Global-brain FC Research Articles

Correlations between alterations in global brain functional connectivity in patients with major depressive disorder and their genetic characteristics

This study aims to elucidate the neuroimaging changes associated with major depressive disorder (MDD) and their relationship with genetic characteristics. We conducted a global-brain functional connectivity (GFC) and genetic-neuroimaging correlation analysis on 42 MDD patients and 42 healthy controls (HCs), exploring the correlation between GFC abnormalities and clinical variables. Results showed that compared to HCs, MDD patients had significantly decreased GFC values in the bilateral posterior cingulate cortex/precuneus and increased GFC values in the left and right cerebellum Crus I/II. Additionally, a negative correlation was observed between the GFC values of the left cerebellum Crus I/II and subjective support scores, as well as social support revalued scale total scores. We identified genes associated with GFC changes in MDD, which are enriched in biological processes such as synaptic transmission and ion transport. Our findings indicate the presence of abnormal GFC values in severe depression, complementing the pathological research on the condition. Furthermore, this study provides preliminary evidence for the correlation between social support levels and brain functional connectivity, offering insights into the potential association between GFC changes and gene expression in MDD patients.

Global-brain functional connectivity related with trait anxiety and its association with neurotransmitters and gene expression profiles

BackgroundNumerous studies have explored the neural correlates of trait anxiety, a predisposing factor for several stress-related disorders. However, the findings from previous studies are inconsistent, which might be due to the limited regions of interest (ROI). A recent approach, named global-brain functional connectivity (GBC), has been demonstrated to address the shortcomings of ROI-based analysis. Furthermore, research on the transcriptome–connectome association has provided an approach to link the microlevel transcriptome profile with the macroscale brain network. In this paper, we aim to explore the neurobiology of trait anxiety with an imaging transcriptomic approach using GBC, biological neurotransmitters, and transcriptome profiles. MethodsUsing a sample of resting-state fMRI data, we investigated trait anxiety-related alteration in GBC. We further used behavioral analysis, spatial correlation analysis, and postmortem gene expression to separately assess the cognitive functions, neurotransmitters, and transcriptional profiles related to alteration in GBC in individuals with trait anxiety. ResultsGBC values in the ventromedial prefrontal cortex and the precuneus were negatively correlated with levels of trait anxiety. This alteration was correlated with behavioral terms including social cognition, emotion, and memory. A strong association was revealed between trait anxiety-related alteration in GBC and neurotransmitters, including dopaminergic, serotonergic, GABAergic, and glutamatergic systems in the ventromedial prefrontal cortex and the precuneus. The transcriptional profiles explained the functional connectivity, with correlated genes enriched in transmembrane signaling. LimitationsSeveral limitations should be taken into account in this research. For example, future research should consider using some different approaches based on dynamic or task-based FC analysis, include more neurotransmitter receptors, additional gene expression data from different samples or more genes related to other stress-related disorders. Meanwhile, it is of great significance to include a larger sample size of individuals with a diagnosis of MDD or other disorders for analysis and comparison and apply stricter multiple-comparison correction and threshold settings in future research. ConclusionsOur research employed multimodal data to investigate GBC in the context of trait anxiety and to establish its associations with neurotransmitters and transcriptome profiles. This approach may improve understanding of the neural mechanism, together with the biological and molecular genetic foundations of GBC in trait anxiety.

Global Functional Connectivity Analysis Indicating Dysconnectivity of the Hate Circuit in Major Depressive Disorder.

BackgroundAbnormalities of functional connectivity (FC) in certain brain regions are closely related to the pathophysiology of major depressive disorder (MDD). Findings are inconsistent with different presuppositions in regions of interest. Our research focused on voxel-wise brain-wide FC changes in patients with MDD in an unbiased manner.MethodWe examined resting-state functional MRI in 23 patients with MDD and 26 healthy controls. Imaging data were analyzed by using global-brain FC (GFC) and used to explore the correlation of abnormal GFC values with clinical variables.ResultsIncreased GFC values in the left medial superior frontal gyrus (SFGmed) and decreased GFC values in the right supplementary motor area (SMA) were observed in the patients with MDD compared with the controls. The decreased GFC values in the right SMA had a positive correlation with vitamin D and Hamilton Anxiety Scale (HAM-A) scores.ConclusionAbnormal GFC in the hate circuit, particularly increased GFC in the left SFGmed and decreased GFC in the right SMA, appears to be a new sight for comprehending the pathological alterations in MDD.

