Cytoarchitectonic Areas of the Gyrus ambiens in the Human Brain

The Gyrus ambiens is a gross anatomical prominence in the medial temporal lobe (MTL), associated closely with Brodmann area 34 (BA34). It is formed largely by the medial intermediate subfield of the entorhinal cortex (EC) [Brodmann area 28 (BA28)]. Although the MTL has been widely studied due to its well-known role on memory and spatial information, the anatomical relationship between G. ambiens, BA34, and medial intermediate EC subfield has not been completely defined, in particular whether BA34 is part of the EC or a different type of cortex. In order to clarify this issue, we carried out a detailed analysis of 37 human MTLs, determining the exact location of medial intermediate EC subfield and its extent within the G. ambiens, its cortical thickness, and the histological–MRI correspondence of the G. ambiens with the medial intermediate EC subfield in 10 ex vivo MRI. Our results show that the G. ambiens is limited between two small sulci in the medial aspect of the MTL, which correspond almost perfectly to the extent of the medial intermediate EC subfield, although the rostral and caudal extensions of the G. ambiens may extend to the olfactory (rostrally) and intermediate (caudally) entorhinal subfields. Moreover, the cortical thickness averaged 2.5 mm (1.3 mm for layers I–III and 1 mm for layers V–VI). Moreover, distance among different landmarks visible in the MRI scans which are relevant to the identification of the G. ambiens in MRI are provided. These results suggest that BA34 is a part of the EC that fits best with the medial intermediate subfield. The histological data, together with the ex vivo MRI identification and thickness of these structures may be of use when assessing changes in MRI scans in clinical settings, such as Alzheimer disease

Born too early and too small: higher order cognitive function and brain at risk at ages 8–16

Prematurity presents a risk for higher order cognitive functions. Some of these deficits manifest later in development, when these functions are expected to mature. However, the causes and consequences of prematurity are still unclear. We conducted a longitudinal study to first identify clinical predictors of ultrasound brain abnormalities in 196 children born very preterm (VP; gestational age 32 weeks) and with very low birth weight (VLBW; birth weight 1500 g). At ages 8–16, the subset of VP-VLBW children without neurological findings (124) were invited for a neuropsychological assessment and an MRI scan (41 accepted). Of these, 29 met a rigorous criterion for MRI quality and an age, and gender-matched control group (n = 14) was included in this study. The key findings in the VP-VLBW neonates were: (a) 37% of the VP-VLBW neonates had ultrasound brain abnormalities; (b) gestational age and birth weight collectively with hospital course (i.e., days in hospital, neonatal intensive care, mechanical ventilation and with oxygen therapy, surgeries, and retinopathy of prematurity) predicted ultrasound brain abnormalities. At ages 8–16, VP-VLBW children showed: a) lower intelligent quotient (IQ) and executive function; b) decreased gray and white matter (WM) integrity; (c) IQ correlated negatively with cortical thickness in higher order processing cortical areas. In conclusion, our data indicate that facets of executive function and IQ are the most affected in VP-VLBW children likely due to altered higher order cortical areas and underlying WMThis study was supported by the Spanish Government Institute Carlos III (FIS Pl11/02860), Spanish Ministry of Health to MM-L, and the University of Castilla-La Mancha mobility Grant VA1381500149

Frontal and insular input to the dorsolateral temporal pole in primates: Implications for auditory memory

The temporal pole (TP) has been involved in multiple functions from emotional and social behavior, semantic processing,memory, language in humans and epilepsy surgery, to the fronto-temporal neurodegenerative disorder (semantic) dementia. However, the role of the TP subdivisions is still unclear, in part due to the lack of quantitative data about TP connectivity. This study focuses in the dorsolateral subdivision of the TP: area 38DL. Area 38DL main input originates in the auditory processing areas of the rostral superior temporal gyrus. Among other connections, area 38DL conveys this auditory highly processed information to the entorhinal, rostral perirhinal, and posterior parahippocampal cortices, presumably for storage in long-term memory (Muñoz-López et al., 2015). However, the connections of the TP with cortical areas beyond the temporal cortex suggest that this area is part of a wider network. With the aim to quantitatively determine the topographical, laminar pattern and weighting of the lateral TP afferents from the frontal and insular cortices, we placed a total of 11 tracer injections of the fluorescent retrograde neuronal tracers Fast Blue and Diamidino Yellow at different levels of the lateral TP in rhesus monkeys. The results showed that circa 50% of the total cortical input to area 38DL originates in medial frontal areas 14, 25, 32, and 24 (25%); orbitofrontal areas Pro and PAll (15%); and the agranular, parainsular and disgranular insula (10%). This study sets the anatomical bases to better understand the function of the dorsolateral division of the TP. More specifically, these results suggest that area 38DL forms part of the wider limbic circuit that might contribute, among other functions, with an auditory component to multimodal memory processing

