Nicola Palomero-Gallagher

A stereological approach to human cortical architecture: Identification and delineation of cortical areas

Stereology offers a variety of procedures to analyze quantitatively the regional and laminar organization in cytoarchitectonically defined areas of the human cerebral cortex. Conventional anatomical atlases are of little help in localizing specific cortical areas, since most of them are based on a single brain and use highly observer-dependent criteria for the delineation of cortical areas. In consequence, numerous cortical maps exist which greatly differ with respect to number, position, size and extent of cortical areas. We describe a novel algorithm-based procedure for the delineation of cortical areas, which exploits the automated estimation of volume densities of cortical cell bodies. Spatial sampling of the laminar pattern is performed with density profiles, followed by multivariate analysis of the profiles shape, which locates the cytoarchitectonic borders between neighboring cortical areas at sites where the laminar pattern changes significantly. The borders are then mapped to a human brain atlas system comprising tools for three dimensional reconstruction, visualization and morphometric analysis. A sample of brains with labeled cortical areas is warped into the reference brain of the atlas system in order to generate a population map of the cortical areas, which describes the intersubject variability in spatial conformation of cortical areas. These population maps provide a novel tool for the interpretation of images obtained with functional imaging techniques.

Multimodal characterisation of cortical areas by multivariate analyses of receptor binding and connectivity data

Cortical areas are regarded as fundamental structural and functional units within the information processing networks of the brain. Their properties have been described extensively by cyto-, myelo- and chemo-architectonics, cortical and extracortical connectivity patterns, receptive field mapping, activation properties, lesion effects, and other structural and functional characteristics. Systematic integrative approaches aiming at multimodal characterisations of cortical areas or at the delineation of global features of the cortical network, however, are still scarce and usually limited to a single data modality, such as cytoarchitectonical or tract tracing data. Here we describe a methodological framework for the systematic evaluation, comparison and integration of different data modalities from the brain and demonstrate its practical application and significance in the analysis of receptor binding and connectivity data within the motor and visual cortices of macaque monkeys. The framework builds on algorithmic methods to convert data between different cortical parcellation schemes, as well as on statistical techniques for the exploration of multivariate data sets comprising data of different types and scales. Thereby, we establish a relationship between intrinsic area properties as expressed by quantitative receptor binding, and extrinsic inter-area communication, which relies on anatomical connectivity. Our analyses provide preliminary evidence for a good correspondence of these two data types in the motor cortex, and their partial discrepancy in the visual cortex, raising hypotheses about the different organisational aspects highlighted by receptors and connectivity. The methodological framework presented here is flexible enough to accommodate a wide range of further data modalities, and is specific enough to permit novel insights and predictions concerning brain organisation. Thus, this approach promises to be very useful in the endeavour to characterise multimodal structure-function relationships in the brain.

Social reward improves the voluntary control over localized brain activity in fMRI-based neurofeedback training.

Neurofeedback (NF) based on real-time functional magnetic resonance imaging (rt-fMRI) allows voluntary regulation of the activity in a selected brain region. For the training of this regulation, a well-designed feedback system is required. Social reward may serve as an effective incentive in NF paradigms, but its efficiency has not yet been tested. Therefore, we developed a social reward NF paradigm and assessed it in comparison with a typical visual NF paradigm (moving bar). We trained twenty-four healthy participants, on three consecutive days, to control activation in dorsal anterior cingulate cortex (ACC) with fMRI-based NF. In the social feedback group, an avatar gradually smiled when ACC activity increased, whereas in the standard feedback group, a moving bar indicated the activation level. In order to assess a transfer of the NF training both groups were asked to up-regulate their brain activity without receiving feedback immediately before and after the NF training (pre- and post-test). Finally, the effect of the acquired NF training on ACC function was evaluated in a cognitive interference task (Simon task) during the pre- and post-test. Social reward led to stronger activity in the ACC and reward-related areas during the NF training when compared to standard feedback. After the training, both groups were able to regulate ACC without receiving feedback, with a trend for stronger responses in the social feedback group. Moreover, despite a lack of behavioral differences, significant higher ACC activations emerged in the cognitive interference task, reflecting a stronger generalization of the NF training on cognitive interference processing after social feedback. Social reward can increase self-regulation in fMRI-based NF and strengthen its effects on neural processing in related tasks, such as cognitive interference. A particular advantage of social feedback is that a direct external reward is provided as in natural social interactions, opening perspectives for implicit learning paradigms.

