Revealing Topological Organization of Human Brain Functional Networks with Resting-State Functional near Infrared Spectroscopy

Background

The human brain is a highly complex system that can be represented as a structurally interconnected and functionally synchronized network, which assures both the segregation and integration of information processing. Recent studies have demonstrated that a variety of neuroimaging and neurophysiological techniques such as functional magnetic resonance imaging (MRI), diffusion MRI and electroencephalography/magnetoencephalography can be employed to explore the topological organization of human brain networks. However, little is known about whether functional near infrared spectroscopy (fNIRS), a relatively new optical imaging technology, can be used to map functional connectome of the human brain and reveal meaningful and reproducible topological characteristics.

Results

We utilized resting-state fNIRS (R-fNIRS) to investigate the topological organization of human brain functional networks in 15 healthy adults. Brain networks were constructed by thresholding the temporal correlation matrices of 46 channels and analyzed using graph-theory approaches. We found that the functional brain network derived from R-fNIRS data had efficient small-world properties, significant hierarchical modular structure and highly connected hubs. These results were highly reproducible both across participants and over time and were consistent with previous findings based on other functional imaging techniques.

Conclusions

Our results confirmed the feasibility and validity of using graph-theory approaches in conjunction with optical imaging techniques to explore the topological organization of human brain networks. These results may expand a methodological framework for utilizing fNIRS to study functional network changes that occur in association with development, aging and neurological and psychiatric disorders.     

Glutathione-S-Transferase Activity in the Brain: Species, Sex, Regional, and Age Differences

Abstract: Glutathione- S -transferase activity in the brain of male mammals (rat and mouse) was found to be relatively lower than in that of females. In contrast, the male aves (pigeon, kite, vulture, and crow) exhibited comparatively higher activity of brain glutathione- S -transferase than the corresponding females. Postnatal development of cytosolic glutathione-S-transferase activity in the rat brain was also investigated. The day-7 rats showed a low activity of 48 nmol/min/mg protein that gradually increased 3.2-fold over the age of 28 days. No striking differences in brain enzyme activities were observed between the 35- and 90-day-old rats. Discrete brain regions of immature rats were found to possess considerable but lower quantities of glutathione- S -transferase activity than those of the adults. The activity increased with the onset of development and attained a steady state after 21 days of age.     

Development of Large-Scale Functional Brain Networks in Children

The ontogeny of large-scale functional organization of the human brain is not well understood. Here we use network analysis of intrinsic functional connectivity to characterize the organization of brain networks in 23 children (ages 7–9 y) and 22 young-adults (ages 19–22 y). Comparison of network properties, including path-length, clustering-coefficient, hierarchy, and regional connectivity, revealed that although children and young-adults' brains have similar “small-world” organization at the global level, they differ significantly in hierarchical organization and interregional connectivity. We found that subcortical areas were more strongly connected with primary sensory, association, and paralimbic areas in children, whereas young-adults showed stronger cortico-cortical connectivity between paralimbic, limbic, and association areas. Further, combined analysis of functional connectivity with wiring distance measures derived from white-matter fiber tracking revealed that the development of large-scale brain networks is characterized by weakening of short-range functional connectivity and strengthening of long-range functional connectivity. Importantly, our findings show that the dynamic process of over-connectivity followed by pruning, which rewires connectivity at the neuronal level, also operates at the systems level, helping to reconfigure and rebalance subcortical and paralimbic connectivity in the developing brain. Our study demonstrates the usefulness of network analysis of brain connectivity to elucidate key principles underlying functional brain maturation, paving the way for novel studies of disrupted brain connectivity in neurodevelopmental disorders such as autism.     

Disrupted Topological Organization in Whole-Brain Functional Networks of Heroin-Dependent Individuals: A Resting-State fMRI Study

Neuroimaging studies have shown that heroin addiction is related to abnormalities in widespread local regions and in the functional connectivity of the brain. However, little is known about whether heroin addiction changes the topological organization of whole-brain functional networks. Seventeen heroin-dependent individuals (HDIs) and 15 age-, gender-matched normal controls (NCs) were enrolled, and the resting-state functional magnetic resonance images (RS-fMRI) were acquired from these subjects. We constructed the brain functional networks of HDIs and NCs, and compared the between-group differences in network topological properties using graph theory method. We found that the HDIs showed decreases in the normalized clustering coefficient and in small-worldness compared to the NCs. Furthermore, the HDIs exhibited significantly decreased nodal centralities primarily in regions of cognitive control network, including the bilateral middle cingulate gyrus, left middle frontal gyrus, and right precuneus, but significantly increased nodal centralities primarily in the left hippocampus. The between-group differences in nodal centralities were not corrected by multiple comparisons suggesting these should be considered as an exploratory analysis. Moreover, nodal centralities in the left hippocampus were positively correlated with the duration of heroin addiction. Overall, our results indicated that disruptions occur in the whole-brain functional networks of HDIs, findings which may be helpful in further understanding the mechanisms underlying heroin addiction.     

