Abnormal 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 Density in Type 2 Diabetes Mellitus with and without Mild Cognitive Impairment.

Although disturbed functional connectivity is known to be a factor influencing cognitive impairment, the neuropathological mechanisms underlying the cognitive impairment caused by type 2 diabetes mellitus (T2DM) remain unclear. To characterize the neural mechanisms underlying T2DM-related brain damage, we explored the altered functional architecture patterns in different cognitive states in T2DM patients. Thirty-seven T2DM patients with normal cognitive function (DMCN), 40 T2DM patients with mild cognitive impairment (MCI) (DMCI), and 40 healthy controls underwent neuropsychological assessments and resting-state functional MRI examinations. Functional connectivity density (FCD) analysis was performed, and the relationship between abnormal FCD and clinical/cognitive variables was assessed. The regions showing abnormal FCD in T2DM patients were mainly located in the temporal lobe and cerebellum, but the abnormal functional architecture was more extensive in DMCI patients. Moreover, in comparison with the DMCN group, DMCI patients showed reduced long-range FCD in the left superior temporal gyrus (STG), which was correlated with the Rey auditory verbal learning test score in all T2DM patients. Thus, DMCI patients show functional architecture abnormalities in more brain regions involved in higher-level cognitive function (executive function and auditory memory function), and the left STG may be involved in the neuropathology of auditory memory in T2DM patients. These findings provide some new insights into understanding the neural mechanisms underlying T2DM-related cognitive impairment.

Differential Abnormality in Functional Connectivity Density in Preclinical and Early-Stage Alzheimer's Disease.

BackgroundBoth subjective cognitive decline (SCD) and amnestic mild cognitive impairment (aMCI) have a high risk of progression to Alzheimer's disease (AD). While most of the available evidence described changes in functional connectivity (FC) in SCD and aMCI, there was no confirmation of changes in functional connectivity density (FCD) that have not been confirmed. Therefore, the purpose of this study was to investigate the specific alterations in resting-state FCD in SCD and aMCI and further assess the extent to which these changes can distinguish the preclinical and early-stage AD.MethodsA total of 57 patients with SCD, 59 patients with aMCI, and 78 healthy controls (HC) were included. The global FCD, local FCD, and long-range FCD were calculated for each voxel to identify brain regions with significant FCD alterations. The brain regions with abnormal FCD were then used as regions of interest for FC analysis. In addition, we calculated correlations between neuroimaging alterations and cognitive function and performed receiver-operating characteristic analyses to assess the diagnostic effect of the FCD and FC alterations on SCD and aMCI.ResultsFCD mapping revealed significantly increased global FCD in the left parahippocampal gyrus (PHG.L) and increased long-range FCD in the left hippocampus for patients with SCD when compared to HCs. However, when compared to SCD, patients with aMCI showed significantly decreased global FCD and long-range FCD in the PHG.L. The follow-up FC analysis further revealed significant variations between the PHG.L and the occipital lobe in patients with SCD and aMCI. In addition, patients with SCD also presented significant changes in FC between the left hippocampus, the left cerebellum anterior lobe, and the inferior temporal gyrus. Moreover, changes in abnormal indicators in the SCD and aMCI groups were significantly associated with cognitive function. Finally, combining FCD and FC abnormalities allowed for a more precise differentiation of the clinical stages.ConclusionTo our knowledge, this study is the first to investigate specific alterations in FCD and FC for both patients with SCD and aMCI and confirms differential abnormalities that can serve as potential imaging markers for preclinical and early-stage Alzheimer's disease (AD). Also, it adds a new dimension of understanding to the diagnosis of SCD and aMCI as well as the evaluation of disease progression.

Altered functional connectivity density in mild cognitive impairment with moxibustion treatment: A resting-state fMRI study

PurposeMild cognitive impairment (MCI) is a general neurodegenerative disease. Moxibustion has been shown to have remarkable effect on cognitive improvement, however, less is known about the effect of moxibustion on MCI and its underlying neural mechanism. This study aimed to investigate the ameliorative brain network in MCI after treatments of acupoint-related moxibustion. MethodsResting-state functional MRI were derived from 47 MCI patients and 30 healthy controls (HCs). Patients were randomized as Tiaoshen YiZhi (TSYZ, n = 27) and sham (SHAM, n = 20) acupoint moxibustion groups. Functional connectivity density (FCD) method and repeated-measures two-way analysis of variance (ANOVA) were performed to ascertain the interaction effects between groups (TSYZ and SHAM) and time (baseline and post-treatment). Abnormal FCD was examined between baseline and post-treatment in TSYZ and SHAM groups, respectively. ResultsCompared with HCs, MCI showed altered FCD in the middle frontal cortex (MFC), inferior frontal cortex, temporal pole, thalamus and middle cingulate cortex. After moxibustion treatment in MCI, 1) a significant time-by-groups interaction was observed in the medial prefrontal cortex (mPFC); 2) abnormal long-range FCD (lrFCD) in the mPFC and MFC were modulated in TSYZ group; 3) significantly improved clinical symptoms; 4) changed lrFCD in the MFC was significantly negatively correlated with the increased Montreal Cognitive Assessment scores in TSYZ group. ConclusionsThese imaging findings suggest that treatments of acupoint-related moxibustion could improve lrFCD in certain regions related to self-related cognitive and decision making. Our study might promote understanding of MCI neural mechanisms and expand the clinical application of moxibustion in MCI.

