Evaluation of surface-based hippocampal registration using ground-truth subfield definitions.

The hippocampus is an archicortical structure, consisting of subfields with unique circuits. Understanding its microstructure, as proxied by these subfields, can improve our mechanistic understanding of learning and memory and has clinical potential for several neurological disorders. One prominent issue is how to parcellate, register, or retrieve homologous points between two hippocampi with grossly different morphologies. Here, we present a surface-based registration method that solves this issue in a contrast-agnostic, topology-preserving manner. Specifically, the entire hippocampus is first analytically unfolded, and then samples are registered in 2D unfolded space based on thickness, curvature, and gyrification. We demonstrate this method in seven 3D histology samples and show superior alignment with respect to subfields using this method over more conventional registration approaches.

Patient-specific models link neurotransmitter receptor mechanisms with motor and visuospatial axes of Parkinson's disease.

Parkinson's disease involves multiple neurotransmitter systems beyond the classical dopaminergic circuit, but their influence on structural and functional alterations is not well understood. Here, we use patient-specific causal brain modeling to identify latent neurotransmitter receptor-mediated mechanisms contributing to Parkinson's disease progression. Combining the spatial distribution of 15 receptors from post-mortem autoradiography with 6 neuroimaging-derived pathological factors, we detect a diverse set of receptors influencing gray matter atrophy, functional activity dysregulation, microstructural degeneration, and dendrite and dopaminergic transporter loss. Inter-individual variability in receptor mechanisms correlates with symptom severity along two distinct axes, representing motor and psychomotor symptoms with large GABAergic and glutamatergic contributions, and cholinergically-dominant visuospatial, psychiatric and memory dysfunction. Our work demonstrates that receptor architecture helps explain multi-factorial brain re-organization, and suggests that distinct, co-existing receptor-mediated processes underlie Parkinson's disease.

Cytoarchitectonic, receptor distribution and functional connectivity analyses of the macaque frontal lobe.

Based on quantitative cyto- and receptor architectonic analyses, we identified 35 prefrontal areas, including novel subdivisions of Walker's areas 10, 9, 8B, and 46. Statistical analysis of receptor densities revealed regional differences in lateral and ventrolateral prefrontal cortex. Indeed, structural and functional organization of subdivisions encompassing areas 46 and 12 demonstrated significant differences in the interareal levels of α2 receptors. Furthermore, multivariate analysis included receptor fingerprints of previously identified 16 motor areas in the same macaque brains and revealed 5 clusters encompassing frontal lobe areas. We used the MRI datasets from the non-human primate data sharing consortium PRIME-DE to perform functional connectivity analyses using the resulting frontal maps as seed regions. In general, rostrally located frontal areas were characterized by bigger fingerprints, that is, higher receptor densities, and stronger regional interconnections. Whereas more caudal areas had smaller fingerprints, but showed a widespread connectivity pattern with distant cortical regions. Taken together, this study provides a comprehensive insight into the molecular structure underlying the functional organization of the cortex and, thus, reconcile the discrepancies between the structural and functional hierarchical organization of the primate frontal lobe. Finally, our data are publicly available via the EBRAINS and BALSA repositories for the entire scientific community.

Cortical depth-dependent human fMRI of resting-state networks using EPIK.