Abnormal global-brain functional connectivity and its relationship with cognitive deficits in drug-naive first-episode adolescent-onset schizophrenia.

Abnormal functional connectivity (FC) has been reported in drug-naive first-episode adolescent-onset schizophrenia (AOS) with inconsistent results due to differently selected regions of interest. The voxel-wise global-brain functional connectivity (GFC) analysis can help explore abnormal FC in an unbiased way in AOS. A total of 48 drug-naive first-episode AOS as well as 31 sex-, age- and education-matched healthy controls were collected. Data were subjected to GFC, correlation analysis and support vector machine analyses. Compared with healthy controls, the AOS group exhibited increased GFC in the right middle frontal gyrus (MFG), and decreased GFC in the right inferior temporal gyrus, left superior temporal gyrus (STG)/precentral gyrus/postcentral gyrus, right posterior cingulate cortex /precuneus and bilateral cuneus. After the Benjamini-Hochberg correction, significantly negative correlations between GFC in the bilateral cuneus and Trail-Making Test: Part A (TMT-A) scores (r=-0.285, p=0.049), between GFC in the left STG/precentral gyrus/postcentral gyrus and TMT-A scores (r=-0.384, p=0.007), and between GFC in the right MFG and the fluency scores (r=-0.335, p=0.020) in the patients. GFC in the left STG/precentral gyrus/postcentral gyrus has a satisfactory accuracy (up to 86.08%) in classifying patients from controls. AOS shows abnormal GFC in the brain areas of multiple networks, which bears cognitive significance. These findings suggest potential abnormalities in processing self-monitoring and sensory prediction, which further elucidate the pathophysiology of AOS.

Increased Global-Brain Functional Connectivity Is Associated with Dyslipidemia and Cognitive Impairment in First-Episode, Drug-Naive Patients with Bipolar Disorder.

Objectives Previous researches have demonstrated that abnormal functional connectivity (FC) is associated with the pathophysiology of bipolar disorder (BD). However, inconsistent results were obtained due to different selections of regions of interest in previous researches. This study is aimed at examining voxel-wise brain-wide functional connectivity (FC) alterations in the first-episode, drug-naive patient with BD in an unbiased way. Methods A total of 35 patients with BD and 37 age-, sex-, and education-matched healthy controls underwent resting-state functional magnetic resonance imaging (rs-fMRI). Global-brain FC (GFC) was applied to analyze the image data. Support vector machine (SVM) was adopted to probe whether GFC abnormalities could be used to identify the patients from the controls. Results Patients with BD exhibited increased GFC in the left inferior frontal gyrus (LIFG), pars triangularis and left precuneus (PCu)/superior occipital gyrus (SOG). The left PCu belongs to the default mode network (DMN). Furthermore, increased GFC in the LIFG, pars triangularis was positively correlated with the triglycerides (TG) and low-density lipoprotein cholesterol (LDL-C) and negatively correlated with the scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) coding test and Stroop color. Increased GFC values in the left PCu/SOG can be applied to discriminate patients from controls with preferable sensitivity (80.00%), specificity (75.68%), and accuracy (77.78%). Conclusions This study found increased GFC in the brain regions of DMN; LIFG, pars triangularis; and LSOG, which was associated with dyslipidemia and cognitive impairment in patients with BD. Moreover, increased GFC values in the left PCu/SOG may be utilized as a potential biomarker to differentiate patients with BD from controls.

Voxel-Wise Brain-Wide Functional Connectivity Abnormalities in Patients with Primary Blepharospasm at Rest.

Background Primary blepharospasm (BSP) is one of the most common focal dystonia and its pathophysiological mechanism remains unclear. An unbiased method was used in patients with BSP at rest to observe voxel-wise brain-wide functional connectivity (FC) changes. Method A total of 48 subjects, including 24 untreated patients with BSP and 24 healthy controls, were recruited to undergo functional magnetic resonance imaging (fMRI). The method of global-brain FC (GFC) was adopted to analyze the resting-state fMRI data. We designed the support vector machine (SVM) method to determine whether GFC abnormalities could be utilized to distinguish the patients from the controls. Results Relative to healthy controls, patients with BSP showed significantly decreased GFC in the bilateral superior medial prefrontal cortex/anterior cingulate cortex (MPFC/ACC) and increased GFC in the right postcentral gyrus/precentral gyrus/paracentral lobule, right superior frontal gyrus (SFG), and left paracentral lobule/supplement motor area (SMA), which were included in the default mode network (DMN) and sensorimotor network. SVM analysis showed that increased GFC values in the right postcentral gyrus/precentral gyrus/paracentral lobule could discriminate patients from controls with optimal accuracy, specificity, and sensitivity of 83.33%, 83.33%, and 83.33%, respectively. Conclusion This study suggested that abnormal GFC in the brain areas associated with sensorimotor network and DMN might underlie the pathophysiology of BSP, which provided a new perspective to understand BSP. GFC in the right postcentral gyrus/precentral gyrus/paracentral lobule might be utilized as a latent biomarker to differentiate patients with BSP from controls.

