Short-range Functional Connectivity Density Research Articles

Abnormal functional connectivity density involvement in freezing of gait and its application for subtyping Parkinson's disease.

The pathophysiological mechanisms at work in Parkinson's disease (PD) patients with freezing of gait (FOG) remain poorly understood. Functional connectivity density (FCD) could provide an unbiased way to analyse connectivity across the brain. In this study, a total of 23 PD patients with FOG (PD FOG + patients), 26 PD patients without FOG (PD FOG- patients), and 22 healthy controls (HCs) were recruited, and their resting-state functional magnetic resonance imaging (rs-fMRI) images were collected. FCD mapping was first performed to identify differences between groups. Pearson correlation analysis was used to explore relationships between FCD values and the severity of FOG. Then, a machine learning model was employed to classify each pair of groups. PD FOG + patients showed significantly increased short-range FCD in the precuneus, cingulate gyrus, and fusiform gyrus and decreased long-range FCD in the frontal gyrus, temporal gyrus, and cingulate gyrus. Short-range FCD values in the middle temporal gyrus and inferior temporal gyrus were positively correlated with FOG questionnaire (FOGQ) scores, and long-range FCD values in the middle frontal gyrus were negatively correlated with FOGQ scores. Using FCD in abnormal regions as input, a support vector machine (SVM) classifier can achieve classification with good performance. The mean accuracy values were 0.895 (PD FOG + vs. HC), 0.966 (PD FOG- vs. HC), and 0.897 (PD FOG + vs. PD FOG-). This study demonstrates that PD FOG + patients showed altered short- and long-range FCD in several brain regions involved in action planning and control, motion processing, emotion, cognition, and object recognition.

Altered Functional Connectivity of Basal Ganglia in Mild Cognitive Impairment and Alzheimer's Disease.

(1) Background: Alzheimer's disease (AD), an age-progressive neurodegenerative disease that affects cognitive function, causes changes in the functional connectivity of the default-mode network (DMN). However, the question of whether AD-related changes occur in the functional connectivity of the basal ganglia has rarely been specifically analyzed. This study aimed to measure the changes in basal ganglia functional connectivity among patients with AD and mild cognitive impairment (MCI) in their resting state using the functional connectivity density (FCD) value, the functional connectivity (FC) intensity, and the graph theory index, and to confirm their influence on clinical manifestations. (2) Methods: Resting-state functional MRI (rs-fMRI) and neuropsychological data from 48 participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) were used for analyses. The 48 ADNI participants comprised 16 patients with AD, 16 patients with MCI, and 16 normal controls (NCs). The functional connectivity of basal ganglia was evaluated by FCDs, FC strength, and graph theory index. We compared voxel-based FCD values between groups to show specific regions with significant variation and significant connectivity from ROI conduction to ROI analysis. Pearson's correlation analyses between functional connectivity and several simultaneous clinical variables were also conducted. Additionally, receiver operating characteristic (ROC) analyses associated with classification were conducted for both FCD values and graph theory indices. (3) Results: The level of FCD in patients with cognitive impairment showed obvious abnormalities (including short-range and long-range FCD). In addition to DMN-related regions, aberrant functional connectivity was also found to be present in the basal ganglia, especially in the caudate and amygdala. The FCD values of the basal ganglia (involving the caudate and amygdala) were closely related to scores from the Mini-Mental State Examination (MMSE) and the Functional Activities Questionnaire (FAQ); meanwhile, the graph theory indices (involving global efficiency and degree) of the basal ganglia (involving the caudate, amygdala, and putamen) were also found to be closely correlated with MMSE scores. In ROC analyses of both FCD and graph theory, the amygdala was of the utmost importance in the early-stage detection of MCI; additionally, the caudate nucleus was found to be crucial in the progression of cognitive decline and AD diagnosis. (4) Conclusions: It was systematically confirmed that there is a phenomenon of change in the functional connections in the basal ganglia during cognitive decline. The findings of this study could improve our understanding of AD and MCI pathology in the basal ganglia and make it possible to propose new targets for AD treatment in further studies.

Pre-diabetes is associated with altered functional connectivity density in cortical regions of the default-mode network.

