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The primate amygdala serves to evaluate emotional content of sensory inputs and modulate emotional and social behaviors; it modulates cognitive, multisensory and autonomic circuits predominantly via the basal (BA), lateral (LA), and central (CeA) nuclei, respectively. Based on recent electrophysiological evidence suggesting mesoscale (millimeters-scale) nature of intra-amygdala functional organization, we have investigated the connectivity of these nuclei using Infrared Neural Stimulation of single mesoscale sites coupled with mapping in ultrahigh field 7T functional Magnetic Resonance Imaging (INS-fMRI). Stimulation of multiple sites within amygdala of single individuals evoked 'mesoscale functional connectivity maps', allowing comparison of BA, LA and CeA connected brainwide networks. This revealed a mesoscale nature of connected sites, complementary spatial patterns of functional connectivity, and topographic relationships of nucleus-specific connections. Our data reveal a functional architecture of systematically organized brainwide networks mediating sensory, cognitive, and autonomic influences from the amygdala., Competing Interests: Competing interests: Authors declare that they have no competing interests.

In Alzheimer´s disease (AD), hyperphosphorylated tau spreads along the cerebral cortex in a stereotypical pattern that parallels cognitive deterioration. Tau seems to spread transsynaptically along cortico-cotical pathways that, according to synaptic tract-tracing studies in nonhuman primates, have specific laminar patterns related to the cortical type of the connected areas. This relation is described in the Structural Model. In the present article, we study the laminar distribution of hyperphosphorylated tau, labeled with the antibody AT8, along temporal cortical types in postmortem human brains with different AD stages to test the predictions of the Structural Model. Brains from donors without dementia had scant AT8-immunorreactive (AT8-ir) neurons in allo-, meso-, and isocortical types. In early AD stages, the mesocortical dysgranular type, including part of the transentorhinal cortex, had the highest AT8 immunostaining and AT8-ir neurons density. In advanced AD stages, AT8 immunostaining increased along the isocortical types until reaching the auditory koniocortex. Regarding laminar patterns, in early AD stages there were more AT8-ir neurons in supragranular layers in each de novo involved neocortical type; in advanced AD stages, AT8-ir neurons were equally distributed in supra- and infragranular layers. These AT8-ir laminar patterns are compatible with the predictions of the Structural Model. In summary, we show that hyperphosphorylated tau initially accumulates in allo-, meso-, and isocortical types, offer a proof of concept for the validity of the Structural Model to predict synaptic pathway organization in the human cerebral cortex, and highlight the relevance of nonhuman primate tract-tracing studies to understand human neuropathology., (© 2024 The Authors. The Journal of Comparative Neurology published by Wiley Periodicals LLC.)

The entorhinal cortex (EC, A28) is linked through reciprocal pathways with nearby perirhinal and visual, auditory, and multimodal association cortices in the temporal lobe, in pathways associated with the flow of information for memory processing. The density and laminar organization of these pathways is not well understood in primates. We studied interconnections within the ventral temporal lobe in young adult rhesus monkeys of both sexes with the aid of neural tracers injected in temporal areas (Ts1, Ts2, TE1, area 36, temporal polar area TPro, and area 28) to determine the density and laminar distribution of projection neurons within the temporal lobe. These temporal areas can be categorized into three different cortical types based on their laminar architecture: the sensory association areas Ts1, Ts2, and TE1 have six layers (eulaminate); the perirhinal limbic areas TPro and area 36 have an incipient layer IV (dysgranular); and area 28 lacks layer IV (agranular). We found that (1) temporal areas that are similar in laminar architecture by cortical type are strongly interconnected, and (2) the laminar pattern of connections is dependent on the difference in cortical laminar structure between linked areas. Thus, agranular A28 is more strongly connected with other agranular/dysgranular areas than with eulaminate cortices. Further, A28 predominantly projected via feedback-like pathways that originated in the deep layers, and received feedforward-like projections from areas of greater laminar differentiation, which emanated from the upper layers. Our results are consistent with the Structural Model, which relates the density and laminar distribution of connections to the relationship of the laminar structure between the linked areas. These connections were viewed in the context of the inhibitory microenvironment of A28, which is the key recipient of pathways from the cortex and of the output of hippocampus. Our findings revealed a higher population of calretinin (CR)-expressing neurons in EC, with a significantly higher density in its lateral division. Medial EC had a higher density of CR neurons in the deep layers, particularly in layer Va. In contrast, parvalbumin (PV) neurons were more densely distributed in the deep layers of the lateral subdivisions of rostral EC, especially in layer Va, whereas the densities of calbindin (CB) neurons in the medial and lateral EC were comparable in all layers, except for layer IIIa, in which medial EC had a higher CB population than the lateral. The pattern of connections in the inhibitory microenvironment of EC, which sends and receives input from the hippocampus, may shed light on signal propagation in this network associated with diverse aspects of memory, and disruptions in neurologic and psychiatric diseases that affect this region., (© 2023 Wiley Periodicals LLC.)

The interpretation of massive high-throughput gene expression data requires computational and biological analyses to identify statistically and biologically significant differences, respectively. There are abundant sources that describe computational tools for statistical analysis of massive gene expression data but few address data analysis for biological significance. In the present article we exemplify the importance of selecting the proper biological context in the human brain for gene expression data analysis and interpretation. For this purpose, we use cortical type as conceptual tool to make predictions about gene expression in areas of the human temporal cortex. We predict that the expression of genes related to glutamatergic transmission would be higher in areas of simpler cortical type, the expression of genes related to GABAergic transmission would be higher in areas of more complex cortical type, and the expression of genes related to epigenetic regulation would be higher in areas of simpler cortical type. Then, we test these predictions with gene expression data from several regions of the human temporal cortex obtained from the Allen Human Brain Atlas. We find that the expression of several genes shows statistically significant differences in agreement with the predicted gradual expression along the laminar complexity gradient of the human cortex, suggesting that simpler cortical types may have greater glutamatergic excitability and epigenetic turnover compared to more complex types; on the other hand, complex cortical types seem to have greater GABAergic inhibitory control compared to simpler types. Our results show that cortical type is a good predictor of synaptic plasticity, epigenetic turnover, and selective vulnerability in human cortical areas. Thus, cortical type can provide a meaningful context for interpreting high-throughput gene expression data in the human cerebral cortex., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Sancha-Velasco, Uceda-Heras and García-Cabezas.)