Reduced Global-Brain Functional Connectivity of the Cerebello-Thalamo-Cortical Network in Patients With Dry Eye Disease.

Background: The pathophysiology of patients with dry eye disease (DED) is associated with abnormal functional connectivity (FC). The present study aims to probe alterations of voxel-wise brain-wide FC in patient with DED at rest in an unbiased way.Method: A total of 20 patients with DED and 23 controls matched by age, sex, and years of education underwent resting-state functional magnetic resonance imaging scans. Global-brain FC (GFC) was adopted to analyze the images. Support vector machine (SVM) was utilized to differentiate the patients from the controls.Results: Compared with the controls, patients with DED exhibited decreased GFC in the right cerebellum lobule VIII/inferior semi-lunar lobule and left thalamus that belonged to the cerebello-thalamo-cortical network. The GFC values in the left thalamus were positively correlated to the illness duration (r = 0.589, p = 0.006) in the patients. Decreased GFC values in the left thalamus could be used to discriminate the patients from the controls with optimal accuracy, sensitivity and specificity (88.37, 85.00, and 91.30%).Conclusions: Our findings indicate that decreased GFC in the brain regions associated with cerebello-thalamo-cortical network may provide a new insight for understanding the pathological changes of FC in DED. GFC values in the left thalamus may be utilized as a potential biomarker to identify the patients from the controls.

Altered Global Brain Functional Connectivity in Drug-Naive Patients With Obsessive-Compulsive Disorder.

Abnormal functional connectivity (FC) within discrete brain networks is involved in the pathophysiology of obsessive-compulsive disorder (OCD) with inconsistent results. In the present study, we investigated the FC patterns of 40 drug-naive patients with OCD and 38 healthy controls (HCs) through an unbiased voxel-wise global brain FC (GFC) analysis at rest. Compared with HCs, patients with OCD showed decreased GFC within the default mode network (DMN) (i.e., left posterior cingulate cortex/lingual gyrus) and sensorimotor network (i.e., left precentral gyrus/postcentral gyrus) and increased GFC within the executive control network (ECN) (i.e., left dorsal lateral prefrontal cortex and left inferior parietal lobule). Receiver operating characteristic curve analyses further indicated that the altered GFC values within the DMN, ECN, and sensorimotor network may be used as neuroimaging markers to differentiate patients with OCD from HCs. These findings indicated the aberrant FC patterns of the DMN, ECN, and sensorimotor network associated with the pathophysiology of OCD and provided new insights into the changes in brain organization function in OCD.

Reduced Global-Brain Functional Connectivity and Its Relationship With Symptomatic Severity in Cervical Dystonia.

Background: Altered functional connectivity (FC) is related to pathophysiology of patients with cervical dystonia (CD). However, inconsistent results may be obtained due to different selected regions of interest. We explored voxel-wise brain-wide FC changes in patients with CD at rest in an unbiased manner and analyzed their correlations with symptomatic severity using the Tsui scale.Method: A total of 19 patients with CD and 21 sex- and age-matched healthy controls underwent resting-state functional magnetic resonance imaging scans. Global-brain FC (GFC) was applied to analyze the images. Support vector machine was used to distinguish the patients from the controls.Results: Patients with CD exhibited decreased GFC in the right precentral gyrus and right supplementary motor area (SMA) that belonged to the M1-SMA motor network. Significantly negative correlation was observed between GFC values in the right precentral gyrus and symptomatic severity in the patients (r = −0.476, p = 0.039, uncorrected). Decreased GFC values in these two brain regions could be utilized to differentiate the patients from the controls with good accuracies, sensitivities and specificities (83.33, 85.71, and 80.95% in the right precentral gyrus; and 87.59, 89.49, and 85.71% in the right SMA).Conclusions: Our investigation suggests that patients with CD show reduced GFC in brain regions of the M1-SMA motor network and provides further insights into the pathophysiology of CD. GFC values in the right precentral gyrus and right SMA may be used as potential biomarkers to recognize the patients from the controls.