Introduction: Recent laminar-fMRI studies have substantially improved understanding of the evoked cortical responses in multiple sub-systems; in contrast, the laminar component of resting-state networks spread over the whole brain has been less studied due to technical limitations. Animal research strongly suggests that the supragranular layers of the cortex play a critical role in maintaining communication within the default mode network (DMN); however, whether this is true in this and other human cortical networks remains unclear. Methods: Here, we used EPIK, which offers unprecedented coverage at sub-millimeter resolution, to investigate cortical broad resting-state dynamics with depth specificity in healthy volunteers. Results: Our results suggest that human DMN connectivity is primarily supported by intermediate and superficial layers of the cortex, and furthermore, the preferred cortical depth used for communication can vary from one network to another. In addition, the laminar connectivity profile of some networks showed a tendency to change upon engagement in a motor task. In line with these connectivity changes, we observed that the amplitude of the low-frequency-fluctuations (ALFF), as well as the regional homogeneity (ReHo), exhibited a different laminar slope when subjects were either performing a task or were in a resting state (less variation among laminae, i.e., lower slope, during task performance compared to rest). Discussion: The identification of varied laminar profiles concerning network connectivity, ALFF, and ReHo, observed across two brain states (task vs. rest) has major implications for the characterization of network-related diseases and suggests the potential diagnostic value of laminar fMRI in psychiatric disorders, e.g., to differentiate the cortical dynamics associated with disease stages linked, or not linked, to behavioral changes. The evaluation of laminar-fMRI across the brain encompasses computational challenges; nonetheless, it enables the investigation of a new dimension of the human neocortex, which may be key to understanding neurological disorders from a novel perspective.

A new map of the rat isocortex and proisocortex: cytoarchitecture and M2 receptor distribution patterns.

Neurotransmitters and their receptors are key molecules in information transfer between neurons, thus enabling inter-areal communication. Therefore, multimodal atlases integrating the brain's cyto- and receptor architecture constitute crucial tools to understand the relationship between its structural and functional segregation. Cholinergic muscarinic M2 receptors have been shown to be an evolutionarily conserved molecular marker of primary sensory areas in the mammalian brain. To complement existing rodent atlases, we applied a silver cell body staining and quantitative in vitro receptor autoradiographic visualization of M2 receptors to alternating sections throughout the entire brain of five adult male Wistar rats (three sectioned coronally, one horizontally, one sagittally). Histological sections and autoradiographs were scanned at a spatial resolution of 1 µm and 20 µm per pixel, respectively, and files were stored as 8 bit images. We used these high-resolution datasets to create an atlas of the entire rat brain, including the olfactory bulb, cerebellum and brainstem. We describe the cyto- and M2 receptor architectonic features of 48 distinct iso- and proisocortical areas across the rat forebrain and provide their mean M2 receptor density. The ensuing parcellation scheme, which is discussed in the framework of existing comprehensive atlasses, includes the novel subdivision of mediomedial secondary visual area Oc2MM into anterior (Oc2MMa) and posterior (Oc2MMp) parts, and of lateral visual area Oc2L into rostrolateral (Oc2Lr), intermediate dorsolateral (Oc2Lid), intermediate ventrolateral (Oc2Liv) and caudolateral (Oc2Lc) secondary visual areas. The M2 receptor densities and the comprehensive map of iso-and proisocortical areas constitute useful tools for future computational and neuroscientific studies.

Gradients of neurotransmitter receptor expression in the macaque cortex.

Dynamics and functions of neural circuits depend on interactions mediated by receptors. Therefore, a comprehensive map of receptor organization across cortical regions is needed. In this study, we used in vitro receptor autoradiography to measure the density of 14 neurotransmitter receptor types in 109 areas of macaque cortex. We integrated the receptor data with anatomical, genetic and functional connectivity data into a common cortical space. We uncovered a principal gradient of receptor expression per neuron. This aligns with the cortical hierarchy from sensory cortex to higher cognitive areas. A second gradient, driven by serotonin 5-HT1A receptors, peaks in the anterior cingulate, default mode and salience networks. We found a similar pattern of 5-HT1A expression in the human brain. Thus, the macaque may be a promising translational model of serotonergic processing and disorders. The receptor gradients may enable rapid, reliable information processing in sensory cortical areas and slow, flexible integration in higher cognitive areas.

Relationships between neurotransmitter receptor densities and expression levels of their corresponding genes in the human hippocampus.

