Alterations In Functional Network Connectivity Research Articles

Transdiagnostic and Disorder-Specific Resting-State Functional Network Alterations in Alcohol Use Disorder, Schizophrenia, Bipolar Affective Disorder and Obsessive-Compulsive Disorder

Introduction The ICD and DSM diagnostic categories do not represent entirely distinct entities because several cognitive impairments are shared across psychiatric disorders. Such shared cognitive impairments are hypothesized to be caused by common neurobiological substrates, one of which is transdiagnostic alterations in functional network connectivity (FNC). Objectives To investigate and compare the within-network functional connectivity (WNFC) and between-network functional connectivity (BNFC) in alcohol use disorder (AUD), schizophrenia (SCZ), bipolar affective disorder (BPAD), obsessive-compulsive disorder (OCD) and healthy controls (HC) using resting-state fMRI employing a data-driven exploratory approach. Methods The current study was a secondary analysis of data from the ADBS project in India. After pre-processing of fMRI data, a spatially and temporally constrained group-independent component analysis in the GIFT toolbox was performed using the NeuroMark templates to generate 53 independent components (ICs). These components were divided into seven functional domains including subcortical (SC), auditory (AU), sensorimotor (SM), visual (VI), cognitive-control (CC), default-mode (DM), and cerebellar (CB). To investigate the FNC correlations associated with group status (patients or HC) univariate models were applied which were subjected to corrections for multiple comparisons at an alpha=0.05 significance level using the FDR. Results The overall sample size was 249 [AUD=35, SCZ=44, BPAD=48, OCD=53, and HC=69]. Transdiagnostic WNFC alterations largely involved dysconnectivity in the CC, DM, and SC domains, resulting in ICs with both increased and decreased WNFC. Transdiagnostic BNFC alterations were primarily in the form of increased connectivity of the SC domain with various cortical domains whereas reduced connectivity was noted between AU, VI, SM, and CB domains. There was AUD-specific hyperconnectivity in the CC domain and SCZ-specific hyperconnectivity in the DM domain, and dysconnectivity in the SC domain. BPAD-specific hyperconnectivity was identified in DM and SC domains in addition to increased connectivity between CB and SM domains and decreased connectivity between CB and SC domains. All results were significant at p ≤ 0.05; [FDR] q= 0.05. Conclusions Our transdiagnostic WNFC alterations corresponded to the central executive network, default mode network, salience network, and CSTC loop, which provided transdiagnostic evidence for the triple network model of psychopathology and underlined the relevance of subcortical dysconnectivity in this model. Furthermore, our BNFC changes showed subcortical hyperconnectivity with many cortical networks, underscoring its relevance as a potential target for transdiagnostic therapeutic interventions. Disclosure of Interest None Declared

The Relationship Between Vitamin D, Clinical Manifestations, and Functional Network Connectivity in Female Patients With Major Depressive Disorder.

Evidence suggests the pivotal role of vitamin D in the pathophysiology of major depressive disorder (MDD) via its effects on the brain. Gender differences exist in both depression and vitamin D level. Our objective was to investigate the association between gender, vitamin D, clinical manifestations, and functional network connectivity in a large sample of MDD patients and healthy controls. Resting-state functional MRI data were collected from 122 patients and 119 controls, with independent component analysis adopted to examine large-scale inter- and intranetwork functional connectivity. Serum concentration of vitamin D (SCVD) and clinical manifestations were also assessed. MDD patients exhibited lower SCVD than controls in females but not males. Moreover, we identified a female-specific association between lower SCVD and poorer cognitive performance. Concurrently, MDD-related functional network connectivity changes were correlated with SCVD in females as well as depression and anxiety symptoms in female patients. Remarkably, MDD- and SCVD-related functional network connectivity alterations mediated the associations between SCVD and cognition in females. Aside from providing evidence for a female-specific neurobiological mechanism whereby low vitamin D might contribute to MDD and its associated clinical characteristics, our findings inform a novel conceptualization that adjuvant vitamin D supplementation therapy may yield clinical benefits in improving treatment outcomes in female patients with MDD.