Reduced connectivity in anterior cingulate cortex as an early predictor for treatment response in drug-naive, first-episode schizophrenia: A global-brain functional connectivity analysis

BackgroundAntipsychotic medications may have acute effect on brain functional connectivity (FC) after only a few days of treatment. It is unclear if early changes in FC can predict treatment response in patients with schizophrenia. MethodsThe study included 32 patients with drug-naive, first-episode schizophrenia and 32 healthy controls. Resting-state functional magnetic resonance imaging was obtained from the patients at two time-points (pre-treatment baseline and 1 week after treatment) and healthy controls at baseline. Patients were treated with olanzapine for 8 weeks, and clinical symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS) at three time points (baseline, 1 week and 8 weeks after treatment). Imaging data were analyzed using global-brain FC (GFC) and support vector regression (SVR). ResultsAt baseline, an increased GFC was observed in bilateral anterior cingulate cortex (ACC) in patients compared with healthy controls. After 1 week of olanzapine treatment, patients showed decreased GFC in bilateral ACC compared to the baseline values. SVR analysis suggested a positive relationship between GFC changes in bilateral ACC at week 1 and improvement in negative symptoms at week 8 (r = 0.957, p < 0.001). ConclusionAn early decrease in GFC in bilateral ACC may serve as a predictor for treatment response in patients with schizophrenia. If further confirmed, our finding may be able to help clinicians decide, during the early treatment course, whether the patient should stay on the chosen antipsychotic medication or switch to a different one.

Voxel-based global-brain functional connectivity alterations in first-episode drug-naive patients with somatization disorder

BackgroundAltered functional connectivity (FC) is associated with the pathophysiology of patients with somatization disorder (SD). However, inconsistent results were obtained due to different selections of regions of interest (ROIs) in previous researches. This study aims to examine voxel-wise brain-wide FC alterations in patients with first-episode, drug-naive SD in an unbiased way. MethodsA total of 25 patients with SD and 28 age-, sex-, and education-matched healthy controls underwent resting-state functional magnetic resonance imaging. Global-brain FC (GFC) was applied to analyze the images. Receiver operating characteristic curves and support vector machine were used to differentiate the patients from the controls. ResultsCompared with healthy controls, patients with SD exhibited increased GFC in the right inferior temporal gyrus (t-value = 4.0663, p < 0.001) and left superior occipital gyrus (t-value = 3.8197, p < 0.001). Decreased GFC in the right insula (t-value = ‒4.1667, p < 0.001) was observed in the patients relative to the controls. The GFC values in the right insula of the patients were positively correlated to their scores of the sleep subscale of the Hamilton Depression Scale (r = 0.455, p = 0.022) and the lie subscale of the Eysenck Personality Questionnaire (r = 0.436, p = 0.029). A combination of GFC values in the right insula and left superior occipital gyrus can be applied to discriminate the patients from the controls with optimal sensitivity, specificity, and accuracy of 88.00%, 85.71%, and 86.79%, respectively. ConclusionsOur study indicates that patients with SD show abnormal GFC in the brain areas of insula-centered sensorimotor network, and thus providing a new perspective for understanding the pathological changes of FC in SD. Furthermore, a combination of the GFC values in the right insula and left superior occipital gyrus may be used as a potential biomarker to identify the patients from the controls.

Enhanced Global-Brain Functional Connectivity in the Left Superior Frontal Gyrus as a Possible Endophenotype for Schizophrenia.

The notion of dysconnectivity in schizophrenia has been put forward for many years and results in substantial attempts to explore altered functional connectivity (FC) within different networks with inconsistent results. Clinical, demographical, and methodological heterogeneity may contribute to the inconsistency. Forty-four patients with first-episode, drug-naive schizophrenia, 42 unaffected siblings of schizophrenia patients and 44 healthy controls took part in this study. Global-brain FC (GFC) was employed to analyze the imaging data. Compared with healthy controls, patients with schizophrenia and unaffected siblings shared enhanced GFC in the left superior frontal gyrus (SFG). In addition, patients had increased GFC mainly in the thalamo-cortical network, including the bilateral thalamus, bilateral posterior cingulate cortex (PCC)/precuneus, left superior medial prefrontal cortex (MPFC), right angular gyrus, and right SFG/middle frontal gyrus and decreased GFC in the left ITG/cerebellum Crus I. No other altered GFC values were observed in the siblings group relative to the control group. Further ROC analysis showed that increased GFC in the left SFG could separate the patients or the siblings from the controls with acceptable sensitivities. Our findings suggest that increased GFC in the left SFG may serve as a potential endophenotype for schizophrenia.