Neurotransmitter receptors are key molecules in signal transmission, their alterations are associated with brain dysfunction. Relationships between receptors and their corresponding genes are poorly understood, especially in humans. We combined in vitro receptor autoradiography and RNA sequencing to quantify, in the same tissue samples (7 subjects), the densities of 14 receptors and expression levels of their corresponding 43 genes in the Cornu Ammonis (CA) and dentate gyrus (DG) of human hippocampus. Significant differences in receptor densities between both structures were found only for metabotropic receptors, whereas significant differences in RNA expression levels mostly pertained ionotropic receptors. Receptor fingerprints of CA and DG differ in shapes but have similar sizes; the opposite holds true for their "RNA fingerprints", which represent the expression levels of multiple genes in a single area. In addition, the correlation coefficients between receptor densities and corresponding gene expression levels vary widely and the mean correlation strength was weak-to-moderate. Our results suggest that receptor densities are not only controlled by corresponding RNA expression levels, but also by multiple regionally specific post-translational factors.

Hippocampal metabolic subregions and networks: Behavioral, molecular, and pathological aging profiles.

INTRODUCTION: Hippocampal local and network dysfunction is the hallmark of Alzheimer's disease (AD). METHODS: We characterized the spatial patterns of hippocampus differentiation based on brain co-metabolism in healthy elderly participants and demonstrated their relevance to study local metabolic changes and associated dysfunction in pathological aging. RESULTS: The hippocampus can be differentiated into anterior/posterior and dorsal cornu ammonis (CA)/ventral (subiculum) subregions. While anterior/posterior CA show co-metabolism with different regions of the subcortical limbic networks, the anterior/posterior subiculum are parts of cortical networks supporting object-centered memory and higher cognitive demands, respectively. Both networks show relationships with the spatial patterns of gene expression pertaining to cell energy metabolism and AD's process. Finally, while local metabolism is generally lower in posterior regions, the anterior-posterior imbalance is maximal in late mild cognitive impairment with the anterior subiculum being relatively preserved. DISCUSSION: Future studies should consider bidimensional hippocampal differentiation and in particular the posterior subicular region to better understand pathological aging.

Architecture and connectivity of the human angular gyrus and of its homolog region in the macaque brain.

The angular gyrus roughly corresponds to Brodmann's area 39, which is a multimodal association brain region located in the posterior apex of the human inferior parietal lobe, at its interface with the temporal and occipital lobes. It encompasses two cyto- and receptor architectonically distinct areas: caudal PGp and rostral PGa. The macaque brain does not present an angular gyrus in the strict sense, and the establishment of homologies was further hindered by the fact that Brodmann defined a single cytoarchitectonic area covering the entire guenon inferior parietal lobule in the monkey brain, i.e. area 7. Latter architectonic studies revealed the existence of 6 architectonically distinct areas within macaque area 7, further connectivity and functional imaging studies supported the hypothesis that the most posterior of these macaque areas, namely Opt and PG, may constitute the homologs of human areas PGp and PGa, respectively. The present review provides an overview of the cyto-, myelo and receptor architecture of human areas PGp and PGa, as well as of their counterparts in the macaque brain, and summarizes current knowledge on the connectivity of these brain areas. Finally, the present study elaborates on the rationale behind the definition of these homologies and their importance in translational studies.

Mapping Cytoarchitectonics and Receptor Architectonics to Understand Brain Function and Connectivity.

This review focuses on cytoarchitectonics and receptor architectonics as biological correlates of function and connectivity. It introduces the 3-dimensional cytoarchitectonic probabilistic maps of cortical areas and nuclei of the Julich-Brain Atlas, available at EBRAINS, to study structure-function relationships. The maps are linked to the BigBrain as microanatomical reference model and template space. The siibra software tool suite enables programmatic access to the maps and to receptor architectonic data that are anchored to brain areas. Such cellular and molecular data are tools for studying magnetic resonance connectivity including modeling and simulation. At the end, we highlight perspectives of the Julich-Brain as well as methodological considerations. Thus, microstructural maps as part of a multimodal atlas help elucidate the biological correlates of large-scale networks and brain function with a high level of anatomical detail, which provides a basis to study brains of patients with psychiatric disorders.

