Long-range Functional Connectivity Density Research Articles

Abnormal Functional Connectivity Density in Post-traumatic Stress Disorder.

Post-traumatic stress disorder (PTSD) is a psychiatric disorder that occurs in individuals who have experienced life-threatening mental traumas. Previous neuroimaging studies have indicated that the pathology of PTSD may be associated with the abnormal functional integration among brain regions. In the current study, we used functional connectivity density (FCD) mapping, a novel voxel-wise data-driven approach based on graph theory, to explore aberrant FC through the resting-state functional magnetic resonance imaging of the PTSD. We calculated both short- and long-range FCD in PTSD patients and healthy controls (HCs). Compared with HCs, PTSD patients showed significantly increased long-range FCD in the left dorsolateral prefrontal cortex (DLPFC), but no abnormal short-range FCD was found in PTSD. Furthermore, seed-based FC analysis of the left DLPFC showed increased connectivity in the left superior parietal lobe and visual cortex of PTSD patients. The results suggested that PTSD patients experienced a disruption of intrinsic long-range functional connections in the fronto-parietal network and visual cortex, which are associated with attention control and visual information processing.

Altered functional connectivity density in high myopia

Abnormal visual experience can affect the brain structure and function. Visual functional performances of high myopia (HM) individuals were observed to be abnormal in contrast to emmetropics, even with a corrected visual acuity. Attention deficits and brain morphological changes have been revealed in the HM, but it is unknown whether there are functional connectivity (FC) alterations. The current study combined the resting-state functional connectivity density (FCD) mapping and seed-based correlation analysis to investigate FC alterations in the brain of HM. In our results, the HM exhibited decreased short- and long-range FCD in the posterior cingulate cortex/precuneus and decreased long-range FCD in the inferior temporal gyrus, supramarginal gyrus and rostrolateral prefrontal cortex. Specially, long-range FCD in the rostrolateral prefrontal cortex showed a significant positive correlation with the uncorrected visual acuity in the HM. Moreover, the HM showed significantly decreased FC not only between the supramarginal gyrus and rostrolateral prefrontal cortex, but also between networks they belong to, the ventral attention and frontoparietal control networks. These results provide evidence for the FC changes in the HM and may help to understand the attention deficits in myopes.

Abnormal functional connectivity density in first-episode, drug-naive adult patients with major depressive disorder

Previous studies have found evidence of brain functional connectivity (FC) changes with pre-selected region-of-interest (ROI) method in major depressive disorder (MDD). However, these studies could not completely exclude personal inequality when drawing ROIs manually and did not measure the total number of FC for each voxel. Here, we firstly applied functional connectivity density (FCD) mapping, a voxel-based analysis to locate the hubs with amount changes of FC between 22 first-episode, drug-naive adult MDD patients and 22 healthy control (HC) subjects. Both short-range (local) FCD and long-range (distal) FCD were measured. The relationships of FCD changes with Hamilton Depression Rating Scale (HAMD) scores and illness duration were also explored. Compared with the HC group, MDD patients showed significantly decreased short-range FCD in the left superior temporal gyrus (STG), the right orbital frontal cortex (OFC) and bilateral precuneus, while significantly decreased long-range FCD was found in bilateral middle occipital gyrus (MOG), superior occipital gyrus (SOG) and right calcarine. These results firstly demonstrated both local and distal alterations of connection amount at voxel level, and highlighted that the OFC, the precuneus, the STG and the visual cortex were important brain network hubs for first-episode, drug-naive adult MDD patients. Our findings were complementary for previous structural and functional studies in MDD patients, and provided new evidence of the dysfunction of connection hubs in the pathophysiology of MDD at voxel level.

Functional Connectivity Density Mapping of Depressive Symptoms and Loneliness in Non-Demented Elderly Male.

