Disrupted functional connectivity in social anxiety disorder: a resting-state fMRI study

Dysfunction of the corticolimbic circuitry has been highlighted in social anxiety disorder (SAD) during social stimuli. However, few studies have investigated functional connectivity in SAD during the resting state, which may improve our understanding of SAD pathophysiology. The aim of this study was to investigate whether whole-brain functional connectivity might be aberrant in SAD patients, and if so, whether these changes are related to the measured clinical severity. Seventeen SAD patients and 19 healthy controls participated in resting-state functional magnetic resonance imaging. The brain was first divided into 90 paired brain regions and functional connectivity was then estimated by temporal correlation between each of these regions. Furthermore, connections that were significantly disrupted in SAD patients were correlated with clinical severity measured using the Liebowitz Social Anxiety Scale. Compared with healthy controls, SAD patients showed decreased positive connections within the frontal lobe and decreased negative connections between the frontal and occipital lobes. In particular, the weaker negative connections between the frontal lobe, which mainly involved the right median prefrontal cortex, and the occipital lobe had a significant positive correlation with the severity of SAD symptoms. The results support the hypothesis that some abnormalities of functional connectivity exist in SAD patients, which relate to the frontal cortex and occipital cortex. In addition, decreased functional connectivity between the frontal and occipital lobes and within the frontal lobe might be related to abnormal information processing and reflect disturbed neural organization resulting in defective social cognition, which could represent an early imaging biomarker for SAD.     

Aberrant resting-state cerebral blood flow and its connectivity in primary dysmenorrhea on arterial spin labeling MRI

PurposeThis study aimed to clarify the resting-state cerebral blood flow alteration patterns induced by primary dysmenorrhea, investigate the relationships between cerebral blood flow alterations and clinical parameters of patients with primary dysmenorrhea, and explore whether brain regions with abnormal cerebral blood flow also feature functional connectivity changes.MethodsArterial spin labeling imaging and clinical parameters were acquired in 42 patients with primary dysmenorrhea and 41 healthy controls during their menstrual phases. Differences in cerebral blood flow were compared between the two groups, and the clusters with significant group differences were selected as the regions of interest for further statistical analyses.ResultsCompared to healthy controls, patients with primary dysmenorrhea exhibited increased cerebral blood flow in the bilateral precuneus, left posterior cingulate cortex, and right rolandic operculum. Among patients with primary dysmenorrhea, we identified a negative correlation between the cerebral blood flow in the right rolandic operculum and the visual analogue score for anxiety, and greater correlation between the functional connectivity in the precuneus/posterior cingulate cortex and the right middle cingulate cortex, and between the right rolandic operculum and the left inferior parietal lobule and the bilateral postcentral gyrus.DiscussionCerebral blood flow abnormalities associated with primary dysmenorrhea were mainly concentrated in the areas comprising the default mode network in primary dysmenorrhea patients, which could be involved in the central mechanism of primary dysmenorrhea. Cerebral blood flow alteration in the rolandic operculum may underlie an anxiety-induced compulsive tendency in patients with primary dysmenorrhea. Investigating the enhanced connectivity among various pain-related brain regions could improve understanding of the onset and development of primary dysmenorrhea.     

5HTTLPR predicts left fusiform gyrus activation to positive emotional stimuli

This study was designed to replicate and extend past research examining the impact of the serotonin transporter gene-linked polymorphic region (5HTTLPR) on neural activation during emotional processing. Six women with at least one short allele were compared to six age-matched women with long/long alleles of the 5HTTLPR. Participants were shown 36 positive and 36 negative slides from the International Affective Picture Set, while functional images were acquired using a 4-T magnetic resonance imaging scanner. Although we were unable to replicate past research demonstrating relatively increased amygdala activation among individuals with an "s" allele to negative stimuli, women with an s allele evidenced decreased left fusiform gyrus activation to positive emotional stimuli (as expected). We suggest that women with a short allele may be either less attentive or less "expert" with regard to positive emotional stimuli, and ideas for future research are presented.     

