, including artefacts such as folds and tears. In this paper, we present a probabilistic model of spatial deformation that yields reconstructions for multiple histological stains that that are jointly smooth, robust to outliers, and follow the reference shape. The model relies on a spanning tree of latent transforms connecting all the sections and slices of the reference volume, and assumes that the registration between any pair of images can be see as a noisy version of the composition of (possibly inverted) latent transforms connecting the two images. Bayesian inference is used to compute the most likely latent transforms given a set of pairwise registrations between image pairs within and across modalities. We consider two likelihood models: Gaussian (ℓ2 norm, which can be minimised in closed form) and Laplacian (ℓ1 norm, minimised with linear programming). Results on synthetic deformations on multiple MR modalities, show that our method can accurately and robustly register multiple contrasts even in the presence of outliers. The framework is used for accurate 3D reconstruction of two stains (Nissl and parvalbumin) from the Allen human brain atlas, showing its benefits on real data with severe distortions. Moreover, we also provide the registration of the reconstructed volume to MNI space, bridging the gaps between two of the most widely used atlases in histology and MRI. The 3D reconstructed volumes and atlas registration can be downloaded from https://openneuro.org/datasets/ds003590. The code is freely available at https://github.com/acasamitjana/3dhirest.

Improving stroke care in Nova Scotia, Canada: a population-based project spanning 14 years.

Stroke is a complex disorder that challenges healthcare systems. An audit of in-hospital stroke care in the province of Nova Scotia, Canada, in 2004-2005 indicated that many aspects of care delivery fell short of national best practice recommendations. Stroke care in Nova Scotia was reorganised using a combination of interventions to facilitate systems change and quality improvement. The focus was mainly on implementing evidence-based stroke unit care, augmenting thrombolytic therapy and enhancing dysphagia assessment. Key were the development of a provincial network to facilitate ongoing collaboration and structured information exchange, the creation of the stroke coordinator and stroke physician champion roles, and the implementation of a registry to capture information about adults hospitalised because of stroke or transient ischaemic attack. To evaluate the interventions, a longitudinal analysis compared the audit results with registry data for 2012, 2015 and 2019. The proportion of patients receiving multidisciplinary stroke unit care rose from 22.4% in 2005 to 74.0% in 2019. The proportion of patients who received alteplase increased steadily from 3.2% to 18.5%, and the median delay between hospital arrival and alteplase administration decreased from 102 min to 56 min, without an increase in intracranial haemorrhage. Dysphagia screening increased from 41.4% to 77.4%. More patients were transferred from acute care to a dedicated in-patient rehabilitation unit, and fewer were discharged to residential or long-term care. These enhancements did not prolong length-of-stay in acute care. The network was a critical success factor; competing priorities in the healthcare system were the main challenge to implementing change. A multidimensional, multiyear, improvement intervention yielded substantial and sustained improvements in the process and structure of stroke care in Nova Scotia.

Neighborhood Evictions, Marital/Cohabiting Status, and Preterm Birth among African American Women.

Introduction: Housing stability is an important determinant of health, but no studies to our knowledge have examined the spill-over effects of neighborhood eviction rates on individual risk of preterm birth (PTB) among African American women. Objective: We assessed whether living in a neighborhood with high eviction rates was associated with risk of PTB among African American women, and whether marital/cohabiting status modified the association. Methods: We spatially linked interview, medical record, and current address data from the Life-course Influences on Fetal Environments Study (2009-2011, N=1386) of postpartum African American women from Metropolitan Detroit, Michigan, to publicly available data on block-group level rates of eviction filings and judgements. PTB was defined as birth before 37 completed weeks of gestation and occurred in 16.3% of the sample (n=226). Eviction rate variables were rescaled by their interquartile ranges (75th vs 25th percentiles). Women self-reported whether they were married to, or cohabiting with, the father of their baby during the in-person interview. We used Modified Poisson regression with robust error variance to estimate relative risks of PTB associated with each eviction variable separately and included an interaction term with marital/cohabiting status (P<.10 considered significant) in adjusted models. Results: In the overall sample, neighborhood eviction filings and judgements did not predict PTB, but the associations were modified by marital/cohabiting status (P for interaction = .02, and .06, respectively). Among women who were married/cohabiting, those who lived in neighborhoods with high eviction filings (adjusted relative risk: 1.25, 95% CI: 1.06, 1.47) and eviction judgements (adjusted relative risk: 1.18, 95% CI: 1.05, 1.33) had higher risk of PTB than women who did not. Little evidence of an association was observed for women who were not married/cohabiting. Conclusions: Future studies should examine the mechanisms of the reported associations to identify novel intervention targets (eg, addressing landlord discrimination) and policy solutions (eg, ensuring a living wage and providing affordable housing assistance to everyone who qualifies) to reduce the burden of PTB among African Americans.