Synaptic tract-tracing studies in macaques have provided a wealth of data about cortico-cortical connections that have been used to identify regularities and propose models and theories to explain cortical connectivity. The two most relevant of these models are the distance rule model (DRM) and the structural model (SM). They relate the strength and laminar pattern of cortico-cortical connections to two different factors: Euclidean distance (according to the DRM) and cortical type distance (according to the SM). If both predictive factors were correlated, the DRM and the SM would be compatible, but quite often, two cortical areas of similar cortical type are far apart from each other. In the present article, we have performed a conceptual analysis of the DRM and the SM to obtain predictions from each of the two models about strength and laminar pattern of cortico-cortical connections. We then tested the predictive power of each model with analyses of several cortico-cortical connectivity databases to check which of them provide the most accurate predictions. We conclude that the DRM and the SM capture the decrease in connection strength with increasing Euclidean and cortical type distances, respectively; but, for laminar pattern, type distance is a better predictor than Euclidean distance., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Neuromodulatory afferents to thalamic nuclei are key for information transmission and thus play critical roles in sensory, motor, and limbic processes. Over the course of the last decades, diverse attempts have been made to map and describe subcortical neuromodulatory afferents to the primate thalamus, including axons using acetylcholine, serotonin, dopamine, noradrenaline, adrenaline, and histamine. Our group has been actively involved in this endeavor. The published descriptions on neuromodulatory afferents to the primate thalamus have been made in different laboratories and are not fully comparable due to methodological divergences (for example, fixation procedures, planes of cutting, techniques used to detect the afferents, different criteria for identification of thalamic nuclei…). Such variation affects the results obtained. Therefore, systematic methodological and analytical approaches are much needed. The present article proposes reproducible methodological and terminological frameworks for primate thalamic mapping. We suggest the use of standard stereotaxic planes to produce and present maps of the primate thalamus, as well as the use of the Anglo-American school terminology (vs. the German school terminology) for identification of thalamic nuclei. Finally, a public repository of the data collected under agreed-on frameworks would be a useful tool for looking up and comparing data on the structure and connections of primate thalamic nuclei. Important and agreed-on efforts are required to create, manage, and fund a unified and homogeneous resource of data on the primate thalamus. Likewise, a firm commitment of the institutions to preserve experimental brain material is much needed because neuroscience work with non-human primates is becoming increasingly rare, making earlier material still more valuable., (© 2023. The Author(s).)

Sixty years ago, Friedrich Sanides traced the origin of the tangential expansion of the primate neocortex to two ancestral anlagen in the allocortex of reptiles and mammals, and proposed the Hypothesis on the Dual Origin of the Neocortex. According to Sanides, paraolfactory and parahippocampal gradients of laminar elaboration expanded in evolution by addition of successive concentric rings of gradually different cortical types inside the allocortical ring. Rodents had fewer rings and primates had more rings in the inner part of the cortex. In the present article, we perform cortical type analysis of the neocortex of adult rats, Rhesus macaques, and humans to propose hypotheses on homology of cortical areas applying the principles of the Hypothesis on the Dual Origin of the Neocortex. We show that areas in the outer rings of the neocortex have comparable laminar elaboration in rats and primates, while most 6-layer eulaminate areas in the innermost rings of primate neocortex lack homologous counterparts in rats. We also represent the topological distribution of cortical types in simplified flat maps of the cerebral cortex of monotremes, rats, and primates. Finally, we propose an elaboration of the Hypothesis on the Dual Origin of the Neocortex in the context of modern studies of pallial patterning that integrates the specification of pallial sectors in development of vertebrate embryos. The updated version of the hypothesis of Sanides provides explanation for the emergence of cortical hierarchies in mammals and will guide future research in the phylogenetic origin of neocortical areas., (© 2022. The Author(s).)

The primate thalamus has been subdivided into multiple nuclei and nuclear groups based on cytoarchitectonic, myeloarchitectonic, connectional, histochemical, and genoarchitectonic differences. Regarding parcellation and terminology, two main schools prevailed in the twentieth century: the German and the Anglo-American Schools, which proposed rather different schemes. The German parcellation and terminology has been mostly used for the human thalamus in neurosurgery atlases; the Anglo-American parcellation and terminology is the most used in experimental research on the primate thalamus. In this article, we review the historical development of terminological and parcellation schemes for the primate thalamus over the last 200 years. We trace the technological innovations and conceptual advances in thalamic research that underlie each parcellation, from the use of magnifying lenses to contemporary genoarchitectonic stains during ontogeny. We also discuss the advantages, disadvantages, and practical use of each parcellation., (© 2023. The Author(s).)

Stereotaxis is widely used in clinical neurosurgery, neuroradiosurgery, and neuroimaging. Yet, maps of brain structures obtained from post-mortem human brains are not usually presented in known stereotaxic coordinates. Post-mortem brain data given in stereotaxic coordinates would facilitate comparisons with in vivo human neuroimages and would also facilitate intra and inter-experiment comparisons. In this article, we present a crafted instrument for stereotaxic cutting of post-mortem human brain hemispheres. The instrument consists of a transparent methacrylate plate facing a mirror, four legs, and lateral regularly spaced columns permitting the insertion of large knives in-between the columns. This instrument can be built in any laboratory to obtain human brain slabs in the stereotaxic space of Talairach and Tournoux. We explain in detail the procedure for stereotaxic cutting of human brain hemispheres in the coronal plane, as well as the basis for calculating stereotaxic coordinates of histological sections obtained following the stereotaxic cutting protocol., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 García-Cabezas, Pérez-Santos and Cavada.)

Degeneration of neurons and circuits across the striatum shows stereotyped time-course and spatial topography patterns that are distinct for Huntington's disease, Parkinson's disease, or the Tauopathies. These patterns of neurodegeneration in humans have not yet been systematically related to developmental, connectional, cellular, and chemical factors studied in human and non-human primates, that may underlie potential differences in selective vulnerability across striatal sectors. Relating primate anatomy to human pathology could provide new venues for identifying molecular, cellular, and connectional factors linked to the degeneration of striatal neurons and circuits. This review describes and summarizes several developmental, cellular, structural, and connectional features of the primate striatum in relation to patterns of neurodegeneration in the striatum of humans and of non-human primate models. We review (1) the types of neurons in the primate striatum, (2) the cyto-, myelo-, and chemoarchitecture of the primate striatum, (3) the developmental origin of the striatum in light of modern patterning studies, (4) the organization of corticostriatal projections in relation to cortical types, and (5) the topography and time-course of neuron loss, glial reaction, and protein aggregation induced by neurodegenerative diseases in humans and in non-human primate models across striatal sectors and their corresponding cortical areas. We summarize current knowledge about key aspects of primate striatal anatomy and human pathology and indicate knowledge gaps that should be addressed in future studies. We aim to identify factors for selective vulnerability to neurodegeneration of striatal neurons and circuits and obtain hints that could help elucidate striatal pathology in humans., Competing Interests: Declaration of Competing Interest The authors have no relevant financial or non-financial interests to disclose., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

