Intrinsic Brain Connectivity Research Articles

Connectivity Guided Dimensions of Psychopathology in Youth

Despite a vast body of literature, magnetic resonance imaging research has not yet delivered biomarkers for psychiatry. This is due, in part, to the high comorbidity of mental disorders, calling for a dimensional approach and the computational quantification of these dimensions in both clinical and imaging data. We use canonical correlation analysis (CCA) to investigate associations between anxiety, irritability, and disruptive behavior, three of the most common, impactful psychiatric problems in youth with each other and intrinsic brain connectivity.

Functional connectivity predicts the dispositional use of expressive suppression but not cognitive reappraisal.

IntroductionPrevious research has identified specific brain regions associated with regulating emotion using common strategies such as expressive suppression and cognitive reappraisal. However, most research focuses on a priori regions and directs participants how to regulate, which may not reflect how people naturally regulate outside the laboratory.MethodHere, we used a data‐driven approach to investigate how individual differences in distributed intrinsic functional brain connectivity predict emotion regulation tendency outside the laboratory. Specifically, we used connectome‐based predictive modeling to extract functional connections in the brain significantly related to the dispositional use of suppression and reappraisal. These edges were then used in a predictive model and cross‐validated in novel participants to identify a neural signature that reflects individual differences in the tendency to suppress and reappraise emotion.ResultsWe found a significant neural signature for the dispositional use of suppression, but not reappraisal. Within this whole‐brain signature, the intrinsic connectivity of the default mode network was most informative of suppression tendency. In addition, the predictive performance of this model was significant in males, but not females.ConclusionThese findings help inform how whole‐brain networks of functional connectivity characterize how people tend to regulate emotion outside the laboratory.

Temporal non-local means filtering for studies of intrinsic brain connectivity from individual resting fMRI.

Characterizing functional brain connectivity using resting functional magnetic resonance imaging (fMRI) is challenging due to the relatively small Blood-Oxygen-Level Dependent contrast and low signal-to-noise ratio. Denoising using surface-based Laplace-Beltrami (LB) or volumetric Gaussian filtering tends to blur boundaries between different functional areas. To overcome this issue, a time-based Non-Local Means (tNLM) filtering method was previously developed to denoise fMRI data while preserving spatial structure. The kernel and parameters that define the tNLM filter need to be optimized for each application. Here we present a novel Global PDF-based tNLM filtering (GPDF) algorithm that uses a data-driven kernel function based on a Bayes factor to optimize filtering for spatial delineation of functional connectivity in resting fMRI data. We demonstrate its performance relative to Gaussian spatial filtering and the original tNLM filtering via simulations. We also compare the effects of GPDF filtering against LB filtering using individual in-vivo resting fMRI datasets. Our results show that LB filtering tends to blur signals across boundaries between adjacent functional regions. In contrast, GPDF filtering enables improved noise reduction without blurring adjacent functional regions. These results indicate that GPDF may be a useful preprocessing tool for analyses of brain connectivity and network topology in individual fMRI recordings.

Baseline functional connectivity may predict placebo responses to accelerated rTMS treatment in major depression.

Although in theory sham repetitive transcranial magnetic stimulation (rTMS) has no inherent therapeutic value, nonetheless, such placebo stimulations may have relevant therapeutic effects in clinically depressed patients. On the other hand, antidepressant responses to sham rTMS are quite heterogeneous across individuals and its neural underpinnings have not been explored yet. The current brain imaging study aims to detect baseline neural fingerprints resulting in clinically beneficial placebo rTMS treatment responses. We collected resting‐state functional magnetic resonance imaging data prior to a registered randomized clinical trial of accelerated placebo stimulation protocol in patients documented with treatment‐resistant depression (http://clinicaltrials.gov/show/NCT01832805). In addition to global brain connectivity and rostral anterior cingulate cortex (rACC) seed‐based functional connectivity (FC), elastic‐net regression and cross‐validation procedures were used to identify baseline intrinsic brain connectivity biomarkers for sham‐rTMS responses. Placebo responses to accelerated sham rTMS were correlated with baseline global brain connectivity in the rACC/ventral medial prefrontal cortex (vmPFC). Concerning the rACC seed‐based FC analysis, the placebo response was associated positively with the precuneus/posterior cingulate (PCun/PCC) cortex and negatively with the middle frontal gyrus. Our findings provide first brain imaging evidence for placebo responses to sham stimulation being predictable from rACC rsFC profiles, especially in brain areas implicated in (re)appraisal and self‐focus processes.