Mapping neurotransmitter systems to the structural and functional organization of the human neocortex.

Neurotransmitter receptors support the propagation of signals in the human brain. How receptor systems are situated within macro-scale neuroanatomy and how they shape emergent function remain poorly understood, and there exists no comprehensive atlas of receptors. Here we collate positron emission tomography data from more than 1,200 healthy individuals to construct a whole-brain three-dimensional normative atlas of 19 receptors and transporters across nine different neurotransmitter systems. We found that receptor profiles align with structural connectivity and mediate function, including neurophysiological oscillatory dynamics and resting-state hemodynamic functional connectivity. Using the Neurosynth cognitive atlas, we uncovered a topographic gradient of overlapping receptor distributions that separates extrinsic and intrinsic psychological processes. Finally, we found both expected and novel associations between receptor distributions and cortical abnormality patterns across 13 disorders. We replicated all findings in an independently collected autoradiography dataset. This work demonstrates how chemoarchitecture shapes brain structure and function, providing a new direction for studying multi-scale brain organization.

Correspondence between gene expression and neurotransmitter receptor and transporter density in the human brain.

Neurotransmitter receptors modulate signaling between neurons. Thus, neurotransmitter receptors and transporters play a key role in shaping brain function. Due to the lack of comprehensive neurotransmitter receptor/transporter density datasets, microarray gene expression measuring mRNA transcripts is often used as a proxy for receptor densities. In the present report, we comprehensively test the spatial correlation between gene expression and protein density for a total of 27 neurotransmitter receptors, receptor binding-sites, and transporters across 9 different neurotransmitter systems, using both PET and autoradiography radioligand-based imaging modalities. We find poor spatial correspondences between gene expression and density for all neurotransmitter receptors and transporters except four single-protein metabotropic receptors (5-HT1A, CB1, D2, and MOR). These expression-density associations are related to gene differential stability and can vary between cortical and subcortical structures. Altogether, we recommend using direct measures of receptor and transporter density when relating neurotransmitter systems to brain structure and function.

The inferior frontal sulcus: Cortical segregation, molecular architecture and function.

The inferior frontal sulcus is conceptualized as the landmark delineating ventro-from dorsolateral prefrontal cortex. Functional imaging studies report activations within the sulcus during tasks addressing cognitive control and verbal working memory, while their microstructural correlates are not well defined. Existing microstructural maps, e.g., Brodmann's map, do not distinguish separate areas within the sulcus. We identified six new areas in the inferior frontal sulcus and its junction to the precentral sulcus, ifs1-4, ifj1-ifj2, by combined cytoarchitectonic analysis and receptor autoradiography. A hierarchical cluster analysis of receptor densities of these and neighbouring prefrontal areas revealed that they form a distinct cluster within the prefrontal cortex. Major interhemispheric differences were found in both cyto- and receptorarchitecture. The function of cytoarchitectonically identified areas was explored by comparing probabilistic maps of the areas in stereotaxic space with their functions and co-activation patterns as analysed by means of a coordinate-based meta-analysis. We found a bilateral involvement in working memory, as well as a lateralization of different language-related processes to the left hemisphere, and of music processing and attention to the right-hemispheric areas. Particularly ifj2 might act as a functional hub between the networks. The cytoarchitectonic maps and receptor densities provide a powerful tool to further elucidate the function of these areas. The maps are available through the Human Brain Atlas of the Human Brain Project and serve in combination with the information on the cyto- and receptor architecture of the areas as a resource for brain models and simulations.

Combined analysis of cytoarchitectonic, molecular and transcriptomic patterns reveal differences in brain organization across human functional brain systems.