Background: Depression and loneliness are prevalent and highly correlated phenomena among the elderly and influence both physical and mental health. Brain functional connectivity changes associated with depressive symptoms and loneliness are not fully understood.Methods: A cross-sectional functional MRI study was conducted among 85 non-demented male elders. Geriatric depression scale-short form (GDS) and loneliness scale were used to evaluate the severity of depressive symptoms and loneliness, respectively. Whole brain voxel-wise resting-state functional connectivity density (FCD) mapping was performed to delineate short-range FCD (SFCD) and long-range FCD (LFCD). Regional correlations between depressive symptoms or loneliness and SFCD or LFCD were examined using general linear model (GLM), with age incorporated as a covariate and depressive symptoms and loneliness as predictors.Results: Positive correlations between depressive symptoms and LFCD were observed in left rectal gyrus, left superior frontal gyrus, right supraorbital gyrus, and left inferior temporal gyrus. Positive correlations between depressive symptoms and SFCD were observed in left middle frontal gyrus, left superior frontal gyrus, bilateral superior medial frontal gyrus, left inferior temporal gyrus, and left middle occipital region. Positive correlations between SFCD and loneliness were centered over bilateral lingual gyrus.Conclusion: Depressive symptoms are associated with FCD changes over frontal and temporal regions, which may involve the cognitive control, affective regulation, and default mode networks. Loneliness is associated with FCD changes in bilateral lingual gyri that are known to be important in social cognition. Depressive symptoms and loneliness may be associated with different brain regions in non-demented elderly male.

Altered Long- and Short-Range Functional Connectivity in Patients with Betel Quid Dependence: A Resting-State Functional MRI Study

Objective: Addiction is a chronic relapsing brain disease. Brain structural abnormalities may constitute an abnormal neural network that underlies the risk of drug dependence. We hypothesized that individuals with Betel Quid Dependence (BQD) have functional connectivity alterations that can be described by long- and short-range functional connectivity density(FCD) maps. Methods: We tested this hypothesis using functional magnetic resonance imaging (fMRI) data from subjects of the Han ethnic group in Hainan, China. Here, we examined BQD individuals (n = 33) and age-, sex-, and education-matched healthy controls (HCs) (n = 32) in a rs-fMRI study to observe FCD alterations associated with the severity of BQD. Results: Compared with HCs, long-range FCD was decreased in the right anterior cingulate cortex (ACC) and increased in the left cerebellum posterior lobe (CPL) and bilateral inferior parietal lobule (IPL) in the BQD group. Short-range FCD was reduced in the right ACC and left dorsolateral prefrontal cortex (dlPFC), and increased in the left CPL. The short-range FCD alteration in the right ACC displayed a negative correlation with the Betel Quid Dependence Scale (BQDS) (r=-0.432, P=0.012), and the long-range FCD alteration of left IPL showed a positive correlation with the duration of BQD(r=0.519, P=0.002) in BQD individuals. Conclusions: fMRI revealed differences in long- and short- range FCD in BQD individuals, and these alterations might be due to BQ chewing, BQ dependency, or risk factors for developing BQD.

Aberrant Resting-State Functional Connectivity Density in Patients with Hepatitis B Virus-Related Cirrhosis.

There is increasing evidence that cirrhosis may affect functional connectivity among various brain regions in patients prior to onset of overt hepatic encephalopathy (HE). However, most investigators have focused mainly on alterations in functional connectivity strengths, and the changes in functional connectivity density (FCD) are largely unknown. Here, we investigated alterations in resting-state FCD in patients with hepatitis B virus-related cirrhosis (HBV-RC) without overt HE. Totally, 31 patients with HBV-RC without overt HE and 30 age- and sex-matched healthy controls underwent resting-state functional MRI examinations. FCD mapping was employed to compute local and global FCD maps. Then, short-range and long-range FCD values were calculated and voxel-based comparisons were performed between the two groups. The HBV-RC group showed significant decreases in FCD, including decreased short-range FCDs in the bilateral middle cingulum gyrus/precuneus, the bilateral cuneus, and the left lingual gyrus/inferior occipital gyrus and decreased long-range FCD in the bilateral cuneus/precuneus. In addition, the decreased long-range FCD in the bilateral cuneus/precuneus in the HBV-RC group was related to performance on the psychometric hepatic encephalopathy score (PHES) test. These findings suggest aberrant functional connectivity density in cirrhotic patients prior to overt HE onset, which may provide better insight into understanding the pathophysiological mechanisms underlying the cirrhotic-related cognitive impairment.