Abnormal Functional Connectivity Density in Patients with Dysthyroid Optic Neuropathy

Objective: Functional connectivity density (FCD) mapping was used to investigate abnormalities and factors related to brain functional connectivity in cortical regions of patients with dysthyroid optic neuropathy (DON) and to analyze the pathogenesis of DON further. Methods: Patients diagnosed with thyroid-associated opthalmology (TAO) in the Eye Hospital were enrolled. All patients underwent comprehensive eye examinations and best-corrected visual acuity, visual field (VF) test. MRI data collection and analysis were completed in the 2nd Affiliated Hospital of Wenzhou Medical University. The patients were divided into 2 groups: the DON group, with an average VF, mean deviation (MD) of both eyes < −5 dB, and the non-DON group (nDON group), with an average VF MD of both eyes ≥ −2 dB. Results: A total of 30 TAO patients (14 men, 16 women) with complete data who met the experimental requirements were enrolled. The average age was 48.79 (40–57) years. There were 16 patients in the DON group and 14 patients in the nDON group. No significant differences in age, gender, education level, and the maximum horizontal diameter of either medial rectus muscle were found between the 2 groups. The difference of brain FCD between the 2 groups showed significant abnormal connectivity in the right orbital gyri of the frontal lobe (Frontal_Inf_Orb_R) and the left precuneus in the DON group compared with the nDON group. As demonstrated by decreased FCD values in the right inferior frontal gyrus/orbital part, the relevant brain regions were the left middle temporal gyrus, left precuneus, left middle frontal gyrus, right postcentral gyrus, and brain gyri (excluding the supramarginal gyrus and angular gyrus) below the left parietal bone. The FCD associated with the left precuneus was increased, and the relevant brain areas were the left middle temporal gyrus, right cuneus, superior occipital gyrus, and right fusiform gyrus. A significant correlation was identified between the MD of the binocular VF and brain FCD. Conclusion: The abnormal FCD in the cortex of DON patients suggests that a central nervous system mechanism may be related to the pathogenesis of the DON.

Functional Connectivity Density with Frequency-Dependent Changes in Patients with Diffuse Axonal Injury: A Resting-State Functional Magnetic Resonance Imaging Study.

PurposeWe explored changes in spontaneous brain connectivity in patients with diffuse axonal injury (DAI), assessed via functional connectivity density (FCD) tests using different frequency bands.Patients and MethodsIn all, 23 patients with DAI (17 males and 6 females) and 23 healthy controls (HCs; 17 males and 6 females) were included. Functional magnetic resonance imaging scans were performed when the participants were in a resting state and the FCD levels in three frequency bands (slow-4: 0.027–0.073 Hz, slow-5: 0.01–0.027 Hz, and typical: 0.01–0.08 Hz) were measured. In addition, Pearson’s correlation coefficient was used to explore the relationship between clinical indices and brain regions with abnormal FCD values.ResultsCompared to HCs, DAI patients had significantly greater FCD values in the right extranuclear/limbic lobe/cingulate gyrus and left limbic lobe/hippocampus/parahippocampal gyrus, and significantly lower FCD values in the left precuneus/posterior cingulate gyrus, in the slow-4 band. In the slow-5 band, the DAI patients had higher FCD values in the left inferior temporal gyrus/superior temporal gyrus, left parahippocampal gyrus/limbic lobe, left extranuclear/cingulate gyrus, and right medial frontal gyrus, and lower values in the right inferior frontal gyrus, right inferior parietal lobule, and left cingulate gyrus/limbic lobe. Moreover, compared to HCs, the values in the typical band were higher in the right extranuclear/limbic lobe/hippocampus/parahippocampal gyrus, but were significantly lower in the right precuneus/posterior cingulate gyrus and right inferior parietal lobule/supramarginal gyrus. The abnormal FCD values of these brain regions were linearly correlated with different clinical scale scores.ConclusionDAI patients had abnormal FCD values in various brain regions, indicating disruption to the brain functional network. Moreover, the values were frequency dependent. Our results provide new evidence for the pathogenesis of functional impairment and may explain the neuropathological or compensatory mechanism of the disease.