Insulin resistance and glucose dysregulation are associated with patterns of regional brain hypometabolism characteristic of Alzheimer's disease (AD). As predicted by evidence linking brain glucose metabolism to brain functional connectivity, type 2 diabetes is accompanied by altered functional connectivity density (FCD) in regions highly vulnerable to AD, but whether these alterations start at earlier stages such as pre-diabetes remain to be elucidated. Here, in addition to assessing whether pre-diabetes leads to a functional reorganization of densely connected cortical areas (hubs), we will assess whether such reorganization is conditioned by sex and/or insulin resistance, and contributes to improved cognition. One hundred and forty-four cognitively unimpaired middle-aged and older adults (55-78 years, 79 females), 73 with normoglycemia and 71 with pre-diabetes, underwent resting-state fMRI scanning. We first computed FCD mapping on cortical surfaces to determine the number of short- and long-range functional connections of every vertex in the cortex, and next used hubs showing aberrant FCD as seeds for the resting-state functional connectivity (rs-FC) calculation. ANCOVAs and linear multiple regression analyses adjusted by demographic and cardiometabolic confounders using frequentist and Bayesian approaches were applied. Analyses revealed higher long-range FCD in the right precuneus of pre-diabetic females and lower short-range FCD in the left medial orbitofrontal cortex (mOFC) of pre-diabetic individuals with higher insulin resistance. Although the mOFC also showed altered rs-FC patterns with other regions of the default mode network in pre-diabetic individuals, it was FCD of the precuneus and mOFC, and not the magnitude of their rs-FC, that was associated with better planning abilities and Mini-Mental State Examination (MMSE) scores. Results suggest that being female and/or having high insulin resistance exacerbate pre-diabetes-induced alterations in the FCD of hubs of the default-mode network that are particularly vulnerable to AD pathology. These changes in brain network organization appear to be compensatory for pre-diabetic females, likely assisting them to maintain cognitive functioning at early stages of glucose dysregulation.

Altered Long- and Short-Range Functional Connectivity Density in Patients With Thyroid-Associated Ophthalmopathy: A Resting-State fMRI Study.

Background and PurposeAlthough previous neuroimaging studies have demonstrated emotion- and psychology-associated brain abnormalities in patients with thyroid-associated ophthalmopathy (TAO), the changes of brain functional connectivity in TAO were seldom focused. We aimed to investigate interregional and intraregional functional interactions in patients with TAO by using resting-state functional MRI (rs-fMRI) with long- and short-range functional connectivity density (FCD) analysis.MethodsThirty patients with TAO and 30 well-matched healthy controls (HCs) were recruited in our study. Long- and short-range FCD values were calculated and compared between the two groups. Correlations between long- and short-range FCD values and clinical indicators were analyzed.ResultsCompared with HCs, patients with showed both increased long- and short-range FCDs in the left middle frontal gyrus (MFG), orbital part of superior frontal gyrus (ORBsup), and dorsolateral part of superior frontal gyrus (SFGdor); meanwhile, both decreased long- and short-range FCDs in bilateral postcentral gyrus (PoCG), left superior parietal gyrus (SPG), and inferior parietal (IPL). In addition, patients with TAO showed increased short-range FCD in the right SFGdor, bilateral medial part of superior frontal gyrus (SFGmed), left orbital part of middle frontal gyrus (ORBmid), and orbital part of inferior frontal gyrus (ORBinf), as well as decreased short-range FCD in the right supplementary motor area (SMA) and the left paracentral lobule (PCL) than HCs. Moreover, the short-range value in the left SFGdor showed a negative correlation with Montreal Cognitive Assessment (MoCA) score (r = −0.501, p = 0.005).ConclusionOur findings complemented the functional neural mechanism of TAO, and provided potential neuroimaging markers for assessing the psychiatric, visual, and emotional disturbances in patients with TAO.

Machine Learning Classification of Mild Traumatic Brain Injury Using Whole-Brain Functional Activity: A Radiomics Analysis

Objectives To investigate the classification performance of support vector machine in mild traumatic brain injury (mTBI) from normal controls. Methods Twenty-four mTBI patients (15 males and 9 females; mean age, 38.88 ± 13.33 years) and 24 age and sex-matched normal controls (13 males and 11 females; mean age, 40.46 ± 11.4 years) underwent resting-state functional MRI examination. Seven imaging parameters, including amplitude of low-frequency fluctuation (ALFF), fractional amplitude of low-frequency fluctuation (fALFF), regional homogeneity (ReHo), degree centrality (DC), voxel-mirrored homotopic connectivity (VMHC), long-range functional connectivity density (FCD), and short-range FCD, were entered into the classification model to distinguish the mTBI from normal controls. Results The ability for any single imaging parameters to distinguish the two groups is lower than multiparameter combinations. The combination of ALFF, fALFF, DC, VMHC, and short-range FCD showed the best classification performance for distinguishing the two groups with optimal AUC value of 0.778, accuracy rate of 81.11%, sensitivity of 88%, and specificity of 75%. The brain regions with the highest contributions to this classification mainly include bilateral cerebellum, left orbitofrontal cortex, left cuneus, left temporal pole, right inferior occipital cortex, bilateral parietal lobe, and left supplementary motor area. Conclusions Multiparameter combinations could improve the classification performance of mTBI from normal controls by using the brain regions associated with emotion and cognition.

