Distance-specific functional connectivity strength alterations in human immunodeficiency virus asymptomatic neurocognitive impairment patients: a cross-sectional study.

Background: Asymptomatic neurocognitive impairment (ANI) is the mildest form of human immunodeficiency virus (HIV)-associated neurocognitive disorders (HANDs), and functional connectivity strength (FCS) alternations have been observed in the ANI stage. However, it is not clear whether the FCS alterations are influenced by the anatomical distance. This study sought to investigate distance-specific FCS changes in HIV ANI patients. Methods: In total, 29 patients with HAND and 32 healthy controls (HCs) were enrolled in the study. Between-group differences were detected for short, middle and long range anatomical distance FCS. A correlation analysis was performed to examine the relationship between distance-specific FCS and immunological parameters and neuropsychological tests. A receiver operating characteristic (ROC) analysis was conducted to examine the discriminative performance for HIV ANI patients. Results: In comparison to the HCs, the HAND patients showed increased short-range FCS in the left inferior parietal lobule (IPL), middle-range FCS in the superior temporal gyrus (STG), long-range FCS in the left precuneus (PCC), and decreased FCS in the right postcentral gyrus (PCG) (cluster P<0.05, voxel significance P<0.001). Further, the long-range FCS in the right PCG was negatively correlated with the CD4/CD8 ratio (r=-0.479, 95% confidence interval (CI): -0.735 to -0.104, P=0.015), and the distance-specific FCS also showed good classification performance between the HAND patients and HCs. The left IPL, left STG, right PCG, and left PCC had areas under the curve (AUCs) of 0.875 [95% confidence interval (CI): 0.758-0.949, P<0.0001], 0.806 (95% CI: 0.677-0.900, P<0.0001), 0.855 (95% CI: 0.734-0.935, P<0.0001), and 0.852 (95% CI: 0.754-0.950, P<0.0001), respectively. There was no significant relationship between the distance-specific FCS and the neuropsychological tests. Conclusions: Distance-specific FCS could be used to examine subtle alternations in HIV-infected patients in the ANI stage and help to explain the possible neurophysiological mechanism of HAND.

Single-subject cortical morphological brain networks across the adult lifespan.

Age-related changes in focal cortical morphology have been well documented in previous literature; however, how interregional coordination patterns of the focal cortical morphology reorganize with advancing age is not well established. In this study, we performed a comprehensive analysis of the topological changes in single-subject morphological brain networks across the adult lifespan. Specifically, we constructed four types of single-subject morphological brain networks for 650 participants (aged from 18 to 88 years old), and characterized their topological organization using graph-based network measures. Age-related changes in the network measures were examined via linear, quadratic, and cubic models. We found profound age-related changes in global small-world attributes and efficiency, local nodal centralities, and interregional similarities of the single-subject morphological brain networks. The age-related changes were mainly embodied in cortical thickness networks, involved in frontal regions and highly connected hubs, concentrated on short-range connections, characterized by linear changes, and susceptible to connections between limbic, frontoparietal, and ventral attention networks. Intriguingly, nonlinear (i.e., quadratic or cubic) age-related changes were frequently found in the insula and limbic regions, and age-related cubic changes preferred long-range morphological connections. Finally, we demonstrated that the morphological similarity in cortical thickness between two frontal regions mediated the relationship between age and cognition measured by Cattell scores. Taken together, these findings deepen our understanding of adaptive changes of the human brain with advancing age, which may account for interindividual variations in behaviors and cognition.

Verification of propagation hypothesis in patients with sporadic hand onset amyotrophic lateral sclerosis.