Primate Innovation: Sex,Age and Social Rank Differences

Analysis of an exhaustive survey of primate behavior collated from the published literature revealed significant variation in rates of innovation among individuals of different sex, age and social rank. We searched approximately 1,000 articles in four primatology journals, together with other relevant databases, for examples of innovation. The reported incidence of innovation is higher in males and adults, and lower in females and nonadults, than would be expected by chance given the estimated relative proportions of these groups. Amongst chimpanzees, the only species for which there are sufficient data to consider alone, there is a similar sex difference in the propensity to innovate, but no effect of age. Chimpanzees of low social rank are reported as innovators more frequently than high-ranking chimpanzees are. Male chimpanzees innovate more often than females in sexual, courtship, mating and display contexts; that is, in contexts likely to increase access to mates. The largest number of recorded observations are in the foraging context, wherein contrary to expectations, there is no evidence for female chimpanzees exhibiting more innovation than males. The study is the first extensive investigation of behavioral innovation in primates and provides evidence that much individual variation in the propensity to innovate can be explained in terms of sex, age, and social rank.     

Progressive Gender Differences of Structural Brain Networks in Healthy Adults: A Longitudinal,Diffusion Tensor Imaging Study

Sexual dimorphism in the brain maturation during childhood and adolescence has been repeatedly documented, which may underlie the differences in behaviors and cognitive performance. However, our understanding of how gender modulates the development of structural connectome in healthy adults is still not entirely clear. Here we utilized graph theoretical analysis of longitudinal diffusion tensor imaging data over a five-year period to investigate the progressive gender differences of brain network topology. The brain networks of both genders showed prominent economical “small-world” architecture (high local clustering and short paths between nodes). Additional analysis revealed a more economical “small-world” architecture in females as well as a greater global efficiency in males regardless of scan time point. At the regional level, both increased and decreased efficiency were found across the cerebral cortex for both males and females, indicating a compensation mechanism of cortical network reorganization over time. Furthermore, we found that weighted clustering coefficient exhibited significant gender-time interactions, implying different development trends between males and females. Moreover, several specific brain regions (e.g., insula, superior temporal gyrus, cuneus, putamen, and parahippocampal gyrus) exhibited different development trajectories between males and females. Our findings further prove the presence of sexual dimorphism in brain structures that may underlie gender differences in behavioral and cognitive functioning. The sex-specific progress trajectories in brain connectome revealed in this work provide an important foundation to delineate the gender related pathophysiological mechanisms in various neuropsychiatric disorders, which may potentially guide the development of sex-specific treatments for these devastating brain disorders.     

Sex and Age Differences in Mate-Selection Preferences

For nearly 70?years, studies have shown large sex differences in human mate selection preferences. However, most of the studies were restricted to a limited set of mate selection criteria and to college students, and neglecting relationship status. In this study, 21,245 heterosexual participants between 18 and 65?years of age (mean age 41) who at the time were not involved in a close relationship rated the importance of 82 mate selection criteria adapted from previous studies, reported age ranges for the oldest and youngest partner that they would find acceptable, and responded to 10 yes/no questions about a potential marriage partner. For nearly all mate selection criteria, women were found to be the more demanding sex, although men placed consistently more value on the physical attractiveness of a potential partner than women. Also, the effects of the participants?? age and level of education were nearly negligible. These results demonstrate the robustness of sex differences in mate selection criteria across a substantial age range.     