Abnormal functional connectivity density in patients with major depressive disorder with comorbid insomnia

BackgroundInsomnia is a common comorbidity symptom in patients with major depressive disorder (MDD). However, the brain functional alteration in MDD with higher level insomnia (MDD-HI) and lower level insomnia (MDD-LI) remains unclear. Here, we investigated the association of insomnia with global functional connectivity density (gFCD) in patients with MDD. MethodsA total of 148 participants were recruited and underwent resting-state functional magnetic resonance imaging. A voxel-wise analysis of covariance was employed to explore group differences in gFCD among the MDD-HI, MDD-LI and healthy control (HC) groups. ResultsThe gFCD in the bilateral parahippocampal/hippocampal gyri (PHG/HIP) was higher in the two MDD than in the HC group, and it was higher in the MDD-LI than in the MDD-HI group; the gFCD in the left fusiform area was lower in the MDD than in the HC group. The gFCD in the left inferior temporal gyrus (ITG) was higher in the MDD-HI than in the MDD-LI and HC groups. The gFCD in the left ITG and posterior PHG/HIP was associated with insomnia, while the gFCD in the left anterior PHG/HIP was correlated with non-insomnia depressive symptoms in the MDD group. LimitationsThe cross-sectional design and the use of brief/subjective insomnia assessments. ConclusionsThe present study showed that the abnormal brain features of MDD with different insomnia symptom. Importantly, the posterior and anterior parts of the hippocampus may play different roles in the presence or absence of insomnia in patients with MDD.

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 functional connectivity density in patients with herpes zoster and postherpetic neuralgia.

PurposeThe aim of this study was to explore intrinsic functional connectivity patterns in patients with herpes zoster (HZ) and postherpetic neuralgia (PHN).Patients and methodsThirty-three right-handed HZ patients (13 males; mean age 57.15±9.30 years), 22 right-handed PHN patients (9 males; mean age 66.13±6.77 years), and 28 well-matched healthy controls (HC) (9 males; mean age 54.21±7.72 years) underwent resting-state functional magnetic resonance imaging for intrinsic functional connectivity analyses. Functional connectivity density (FCD) was calculated and compared among the PHN, HZ, and HC groups. In addition, the Pearson correlation coefficient was calculated to compare various clinical indices in the regions with abnormal FCD values.ResultsCompared with the HC, both HZ and PHN patients showed significantly decreased FCD in the precuneus, and patients with HZ displayed significantly increased FCD in the brainstem/limbic lobe/parahippocampalgyrus, whereas patients with PHN displayed significantly increased FCD in the hippocampus (correlation thresholds r=0.25, voxel level of P<0.01 and Gaussian random field theory at a cluster level of P<0.05). However, the FCD was not significantly different between the PHN and HZ patients. Furthermore, the decreased FCD in the precuneus was positively correlated with the visual analog scale score in the PHN group (r=0.672; P=0.001).ConclusionDecreased connectivity of the precuneus occurred in both HZ and PHN patients, indicating a disrupted default-mode network. Furthermore, in the HZ group (initial stage of the virus infection), hyperconnectivity was observed in systems involved in pain transmission and interpretation, but hyperconnectivity only occurred in the hippocampus in the PHN group (neuropathic pain stage).

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.

Disrupted functional connectivity density in irritable bowel syndrome patients.

Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder resulting from a dysregulation of the brain-gut axis. However, its exact neural substrate still remains unclear. This study investigated the changes of intrinsic whole brain functional connectivity pattern in IBS using functional connectivity density (FCD). We acquired resting-state functional magnetic resonance imaging (rs-fMRI) data from thirty-two IBS patients and thirty-two healthy controls. Functional connectivity density, a data-driven algorithm, was used to compute the long-range and short-range FCD values for each voxel in the brain of each subject, implying the amount of distant and local functional connections of cortical hubs. The FCD maps were compared between IBS patients and healthy controls. Pearson correlations analysis was also performed between abnormal FCD values and clinical/psychometric scores in patients. Compared to healthy controls, IBS patients showed concurrently decreased long- and short-range FCD in bilateral anterior midcingulate cortices (aMCC) and inferior parietal lobules (IPL), and decreased long-range FCD in right anterior insula, and decreased short-range FCD in bilateral prefrontal cortices, subgenual anterior cingulate cortices and caudates. IBS patients also had concurrently increased long- and short-range FCD mainly in primary sensorimotor cortices, as well as increased long-range FCD in right supplementary motor area and increased short-range FCD in occipital lobe. In addition, some regions with altered FCD showed abnormal functional connectivity in brain regions involved in pain matrix of IBS patients. Furthermore, the abnormal FCD values in right anterior insula and left caudate showed significant correlation with severity of symptoms and disease duration of IBS patients respectively. In conclusion, patients with IBS have widely disrupted FCD, which decreased in brain regions involved in homeostatic afferent network, emotional arouse, and cognitive regulation, while increased in regions associated with sensorimotor modulation. And the observed functional connectivity alterations unveiled complicated working patterns of pain matrix in IBS patients. This study may provide us with new insight into the underlying brain network topology of IBS.