Functional Connectivity Hubs Could Serve as a Potential Biomarker in Alzheimer's Disease: A Reproducible Study.

Cortical hubs that link functionally specialized neural systems are crucial for cognition. Evidence suggests that the location and organization of hubs are related to Alzheimer's disease (AD). However, two issues remain unclear: (i) where and how hubs change in AD, and (ii) whether hubs could be a potential pre-diagnosis biomarker for mild cognitive impairment (MCI)--a prodromal phase of AD. Accordingly, we examined the functional connectivity density (FCD) in two cohorts of resting-state functional magnetic resonance imaging (fMRI) scans (26 AD, 27 controls; 33 AD, 21 controls) and revealed consistently vulnerable FCD hub regions in AD compared with controls: within the default mode network, short-range FCD decreases in the posterior cingulate cortex and increases in the medial prefrontal cortex; within the frontal lobe, long-range FCD increases in the medial prefrontal cortex, superior frontal gyrus and middle frontal gyrus. Furthermore, FCD correlates with cognitive score and could distinguish MCI from controls with high accuracy (71.08% in dataset 1, 81% in dataset 2). By reflecting a robust and reproducible global shift in brain functions, FCD provides an fMRI biomarker for the underlying mechanism in AD.

Extraversion modulates functional connectivity hubs of resting-state brain networks.

Personality dimension extraversion describes individual differences in social behaviour and socio-emotional functioning. The intrinsic functional connectivity patterns of the brain are reportedly associated with extraversion. However, whether or not extraversion is associated with functional hubs warrants clarification. Functional hubs are involved in the rapid integration of neural processing, and their dysfunction contributes to the development of neuropsychiatric disorders. In this study, we employed the functional connectivity density (FCD) method for the first time to distinguish the energy-efficient hubs associated with extraversion. The resting-state functional magnetic resonance imaging data of 71 healthy subjects were used in the analysis. Short-range FCD was positively correlated with extraversion in the left cuneus, revealing a link between the local functional activity of this region and extraversion in risk-taking. Long-range FCD was negatively correlated with extraversion in the right superior frontal gyrus and the inferior frontal gyrus. Seed-based resting-state functional connectivity (RSFC) analyses revealed that a decreased long-range FCD in individuals with high extraversion scores showed a low long-range functional connectivity pattern between the medial and dorsolateral prefrontal cortex, middle temporal gyrus, and anterior cingulate cortex. This result suggests that decreased RSFC patterns are responsible for self-esteem, self-evaluation, and inhibitory behaviour system that account for the modulation and shaping of extraversion. Overall, our results emphasize specific brain hubs, and reveal long-range functional connections in relation to extraversion, thereby providing a neurobiological basis of extraversion.

Resting-state functional connectivity density mapping of etiology confirmed unilateral pulsatile tinnitus patients: Altered functional hubs in the early stage of disease

Functional magnetic resonance imaging (fMRI) has been widely used to identify altered intrinsic local neural activities and global networks of tinnitus patients. In this study, functional connectivity density (FCD) mapping, a newly developed voxelwise data-driven method based on fMRI, was applied for the first time to measure the functional reorganization pattern in thirty-two unilateral pulsatile tinnitus (PT) patients in the early stage of disease (less than 48months). FCD analysis was employed to compute short-range and long-range FCD values. A correlation analysis with clinical variables was also performed. Compared with normal controls, PT patients showed significantly increased short-range FCD, mainly in the precuneus (PCu), bilateral inferior frontal gyrus (IFG) and middle occipital gyrus (MOG), and increased long-range FCD in the PCu, posterior cingulate cortex (PCC), and bilateral middle frontal gyrus (MFG). In addition, correlation analysis showed positive correlations between PT duration and short-range FCD values in the right MOG. Positive correlations were also found between the disease duration and the long-range FCD value in the PCC. The increased short-/long-range FCD in bilateral dorsal visual areas indicated that the enhanced pathway between the auditory cortex and bilateral dorsal visual areas may have activated the “auditory occipital activations” (AOAs) pathway. The bilaterally altered FCD values in the dorsal visual areas reflected the cooperation of different brain areas. This study is a foundation of the connectivity research in PT patients. Our work may advance the understanding of the disrupted neural network of patients with PT.