Sex and Age Differences in Levothyroxine Dosage Requirement

ObjectiveTo examine the performance of weightbased formulae for estimating the levothyroxine dosage requirement in athyreotic patients and to determine whether formula performance is affected by age, sex, or menstrual status.MethodsIn this prospective study, euthyroid study participants aged 18 to 65 years were followed up after total thyroidectomy at 4 time points: 6-8 weeks, 12-16 weeks, 6 months, and 1 year. Patient weight, serum thyrotropin concentration, and levothyroxine dosage required were recorded at each time point. The postoperative starting levothyroxine dosage was 1.7 mcg/kg daily for patients with benign thyroid disease and 2.2 mcg/kg daily for patients with thyroid cancer. Actual body weight was used to calculate the initial dosage. At steady state, adjustments were made in each patient’s levothyroxine dosage until the target thyrotropin concentration was reached. The levothyroxine dosage required to achieve this goal was documented.ResultsFifty patients were included (37 women, 13 men). Formulae based on actual body weight were accurate in achieving a normal thyrotropin concentration in 48% to 75% of participants. Final dosages to achieve normal thyrotropin values were similar in men (1.43 mcg/kg daily) and menopausal women (1.68 mcg/kg daily), but higher in premenopausal women (2.10 mcg/kg daily). When a formula based on ideal body weight was used, the requirement for menopausal women (2.34 mcg/kg daily) was similar to that of premenopausal women (2.44 mcg/kg daily), but the requirement for men (1.73 mcg/kg daily) remained lower than that observed in both female groups.ConclusionsWhen actual body weight was used to calculate levothyroxine dosage requirement, premenopausal women appeared to have a greater requirement than either menopausal women or men. When ideal weight was used, the requirement of all women was greater than that of men. Perhaps with formulae using actual weight, this apparent sex difference is masked by the greater weight, older age, or altered hormonal milieu of menopausal women. (Endocr Pract. 2010;16:71-79)     

Functional Brain Networks Develop from a “Local to Distributed” Organization

The mature human brain is organized into a collection of specialized functional networks that flexibly interact to support various cognitive functions. Studies of development often attempt to identify the organizing principles that guide the maturation of these functional networks. In this report, we combine resting state functional connectivity MRI (rs-fcMRI), graph analysis, community detection, and spring-embedding visualization techniques to analyze four separate networks defined in earlier studies. As we have previously reported, we find, across development, a trend toward ‘segregation’ (a general decrease in correlation strength) between regions close in anatomical space and ‘integration’ (an increased correlation strength) between selected regions distant in space. The generalization of these earlier trends across multiple networks suggests that this is a general developmental principle for changes in functional connectivity that would extend to large-scale graph theoretic analyses of large-scale brain networks. Communities in children are predominantly arranged by anatomical proximity, while communities in adults predominantly reflect functional relationships, as defined from adult fMRI studies. In sum, over development, the organization of multiple functional networks shifts from a local anatomical emphasis in children to a more “distributed” architecture in young adults. We argue that this “local to distributed” developmental characterization has important implications for understanding the development of neural systems underlying cognition. Further, graph metrics (e.g., clustering coefficients and average path lengths) are similar in child and adult graphs, with both showing “small-world”-like properties, while community detection by modularity optimization reveals stable communities within the graphs that are clearly different between young children and young adults. These observations suggest that early school age children and adults both have relatively efficient systems that may solve similar information processing problems in divergent ways.     

Levels and Age Dependency of Neurofilament Light and Glial Fibrillary Acidic Protein in Healthy Individuals and Their Relation to the Brain Parenchymal Fraction

Background

Neurofilament light (NFL) and Glial Fibrillary Acidic Protein (GFAP) are integral parts of the axonal and astrocytal cytoskeletons respectively and are released into the cerebrospinal fluid (CSF) in cases of cellular damage. In order to interpret the levels of these biomarkers in disease states, knowledge on normal levels in the healthy is required. Another biomarker for neurodegeneration is brain atrophy, commonly measured as brain parenchymal fraction (BPF) using magnetic resonance imaging (MRI). Potential correlations between levels of NFL, GFAP and BPF in healthy individuals have not been investigated.

Objectives

To present levels of NFL and GFAP in healthy individuals stratified for age, and investigate the correlation between them as well as their correlation with BPF.

Methods

The CSF was analysed in 53 healthy volunteers aged 21 to 70 (1 sample missing for GFAP analysis) and 48 of the volunteers underwent determination of BPF using MRI.

Results

Mean (±SD) NFL was 355 ng/L (±214), mean GFAP was 421 ng/L (±129) and mean BPF was 0.867 (±0.035). All three biomarkers correlated with age. NFL also correlated with both GFAP and BPF. When controlled for age, only the correlation between NFL and GFAP retained statistical significance.

Conclusions

This study presents data on age-stratified levels of NFL and GFAP in the CSF of healthy individuals. There is a correlation between levels of NFL and GFAP and both increase with age. A correlation between NFL and BPF was also found, but did not retain statistical significance if controlled for age.     