Cortical layers: Cyto-, myelo-, receptor- and synaptic architecture in human cortical areas

Cortical layers have classically been identified by their distinctive and prevailing cell types and sizes, as well as the packing densities of cell bodies or myelinated fibers. The densities of multiple receptors for classical neurotransmitters also vary across the depth of the cortical ribbon, and thus determine the neurochemical properties of cyto- and myeloarchitectonic layers. However, a systematic comparison of the correlations between these histologically definable layers and the laminar distribution of transmitter receptors is currently lacking. We here analyze the densities of 17 different receptors of various transmitter systems in the layers of eight cytoarchitectonically identified, functionally (motor, sensory, multimodal) and hierarchically (primary and secondary sensory, association) distinct areas of the human cerebral cortex. Maxima of receptor densities are found in different layers when comparing different cortical regions, i.e. laminar receptor densities demonstrate differences in receptorarchitecture between isocortical areas, notably between motor and primary sensory cortices, specifically the primary visual and somatosensory cortices, as well as between allocortical and isocortical areas. Moreover, considerable differences are found between cytoarchitectonical and receptor architectonical laminar patterns. Whereas the borders of cyto- and myeloarchitectonic layers are well comparable, the laminar profiles of receptor densities rarely coincide with the histologically defined borders of layers. Instead, highest densities of most receptors are found where the synaptic density is maximal, i.e. in the supragranular layers, particularly in layers II-III. The entorhinal cortex as an example of the allocortex shows a peculiar laminar organization, which largely deviates from that of all the other cortical areas analyzed here.

The telencephalon of the Göttingen minipig, cytoarchitecture and cortical surface anatomy

During the last 20xa0years pigs have become increasingly popular in large animal translational neuroscience research as an economical and ethical feasible substitute to non-human primates. The anatomy of the pig telencephalon is, however, not well known. We present, accordingly, a detailed description of the surface anatomy and cytoarchitecture of the Göttingen minipig telencephalon based on macrophotos and consecutive high-power microphotographs of 15xa0μm thick paraffin embedded Nissl-stained coronal sections. In 1-year-old specimens the formalin perfused brain measures approximately 55xa0×xa047xa0×xa036xa0mm (length, width, height) and weighs around 69xa0g. The telencephalic part of the Göttingen minipig cerebrum covers a large surface area, which can be divided into a neocortical gyrencephalic part located dorsal to the rhinal fissure, and a ventral subrhinal part dominated by olfactory, amygdaloid, septal, and hippocampal structures. This part of the telencephalon is named the subrhinal lobe, and based on cytoarchitectural and sulcal anatomy, can be discerned from the remaining dorsally located neocortical perirhinal/insular, pericallosal, frontal, parietal, temporal, and occipital lobes. The inner subcortical structure of the minipig telencephalon is dominated by a prominent ventricular system and large basal ganglia, wherein the putamen and the caudate nucleus posterior and dorsally are separated into two entities by the internal capsule, whereas both structures ventrally fuse into a large accumbens nucleus. The presented anatomical data is accompanied by surface renderings and high-power macrophotographs illustrating the telencephalic sulcal pattern, and the localization of the identified lobes and cytoarchitectonic areas. Additionally, 24 representative Nissl-stained telencephalic coronal sections are presented as supplementary material in atlas form on http://www.cense.dk/minipig_atlas/index.html and referred to as S1–S24 throughout the manuscript.

