White Matter Functional Connectivity Research Articles

Intracranial electrophysiological and structural basis of BOLD functional connectivity in human brain white matter

While functional MRI (fMRI) studies have mainly focused on gray matter, recent studies have consistently found that blood-oxygenation-level-dependent (BOLD) signals can be reliably detected in white matter, and functional connectivity (FC) has been organized into distributed networks in white matter. Nevertheless, it remains unclear whether this white matter FC reflects underlying electrophysiological synchronization. To address this question, we employ intracranial stereotactic-electroencephalography (SEEG) and resting-state fMRI data from a group of 16 patients with drug-resistant epilepsy. We find that BOLD FC is correlated with SEEG FC in white matter, and this result is consistent across a wide range of frequency bands for each participant. By including diffusion spectrum imaging data, we also find that white matter FC from both SEEG and fMRI are correlated with white matter structural connectivity, suggesting that anatomical fiber tracts underlie the functional synchronization in white matter. These results provide evidence for the electrophysiological and structural basis of white matter BOLD FC, which could be a potential biomarker for psychiatric and neurological disorders.

Disrupted White Matter Functional Connectivity With the Cerebral Cortex in Migraine Patients.

Background: In attempts to understand the migraine patients’ overall brain functional architecture, blood oxygenation level-dependent (BOLD) signals in the white matter (WM) and gray matter (GM) were considered in the current study. Migraine, a severe and multiphasic brain condition, is characterized by recurrent attacks of headaches. BOLD fluctuations in a resting state exhibit similar temporal and spectral profiles in both WM and GM. It is feasible to explore the functional interactions between WM tracts and GM regions in migraine.Methods: Forty-eight migraineurs without aura (MWoA) and 48 healthy controls underwent resting-state functional magnetic resonance imaging. Pearson’s correlations between the mean time courses of 48 white matter (WM) bundles and 82 gray matter (GM) regions were computed for each subject. Two-sample t-tests were performed on the Pearson’s correlation coefficients (CC) to compare the differences between the MWoA and healthy controls in the GM-averaged CC of each bundle and the WM-averaged CC of each GM region.Results: The MWoAs exhibited an overall decreased average temporal CC between BOLD signals in 82 GM regions and 48 WM bundles compared with healthy controls, while little was increased. In particular, WM bundles such as left anterior corona radiata, left external capsule and bilateral superior longitudinal fasciculus had significantly decreased mean CCs with GM in MWoA. On the other hand, 16 GM regions had significantly decreased mean CCs with WM in MWoA, including some areas that are parts of the somatosensory regions, auditory cortex, temporal areas, frontal areas, cingulate cortex, and parietal cortex.Conclusion: Decreased functional connections between WM bundles and GM regions might contribute to disrupted functional connectivity between the parts of the pain processing pathway in MWoAs, which indicated that functional and connectivity abnormalities in cortical regions may not be limited to GM regions but are instead associated with functional abnormalities in WM tracts.

White Matter Functional Connectivity in Resting-State fMRI: Robustness, Reliability, and Relationships to Gray Matter.

A comprehensive characterization of the spatiotemporal organization in the whole brain is critical to understand both the function and dysfunction of the human brain. Resting-state functional connectivity (FC) of gray matter (GM) has helped in uncovering the inherent baseline networks of brain. However, the white matter (WM), which composes almost half of brain, has been largely ignored in this characterization despite studies indicating that FC in WM does change during task and rest functional magnetic resonance imaging (fMRI). In this study, we identify 9 white matter functional networks (WM-FNs) and 9 gray matter functional networks (GM-FNs) of resting fMRI. Intraclass correlation coefficient (ICC) was calculated on multirun fMRI data to estimate the reliability of static functional connectivity (SFC) and dynamic functional connectivity (DFC). Associations between SFC, DFC, and their respective ICCs are estimated for GM-FNs, WM-FNs, and GM-WM-FNs. SFC of GM-FNs were stronger than that of WM-FNs, but the corresponding DFC of GM-FNs was lower, indicating that WM-FNs were more dynamic. Associations between SFC, DFC, and their ICCs were similar in both GM- and WM-FNs. These findings suggest that WM fMRI signal contains rich spatiotemporal information similar to that of GM and may hold important cues to better establish the functional organization of the whole brain.