Early-life Dentine Manganese Concentrations and Intrinsic Functional Brain Connectivity in Adolescents and Young Adults

Early-life Dentine Manganese Concentrations and Intrinsic Functional Brain Connectivity in Adolescents and Young Adults

Psychological resilience mediates associations of political attitudes with intrinsic functional brain connectivity

Psychological resilience mediates associations of political attitudes with intrinsic functional brain connectivity

Early-life dentine manganese concentrations and intrinsic functional brain connectivity in adolescents: A pilot study.

Maturational processes in the developing brain are disrupted by exposure to environmental toxicants, setting the stage for deviant developmental trajectories. Manganese (Mn) is an essential nutrient that is neurotoxic at high levels of exposure, particularly affecting the basal ganglia and prefrontal cortex. Both the intensity and timing of exposure matter; deciduous teeth can be used to retrospectively and objectively determine early-life windows of vulnerability. The aim of this pilot study was to examine associations between prenatal, early postnatal and childhood dentine Mn concentrations and intrinsic functional connectivity (iFC) of adolescents’ brains. 14 adolescents (12–18 years; 6 girls) from northern Italian regions with either current, historic or no Mn contamination, completed a 10-minute resting state functional Magnetic Resonance Imaging (MRI) scan in an 1.5T MRI scanner. We estimated prenatal, early postnatal and childhood Mn concentrations in deciduous teeth using laser ablation-inductively coupled plasma-mass spectrometry. We performed seed-based correlation analyses, focusing on six subcortical seeds (left and right caudate, putamen, pallidum) and one cortical seed (bilateral middle frontal gyrus) from Harvard-Oxford atlases. We examined linear and quadratic correlations between log-transformed Mn concentrations and seed-based iFC (Bonferroni-corrected p<0.0023), controlling for either socio-economic status, sex or age. Dentine Mn concentrations (Mn:Calcium ratio) were highest during the prenatal period (median = 0.48) and significantly declined during the early postnatal (median = 0.14) and childhood periods (median = 0.006). Postnatal Mn concentrations were associated with: 1) increased iFC between the middle frontal gyrus and medial prefrontal cortex; 2) decreased iFC between the right putamen and pre- and postcentral gyrus. Together, these findings suggest that early postnatal Mn concentrations are associated with increased iFC within cognitive control brain areas, but decreased iFC between motor areas in adolescents. Future studies should replicate these findings in larger samples, and link brain connectivity measures to cognitive and motor outcomes.

Reduced semantic control in older adults is linked to intrinsic DMN connectivity

Ageing provides an interesting window into semantic cognition: while younger adults generally outperform older adults on many cognitive tasks, knowledge continues to accumulate over the lifespan and consequently, the semantic store (i.e., vocabulary size) remains stable (or even improves) during healthy ageing. Semantic cognition involves the interaction of at least two components – a semantic store and control processes that interact to ensure efficient and context-relevant use of representations. Given older adults perform less well on tasks measuring executive control, their ability to access the semantic store in a goal driven manner may be compromised. Older adults also consistently show reductions in intrinsic brain connectivity, and we examined how these brain changes relate to age-related changes in semantic performance. We found that while older participants outperformed their younger counterparts on tests of vocabulary size (i.e., NART), younger participants were faster and more accurate in tasks requiring semantic control, and these age differences correlated with measures of intrinsic connectivity between the anterior temporal lobe (ATL) and medial prefrontal cortex (mPFC), within the default mode network. Higher intrinsic connectivity from right ATL to mPFC at rest related to better performance on verbal (but not picture) semantic tasks, and older adults showed an exaggerated version of this pattern, suggesting that this within-DMN connectivity may become more important for conceptual access from words as we age. However, this appeared to be at the expense of control over semantic retrieval – there was little relationship between connectivity and performance for strong associations in either group, but older adults with stronger connectivity showed particularly inefficient retrieval of weak associations. Older adults may struggle to harness the default mode network to support demanding patterns of semantic retrieval, resulting in a performance cost.