Detection of prenatal alcohol exposure using machine learning classification of resting-state functional network connectivity data.

Fetal Alcohol Spectrum Disorder (FASD), a wide range of physical and neurobehavioral abnormalities associated with prenatal alcohol exposure (PAE), is recognized as a significant public health concern. Advancements in the diagnosis of FASD have been hindered by a lack of consensus in diagnostic criteria and limited use of objective biomarkers. Previous research from our group utilized resting-state functional magnetic resonance imaging (fMRI) to measure functional network connectivity (FNC), which revealed several sex- and region-dependent alterations in FNC as a result of moderate PAE relative to controls. Considering that FNC is sensitive to moderate PAE, this study explored the use of FNC data and machine learning methods to detect PAE among a sample of rodents exposed to alcohol prenatally and controls. We utilized previously acquired resting state fMRI data collected from adult rats exposed to moderate levels of prenatal alcohol (PAE) or a saccharin control solution (SAC) to assess FNC of resting state networks extracted by spatial group independent component analysis (GICA). FNC data were subjected to binary classification using support vector machine (SVM) -based algorithms and leave-one-out-cross validation (LOOCV) in an aggregated sample of males and females (n=48; 12 male PAE, 12 female PAE, 12 male SAC, 12 female SAC), a males-only sample (n=24; 12 PAE, 12 SAC), and a females-only sample (n=24; 12 PAE, 12 SAC). Results revealed that a quadratic SVM (QSVM) kernel was significantly effective for PAE detection in females. QSVM kernel-based classification resulted in accuracy rates of 62.5% for all animals, 58.3% for males, and 79.2% for females. Additionally, qualitative evaluation of QSVM weights implicates an overarching theme of several hippocampal and cortical networks in contributing to the formation of correct classification decisions by QSVM. Our results suggest that binary classification using QSVM and adult female FNC data is a potential candidate for the translational development of novel and non-invasive techniques for the identification of FASD.

Impact of childhood adversity on network reconfiguration dynamics during working memory in hypogonadal women

Many women with no history of cognitive difficulties experience executive dysfunction during menopause. Significant adversity during childhood negatively impacts executive function into adulthood and may be an indicator of women at risk of a mid-life cognitive decline. Previous studies have indicated that alterations in functional network connectivity underlie these negative effects of childhood adversity. There is growing evidence that functional brain networks are not static during executive tasks; instead, such networks reconfigure over time. Optimal dynamics are necessary for efficient executive function; while too little reconfiguration is insufficient for peak performance, too much reconfiguration (supra-optimal reconfiguration) is also maladaptive and associated with poorer performance. Here we examined the impact of adverse childhood experiences (ACEs) on network flexibility, a measure of dynamic reconfiguration, during a letter n-back task within three networks that support executive function: frontoparietal, salience, and default mode networks. Several animal and human subject studies have suggested that childhood adversity exerts lasting effects on executive function via serotonergic mechanisms. Tryptophan depletion (TD) was used to examine whether serotonin function drives ACE effects on network flexibility. We hypothesized that ACE would be associated with higher flexibility (supra-optimal flexibility) and that TD would further increase this measure. Forty women underwent functional imaging at two time points in this double-blind, placebo controlled, crossover study. Participants also completed the Penn Conditional Exclusion Test, a task assessing abstraction and mental flexibility. The effects of ACE and TD were evaluated using generalized estimating equations. ACE was associated with higher flexibility across networks (frontoparietal β = 0.00748, D = 2.79, p = 0.005; salience β = 0.00679, D = 3.02, p = 0.003; and default mode β = 0.00910, D = 3.53, p = 0.0004). While there was no interaction between ACE and TD, active TD increased network flexibility in both ACE groups in comparison to sham depletion (frontoparietal β = 0.00489, D = 2.15, p = 0.03; salience β = 0.00393, D = 1.91, p = 0.06; default mode β = 0.00334, D = 1.73, p = 0.08). These results suggest that childhood adversity has lasting impacts on dynamic reconfiguration of functional brain networks supporting executive function and that decreasing serotonin levels may exacerbate these effects.