Tractography-Pathology Correlations in Traumatic Brain Injury: A TRACK-TBI Study.

Diffusion tractography magnetic resonance imaging (MRI) can infer changes in network connectivity in patients with traumatic brain injury (TBI), but the pathological substrates of disconnected tracts have not been well defined because of a lack of high-resolution imaging with histopathological validation. We developed an ex vivo MRI protocol to analyze tract terminations at 750-µm isotropic resolution, followed by histopathological evaluation of white matter pathology, and applied these methods to a 60-year-old man who died 26 days after TBI. Analysis of 74 cerebral hemispheric white matter regions revealed a heterogeneous distribution of tract disruptions. Associated histopathology identified variable white matter injury with patchy deposition of amyloid precursor protein (APP), loss of neurofilament-positive axonal processes, myelin dissolution, astrogliosis, microgliosis, and perivascular hemosiderin-laden macrophages. Multiple linear regression revealed that tract disruption strongly correlated with the density of APP-positive axonal swellings and neurofilament loss. Ex vivo diffusion MRI can detect tract disruptions in the human brain that reflect axonal injury.

7 Tesla MRI of the ex vivo human brain at 100 micron resolution.

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.

Joint registration and synthesis using a probabilistic model for alignment of MRI and histological sections.

Nonlinear registration of 2D histological sections with corresponding slices of MRI data is a critical step of 3D histology reconstruction algorithms. This registration is difficult due to the large differences in image contrast and resolution, as well as the complex nonrigid deformations and artefacts produced when sectioning the sample and mounting it on the glass slide. It has been shown in brain MRI registration that better spatial alignment across modalities can be obtained by synthesising one modality from the other and then using intra-modality registration metrics, rather than by using information theory based metrics to solve the problem directly. However, such an approach typically requires a database of aligned images from the two modalities, which is very difficult to obtain for histology and MRI. Here, we overcome this limitation with a probabilistic method that simultaneously solves for deformable registration and synthesis directly on the target images, without requiring any training data. The method is based on a probabilistic model in which the MRI slice is assumed to be a contrast-warped, spatially deformed version of the histological section. We use approximate Bayesian inference to iteratively refine the probabilistic estimate of the synthesis and the registration, while accounting for each other's uncertainty. Moreover, manually placed landmarks can be seamlessly integrated in the framework for increased performance and robustness. Experiments on a synthetic dataset of MRI slices show that, compared with mutual information based registration, the proposed method makes it possible to use a much more flexible deformation model in the registration to improve its accuracy, without compromising robustness. Moreover, our framework also exploits information in manually placed landmarks more efficiently than mutual information: landmarks constrain the deformation field in both methods, but in our algorithm, it also has a positive effect on the synthesis - which further improves the registration. We also show results on two real, publicly available datasets: the Allen and BigBrain atlases. In both of them, the proposed method provides a clear improvement over mutual information based registration, both qualitatively (visual inspection) and quantitatively (registration error measured with pairs of manually annotated landmarks).

Regulators of G-protein signaling 2 and 4 differentially regulate cocaine-induced rewarding effects.