Both projection and commissural pathways are disrupted in individuals with chronic stroke: investigating microstructural white matter correlates of motor recovery

ABSTRACT: BACKGROUND: Complete recovery of motor function after stroke is rare with deficits persisting into the chronic phase of recovery. Diffusion tensor imaging (DTI) can evaluate relationships between white matter microstructure and motor function after stroke. The objective of this investigation was to characterize microstructural fiber integrity of motor and sensory regions of the corpus callosum (CC) and descending motor outputs of the posterior limb of the internal capsule (PLIC) in individuals with chronic stroke and evaluate the relationships between white matter integrity and motor function. RESULTS: Standardized measures of upper extremity motor function were measured in thirteen individuals with chronic stroke. Manual dexterity was assessed in thirteen healthy age-matched control participants. DTI scans were completed for each participant. Fractional anisotropy (FA) of a cross-section of sensory and motor regions of the CC and the PLIC bilaterally were quantified. Multivariate analysis of variance evaluated differences between stroke and healthy groups. Correlational analyses were conducted for measures of motor function and FA. The stroke group exhibited reduced FA in the sensory (p = 0.001) region of the CC, contra- (p = 0.032) and ipsilesional (p = 0.001) PLIC, but not the motor region of the CC (p = 0.236). In the stroke group, significant correlations between contralesional PLIC FA and level of physical impairment (p = 0.005), grip strength (p = 0.006) and hand dexterity (p = 0.036) were observed. CONCLUSIONS: Microstructural status of the sensory region of the CC is reduced in chronic stroke. Future work is needed to explore relationships between callosal sensorimotor fiber integrity and interhemispheric interactions post-stroke. In addition, contralesional primary motor output tract integrity is uniquely and closely associated with multiple dimensions of motor recovery in the chronic phase of stroke suggesting it may be an important biomarker of overall motor recovery.     

A serial functional connectivity MRI study in healthy individuals assessing the variability of connectivity measures: reduced interhemispheric connectivity in the motor network during continuous performance

To date, little data is available on the reproducibility of functional connectivity MRI (fcMRI) studies. Here, we tested the variability and reproducibility of both the functional connectivity itself and different statistical methods to analyze this phenomenon. In the main part of our study, we repeatedly examined two healthy subjects in 10 sessions over 6 months with fcMRI. Cortical areas involved in motor function were examined under two different cognitive states: during continuous performance (CP) of a flexion/extension task of the fingers of the right hand and while subjects were at rest. Connectivity to left primary motor cortex (lSM1) was calculated by correlation analysis. The resulting correlation coefficients were transformed to z-scores of the standard normal distribution. For each subject, multisession statistical analyses were carried out with the z-score maps of the resting state (RS) and the CP experiments. First, voxel based t tests between the two groups of fcMRI experiments were performed. Second, ROI analyses were carried out for contralateral right SM1 and for supplementary motor area (SMA). For both ROI, mean and maximum z-score were calculated for each experiment. Also, the fraction of significantly (P<.05) correlated voxels (FCV) in each ROI was calculated. To evaluate the differences between the RS and the CP condition, paired t tests were performed for the mean and maximum z-scores, and Wilcoxon signed ranks tests for matched pairs were carried out for the FCV. All statistical methods and connectivity measures under investigation yielded a distinct loss in left–right SM1 connectivity under the CP condition. For SMA, interindividual differences were apparent. We therefore repeated the fcMRI experiments and the ROI analyses in a group of seven healthy subjects (including the two subjects of the main study). In this substudy, we were able to verify the reduction of left–right SM1 connectivity during unilateral performance. Still, the direction of SMA to lSM1 connectivity change during the CP condition remained undefined as four subjects showed a connectivity increase and three showed a decrease. In summary, we were able to demonstrate a distinct reduction in left–right SM1 synchrony in the CP condition compared to the RS both in the longitudinal and in the multisubject study. This effect was reproducible with all statistical methods and all measures of connectivity under investigation. We conclude that despite intra- and interindividual variability, serial and cross-sectional assessment of functional connectivity reveals stable and reliable results.     

fMRI assessment of thalamocortical connectivity during attentional performance

Functional magnetic resonance imaging (fMRI) studies have shown dysfunction in key areas associated with the thalamocortical circuit in patients with schizophrenia. This study examined the functional connectivity involving the frontal-thalamic circuitry during a spatial focusing-of-attention task in 18 unmedicated patients with schizophrenia and 38 healthy controls. Functional connectivity was analyzed by assigning seed regions (in the thalamic nuclei (mediodorsal nucleus (MDN), pulvinar, anterior nucleus (AN)), the dorsolateral prefrontal cortex (Brodmann areas 9 and 46), and the caudate), and correlating their respective activity with that in the non-seed regions voxel-wise. Functional connectivity analysis demonstrated that functional connectivity was significantly impaired in patients, e.g., between the right pulvinar and regions such as the prefrontal and temporal cortices and the cerebellum. On the other hand, enhanced functional connectivity was found in patients e.g., between the AN and regions such as the prefrontal and temporal cortices. In addition, the patients had significantly lower task performance and less (but non-significant) brain activation than those of controls. These results revealed disturbed functional integration in schizophrenia, and suggested that the functional connectivity abnormalities in the thalamocortical circuitry, especially the frontal-thalamic circuitry, may underlie the attention deficits in schizophrenia patients. Further, this study suggested that functional connectivity analysis might be more sensitive than brain activation analysis in detecting the functional abnormalities in schizophrenia.     