Disrupted functional connectivity in white matter resting-state networks in unilateral temporal lobe epilepsy.

Unilateral temporal lobe epilepsy (TLE) is the most common type of focal epilepsy characterized by foci in the unilateral temporal lobe grey matters of regions such as the hippocampus. However, it remains unclear how the functional features of white matter are altered in TLE. In the current study, resting-state functional magnetic resonance imaging (fMRI) was performed on 71 left TLE (LTLE) patients, 79 right TLE (RTLE) patients and 47 healthy controls (HC). Clustering analysis was used to identify fourteen white matter networks (WMN). The functional connectivity (FC) was calculated among WMNs and between WMNs and grey matter. Furthermore, the FC laterality of hemispheric WMNs was assessed. First, both patient groups showed decreased FCs among WMNs. Specifically, cerebellar white matter illustrated decreased FCs with the cerebral superficial WMNs, implying a dysfunctional interaction between the cerebellum and the cerebral cortex in TLE. Second, the FCs between WMNs and the ipsilateral hippocampus (grey matter foci) were also reduced in patient groups, which may suggest insufficient functional integration in unilateral TLE. Interestingly, RTLE showed more severe abnormalities of white matter FCs, including links to the bilateral hippocampi and temporal white matter, than LTLE. Taken together, these findings provide functional evidence of white matter abnormalities, extending the understanding of the pathological mechanism of white matter impairments in unilateral TLE.

Effect of jet lag on brain white matter functional connectivity.

A long-haul flight across more than five time zones may produce a circadian rhythm sleep disorder known as jet lag. Little is known about the effect of jet lag on white matter (WM) functional connectivity (FC). The present study is to investigate changes in WM FC in subjects due to recovery from jet lag after flying across six time zones. Here, resting-state functional magnetic resonance imaging was performed in 23 participants within 24 hours of flying and again 50 days later. Gray matter (GM) and WM networks were identified by k-means clustering. WM FC and functional covariance connectivity (FCC) were analyzed. Next, a sliding window method was used to establish dynamic WM FC. WM static and dynamic FC and FCC were compared between when participants had initially completed their journey and 50 days later. Emotion was assessed using the Positive and Negative Affect Schedule and the State Anxiety Inventory. All participants were confirmed to have jet lag symptoms by the Columbian Jet Lag Scale. The static FC strengthes of cingulate network (WM7)- sensorimotor network and ventral frontal network- visual network were lower after the long-haul flight compared with recovery. Corresponding results were obtained for the dynamic FC analysis. The analysis of FCC revealed weakened connections between the WM7 and several other brain networks, especially the precentral/postcentral network. Moreover, a negative correlation was found between emotion scores and the FC between the WM7 and sensorimotor related regions. The results of this study provide further evidence for the existence of WM networks and show that jet lag is associated with alterations in static and dynamic WM FC and FCC, especially in sensorimotor networks. Jet lag is a complex problem that not only is related to sleep rhythm but also influences emotion.

Abnormal white matter functional connectivity density in antipsychotic-naive adolescents with schizophrenia

ObjectivesThis study aimed to assess the white matter (WM) functional hubs and abnormal functional connectivity pattern in adolescents with schizophrenia (AOS) and to explore the potential mechanisms. MethodsBased on resting-state fMRI data, we measured the WM functional connectivity density (FCD) at local- and long- ranges in 39 AOS and 31 healthy controls (HCs). Group comparison was conducted between the two groups. Spearman rank correlation analysis between the altered WM FCD and clinical PANSS scores was performed. ResultsIn the local scale, the functional hubs of the WM were mainly located in the corona radiata and cerebellum. Compared with HCs, AOS patients exhibited decreased FCD in the superior corona radiata. In the long-range, the functional hubs of the WM were mainly located in the external capsule and pons. AOS patients exhibited increased FCD in the cingulum but decreased FCD in the right dorsal raphe nuclei (DR). Furthermore, the aberrant long-range FCD in the right DR was inversely proportional to the clinical symptoms. ConclusionThese findings indicated that the pathophysiology of schizophrenia may also lie in WM functional dysconnectivity. SignificanceThe current results provided initial evidence for the hypothesis of abnormal WM functional connectivity in schizophrenia.