High-level characterizations of the primate cerebral cortex sit between two extremes: on one end the cortical mantle is seen as a mosaic of structurally and functionally unique areas, and on the other it is seen as a uniform six-layered structure in which functional differences are defined solely by extrinsic connections. Neither of these extremes captures the crucial neuroanatomical finding: that the cortex exhibits systematic gradations in architectonic structure. These gradations have been shown to predict cortico-cortical connectivity, which in turn suggests powerful ways to ground connectomics in anatomical structure, and by extension cortical function. A challenge to widespread use of this concept is the labor-intensive and invasive nature of histological staining, which is the primary means of recognizing anatomical gradations. Here we show that a novel computational analysis technique can provide a coarse-grained picture of cortical variation. For each of 78 cortical areas spanning the entire cortical mantle of the rhesus macaque, we created a high dimensional set of anatomical features derived from captured images of cortical tissue stained for myelin and SMI-32. The method involved semi-automated de-noising of images, and enabled comparison of brain areas without hand-labeling of features such as layer boundaries. We applied multidimensional scaling (MDS) to the dataset to visualize similarity among cortical areas. This analysis shows a systematic variation between weakly laminated (limbic) cortices and sharply laminated (eulaminate) cortices. We call this smooth continuum the "cortical spectrum". We also show that this spectrum is visible within subsystems of the cortex: the occipital, parietal, temporal, motor, prefrontal, and insular cortices. We compared the MDS-derived spectrum with a spectrum produced using T1- and T2-weighted magnetic resonance imaging (MRI) data derived from macaque, and found close agreement of the two coarse-graining methods. This suggests that T1w/T2w data, routinely obtained in human MRI studies, can serve as an effective proxy for data derived from high-resolution histological methods. More generally, this approach shows that the cortical spectrum is robust to the specific method used to compare cortical areas, and is therefore a powerful tool to understand the principles of organization of the primate cortex., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 John, Zikopoulos, García-Cabezas and Barbas.)

Dopaminergic denervation in patients with Parkinson's disease is associated with changes in brain metabolism. Cerebral in-vivo mapping of glucose metabolism has been studied in severe stable parkinsonian monkeys, but data on brain metabolic changes in early stages of dopaminergic depletion of this model is lacking. Here, we report cerebral metabolic changes associated with progressive nigrostriatal lesion in the pre-symptomatic and symptomatic stages of the progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkey model of Parkinson's Disease. Monkeys (Macaca fascicularis) received MPTP injections biweekly to induce progressive grades of dopamine depletion. Monkeys were sorted according to motor scale assessments in control, asymptomatic, recovered, mild, and severe parkinsonian groups. Dopaminergic depletion in the striatum and cerebral metabolic patterns across groups were studied in vivo by positron emission tomography (PET) using monoaminergic ([ 11 C]-dihydrotetrabenazine; 11 C-DTBZ) and metabolic (2-[ 18 F]-fluoro-2-deoxy-d-glucose; 18 F-FDG) radiotracers. 11 C-DTBZ-PET analysis showed progressive decrease of binding potential values in the striatum of monkeys throughout MPTP administration and the development of parkinsonian signs. 18 F-FDG analysis in asymptomatic and recovered animals showed significant hypometabolism in temporal and parietal areas of the cerebral cortex in association with moderate dopaminergic nigrostriatal depletion. Cortical hypometabolism extended to involve a larger area in mild parkinsonian monkeys, which also exhibited hypermetabolism in the globus pallidum pars interna and cerebellum. In severe parkinsonian monkeys, cortical hypometabolism extended further to lateral-frontal cortices and hypermetabolism also ensued in the thalamus and cerebellum. Unbiased histological quantification of neurons in Brodmann's area 7 in the parietal cortex did not reveal neuron loss in parkinsonian monkeys versus controls. Early dopaminergic nigrostriatal depletion is associated with cortical, mainly temporo-parietal hypometabolism unrelated to neuron loss. These findings, together with recent evidence from Parkinson's Disease patients, suggest that early cortical hypometabolism may be associated and driven by subcortical changes that need to be evaluated appropriately. Altogether, these findings could be relevant when potential disease modifying therapies become available., (Copyright © 2022. Published by Elsevier Inc.)

Understanding the origin of Greek and Latin words used as metaphors to label brain structures gives a unique window into how scientific and medical knowledge was produced, preserved, and transmitted through generations. The history of the term thalamus exemplifies the complex historical process that led to the current anatomical terminology. From its first mention by Galen of Pergamon in the 2nd century A.D. to its definitive and current use by Thomas Willis in 1664, the thalamus had an epical journey through 1500 years across Europe, the Middle East, and the North of Africa. The thalamus was confusingly described by Galen, in the Greek language, as a chamber to the brain ventricles. The term thalamus was transferred from Greek to Syriac through the translations of Galen's books done in Baghdad and also from Syriac to Arabic. Then, it was translated in Europe during the Middle Ages from the Arabic versions of Galen's books to Latin. Later, during the Early Renaissance, it was translated again to Latin directly from the Greek versions of Galen's books. Along this epical journey through languages, the term thalamus switched from referring to a hollow structure connected to brain ventricles to naming a solid structure at the rostral end of the brainstem. Finally, the thalamus was translated from Latin to modern languages, where it is used, until today, to name a nuclear complex of subcortical gray matter in the lateral walls of the third ventricle., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 García-Cabezas, Pérez-Santos and Cavada.)

The human cerebral cortex is parcellated in hundreds of areas using neuroanatomy and imaging methods. Alternatively, cortical areas can be classified into few cortical types according to their degree of laminar differentiation. Cortical type analysis is based on the gradual and systematic variation of laminar features observed across the entire cerebral cortex in Nissl stained sections and has profound implications for understanding fundamental aspects of evolution, development, connections, function, and pathology of the cerebral cortex. In this protocol paper, we explain the general principles of cortical type analysis and provide tables with the fundamental features of laminar structure that are studied for this analysis. We apply cortical type analysis to the micrographs of the Atlas of the human cerebral cortex of von Economo and Koskinas and provide tables and maps with the areas of this Atlas and their corresponding cortical type. Finally, we correlate the cortical type maps with the T1w/T2w ratio from widely used reference magnetic resonance imaging scans. The analysis, tables and maps of the human cerebral cortex shown in this protocol paper can be used to predict patterns of connections between areas according to the principles of the Structural Model and determine their level in cortical hierarchies. Cortical types can also predict the spreading of abnormal proteins in neurodegenerative diseases to the level of cortical layers. In summary, cortical type analysis provides a theoretical and practical framework for directed studies of connectivity, synaptic plasticity, and selective vulnerability to neurologic and psychiatric diseases in the human neocortex., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 García-Cabezas, Hacker and Zikopoulos.)