Measuring asymmetric temporal interdependencies in simulated and biological networks

We use a newly developed metric to characterize asymmetric temporal interdependencies in networks of coupled dynamical elements. We studied the formation of temporal ordering in a system of coupled Rossler oscillators for different connectivity ratios and network topologies and also applied the metric to investigate the functional structure of a biological network (cerebral ganglia of Helix snail). In the former example we show how the local ordering evolves to the global one as a function of structural parameters of the network, while in the latter we show spontaneous emergence of functional interdependence between two groups of electrodes.     

Quantitative mapping of diffusion characteristics under the cortical surface

Recent studies have demonstrated regional segregations on several peripheral white matter (WM) regions, which may imply different anatomical or functional characteristics [Cereb Cortex 17(4) 2007 816–25; Neuroimage 37(2) 2007 599–610; J Cogn Neurosci 16(7) 2004 1227–33]. Nonetheless, little is known about overall patterns of peripheral WM across the regions. In this study, diffusion tensor imaging with 2-mm isovoxel resolution and cortical surface mapping were combined to determine peripheral WM structure. Fractional anisotropy (FA) mapping showed consistent regional patterns across the young normal subjects while significant high or low FA values were shown in the motor-somatosensory cortex, prefrontal cortex, temporal, and medial occipital cortex. By adopting both region of interest and connectivity analysis, results were then discussed with structural network properties as well as WM maturation process.     

Low-frequency BOLD fluctuations demonstrate altered thalamocortical connectivity in diabetic neuropathic pain

Background  

In this paper we explored thalamocortical functional connectivity in a group of eight patients suffering from peripheral neuropathic pain (diabetic pain), and compared it with that of a group of healthy subjects. We hypothesized that functional interconnections between the thalamus and cortex can be altered after years of ongoing chronic neuropathic pain.     

Diffusion tensor imaging reveals microstructural alteration of the trigeminal nerve root in classical trigeminal neuralgia without neurovascular compression and correlation with outcome after internal neurolysis

ObjectivesDiffusion tensor imaging (DTI) has been used to detect microstructural alteration and effect of surgical treatment of the trigeminal nerve root (TR) in patients with classical trigeminal neuralgia (CTN) underwent microvascular decompression (MVD). Patients with CTN without neurovascular compression (woNVC) is a special population of TN, however, the pathogenesy of CTN woNVC and the mechanism of internal neurolysis (IN) remain unknown.Materials and methods21 patients with CTN woNVC who underwent IN and 20 healthy controls were included in this study. The differences in the means, kurtosis and skewness of fractional anisotropy (FA) and apparent diffusion coefficient (ADC) between the affected and unaffected nerves in patients and both nerves in controls were investigated by independent t-test and paired t-test respectively. Longitudinal changes of FA and ADC were correlated with outcome of IN via Spearman correlation coefficient.ResultsSignificant differences were found in preoperative mean and kurtosis values for both FA and ADC of the affected side TR, compared to the unaffected side and control group respectively. However, these differences remarkably reduced postoperatively. Further, the Spearman correlation coefficient showed a strong negative correlation between decrease of ADC in the affected side and the surgical outcome in BNI total score.ConclusionThe changes of diffusive property of TR, especially the FA and ADC, provide alternative radiological evidence for evaluating the mechanism of CTN woNVC. The modification of DTI metrics could be an effective factor for providing potential noninvasive biomarkers for determining the prognosis of patients with CTN woNVC underwent IN.     

Detecting functional connectivity in the resting brain: a comparison between ICA and CCA

Independent component analysis (ICA) and cross-correlation analysis (CCA) are general tools for detecting resting-state functional connectivity. In this study, we jointly evaluated these two approaches based on simulated data and in vivo functional magnetic resonance imaging data acquired from 10 resting healthy subjects. The influence of the number of independent components (maps) on the results of ICA was investigated. The influence of the selection of the seeds on the results of CCA was also examined. Our results reveal that significant differences between these two approaches exist. The performance of ICA is superior as compared with that of CCA; in addition, the performance of ICA is not significantly affected by structured noise over a relatively large range. The results of ICA could be affected by the number of independent components if this number is too small, however. Converting the spatially independent maps of ICA into z maps for thresholding tends to overestimate the false-positive rate. However, the overestimation is not very severe and may be acceptable in most cases. The results of CCA are dependent on seeds location. Seeds selected based on different criteria will significantly affect connectivity maps.     