Altered long- and short-range functional connectivity in the patients with end-stage renal disease: a resting-state functional MRI study.

To investigate alterations of functional connectivity density (FCD) in patients with end-stage renal disease (ESRD) by using resting-state functional magnetic resonance imaging (rs-fMRI). Medical research ethics committee approval from Jinling hospital and written informed consent from each subject were obtained. Forty six patients with ESRD, consisting of 21 patients minimal nephrotic encephalopathy (MNE) and 25 non-nephro-encephalopathy (non-NE), as well as 23 healthy controls underwent rs-fMRI. Neuropsychological tests were performed in all subjects, while laboratory tests were performed in ESRD patients. A voxel-wise whole brain functional connectivity analysis was used to generate long- and short-range FCD maps. The maps among MNE, non-NE, and healthy controls groups were compared by using one-way analysis of variance tests. A multiple regression analysis was performed to evaluate the correlations between FCD and the variables of neuropsychological or laboratory tests. Compared with healthy controls, non-NE showed decreased long-range FCD mainly in parietal lobe. Moreover, MNE showed further decreased long-range FCD in bilateral middle prefrontal cortex (MPFC), anterior cingulate cortex (ACC) and right superior frontal gyrus. Meanwhile, non-NE showed decreased short-range FCD mainly in frontal cortex, and further reduction in bilateral ACC and right superior parietal gyrus in MNE. In addition, patients with ESRD mainly exhibited increased long-range FCD in left temporal lobe and caudate; and increased short-range FCD in bilateral orbitofrontal cortex and temporal gyri (P<0.05, AlphaSim corrected). The number connection test type A score, serum creatinine, urea, and dialysis duration showed negative correlation with FCD in some brain regions, while the digital symbol test scores positively correlated with short-range FCD in left inferior parietal lobule (all P<0.05, AlphaSim corrected). The prominent long- and short-range FCD reduction was found mainly in default mode network (DMN) and bilateral frontal and parietal lobes, while the progressively decreased long- and short-range FCD in ACC/MPFC and the long-range FCD in left superior frontal gyrus from non-NE to MNE was associated with cognition dysfunction in ESRD patients.

Long-and short-range functional connectivity density alteration in non-alcoholic cirrhotic patients one month after liver transplantation: A resting-state fMRI study

PurposeTo longitudinally evaluate long- and short-range functional connectivity density (FCD) alteration in cirrhotic patients one month after liver transplantation (LT) and their correlation with cognitive changes by using resting-state functional magnetic resonance imaging (rs-fMRI). MethodsTwenty seven candidates awaiting LT and 24 age-, gender-, and education-matched healthy controls (HCs) were studied. All 27 patients and HCs performed rs-fMRI examinations. Of 27 cirrhotic patients, 13 patients received LT underwent the repeated rs-fMRI examinations one month after LT. Laboratory and psychometric tests were carried out. The long- and short-range FCD maps derived from degree centrality calculation were compared. Correlations between FCD alteration and laboratory/psychometric changes were evaluated as well. ResultsIn cirrhotic patients, most of the brain areas with altered long- and short-range FCD could reverse one month after LT, which was accompanied with cognitive and liver functional improvement. The reduced long-range FCD in right posterior cingulate cortex (PCC) and Left middle frontal gyrus (MFG), and reduced short-range FCD in right precuneus (PCu) persisted in the early period after LT. In addition, one month after LT, the post-LT group showed reduced long-range FCD in right rectus gyrus (REC) and left medial prefrontal cortex (MPFC), and reduced short-range FCD in left middle temporal gyrus (MTG), when compared with the pre-LT group. We found Δdigital symbol test (ΔDST) score positively correlated with long-range ΔFCD in right precentral gyrus (preCG) (r=0.72, P<0.01) and right supplementary motor area (SMA) (r=0.59, P<0.05). ConclusionLT results in favorable effect on cognitive function in cirrhotic patient, which can be reflected by FCD alteration. However, persistence of PCC/PCu functional connectivity disturbance one month after LT indicates complete cognitive function restoration may need a longer time.

