Identifying left and right hemispheres using functional connectivity

The human entorhinal-hippocampal circuitry is characterized by an information-specific functional organization where two routes, that are preferentially connected to the parahippocampal cortex or the perirhinal and retrosplenial cortices, divide the entorhinal cortex as well as hippocampal subiculum and CA1 subregions.

Reading is of enormous importance in our modern information-based society and an essential activity in everyday life. While most children successfully learn to read within a few years, reading acquisition is severely impaired in about 5-10% of children, resulting in a specific reading disorder called “developmental dyslexia”. One of the core deficits of individuals with dyslexia is impaired automatic word recognition, which leads to slow, dysfluent reading. Neuroimaging studies in adult readers have linked this orthographic processing deficit to deficits in a specific section of the left occipitotemporal cortex (the visual word form area; VWFA) involved in visual word processing. However, the exact function of the VWFA and the larger left occipitotemporal VWF-system in healthy children, as well as its dysfunctioning in dyslexic children is still unclear. In addition, since the VWF-system and its core region (the VWFA) are part of the typical language network that encompasses several other regions crucially involved in reading, there is considerable interest in examining the connectivity between those brain areas. This Ph.D. thesis aimed to investigate both the function and functional connectivity comparing control children and children with dyslexia. In Study A we examined (i) two levels of functional specialization of visual word processing − (a) coarse specialization for print and (b) sensitivity to orthographic familiarity of letter strings − in the left occipitotemporal VWFsystem in control children, and (ii) whether these types of specialization were impaired in children with dyslexia. In Study B we investigated (i) the functional connectivity of the VWF-system and other major components of the language network in control children, and (ii) whether these connections were different in dyslexic children. We tested 18 dyslexic and 24 age-matched control children (age 9.7- 12.5 years) while they indicated if visual stimuli (real words, pseudohomophones, pseudowords and false-fonts) sounded like a real word. Five adjacent regions of interest (ROIs) in the bilateral occipitotemporal cortex were selected to cover the full anterior-posterior extent of the VWFsystem. In Study A, we used functional MRI to assess the brain activity in response to four types of visual letter strings varying in orthographic familiarity. In Study B, we used functional connectivity MRI to examine interregional cooperation within the language network, focussing on the VWFA. The results from Study A revealed that control children show a dissociation of two functional levels of specialization within the VWF-system: (1) coarse specialization for print, i.e. different processing of letter strings than of visual control stimuli and (2) sensitivity to orthographic familiarity of letter strings. Furthermore, we showed that both of these functional levels of VWF-system specialization could not be detected in children with dyslexia in the entire VWF-system. To answer the question whether this functional impairment of the VWF-system is associated with impaired cooperation of this system with other language areas, we looked at the functional connectivity of these regions. The results from Study B revealed that, in control children, the functional connections with typical language areas (left inferior parietal lobule and left inferior frontal gyrus) were specific for the VWFA and did not generalize to left occipitotemporal regions neighbouring the VWFA. In addition, we demonstrated that these functional connections between the VWFA and other major language areas are disrupted in children with dyslexia, whereas those of neighbouring areas were not affected. The results of both studies reveal an impairment of both function (of the VWF-system) and functional connectivity (of the VWFA with left inferior parietal and inferior frontal cortex) in dyslexic children. In conclusion, the findings presented in this work demonstrate that (1) word processing deficits in dyslexic children are associated with a pervasive developmental dysfunction of the entire VWF-system, and that (2) brain regions necessary for fluent, skilled reading may not work together properly during reading.

Unprecedented 4D spatiotemporal infant regional cerebral blood flow framework and region-specific physiology–function coupling across infancy were elucidated, highlighting strong physiology–function coupling specifically at the default-mode network to meet extraneuronal metabolic demand for network emergence.