Born Too Early and Too Small: Higher Order Cognitive Function and Brain at Risk at Ages 8-16

Prematurity presents a risk for higher order cognitive functions. Some of these deficits manifest later in development, when these functions are expected to mature. However, the causes and consequences of prematurity are still unclear. We conducted a longitudinal study to first identify clinical predictors of ultrasound brain abnormalities in 196 children born very preterm (VP; gestational age 32 weeks) and with very low birth weight (VLBW; birth weight 1500 g). At ages 8–16, the subset of VP-VLBW children without neurological findings (124) were invited for a neuropsychological assessment and an MRI scan (41 accepted). Of these, 29 met a rigorous criterion for MRI quality and an age, and gender-matched control group (n = 14) was included in this study. The key findings in the VP-VLBW neonates were: (a) 37% of the VP-VLBW neonates had ultrasound brain abnormalities; (b) gestational age and birth weight collectively with hospital course (i.e., days in hospital, neonatal intensive care, mechanical ventilation and with oxygen therapy, surgeries, and retinopathy of prematurity) predicted ultrasound brain abnormalities. At ages 8–16, VP-VLBW children showed: a) lower intelligent quotient (IQ) and executive function; b) decreased gray and white matter (WM) integrity; (c) IQ correlated negatively with cortical thickness in higher order processing cortical areas. In conclusion, our data indicate that facets of executive function and IQ are the most affected in VP-VLBW children likely due to altered higher order cortical areas and underlying W

The medial prefrontal cortex and memory in humans: anatomical segmentation in mri and consequences of at risk prematurity