The delicate balance among primate prefrontal networks is necessary for homeostasis and behavioral flexibility. Dorsolateral prefrontal cortex (dlPFC) is associated with cognition, while the most ventromedial subgenual cingulate area 25 (A25) is associated with emotion and emotional expression. Yet A25 is weakly connected with dlPFC, and it is unknown how the two regions communicate. In rhesus monkeys of both sexes, we investigated how these functionally distinct areas may interact through pregenual anterior cingulate area 32 (A32), which is strongly connected with both. We found that dlPFC innervated the deep layers of A32, while A32 innervated all layers of A25, mostly targeting spines of excitatory neurons. Approximately 20% of A32 terminations formed synapses on inhibitory neurons in A25, notably the powerful parvalbumin inhibitory neurons in the deep layers, and the disinhibitory calretinin neurons in the superficial layers. By innervating distinct inhibitory microenvironments in laminar compartments, A32 is positioned to tune activity in columns of A25. The circuitry of the sequential pathway indicates that when dlPFC is engaged, A32 can dampen A25 output through the parvalbumin inhibitory microsystem in the deep layers of A25. A32 thus may flexibly recruit or reduce activity in A25 to maintain emotional equilibrium, a process that is disrupted in depression. Moreover, pyramidal neurons in A25 had a heightened density of NMDARs, which are the targets of novel rapid-acting antidepressants. Pharmacologic antagonism of NMDARs in patients with depression may reduce excitability in A25, mimicking the effects of the neurotypical serial pathway identified here. SIGNIFICANCE STATEMENT The anterior cingulate is a critical hub in prefrontal networks through connections with functionally distinct areas. Dorsolateral and polar prefrontal areas that are associated with complex cognition are connected with the anterior cingulate in a pattern that allows them to indirectly control downstream activity from the anterior cingulate to the subgenual cingulate, which is associated with heightened activity and negative affect in depression. This set of pathways provides a circuit mechanism for emotional regulation, with the anterior cingulate playing a balancing role for integration of cognitive and emotional processes. Disruption of these pathways may perturb network function and the ability to regulate cognitive and affective processes based on context., (Copyright © 2020 the authors.)

The prosomeric model explains the embryological development of the central nervous system (CNS) shared by all vertebrates as a Bauplan. As a primary event, the early neural plate is patterned by intersecting longitudinal plates and transverse segments, forming a mosaic of progenitor units. The hypothalamus is specified by three prosomeres (hp1, hp2, and the acroterminal domain) of the secondary prosencephalon with corresponding alar and basal plate parts, which develop apart from the diencephalon. Mounting evidence suggests that progenitor units within alar and basal plate parts of hp1 and hp2 give rise to distinct hypothalamic nuclei, which preserve their relative invariant positioning (topology) in the adult brain. Nonetheless, the principles of the prosomeric model have not been applied so far to the hypothalamus of adult primates. We parcellated hypothalamic nuclei in adult rhesus monkeys (Macaca mulatta) using various stains to view architectonic boundaries. We then analyzed the topological relations of hypothalamic nuclei and adjacent hypothalamic landmarks with homology across rodent and primate species to trace the origin of adult hypothalamic nuclei to the alar or basal plate components of hp1 and hp2. We generated a novel atlas of the hypothalamus of the adult rhesus monkey with developmental ontologies for each hypothalamic nucleus. The result is a systematic reinterpretation of the adult hypothalamus whose prosomeric ontology can be used to study relationships between the hypothalamus and other regions of the CNS. Further, our atlas may serve as a tool to predict causal patterns in physiological and pathological pathways involving the hypothalamus.

Background: Dopamine loss beyond the mesostriatal system might be relevant in pathogenic mechanisms and some clinical manifestations in PD. The primate thalamus is densely and heterogeneously innervated with dopaminergic axons, most of which express the dopamine transporter, as does the nigrostriatal system. We hypothesized that dopamine depletion may be present in the thalamus of the parkinsonian brain and set out to ascertain possible regional differences., Methods: The toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine was administered to adult macaque monkeys using a slow intoxication protocol. The treated macaques were classified into 2 groups according to their motor status: nonsymptomatic and parkinsonian. Dopamine innervation was studied with immunohistochemistry for the dopamine transporter. Topographic maps of the dopamine transporter-immunoreactive axon distribution were generated and the total length and length density of these axons stereologically estimated using a 3-dimensional fractionator., Results: Parkinsonian macaques exhibited lower dopamine transporter-immunoreactive axon length density than controls in mediodorsal and centromedian-parafascicular nuclei. Dopamine denervation in the mediodorsal nucleus was already noticeable in nonsymptomatic macaques and was even greater in parkinsonian macaques. Reticular nucleus dopamine transporter-immunoreactive axon length density presented an inverse pattern, increasing progressively to the maximum density seen in parkinsonian macaques. No changes were observed in ventral thalamic nuclei. Dopamine transporter-immunoreactive axon maps supported the quantitative findings., Conclusions: Changes in the dopamine innervation of various thalamic nuclei are heterogeneous and start in the premotor parkinsonian stage. These changes may be involved in some poorly understood nonmotor manifestations of PD. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society., (© 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.)

Studies on the thalamus have mostly focused on sensory relay nuclei, but the organization of pathways associated with emotions is not well understood. We addressed this issue by testing the hypothesis that the primate amygdala acts, in part, like a sensory structure for the affective import of stimuli and conveys this information to the mediodorsal thalamic nucleus, magnocellular part (MDmc). We found that primate sensory cortices innervate amygdalar sites that project to the MDmc, which projects to the orbitofrontal cortex. As in sensory thalamic systems, large amygdalar terminals innervated excitatory relay and inhibitory neurons in the MDmc that facilitate faithful transmission to the cortex. The amygdala, however, uniquely innervated a few MDmc neurons by surrounding and isolating large segments of their proximal dendrites, as revealed by three-dimensional high-resolution reconstruction. Physiologic studies have shown that large axon terminals are found in pathways issued from motor systems that innervate other brain centers to help distinguish self-initiated from other movements. By analogy, the amygdalar pathway to the MDmc may convey signals forwarded to the orbitofrontal cortex to monitor and update the status of the environment in processes deranged in schizophrenia, resulting in attribution of thoughts and actions to external sources., Competing Interests: The authors have declared that no competing interests exist.

Hypotheses and theoretical frameworks are needed to organize and interpret the wealth of data on the organization of cortical networks in humans and animals in the light of development, evolution, and selective vulnerability to pathology. Goulas and colleagues compared several hypotheses of cortical network organization in 4 mammalian species and conclude that (1) the laminar pattern of cortico-cortical connections is better predicted by the Structural Model, which relates cytoarchitectonic differences of cortical areas to their interconnectedness, and (2) the existence of cortico-cortical connections is related to cytoarchitectonic differences and the physical distance between cortical areas. The predictions of the Structural Model can be applied to the human cortex, in which invasive studies are precluded. Goulas and colleagues advance interesting questions regarding the emergence of cortical structure and networks in development and evolution. Validated theories of cortical structure, development, and function can guide studies of cortical networks likely affected in neurodevelopmental disorders., Competing Interests: The authors have declared that no competing interests exist.

