Using Pareto optimality to explore the topology and dynamics of the human connectome

Graph theory has provided a key mathematical framework to analyse the architecture of human brain networks. This architecture embodies an inherently complex relationship between connection topology, the spatial arrangement of network elements, and the resulting network cost and functional performance. An exploration of these interacting factors and driving forces may reveal salient network features that are critically important for shaping and constraining the brain''s topological organization and its evolvability. Several studies have pointed to an economic balance between network cost and network efficiency with networks organized in an ‘economical’ small-world favouring high communication efficiency at a low wiring cost. In this study, we define and explore a network morphospace in order to characterize different aspects of communication efficiency in human brain networks. Using a multi-objective evolutionary approach that approximates a Pareto-optimal set within the morphospace, we investigate the capacity of anatomical brain networks to evolve towards topologies that exhibit optimal information processing features while preserving network cost. This approach allows us to investigate network topologies that emerge under specific selection pressures, thus providing some insight into the selectional forces that may have shaped the network architecture of existing human brains.     

中国古人类颅内模及脑演化研究进展

颅内模保存有脑表面的形态结构,是脑演化研究的直接证据。中国最早复原和研究的颅内模来自20世纪20年代北京周口店遗址发现的3号猿人头骨;此后虽然中国境内也相继发现了一些古人类的头骨化石,但由于古人类标本非常珍贵,不允许对其进行实体解剖,加上多数头骨破碎或者内部附有地层胶结物,导致颅内模无法成功复原。受技术水平及研究手段的限制,研究者一般只是侧重于化石外表形态结构的研究。高分辨率工业CT和3D软件的应用,可以在不损坏标本的情况下,虚拟复原出化石的内部解剖结构,使得一些重要的古人类化石标本的颅内模被复原出来,促进了脑演化的研究。近年来,本文第一作者采用新技术、新方法复原了南京直立人、柳江人等一些重要的中国古人类头骨的颅内模,通过对其颅容量、脑沟回特征、脑不对称性、脑表面的动、静脉血管压迹、各脑叶的大小、形状及比例的研究,获取了中国古人类脑形态特征变化的数据,为探讨东亚地区古人类的演化提供了参考信息。     

Teratoma formation assays with human embryonic stem cells: a rationale for one type of human-animal chimera

Despite a long and valuable history, human-animal chimera research has often been questioned. Among the moral issues raised by chimeras is the concept that integration of human cells into anatomical locations such as the brain might endow animals with "human-like" capacities including self-awareness. We present a justification for one type of human-animal chimera experiment: the evaluation of hES cell developmental potency via teratoma formation in immunodeficient mice. We argue that this experiment raises no significant moral concerns and should be the jurisdiction of animal care and use committees and exempt from formal review by the stem cell research oversight process.     

Inverse identification of region-specific hyperelastic material parameters for human brain tissue

The identification of material parameters accurately describing the region-dependent mechanical behavior of human brain tissue is crucial for computational models used to assist, e.g., the development of safety equipment like helmets or the planning and execution of brain surgery. While the division of the human brain into different anatomical regions is well established, knowledge about regions with distinct mechanical properties remains limited. Here, we establish an inverse parameter identification scheme using a hyperelastic Ogden model and experimental data from multi-modal testing of tissue from 19 anatomical human brain regions to identify mechanically distinct regions and provide the corresponding material parameters. We assign the 19 anatomical regions to nine governing regions based on similar parameters and microstructures. Statistical analyses confirm differences between the regions and indicate that at least the corpus callosum and the corona radiata should be assigned different material parameters in computational models of the human brain. We provide a total of four parameter sets based on the two initial Poisson’s ratios of 0.45 and 0.49 as well as the pre- and unconditioned experimental responses, respectively. Our results highlight the close interrelation between the Poisson’s ratio and the remaining model parameters. The identified parameters will contribute to more precise computational models enabling spatially resolved predictions of the stress and strain states in human brains under complex mechanical loading conditions.

     

Optimization of in vivo high-resolution DTI of non-human primates on a 3T human scanner

Magnetic resonance (MR) diffusion tensor imaging (DTI) has emerged as a unique technique to reveal small anatomical structures of brain by characterizing the diffusion process of water molecules within an image voxel. Combined with fiber tractography techniques, DTI can be further used to reveal white matter fibers and connectivity in the brain non-invasively. The non-human primate brain study provides important supplemental means for human brain exploration since the two species share close anatomical and functional similarities. There is therefore increasing interest in in vivo non-human primate DTI studies. However, several technical challenges need to be addressed to perform non-human primate brain DTI and fiber tractography. We have established an imaging protocol together with a post-acquisition procedure for high-resolution in vivo non-human primate DTI studies using a 3T human clinical scanner. Data acquired with this procedure is appropriate for accurate diffusion tensor quantification and fiber tractography, and is accessible within an acceptable scan time. We investigated in detail the effects of spatial resolution and SNR on diffusion tensor-derived quantities and fiber tractography. Our results should be of general utility for implementation of in vivo non-human primate DTI studies.     