Una precisa caracterización anatómica del estatus del sistema nervioso central es crítica para entender su función y, en poblaciones clínicas, para valorar las causas de los posibles déficits cognitivos. Este trabajo supone un esfuerzo en esa dirección. Por un lado, pretende determinar el estado neuropsicológico de una población de niños prematuros de riesgo. El segundo objetivo consiste en la creación de una herramienta que permita identificar anatómicamente las subáreas de la corteza prefrontal medial, una región que ha sido previamente relacionada con la memoria. Aunque la tasa de supervivencia de niños nacidos prematuramente a riesgo está aumentando, los daños neurológicos y cognitivos de estos niños debidos a episodios de hipoxia/isquemia en el nacimiento son todavía un problema. Las nuevas técnicas en el campo de la neuroimagen proporcionan métodos de estudio cada vez más sofisticados para establecer las posibles consecuencias de la prematuridad de riesgo sobre el cerebro, pero hay todavía preguntas sin resolver a niveles metodológicos, anatómicos, funcionales y clínicos. El sistema límbico de la memoria constituye una de estas cuestiones ya que, aunque se considera vulnerable a episodios de hipoxia/isquemia, tanto el hipocampo, una de sus estructuras centrales, como la memoria dependiente del mismo, están relativamente preservados en niños prematuros, los cuales parecen presentar deficiencias en funciones ejecutivas y sociales. Este estudio pretende comenzar a abordar esta cuestión investigando la corteza prefrontal medial, el componente frontal del sistema límbico de memoria. Aunque esta región frontal ha sido consistentemente relacionada con la memoria, numerosos estudios en modelos animales y en humanos, así como estudios funcionales, defienden el papel de este área en muchas otras funciones superiores tales como toma de decisiones, detección de errores o las relacionadas con comportamientos sociales. Parte de la complejidad anatómica de la corteza frontal medial radica no solo en la en la existencia de varias subáreas citoarquitectónicas, sino también en la gran diversidad en cuanto a la localización de sus límites publicada en estudios anatómicos y de neuroimagen previos. Esto dificulta tanto el establecimiento de las distintas funciones en las que puedan estar implicadas cada una de estas subáreas, como la determinación específica de su vulnerabilidad a los episodios de hipoxia/isquemia causados por la prematuridad. Para investigar esta cuestión, estudiamos en primer lugar un grupo de 29 niños nacidos prematuros de riesgo (edad gestacional<32 semanas; peso al nacer<1500g) y otro de 14 niños de edades similares nacidos a término y que fueron considerados como controles. Ambos grupos fueron evaluados neurológica y neuropsicológicamente, así como en términos de integridad de sustancia gris y blanca medida mediante voxel-based morphometry, tract-based spatial statistics y tractografía. Con el fin de identificar las subáreas de la corteza frontal medial tanto en tejido histológico como en resonancia magnética, un segundo estudio se llevó a cabo para determinar los límites citoarquitectónicos en 11 hemisferios ex vivo procesados para su análisis cito- y mieloarquitectónico. Este segundo estudio permitió la creación de un protocolo de segmentación para las subáreas de la región límbica de la corteza frontal medial (áreas de Brodmann 24, 32, 25 y 14) basado en referencias anatómicas, patrones de surcos y medidas de la longitud de la superficie cortical en secciones coronales. Este protocolo se aplicó a una muestra in vivo generando mapas probabilísticos para cada una de las subáreas límbicas de la corteza frontal medial, los cuales permitieron la identificación anatómica de la localización de los cambios del grupo de prematuros con respecto al grupo control. Usando las referencias obtenidas, el grupo de niños prematuros mostró reducciones significativas en densidad de sustancia gris en las áreas 14 y 25 de la corteza frontal medial, y anisotropía fraccional reducida en las áreas 24, 32, 14 y 25 de esta región, así como en el fórnix y en la sustancia blanca talámica. En la evaluación neuropsicológica, los niños prematuros obtuvieron menores puntuaciones que el grupo control en cociente intelectual, razonamiento perceptivo, recuerdo inmediato de historias y fluidez fonológica, así como mayor proporción de problemas de aprendizaje y peor rendimiento escolar. Las habilidades cognitivas generales y de memoria de trabajo cayeron en el rango medio-bajo, y la relación de éstas con cambios en la corteza frontal medial y en el fórnix sugieren posibles déficits no detectados en componentes ejecutivos de la memoria en niños prematuros que puedan estar afectando a las puntuaciones académicas. Una descripción completa de estos niños tanto neurológica como neuropsicológica permitiría la implementación de estrategias aplicadas de manera individual para mejorar su completa adaptación a la sociedad a largo plazo

Unfolding the Medial Temporal Lobe Cortex to Characterize Neurodegeneration Due to Alzheimer’s Disease Pathology Using Ex vivo Imaging

Neurofibrillary tangle (NFT) pathology in the medial temporal lobe (MTL) is closely linked to neurodegeneration, and is the early pathological change associated with Alzheimer’s Disease (AD). In this work, we investigate the relationship between MTL morphometry features derived from high-resolution ex vivo imaging and histology-based measures of NFT pathology using a topological unfolding framework applied to a dataset of 18 human postmortem MTL specimens. The MTL has a complex 3D topography and exhibits a high degree of inter-subject variability in cortical folding patterns which poses a significant challenge for volumetric registration methods typically used during MRI template construction. By unfolding the MTL cortex, the proposed framework explicitly accounts for the sheet-like geometry of the MTL cortex and provides a two-dimensional reference coordinate space which can be used to implicitly register cortical folding patterns across specimens based on distance along the cortex despite large anatomical variability. Leveraging this framework in a subset of 15 specimens, we characterize the associations between NFTs and morphological features such as cortical thickness and surface curvature and identify regions in the MTL where patterns of atrophy are strongly correlated with NFT pathology

Integrating Color Deconvolution Thresholding and Weakly Supervised Learning for Automated Segmentation of Neurofibrillary Tangle and Neuropil Threads