There is a need to identify new therapeutic targets for the treatment of cocaine addiction due to the rise in cocaine abuse and deaths due to cocaine overdose. Regulator of G protein signaling (RGS) proteins such as RGS2 and RGS4 are widely distributed in brain regions that play a role in drug reward. Importantly, RGS2 and RGS4 negatively regulate G-protein coupled receptor signaling pathways of monoaminergic neurotransmitters that play a role in the rewarding effects of cocaine by enhancing the rate of hydrolysis of Gα-bound guanine nucleotide triphosphate. Thus, the objective of this study was to investigate the effects of cocaine on conditioned place preference (CPP) and locomotor activity in mice that lacked either RGS2 or RGS4 (i.e. knockout (KO) mice) and their wildtype (WT) littermates. Moreover recent studies have reported influence of sex on RGS functioning and hence studies were conducted in both male and female mice. Cocaine-induced CPP was attenuated in male, but not female RGS4 KO mice compared to respective RGS4 WT mice. Cocaine-induced CPP was not influenced by deletion of RGS2 in either male or female mice. Similarly, cocaine-induced locomotor activity was not influenced by deletion of either RGS2 or RGS4 irrespective of sex. Together, the data indicate that the rewarding effects of cocaine were attenuated in the absence of RGS4 expression, but not in the absence of RGS2 expression in a sex-dependent manner. Importantly, these data suggest that RGS4 can serve as a potential target for medications that can be used to treat cocaine addiction.

Multimodal Characterization of the Late Effects of Traumatic Brain Injury: A Methodological Overview of the Late Effects of Traumatic Brain Injury Project.

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.

as-PSOCT: Volumetric microscopic imaging of human brain architecture and connectivity.

Polarization sensitive optical coherence tomography (PSOCT) with serial sectioning has enabled the investigation of 3D structures in mouse and human brain tissue samples. By using intrinsic optical properties of back-scattering and birefringence, PSOCT reliably images cytoarchitecture, myeloarchitecture and fiber orientations. In this study, we developed a fully automatic serial sectioning polarization sensitive optical coherence tomography (as-PSOCT) system to enable volumetric reconstruction of human brain samples with unprecedented sample size and resolution. The 3.5 µm in-plane resolution and 50 µm through-plane voxel size allow inspection of cortical layers that are a single-cell in width, as well as small crossing fibers. We show the abilities of as-PSOCT in quantifying layer thicknesses of the cerebellar cortex and creating microscopic tractography of intricate fiber networks in the subcortical nuclei and internal capsule regions, all based on volumetric reconstructions. as-PSOCT provides a viable tool for studying quantitative cytoarchitecture and myeloarchitecture and mapping connectivity with microscopic resolution in the human brain.

Dementia After Moderate-Severe Traumatic Brain Injury: Coexistence of Multiple Proteinopathies.

We report the clinical, neuroimaging, and neuropathologic characteristics of 2 patients who developed early onset dementia after a moderate-severe traumatic brain injury (TBI). Neuropathological evaluation revealed abundant ß-amyloid neuritic and cored plaques, diffuse ß-amyloid plaques, and frequent hyperphosphorylated-tau neurofibrillary tangles (NFT) involving much of the cortex, including insula and mammillary bodies in both cases. Case 1 additionally showed NFTs in both the superficial and deep cortical layers, occasional perivascular and depth-of-sulci NFTs, and parietal white matter rarefaction, which corresponded with decreased parietal fiber tracts observed on ex vivo MRI. Case 2 additionally showed NFT predominance in the superficial layers of the cortex, hypothalamus and brainstem, diffuse Lewy bodies in the cortex, amygdala and brainstem, and intraneuronal TDP-43 inclusions. The neuropathologic diagnoses were atypical Alzheimer disease (AD) with features of chronic traumatic encephalopathy and white matter loss (Case 1), and atypical AD, dementia with Lewy bodies and coexistent TDP-43 pathology (Case 2). These findings support an epidemiological association between TBI and dementia and further characterize the variety of misfolded proteins that may accumulate after TBI. Analyses with comprehensive clinical, imaging, genetic, and neuropathological data are required to characterize the full clinicopathological spectrum associated with dementias occurring after moderate-severe TBI.

