Investigating the structural network underlying brain-immune interactions using combined histopathology and neuroimaging: a critical review for its relevance in acute and long COVID-19.

Current views on immunity support the idea that immunity extends beyond defense functions and is tightly intertwined with several other fields of biology such as virology, microbiology, physiology and ecology. It is also critical for our understanding of autoimmunity and cancer, two topics of great biological relevance and for critical public health considerations such as disease prevention and treatment. Central to this review, the immune system is known to interact intimately with the nervous system and has been recently hypothesized to be involved not only in autonomic and limbic bio-behaviors but also in cognitive function. Herein we review the structural architecture of the brain network involved in immune response. Furthermore, we elaborate upon the implications of inflammatory processes affecting brain-immune interactions as reported recently in pathological conditions due to SARS-Cov-2 virus infection, namely in acute and post-acute COVID-19. Moreover, we discuss how current neuroimaging techniques combined with ad hoc clinical autopsies and histopathological analyses could critically affect the validity of clinical translation in studies of human brain-immune interactions using neuroimaging. Advances in our understanding of brain-immune interactions are expected to translate into novel therapeutic avenues in a vast array of domains including cancer, autoimmune diseases or viral infections such as in acute and post-acute or Long COVID-19.

Structural connectivity of cytoarchitectonically distinct human left temporal pole subregions: a diffusion MRI tractography study.

The temporal pole (TP) is considered one of the major paralimbic cortical regions, and is involved in a variety of functions such as sensory perception, emotion, semantic processing, and social cognition. Based on differences in cytoarchitecture, the TP can be further subdivided into smaller regions (dorsal, ventrolateral and ventromedial), each forming key nodes of distinct functional networks. However, the brain structural connectivity profile of TP subregions is not fully clarified. Using diffusion MRI data in a set of 31 healthy subjects, we aimed to elucidate the comprehensive structural connectivity of three cytoarchitectonically distinct TP subregions. Diffusion tensor imaging (DTI) analysis suggested that major association fiber pathways such as the inferior longitudinal, middle longitudinal, arcuate, and uncinate fasciculi provide structural connectivity to the TP. Further analysis suggested partially overlapping yet still distinct structural connectivity patterns across the TP subregions. Specifically, the dorsal subregion is strongly connected with wide areas in the parietal lobe, the ventrolateral subregion with areas including constituents of the default-semantic network, and the ventromedial subregion with limbic and paralimbic areas. Our results suggest the involvement of the TP in a set of extensive but distinct networks of cortical regions, consistent with its functional roles.

A proposed structural connectivity matrices approach for the superior fronto-occipital fascicle in the Harvard-Oxford Atlas comparative framework following the Pandya comparative extrapolation principle.

A key set of connections necessary for the most complex brain functions are the long association cortico-cortical fiber tracts. These pathways have been described by the Dejerines and others using post mortem histological or brain dissection techniques. Given methodological limitations, these fiber connections have not been delineated completely in humans. Although the stem portions of fiber tracts have been identified in humans, their precise origins and terminations remain to be determined. By contrast, the origins and terminations as well as the stems of long cortico-cortical association fiber pathways in monkeys have been detailed in the macaque monkey brain using experimental tract tracing methods. Deepak Pandya made major contributions to the delineation of fiber tracts in the monkey brain. In the early 1990s, he compared his observations in monkeys with the original descriptions in humans by the Dejerines. With the advent of diffusion-weighted imaging, Dr. Pandya extended this line of investigation to the human brain with Dr. Nikos Makris. In this translational analysis of long association cortico-cortical fiber tracts, they applied a principle of extrapolation from monkey to human. In the present study, we addressed the reasoning and the complex methodology in translating brain structural connectivity from monkey to human in one cortico-cortical fiber tract, namely the superior fronto-occipital fascicle, which was delineated in both species by Dr. Pandya and colleagues. Furthermore, we represented this information in the form of connectional matrices in the context of the HOA2.0-ComPaRe framework, a homological monkey-to-human translational system used in neuroimaging.

A Proposed Human Structural Brain Connectivity Matrix in the Center for Morphometric Analysis Harvard-Oxford Atlas Framework: A Historical Perspective and Future Direction for Enhancing the Precision of Human Structural Connectivity with a Novel Neuroanatomical Typology.