In search of multimodal brain alterations in Alzheimer's and Binswanger's disease.

Structural and functional brain abnormalities have been widely identified in dementia, but with variable replicability and significant overlap. Alzheimer's disease (AD) and Binswanger's disease (BD) share similar symptoms and common brain changes that can confound diagnosis. In this study, we aimed to investigate correlated structural and functional brain changes in AD and BD by combining resting-state functional magnetic resonance imaging (fMRI) and diffusion MRI. A group independent component analysis was first performed on the fMRI data to extract 49 intrinsic connectivity networks (ICNs). Then we conducted a multi-set canonical correlation analysis on three features, functional network connectivity (FNC) between ICNs, fractional anisotropy (FA) and mean diffusivity (MD). Two inter-correlated components show significant group differences. The first component demonstrates distinct brain changes between AD and BD. AD shows increased cerebellar FNC but decreased thalamic and hippocampal FNC. Such FNC alterations are linked to the decreased corpus callosum FA. AD also has increased MD in the frontal and temporal cortex, but BD shows opposite alterations. The second component demonstrates specific brain changes in BD. Increased FNC is mainly between default mode and sensory regions, while decreased FNC is mainly within the default mode domain and related to auditory regions. The FNC changes are associated with FA changes in posterior/middle cingulum cortex and visual cortex and increased MD in thalamus and hippocampus. Our findings provide evidence of linked functional and structural deficits in dementia and suggest that AD and BD have both common and distinct changes in white matter integrity and functional connectivity.

F76. Persistent Intrinsic Functional Network Connectivity Alterations in Middle-Aged and Older Women With Remitted Depression

F76. Persistent Intrinsic Functional Network Connectivity Alterations in Middle-Aged and Older Women With Remitted Depression

Impact of early life adversity and tryptophan depletion on functional connectivity in menopausal women: A double-blind, placebo-controlled crossover study

During the menopause transition, women are at increased risk of subjective symptoms of executive dysfunction. Evidence from animal and human participant studies suggests adverse childhood experiences (ACE) may be a risk factor for executive complaints during this hormonal transition. Preclinical literature indicates early life adversity effects on serotonin function may play a role in this increased susceptibility. However, the mechanisms underlying this increase in vulnerability in human participants remain relatively unknown. Here we examined the impact of ACE and tryptophan depletion (TD), a paradigm used to lower central serotonin levels, on functional network connectivity in discovery and replication datasets. We hypothesized that ACE would be associated with decreased within-network connectivity. We predicted that TD would further lower connectivity in women with high levels of early adversity, but have no effect in women with low levels of early adversity. Forty women underwent two functional imaging sequences at two time points (141 total scans) in a double-blind, placebo controlled, crossover study. The effects of ACE and TD were evaluated using generalized estimating equations (GEE). As predicted, ACE was associated with lower within-network connectivity. While TD had no effect on connectivity in the low ACE group, TD increased connectivity in the high ACE group. The robust effect of ACE remained significant in the replication dataset, though the ACE×TD interaction did not. Together, these results suggest that early life adversity has lasting impacts on large-scale functional networks underlying executive function. Alterations in functional network connectivity may be one mechanism by which early life adversity increases the risk of cognitive disorders during menopause.

Functional network connectivity alterations in schizophrenia and depression

There is a high degree of overlap between the symptoms of major depressive disorder (MDD) and schizophrenia, but it remains unclear whether the similar symptoms are derived from convergent alterations in functional network connectivity. In this study, we performed a group independent component analysis on resting-state functional MRI data from 20 MDD patients, 24 schizophrenia patients, and 43 matched healthy controls. The functional network connectivity analysis revealed that, compared to healthy controls, the MDD and schizophrenia patients exhibited convergent decreased positive connectivity between the left and right fronto-parietal control network and decreased negative connectivity between the left control and medial visual networks. Furthermore, the MDD patients showed decreased negative connectivity between the left control and auditory networks, and the schizophrenia patients showed decreased positive connectivity between the bilateral control and language networks and decreased negative connectivity between the right control and dorsal attention networks. The convergent network connectivity alterations may underlie the common primary control and regulation disorders, and the divergent connectivity alterations may enable the distinction between the two disorders. All of the convergent and divergent network connectivity alterations were relevant to the control network, suggesting an important role of the network in the pathophysiology of MDD and schizophrenia.