Effect of experimental orthodontic pain on gray and white matter functional connectivity.

AimOver 90% of patients receiving orthodontic treatment experience clinically significant pain. However, little is known about the neural correlates of orthodontic pain and which has therefore been investigated in the present study of healthy subjects using an experimental paradigm.MethodsResting‐state functional magnetic resonance imaging (rsfMRI) was performed in 44 healthy subjects 24 hours after an elastic separator had been introduced between the first and the second molar on the right side of the lower jaw and in 49 age‐ and sex‐matched healthy control (HC) subjects. A K‐means clustering algorithm was used to identify functional gray matter (GM) and white matter (WM) resting‐state networks, and differences in functional connectivity (FC) of GM and WM between the group of subjects with experimental orthodontic pain and HC were analyzed.ResultsTwelve GM networks and 14 WM networks with high stability were identified. Compared with HC, subjects with orthodontic pain showed significantly increased FC between WM12, which includes posterior thalamic radiation and posterior cingulum bundle, and most GM networks. Besides, the WM12 network showed significant differences in FC with three GM‐WM loops involving the default mode network, dorsal attention network, and salience network, respectively.ConclusionsOrthodontic pain is shown to produce an alteration of FC in networks relevant to pain processing, which may be mediated by a WM network relevant to emotion perception and cognitive processing.

Functional connectivity of white matter as a biomarker of cognitive decline in Alzheimer's disease.

ObjectiveIn vivo functional changes in white matter during the progression of Alzheimer’s disease (AD) have not been previously reported. Our objectives are to measure changes in white matter functional connectivity (FC) in an elderly population undergoing cognitive decline as AD develops, to establish their relationship to neuropsychological scores of cognitive abilities, and to assess the performance in prediction of AD using white matter FC measures as features.MethodsAnalyses were conducted using resting state functional MRI and neuropsychological data from 383 ADNI participants, including 136 cognitive normal (CN) controls, 46 with significant memory concern, 83 with early mild cognitive impairment (MCI), 37 with MCI, 46 with late MCI, and 35 with AD dementia. FC metrics between segregated white matter tracts and discrete gray matter volumes or between white matter tracts were quantitatively analyzed and characterized, along with their relationships to 6 cognitive measures. Finally, supervised machine learning was implemented on white matter FCs to classify the participants and performance of the classification was evaluated.ResultsSignificant decreases in FC measures were found in white matter with prominent, specific, regional deficits appearing in late MCI and AD dementia patients from CN. These changes significantly correlated with neuropsychological measurements of impairments in cognition and memory. The sensitivity and specificity of distinguishing AD dementia and CN using white matter FCs were 0.83 and 0.81 respectively.Conclusions and relevanceThe white matter FC decreased in late MCI and AD dementia patients compared to CN participants, and this decrease was correlated with cognitive measures. White matter FC is valuable in the prediction of AD. All these findings suggest that white matter FC may be a promising avenue for understanding functional impairments in white matter tracts during AD progression.

Disrupted white matter functional connectivity in aMCI APOEε4 carriers: a resting-state study.

The ε4 allele of the APOE gene is thought to increase risk from amnestic mild cognitive impairment (aMCI) to Alzheimer's disease. Cognitive decline in the condition is increasingly considered to worsen functional disconnections in brain network composed of gray matter and white matter. Nevertheless, Whether APOEε4 targets specific white matter functional connectivity in patients with aMCI remains mostly unexplored, mainly due to the challenges of detecting BOLD signals in white matter. Here, we applied a novel approach to investigate APOEε4-related specific bundles and cortical area alterations in aMCI subjects, in order to characterize white matter-gray matter functional connectivity differences throughout the brain. We analyzed 75 patients with aMCI and 76 demographically matched normal controls. The aMCI APOEε4 carriers showed decreased functional connectivity located at left corticospinal tract, bilateral posterior limb of internal capsule, and right temporopolaris, which was different from the regions of aMCI-related changes. We further found that recognition scores were positively associated with the right temporopolaris in aMCI APOEε4 carriers. Collectively, the data provide new evidence that APOEε4 genotype exerts a negative impact on neural activity in both gray and white matter in aMCI, which potentially contributes to functional disconnection and memory decline. A novel method provides full-scale measuring effect of disease conditions on functional architecture throughout the brain. Trial registration: https://www.ClinicalTrials.gov (Identifier: NCT02225964). Registered January 2014.