Understanding cognitive functioning in glioma patients: The relevance of IDH-mutation status and functional connectivity.

IntroductionCognitive deficits occur frequently in diffuse glioma patients, but are limitedly understood. An important marker for survival in these patients is isocitrate dehydrogenase (IDH) mutation (IDH‐mut). Patients with IDH‐mut glioma have a better prognosis but more often suffer from epilepsy than patients with IDH‐wildtype (IDH‐wt) glioma, who are generally older and more often have cognitive deficits. We investigated whether global brain functional connectivity differs between patients with IDH‐mut and IDH‐wt glioma, and whether this measure reflects variations in cognitive functioning in these subpopulations beyond the associated differences in age and presence of epilepsy.MethodsWe recorded magnetoencephalography and tested cognitive functioning in 54 diffuse glioma patients (31 IDH‐mut, 23 IDH‐wt). Global functional connectivity between 78 atlas regions spanning the entire cortex was calculated in two frequency bands (theta and alpha). Group differences in global functional connectivity were tested, as was their association with cognitive functioning, controlling for age, education, and presence of epilepsy.ResultsPatients with IDH‐wt glioma had lower functional connectivity in the alpha band than patients with IDH‐mut glioma (p = 0.040, corrected for age and presence of epilepsy). Lower alpha band functional connectivity was associated with poorer cognitive performance (p < 0.034), corrected for age, education, and presence of epilepsy.ConclusionGlobal functional connectivity is lower in patients with IDH‐wt diffuse glioma compared to patients with IDH‐mut diffuse glioma. Moreover, having lower functional alpha connectivity relates to poorer cognitive performance in patients with diffuse glioma, regardless of age, education, and presence of epilepsy.

Multimodal assessment of recovery from coma in a rat model of diffuse brainstem tegmentum injury

Despite the association between brainstem lesions and coma, a mechanistic understanding of coma pathogenesis and recovery is lacking. We developed a coma model in the rat mimicking human brainstem coma, which allowed multimodal analysis of a brainstem tegmentum lesion's effects on behavior, cortical electrophysiology, and global brain functional connectivity. After coma induction, we observed a transient period (∼1h) of unresponsiveness accompanied by cortical burst-suppression. Comatose rats then gradually regained behavioral responsiveness concurrent with emergence of delta/theta-predominant cortical rhythms in primary somatosensory cortex. During the acute stage of coma recovery (∼1–8h), longitudinal resting-state functional MRI revealed an increase in functional connectivity between subcortical arousal nuclei in the thalamus, basal forebrain, and basal ganglia and cortical regions implicated in awareness. This rat coma model provides an experimental platform to systematically study network-based mechanisms of coma pathogenesis and recovery, as well as to test targeted therapies aimed at promoting recovery of consciousness after coma.

Abnormal Global Brain Functional Connectivity in Primary Insomnia Patients: A Resting-State Functional MRI Study.

Background: Resting-state functional magnetic resonance imaging (fMRI) studies have uncovered the disruptions of functional brain networks in primary insomnia (PI) patients. However, the etiology and pathogenesis underlying this disorder remains ambiguous, and the insomnia related symptoms are influenced by a complex network organization in the brain. The purpose of this study was to explore the abnormal intrinsic functional hubs in PI patients using a voxel-wise degree centrality (DC) analysis and seed-based functional connectivity (FC) approach.Methods: A total of 26 PI patients and 28 healthy controls were enrolled, and they underwent resting-state fMRI. Degree centrality was measured across the whole brain, and group differences in DC were compared. The peak points, which significantly altered DC between the two groups, were defined as the seed regions and were further used to calculate FC of the whole brain. Later, correlation analyses were performed between the changes in brain function and clinical features.Results: Primary insomnia patients showed DC values lower than healthy controls in the left inferior frontal gyrus (IFG) and middle temporal gyrus (MTG) and showed a higher DC value in the right precuneus. The seed-based analyses demonstrated decreased FC between the left MTG and the left posterior cingulate cortex (PCC), and decreased FC was observed between the right precuneus and the right lateral occipital cortex. Reduced DC in the left IFG and decreased FC in the left PCC were positively correlated with the Pittsburgh sleep quality index and the insomnia severity index.Conclusions: This study revealed that PI patients exhibited abnormal intrinsic functional hubs in the left IFG, MTG, and the right precuneus, as well as abnormal seed-based FC in these hubs. These results contribute to better understanding of how brain function influences the symptoms of PI.