OBJECTIVE: If lesions in sporadic amyotrophic lateral sclerosis (ALS) originate from a single focal onset site and spread contiguously by prion-like cell-to-cell propagation at a constant speed, the lesion spread time should be proportional to the anatomical distance. We verify this model in the patients. METHODS: In 29 sporadic ALS patients with hand onset followed by spread to shoulder and leg, we retrospectively evaluated the inter/intra-regional spread time ratio: time interval of symptoms from hand-to-leg divided by that from hand-to-shoulder. We also obtained the corresponding inter-/intra-regional distance ratios of spinal cord from magnetic resonance imaging of 12 patients, and those of primary motor cortex from coordinates using neuroimaging software. RESULTS: Inter-/intra-regional spread time ratios ranged from 0.29 to 6.00 (median 1.20). Distance ratios ranged from 1.85 to 2.86 in primary motor cortex and from 5.79 to 8.67 in spinal cord. Taken together with clinical manifestations, of 27 patients with the requisite information available, lesion spreading was consistent with the model in primary motor cortex in 4 (14.8%) patients, and in spinal cord in only 1 (3.7%) patient. However, in more patients (12 of 29 patients: 41.4%), the inter-regional spread times in a long anatomical distance of hand-to-leg were shorter than or equal to the intra-regional spread times in a short anatomical distance of hand-to-shoulder. CONCLUSION: Contiguous cell-to-cell propagation at a constant speed might not play a major role at least in distant lesion spreading of ALS. Several mechanisms can be responsible for progression in ALS.

Anatomical distance affects functional connectivity at rest in medicine-free obsessive-compulsive disorder.

BACKGROUND: Brain functional abnormalities at rest have been observed in obsessive-compulsive disorder (OCD). However, whether and how anatomical distance influences functional connectivity (FC) at rest is ambiguous in OCD. METHODS: Using resting-state functional magnetic resonance imaging data, we calculated the FC of each voxel in the whole-brain and divided FC into short- and long-range FCs in 40 medicine-free patients with OCD and 40 healthy controls (HCs). A support vector machine (SVM) was used to determine whether the altered short- and long-range FCs could be utilized to distinguish OCD from HCs. RESULTS: Patients had lower short-range positive FC (spFC) and long-range positive FC (lpFC) in the left precentral/postcentral gyrus (t = -5.57 and -5.43; P < 0.05, GRF corrected) and higher lpFC in the right thalamus/caudate, left thalamus, left inferior parietal lobule (IPL) and left cerebellum CrusI/VI (t = 4.59, 4.61, 4.41, and 5.93; P < 0.05, GRF corrected). Furthermore, lower spFC in the left precentral/postcentral gyrus might be used to distinguish OCD from HCs with an accuracy of 80.77%, a specificity of 81.58%, and a sensitivity of 80.00%. CONCLUSION: These findings highlight that anatomical distance has an effect on the whole-brain FC patterns at rest in OCD. Meanwhile, lower spFC in the left precentral/postcentral gyrus might be applied in distinguishing OCD from HCs.

Enhanced positive functional connectivity strength in left-sided chronic subcortical stroke.

Patients with stroke often exhibit evidence of abnormal functional connectivity (FC). However, whether and how anatomical distance affects FC at rest remains unclear in patients with chronic subcortical stroke. Eighty-six patients with chronic (more than six months post-onset) subcortical stroke (44 left-sided patients and 42 right-sided patients) with different degrees of functional recovery, and 75 matched healthy controls underwent resting-state functional magnetic resonance imaging scanning. Positive functional connectivity strength (FCS) was computed for each voxel in the brain using a data-driven whole-brain resting state FCS method, which was further divided into short- and long-range FCS. Compared with healthy controls, patients with left-sided infarctions exhibited stronger global- and long-range FCS in the left sensorimotor cortex (SMC), and no significant intergroup difference was found for short-range FCS. No significant differences were found between the patients with right-sided infarctions and healthy controls for global, long- and short-range FCS. These findings suggested that the positive FCS alteration was connection-distance dependent within patients with left-sided chronic subcortical stroke. Also, a positive correlation was found between the FCS in the left SMC and the accuracy of the Flanker test, reflecting a compensatory FCS alteration for altered attention and executive function abilities exhibited by those with left-sided stroke.

Brain networks modeling for studying the mechanism underlying the development of Alzheimer's disease.