Resolving Anatomical and Functional Structure in Human Brain Organization: Identifying Mesoscale Organization in Weighted Network Representations

Human brain anatomy and function display a combination of modular and hierarchical organization, suggesting the importance of both cohesive structures and variable resolutions in the facilitation of healthy cognitive processes. However, tools to simultaneously probe these features of brain architecture require further development. We propose and apply a set of methods to extract cohesive structures in network representations of brain connectivity using multi-resolution techniques. We employ a combination of soft thresholding, windowed thresholding, and resolution in community detection, that enable us to identify and isolate structures associated with different weights. One such mesoscale structure is bipartivity, which quantifies the extent to which the brain is divided into two partitions with high connectivity between partitions and low connectivity within partitions. A second, complementary mesoscale structure is modularity, which quantifies the extent to which the brain is divided into multiple communities with strong connectivity within each community and weak connectivity between communities. Our methods lead to multi-resolution curves of these network diagnostics over a range of spatial, geometric, and structural scales. For statistical comparison, we contrast our results with those obtained for several benchmark null models. Our work demonstrates that multi-resolution diagnostic curves capture complex organizational profiles in weighted graphs. We apply these methods to the identification of resolution-specific characteristics of healthy weighted graph architecture and altered connectivity profiles in psychiatric disease.     

Differences in Fecal Microbiota in Different European Study Populations in Relation to Age, Gender, and Country: a Cross-Sectional Study

A cross-sectional study on intestinal microbiota composition was performed on 230 healthy subjects at four European locations in France, Germany, Italy, and Sweden. The study participants were assigned to two age groups: 20 to 50 years (mean age, 35 years; n = 85) and >60 years (mean age, 75 years; n = 145). A set of 14 group- and species-specific 16S rRNA-targeted oligonucleotide probes was applied to the analysis of fecal samples by fluorescence in situ hybridization coupled with flow cytometry. Marked country-age interactions were observed for the German and Italian study groups. These interactions were inverse for the predominant bacterial groups Eubacterium rectale-Clostridium coccoides and Bacteroides-Prevotella. Differences between European populations were observed for the Bifidobacterium group only. Proportions of bifidobacteria were two- to threefold higher in the Italian study population than in any other study group, and this effect was independent of age. Higher proportions of enterobacteria were found in all elderly volunteers independent of the location. Gender effects were observed for the Bacteroides-Prevotella group, with higher levels in males than in females. In summary, age-related differences in the microbiota makeup were detected but differed between the study populations from the four countries, each showing a characteristic colonization pattern.     

Sex Differences and Activity of the Left and Right Brain Hemispheres

The problem is reviewed of sex differences and the brain organization of the visual-spatial and verbal-cognitive functions both in adults and in the 5–15-year old children. Characteristic of men are the integral strategy of the face image recognition, specialization of the right hemisphere for visual-spatial functions, and the tonic inhibitory effect of the right hemisphere on the left one. Typical of women are the fragmented type of the image recognition, the equality of the brain hemispheres functions at the unfamiliar face recognition, and predominance of the left hemisphere by accuracy of the object localization in the visual field. It is possible that the general strategy of the recognition in women is not realized due to the right hemisphere submitted to the interfering effect of the left hemisphere. Analysis of sex differences in distribution of verbal functions shows that the capability for the verbal learning at the age of 5 years and older is higher in girls than in boys. Such capability seems to be accounted for by the superiority of the left hemisphere in girls in this type of its activity and by its earlier development and maturation. The phenomenon of semantic paralexia appearing more often in boys is accounted for by inclusion of lexical-semantic fields of the right hemisphere symmetric areas in the verbal-cognitive activity There are reasons to believe that the higher capability in girls for the verbal learning is mainly due to processes of the auditory-verbal integration within the limits of the left hemisphere, whereas this verbal ability in boys depends on the relative predominance of the interhemispheric connections.     

Brain Organization in a Reptile Lacking Sex Chromosomes: Effects of Gonadectomy and Exogenous Testosterone