A complete structural definition of the human nervous system must include delineation of its wiring diagram (e.g., Swanson LW. Brain architecture: understanding the basic plan, 2012). The complete formulation of the human brain circuit diagram (BCD [Front Neuroanat. 2020;14:18]) has been hampered by an inability to determine connections in their entirety (i.e., not only pathway stems but also origins and terminations). From a structural point of view, a neuroanatomic formulation of the BCD should include the origins and terminations of each fiber tract as well as the topographic course of the fiber tract in three dimensions. Classic neuroanatomical studies have provided trajectory information for pathway stems and their speculative origins and terminations [Dejerine J and Dejerine-Klumpke A. Anatomie des Centres Nerveux, 1901; Dejerine J and Dejerine-Klumpke A. Anatomie des Centres Nerveux: Méthodes générales d'étude-embryologie-histogénèse et histologie. Anatomie du cerveau, 1895; Ludwig E and Klingler J. Atlas cerebri humani, 1956; Makris N. Delineation of human association fiber pathways using histologic and magnetic resonance methodologies; 1999; Neuroimage. 1999 Jan;9(1):18-45]. We have summarized these studies previously [Neuroimage. 1999 Jan;9(1):18-45] and present them here in a macroscale-level human cerebral structural connectivity matrix. A matrix in the present context is an organizational construct that embodies anatomical knowledge about cortical areas and their connections. This is represented in relation to parcellation units according to the Harvard-Oxford Atlas neuroanatomical framework established by the Center for Morphometric Analysis at Massachusetts General Hospital in the early 2000s, which is based on the MRI volumetrics paradigm of Dr. Verne Caviness and colleagues [Brain Dev. 1999 Jul;21(5):289-95]. This is a classic connectional matrix based mainly on data predating the advent of DTI tractography, which we refer to as the "pre-DTI era" human structural connectivity matrix. In addition, we present representative examples that incorporate validated structural connectivity information from nonhuman primates and more recent information on human structural connectivity emerging from DTI tractography studies. We refer to this as the "DTI era" human structural connectivity matrix. This newer matrix represents a work in progress and is necessarily incomplete due to the lack of validated human connectivity findings on origins and terminations as well as pathway stems. Importantly, we use a neuroanatomical typology to characterize different types of connections in the human brain, which is critical for organizing the matrices and the prospective database. Although substantial in detail, the present matrices may be assumed to be only partially complete because the sources of data relating to human fiber system organization are limited largely to inferences from gross dissections of anatomic specimens or extrapolations of pathway tracing information from nonhuman primate experiments [Front Neuroanat. 2020;14:18, Front Neuroanat. 2022;16:1035420, and Brain Imaging Behav. 2021;15(3):1589-1621]. These matrices, which embody a systematic description of cerebral connectivity, can be used in cognitive and clinical studies in neuroscience and, importantly, to guide research efforts for further elucidating, validating, and completing the human BCD [Front Neuroanat. 2020;14:18].

A preliminary choroid plexus volumetric study in individuals with psychosis.

The choroid plexus (ChP) is part of the blood-cerebrospinal fluid barrier, regulating brain homeostasis and the brain's response to peripheral events. Its upregulation and enlargement are considered essential in psychosis. However, the timing of the ChP enlargement has not been established. This study introduces a novel magnetic resonance imaging-based segmentation method to examine ChP volumes in two cohorts of individuals with psychosis. The first sample consists of 41 individuals with early course psychosis (mean duration of illness = 1.78 years) and 30 healthy individuals. The second sample consists of 30 individuals with chronic psychosis (mean duration of illness = 7.96 years) and 34 healthy individuals. We utilized manual segmentation to measure ChP volumes. We applied ANCOVAs to compare normalized ChP volumes between groups and partial correlations to investigate the relationship between ChP, LV volumes, and clinical characteristics. Our segmentation demonstrated good reliability (.87). We further showed a significant ChP volume increase in early psychosis (left: p < .00010, right: p < .00010) and a significant positive correlation between higher ChP and higher LV volumes in chronic psychosis (left: r = .54, p = .0030, right: r = .68; p < .0010). Our study suggests that ChP enlargement may be a marker of acute response around disease onset. It might also play a modulatory role in the chronic enlargement of lateral ventricles, often reported in psychosis. Future longitudinal studies should investigate the dynamics of ChP enlargement as a promising marker for novel therapeutic strategies.

HOA2.0-ComPaRe: A next generation Harvard-Oxford Atlas comparative parcellation reasoning method for human and macaque individual brain parcellation and atlases of the cerebral cortex.