Alzheimer's disease is a primary age-related neurodegenerative disorder that can result in impaired cognitive and memory functions. Although connections between changes in brain networks of Alzheimer's disease patients have been established, the mechanisms that drive these alterations remain incompletely understood. This study, which was conducted in 2018 at Northeastern University in China, included data from 97 participants of the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset covering genetics, imaging, and clinical data. All participants were divided into two groups: normal control (n = 52; 20 males and 32 females; mean age 73.90 ± 4.72 years) and Alzheimer's disease (n = 45, 23 males and 22 females; mean age 74.85 ± 5.66). To uncover the wiring mechanisms that shaped changes in the topology of human brain networks of Alzheimer's disease patients, we proposed a local naïve Bayes brain network model based on graph theory. Our results showed that the proposed model provided an excellent fit to observe networks in all properties examined, including clustering coefficient, modularity, characteristic path length, network efficiency, betweenness, and degree distribution compared with empirical methods. This proposed model simulated the wiring changes in human brain networks between controls and Alzheimer's disease patients. Our results demonstrate its utility in understanding relationships between brain tissue structure and cognitive or behavioral functions. The ADNI was performed in accordance with the Good Clinical Practice guidelines, US 21CFR Part 50-Protection of Human Subjects, and Part 56-Institutional Review Boards (IRBs)/Research Good Clinical Practice guidelines Institutional Review Boards (IRBs)/Research Ethics Boards (REBs).

Brain Network Modeling Based on Mutual Information and Graph Theory for Predicting the Connection Mechanism in the Progression of Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive disease that causes problems of cognitive and memory functions decline. Patients with AD usually lose their ability to manage their daily life. Exploring the progression of the brain from normal controls (NC) to AD is an essential part of human research. Although connection changes have been found in the progression, the connection mechanism that drives these changes remains incompletely understood. The purpose of this study is to explore the connection changes in brain networks in the process from NC to AD, and uncovers the underlying connection mechanism that shapes the topologies of AD brain networks. In particular, we propose a mutual information brain network model (MINM) from the perspective of graph theory to achieve our aim. MINM concerns the question of estimating the connection probability between two cortical regions with the consideration of both the mutual information of their observed network topologies and their Euclidean distance in anatomical space. In addition, MINM considers establishing and deleting connections, simultaneously, during the networks modeling from the stage of NC to AD. Experiments show that MINM is sufficient to capture an impressive range of topological properties of real brain networks such as characteristic path length, network efficiency, and transitivity, and it also provides an excellent fit to the real brain networks in degree distribution compared to experiential models. Thus, we anticipate that MINM may explain the connection mechanism for the formation of the brain network organization in AD patients.

Abnormal long- and short-range functional connectivity in adolescent-onset schizophrenia patients: A resting-state fMRI study.

BACKGROUND: Human brain is a topologically complex network embedded in anatomical space, and anatomical distance may affect functional connectivity (FC) in schizophrenia. However, little is known if and how this effect occurs in adolescent-onset schizophrenia (AOS). METHODS: We explored long- and short-range FC through resting-state functional magnetic resonance imaging in 48 first-episode, drug-naive AOS patients and 31 healthy controls, and we examined if these abnormalities could be utilized to separate patients from controls using receiver operating characteristic curves and support vector machines (SVM). RESULTS: Patients had increased long-range positive FC (lpFC) and short-range positive FC (spFC) in the right middle frontal gyrus and right superior medial prefrontal cortex within the anterior default mode network (DMN), decreased lpFC and spFC in several regions of the posterior DMN, and decreased lpFC within the important hubs of salience network (SN). The decreased lpFC in the left superior temporal gyrus was positively correlated with cognitive impairment. We found that SVM has high accuracy (up to 92.4%) in classifying patients and control. CONCLUSION: Disrupted anatomical distance would underlie network-level dysconnectivity, highlighting the importance of the DMN and SN in the neurodevelopment of schizophrenia. Abnormalities of long- and short-range FC in brain regions could discriminate patients from controls with high accuracy.

Anatomical distance affects cortical-subcortical connectivity in first-episode, drug-naive somatization disorder.