The classical theory of cortical systematic variation has been independently described in reptiles, monotremes, marsupials and placental mammals, including primates, suggesting a common bauplan in the evolution of the cortex. The Structural Model is based on the systematic variation of the cortex and is a platform for advancing testable hypotheses about cortical organization and function across species, including humans. The Structural Model captures the overall laminar structure of areas by dividing the cortical architectonic continuum into discrete categories (cortical types), which can be used to test hypotheses about cortical organization. By type, the phylogenetically ancient limbic cortices-which form a ring at the base of the cerebral hemisphere-are agranular if they lack layer IV, or dysgranular if they have an incipient granular layer IV. Beyond the dysgranular areas, eulaminate type cortices have six layers. The number and laminar elaboration of eulaminate areas differ depending on species or cortical system within a species. The construct of cortical type retains the topology of the systematic variation of the cortex and forms the basis for a predictive Structural Model, which has successfully linked cortical variation to the laminar pattern and strength of cortical connections, the continuum of plasticity and stability of areas, the regularities in the distribution of classical and novel markers, and the preferential vulnerability of limbic areas to neurodegenerative and psychiatric diseases. The origin of cortical types has been recently traced to cortical development, and helps explain the variability of diseases with an onset in ontogeny.

Autism is a neurodevelopmental connectivity disorder characterized by cortical network disorganization and imbalance in excitation/inhibition. However, little is known about the development of autism pathology and the disruption of laminar-specific excitatory and inhibitory cortical circuits. To begin to address these issues, we examined layer 1 of the lateral prefrontal cortex (LPFC), an area with prolonged development and maturation that is affected in autism. We focused on layer 1 because it contains a distinctive, diverse population of interneurons and glia, receives input from feedback and neuromodulatory pathways, and plays a critical role in the development, maturation, and function of the cortex. We used unbiased quantitative methods at high resolution to study the morphology, neurochemistry, distribution, and density of neurons and myelinated axons in post-mortem brain tissue from children and adults with and without autism. We cross-validated our findings through comparisons with neighboring anterior cingulate cortices and optimally-fixed non-human primate tissue. In neurotypical controls we found an increase in the density of myelinated axons from childhood to adulthood. Neuron density overall declined with age, paralleled by decreased density of inhibitory interneurons labeled by calretinin (CR), calbindin (CB), and parvalbumin (PV). Importantly, we found PV neurons in layer 1 of typically developing children, previously detected only perinatally. In autism there was disorganization of cortical networks within layer 1: children with autism had increased variability in the trajectories and thickness of myelinated axons in layer 1, while adults with autism had a reduction in the relative proportion of thin axons. Neurotypical postnatal changes in layer 1 of LPFC likely underlie refinement of cortical activity during maturation of cortical networks involved in cognition. Our findings suggest that disruption of the maturation of feedback pathways, rather than interneurons in layer 1, has a key role in the development of imbalance between excitation and inhibition in autism.

Humans engage in many daily activities that rely on working memory, the ability to hold and sequence information temporarily to accomplish a task. We focus on the process of working memory, based on circuit mechanisms for attending to relevant signals and suppressing irrelevant stimuli. We discuss that connections critically depend on the systematic variation in laminar structure across all cortical systems. Laminar structure is used to group areas into types regardless of their placement in the cortex, ranging from low-type agranular areas that lack layer IV to high-type areas that have six well-delineated layers. Connections vary in laminar distribution and strength based on the difference in type between linked areas, according to the "structural model" (Barbas H, Rempel-Clower N. Cereb Cortex 7: 635-646, 1997). The many possible pathways thus vary systematically by laminar distribution and strength, and they interface with excitatory neurons to select relevant stimuli and with functionally distinct inhibitory neurons that suppress activity at the site of termination. Using prefrontal pathways, we discuss how systematic architectonic variation gives rise to diverse pathways that can be recruited, along with amygdalar and hippocampal pathways that provide sensory, affective, and contextual information. The prefrontal cortex is also connected with thalamic nuclei that receive the output of the basal ganglia and cerebellum, which may facilitate fast sequencing of information. The complement of connections and their interface with distinct inhibitory neurons allows dynamic recruitment of areas and shifts in cortical rhythms to meet rapidly changing demands of sequential components of working memory tasks.

The phenotype of neurons and their connections depend on complex genetic and epigenetic processes that regulate the expression of genes in the nucleus during development and throughout life. Here we examined the distribution of nuclear chromatin patters in relation to the epigenetic landscape, phenotype and connections of neurons with a focus on the primate cerebral cortex. We show that nuclear patterns of chromatin in cortical neurons are related to neuron size and cortical connections. Moreover, we point to evidence that reveals an orderly sequence of events during development, linking chromatin and gene expression patterns, neuron morphology, function, and connections across cortical areas and layers. Based on this synthesis, we posit that systematic studies of changes in chromatin patterns and epigenetic marks across cortical areas will provide novel insights on the development and evolution of cortical networks, and their disruption in connectivity disorders of developmental origin, like autism. Achieving this requires embedding and interpreting genetic, transcriptional, and epigenetic studies within a framework that takes into consideration distinct types of neurons, local circuit interactions, and interareal pathways. These features vary systematically across cortical areas in parallel with laminar structure and are differentially affected in disorders. Finally, based on evidence that autism-associated genetic polymorphisms are especially prominent in excitatory neurons and connectivity disruption affects mostly limbic cortices, we employ this systematic approach to propose novel, targeted studies of projection neurons in limbic areas to elucidate the emergence and time-course of developmental disruptions in autism.

Noninvasive imaging and tractography methods have yielded information on broad communication networks but lack resolution to delineate intralaminar cortical and subcortical pathways in humans. An important unanswered question is whether we can use the wealth of precise information on pathways from monkeys to understand connections in humans. We addressed this question within a theoretical framework of systematic cortical variation and used identical high-resolution methods to compare the architecture of cortical gray matter and the white matter beneath, which gives rise to short- and long-distance pathways in humans and rhesus monkeys. We used the prefrontal cortex as a model system because of its key role in attention, emotions, and executive function, which are processes often affected in brain diseases. We found striking parallels and consistent trends in the gray and white matter architecture in humans and monkeys and between the architecture and actual connections mapped with neural tracers in rhesus monkeys and, by extension, in humans. Using the novel architectonic portrait as a base, we found significant changes in pathways between nearby prefrontal and distant areas in autism. Our findings reveal that a theoretical framework allows study of normal neural communication in humans at high resolution and specific disruptions in diverse psychiatric and neurodegenerative diseases.

