Lianne H. Scholtens

Linking Macroscale Graph Analytical Organization to Microscale Neuroarchitectonics in the Macaque Connectome

Macroscale connectivity of the mammalian brain has been shown to display several characteristics of an efficient communication network architecture. In parallel, at the microscopic scale, histological studies have extensively revealed large interregional variation in cortical neural architectonics. However, how these two “scales” of cerebrum organization are linked remains an open question. Collating and combining data across multiple studies on the cortical cytoarchitecture of the macaque cortex with information on macroscale anatomical wiring derived from tract tracing studies, this study focuses on examining the interplay between macroscale organization of the macaque connectome and microscale cortical neuronal architecture. Our findings show that both macroscale degree as well as the topological role in the overall network are related to the level of neuronal complexity of cortical regions at the microscale, showing (among several effects) a positive overall association between macroscale degree and metrics of microscale pyramidal complexity. Macroscale hub regions, together forming a densely interconnected “rich club,” are noted to display a high level of neuronal complexity, findings supportive of a high level of integrative neuronal processes to occur in these regions. Together, we report on cross-scale observations that jointly suggest that a regions microscale neuronal architecture is tuned to its role in the global brain network.

Bridging Cytoarchitectonics and Connectomics in Human Cerebral Cortex

The rich variation in cytoarchitectonics of the human cortex is well known to play an important role in the differentiation of cortical information processing, with functional multimodal areas noted to display more branched, more spinous, and an overall more complex cytoarchitecture. In parallel, connectome studies have suggested that also the macroscale wiring profile of brain areas may have an important contribution in shaping neural processes; for example, multimodal areas have been noted to display an elaborate macroscale connectivity profile. However, how these two scales of brain connectivity are related—and perhaps interact—remains poorly understood. In this communication, we combined data from the detailed mappings of early twentieth century cytoarchitectonic pioneers Von Economo and Koskinas (1925) on the microscale cellular structure of the human cortex with data on macroscale connectome wiring as derived from high-resolution diffusion imaging data from the Human Connectome Project. In a cross-scale examination, we show evidence of a significant association between cytoarchitectonic features of human cortical organization—in particular the size of layer 3 neurons—and whole-brain corticocortical connectivity. Our findings suggest that aspects of microscale cytoarchitectonics and macroscale connectomics are related. SIGNIFICANCE STATEMENT One of the most widely known and perhaps most fundamental properties of the human cortex is its rich variation in cytoarchitectonics. At the same time, neuroimaging studies have also revealed cortical areas to vary in their level of macroscale connectivity. Here, we provide evidence that aspects of local cytoarchitecture are associated with aspects of global macroscale connectivity, providing insight into the question of how the scales of micro-organization and macro-organization of the human cortex are related.

Comparison of diffusion tractography and tract‐tracing measures of connectivity strength in rhesus macaque connectome

With the mapping of macroscale connectomes by means of in vivo diffusion‐weighted MR Imaging (DWI) rapidly gaining in popularity, one of the necessary steps is the examination of metrics of connectivity strength derived from these reconstructions. In the field of human macroconnectomics the number of reconstructed fiber streamlines (NOS) is more and more used as a metric of cortico‐cortical interareal connectivity strength, but the link between DWI NOS and in vivo animal tract‐tracing measurements of anatomical connectivity strength remains poorly understood. In this technical report, we communicate on a comparison between DWI derived metrics and tract‐tracing metrics of projection strength. Tract‐tracing information on projection strength of interareal pathways was extracted from two commonly used macaque connectome datasets, including (1) the CoCoMac database of collated tract‐tracing experiments of the macaque brain and (2) the high‐resolution tract‐tracing dataset of Markov and Kennedy and coworkers. NOS and density of reconstructed fiber pathways derived from DWI data acquired across 10 rhesus macaques was found to positively correlate to tract‐tracing based measurements of connectivity strength across both the CoCoMac and Markov dataset (both P < 0.001), suggesting DWI NOS to form a valid method of assessment of the projection strength of white matter pathways. Our findings provide confidence of in vivo DWI connectome reconstructions to represent fairly realistic estimates of the wiring strength of white matter projections. Our cross‐modal comparison supports the notion of in vivo DWI to be a valid methodology for robust description and interpretation of brain wiring. Hum Brain Mapp 36:3064–3075, 2015.