Altered intrinsic brain activity associated with outcome in frontal lobe epilepsy

Frontal lobe epilepsy (FLE) is the second most common type of the focal epilepsies. Our understanding of this disease has been revolutionized over the past decade, but variable treatment outcomes persist and the underlying functional mechanisms responsible for this have yet to be deciphered. This study was designed to determine how intrinsic brain connectivity related to treatment response in patients with FLE. 50 patients with FLE and 28 healthy controls were enrolled in this study and underwent functional MRI at baseline. At the end of 12-month follow up period, all patients with FLE were classified, based on their responses to AEDs treatment, into drug-responsive and drug-refractory groups. The amplitude of low-frequency fluctuation (ALFF) was calculated amongst the three groups in order to detect regional neural function integration. The responsive group showed decreased ALFF only in the left ventromedial prefrontal cortex (vmPFC), while the refractory group showed decreased ALFF in the left vmPFC, right superior frontal gyrus (SFG), and supramarginal gyrus (SMG) relative to healthy controls. In addition, both the responsive and refractory groups showed increased ALFF in the precuneus and postcentral gyrus when compared to the healthy controls. Furthermore, the refractory group exhibited significantly decreased ALFF in the left vmPFC, right SFG and SMG, relative to the responsive group. Focal spontaneous activity, as assessed by ALFF, was associated with response to antiepileptic treatment in patients with FLE. Patients with refractory frontal lobe epilepsy exhibited decreased intrinsic brain activity. Our findings provide novel neuroimaging evidence into the mechanisms of medically-intractable FLE at the brain level.

Sex-related pattern of intrinsic brain connectivity in drug-naïve Parkinson's disease patients.

Sex difference is related to specific clinical features in PD patients over the disease course. To investigate the potential sex-difference effect on the spontaneous neuronal activity within the most reported resting-state networks in early untreated PD patients and its correlation with baseline and longitudinal clinical features. Fifty-six drug-naïve PD patients (30/26 male/female) and 30 (15/15 male/female) matched controls were enrolled in the study. Topological and spectral resting-state functional MRI features of the sensorimotor, dorsal and ventral attention, frontoparietal, and default-mode networks were analyzed for possible sex-difference effects in both PD patients and controls groups. Additionally, a region-of-interest analysis was performed to test for a sex effect on basal ganglia connectivity. Multivariate ordinal regression was used to investigate whether connectivity findings at baseline were predictors of motor impairment over a 2-year follow-up period. Compared to female PD patients and controls, male PD patients showed an abnormal spectral composition of the sensorimotor and dorsal attention networks in the slow-5 band. The region-of-interest analysis showed an increased connectivity within the basal ganglia in female PD patients compared to males. Functional sensorimotor connectivity changes at baseline showed to be an independent predictor of disease severity at 2-year follow-up. Our findings revealed the presence of a disease-related, sex-specific cortical and subcortical connectivity pattern within the sensorimotor network, in the early stage of PD. We hypothesize that these findings may be related to the presence of different sex-specific nigrostriatal dopaminergic pathways and might predict PD progression. © 2019 International Parkinson and Movement Disorder Society.

The effects of high-frequency repetitive transcranial magnetic stimulation on resting-state functional connectivity in obese adults.

We conducted a 4-week randomized, sham-controlled, single-blind, parallel-group trial to examine the effect of repetitive transcranial magnetic stimulation (rTMS) delivered to the left dorsolateral prefrontal cortex (DLPFC) on functional brain connectivity and body weight in adults with obesity. Of the 45 volunteers with obesity, aged between 18 and 70 years (body mass index [BMI] ≥25 kg/m2 according to the obesity criterion for an Asian population), 36 participants (54.1 ± 11.0 years, BMI 30.2 ± 3.5 kg/m2 , 77.8% female) completed the 4 weeks of follow-up, undergoing two resting state fMRI scans (20 in the real stimulation group and 16 in the sham stimulation group). A total of eight sessions of high-frequency rTMS targeting the left DLPFC were provided over a period of 4 weeks (5-second trains with 25-second inter-train intervals, 10 Hz, 110% motor threshold; 2000 pulses over 20 minutes). Participants in the real stimulation group showed significantly greater weight loss from baseline following the eight session of rTMS (-2.53 ± 2.41 kg vs 0.38 ± 1.13 kg, P < 0.01). For intrinsic brain connectivity comparisons, the between-ness centrality values within the right frontoparietal network tended to increase with rTMS, and a significant interaction effect was identified for time (pre vs post) × rTMS (real vs sham) in the right frontoparietal network (P = 0.031, FDR corrected). We observed that rTMS selectively increased resting state functional connectivity within the right frontoparietal network. Our findings suggest that high-frequency rTMS to the left DLPFC might strengthen the frontoparietal network that orchestrates top-down inhibitory control to reduce food intake.