Resting-State Functional Magnetic Resonance Imaging and Functional Connectivity Density Mapping in Patients With Optic Neuritis.

Background: Using resting-state functional connectivity (rsFC), we investigated alternations in spontaneous brain activities reflected by functional connectivity density (FCD) in patients with optic neuritis (ON).Methods: We enrolled 28 patients with ON (18 males, 10 females) and 24 healthy controls (HCs; 16 males, 8 females). All subjects underwent functional magnetic resonance imaging (fMRI) in a quiet state to determine the values of rsFC, long-range FCD (longFCD), and short-range FCD (IFCD). Receiver operating characteristic (ROC) curves were generated to distinguish patients from HCs.Results: The ON group exhibited obviously lower longFCD values in the left inferior frontal gyrus triangle, the right precuneus and the right anterior cingulate, and paracingulate gyri/median cingulate and paracingulate gyri. The left median cingulate and paracingulate gyri and supplementary motor area (SMA) were also significantly lower. Obviously reduced IFCD values were observed in the left middle temporal gyrus/angular gyrus/SMA and right cuneus/SMA compared with HCs.Conclusion: Abnormal neural activities were found in specific brain regions in patients with ON. Specifically, they showed significant changes in rsFC, longFCD, and IFCD values. These may be useful to identify the specific mechanism of change in brain function in ON.

Disrupted balance of long and short-range functional connectivity density in Alzheimer's disease (AD) and mild cognitive impairment (MCI) patients: a resting-state fMRI study.

BackgroundAlzheimer’s disease (AD) is an age-progressive neurodegenerative disorder that affects cognitive function. There have been several functional connectivity (FC) strengths; however, FC density needs more development in AD. Therefore, this study wanted to determine the alternations in resting-state functional connectivity density (FCD) induced by Alzheimer’s and mild cognitive impairment (MCI).MethodsOne hundred and eleven AD patients, 29 MCI patients, and 73 healthy controls (age- and sex-matched) were recruited and assessed using resting-state functional magnetic resonance imaging (MRI) scanning. The ultra-fast graph theory called FCD mapping was used to calculate the voxel-wise short- and long-range FCD values of the brain. We performed voxel-based between-group comparisons of FCD values to show the cerebral regions with significant FCD alterations. We performed Pearson’s correlation analyses between aberrant functional connectivity densities and several clinical variables with adjustment for age and sex.ResultsPatients with cognition decline showed significantly abnormal long-range FCD in the cerebellum crus I, right insula, left inferior frontal gyrus, left superior frontal gyrus, left inferior frontal gyrus, and right middle frontal gyrus. The short-range FCD changed in the cerebellum crus I, left inferior frontal gyrus, left superior occipital gyrus, and right middle frontal gyrus. The long- and short-range functional connectivity in the left inferior frontal gyrus was positively correlated with Mini-mental State Examination (MMSE) scores.ConclusionsFCD in the identified regions reflects mechanism and compensation for loss of cognitive function. These findings could improve the pathology of AD and MCI and supply a neuroimaging marker for AD and MCI.

P.427 Effect of autogenic training on brain activity in migraineurs without aura

Migraine is one of the most prevalent neurological disorders which is suggested to be associated with dysfunctions of the central nervous system. The purpose of the present study was to detect the altered functional connectivity architecture in the large-scale network of the whole brain in migraine without aura (MWoA). Meanwhile, the brain functional hubs which are targeted by MWoA could be identified. A new voxel-based method named functional connectivity density (FCD) mapping was applied to resting-state functional magnetic resonance imaging data of 55 female MWoA patients and 44 age-matched female healthy controls (HC). Comparing to HC, MWoA patients showed abnormal short-range FCD values in bilateral hippocampus, bilateral insula, right amygdale, right anterior cingulate cortex, bilateral putamen, bilateral caudate nucleus and the prefrontal cortex. The results suggested decreased intraregional connectivity of these pain-related brain regions in female MWoA. In addition, short-range FCD values in left prefrontal cortex, putamen and caudate nucleus were significantly negatively correlated with duration of disease in MWoA group, implying the repeated migraine attacks over time may consistently affect the resting-state functional connectivity architecture of these brain hubs. Our findings revealed the dysfunction of brain hubs in female MWoA, and suggested the left prefrontal cortex, putamen and caudate nucleus served as sensitive neuroimaging markers for reflecting the disease duration of female MWoA. This may provide us new insights into the changes in the organization of the large-scale brain network in MWoA.