BACKGROUND: Brain structural and functional alterations in the cortical-subcortical circuits have been observed in somatization disorder (SD). However, whether and how anatomical distance affects the cortical-subcortical connectivity in SD remain unclear. This study aims to examine whether anatomical distance affects the cortical-subcortical in first-episode, drug-naive SD. METHODS: Twenty-five first-episode, drug-naive patients with SD and twenty-eight healthy controls were recruited for a resting-state scan. Regional functional connectivity strength (FCS) was calculated for each voxel in the brain, which was further divided into short- and long-range FCSs. Correlation analyses were conducted between abnormal FCS and clinical/cognitive variables in the patients. RESULTS: Compared with the controls, the patients showed increased short-range positive FCS (spFCS) in the right superior frontal gyrus (SFG) and decreased spFCS in the left pallidum, and increased long-range positive FCS (lpFCS) in the left middle frontal gyrus and right inferior temporal gyrus (ITG). Positive correlations were observed between the spFCS values in the right SFG and Eysenck Personality Questionnaire psychoticism scores (r=0.441, p=0.027, uncorrected) and between the lpFCS values in the right ITG and scores of digit symbol-coding of Wechsler Adult Intelligence Scale (r=0.416, p=0.039, uncorrected) in the patients CONCLUSIONS: The patients exhibited increased spFCS/lpFCS in the cortical regions and decreased spFCS in the subcortical regions. The left pallidum is first reported here to show decreased spFCS in SD. The present results suggest that abnormal cortical-subcortical circuits may play an important role in SD neurobiology.

Olanzapine modulation of long- and short-range functional connectivity in the resting brain in a sample of patients with schizophrenia.

Treatment effects of antipsychotic drugs on cerebral function are seldom examined. Exploring functional connectivity (FC) in drug-free schizophrenia patients before and after antipsychotic treatment can improve the understanding of antipsychotic drug mechanisms. A total of 17 drug-free patients with recurrent schizophrenia and 24 healthy controls underwent resting-state functional magnetic resonance imaging scans. Long- and short-range FC strengths (FCS) were calculated for each participant. Compared with the controls, the patients at baseline exhibited increased long-range positive FCS (lpFCS) in the bilateral inferior parietal lobule (IPL) and decreased lpFCS in the brain regions of the default-mode network (DMN) regions and sensorimotor circuits of the brain. By contrast, increased short-range positive FCS was observed in the right IPL of the patients at baseline compared with the controls. After treatment with olanzapine, increased FC in the DMN and sensorimotor circuits of the brain was noted, whereas decreased FC was observed in the left superior temporal gyrus (STG). Moreover, the alterations of the FCS values and the reductions in symptom severity among the patients after treatment were correlated. The present study provides evidence that olanzapine normalizes the abnormalities of long- and short-range FCs in schizophrenia. FC reductions in the right IPL may be associated with early treatment response, whereas those in the left STG may be related to poor treatment outcome.

Decreased long- and short-range functional connectivity at rest in drug-naive major depressive disorder.

BACKGROUND: Abnormal functional connectivity has been observed in major depressive disorder. Anatomical distance may affect functional connectivity in patients with major depressive disorder. However, whether and how anatomical distance affects functional connectivity at rest remains unclear in drug-naive patients with major depressive disorder. METHODS: Forty-four patients with major depressive disorder, as well as 44 age-, sex- and education-matched healthy controls, underwent resting-state functional magnetic resonance imaging scanning. Regional functional connectivity strength was calculated for each voxel in the whole brain, which was further divided into short- and long-range functional connectivity strength. RESULTS: The patients showed decreased long-range positive functional connectivity strength in the right inferior parietal lobule, as well as decreased short-range positive functional connectivity strength in the right insula and right superior temporal gyrus relative to those of the controls. No significant correlations existed between abnormal functional connectivity strength and the clinical variables of the patients. CONCLUSION: The findings revealed that anatomical distance decreases long- and short-range functional connectivity strength in patients with major depressive disorder, which may underlie the neurobiology of major depressive disorder.

Increased short-range and long-range functional connectivity in first-episode, medication-naive schizophrenia at rest.