Effect of Jet Lag on Brain White Matter Functional Connectivity

Background: A long haul flight across more than five time zones may produce a circadian rhythm sleep disorder known as Jet Lag. Little is know about the effect of Jet Lag on white matter (WM) functional connectivity (FC). Methods: Resting-state functional Magnetic Resonance Imaging was performed in 23 participants within 24 hours of flying and again 50-days later. Gray (GM) and WM networks were identified by K-means clustering. WM FC and Functional Covariance Connectivity (FCC) analyzed. Next, a sliding window method was used to establish dynamic WM FC. WM static and dynamic FC and FCC were compared between when participants had initially completed their journey and 50-days later. Emotion was assessed by using the Positive and Negative Affect Schedule and the State Anxiety Inventory. All subjects were confirmed to have experienced Jet Lag by the Columbian Jet Lag Scale. Findings: The static FC of WM7-GM7, and WM14-GM4, were lower after the long haul flight compared with recovery. Corresponding results were obtained for the dynamic FC analysis. FCC between the cingulate network (WM7) and several brain networks was weaken and especially precentral/postcentral network. Emotion scores were negatively correlated with the FC between the WM7 and sensorimotor related regions. Interpretation: The results of this study provide further evidence for the existence of WM networks and show that Jet Lag is associated with alterations in static and dynamic WM FC and FCC especially in sensori-motor networks. Jet Lag is a complex problem which not only related with sleep rhythm but also influence emotion. Funding Statement: This study was supported by the National Natural Science Foundation (Grant Nos. 81971595, 81771812, 81761128023 and 81621003). Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT, Grant No. IRT16R52) of China, and the Science and Technology Department of Sichuan Province (2018SZ0391) and the Innovation Spark Project of Sichuan University (No. 2019SCUH0003). Declaration of Interests: The authors have no conflict of interest to declare. Ethics Approval Statement: The study was approved by the West China Hospital Ethics Committee of Sichuan University and prior to any investigations being performed each subject gave fully informed written consent of their willingness to participate.

Resting-state white matter-cortical connectivity in non-human primate brain

Numerous studies have used functional magnetic resonance imaging (fMRI) to characterize functional connectivity between cortical regions by analyzing correlations in blood oxygenation level dependent (BOLD) signals in a resting state. However, to date, there have been only a handful of studies reporting resting state BOLD signals in white matter. Nonetheless, a growing number of reports has emerged in recent years suggesting white matter BOLD signals can be reliably detected, though their biophysical origins remain unclear. Moreover, recent studies have identified robust correlations in a resting state between signals from cortex and specific white matter tracts. In order to further validate and interpret these findings, we studied a non-human primate model to investigate resting-state connectivity patterns between parcellated cortical volumes and specific white matter bundles. Our results show that resting-state connectivity patterns between white and gray matter structures are not randomly distributed but share notable similarities with diffusion- and histology-derived anatomic connectivities. This suggests that resting-state BOLD correlations between white matter fiber tracts and the gray matter regions to which they connect are directly related to the anatomic arrangement and density of WM fibers. We also measured how different levels of baseline neural activity, induced by varying levels of anesthesia, modulate these patterns. As anesthesia levels were raised, we observed weakened correlation coefficients between specific white matter tracts and gray matter regions while key features of the connectivity pattern remained similar. Overall, results from this study provide further evidence that neural activity is detectable by BOLD fMRI in both gray and white matter throughout the resting brain. The combined use of gray and white matter functional connectivity could also offer refined full-scale functional parcellation of the entire brain to characterize its functional architecture.

White matter functional connectivity as an additional landmark for dominant temporal lobectomy

Dominant temporal lobectomy is classically performed based on two criteria: a perfect knowledge of the temporo-mesial microsurgical anatomy and cortical landmarks laterally. However, the functional anatomy of the subcortical white...