Altered long- and short-range functional connectivity density associated with poor sleep quality in patients with chronic insomnia disorder: A resting-state fMRI study.

IntroductionPrevious neuroimaging studies have suggested that brain functional impairment and hyperarousal occur during the daytime among patients with chronic insomnia disorder (CID); however, alterations to the brain's intrinsic functional architecture and their association with sleep quality have not yet been documented.MethodsIn this study, our aim was to investigate the insomnia‐related alterations to the intrinsic connectome in patients with CID (n = 27) at resting state, with a data‐driven approach based on graph theory assessment and functional connectivity density (FCD), which can be interpreted as short‐range (intraregional) or long‐range (interregional) mapping.ResultsCompared with healthy controls with good sleep, CID patients showed significantly decreased long‐range FCD in the dorsolateral prefrontal cortices and the putamen. These patients also showed decreased short‐range FCD in their multimodal‐processing regions, executive control network, and supplementary motor‐related areas. Furthermore, several regions showed increased short‐range FCD in patients with CID, implying hyper‐homogeneity of local activity.ConclusionsTogether, these findings suggest that insufficient sleep during chronic insomnia widely affects cortical functional activities, including disrupted FCD and increased short‐range FCD, which is associated with poor sleep quality.

Altered Functional Connectivity Density in Young Survivors of Acute Lymphoblastic Leukemia Using Resting-State fMRI.

ObjectiveUsing functional connectivity density (FCD) mapping measured by resting-state functional magnetic resonance imaging (rs-fMRI), an ultrafast data-driven graph theory approach, we attempted to study the abnormalities in neural activity of young survivors of acute lymphoblastic leukemia (ALL) and to explore the neuropathological evidence of chemotherapy-related cognitive impairment of patients.MethodsTwenty young survivors of ALL and 18 well-matched healthy controls (HCs) were recruited in this study. All ALL patients and healthy controls underwent rs-fMRI scans and completed neurocognitive testing. The between-group differences in short-range and long-range FCD were calculated by the option of degree centrality (DC) in MATLAB software after preprocessing. The correlations between the FCD value and each of the neurocognitive outcomes were analyzed in the ALL patients.ResultsThe group-averaged FCD maps showed similar spatial patterns between the two groups. Compared with the HCs, ALL patients showed decreased long-range FCD in regions of the bilateral lingual gyrus, cingulate cortex, hippocampal gyrus, and right calcarine fissure. Simultaneously, decreased regions in the short-range FCD map were the bilateral lingual gyrus, cingulate cortex, parahippocampal gyrus and right calcarine fissure. Increased functional connectivity (FC) was observed between the region with decreased long-range FCD and the posterior cerebellar lobe, and decreased FC was observed between the region and the middle occipital gyrus, cuneus and lingual gyrus. Thus, there existed no brain areas with increased FCD. The decreased short-range FCD value of ALL patients was positively correlated with the score on the Digit Span Test (Forward), and the increased FC value was negatively correlated with the score on the Trail Making Test part A.ConclusionOur results suggest the altered functional connectivity of young survivors of ALL in the posterior region of the brain and posterior lobe of the cerebellum. Alterations in spontaneous neuronal activity seem to parallel the neurocognitive testing, which indicates that the rs-fMRI could be used as a neuroimaging marker for neurological impairment in ALL patients.

Resting-State Functional MRI Study Demonstrates That the Density of Functional Connectivity Density Mapping Changes in Patients with Acute Eye Pain.