Effects of chronic and acute stimulants on brain functional connectivity hubs

The spatial distribution and strength of information processing ‘hubs’ are essential features of the brain׳s network topology, and may thus be particularly susceptible to neuropsychiatric disease. Despite growing evidence that drug addiction alters functioning and connectivity of discrete brain regions, little is known about whether chronic drug use is associated with abnormalities in this network-level organization, and if such abnormalities could be targeted for intervention. We used functional connectivity density (FCD) mapping to evaluate how chronic and acute stimulants affect brain hubs (i.e., regions with many short-range or long-range functional connections). Nineteen individuals with cocaine use disorders (CUD) and 15 healthy controls completed resting-state fMRI scans following a randomly assigned dose of methylphenidate (MPH; 20mg) or placebo. Short-range and long-range FCD maps were computed for each participant and medication condition. CUD participants had increased short-range and long-range FCD in the ventromedial prefrontal cortex, posterior cingulate/precuneus, and putamen/amygdala, which in areas of the default mode network correlated with years of use. Across participants, MPH decreased short-range FCD in the thalamus/putamen, and decreased long-range FCD in the supplementary motor area and postcentral gyrus. Increased density of short-range and long-range functional connections to default mode hubs in CUD suggests an overrepresentation of these resource-expensive hubs. While the effects of MPH on FCD were only partly overlapping with those of CUD, MPH-induced reduction in the density of short-range connections to the putamen/thalamus, a network of core relevance to habit formation and addiction, suggests that some FCD abnormalities could be targeted for intervention.This article is part of a Special Issue entitled SI:Addiction circuits.

Abnormal functional connectivity density in children with anisometropic amblyopia at resting-state

Amblyopia is a developmental disorder resulting from anomalous binocular visual input in early life. Task-based neuroimaging studies have widely investigated cortical functional impairments in amblyopia, but changes in spontaneous neuronal functional activities in amblyopia remain largely unknown. In the present study, functional connectivity density (FCD) mapping, an ultrafast data-driven method based on fMRI, was applied for the first time to investigate changes in cortical functional connectivities in amblyopia during the resting-state. We quantified and compared both short- and long-range FCD in both the brains of children with anisometropic amblyopia (AAC) and normal sighted children (NSC). In contrast to the NSC, the AAC showed significantly decreased short-range FCD in the inferior temporal/fusiform gyri, parieto-occipital and rostrolateral prefrontal cortices, as well as decreased long-range FCD in the premotor cortex, dorsal inferior parietal lobule, frontal-insular and dorsal prefrontal cortices. Furthermore, most regions with reduced long-range FCD in the AAC showed decreased functional connectivity with occipital and posterior parietal cortices in the AAC. The results suggest that chronically poor visual input in amblyopia not only impairs the brain׳s short-range functional connections in visual pathways and in the frontal cortex, which is important for cognitive control, but also affects long-range functional connections among the visual areas, posterior parietal and frontal cortices that subserve visuomotor and visual-guided actions, visuospatial attention modulation and the integration of salient information. This study provides evidence for abnormal spontaneous brain activities in amblyopia.

Functional Connectivity Density in Congenitally and Late Blind Subjects

Visual deprivation during different developmental periods leads to different structural and functional alterations in the brain; however, the effects of visual deprivation on the spontaneous functional organization of the brain remain largely unknown. In this study, we used voxel-based functional connectivity density (FCD) analyses to investigate the effects of visual deprivation during different developmental periods on the spontaneous functional organization of the brain. Compared with the sighted controls (SC), both the congenitally blind (CB) and the late blind (LB) exhibited decreased short- and long-range FCDs in the primary visual cortex (V1) and decreased long-range FCDs in the primary somatosensory and auditory cortices. Although both the CB and LB exhibited increased short-range FCD in the dorsal visual stream, the CB exhibited greater increases in the short- and long-range FCDs in the ventral visual stream and hippocampal complex compared with the LB. Moreover, the short-range FCD of the left V1 exhibited a significant positive correlation with the duration of blindness in the LB. Our findings suggest that visual deprivation before the developmental sensitive period can induce more extensive brain functional reorganization than does visual deprivation after the sensitive period, which may underlie an enhanced capacity for processing nonvisual information in the CB.