Abnormal functional connectivity density in patients with ischemic white matter lesions: An observational study.

White matter lesions (WMLs) are frequently detected in elderly people. Previous structural and functional studies have demonstrated that WMLs are associated with cognitive and motor decline. However, the underlying mechanism of how WMLs lead to cognitive decline and motor disturbance remains unclear. We used functional connectivity density mapping (FCDM) to investigate changes in brain functional connectivity in 16 patients with ischemic WMLs and 13 controls. Both short- and long-range FCD maps were computed, and group comparisons were performed between the 2 groups. A correlation analysis was further performed between regions with altered FCD and cognitive test scores (Mini-Mental State Examination [MMSE] and Montreal Cognitive Assessment [MoCA]) in the patient group. We found that patients with ischemic WMLs showed reduced short-range FCD in the temporal cortex, primary motor cortex, and subcortical region, which may account for inadequate top-down attention, impaired motor, memory, and executive function associated with WMLs. The positive correlation between primary motor cortex and MoCA scores may provide evidence for the influences of cognitive function on behavioral performance. The inferior parietal cortex exhibited increased short-range FCD, reflecting a hyper bottom-up attention to compensate for the inadequate top-down attention for language comprehension and information retrieval in patients with WMLs. Moreover, the prefrontal and primary motor cortex showed increased long-range FCD and the former positively correlated with MoCA scores, which may suggest a strategy of cortical functional reorganization to compensate for motor and executive deficits. Our findings provide new insights into how WMLs cause cognitive and motor decline from cortical functional connectivity perspective.

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.

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.

Altered functional connectivity density in major depressive disorder at rest.

Major depressive disorder is characterized by abnormal brain connectivity at rest. Currently, most studies investigating resting-state activity rely on a priori restrictions on specific networks or seed regions, which may bias observations. We hence sought to elicit functional alterations in a hypothesis-free approach. We applied functional connectivity density (FCD) to identify abnormal connectivity for each voxel in the whole brain separately. Comparing resting-state fMRI in 21 MDD patients and 23 matched healthy controls, we identified atypical connections for regions exhibiting abnormal FCD and compared our results to those of an independent component analysis (ICA) on networks previously investigated in MDD. Patients showed reduced FCD in mid-cingulate cortex (MCC) and increased FCD in occipital cortex (OCC). These changes in global FCD were driven by abnormal local connectivity changes and reduced functional connectivity (FC) toward the left amygdala for MCC, and increased FC toward the right supplementary motor area for OCC. The altered connectivity was not reflected in ICA comparison of the salience and visual networks. Abnormal FC in MDD is present in cingulate and OCC in terms of global FCD. This converges with previous structural and metabolic findings; however, these particular changes in connectivity would not have been identified using canonical seed regions or networks. This implies the importance of FC measures in the investigation of brain pathophysiology in depression.

Abnormal functional connectivity density in Parkinson's disease

The pathology of Parkinson's disease (PD) is not confined to the nigrostriatal pathway, but also involves widespread cerebral cortical areas. Using seed-based resting state functional connectivity, many previous studies have demonstrated that PD patients have abnormal functional integration. However, this technique strongly relies on a priori selection of the seed regions and may miss important unpredictable findings. Using an ultrafast voxel-wise functional connectivity density approach, this study performed a whole brain functional connectivity analysis to investigate the abnormal resting-state functional activities in PD patients. Compared with healthy controls, PD patients exhibited decreased short-range functional connectivity densities in regions that were mainly located in the ventral visual pathway and decreased long-range functional connectivity densities in the right middle and superior frontal gyrus, which have been speculated to be associated with visual hallucinations and cognitive dysfunction, respectively. PD patients also exhibited increased short- and long-range functional connectivity densities in the bilateral precuneus and posterior cingulate cortex, which may represent a compensatory process for maintaining normal brain function. The observed functional connectivity density alterations might be related to the disturbed structural connectivity of PD patients, leading to abnormal functional integration. Our results suggest that functional connectivity density mapping may provide a useful means to assess PD-related neurodegeneration and to study the pathophysiology of PD.

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.