PurposeBrain function in patients with acute eye pain (EP) has not been extensively studied. An understanding of the alterations in short-range functional connectivity density (shortFCD) and long-range functional connectivity density (longFCD) in patients with EP remains elusive. The aim of the present study was to compare the functional connectivity density (FCD) between patients with EP and healthy controls (HCs) using resting-state functional connectivity.MethodsA total of 40 patients with EP (26 males and 14 females) and 40 HCs (26 males and 14 females) of similar age underwent functional magnetic resonance (MR) examination at the resting state. The shortFCD and longFCD values were compared using the one-sample t-test. The differences between patients with EP and the HCs were evaluated using receiver operating characteristic (ROC) curves.ResultsIn the patients with EP, significantly reduced shortFCD values were observed in the left posterior lobe of the cerebellum, right inferior parietal lobule, and left anterior lobe of the cerebellum, and significantly reduced longFCD values were observed in both the left and right posterior lobe of the cerebellum. Significantly increased shortFCD values were also observed in both superior frontal gyri (Brodmann area 6), and increased longFCD values were observed in the left inferior temporal gyrus and left superior frontal gyri (Brodmann area 11). Compared with the HCs, less reduction was noted among the shortFCD values of patients with EP in the right posterior lobe of the cerebellum, right supramarginal gyrus, left middle temporal gyrus, bilateral superior frontal gyri, and bilateral caudate nuclei.ConclusionEP patients shown variation of binarized shortFCD and long FCD in brain areas including premotor cortex, ventral cortical visual system, newest part of the cerebellum, cerebellum control unconscious proprioception, inhibition of involuntary movement, somatosensory association cortex, nucleus involving reward system and ventral cortical visual system which might provide an explanation of brain functional compensation for chronic eye pain and visual impairment in the EP patients.

Altered resting-state functional connectivity density in patients with neuromyelitis optica-spectrum disorders

BackgroundNeuromyelitis optica spectrum disorder (NMOSD) is an autoimmune, demyelinating disorder, accompanied by abnormal spontaneous activity of the brain and impairment of the retina and optic nerve. Functional connectivity density (FCD) map, a graph theory method, was applied to explore the functional connectivity alterations of brian in NMOSD patients and investigate the alterations of FCD to the structural and microvascular changes around the optic nerve head (ONH). MethodsNineteen NMOSD patients and 22 healthy controls (HCs) were included in our study. All participants underwent resting-state functional magnetic resonance imaging (fMRI) scans of the brain, and ophthalmological examinations included optical coherence tomographic angiography (OCT-A) imaging, visual acuity (VA), and intraocular pressure (IOP). The long- and short-range FCD was calculated by the fMRI graph theory method and two-sample t-tests were performed to compare the discrepancy of FCD between NMOSD and HCs. OCT-A imaging was used to obtain the structure (peripapillary retinal nerve fiber layer, pRNFL) and microvessels (radial peripapillary capillary, RPC) details around the ONH. The association between the long- and short-range FCD values with the structural and microvascular variation around the ONH were evaluated using Spearman's correlation. ResultsSignificantly decreased (corrected p < 0.05) long-range FCD was seen in the right superior parietal gyrus (SPG) in patients with NMOSD when compared to HCs. Increased long-range FCD was seen in the right fusiform gyrus (FFG), left orbital part of superior frontal orbital gyrus (ORBsup) and left anterior cingulum and paracingulate gyri (ACG) in NMOSD patients (corrected p < 0.05). The regions with reduced short-range FCD in NMOSD were the left angular gyrus (ANG) and right SPG (corrected p < 0.05). Increased short-range FCD was shown (corrected p < 0.05) in the right FFG of NMOSD. The pRNFL thickness and RPC density in all participants were negatively correlated with the long-range FCD values in the right FFG, left ORBsup, and left ACG as well as short-range FCD values in the right FFG, besides, both were positively correlated with the long-range FCD values in the right SPG and short-range FCD values in the left ANG and right SPG (p < 0.05). ConclusionOur study demonstrates that patients with NMOSD have widespread brain dysfunction after optic neuritis attacks which shows as impairment of widespread spatial distribution in long- and short-range FCD. Structural and microvascular changes around the ONH are associated with neural changes in the brain.

Resting-state functional magnetic resonance imaging (fMRI) and functional connectivity density mapping in patients with corneal ulcer.

PurposeTo investigate alternations in spontaneous brain activities reflected by functional connectivity density (FCD) in patients with corneal ulcer (CU) using resting-state functional connectivity (rsFC).MethodsWe recruited 24 patients with CU (12 males, 12 females), and 24 healthy controls (HCs; 12 males, 12 females) matched for age, gender and education status. Functional magnetic resonance imaging examinations were performed on all subjects in a resting state and the following parameters determined: rsFC, long-range FCD (longFCD) and short-range FCD (IFCD). Receiver operating characteristic (ROC) curves were then used to differentiate patients with CU from HCs.ResultsCompared with HCs, CU patients showed significantly reduced rsFC values in the right cerebellum posterior lobe gyrus, right middle frontal gyrus/inferior frontal gyrus/superior frontal gyrus and left inferior parietal lobule/precuneus. Significantly reduced longFCD values were found in the right hippocampus/inferior temporal gyrus and the left inferior temporal gyrus. Moreover, compared with HCs, IFCD values were significantly reduced in the left inferior temporal gyrus/middle temporal gyrus, left limbic lobe/medial frontal gyrus, and left precuneus/limbic lobe, but were significantly increased in the right insula/superior temporal gyrus, left superior temporal gyrus/inferior frontal gyrus/insula, right superior temporal gyrus/postcentral gyrus, and left precentral gyrus.ConclusionsPatients with CU exhibited alterations in spontaneous brain activities in several brain areas. These novel findings may help to reveal the neuropathological mechanisms underlying CU.This study provides a direction for further exploration of underlying neural mechanisms of CU and facilitate the clinical diagnosis and treatment of CU.