Simulating disease propagation across white matter connectome reveals anatomical substrate for neuropathology staging in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, characterized by progressive loss of motor function. While the pathogenesis of ALS remains largely unknown, recent histological examinations of Brettschneider and colleagues have proposed four time-sequential stages of neuropathology in ALS based on levels of phosphorylated 43kDa TAR DNA-binding protein (pTDP-43) aggregation. What governs dissemination of these aggregates between segregated regions of the brain is unknown. Here, we cross-reference stages of pTDP-43 pathology with in vivo diffusion weighted imaging data of 215 adult healthy control subjects, and reveal that regions involved in pTDP-43 pathology form a strongly interconnected component of the brain network (p=0.04) likely serving as an anatomical infrastructure facilitating pTDP-43 spread. Furthermore, brain regions of subsequent stages of neuropathology are shown to be more closely interconnected than regions of more distant stages (p=0.002). Computational simulation of disease spread from first-stage motor regions across the connections of the brain network reveals a pattern of pTDP-43 aggregation that reflects the stages of sequential involvement in neuropathology (p=0.02), a pattern in favor of the hypothesis of pTDP-43 pathology to spread across the brain along axonal pathways. Our findings thus provide computational evidence of disease spread in ALS to be directed and constrained by the topology of the anatomical brain network.

Associated Microscale Spine Density and Macroscale Connectivity Disruptions in Schizophrenia

BACKGROUND Schizophrenia is often described as a disorder of dysconnectivity, with disruptions in neural connectivity reported on the cellular microscale as well as the global macroscale level of brain organization. How these effects on these two scales are related is poorly understood. METHODS First (part I of this study), we collated data on layer 3 pyramidal spine density of the healthy brain from the literature and cross-analyzed these data with new data on macroscale connectivity as derived from diffusion imaging. Second (part II of this study), we examined how alterations in regional spine density in schizophrenia are related to changes in white matter connectivity. Data on group differences in spine density were collated from histology reports in the literature and examined in a meta-regression analysis in context of alterations in macroscale white matter connectivity as derived from diffusion imaging data of a (separately acquired) group of 61 patients and 55 matched control subjects. RESULTS Densely connected areas of the healthy human cortex were shown to overlap with areas that display high pyramidal complexity, with pyramidal neurons that are more spinous (p = .0027) compared with pyramidal neurons in areas of low macroscale connectivity. Cross-scale meta-regression analysis showed a significant association between regional variation in level of disease-related spine density reduction in schizophrenia and regional level of decrease in macroscale connectivity (two data sets examined, p = .0028 and p = .0011). CONCLUSIONS Our study presents evidence that regional disruptions in microscale neuronal connectivity in schizophrenia go hand in hand with changes in macroscale brain connectivity.

Linking contemporary high resolution magnetic resonance imaging to the von economo legacy : A study on the comparison of MRI cortical thickness and histological measurements of cortical structure

The cerebral cortex is a distinctive part of the mammalian nervous system, displaying a spatial variety in cyto‐, chemico‐, and myelinoarchitecture. As part of a rich history of histological findings, pioneering anatomists von Economo and Koskinas provided detailed mappings on the cellular structure of the human cortex, reporting on quantitative aspects of cytoarchitecture of cortical areas. Current day investigations into the structure of human cortex have embraced technological advances in Magnetic Resonance Imaging (MRI) to assess macroscale thickness and organization of the cortical mantle in vivo. However, direct comparisons between current day MRI estimates and the quantitative measurements of early anatomists have been limited. Here, we report on a simple, but nevertheless important cross‐analysis between the histological reports of von Economo and Koskinas on variation in thickness of the cortical mantle and MRI derived measurements of cortical thickness. We translated the von Economo cortical atlas to a subdivision of the commonly used Desikan–Killiany atlas (as part of the FreeSurfer Software package and a commonly used parcellation atlas in studies examining MRI cortical thickness). Next, values of “width of the cortical mantle” as provided by the measurements of von Economo and Koskinas were correlated to cortical thickness measurements derived from high‐resolution anatomical MRI T1 data of 200+ subjects of the Human Connectome Project (HCP). Cross‐correlation revealed a significant association between group‐averaged MRI measurements of cortical thickness and histological recordings (r = 0.54, P < 0.001). Further validating such a correlation, we manually segmented the von Economo parcellation atlas on the standardized Colin27 brain dataset and applied the obtained three‐dimensional von Economo segmentation atlas to the T1 data of each of the HCP subjects. Highly consistent with our findings for the mapping to the Desikan–Killiany regions, cross‐correlation between in vivo MRI cortical thickness and von Economo histology‐derived values of cortical mantle width revealed a strong positive association (r = 0.62, P < 0.001). Linking todays state‐of‐the‐art T1‐weighted imaging to early histological examinations our findings indicate that MRI technology is a valid method for in vivo assessment of thickness of human cortex. Hum Brain Mapp 36:3038–3046, 2015.