Single-subject manual independent component analysis and resting state fMRI connectivity outcomes in patients with juvenile absence epilepsy

The quality of fMRI data impacts functional connectivity measures and consequently, the decisions that clinicians and researchers make regarding functional connectivity interpretation. The present study used resting state fMRI to investigate resting state network connectivity in a sample of patients with Juvenile Absence Epilepsy. Single-subject manual independent component analysis was used in two levels, whereby all noise components were removed, and cerebrospinal fluid pulsation components only were isolated and removed. Improved temporal signal to noise ratios and functional connectivity metrics were observed in each of the cleaning levels for both epilepsy and control cohorts. Results showed full, single-subject manual independent component analysis reduced the number of functional connectivity correlations and increased the strength of these correlations. Similar effects were also observed for the cerebrospinal fluid pulsation only cleaned data relative to the uncleaned, and fully cleaned data. Single-subject manual independent component analysis coupled with short TR multiband acquisition can significantly improve the validity of findings derived from fMRI data sets.     

Crossing fibers, diffractions and nonhomogeneous magnetic field: correction of artifacts by bipolar gradient pulses

In recent years, diffusion tensor imaging (DTI) and its variants have been used to describe fiber orientations and q-space diffusion MR was proposed as a means to obtain structural information on a micron scale. Therefore, there is an increasing need for complex phantoms with predictable microcharacteristics to challenge different indices extracted from the different diffusion MR techniques used. The present study examines the effect of diffusion pulse sequence on the signal decay and diffraction patterns observed in q-space diffusion MR performed on micron-scale phantoms of different geometries and homogeneities. We evaluated the effect of the pulse gradient stimulated-echo, the longitudinal eddy current delay (LED) and the bipolar LED (BPLED) pulse sequences. Interestingly, in the less homogeneous samples, the expected diffraction patterns were observed only when diffusion was measured with the BPLED sequence. We demonstrated the correction ability of bipolar diffusion gradients and showed that more accurate physical parameters are obtained when such a diffusion gradient scheme is used. These results suggest that bipolar gradient pulses may result in more accurate data if incorporated into conventional diffusion-weighted imaging and DTI.     

Symbiotic relationship between brain structure and dynamics

Background  

Brain structure and dynamics are interdependent through processes such as activity-dependent neuroplasticity. In this study, we aim to theoretically examine this interdependence in a model of spontaneous cortical activity. To this end, we simulate spontaneous brain dynamics on structural connectivity networks, using coupled nonlinear maps. On slow time scales structural connectivity is gradually adjusted towards the resulting functional patterns via an unsupervised, activity-dependent rewiring rule. The present model has been previously shown to generate cortical-like, modular small-world structural topology from initially random connectivity. We provide further biophysical justification for this model and quantitatively characterize the relationship between structure, function and dynamics that accompanies the ensuing self-organization.     

Sources of T1 variance in normal human white matter

The major factors contributing to T1 variance at 0.5 T in white matter were studied in healthy people. Anatomical location of the white matter sampled and differences between individuals contributed 74% of the total variance in serial measurements of the same subjects. There was also significant change over time within an individual subject that could not be attributed to machine drift. This information permitted estimates to be made concerning adequate sample size in future studies that examine for pathological white matter T1 change.     

A virtual trajectory model predicts differences in vocal fold kinematics in individuals with vocal hyperfunction

A simple, one degree of freedom virtual trajectory model of vocal fold kinematics was developed to investigate whether kinematic features of vocal fold movement confirm increased muscle stiffness. Model simulations verified that increases in stiffness were associated with changes in kinematic parameters, suggesting that increases in gesture rate would affect kinematic features to a lesser degree in vocal hyperfunction patients given the increased levels of muscle tension they typically employ to phonate. This hypothesis was tested experimentally in individuals with muscle tension dysphonia (MTD; N = 10) and vocal nodules (N = 10) relative to controls with healthy normal voice (N = 10) who were examined with trans-nasal endoscopy during a simple vocal fold abductory-adductory task. Kinematic measures in MTD patients were less affected by increased gesture rate, consistent with the hypothesis that these individuals have elevated typical laryngeal muscle tension. Group comparisons of the difference between medium and fast gesture rates (Mann-Whitney, one-tailed) showed statistically significant differences between the control and MTD individuals on the two kinematic features examined (p<0.05). Results in nodules participants were mixed and are discussed independently. The findings support the potential use of vocal fold kinematics as an objective clinical assay of vocal hyperfunction.     