Developmental malformations (dysgenesis) of the corpus callosum lead to neurological conditions with a broad range of clinical presentations. Investigating the altered brain connectivity patterns is crucial to understanding both adaptive and maladaptive neuroplasticity in corpus callosum dysgenesis patients. Here, we acquired structural diffusion-weighted and resting-state functional MRI data from a cohort of 11 corpus callosum dysgenesis patients (five with agenesis and six with hypoplasia) and compared their structural and functional connectivity patterns to healthy subjects selected from the Human Connectome Project. We found that these patients have fewer structural inter- and intra-hemispheric brain connections relative to healthy controls. Interestingly, the patients with callosal agenesis have a scant number of inter-hemispheric connections but manage to maintain the full integrity of functional connectivity between the same cortical regions as the healthy subjects. On the other hand, the hypoplasic group presented abnormal structural and functional connectivity patterns relative to healthy controls while maintaining the same total amount of functional connections. These results demonstrate that acallosal patients can compensate for having fewer structural brain connections and present functional adaptation. However, hypoplasics present atypical structural connections to different brain regions, leading to entirely new and abnormal functional brain connectivity patterns.

The pathogenesis of Alzheimer's disease (AD) remains unclear, but revealing individual differences in functional connectivity (FC) may provide insights and improve diagnostic precision. A hierarchical clustering-based autoencoder with functional connectivity was proposed to categorize 82 AD patients from the Alzheimer's Disease Neuroimaging Initiative. Compared to directly performing clustering, using an autoencoder to reduce the dimensionality of the matrix can effectively eliminate noise and redundant information in the data, extract key features, and optimize clustering performance. Subsequently, subtype differences in clinical and graph theoretical metrics were assessed. Results indicate a significant inter-subject heterogeneity in the degree of FC disruption among AD patients. We have identified two neurophysiological subtypes: subtype I exhibits widespread functional impairment across the entire brain, while subtype II shows mild impairment in the Limbic System region. What is worth noting is that we also observed significant differences between subtypes in terms of neurocognitive assessment scores associations with network functionality, and graph theory metrics. Our method can accurately identify different functional disruptions in subtypes of AD, facilitating personalized treatment and early diagnosis, ultimately improving patient outcomes.

The contribution of structural connectivity to functional brain states remains poorly understood. We present a mathematical and computational study suited to assess the structure–function issue, treating a system of Jansen–Rit neural mass nodes with heterogeneous structural connections estimated from diffusion MRI data provided by the Human Connectome Project. Via direct simulations we determine the similarity of functional (inferred from correlated activity between nodes) and structural connectivity matrices under variation of the parameters controlling single-node dynamics, highlighting a nontrivial structure–function relationship in regimes that support limit cycle oscillations. To determine their relationship, we firstly calculate network instabilities giving rise to oscillations, and the so-called ‘false bifurcations’ (for which a significant qualitative change in the orbit is observed, without a change of stability) occurring beyond this onset. We highlight that functional connectivity (FC) is inherited robustly from structure when node dynamics are poised near a Hopf bifurcation, whilst near false bifurcations, and structure only weakly influences FC. Secondly, we develop a weakly coupled oscillator description to analyse oscillatory phase-locked states and, furthermore, show how the modular structure of FC matrices can be predicted via linear stability analysis. This study thereby emphasises the substantial role that local dynamics can have in shaping large-scale functional brain states.

Neuroimaging studies, such as the Human Connectome Project (HCP), often collect multifaceted data to study the human brain. However, these data are often analyzed in a pairwise fashion, which can hinder our understanding of how different brain-related measures interact. In this study, we analyze the multi-block HCP data using data integration via analysis of subspaces (DIVAS). We integrate structural and functional brain connectivity, substance use, cognition, and genetics in an exhaustive five-block analysis. This gives rise to the important finding that genetics is the single data modality most predictive of brain connectivity, outside of brain connectivity itself. Nearly 14% of the variation in functional connectivity (FC) and roughly 12% of the variation in structural connectivity (SC) is attributed to shared spaces with genetics. Moreover, investigations of shared space loadings provide interpretable associations between particular brain regions and drivers of variability. Novel Jackstraw hypothesis tests are developed for the DIVAS framework to establish statistically significant loadings. For example, in the (FC, SC, and substance use) subspace, these novel hypothesis tests highlight largely negative functional and structural connections suggesting the brain's role in physiological responses to increased substance use. Our findings are validated on genetically relevant subjects not studied in the main analysis.