Altered functional connectivity density in primary angle-closure glaucoma patients at resting-state.

Primary angle-closure glaucoma (PACG) is a neurodegenerative disease. Previous structural and functional studies of functional magnetic resonance imaging (fMRI) have demonstrated widespread dysfunction of spontaneous activity in the PACG brain. In this study, we applied a data-driven graph theory approach of functional connectivity density (FCD) mapping to investigate the altered local and global functional connectivity (FC) of the cortex in PACG. Forty-five PACG patients (53.28±10.79 years, 17 males/28 females) and 46 well-matched healthy controls (HCs) (52.67±11.01 years,18 males/28 females) received resting-state fMRI scans. All PACG patients finished complete ophthalmologic examinations, including retinal nerve fiber layer thickness (RNFLT), intraocular pressure (IOP), average cup to disc ratio (A-C/D), and vertical cup to disc ratio (V-C/D). We calculated the between-group FCD difference for short-range and long-range in each voxel. Then, we generated the intrinsic FC of the seed region with the whole brain. Finally, correlations were investigated between FCD value of the altered regions and clinical variables. PACG patients showed increased short-range FCD in the left inferior frontal gyrus (IFG)/insula/parahippocampal gyrus and right IFG/insula (P<0.05, corrected), compared with the HCs. Simultaneously, the decreased regions in short-range FCD map were the occipital/cuneus/precuneus/superior parietal/postcentral lobe (P<0.05, corrected). In the PACG groups, decreased long-range FCD was observed in the left middle frontal gyrus compared to the HC (P<0.05, corrected). RNFLT was positively correlated with decreased short-range FCD value of the occipital/cuneus/precuneus/superior parietal/postcentral lobes, and the A-C/D was negatively correlated with the increased short-range FCD value of the left IFG/insula/parahippocampal gyrus, and the right IFG/insula. Our findings suggest that PACG can induce extensive brain dysfunction, and showed different spatial distribution in short- and long-range FCD.

Disrupted Balance of Long- and Short-Range Functional Connectivity Density in Type 2 Diabetes Mellitus: A Resting-State fMRI Study.

Previous studies have shown that type 2 diabetes mellitus (T2DM) can accelerate the rate of cognitive decline in patients. As an organ with high energy consumption, the brain network balances between lower energy consumption and higher information transmission efficiency. However, T2DM may modify the proportion of short- and long-range connections to adapt to the inadequate energy supply and to respond to various cognitive tasks under the energy pressure caused by homeostasis alterations in brain glucose metabolism. On the basis of the above theories, this study determined the abnormal functional connections of the brain in 32 T2DM patients compared with 32 healthy control (HC) subjects using long- and short-range functional connectivity density (FCD) analyses with resting-state fMRI data. The cognitive function level in these patients was also evaluated by neuropsychological tests. Moreover, the characteristics of abnormal FCD and their relationships with cognitive impairment were investigated in T2DM patients. Compared with the HC group, T2DM patients exhibited decreased long-range FCD in the left calcarine and left lingual gyrus and increased short-range FCD in the right angular gyrus and medial part of the left superior frontal gyrus (p < 0.05, Gaussian random-field theory corrected). In T2DM patients, the FCD z scores of the medial part of the left superior frontal gyrus were negatively correlated with the time cost in part B of the Trail Making Test (ρ = -0.422, p = 0.018). In addition, the FCD z scores of the right angular gyrus were negatively correlated with the long-term delayed recall scores of the Auditory Verbal Learning Test (ρ = -0.356, p = 0.049) and the forward scores of the Digital Span Test (ρ = -0.373, p = 0.039). T2DM patients exhibited aberrant long-range and short-range FCD patterns, which may suggest brain network reorganization at the expense of losing the integration of long-range FCD to adapt to the deficiency in energy supply. These changes may be associated with cognitive decline in T2DM patients.