Comprehensive cellular-resolution atlas of the adult human brain.

Detailed anatomical understanding of the human brain is essential for unraveling its functional architecture, yet current reference atlases have major limitations such as lack of whole-brain coverage, relatively low image resolution, and sparse structural annotation. We present the first digital human brain atlas to incorporate neuroimaging, high-resolution histology, and chemoarchitecture across a complete adult female brain, consisting of magnetic resonance imaging (MRI), diffusion-weighted imaging (DWI), and 1,356 large-format cellular resolution (1 µm/pixel) Nissl and immunohistochemistry anatomical plates. The atlas is comprehensively annotated for 862 structures, including 117 white matter tracts and several novel cyto- and chemoarchitecturally defined structures, and these annotations were transferred onto the matching MRI dataset. Neocortical delineations were done for sulci, gyri, and modified Brodmann areas to link macroscopic anatomical and microscopic cytoarchitectural parcellations. Correlated neuroimaging and histological structural delineation allowed fine feature identification in MRI data and subsequent structural identification in MRI data from other brains. This interactive online digital atlas is integrated with existing Allen Institute for Brain Science gene expression atlases and is publicly accessible as a resource for the neuroscience community. J. Comp. Neurol. 524:3127-3481, 2016. © 2016 The Authors The Journal of Comparative Neurology Published by Wiley Periodicals, Inc.

H.M.'s contributions to neuroscience: a review and autopsy studies.

H.M., Henry Molaison, was one of the world's most famous amnesic patients. His amnesia was caused by an experimental brain operation, bilateral medial temporal lobe resection, carried out in 1953 to relieve intractable epilepsy. He died on December 2, 2008, and that night we conducted a wide variety of in situ MRI scans in a 3 T scanner at the Massachusetts General Hospital (Mass General) Athinoula A. Martinos Center for Biomedical Imaging. For the in situ experiments, we acquired a full set of standard clinical scans, 1 mm isotropic anatomical scans, and multiple averages of 440 µm isotropic anatomical scans. The next morning, H.M.'s body was transported to the Mass General Morgue for autopsy. The photographs taken at that time provided the first documentation of H.M.'s lesions in his physical brain. After tissue fixation, we obtained ex vivo structural data at ultra-high resolution using 3 T and 7 T magnets. For the ex vivo acquisitions, the highest resolution images were 210 µm isotropic. Based on the MRI data, the anatomical areas removed during H.M.'s experimental operation were the medial temporopolar cortex, piriform cortex, virtually all of the entorhinal cortex, most of the perirhinal cortex and subiculum, the amygdala (except parts of the dorsal-most nuclei-central and medial), anterior half of the hippocampus, and the dentate gyrus (posterior head and body). The posterior parahippocampal gyrus and medial temporal stem were partially damaged. Spared medial temporal lobe tissue included the dorsal-most amygdala, the hippocampal-amygdalo-transition-area, ∼2 cm of the tail of the hippocampus, a small part of perirhinal cortex, a small portion of medial hippocampal tissue, and ∼2 cm of posterior parahippocampal gyrus. H.M.'s impact on the field of memory has been remarkable, and his contributions to neuroscience continue with a unique dataset that includes in vivo, in situ, and ex vivo high-resolution MRI.

Transcriptional landscape of the prenatal human brain.

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.

Radial and tangential neuronal migration pathways in the human fetal brain: anatomically distinct patterns of diffusion MRI coherence.

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.

Predicting the location of human perirhinal cortex, Brodmann's area 35, from MRI.

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 (1 mm × 1 mm × 1 mm) to construct pial/white matter surfaces in FreeSurfer and scanned again at high resolution (120 µm × 120 µm × 120 µm) 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.

Surface based analysis of diffusion orientation for identifying architectonic domains in the in vivo human cortex.

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.