Searching through functional space reveals distributed visual,auditory, and semantic coding in the human brain

The extent to which brain functions are localized or distributed is a foundational question in neuroscience. In the human brain, common fMRI methods such as cluster correction, atlas parcellation, and anatomical searchlight are biased by design toward finding localized representations. Here we introduce the functional searchlight approach as an alternative to anatomical searchlight analysis, the most commonly used exploratory multivariate fMRI technique. Functional searchlight removes any anatomical bias by grouping voxels based only on functional similarity and ignoring anatomical proximity. We report evidence that visual and auditory features from deep neural networks and semantic features from a natural language processing model, as well as object representations, are more widely distributed across the brain than previously acknowledged and that functional searchlight can improve model-based similarity and decoding accuracy. This approach provides a new way to evaluate and constrain computational models with brain activity and pushes our understanding of human brain function further along the spectrum from strict modularity toward distributed representation.     

A higher order motion region in human inferior parietal lobule: evidence from fMRI

The proposal that motion is processed by multiple mechanisms in the human brain has received little anatomical support so far. Here, we compared higher- and lower-level motion processing in the human brain using functional magnetic resonance imaging. We observed activation of an inferior parietal lobule (IPL) motion region by isoluminant red-green gratings when saliency of one color was increased and by long-range apparent motion at 7 Hz but not 2 Hz. This higher order motion region represents the entire visual field, while traditional motion regions predominantly process contralateral motion. Our results suggest that there are two motion-processing systems in the human brain: a contralateral lower-level luminance-based system, extending from hMT/V5+ into dorsal IPS and STS, and a bilateral higher-level saliency-based system in IPL.     

Identification of a noradrenaline-rich subdivision of the human nucleus accumbens

The nucleus accumbens, situated at the junction between rostral pre-commissural caudate and putamen, is now considered to be critically involved in rewarding and motivational functions mediated by the neurotransmitter dopamine. However, in the human, the precise anatomical boundaries of this nucleus are still undetermined and controversy exists as to the extent to which nucleus accumbens activity is controlled by noradrenaline, a related neurotransmitter now much neglected (in favor of dopamine) by the scientific community. Here we resolve the question of noradrenaline in the human nucleus accumbens and identify, in autopsied brain of normal subjects, a small subdivision of the caudomedial portion of this nucleus that selectively contains strikingly high levels of noradrenaline and thus represents the only area in human brain having equally high levels of both noradrenaline and dopamine. The presence of very high, localized noradrenaline concentrations in the caudomedial nucleus accumbens implies a special biological role for this neurotransmitter in human brain motivational processes.     

Iodine levels in different regions of the human brain

BackgroundIodine is a key component of the thyroid hormones thyroxine (T4) and triiodothyronine (T3), which are crucial for proper growth and development of the human body. In particular, a great body of literature has been published on the link between thyroid hormones and brain development and functioning. However, there is a lack of knowledge on the iodine levels in the human brain. The aim of this work was to determine the brain iodine levels and to contribute to the establishment of “reference” levels for iodine in the different anatomical and functional regions of normal (i.e., subjects without neurological or psychiatric diseases) human brain.MethodsThe iodine levels were determined in 14 brain regions of 52 dead subjects without evidence of neurological or psychiatric disease (n = 728 samples). Iodine was extracted from brain samples using a standard procedure and determined by inductively coupled plasma – mass spectrometry (ICP-MS).ResultsFour subjects presented abnormally high brain iodine levels (26.0 ± 14.2 μg/g) and were excluded from the overall data analysis. The average brain iodine levels for the remaining 48 subjects was 0.14 ± 0.13 μg/g dry weight. Iodine showed very heterogeneous distribution across the different brain regions, with the frontal cortex, caudate nucleus and putamen showing the highest levels. Interestingly, these brain regions are closely related to cognitive function. Iodine levels also showed a tendency to increase with age. The high levels observed in four subjects seemed to be related to previous exposure to iodine-based contrast agents widely used in radiology and computed tomography exams.ConclusionsThis paper provides important data on iodine levels at different brain regions in “normal” people, which can be used to interpret eventual imbalances in subjects with mental disorders and neurodegenerative diseases.     