Abnormal Functional Connectivity Density in Post-Stroke Aphasia.

Post-stroke aphasia (PSA), which refers to the loss or impairment of language, is typically caused by left hemisphere lesions. Previous neuroimaging studies have indicated that the pathology of PSA may be related to abnormalities in functional integration. In this study, we used resting-state functional magnetic resonance imaging (rs-fMRI) to examine functional connectivity density (FCD) in PSA. We compared short- and long-range FCD between individuals with PSA (n = 17) and healthy controls (HC, n = 20). We then performed Pearson's correlation analysis on the FCD values from the affected brain regions and the speech scores in the PSA group. Compared with HCs, individuals with PSA showed increased short-range FCD in the contralesional temporal gyrus, the inferior frontal gyrus, the thalamus, the insula, and the mesial temporal gyrus [hippocampus/parahippocampus (HIP/ParaHIP)]. PSA demonstrated an increased long-range FCD in the contralesional mesial temporal gyrus (HIP/ParaHIP). PSA also displayed decreased short-range FCD in the ipsilesional part of the frontal gyrus, the caudate, the thalamus, the fusiform gyrus, and the mesial temporal gyrus (HIP/ParaHIP), and decreased long-range FCD in the ipsilesional superior temporal gyrus, the fusiform gyrus, and the mesial temporal gyrus (HIP/ParaHIP). The decreased long-range FCD in the left superior temporal gyrus in PSA subjects was positively correlated with the spontaneous speech score. The altered FCD observed due to disrupted functional connectivity after stroke may lead to language production, semantic processing, and cognitive impairments. Our findings expand previous functional studies on stroke and provide new evidence of the intraregional and interregional interactions at the voxel level in the pathophysiology of PSA.

Abnormal Functional Connectivity Density in Amyotrophic Lateral Sclerosis.

Purpose: Amyotrophic lateral sclerosis (ALS) is a motor neuro-degenerative disorder that also damages extra-motor neural pathways. A significant proportion of existing evidence describe alterations in the strengths of functional connectivity, whereas the changes in the density of these functional connections have not been explored. Therefore, our study seeks to identify ALS-induced alternations in the resting-state functional connectivity density (FCD).Methods: Two groups comprising of 38 ALS patients and 35 healthy participants (age and gender matched) were subjected to the resting-state functional magnetic resonance imaging (MRI) scanning. An ultra-fast graph theory method known as FCD mapping was utilized to calculate the voxel-wise short- and long-range FCD values of the brain for each participant. FCD values of patients and controls were compared based on voxels in order to discern cerebral regions that possessed significant FCD alterations. For areas demonstrating a group effect of atypical FCD in ALS, seed-based functional connectivity analysis was then investigated. Partial correlation analyses were carried out between aberrant FCDs and several clinical variables, controlling for age, gender, and total intracranial volume.Results: Patients with ALS were found to have decreased short-range FCD in the primary motor cortex and increased long-range FCD in the premotor cortex. Extra-motor areas that also displayed extensive FCD alterations encompassed the temporal cortex, insula, cingulate gyrus, occipital cortex, and inferior parietal lobule. Seed-based correlation analysis further demonstrated that these regions also possessed disrupted functional connectivity. However, no significant correlations were identified between aberrant FCDs and clinical variables.Conclusion: FCD changes in the regions identified represent communication deficits and impaired functional brain dynamics, which might underlie the motor, motor control, language, visuoperceptual and high-order cognitive deficits in ALS. These findings support the fact that ALS is a disorder affecting multiple systems. We gain a deeper insight of the neural mechanisms underlying ALS.

Altered Long- and Short-Range Functional Connectivity Density in Healthy Subjects After Sleep Deprivations.