Antidepressant Effects of Electroconvulsive Therapy Unrelated to the Brain's Functional Network Connectivity alterations at an Individual Level.

Background:Electroconvulsive therapy (ECT) can alleviate the symptoms of treatment-resistant depression (TRD). Functional network connectivity (FNC) is a newly developed method to investigate the brain's functional connectivity patterns. The first aim of this study was to investigate FNC alterations between TRD patients and healthy controls. The second aim was to explore the relationship between the ECT treatment response and pre-ECT treatment FNC alterations in individual TRD patients.Methods:This study included 82 TRD patients and 41 controls. Patients were screened at baseline and after 2 weeks of treatment with a combination of ECT and antidepressants. Group information guided-independent component analysis (GIG-ICA) was used to compute subject-specific functional networks (FNs). Grassmann manifold and step-wise forward component selection using support vector machines were adopted to perform the FNC measure and extract the functional networks' connectivity patterns (FCP). Pearson's correlation analysis was used to calculate the correlations between the FCP and ECT response.Results:A total of 82 TRD patients in the ECT group were successfully treated. On an average, 8.50 ± 2.00 ECT sessions were conducted. After ECT treatment, only 42 TRD patients had an improved response to ECT (the Hamilton scores reduction rate was more than 50%), response rate 51%. 8 FNs (anterior and posterior default mode network, bilateral frontoparietal network, audio network, visual network, dorsal attention network, and sensorimotor network) were obtained using GIG-ICA. We did not found that FCPs were significantly different between TRD patients and healthy controls. Moreover, the baseline FCP was unrelated to the ECT treatment response.Conclusions:The FNC was not significantly different between the TRD patients and healthy controls, and the baseline FCP was unrelated to the ECT treatment response. These findings will necessitate that we modify the experimental scheme to explore the mechanisms underlying ECT's effects on depression and explore the specific predictors of the effects of ECT based on the pre-ECT treatment magnetic resonance imaging.

Preserving Cognition in Children With Diabetes: Do Alterations in Functional Network Connectivity Play a Role?

Whether, and to what extent, type 1 diabetes (T1D) affects the brains of children and adolescents has been debated for more than 30 years. Early studies found that children and adolescents with T1D were more likely to perform somewhat poorer than their healthy peers on tasks of mental efficiency that required rapid responses and sustained attention, as well as on measures of executive functioning that required problem-solving and planning (1). It was assumed, but not proven, that these between-group differences were a consequence of differences in brain integrity. Only when researchers began using MRI techniques was there unequivocal evidence that diabetes in childhood is accompanied by gross structural changes to the brain, including relative reductions in gray matter density in multiple cortical regions and microstructural abnormalities in major white matter tracts (2,3). Furthermore, these effects were most pronounced in those who developed diabetes early in life and were evident within 2–4 years of disease onset (4–7). One might expect that a significant loss of neurons, accompanied by axonal damage relatively early in life, would lead to increasingly serious cognitive impairment over time in people with diabetes. Interestingly, that does not appear to be the case. Cross-sectional studies of children and young adults with T1D do not show a significant worsening of performance with increasing age or disease duration (8), nor were marked declines in cognition seen in the adolescents and adults participating in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions …

Dynamic functional network connectivity in idiopathic generalized epilepsy with generalized tonic-clonic seizure.