Affected connectivity organization of the reward system structure in obesity

With the prevalence of obesity rapidly increasing worldwide, understanding the processes leading to excessive eating behavior becomes increasingly important. Considering the widely recognized crucial role of reward processes in food intake, we examined the white matter wiring and integrity of the anatomical reward network in obesity. Anatomical wiring of the reward network was reconstructed derived from diffusion weighted imaging in 31 obese participants and 32 normal-weight participants. Network wiring was compared in terms of the white matter volume as well as in terms of white matter microstructure, revealing lower number of streamlines and lower fiber integrity within the reward network in obese subjects. Specifically, the orbitofrontal cortex and striatum nuclei including accumbens, caudate and putamen showed lower strength and network clustering in the obesity group as compared to healthy controls. Our results provide evidence for obesity-related disruptions of global and local anatomical connectivity of the reward circuitry in regions that are key in the reinforcing mechanisms of eating-behavior processes.

Multimodal analysis of cortical chemoarchitecture and macroscale fMRI resting-state functional connectivity

The cerebral cortex is well known to display a large variation in excitatory and inhibitory chemoarchitecture, but the effect of this variation on global scale functional neural communication and synchronization patterns remains less well understood. Here, we provide evidence of the chemoarchitecture of cortical regions to be associated with large‐scale region‐to‐region resting‐state functional connectivity. We assessed the excitatory versus inhibitory chemoarchitecture of cortical areas as an ExIn ratio between receptor density mappings of excitatory (AMPA, M1) and inhibitory (GABAA, M2) receptors, computed on the basis of data collated from pioneering studies of autoradiography mappings as present in literature of the human (2 datasets) and macaque (1 dataset) cortex. Cortical variation in ExIn ratio significantly correlated with total level of functional connectivity as derived from resting‐state functional connectivity recordings of cortical areas across all three datasets (human I: P = 0.0004; human II: P = 0.0008; macaque: P = 0.0007), suggesting cortical areas with an overall more excitatory character to show higher levels of intrinsic functional connectivity during resting‐state. Our findings are indicative of the microscale chemoarchitecture of cortical regions to be related to resting‐state fMRI connectivity patterns at the global systems level of connectome organization. Hum Brain Mapp 37:3103–3113, 2016.

Topological organization of connectivity strength in the rat connectome.

The mammalian brain is a complex network of anatomically interconnected regions. Animal studies allow for an invasive measurement of the connections of these networks at the macroscale level by means of neuronal tracing of axonal projections, providing a unique opportunity for the formation of detailed ‘connectome maps’. Here we analyzed the macroscale connectome of the rat brain, including detailed information on the macroscale interregional pathways between 67 cortical and subcortical regions as provided by the high-quality, open-access BAMS-II database on rat brain anatomical projections, focusing in particular on the non-uniform distribution of projection strength across pathways. First, network analysis confirmed a small-world, modular and rich club organization of the rat connectome; findings in clear support of previous studies on connectome organization in other mammalian species. More importantly, analyzing network properties of different connection weight classes, we extend previous observations by showing that pathways with different topological roles have significantly different levels of connectivity strength. Among other findings, intramodular connections are shown to display a higher connectivity strength than intermodular connections and hub-to-hub rich club connections are shown to include significantly stronger pathways than connections spanning between peripheral nodes. Furthermore, we show evidence indicating that edges of different weight classes display different topological structures, potentially suggesting varying roles and origins of pathways in the mammalian brain network.

Cortical chemoarchitecture shapes macroscale effective functional connectivity patterns in macaque cerebral cortex.

The mammalian cortex is a complex system of—at the microscale level—interconnected neurons and—at the macroscale level—interconnected areas, forming the infrastructure for local and global neural processing and information integration. While the effects of regional chemoarchitecture on local cortical activity are well known, the effect of local neurotransmitter receptor organization on the emergence of large scale region‐to‐region functional interactions remains poorly understood. Here, we examined reports of effective functional connectivity—as measured by the action of strychnine administration acting on the chemical balance of cortical areas—in relation to underlying regional variation in microscale neurotransmitter receptor density levels in the macaque cortex. Linking cortical variation in microscale receptor density levels to collated information on macroscale functional connectivity of the macaque cortex, we show macroscale patterns of effective corticocortical functional interactions—and in particular, the strength of connectivity of efferent macroscale pathways—to be related to the ratio of excitatory and inhibitory neurotransmitter receptor densities of cortical areas. Our findings provide evidence for the microscale chemoarchitecture of cortical areas to have a direct stimulating influence on the emergence of macroscale functional connectivity patterns in the mammalian brain. Hum Brain Mapp 37:1856–1865, 2016.