DISC1 Ser704Cys impacts thalamic-prefrontal connectivity.

The Disrupted-in-Schizophrenia 1 (DISC1) gene has been thought as a putative susceptibility gene for various psychiatric disorders, and DISC1 Ser704Cys is associated with variations of brain morphology and function. Moreover, our recent diffusion magnetic resonance imaging (dMRI) study reported that DISC1 Ser704Cys was associated with information transfer efficiency in the brain anatomical network. However, the effects of the DISC1 gene on functional brain connectivity and networks, especially for thalamic-prefrontal circuit, which are disrupted in various psychiatric disorders, are largely unknown. Using a functional connectivity density (FCD) mapping method based on functional magnetic resonance imaging data in a large sample of healthy Han Chinese subjects, we first investigated the association between DISC1 Ser704Cys and short- and long-range FCD hubs. Compared with Ser homozygotes, Cys-allele individuals had increased long-range FCD hubs in the bilateral thalami. The functional and anatomical connectivity of the thalamus to the prefrontal cortex was further analyzed. Significantly increased thalamic-prefrontal functional connectivity and decreased thalamic-prefrontal anatomical connectivity were found in DISC1 Cys-allele carriers. Our findings provide consistent evidence that the DISC1 Ser704Cys polymorphism influences the thalamic-prefrontal circuits in humans and may provide new insights into the neural mechanisms that link DISC1 and the risk for psychiatric disorders.Electronic supplementary materialThe online version of this article (doi:10.1007/s00429-013-0640-5) contains supplementary material, which is available to authorized users.

Abnormal Functional Connectivity in Children with Attention-Deficit/Hyperactivity Disorder

Attention-deficit/hyperactivity disorder (ADHD) is typically characterized by symptoms of inattention and hyperactivity/impulsivity, but there is increased recognition of a motivation deficit too. This neuropathology may reflect dysfunction of both attention and reward-motivation networks. To test this hypothesis, we compared the functional connectivity density between 247 ADHD and 304 typically developing control children from a public magnetic resonance imaging database. We quantified short- and long-range functional connectivity density in the brain using an ultrafast data-driven approach. Children with ADHD had lower connectivity (short- and long-range) in regions of the dorsal attention (superior parietal cortex) and default-mode (precuneus) networks and in cerebellum and higher connectivity (short-range) in reward-motivation regions (ventral striatum and orbitofrontal cortex) than control subjects. In ADHD children, the orbitofrontal cortex (region involved in salience attribution) had higher connectivity with reward-motivation regions (striatum and anterior cingulate) and lower connectivity with superior parietal cortex (region involved in attention processing). The enhanced connectivity within reward-motivation regions and their decreased connectivity with regions from the default-mode and dorsal attention networks suggest impaired interactions between control and reward pathways in ADHD that might underlie attention and motivation deficits in ADHD.

Aging and functional brain networks

Aging is associated with changes in human brain anatomy and function and cognitive decline. Recent studies suggest the aging decline of major functional connectivity hubs in the “default-mode” network (DMN). Aging effects on other networks, however, are largely unknown. We hypothesized that aging would be associated with a decline of short- and long-range functional connectivity density (FCD) hubs in the DMN. To test this hypothesis we evaluated resting-state datasets corresponding to 913 healthy subjects from a public magnetic resonance imaging database using functional connectivity density mapping, a voxelwise and data-driven approach together with parallel computing. Aging was associated with pronounced long-range FCD decreases in DMN and dorsal attention network (DAN) and with increases in somatosensory and subcortical networks. Aging effects in these networks were stronger for long-range than for short-range FCD and were also detected at the level of the main functional hubs. Females had higher short- and long-range FCD in DMN and lower FCD in the somatosensory network than males, but the gender by age interaction effects were not significant for any of the networks or hubs. These findings suggest that long-range connections may be more vulnerable to aging effects than short-range connections and that in addition to the DMN the DAN is also sensitive to aging effects, which could underlie the deterioration of attention processes that occurs with aging.