Probabilistic Clustering of the Human Connectome Identifies Communities and Hubs

A fundamental assumption in neuroscience is that brain function is constrained by its structural properties. This motivates the idea that the brain can be parcellated into functionally coherent regions based on anatomical connectivity patterns that capture how different areas are interconnected. Several studies have successfully implemented this idea in humans using diffusion weighted MRI, allowing parcellation to be conducted in vivo. Two distinct approaches to connectivity-based parcellation can be identified. The first uses the connection profiles of brain regions as a feature vector, and groups brain regions with similar connection profiles together. Alternatively, one may adopt a network perspective that aims to identify clusters of brain regions that show dense within-cluster and sparse between-cluster connectivity. In this paper, we introduce a probabilistic model for connectivity-based parcellation that unifies both approaches. Using the model we are able to obtain a parcellation of the human brain whose clusters may adhere to either interpretation. We find that parts of the connectome consistently cluster as densely connected components, while other parts consistently result in clusters with similar connections. Interestingly, the densely connected components consist predominantly of major cortical areas, while the clusters with similar connection profiles consist of regions that have previously been identified as the ‘rich club’; regions known for their integrative role in connectivity. Furthermore, the probabilistic model allows quantification of the uncertainty in cluster assignments. We show that, while most clusters are clearly delineated, some regions are more difficult to assign. These results indicate that care should be taken when interpreting connectivity-based parcellations obtained using alternative deterministic procedures.     

Adaptive strategy for the statistical analysis of connectomes

We study an adaptive statistical approach to analyze brain networks represented by brain connection matrices of interregional connectivity (connectomes). Our approach is at a middle level between a global analysis and single connections analysis by considering subnetworks of the global brain network. These subnetworks represent either the inter-connectivity between two brain anatomical regions or by the intra-connectivity within the same brain anatomical region. An appropriate summary statistic, that characterizes a meaningful feature of the subnetwork, is evaluated. Based on this summary statistic, a statistical test is performed to derive the corresponding p-value. The reformulation of the problem in this way reduces the number of statistical tests in an orderly fashion based on our understanding of the problem. Considering the global testing problem, the p-values are corrected to control the rate of false discoveries. Finally, the procedure is followed by a local investigation within the significant subnetworks. We contrast this strategy with the one based on the individual measures in terms of power. We show that this strategy has a great potential, in particular in cases where the subnetworks are well defined and the summary statistics are properly chosen. As an application example, we compare structural brain connection matrices of two groups of subjects with a 22q11.2 deletion syndrome, distinguished by their IQ scores.     

The collection and processing of human brain tissue for research

To further understand the neuroanatomy, neurochemistry and neuropathology of the normal and diseased human brain, it is essential to have access to human brain tissue where the biological and chemical nature of the tissue is optimally preserved. We have established a human brain bank where brain tissue is optimally processed and stored in order to provide a resource to facilitate neuroscience research of the human brain in health and disease. A donor programme has been established in consultation with the community to provide for the post-mortem donation of brain tissue to the brain bank. We are using this resource of human brain tissue to further investigate the basis of normal neuronal functioning in the human brain as well as the mechanisms of neuronal dysfunction and degeneration in neurodegenerative diseases. We have established a protocol for the preservation of post-mortem adult human brain tissue firstly by snap-freezing unfixed brain tissue and secondly by chemical fixation and then storage of this tissue at -80 degrees C in a human brain bank. Several research techniques such as receptor autoradiography, DNA and RNA analysis, are carried out on the unfixed tissue and immunohistochemical and histological analysis is carried out on the fixed human tissue. Comparison of tissue from normal control cases and from cases with neurodegenerative disorders is carried out in order to document the changes that occur in the brain in these disorders and to further investigate the underlying pathogenesis of these devastating neurological diseases.     

Adult human brain cell culture for neuroscience research

Studies of the brain have progressed enormously through the use of in vivo and in vitro non-human models. However, it is unlikely such studies alone will unravel the complexities of the human brain and so far no neuroprotective treatment developed in animals has worked in humans. In this review we discuss the use of adult human brain cell culture methods in brain research to unravel the biology of the normal and diseased human brain. The advantages of using adult human brain cells as tools to study human brain function from both historical and future perspectives are discussed. In particular, studies using dissociated cultures of adult human microglia, astrocytes, oligodendrocytes and neurons are described and the applications of these types of study are evaluated. Alternative sources of human brain cells such as adult neural stem cells, induced pluripotent stem cells and slice cultures of adult human brain tissue are also reviewed. These adult human brain cell culture methods could benefit basic research and more importantly, facilitate the translation of basic neuroscience research to the clinic for the treatment of brain disorders.     