Brain areas show specific cellular, molecular, and gene expression patterns that are linked to function, but their precise relationships are largely unknown. To unravel these structure-function relationships, a combined analysis of 53 neurotransmitter receptor genes, receptor densities of six transmitter systems and cytoarchitectonic data of the auditory, somatosensory, visual, motor systems was conducted. Besides covariation of areal gene expression with receptor density, the study reveals specific gene expression patterns in functional systems, which are most prominent for the inhibitory GABAA and excitatory glutamatergic NMDA receptors. Furthermore, gene expression-receptor relationships changed in a systematic manner according to information flow from primary to higher associative areas. The findings shed new light on the relationship of anatomical, functional, and molecular and transcriptomic principles of cortical segregation towards a more comprehensive understanding of human brain organization.

Mapping of whole-cerebrum resting-state networks using ultra-high resolution acquisition protocols.

Resting-state functional magnetic resonance imaging (fMRI) has been used in numerous studies to map networks in the brain that employ spatially disparate regions. However, attempts to map networks with high spatial resolution have been hampered by conflicting technical demands and associated problems. Results from recent fMRI studies have shown that spatial resolution remains around 0.7 × 0.7 × 0.7 mm3 , with only partial brain coverage. Therefore, this work aims to present a novel fMRI technique that was developed based on echo-planar-imaging with keyhole (EPIK) combined with repetition-time-external (TR-external) EPI phase correction. Each technique has been previously shown to be effective in enhancing the spatial resolution of fMRI, and in this work, the combination of the two techniques into TR-external EPIK provided a nominal spatial resolution of 0.51 × 0.51 × 1.00 mm3 (0.26 mm3 voxel) with whole-cerebrum coverage. Here, the feasibility of using half-millimetre in-plane TR-external EPIK for resting-state fMRI was validated using 13 healthy subjects and the corresponding reproducible mapping of resting-state networks was demonstrated. Furthermore, TR-external EPIK enabled the identification of various resting-state networks distributed throughout the brain from a single fMRI session, with mapping fidelity onto the grey matter at 7T. The high-resolution functional image further revealed mesoscale anatomical structures, such as small cerebral vessels and the internal granular layer of the cortex within the postcentral gyrus.

Receptor architecture of macaque and human early visual areas: not equal, but comparable.

Existing cytoarchitectonic maps of the human and macaque posterior occipital cortex differ in the number of areas they display, thus hampering identification of homolog structures. We applied quantitative in vitro receptor autoradiography to characterize the receptor architecture of the primary visual and early extrastriate cortex in macaque and human brains, using previously published cytoarchitectonic criteria as starting point of our analysis. We identified 8 receptor architectonically distinct areas in the macaque brain (mV1d, mV1v, mV2d, mV2v, mV3d, mV3v, mV3A, mV4v), and their respective counterpart areas in the human brain (hV1d, hV1v, hV2d, hV2v, hV3d, hV3v, hV3A, hV4v). Mean densities of 14 neurotransmitter receptors were quantified in each area, and ensuing receptor fingerprints used for multivariate analyses. The 1st principal component segregated macaque and human early visual areas differ. However, the 2nd principal component showed that within each species, area-specific differences in receptor fingerprints were associated with the hierarchical processing level of each area. Subdivisions of V2 and V3 were found to cluster together in both species and were segregated from subdivisions of V1 and from V4v. Thus, comparative studies like this provide valuable architectonic insights into how differences in underlying microstructure impact evolutionary changes in functional processing of the primate brain and, at the same time, provide strong arguments for use of macaque monkey brain as a suitable animal model for translational studies.

A short review on emotion processing: a lateralized network of neuronal networks.