The anterior cingulate cortex (ACC) and posterior orbitofrontal cortex (pOFC) are associated with emotional regulation. These regions are old in phylogeny and have widespread connections with eulaminate neocortices, intricately linking areas associated with emotion and cognition. The ACC and pOFC have distinct cortical and subcortical connections and are also interlinked, but the pattern of their connections-which may be used to infer the flow of information between them-is not well understood. Here we found that pathways from ACC area 32 innervated all pOFC areas with a significant proportion of large and efficient terminals, seen at the level of the system and the synapse. The pathway from area 32 targeted overwhelmingly elements of excitatory neurons in pOFC, with few postsynaptic sites found on presumed inhibitory neurons. Moreover, pathways from area 32 originated mostly in the upper layers and innervated preferentially the middle-deep layers of the least differentiated pOFC areas, in a pattern reminiscent of feedforward communication. Pathway terminations from area 32 overlapped in the deep layers of pOFC with output pathways that project to the thalamus and the amygdala, and may have cascading downstream effects on emotional and cognitive processes and their disruption in psychiatric disorders., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Research on plasticity markers in the cerebral cortex has largely focused on their timing of expression and role in shaping circuits during critical and normal periods. By contrast, little attention has been focused on the spatial dimension of plasticity-stability across cortical areas. The rationale for this analysis is based on the systematic variation in cortical structure that parallels functional specialization and raises the possibility of varying levels of plasticity. Here, we investigated in adult rhesus monkeys the expression of markers related to synaptic plasticity or stability in prefrontal limbic and eulaminate areas that vary in laminar structure. Our findings revealed that limbic areas are impoverished in three markers of stability: intracortical myelin, the lectin Wisteria floribunda agglutinin, which labels perineuronal nets, and parvalbumin, which is expressed in a class of strong inhibitory neurons. By contrast, prefrontal limbic areas were enriched in the enzyme calcium/calmodulin-dependent protein kinase II (CaMKII), known to enhance plasticity. Eulaminate areas have more elaborate laminar architecture than limbic areas and showed the opposite trend: they were enriched in markers of stability and had lower expression of the plasticity-related marker CaMKII. The expression of glial fibrillary acidic protein (GFAP), a marker of activated astrocytes, was also higher in limbic areas, suggesting that cellular stress correlates with the rate of circuit reshaping. Elevated markers of plasticity may endow limbic areas with flexibility necessary for learning and memory within an affective context, but may also render them vulnerable to abnormal structural changes, as seen in neurologic and psychiatric diseases., (© 2017 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

The estimation of the number or density of neurons and types of glial cells and their relative proportions in different brain areas are at the core of rigorous quantitative neuroanatomical studies. Unfortunately, the lack of detailed, updated, systematic and well-illustrated descriptions of the cytology of neurons and glial cell types, especially in the primate brain, makes such studies especially demanding, often limiting their scope and broad use. Here, following an extensive analysis of histological materials and the review of current and classical literature, we compile a list of precise morphological criteria that can facilitate and standardize identification of cells in stained sections examined under the microscope. We describe systematically and in detail the cytological features of neurons and glial cell types in the cerebral cortex of the macaque monkey and the human using semithin and thick sections stained for Nissl. We used this classical staining technique because it labels all cells in the brain in distinct ways. In addition, we corroborate key distinguishing characteristics of different cell types in sections immunolabeled for specific markers counterstained for Nissl and in ultrathin sections processed for electron microscopy. Finally, we summarize the core features that distinguish each cell type in easy-to-use tables and sketches, and structure these key features in an algorithm that can be used to systematically distinguish cellular types in the cerebral cortex. Moreover, we report high inter-observer algorithm reliability, which is a crucial test for obtaining consistent and reproducible cell counts in unbiased stereological studies. This protocol establishes a consistent framework that can be used to reliably identify and quantify cells in the cerebral cortex of primates as well as other mammalian species in health and disease.

Pathways from cortical and subcortical structures give the prefrontal cortex a panoramic view of the sensory environment and the internal milieu of motives and drives. The prefrontal cortex also receives privileged information from the output of the basal ganglia and cerebellum and innervates widely the inhibitory thalamic reticular nucleus that gates thalamo-cortical communication. Connections, in general, are strongly related to the systematic structural variation of the cortex that can be traced to development. Insights from development have profound implications for the special connections of the prefrontal cortex for executive control, learning and memory, and vulnerability in psychiatric and neurologic diseases., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The organization of the inhibitory intercalated cell masses (IM) of the primate amygdala is largely unknown despite their key role in emotional processes. We studied the structural, topographic, neurochemical and intrinsic connectional features of IM neurons in the rhesus monkey brain. We found that the intercalated neurons are not confined to discrete cell clusters, but form a neuronal net that is interposed between the basal nuclei and extends to the dorsally located anterior, central, and medial nuclei of the amygdala. Unlike the IM in rodents, which are prominent in the anterior half of the amygdala, the primate inhibitory net stretched throughout the antero-posterior axis of the amygdala, and was most prominent in the central and posterior extent of the amygdala. There were two morphologic types of intercalated neurons: spiny and aspiny. Spiny neurons were the most abundant; their somata were small or medium size, round or elongated, and their dendritic trees were round or bipolar, depending on location. The aspiny neurons were on average slightly larger and had varicose dendrites with no spines. There were three non-overlapping neurochemical populations of IM neurons, in descending order of abundance: (1) Spiny neurons that were positive for the striatal associated dopamine- and cAMP-regulated phosphoprotein (DARPP-32+); (2) Aspiny neurons that expressed the calcium-binding protein calbindin (CB+); and (3) Aspiny neurons that expressed nitric oxide synthase (NOS+). The unique combinations of structural and neurochemical features of the three classes of IM neurons suggest different physiological properties and function. The three types of IM neurons were intermingled and likely interconnected in distinct ways, and were innervated by intrinsic neurons within the amygdala, or by external sources, in pathways that underlie fear conditioning and anxiety., (Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.)

The aortopulmonary window is a rare cause of heart failure in the neonate. It must be ruled out if there are signs of pulmonary edema without the most frequent left-right shunts. We report the echocardiographic images of a newborn who was admitted with symptoms of heart failure at our institution., (Copyright © 2014 Instituto Nacional de Cardiología Ignacio Chávez. Published by Masson Doyma México S.A. All rights reserved.)

The stratified motor cortex is variously thought to either lack or contain layer 4. Yamawaki et al. described a functional layer 4 in mouse motor cortex with properties and connections similar to layer 4 in sensory areas. Their results bolster a theoretical framework suggesting all primary cortical areas are equivalent., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Behavioral and functional studies in humans suggest that attention plays a key role in activating the primary olfactory cortex through an unknown circuit mechanism. We report that a novel pathway from the anterior cingulate cortex, an area which has a key role in attention, projects directly to the primary olfactory cortex in rhesus monkeys, innervating mostly the anterior olfactory nucleus. Axons from the anterior cingulate cortex formed synapses mostly with spines of putative excitatory pyramidal neurons and with a small proportion of a neurochemical class of inhibitory neurons that are thought to have disinhibitory effect on excitatory neurons. This novel pathway from the anterior cingulate is poised to exert a powerful excitatory effect on the anterior olfactory nucleus, which is a critical hub for odorant processing via extensive bilateral connections with primary olfactory cortices and the olfactory bulb. Acting on the anterior olfactory nucleus, the anterior cingulate may activate the entire primary olfactory cortex to mediate the process of rapid attention to olfactory stimuli., Competing Interests: The authors declare that they have no conflict of interest.