Morphological differences between minicolumns in human and nonhuman primate cortex

Our study performed a quantitative investigation of minicolumns in the planum temporale (PT) of human, chimpanzee, and rhesus monkey brains. This analysis distinguished minicolumns in the human cortex from those of the other nonhuman primates. Human cell columns are larger, contain more neuropil space, and pack more cells into the core area of the column than those of the other primates tested. Because the minicolumn is a basic anatomical and functional unit of the cortex, this strong evidence showed reorganization in this area of the human brain. The relationship between the minicolumn and cortical volume is also discussed.     

Proteases of human brain

Growing appreciation of the multiple functions of proteolytic enzymes in intracellular protein degradation and post-translational modification, in the release of biologically active macromolecules and peptides from precursors and in cellular protein regulation and quality control has stimulated interest in proteases in neurobiology and neuropathology. In this article, the proteinases and peptidases thus far studied in the human central nervous system are reviewed with respect to their enzymology, anatomical and cytological distributions and contributions to neurological and psychiatric disease states. Though information concerning brain proteases in man is fragmentary, it suffices to establish the importance of these complex systems for advancing knowledge of human cerebral function in health and disease.The authors are privileged to submit this contribution for the Special Issue of Neurochemical Research honoring Professor K. A. C. Elliott—distinguished pioneer in neurochemistry and a cherished mentor and former colleague of one of us (AP).     

Reproducible reference frame for in vitro testing of the human vertebrae

Definition of an anatomical reference frame is necessary for in vitro biomechanical testing. Nevertheless, there is neither a clear recommendation, nor consensus in the literature concerning an anatomical reference frame for in vitro testing of the human vertebrae. The scope of this work is to define a reference frame for the human vertebrae for in vitro applications. The proposed anatomical reference frame relies on alignment of well-defined points on the endplates, and on two landmarks on the posterior wall. The repeatability of the proposed alignment procedure has been tested in vitro by 5 operators, on 7 specimens. Furthermore, the feasibility and repeatability of the proposed procedure was assessed in silico, using CT-scans of the same specimens.     

Characteristics of brain connectivity during verbal fluency test: Convolutional neural network for functional near-infrared spectroscopy analysis

Human connectome describes the complicated connection matrix of nervous system among human brain. It also possesses high potential of assisting doctors to monitor the brain injuries and recoveries in patients. In order to unravel the enigma of neuron connections and functions, previous research has strived to dig out the relations between neurons and brain regions. Verbal fluency test (VFT) is a general neuropsychological test, which has been used in functional connectivity investigations. In this study, we employed convolutional neural network (CNN) on a brain hemoglobin concentration changes (ΔHB) map obtained during VFT to investigate the connections of activated brain areas and different mental status. Our results show that feature of functional connectivity can be identified accurately with the employment of CNN on ΔHB mapping, which is beneficial to improve the understanding of brain functional connections.     

Cortical network from human embryonic stem cells

The connection of embryonic stem cell technology and developmental biology provides valuable tools to decipher the mechanisms underlying human brain development and diseases, especially among neuronal populations, that are not readily available in primary cultures. It is obviously the case of neurons forming the human cerebral cortex. In the images that are presented, the neurons were generated in vitro from human embryonic stem cells via forebrain-like progenitors. Maintained in culture for prolonged time, they acquired a mainly glutamatergic phenotype and morphological characteristics of cortical pyramidal neurons, including dendritic spines, and formed spectacular networks.     

Three brain collections for comparative neuroanatomy and neuroimaging

In the context of increasing extinction rates and the potential loss of essential evolutionary biological and anthropological information, it is an important task to support efforts to prepare, preserve, and curate collections of histological brain sections; to disseminate information on such collections in the neuroscience community; and to make the collections publicly available. This review emphasizes the importance of complete, serially sectioned human brains of different ontogenetic stages as well as those of adult and old human individuals for neurobiological and medical research. Such histological sections enable microstructural analyses and anatomical evaluations of functional and structural neuroimaging data, for example, based on magnetic resonance imaging. Here, this review provides the first detailed and updated account of the content of the Stephan, Zilles, and Zilles-Amunts collections, which consist of serially sectioned and cell body- and myelin-stained histological preparations. Finally, this review will give an overview of past and recent research using these collections to increase our understanding of the detailed patterns of divergent brain evolution in primates as well as of the structural organization of the human brain.