Objective: To investigate the brain functional organization induced by sleep deprivation (SD) using functional connectivity density (FCD) analysis.Methods: Twenty healthy subjects (12 female, 8 male; mean age, 20.6 ± 1.9 years) participated a 24 h sleep deprivation (SD) design. All subjects underwent the MRI scan and attention network test twice, once during rested wakefulness (RW) status, and the other was after 24 h acute SD. FCD was divided into the shortFCD and longFCD. Receiver operating characteristic (ROC) curve was used to evaluate the discriminating ability of those FCD differences in brain areas during the SD status from the RW status, while Pearson correlations was used to evaluate the relationships between those differences and behavioral performances.Results: Subjects at SD status exhibited lower accuracy rate and longer reaction time relative to RW status. Compared with RW, SD had a significant decreased shortFCD in the left cerebellum posterior lobe, right cerebellum anterior lobe, and right orbitofrontal cortex, and increased shortFCD in the left occipital gyrus, bilateral thalamus, right paracentral lobule, bilateral precentral gyrus, and bilateral postcentral gyrus. Compared with RW, SD had a significant increased longFCD in the right precentral gyrus, bilateral postcentral gyrus, and right visuospatial network, and decreased longFCD in the default mode network. The area under the curve values of those specific FCD differences in brain areas were (mean ± std, 0.933 ± 0.035; 0.863~0.977). Further ROC curve analysis demonstrated that the FCD differences in those brain areas alone discriminated the SD status from the RW status with high degree of sensitivities (89.19 ± 6%; 81.3~100%) and specificities (89.15 ± 6.87%; 75~100%). Reaction time showed a negative correlation with the right orbitofrontal cortex (r = −0.48, p = 0.032), and accuracy rate demonstrated a positive correlation with the right default mode network (r = 0.573, p = 0.008).Conclusions: The longFCD and shortFCD analysis might be potential indicator biomarkers to locate the underlying altered intrinsic brain functional organization disturbed by SD. SD sustains the cognitive performance by the decreased high-order cognition related areas and the arousal and sensorimotor related areas.

Abnormal functional connectivity density in sleep-deprived subjects.

Sleep deprivation (SD) can alter the intrinsic brain functional organization. However, its effects on intrinsic low-frequency connectivity in the whole brain have not been well characterized. In this study, we used voxel-based functional connectivity density (FCD) analysis to investigate the effects of SD on the spontaneous functional organization of the brain. Thirty-seven healthy participants underwent this within-subject crossover functional magnetic resonance imaging (fMRI) study during rested wakefulness (RW) and after 36h of total sleep deprivation (TSD). Decreased long-/short-range FCDs were observed in the posterior cingulate cortex, precuneus, inferior parietal lobule, dorsolateral prefrontal cortex, dorsomedial prefrontal cortex, and ventromedial prefrontal cortex. Increased long-/short-range FCDs were found in the sensory integration and arousal regulating areas, including the postcentral gyrus, thalamus, superior temporal gyrus, and occipital-temporal cortex. Moreover, a significant negative correlation was found between the short-range FCD of the PCC and the reaction time of Psychomotor Vigilance Task. In the present study, spontaneous functional organization with significant group-wise differences between RW and TSD sessions was identified. Our findings extend our understanding of the neural mechanism of how brain activity is altered in sleep-deprived individuals.

Apolipoprotein E polymorphism affects brain functional connectivity density in healthy young adults: a resting-state functional MRI

Objective To explore the aberrance of brain activity in healthy young adults with apolipoprotein E (APOE) e2, e3 and e4 allele by the method of functional connectivity density (FCD) . Method Two hundred and thirteen young healthy adults underwent the 3 T resting-state functional MRI, the neuropsychological tests and genotype testing for e2, e3 and e4 allele. Age -and gender-matched individuals, including 14 subjects with APOE e2, 31 subjects with APOE e4 and 31 subjects with APOE e3 were enrolled for final analysis. FCD mapping was used to compare the brain functional connective networks among the three groups. All results were corrected with a Gaussian random field (GRF) (voxel-level of P<0.01 and joint cluster-level of P<0.05) . Correlation analysis was performed between abnormal short -and long-range FCD values and neuropsychological scores. Results Compared with APOE e3 carriers, the short -and long-range FCD values of APOE e2 carriers were increased in the frontal lobe, particularly in the medial prefrontal lobe (37 voxels, t=3.54) , anterior cingulate cortex (36 voxels, t=3.19) and orbital frontal cortex (41 voxels, t=3.72) , while APOE e4 carriers showed decreased short-range FCD in the bilateral cuneus (38 voxels, t=-3.68) . Moreover, the long-range FCD values of APOE e4 group were decreased in right orbital frontal cortex (46 voxels, t=-4.56) and increased in the right inferior parietal lobe (31 voxels, t=3.49) compared with that of APOE e2 group. No significant correlation was detected with Bonferroni correction. Conclusions The opposite FCD alteration in cuneus and inferior parietal lobe might be the early existence of inhibitory and compensatory mechanism modulated by the e4 allele in the young age, while the increased FCD in frontal lobe might be the underlying protective mechanism of delaying the onset of Alzheimer's disease. Key words: APOE polymorphism; Functional connectivity density; Alzheimer disease