There are opposing views about the status of layer IV in the primary motor cortex (area 4). Cajal described a layer IV in area 4 of adult humans. In contrast, Brodmann found layer IV in developmental but not in adult primates and called area 4 'agranular'. We addressed this issue in rhesus monkeys using the neural marker SMI-32, which labels neurons in lower layer III and upper layer V, but not in layer IV. SMI-32 delineated a central unlabeled cortical stripe in area 4 that corresponds to layer IV, which was populated with small interneurons also found in layer IV in 'granular' areas (such as area 46). We distinguished layer IV interneurons from projection neurons in the layers above and below using cellular criteria. The commonly used term 'agranular' for area 4 is also used for the phylogenetically ancient limbic cortices, confusing areas that differ markedly in laminar structure. This issue pertains to the systematic variation in the architecture across cortices, traced from limbic cortices through areas with increasingly more elaborate laminar structure. The principle of systematic variation can be used to predict laminar patterns of connections across cortical systems. This principle places area 4 and agranular anterior cingulate cortices at opposite poles of the graded laminar differentiation of motor cortices. The status of layer IV in area 4 thus pertains to core organisational features of the cortex, its connections and evolution., (© 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Objective: To assess the presence of early bladder abnormalities in a prenatally corrected and uncorrected animal model of Myelomeningocele (MMC)., Method: A MMC-like lesion was surgically created in 18 fetal lambs between the 60th and the 80th day of gestation. Eight of them did not undergo fetal repair (group A), three were repaired with an open two-layer closure (group B), three using BioGlue® (groupC) and four fetoscopically (group D). At term, bladders were examined macroscopically and histopathological changes were assessed using H-E and Masson Trichrome., Results: Five animals in group A (5/8, 62%), two in group B (2/3, 66%), one in group C (1/3, 33%) and one in group D (1/4, 25%) survived. Macroscopically bladders in group A were severely dilated and showed thinner walls. Microscopically they showed a thin layer of colagenous tissue (Blue layer. BL) lying immediately subjacent to the urothelium. The muscular layers were thinner. Non compliant pattern with thick wall and low capacity was also found in the non corrected model. Group B and the control showed preservation of muscular layers and absence of BL. Groups C and D presented BL but also preservation of muscular layers., Conclusion: Bladder changes in a surgically-induced model of MMC can be described using histopathological data. Both extremes of bladder changes can be observed in the model. These changes were completely prevented with open fetal surgery and partially with other coverage modalities., (Copyright © 2013 AEU. Published by Elsevier Espana. All rights reserved.)

Thalamic nuclei associated with language including the ventral lateral, ventral anterior, intralaminar and mediodorsal form a hub that uniquely receives the output of the basal ganglia and cerebellum, and is connected with frontal (premotor and prefrontal) cortices through two parallel circuits: a thalamic pathway targets the middle frontal cortical layers focally, and the other innervates widely cortical layer 1, poised to recruit other cortices and thalamic nuclei for complex cognitive operations. Return frontal pathways to the thalamus originate from cortical layers 6 and 5. Information through this integrated thalamo-cortical system is gated by the inhibitory thalamic reticular nucleus and modulated by dopamine, representing a specialization in primates. The intricate dialogue of distinct thalamic nuclei with the basal ganglia, cerebellum, and specific dorsolateral prefrontal and premotor cortices associated with language, suggests synergistic roles in the complex but seemingly effortless sequential transformation of cognitive operations for speech production in humans., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: Management of locally advanced rectal cancer (RC) consists of neoadjuvant chemoradiotherapy (CRT) with fluoropyrimidines, followed by total mesorectal excision. We sought to evaluate the expression of selected genes, some of which were derived from a previous undirected SAGE (serial analysis of gene expression)-based approach, before and after CRT, to identify mechanisms of resistance., Methods: This retrospective cohort study included 129 consecutive patients. Quantitative polymerase chain reaction of 53 candidate genes was performed on the biopsy specimen before treatment and on the surgical specimen after CRT. A paired-samples t test was performed to determine genes that were significantly changed after CRT. The result was correlated with patients' disease-free survival., Results: Twenty-two genes were significantly upregulated, and two were significantly downregulated. Several of the upregulated genes have roles in cell cycle control; these include CCNB1IP1, RCC1, EEF2, CDKN1, TFF3, and BCL2. The upregulation of TFF3 was associated with worse disease-free survival on multivariate analyses (hazard ratio, 2.64; P=.027). Patients whose surgical specimens immunohistochemically showed secretion of TFF3 into the lumen of the tumoral microglands had a higher risk of relapse (hazard ratio, 2.51; P=.014). In vitro experiments showed that DLD-1 cells stably transfected with TFF3 were significantly less sensitive to 5-fluorouracil and showed upregulation of genes involved in the transcriptional machinery and in resistance to apoptosis., Conclusion: Upregulation of TFF3 after CRT for RC is associated with a higher risk of relapse. The physiological role of TFF3 in restoring the mucosa during CRT could be interfering with treatment efficacy. Our results could reveal not only a novel RC prognostic marker but also a therapeutic target., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Uveal melanoma is extremely rare in children. Its clinical and histopathological features have been reported to be similar to those observed in adults. The tumor usually presents as a sessile or dome-shaped mass with secondary nonrhegmatogenous retinal detachment. We report a 19-month-old boy with a choroidal melanoma presenting as hemorrhagic retinal detachment and buphthalmos. The eye was enucleated, but the child subsequently died from systemic metastases., (Copyright © 2011 American Association for Pediatric Ophthalmology and Strabismus. Published by Mosby, Inc. All rights reserved.)

The onset of Parkinson's disease (PD) is characterized by focal motor features in one body part, which are usually correlated with greater dopaminergic depletion in the contralateral posterior putamen. The role of dopamine (DA) hemispheric differences in the onset and progression of motor symptoms of PD, however, remains undefined. Previous studies have demonstrated that unilateral manipulations of one nigrostriatal system affect contralateral DA turnover, indicating a functional and compensatory inter-dependence of the two nigrostriatal systems. In preliminary data obtained by our group from asymmetric PD patients, a higher asymmetry index as measured by 6-[(18)F]fluoro-L-dopa ((18) F-DOPA) positron emission tomography (PET) was associated with a higher threshold (i.e., greater dopaminergic loss) for the onset of motor symptoms in the less-affected side. To further elucidate the underlying basis for this, we carried out a complementary study in monkeys using PET to assess and correlate the degree of dopaminergic striatal depletion with motor activity. Control and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated monkeys with symmetrical lesions were characterized behaviorally and with (18)F-DOPA PET. In parallel, an acute lesion was inflicted in the nigrostriatal projection unilaterally in one monkey, generating a 30% dopaminergic depletion in the ipsilateral striatum, which was not associated with any noticeable parkinsonian feature or deficit. The monkey remained asymptomatic for several months. Subsequently, this monkey received systemic MPTP, following which motor behavior and PET were repeatedly evaluated during progression of parkinsonian signs. The brains of all monkeys were processed using immunohistochemical methods. Our results suggest that the onset of motor signs is related to and influenced by the dopaminergic status of the less-affected, contralateral striatum. Although this work is still preliminary, the study agrees with our general hypothesis of hemispheric inter-dependence in the compensation of striatal DA deficit in PD.