Idiopathic generalized epilepsy (IGE) has been linked with disrupted intra-network connectivity of multiple resting-state networks (RSNs); however, whether impairment is present in inter-network interactions between RSNs, remains largely unclear. Here, 50 patients with IGE characterized by generalized tonic-clonic seizures (GTCS) and 50 demographically matched healthy controls underwent resting-state fMRI scans. A dynamic method was implemented to investigate functional network connectivity (FNC) in patients with IGE-GTCS. Specifically, independent component analysis was first carried out to extract RSNs, and then sliding window correlation approach was employed to obtain dynamic FNC patterns. Finally, k-mean clustering was performed to characterize six discrete functional connectivity states, and state analysis was conducted to explore the potential alterations in FNC and other dynamic metrics. Our results revealed that state-specific FNC disruptions were observed in IGE-GTCS and the majority of aberrant functional connectivity manifested itself in default mode network. In addition, temporal metrics derived from state transition vectors were altered in patients including the total number of transitions across states and the mean dwell time, the fraction of time spent and the number of subjects in specific FNC state. Furthermore, the alterations were significantly correlated with disease duration and seizure frequency. It was also found that dynamic FNC could distinguish patients with IGE-GTCS from controls with an accuracy of 77.91% (P < 0.001). Taken together, this study not only provided novel insights into the pathophysiological mechanisms of IGE-GTCS but also suggested that the dynamic FNC analysis was a promising avenue to deepen our understanding of this disease. Hum Brain Mapp 38:957-973, 2017. © 2016 Wiley Periodicals, Inc.

Moderate Prenatal Alcohol Exposure Alters Functional Connectivity in the Adult Rat Brain.

Past studies of moderate prenatal alcohol exposure (PAE) have focused on specific brain regions, neurotransmitter systems, and behaviors. However, the effects of PAE on brain function and behavior are complex and not limited to discrete brain regions. Thus, there is a critical need to understand the global effects of moderate PAE on neural function. A primary aim of this research was to explore the functional relationships in neural activity of spatially distinct areas by applying a widely used computational algorithm-group-independent component analysis (gICA)-to resting-state functional magnetic resonance imaging data from rats exposed to either an alcohol or saccharin control solution via maternal consumption during pregnancy. Long-Evans rat dams consumed either 5% (v/v) alcohol or a saccharin control solution throughout gestation. Adult offspring from each prenatal treatment group were anesthetized for functional, structural, and perfusion magnetic resonance-based image acquisition sequences. gICA was applied to the functional data to extract components. To determine connectivity, component time-course correlations were computed and compared. Additionally, spectral power analyses were utilized as an additional measure of functional connectivity. Finally, blood perfusion-assessed by arterial spin labeling-and whole-brain volumetric analyses were evaluated. Analyses revealed 17 components in several brain regions such as the cortex, hippocampus, and thalamus. PAE was associated with reductions in coordinated activity between components, especially in males. PAE was also associated with reductions in low-frequency spectral power, an effect that was more robust in females. Brain volumetric analyses revealed sex-dependent reductions in females while blood flow analyses revealed sex-dependent reductions in males. Moderate PAE leads to persistent changes in functional connectivity in the absence of whole-brain volume or blood flow measures. Future studies will investigate the relationships between alterations in functional network connectivity and behavior.

Age-Related Changes in Task Related Functional Network Connectivity

Aging has a multi-faceted impact on brain structure, brain function and cognitive task performance, but the interaction of these different age-related changes is largely unexplored. We hypothesize that age-related structural changes alter the functional connectivity within the brain, resulting in altered task performance during cognitive challenges. In this neuroimaging study, we used independent components analysis to identify spatial patterns of coordinated functional activity involved in the performance of a verbal delayed item recognition task from 75 healthy young and 37 healthy old adults. Strength of functional connectivity between spatial components was assessed for age group differences and related to speeded task performance. We then assessed whether age-related differences in global brain volume were associated with age-related differences in functional network connectivity. Both age groups used a series of spatial components during the verbal working memory task and the strength and distribution of functional network connectivity between these components differed across the age groups. Poorer task performance, i.e. slower speed with increasing memory load, in the old adults was associated with decreases in functional network connectivity between components comprised of the supplementary motor area and the middle cingulate and between the precuneus and the middle/superior frontal cortex. Advancing age also led to decreased brain volume; however, there was no evidence to support the hypothesis that age-related alterations in functional network connectivity were the result of global brain volume changes. These results suggest that age-related differences in the coordination of neural activity between brain regions partially underlie differences in cognitive performance.