Comparative structural neuroanatomy is a cornerstone for understanding human brain structure and function. A parcellation framework that relates systematically to fundamental principles of histological organization is an essential step in generating structural comparisons between species. In the present investigation, we developed a comparative parcellation reasoning system (ComPaRe), which is a formal ontological system in human and non-human primate brains based on the cortical cytoarchitectonic mapping used for both species as detailed by Brodmann. ComPaRe provides a theoretical foundation for mapping neural systems in humans and other species using neuroimaging. Based on this approach, we revised the methodology of the original Harvard-Oxford Atlas (HOA) system of brain parcellation to produce a comparative framework for the human (hHOA) and the rhesus monkey (mHOA) brains, which we refer to as HOA2.0-ComPaRe. In addition, we used dedicated segmentation software in the publicly available 3D Slicer platform to parcellate an individual human and rhesus monkey brain. This method produces quantitative morphometric parcellations in the individual brains. Based on these parcellations we created a representative template and 3D brain atlas for the two species, each based on a single subject. Thus, HOA2.0-ComPaRe provides a theoretical foundation for mapping neural systems in humans and other species using neuroimaging, while also representing a significant revision of the original human and macaque monkey HOA parcellation schemas. The methodology and atlases presented here can be used in basic and clinical neuroimaging for morphometric (volumetric) analysis, further generation of atlases, as well as localization of function and structural lesions.

Anatomically curated segmentation of human subcortical structures in high resolution magnetic resonance imaging: An open science approach.

Magnetic resonance imaging (MRI)-based brain segmentation has recently been revolutionized by deep learning methods. These methods use large numbers of annotated segmentations to train algorithms that have the potential to perform brain segmentations reliably and quickly. However, training data for these algorithms are frequently obtained from automated brain segmentation systems, which may contain inaccurate neuroanatomy. Thus, the neuroimaging community would benefit from an open source database of high quality, neuroanatomically curated and manually edited MRI brain images, as well as the publicly available tools and detailed procedures for generating these curated data. Manual segmentation approaches are regarded as the gold standard for brain segmentation and parcellation. These approaches underpin the construction of neuroanatomically accurate human brain atlases. In addition, neuroanatomically precise definitions of MRI-based regions of interest (ROIs) derived from manual brain segmentation are essential for accuracy in structural connectivity studies and in surgical planning for procedures such as deep brain stimulation. However, manual segmentation procedures are time and labor intensive, and not practical in studies utilizing very large datasets, large cohorts, or multimodal imaging. Automated segmentation methods were developed to overcome these issues, and provide high data throughput, increased reliability, and multimodal imaging capability. These methods utilize manually labeled brain atlases to automatically parcellate the brain into different ROIs, but do not have the anatomical accuracy of skilled manual segmentation approaches. In the present study, we developed a custom software module for manual editing of brain structures in the freely available 3D Slicer software platform that employs principles and tools based on pioneering work from the Center for Morphometric Analysis (CMA) at Massachusetts General Hospital. We used these novel 3D Slicer segmentation tools and techniques in conjunction with well-established neuroanatomical definitions of subcortical brain structures to manually segment 50 high resolution T1w MRI brains from the Human Connectome Project (HCP) Young Adult database. The structural definitions used herein are associated with specific neuroanatomical ontologies to systematically interrelate histological and MRI-based morphometric definitions. The resulting brain datasets are publicly available and will provide the basis for a larger database of anatomically curated brains as an open science resource.

MRI-based Parcellation and Morphometry of the Individual Rhesus Monkey Brain: the macaque Harvard-Oxford Atlas (mHOA), a translational system referencing a standardized ontology.

Investigations of the rhesus monkey (Macaca mulatta) brain have shed light on the function and organization of the primate brain at a scale and resolution not yet possible in humans. A cornerstone of the linkage between non-human primate and human studies of the brain is magnetic resonance imaging, which allows for an association to be made between the detailed structural and physiological analysis of the non-human primate and that of the human brain. To further this end, we present a novel parcellation method and system for the rhesus monkey brain, referred to as the macaque Harvard-Oxford Atlas (mHOA), which is based on the human Harvard-Oxford Atlas (HOA) and grounded in an ontological and taxonomic framework. Consistent anatomical features were used to delimit and parcellate brain regions in the macaque, which were then categorized according to functional systems. This system of parcellation will be expanded with advances in technology and, like the HOA, will provide a framework upon which the results from other experimental studies (e.g., functional magnetic resonance imaging (fMRI), physiology, connectivity, graph theory) can be interpreted.