Human Pregenual Anterior Cingulate Cortex: Structural, Functional, and Connectional Heterogeneity

Abstract The human pregenual anterior cingulate cortex (pACC) encompasses 7 distinct cyto- and receptorarchitectonic areas. We lack a detailed understanding of the functions in which they are involved, and stereotaxic maps are not available. We present an integrated structural/functional map of pACC based on probabilistic cytoarchitectonic mapping and meta-analytic connectivity modeling and quantitative functional decoding. Due to the restricted spatial resolution of functional imaging data relative to the microstructural parcellation, areas p24a of the callosal sulcus and p24b on the surface of the cingulate gyrus were merged into a “gyral component” (p24ab) of area p24, and areas pv24c, pd24cv, and pd24cd, located within the cingulate sulcus were merged into a “sulcal component” (p24c) for meta-analytic analysis. Area p24ab was specifically associated with interoception, p24c with the inhibition of action, and p32, which was also activated by emotion induction tasks pertaining negatively valenced stimuli, with the ability to experience empathy. Thus, area p32 could be classified as cingulate association cortex playing a crucial role in the cognitive regulation of emotion. By this spectrum of functions, pACC is a structurally and functionally heterogeneous region, clearly differing from other parts of the anterior and middle cingulate cortex.

Multiple Transmitter Receptors in Regions and Layers of the Human Cerebral Cortex

We measured the densities (fmol/mg protein) of 15 different receptors of various transmitter systems in the supragranular, granular and infragranular strata of 44 areas of visual, somatosensory, auditory and multimodal association systems of the human cerebral cortex. Receptor densities were obtained after labeling of the receptors using quantitative in vitro receptor autoradiography in human postmortem brains. The mean density of each receptor type over all cortical layers and of each of the three major strata varies between cortical regions. In a single cortical area, the multi-receptor fingerprints of its strata (i.e., polar plots, each visualizing the densities of multiple different receptor types in supragranular, granular or infragranular layers of the same cortical area) differ in shape and size indicating regional and laminar specific balances between the receptors. Furthermore, the three strata are clearly segregated into well definable clusters by their receptor fingerprints. Fingerprints of different cortical areas systematically vary between functional networks, and with the hierarchical levels within sensory systems. Primary sensory areas are clearly separated from all other cortical areas particularly by their very high muscarinic M2 and nicotinic α4β2 receptor densities, and to a lesser degree also by noradrenergic α2 and serotonergic 5-HT2 receptors. Early visual areas of the dorsal and ventral streams are segregated by their multi-receptor fingerprints. The results are discussed on the background of functional segregation, cortical hierarchies, microstructural types, and the horizontal (layers) and vertical (columns) organization in the cerebral cortex. We conclude that a cortical column is composed of segments, which can be assigned to the cortical strata. The segments differ by their patterns of multi-receptor balances, indicating different layer-specific signal processing mechanisms. Additionally, the differences between the strata-and area-specific fingerprints of the 44 areas reflect the segregation of the cerebral cortex into functionally and topographically definable groups of cortical areas (visual, auditory, somatosensory, limbic, motor), and reveals their hierarchical position (primary and unimodal (early) sensory to higher sensory and finally to multimodal association areas). Highlights Densities of transmitter receptors vary between areas of human cerebral cortex. Multi-receptor fingerprints segregate cortical layers. The densities of all examined receptor types together reach highest values in the supragranular stratum of all areas. The lowest values are found in the infragranular stratum. Multi-receptor fingerprints of entire areas and their layers segregate functional systems Cortical types (primary sensory, motor, multimodal association) differ in their receptor fingerprints.

Post-mortem inference of the human hippocampal connectivity and microstructure using ultra-high field diffusion MRI at 11.7 T

The human hippocampus plays a key role in memory management and is one of the first structures affected by Alzheimer’s disease. Ultra-high magnetic resonance imaging provides access to its inner structure in vivo. However, gradient limitations on clinical systems hinder access to its inner connectivity and microstructure. A major target of this paper is the demonstration of diffusion MRI potential, using ultra-high field (11.7 T) and strong gradients (750 mT/m), to reveal the extra- and intra-hippocampal connectivity in addition to its microstructure. To this purpose, a multiple-shell diffusion-weighted acquisition protocol was developed to reach an ultra-high spatio-angular resolution with a good signal-to-noise ratio. The MRI data set was analyzed using analytical Q-Ball Imaging, Diffusion Tensor Imaging (DTI), and Neurite Orientation Dispersion and Density Imaging models. High Angular Resolution Diffusion Imaging estimates allowed us to obtain an accurate tractography resolving more complex fiber architecture than DTI models, and subsequently provided a map of the cross-regional connectivity. The neurite density was akin to that found in the histological literature, revealing the three hippocampal layers. Moreover, a gradient of connectivity and neurite density was observed between the anterior and the posterior part of the hippocampus. These results demonstrate that ex vivo ultra-high field/ultra-high gradients diffusion-weighted MRI allows the mapping of the inner connectivity of the human hippocampus, its microstructure, and to accurately reconstruct elements of the polysynaptic intra-hippocampal pathway using fiber tractography techniques at very high spatial/angular resolutions.