Abnormally phosphorylated tau proteins are known to be a major indicator of Alzheimer's Disease (AD) with strong association with memory loss and cognitive decline. Automated generation of pixel-wise accurate neurofibrillary tangles (NFTs) and neuropil threads (NTs) segmentation is a challenging task, due to lack of ground truth segmentation data of these abnormal tau pathology. This problem is most prominent in the case of segmenting NTs, where the small threadlike morphology makes pixel-wise labeling a laborious task and unrealistic for large-scale studies. Lack of ground truth data poses a significant limitation for many learning-based methods to generate accurate segmentations of NFTs and NTs. This work presents an automated pipeline for pixel level segmentation of NFTs and NTs that does not rely on ground truth segmentation data. The pipeline is composed of four main steps: (1) color deconvolution is used to separate histopathology images into staining channels (DAB, Hematoxylin, and Eosin), (2) Otsu's thresholding is used on the DAB stain channel to generate pixel level segmentation of abnormal tau proteins staining, (3) a weakly-supervised learning paradigm (WildCat), using only global descriptors of images, is used to generate density maps of potential regions of NFTs and NTs, and (4) density maps and segmentations are then integrated using connected component analysis to localize NFTs and NTs in the detected tau segmentations. Our results show high global classification accuracy for NFTs (Acc:0.96) and NTs (Acc:0.91), and statistically significant distinctions when evaluating the percent area occupied of the detected NTs relative to expert ratings of NTs severity. Qualitative assessment of the NFTs and NTs results showed accurate pixel-level segmentations of the NFTs, while modest performance for NTs

Ex vivo MRI atlas of the human medial temporal lobe : characterizing neurodegeneration due to tau pathology

Tau neurofibrillary tangle (NFT) pathology in the medial temporal lobe (MTL) is closely linked to neurodegeneration, and is the early pathological change associated with Alzheimer’s disease (AD). To elucidate patterns of structural change in the MTL specifically associated with tau pathology, we compared high-resolution ex vivo MRI scans of human postmortem MTL specimens with histology-based pathological assessments of the MTL. MTL specimens were obtained from twenty-nine brain donors, including patients with AD, other dementias, and individuals with no known history of neurological disease. Ex vivo MRI scans were combined using a customized groupwise diffeomorphic registration approach to construct a 3D probabilistic atlas that captures the anatomical variability of the MTL. Using serial histology imaging in eleven specimens, we labelled the MTL subregions in the atlas based on cytoarchitecture. Leveraging the atlas and neuropathological ratings of tau and TAR DNA-binding protein 43 (TDP-43) pathology severity, morphometric analysis was performed to correlate regional MTL thickness with the severity of tau pathology, after correcting for age and TDP-43 pathology. We found significant correlations between tau pathology and thickness in the entorhinal cortex (ERC) and stratum radiatum lacunosum moleculare (SRLM). When focusing on cases with low levels of TDP-43 pathology, we found strong associations between tau pathology and thickness in the ERC, SRLM and the subiculum/cornu ammonis 1 (CA1) subfields of the hippocampus, consistent with early Braak stages

Three-dimensional mapping of neurofibrillary tangle burden in the human medial temporal lobe

Tau protein neurofibrillary tangles are closely linked to neuronal/synaptic loss and cognitive decline in Alzheimer's disease and related dementias. Our knowledge of the pattern of neurofibrillary tangle progression in the human brain, critical to the development of imaging biomarkers and interpretation of in vivo imaging studies in Alzheimer's disease, is based on conventional two-dimensional histology studies that only sample the brain sparsely. To address this limitation, ex vivo MRI and dense serial histological imaging in 18 human medial temporal lobe specimens (age 75.3 ± 11.4 years, range 45 to 93) were used to construct three-dimensional quantitative maps of neurofibrillary tangle burden in the medial temporal lobe at individual and group levels. Group-level maps were obtained in the space of an in vivo brain template, and neurofibrillary tangles were measured in specific anatomical regions defined in this template. Three-dimensional maps of neurofibrillary tangle burden revealed significant variation along the anterior-posterior axis. While early neurofibrillary tangle pathology is thought to be confined to the transentorhinal region, we found similar levels of burden in this region and other medial temporal lobe subregions, including amygdala, temporopolar cortex, and subiculum/cornu ammonis 1 hippocampal subfields. Overall, the three-dimensional maps of neurofibrillary tangle burden presented here provide more complete information about the distribution of this neurodegenerative pathology in the region of the cortex where it first emerges in Alzheimer's disease, and may help inform the field about the patterns of pathology spread, as well as support development and validation of neuroimaging biomarkers