3D Exploration of the Brainstem in 50-Micron Resolution MRI.

The brainstem, a structure of vital importance in mammals, is currently becoming a principal focus in cognitive, affective, and clinical neuroscience. Midbrain, pontine and medullary structures serve as the conduit for signals between the forebrain and spinal cord, are the epicenter of cranial nerve-circuits and systems, and subserve such integrative functions as consciousness, emotional processing, pain, and motivation. In this study, we parcellated the nuclear masses and the principal fiber pathways that were visible in a high-resolution T2-weighted MRI dataset of 50-micron isotropic voxels of a postmortem human brainstem. Based on this analysis, we generated a detailed map of the human brainstem. To assess the validity of our maps, we compared our observations with histological maps of traditional human brainstem atlases. Given the unique capability of MRI-based morphometric analysis in generating and preserving the morphology of 3D objects from individual 2D sections, we reconstructed the motor, sensory and integrative neural systems of the brainstem and rendered them in 3D representations. We anticipate the utilization of these maps by the neuroimaging community for applications in basic neuroscience as well as in neurology, psychiatry, and neurosurgery, due to their versatile computational nature in 2D and 3D representations in a publicly available capacity.

How Human Is Human Connectional Neuroanatomy?

The structure of the human brain has been studied extensively. Despite all the knowledge accrued, direct information about connections, from origin to termination, in the human brain is extremely limited. Yet there is a widespread misperception that human connectional neuroanatomy is well-established and validated. In this article, we consider what is known directly about human structural and connectional neuroanatomy. Information on neuroanatomical connections in the human brain is derived largely from studies in non-human experimental models in which the entire connectional pathway, including origins, course, and terminations, is directly visualized. Techniques to examine structural connectivity in the human brain are progressing rapidly; nevertheless, our present understanding of such connectivity is limited largely to data derived from homological comparisons, particularly with non-human primates. We take the position that an in-depth and more precise understanding of human connectional neuroanatomy will be obtained by a systematic application of this homological approach.

Individual variations of the human corticospinal tract and its hand-related motor fibers using diffusion MRI tractography.

The corticospinal tract (CST) is one of the most well studied tracts in human neuroanatomy. Its clinical significance can be demonstrated in many notable traumatic conditions and diseases such as stroke, spinal cord injury (SCI) or amyotrophic lateral sclerosis (ALS). With the advent of diffusion MRI and tractography the computational representation of the human CST in a 3D model became available. However, the representation of the entire CST and, specifically, the hand motor area has remained elusive. In this paper we propose a novel method, using manually drawn ROIs based on robustly identifiable neuroanatomic structures to delineate the entire CST and isolate its hand motor representation as well as to estimate their variability and generate a database of their volume, length and biophysical parameters. Using 37 healthy human subjects we performed a qualitative and quantitative analysis of the CST and the hand-related motor fiber tracts (HMFTs). Finally, we have created variability heat maps from 37 subjects for both the aforementioned tracts, which could be utilized as a reference for future studies with clinical focus to explore neuropathology in both trauma and disease states.

Variability and anatomical specificity of the orbitofrontothalamic fibers of passage in the ventral capsule/ventral striatum (VC/VS): precision care for patient-specific tractography-guided targeting of deep brain stimulation (DBS) in obsessive compulsive disorder (OCD).

Deep Brain Stimulation (DBS) is a neurosurgical procedure that can reduce symptoms in medically intractable obsessive-compulsive disorder (OCD). Conceptually, DBS of the ventral capsule/ventral striatum (VC/VS) region targets reciprocal excitatory connections between the orbitofrontal cortex (OFC) and thalamus, decreasing abnormal reverberant activity within the OFC-caudate-pallidal-thalamic circuit. In this study, we investigated these connections using diffusion magnetic resonance imaging (dMRI) on human connectome datasets of twenty-nine healthy young-adult volunteers with two-tensor unscented Kalman filter based tractography. We studied the morphology of the lateral and medial orbitofrontothalamic connections and estimated their topographic variability within the VC/VS region. Our results showed that the morphology of the individual orbitofrontothalamic fibers of passage in the VC/VS region is complex and inter-individual variability in their topography is high. We applied this method to an example OCD patient case who underwent DBS surgery, formulating an initial proof of concept for a tractography-guided patient-specific approach in DBS for medically intractable OCD. This may improve on current surgical practice, which involves implanting all patients at identical stereotactic coordinates within the VC/VS region.