Brain Connectivity: A Journal of Clinical Neurology, Neuroscience, and Neuroimaging Advancing the Field of Neurology.

Connectomics Sheds New Light on Alzheimer’s Disease

Hitting the Target of Image-Guided Psychiatry?

Depression is associated with poor sleep quality. Understanding the neural connectivity that underlies both conditions and mediates the association between them is likely to lead to better-directed treatments for depression and associated sleep problems. To identify the brain areas that mediate the association of depressive symptoms with poor sleep quality and advance understanding of the differences in brain connectivity in depression. This study collected data from participants in the Human Connectome Project using the Adult Self-report of Depressive Problems portion of the Achenbach Adult Self-Report for Ages 18-59, a survey of self-reported sleep quality, and resting-state functional magnetic resonance imaging. Cross-validation of the sleep findings was conducted in 8718 participants from the UK Biobank. Correlations between functional connectivity, scores on the Adult Self-Report of Depressive Problems, and sleep quality. A total of 1017 participants from the Human Connectome Project (of whom 546 [53.7%] were female; age range, 22 to 35 years) drawn from a general population in the United States were included. The Depressive Problems score was positively correlated with poor sleep quality (r = 0.371; P < .001). A total of 162 functional connectivity links involving areas associated with sleep, such as the precuneus, anterior cingulate cortex, and the lateral orbitofrontal cortex, were identified. Of these links, 39 were also associated with the Depressive Problems scores. The brain areas with increased functional connectivity associated with both sleep and Depressive Problems scores included the lateral orbitofrontal cortex, dorsolateral prefrontal cortex, anterior and posterior cingulate cortices, insula, parahippocampal gyrus, hippocampus, amygdala, temporal cortex, and precuneus. A mediation analysis showed that these functional connectivities underlie the association of the Depressive Problems score with poor sleep quality (β = 0.0139; P < .001). The implication of these findings is that the increased functional connectivity between these brain regions provides a neural basis for the association between depression and poor sleep quality. An important finding was that the Depressive Problems scores in this general population were correlated with functional connectivities between areas, including the lateral orbitofrontal cortex, cingulate cortex, precuneus, angular gyrus, and temporal cortex. The findings have implications for the treatment of depression and poor sleep quality.

Background: Left-handed individuals may experience performance disadvantages in right-hand-oriented environments; however, these circumstances could also foster adaptability, potentially leading to greater executive function. Switching ability, a component of executive function, reflects flexibility in adjusting to environmental changes. Prior research on left-handers' executive function has yielded inconsistent results. Additionally, many tests have not controlled for confounding factors, such as attention, sequencing, and motor processes. Purpose: Accordingly, the present study aimed to examine differences in executive function between left- and right-handed participants while controlling for significant confounding factors. Research Design: A cross-sectional comparative design was employed. Study Sample: The participants included 25 right-handed and 26 left-handed individuals. Data Collection and/or Analysis: The present study used the Delis-Kaplan Executive Function System (D-KEFS) Trail Making Test (TMT) to examine differences in executive function between left- and right-handed participants. Results: It was hypothesized that handedness would significantly influence performance, with left-handers demonstrating superior switching ability compared with right-handers. Results revealed significant differences in sequencing errors on TMT Condition 4, with right-handed participants making fewer errors than left-handed participants, whose higher error rates suggest disadvantaged switching abilities. Furthermore, left-handed participants were more likely to commit specific number and letter sequencing errors, which may have been influenced by the interaction of impulsivity with stimulus-response incompatibility, biomechanical inefficiency, and attentional or scanning bias. Conclusions: These findings suggest that left-handed participants may demonstrate relatively disadvantaged switching abilities under the tested conditions, potentially influenced by multiple interacting cognitive and motor factors.