OBJECTIVE: Schizophrenia is conceived as a disconnection syndrome and anatomical distance may affect functional connectivity (FC) in schizophrenia patients. However, whether and how anatomical distance affects FC remains unclear in first-episode, medication-naive schizophrenia at rest. METHODS: Forty-nine schizophrenia patients and 50 age-, sex-, and education-matched healthy controls underwent resting-state functional magnetic resonance imaging scanning. Regional FC strength was computed for each voxel in the brain, which was further divided into short-range and long-range FC strength. RESULTS: The patients exhibited increased short-range positive FC strength in the left superior medial frontal gyrus, and increased long-range positive FC strength in the right angular gyrus and bilateral posterior cingulate cortex (PCC)/precuneus compared with the controls. Further seed-based FC analysis showed that the left superior medial frontal gyrus had increased short-range FC with the right inferior frontal gyrus, while the right angular gyrus and bilateral PCC/precuneus had increased long-range FC with the prefrontal gyrus. No significant correlation was observed between abnormal FC strength and clinical variables in the patient group. CONCLUSIONS: The findings reveal a pattern of increased anatomical distance affecting FC in the patients, with the results of increased short-range positive FC strength in the anterior default-mode network (DMN) and increased long-range positive FC strength in the posterior DMN in schizophrenia, and highlight the importance of the DMN in the neurobiology of schizophrenia.

Anatomical distance affects functional connectivity in patients with schizophrenia and their siblings.

BACKGROUND: The efficiency of human brain depends on the integrity of both long- and short-range connections, but the long-range connections need to be "penalized" to reduce overall wiring costs. This principle, termed as the anatomical distance function (ADF), refers to the presence of an inverse relationship between anatomical distance and connectivity. A crucial developmental feature that occurs in normal adolescence is the weakening of ADF, which is characterized by a selective strengthening of long-distance connections. Schizophrenia is associated with widespread dysconnectivity that is linked to aberrant cortical development. METHODS: We studied the ADF in adults with schizophrenia (n = 28), their age-matched siblings (n = 28), and healthy controls (n = 60). We investigated the proportional abnormalities in the long-range connections involving interhemispheric, subcortical, frontal, and salience network regions and localized the connections showing most significant changes in schizophrenia. The groups were discriminated on the basis of short- and long-range connectivity using a machine-learning algorithm. RESULTS: Both patients and their siblings showed abnormally pronounced ADF. This was associated with a disproportionate reduction in the number of long-range connections, affecting the subcortical, interhemispheric, and the salience network connections. The abnormalities in long-range connections had superior ability to accurately identify group membership. CONCLUSIONS: A crucial organizing principle of the brain architecture that becomes apparent during normal adolescence is disturbed in schizophrenia. While siblings show some evidence of compensating for this deficit, patients lack putative compensatory changes. Age-related shift in ADF provides an explanatory framework for the developmental emergence of widespread dysconnectivity that is influenced by genetic risk in schizophrenia.

The trade-off between wiring cost and network topology in white matter structural networks in health and migraine.

The human brain organization of cortical networks has optimized trade-off architecture for the economical minimization of connection distance and maximizing valuable topological properties; however, whether this network configuration is disrupted in chronic migraine remains unknown. Here, employing the diffusion tensor imaging and graph theory approaches to construct white matter networks in 26 patients with migraine (PM) and 26 gender-matched healthy controls (HC), we investigated relationships between structural connectivity, cortical network architecture and anatomical distance in the two groups separately. Compared with the HC group, the patients showed longer global distance connection in PM, with proportionally less short-distance and more medium-distance; correspondingly, the patients showed abnormal global topology in their structural networks, mainly presented as a higher clustering coefficient. Moreover, the abnormal association between these two network features was also found. Intriguingly, the network measure that combined the nodal anatomical distance and network topology could distinguish PM from HC with high accuracy of 90.4%. We also demonstrated a high reproducibility of our findings across different parcellation schemes. Our results demonstrated that long-term migraine may result in a abnormal optimization of a trade-off between wiring cost and network topology in white matter structural networks and highlights the potential for combining spatial and topological aspects as a network marker, which may provide valuable insights into the understanding of brain network reorganization that could be attributed to the underlying pathophysiology resulting from migraine.