Multi-tensor investigation of orbitofrontal cortex tracts affected in subcaudate tractotomy.

Subcaudate tractotomy (SCT) is a neurosurgical lesioning procedure that can reduce symptoms in medically intractable obsessive compulsive disorder (OCD). Due to the putative importance of the orbitofrontal cortex (OFC) in symptomatology, fibers that connect the OFC, SCT lesion, and either the thalamus or brainstem were investigated with two-tensor tractography using an unscented Kalman filter approach. From this dataset, fibers were warped to Montreal Neurological Institute space, and probability maps with center-of-mass analysis were subsequently generated. In comparing fibers from the same OFC region, including medial OFC (mOFC), central OFC (cOFC), and lateral OFC (lOFC), the area of divergence for fibers connected with the thalamus versus the brainstem is posterior to the anterior commissure. At the anterior commissure, fibers connected with the thalamus run dorsal to those connected with the brainstem. As OFC fibers travel through the ventral aspect of the internal capsule, lOFC fibers are dorsal to cOFC and mOFC fibers. Using neuroanatomical comparison, tracts coursing between the OFC and thalamus are likely part of the anterior thalamic radiations, while those between the OFC and brainstem likely belong to the medial forebrain bundle. These data support the involvement of the OFC in OCD and may be relevant to creating differential lesional procedures of specific tracts or to developing deep brain stimulation programming paradigms.

The prefrontal cortex: comparative architectonic organization in the human and the macaque monkey brains.

Detailed cytoarchitectonic studies of the human cerebral cortex appeared during the first quarter of the 20th century. The incorporation of the cytoarchitectonic map by Brodmann (1909) in the Talairach proportional stereotaxic space (Talairach and Tournoux, 1988) has established the Brodmann numerical nomenclature as the basis for describing the cortical location of structural and functional findings obtained with modern neuroimaging. In experimental anatomical and physiological investigations of the macaque monkey performed during the last 50 years, the numerical architectonic nomenclature used to describe findings in the prefrontal cortex has been largely based on the map by Walker (1940). Unfortunately, the map by Walker was not based on a comparative investigation of the cytoarchitecture of the human and macaque monkey prefrontal cortex and, as a result, the nomenclature and the criteria for demarcating areas in the two primate species are not always consistent. These discrepancies are a major obstacle in the ability to compare experimental findings from nonhuman primates with results obtained in functional and structural neuroimaging of the human brain. The present article outlines these discrepancies in the classical maps and describes comparative investigations of the cytoarchitecture of the prefrontal cortex of the macaque monkey and human (Petrides and Pandya, 1994, 1999, 2002a) in order to resolve these discrepancies and enable easy translation of experimental research in the monkey to findings in the human brain obtained with modern neuroimaging.

The cortical connectivity of the prefrontal cortex in the monkey brain.

One dimension of understanding the functions of the prefrontal cortex is knowledge of cortical connectivity. We have surveyed three aspects of prefrontal cortical connections: local projections (within the frontal lobe), the termination patterns of long association (post-Rolandic) projections, and the trajectories of major fiber pathways. The local connections appear to be organized in relation to dorsal (hippocampal origin) and ventral (paleocortical origin) architectonic trends. According to the proposal of a dual origin of the cerebral cortex, cortical areas can be traced as originating from archicortex (hippocampus) on the one hand, and paleocortex, on the other hand, in a stepwise manner (e.g., Sanides, 1969; Pandya and Yeterian, 1985). Prefrontal areas within each trend are connected with less architectonically differentiated areas, and also with more differentiated areas. Such organization may allow for the systematic exchange of information within each architectonic trend. The long connections of the prefrontal cortex with post-Rolandic regions seem to be organized preferentially in relation to dorsal and ventral prefrontal architectonic trends. Prefrontal areas are connected with post-Rolandic auditory, visual and somatosensory association areas, and with multimodal and paralimbic regions. This long connectivity likely works in conjunction with local connections to serve prefrontal cortical functions. The afferent and efferent connections of the prefrontal cortex with post-Rolandic regions are conveyed by specific long association pathways. These pathways as well appear to be organized in relation to dorsal and ventral prefrontal architectonic trends. Finally, although prefrontal areas have preferential connections in relation to dual architectonic trends, it is clear that there are interconnections between and among areas in each trend, which may provide a substrate for the overall integrative function of the prefrontal cortex. Prefrontal corticocortical connectivity may help to elucidate both region-specific and integrative perspectives on the functions of the prefrontal cortex.