Differences in corticocerebral structure and function between males and females and their effects on behavior and the prevalence of various neuropsychiatric disorders have been considered as a fundamental topic in various fields of neuroscience. Recent studies on working memory (WM) reported the impact of sex on brain connectivity patterns, which reflect the important role of functional connectivity in the sex topic. Working memory, one of the most important cognitive tasks performed by regions of the PFC, can provide evidence regarding the presence of a difference between males and females. The present study aimed to assess sex differences in brain functional connectivity during working memory-related tasks by using functional near-infrared spectroscopy (fNIRS). In this regard, nine males and nine females completed a dual n-back working memory task with two target inputs of color and location stimuli in three difficulty levels (n = 0, 1, 2). Functional connectivity matrices were extracted for each subject for each memory load level. Females made less errors than males while spending more time performing the task for all workload levels except in 0-back related to the color stimulus, where the reaction time of females was shorter than males. The results of functional connectivity reveal the inverse behavior of two hemispheres at different memory workload levels between males and females. In the left hemisphere, males exhibited stronger connectivity compared to the females, while stronger connectivity was observed in the females' right hemisphere. Furthermore, an inverse trend was detected in the channel pairs with significant connectivity in the right hemisphere of males (falling) and females (rising) by enhancing working memory load level. Considering both behavioral and functional results for two sexes demonstrated a better performance in females due to the more effective use of the brain. The results indicate that sex affects functional connectivity between different areas in both hemispheres of the brain during cognitive tasks of varying difficulty levels although the general impression is that spatial capabilities are considered as a performance of the brain's right hemisphere. These results reinforce the presence of a sex effect in the functional imaging studies of hemodynamic function and emphasize the importance of evaluating brain network connectivity for achieving a better scientific understanding of sex differences.

We report on the functional connectivity (FC), its intraclass correlation (ICC), and heritability among 70 areas of the human cerebral cortex. FC was estimated as the Pearson correlation between averaged prewhitened Blood Oxygenation Level-Dependent time series of cortical areas in 988 young adult participants in the Human Connectome Project. Pairs of areas were assigned to three groups, namely homotopic (same area in the two hemispheres), ipsilateral (both areas in the same hemisphere), and heterotopic (nonhomotopic areas in different hemispheres). ICC for each pair of areas was computed for six genetic groups, namely monozygotic (MZ) twins, dizygotic (DZ) twins, singleton siblings of MZtwins (MZsb), singleton siblings of DZ twins (DZsb), non-twin siblings (SB), and unrelated individuals (UNR). With respect to FC, we found the following. (a) Homotopic FC was stronger than ipsilateral and heterotopic FC; (b) average FCs of left and right cortical areas were highly and positively correlated; and (c) FC varied in a systematic fashion along the anterior-posterior and inferior-superior dimensions, such that it increased from anterior to posterior and from inferior to superior. With respect to ICC, we found the following. (a) Homotopic ICC was significantly higher than ipsilateral and heterotopic ICC, but the latter two did not differ significantly from each other; (b) ICC was highest for MZ twins; (c) ICC of DZ twins was significantly lower than that of the MZ twins and higher than that of the three sibling groups (MZsb, DZsb, SB); and (d) ICC was close to zero for UNR. Finally, with respect to heritability, it was highest for homotopic areas, followed by ipsilateral, and heterotopic; however, it did not differ statistically significantly from each other.

In contradiction to the crossing of all retinal fibers in the lateral-eye species, the retinal fibers of binocular vision in frontal-eye species run either ipsilaterally or cross the midline twice to terminate the ipsilateral cerebral hemisphere.[1][1] It is hypothesized that carrying separated