In mammals, males and females differ both genetically and hormonally, making it difficult to assess the relative contributions of genetic constitution and fetal environment in the process of sexual differentiation. Many reptiles lack sex chromosomes, relying instead on the temperature of incubation to determine sex. In the leopard gecko (Eublepharis macularius), an incubation temperature of 26°C produces all females, whereas 32.5°C results in mostly males. Incubation temperature is the primary determinant of differences both within and between the sexes in growth, physiology, and sociosexual behavior, as well as the volume and metabolic capacity of specific brain nuclei. To determine if incubation temperature organizes the brain directly rather than via gonadal sex hormones, the gonads of male and female leopard geckos from the two incubation temperatures were removed and, in some instances, animals were given exogenous testosterone. In vertebrates with sex chromosomes, the size of sexually dimorphic nuclei are sensitive to hormone levels in adulthood, but in all species studied to date, these changes are restricted to the male. Therefore, after behavior tests, morphometrics of certain limbic and nonlimbic brain areas were determined. Because nervous system tissue depends on oxidative metabolism for energy production and the level of cytochrome oxidase activity is coupled to the functional level of neuronal activity, cytochrome oxidase histochemistry also was performed on the same brains. Hormonal manipulation had little effect on the volume of the preoptic area or ventromedial hypothalamus in geckos from the all-female incubation temperature, but significantly influenced the volumes of these brain areas in males and females from the male-biased incubation temperature. A similar relationship was found for cytochrome oxidase activity of the anterior hypothalamus, amygdala, dorsal ventricular ridge, and septum. The only sex difference observed was found in the ventromedial hypothalamus; males showed no significant changes in cytochrome oxidase activity with hormonal manipulation, but females from both incubation temperatures were affected similarly. The results indicate that incubation temperature organizes the brain directly rather than via hormones arising from its sex-determining function. This is the first demonstration in a vertebrate that factors other than steroid hormones can modify the organization and functional activity of sexually differentiated brain areas.     

Individual Features of Functional Brain Organization in Seven-to-Eight-Year-Old Children with Mental Retardation during the Processing of Visuospatial Information

A complex neuropsychological and electrophysiological analysis of the processing of visuospatial information was carried out in seven-to-eight-year-old mentally retarded children. A neuropsychological examination revealed the children with strong functional immaturity of left- and right-hemispheric structures. An analysis of the EEG parameters showed that specific features of intercentral integration during visuospatial performance in children with mental retardation depend on the type of hemispheric insufficiency. In right-hemispheric immaturity, ensembles of the regions of the left hemisphere become functionally significant, whereas in left-hemispheric immaturity, cortical areas, predominantly of the right hemisphere, become involved in interaction.     

Erratum to: Functional Brain Organization of Global and Local Visual Perception: An Event-Related Potentials Study

Adult subjects were asked to recognize a hierarchical visual stimulus (a letter) while their attention was drawn to either the global or local level of the stimulus. Event-related potentials (ERP) and behavioral indices (reaction time and percentage of correct responses) were measured. An analysis of behavioral indices showed the global level precedence effect, i.e. the increase in a small letter recognition time when this letter is a part of incongruent stimulus. An analysis of ERP components showed level-related (global vs. local) differences in the timing and topography of the brain organization of perceptual processing and regulatory mechanisms of attention. Visual recognition at the local level was accompanied by (1) stronger activation of the visual associative areas (P _z and T ₆) at the stage of sensory features analysis (P1 ERP component), (2) involvement mainly of inferior temporal cortices of the right hemisphere (T ₆) at the stage of sensory categorization (P2 ERP component), and (3) involvement of prefrontal cortex of the right hemisphere at the stage of selection of the relevant features of the target (N2 ERP component). Visual recognition at the global level was accompanied by (1) pronounced involvement of mechanisms of early sensory selection (N1 ERP component), (2) prevailing activation of parietal cortex of the right hemisphere (P ₄) at the stage of sensory categorization (P2 ERP component) as well as at the stage of the target stimulus identification (P3 ERP component). We suggested that perception of the hierarchical stimulus at the global level is related primarily to the analysis of its spatial features in the dorsal visual system whereas the perception at the local level primarily involves an analysis of the object-related features in the ventral visual system.     

Altered Topological Organization of White Matter Structural Networks in Patients with Neuromyelitis Optica

Objective

To investigate the topological alterations of the whole-brain white-matter (WM) structural networks in patients with neuromyelitis optica (NMO).

Methods

The present study involved 26 NMO patients and 26 age- and sex-matched healthy controls. WM structural connectivity in each participant was imaged with diffusion-weighted MRI and represented in terms of a connectivity matrix using deterministic tractography method. Graph theory-based analyses were then performed for the characterization of brain network properties. A multiple linear regression analysis was performed on each network metric between the NMO and control groups.

Results

The NMO patients exhibited abnormal small-world network properties, as indicated by increased normalized characteristic path length, increased normalized clustering and increased small-worldness. Furthermore, largely similar hub distributions of the WM structural networks were observed between NMO patients and healthy controls. However, regional efficiency in several brain areas of NMO patients was significantly reduced, which were mainly distributed in the default-mode, sensorimotor and visual systems. Furthermore, we have observed increased regional efficiency in a few brain regions such as the orbital parts of the superior and middle frontal and fusiform gyri.

Conclusion

Although the NMO patients in this study had no discernible white matter T2 lesions in the brain, we hypothesize that the disrupted topological organization of WM networks provides additional evidence for subtle, widespread cerebral WM pathology in NMO.