Voxel-wise brain-wide functional connectivity abnormalities in first-episode, drug-naive patients with major depressive disorder.

Due to different foci and single sample across studies, abnormal functional connectivity (FC) has been implicated in the pathophysiology of major depressive disorder (MDD) with inconsistent results. The inconsistency may reflect a combination of clinical and methodological variability, which leads to limited reproducibility of these findings. The samples included 59 patients with MDD and 31 controls from Sample 1, 29 patients with MDD and 24 controls from Sample 2, and 31 patients with schizophrenia and 37 controls from Sample 3. Global-brain FC (GFC) and an overlapping technique were applied to analyze the imaging data. Compared with healthy controls, patients with MDD in Samples 1 and 2 showed increased GFC in the overlapped brain areas, including the bilateral insula, right inferior parietal lobule (IPL), and right supramarginal gyrus/IPL. By contrast, decreased GFC in the overlapped brain areas, including the bilateral posterior cingulate cortex/presuneus and left calcarine cortex, was found in patients with MDD. In addition, patients with schizophrenia in Sample 3 did not show any GFC abnormalities in the overlapped areas from the results of Samples 1 and 2. The present study is the first to examine voxel-wise brain-wide FC in MDD with two independent samples by using an overlapping technique. The results indicate that aberrant FC patterns of insula-centered sensorimotor circuit may account for the pathophysiology of MDD.

Increased Stability and Breakdown of Brain Effective Connectivity During Slow-Wave Sleep: Mechanistic Insights from Whole-Brain Computational Modelling

Recent research has found that the human sleep cycle is characterised by changes in spatiotemporal patterns of brain activity. Yet, we are still missing a mechanistic explanation of the local neuronal dynamics underlying these changes. We used whole-brain computational modelling to study the differences in global brain functional connectivity and synchrony of fMRI activity in healthy humans during wakefulness and slow-wave sleep. We applied a whole-brain model based on the normal form of a supercritical Hopf bifurcation and studied the dynamical changes when adapting the bifurcation parameter for all brain nodes to best match wakefulness and slow-wave sleep. Furthermore, we analysed differences in effective connectivity between the two states. In addition to significant changes in functional connectivity, synchrony and metastability, this analysis revealed a significant shift of the global dynamic working point of brain dynamics, from the edge of the transition between damped to sustained oscillations during wakefulness, to a stable focus during slow-wave sleep. Moreover, we identified a significant global decrease in effective interactions during slow-wave sleep. These results suggest a mechanism for the empirical functional changes observed during slow-wave sleep, namely a global shift of the brain’s dynamic working point leading to increased stability and decreased effective connectivity.

Loss of ‘Small-World’ Networks in Alzheimer's Disease: Graph Analysis of fMRI Resting-State Functional Connectivity

BackgroundLocal network connectivity disruptions in Alzheimer's disease patients have been found using graph analysis in BOLD fMRI. Other studies using MEG and cortical thickness measures, however, show more global long distance connectivity changes, both in functional and structural imaging data. The form and role of functional connectivity changes thus remains ambiguous. The current study shows more conclusive data on connectivity changes in early AD using graph analysis on resting-state condition fMRI data.Methodology/Principal Findings18 mild AD patients and 21 healthy age-matched control subjects without memory complaints were investigated in resting-state condition with MRI at 1.5 Tesla. Functional coupling between brain regions was calculated on the basis of pair-wise synchronizations between regional time-series. Local (cluster coefficient) and global (path length) network measures were quantitatively defined. Compared to controls, the characteristic path length of AD functional networks is closer to the theoretical values of random networks, while no significant differences were found in cluster coefficient. The whole-brain average synchronization does not differ between Alzheimer and healthy control groups. Post-hoc analysis of the regional synchronization reveals increased AD synchronization involving the frontal cortices and generalized decreases located at the parietal and occipital regions. This effectively translates in a global reduction of functional long-distance links between frontal and caudal brain regions.Conclusions/SignificanceWe present evidence of AD-induced changes in global brain functional connectivity specifically affecting long-distance connectivity. This finding is highly relevant for it supports the anterior-posterior disconnection theory and its role in AD. Our results can be interpreted as reflecting the randomization of the brain functional networks in AD, further suggesting a loss of global information integration in disease.