Central serotonin modulates neural responses to virtual violent actions in emotion regulation networks

Disruptions in the cortico-limbic emotion regulation networks have been linked to depression, anxiety, impulsivity, and aggression. Altered transmission of the central nervous serotonin (5-HT) contributes to dysfunctions in the cognitive control of emotions. To date, studies relating to pharmaco-fMRI challenging of the 5-HT system have focused on emotion processing for facial expressions. We investigated effects of a single-dose selective 5-HT reuptake inhibitor (escitalopram) on emotion regulation during virtual violence. For this purpose, 38 male participants played a violent video game during fMRI scanning. The SSRI reduced neural responses to violent actions in right-hemispheric inferior frontal gyrus and medial prefrontal cortex encompassing the anterior cingulate cortex (ACC), but not to non-violent actions. Within the ACC, the drug effect differentiated areas with high inhibitory 5-HT1A receptor density (subgenual s25) from those with a lower density (pregenual p32, p24). This finding links functional responses during virtual violent actions with 5-HT neurotransmission in emotion regulation networks, underpinning the ecological validity of the 5-HT model in aggressive behavior. Available 5-HT receptor density data suggest that this SSRI effect is only observable when inhibitory and excitatory 5-HT receptors are balanced. The observed early functional changes may impact patient groups receiving SSRI treatment.

Brodmann's area 40 as revealed by quantitative receptor autoradiography

Brodmann’s area 40 is located on the supramarginal gyrus (1). It is a matter of ongoing debate whether it forms part of Wemicke’s area, not a mere semantic centre for language, but a place of convergence of cortico-cortical interactions in which sounds are mapped into words and cross-modal associations occur with other sensory regions that convey meaning to these words (2). Brodmann only vaguely described the borders of area 40: The dorsal delimitation lies within the intraparietal sulcus. Ventrally, no sharp boundaries with area 22 exist. Area 40 is separated anteriorly from areas 2 and 43 by the inferior postcentral sulcus and the posterior subcentral sulcus. Caudally, it is adjacent to area 39, the border between both areas being located within the sulcus of Jensen, which is present in only 24% of right and 80% of left hemispheres (3). Latter cytoand myeloarchitectonical studies have described the existence of subareas within area 40 (4), and it has even been postulated that area 40 could be, in fact, two independent areas (5). In the present study we have analysed the cytoand receptorarchitecture of the inferior parietal cortex. A first step was to analyse whether area 40 can be further subdivided on the basis of its receptor architecture. Serial frontal sections of complete hemispheres from five human brains were used to analyse noradrenergic, GABAergic, glutamatergic, cholinergic and serotoninergic receptors. Cell bodies were silver stained on adjacent sections for cytoarchitectonical analysis. Localised changes of receptor distribution patterns were found at sites where Brodmann approximately displayed the outer borders of area 40. However, the distribution patterns of some of these receptors (AMPA, NMDA and alpha2 receptors) suggest a further subdivision of BA 40 into a dorsal part with lower receptor densities and a rostral part with higher receptor concentrations. The latter results support the idea of necessary subdivisions of BA 40 into at least two areas. This Human Brain ProjectMeuroinformatics research is funded jointly by the Deutsche Forschungsgemeinschaft (SFB 194/A6), National Institute of Mental Health, National Institute of Neurological Disorders and Stroke, National Institute on Drug Abuse, and the National Cancer Institute.