Aim: Tumour regression grade (TRG) as defined by Rödel et al. has been used as an independent prognostic factor for rectal carcinoma after preoperative treatment by chemoradiotherapy (CRT). Determination of TRG 2 and 3, semiquantitatively defined as more or less than 50% tumour regression, respectively, does not appear to correlate with prognosis. The purpose of this study was to find an immunohistochemical pattern to permit improved stratification of intermediate responders defined by disease free (DFS) and overall survival (OS)., Method: Immunohistochemistry of EGFR (epidermal growth factor receptor), VEGF (vascular endothelial growth factor), CD133 antibody, p53 antibody and Ki67 antibody was evaluated using tissue microarrays (TMA) on post-treatment surgical specimens from 88 patients. CD133 expression was confirmed in the whole section when available., Results: At a median follow-up of 40 months, TRG was found to be an independent predictor of DFS (P = 0.05) and OS (P = 0.001) but no differences were found between TRG 2 and 3 in terms of DFS (P = 0.74) or OS (P = 0.41). The results of TMA showed an immunohistochemically poor prognostic profile for intermediate responders configured by negativity of CD133 expression. However, when examining CD133 expression in the whole section, there was an intermediate correlation with TMA and the prognostic significance was lost., Conclusion: The results did not confirm the value of immunohistochemistry in predicting the prognosis of patients with rectal cancer following neoadjuvant chemoradiotherapy. This questions the accuracy of TMA in detecting CD133 expression in this setting., (© 2011 The Authors. Colorectal Disease © 2011 The Association of Coloproctology of Great Britain and Ireland.)

The cerebral cortex of large mammals undergoes massive surface area expansion and folding during development. Specific mechanisms to orchestrate the growth of the cortex in surface area rather than in thickness are likely to exist, but they have not been identified. Analyzing multiple species, we have identified a specialized type of progenitor cell that is exclusive to mammals with a folded cerebral cortex, which we named intermediate radial glia cell (IRGC). IRGCs express Pax6 but not Tbr2, have a radial fiber contacting the pial surface but not the ventricular surface, and are found in both the inner subventricular zone and outer subventricular zone (OSVZ). We find that IRGCs are massively generated in the OSVZ, thus augmenting the numbers of radial fibers. Fanning out of this expanding radial fiber scaffold promotes the tangential dispersion of radially migrating neurons, allowing for the growth in surface area of the cortical sheet. Accordingly, the tangential expansion of particular cortical regions was preceded by high proliferation in the underlying OSVZ, whereas the experimental reduction of IRGCs impaired the tangential dispersion of neurons and resulted in a smaller cortical surface. Thus, the generation of IRGCs plays a key role in the tangential expansion of the mammalian cerebral cortex.

Purpose: Preoperative chemoradiotherapy (CRT) is the treatment of choice for rectal cancer (RC), but half of the patients do not respond, suffer unnecessary toxicities, and surgery delays. We aimed to develop a model that could predict a clinically meaningful response to CRT by using formalin-fixed paraffin-embedded (FFPE) biopsies., Experimental Design: We first carried out an exploratory screening of candidate genes by using SAGE technology to evaluate dynamic changes in the RC transcriptome in selected refractory patients before and after CRT. Next, 53 genes (24 from SAGE and 29 from the literature) were analyzed by qPCR arrays in FFPE initial biopsies from 94 stage II/III RC patients who were preoperatively treated with CRT. Tumor response was defined by using Dworak's tumor regression grade (2-3-4 vs. 0-1). Multivariate Cox methods and stepwise algorithms were applied to generate an optimized predictor of response and outcome., Results: In the training cohort (57 patients), a 13-gene signature predicted tumor response with 86% accuracy, 87% sensitivity, and 82% specificity. In a testing cohort (37 patients), the model correctly classified 6 of 7 nonresponders, with an overall accuracy of 76%. A signature-based score identified patients with a higher risk of relapse in univariate (3-year disease-free survival 64% vs. 90%, P = 0.001) and multivariate analysis (HR = 4.35 95% CI: 1.2-15.75, P = 0.02), in which it remained the only statistically significant prognostic factor., Conclusions: A basal 13-gene signature efficiently predicted CRT response and outcome. Multicentric validation by the GEMCAD collaborative group is currently ongoing. If confirmed, the predictor could be used to improve patient selection in RC studies., (©2011 AACR.)

A case of psoriasiform dermatitis in an adult male rhesus macaque is reported. Appearing spontaneously, the condition presented the clinical and histopathological features of human palmoplantar nonpustular psoriasis. The animal developed multiple scaly plaques on his palms and soles, as well as nail hyperkeratosis and widening of the nail root. Microscopically, the skin lesions showed epidermal hyperkeratosis with multifocal parakeratosis, neutrophil microabscesses in the stratum corneum, a loss of granule cell layer under the microabscesses, acanthosis, and elongation of the rete ridges; the superficial dermis showed a dense inflammatory infiltrate containing lymphocytes, macrophages and neutrophils, as well as dilated and tortuous blood vessels. The lesions improved for 15 days after intramuscular corticosteroid depot therapy and worsened slightly afterwards. Later, a spontaneous, progressive remission coincided with the beginning of spring and lasted until the end of summer; the skin lesions practically disappeared during this period, and the nails looked nearly normal. During the next autumn and winter only nail hyperkeratosis was present. Serum analyses showed hyperproteinaemia and hyperglobulinaemia during the outbreak phase and normal values during remission. The clinical and histopathological features of this case, as well as its evolution, are compared with the three other reported cases of psoriasiform skin lesions in nonhuman primates. To the authors' knowledge, this is the first report of a definite palmoplantar nonpustular psoriasiform dermatitis in a rhesus macaque., (© 2010 The Authors. Journal compilation © 2010 ESVD and ACVD.)

Purpose: The purpose of this study is to describe the malformations of cortical development detected in a model of cerebrospinal fluid (CSF) leakage and the influence of surgical closure technique on developmental outcome., Methods: Using a surgically induced model of myelomeningocele (MMC) in sheep, we studied the effects of different repair methods upon the development of hydrocephalus, the presence of the Arnold-Chiari II (AC-II) hindbrain malformation, and cerebral cortex developmental anomalies using gross and histologic (hematoxylin and eosin and Nissl staining) study techniques., Results: A malformed cerebral cortex, including 2 anomalous cortical folding patterns, and lower brain weights were observed in the untreated animals. Hydrocephalus and AC-II malformations were also found in this group. These malformations were mostly prevented with prenatal 2-layer closure., Conclusions: Cerebral cortical malformations and hydrocephalus, in addition to the AC-II hindbrain malformation, are disorders caused by fetal CSF leakage. These malformations were prevented with the technique of MMC closure currently used in humans. Both observations magnify the importance of the second hit associated with chronic CSF leakage, in addition to the primary defect causing the MMC, in the development of the malformation complex., (Copyright © 2011 Elsevier Inc. All rights reserved.)