Can MRI Contribute to the Understanding and Therapy of Mental Diseases?

The nowadays most accepted hypothesis of the origin of mental diseases is an impaired connectivity between various brain areas. Magnetic resonance tractography reveals structural connectivities through neuronal fibers and resting state functional imaging allows one to visualize functional connectivities. The detection of the small signal changes needs the highest sensitivity and the magnetic resonance imaging scans must be repeated as fast as possible. Statistical evaluation and cross correlation of the signals in all voxels show synchrony of signal-level fluctuations even in remote brain areas. This makes it possible to establish brain networks. The most important of them are the default mode network, the salience network, and the central executive network. Applications to schizophrenia and depression will be discussed. In deep brain stimulation, the excitation, currently used for therapy of Parkinson’s disease, is now introduced for therapy of major depressive disorder and can be taylored to the necessary brain location.     

Changes in structural and functional connectivity during two years of fingolimod therapy for multiple sclerosis

BackgroundFingolimod, an oral drug, has been reported to reduce relapse rate in multiple sclerosis (MS). However disease progression may still occur in spite of control of inflammation. Functional imbalances within and between cerebral networks associated with disruption of structural and functional network integrity, have been reported in MS. An effective therapy is expected to stabilize such functional network integrity.ObjectiveThe purpose of this study was to investigate changes in structural and resting-state functional connectivity of motor and cognitive networks, and associated changes in neurologic scores in MS, during 2 years of fingolimod therapy.MethodsTwenty five subjects with MS were recruited for this study. Subjects were scanned with diffusion tensor imaging (DTI) and resting-state functional connectivity MRI (fcMRI) scan protocol at 3 T with 6-month interval over a period of 2 years. Neurologic performance scores of motor and cognitive performances were also obtained.ResultsDTI measures worsened during the 1st year and then stabilized; any trend of stabilization of fcMRI was delayed until the 2nd year. While motor performance did not change, cognitive performance showed improvement. Several baseline DTI measures correlated with relevant neurologic scores.ConclusionInitial worsening of motor and cognitive network was reported after 1 year of treatment, but seems DTI and fcMRI measures seem to stabilize after around one year fingolimod therapy.     

Inferring Excitatory and Inhibitory Connections in Neuronal Networks

The comprehension of neuronal network functioning, from most basic mechanisms of signal transmission to complex patterns of memory and decision making, is at the basis of the modern research in experimental and computational neurophysiology. While mechanistic knowledge of neurons and synapses structure increased, the study of functional and effective networks is more complex, involving emergent phenomena, nonlinear responses, collective waves, correlation and causal interactions. Refined data analysis may help in inferring functional/effective interactions and connectivity from neuronal activity. The Transfer Entropy (TE) technique is, among other things, well suited to predict structural interactions between neurons, and to infer both effective and structural connectivity in small- and large-scale networks. To efficiently disentangle the excitatory and inhibitory neural activities, in the article we present a revised version of TE, split in two contributions and characterized by a suited delay time. The method is tested on in silico small neuronal networks, built to simulate the calcium activity as measured via calcium imaging in two-dimensional neuronal cultures. The inhibitory connections are well characterized, still preserving a high accuracy for excitatory connections prediction. The method could be applied to study effective and structural interactions in systems of excitable cells, both in physiological and in pathological conditions.     

Epilepsy is related to theta band brain connectivity and network topology in brain tumor patients

Background  

Both epilepsy patients and brain tumor patients show altered functional connectivity and less optimal brain network topology when compared to healthy controls, particularly in the theta band. Furthermore, the duration and characteristics of epilepsy may also influence functional interactions in brain networks. However, the specific features of connectivity and networks in tumor-related epilepsy have not been investigated yet. We hypothesize that epilepsy characteristics are related to (theta band) connectivity and network architecture in operated glioma patients suffering from epileptic seizures. Included patients participated in a clinical study investigating the effect of levetiracetam monotherapy on seizure frequency in glioma patients, and were assessed at two time points: directly after neurosurgery (t1), and six months later (t2). At these time points, magnetoencephalography (MEG) was recorded and information regarding clinical status and epilepsy history was collected. Functional connectivity was calculated in six frequency bands, as were a number of network measures such as normalized clustering coefficient and path length.