Emotions are valenced mental responses and associated physiological reactions that occur spontaneously and automatically in response to internal or external stimuli, and can influence our behavior, and can themselves be modulated to a certain degree voluntarily or by external stimuli. They are subserved by large-scale integrated neuronal networks with epicenters in the amygdala and the hippocampus, and which overlap in the anterior cingulate cortex. Although emotion processing is accepted as being lateralized, the specific role of each hemisphere remains an issue of controversy, and two major hypotheses have been proposed. In the right-hemispheric dominance hypothesis, all emotions are thought to be processed in the right hemisphere, independent of their valence or of the emotional feeling being processed. In the valence lateralization hypothesis, the left is thought to be dominant for the processing of positively valenced stimuli, or of stimuli inducing approach behaviors, whereas negatively valenced stimuli, or stimuli inducing withdrawal behaviors, would be processed in the right hemisphere. More recent research points at the existence of multiple interrelated networks, each associated with the processing of a specific component of emotion generation, i.e., its generation, perception, and regulation. It has thus been proposed to move from hypotheses supporting an overall hemispheric specialization for emotion processing toward dynamic models incorporating multiple interrelated networks which do not necessarily share the same lateralization patterns.

Personalized brain models identify neurotransmitter receptor changes in Alzheimer's disease.

Alzheimer's disease involves many neurobiological alterations from molecular to macroscopic spatial scales, but we currently lack integrative, mechanistic brain models characterizing how factors across different biological scales interact to cause clinical deterioration in a way that is subject-specific or personalized. As important signalling molecules and mediators of many neurobiological interactions, neurotransmitter receptors are promising candidates for identifying molecular mechanisms and drug targets in Alzheimer's disease. We present a neurotransmitter receptor-enriched multifactorial brain model, which integrates spatial distribution patterns of 15 neurotransmitter receptors from post-mortem autoradiography with multiple in vivo neuroimaging modalities (tau, amyloid-ß and glucose PET, and structural, functional and arterial spin labelling MRI) in a personalized, generative, whole-brain formulation. In a heterogeneous aged population (n = 423, ADNI data), models with personalized receptor-neuroimaging interactions showed a significant improvement over neuroimaging-only models, explaining about 70% (±20%) of the variance in longitudinal changes to the six neuroimaging modalities. In Alzheimer's disease patients (n = 25, ADNI data), receptor-imaging interactions explained up to 39.7% (P < 0.003, family-wise error-rate-corrected) of inter-individual variability in cognitive deterioration, via an axis primarily affecting executive function. Notably, based on their contribution to the clinical severity in Alzheimer's disease, we found significant functional alterations to glutamatergic interactions affecting tau accumulation and neural activity dysfunction and GABAergic interactions concurrently affecting neural activity dysfunction, amyloid and tau distributions, as well as significant cholinergic receptor effects on tau accumulation. Overall, GABAergic alterations had the largest effect on cognitive impairment (particularly executive function) in our Alzheimer's disease cohort (n = 25). Furthermore, we demonstrate the clinical applicability of this approach by characterizing subjects based on individualized 'fingerprints' of receptor alterations. This study introduces the first robust, data-driven framework for integrating several neurotransmitter receptors, multimodal neuroimaging and clinical data in a flexible and interpretable brain model. It enables further understanding of the mechanistic neuropathological basis of neurodegenerative progression and heterogeneity, and constitutes a promising step towards implementing personalized, neurotransmitter-based treatments.

A dopamine gradient controls access to distributed working memory in the large-scale monkey cortex.

Dopamine is required for working memory, but how it modulates the large-scale cortex is unknown. Here, we report that dopamine receptor density per neuron, measured by autoradiography, displays a macroscopic gradient along the macaque cortical hierarchy. This gradient is incorporated in a connectome-based large-scale cortex model endowed with multiple neuron types. The model captures an inverted U-shaped dependence of working memory on dopamine and spatial patterns of persistent activity observed in over 90 experimental studies. Moreover, we show that dopamine is crucial for filtering out irrelevant stimuli by enhancing inhibition from dendrite-targeting interneurons. Our model revealed that an activity-silent memory trace can be realized by facilitation of inter-areal connections and that adjusting cortical dopamine induces a switch from this internal memory state to distributed persistent activity. Our work represents a cross-level understanding from molecules and cell types to recurrent circuit dynamics underlying a core cognitive function distributed across the primate cortex.