Statistical Significance Assessment of Phase Synchrony in the Presence of Background Couplings: An ECoG Study.

Statistical significance testing is a necessary step in connectivity analysis. Several statistical test methods have been employed to assess the significance of functional connectivity, but the performance of these methods has not been thoroughly evaluated. In addition, the effects of the intrinsic brain connectivity and background couplings on performance of statistical test methods in task-based studies have not been investigated yet. The background couplings may exist independent of cognitive state and can be observed on both pre- and post-stimulus time intervals. The background couplings may be falsely detected by a statistical test as task-related connections, which can mislead interpretations of the task-related functional networks. The aim of this study was to investigate the relative performance of four commonly used non-parametric statistical test methods-surrogate, demeaned surrogate, bootstrap resampling, and Monte Carlo permutation methods-in the presence of background couplings and noise, with different signal-to-noise ratios (SNRs). Using simulated electrocorticographic (ECoG) datasets and phase locking value (PLV) as a measure of functional connectivity, we evaluated the performances of the statistical test methods utilizing sensitivity, specificity, accuracy, and receiver operating curve (ROC) analysis. Furthermore, we calculated optimal p values for each statistical test method using the ROC analysis, and found that the optimal p values were increased by decreasing the SNR. We also found that the optimal p value of the bootstrap resampling was greater than that of other methods. Our results from the simulation datasets and a real ECoG dataset, as an illustrative case report, revealed that the bootstrap resampling is the most efficient non-parametric statistical test for identifying the significant PLV of ECoG data, especially in the presence of background couplings.

Intrinsic functional connectivity during continuous maintenance and suppression of emotion in bipolar disorder.

Resting-state connectivity studies, which examine unconstrained low frequency BOLD fluctuations, have reported inconsistent abnormalities in bipolar disorder (BP). In this study, we investigated intrinsic brain connectivity under the constraints of a Continuous Emotion Regulation Task (CERT) in BP patients in depressed (BPD) and manic (BPM) states, along with healthy control participants. Medication-free participants, with either a diagnosis of BP (BPD = 27, BPM = 30) or healthy controls (N = 33) were included. We collected 2 fMRI scans using the CERT paradigm, in which participants continuously watched negative pictures and either maintained emotions (MAINTAIN) or suppressed emotion using reappraisal techniques (SUPPRESS). Network-based statistic and graph theory analyses were examined for (i) the main effect of condition (within-group) and (ii) group and condition interactions. In healthy participants, MAINTAIN largely involved occipital and parietal cortices (p < .001), whereas SUPPRESS also recruited the frontal and cingulate cortices (p = .023). The interaction between group (BPD vs. BPM) and condition revealed a network involving the inferior frontal lobe which was stronger during MAINTAIN for BPD and during SUPPRESS for BPM (p = .037). Graph theory properties (i.e., clustering coefficient) for key nodes also evidenced significant group by condition interactions. We observed BP-related changes in network properties involved in normal and abnormal emotion regulation, which provide insights into the neural bases for affective disturbances in BP.

S14. Intrinsic Brain Connectivity Moderators of Psychotherapy Response and Changes in PTSD: A Combined Connectomic, Network Level, and Seeded Connectivity Approach

S14. Intrinsic Brain Connectivity Moderators of Psychotherapy Response and Changes in PTSD: A Combined Connectomic, Network Level, and Seeded Connectivity Approach

O15. Intrinsic Brain Connectivity Moderators of Psychotherapy Response and Changes in PTSD: A Combined Connectomic, Network Level, and Seeded Connectivity Approach

O15. Intrinsic Brain Connectivity Moderators of Psychotherapy Response and Changes in PTSD: A Combined Connectomic, Network Level, and Seeded Connectivity Approach

Intrinsic Functional Brain Connectivity Predicts Onset of Major Depression Disorder in Adolescence: A Pilot Study.

Children with familial risk for major depressive disorder (MDD) have elevated risk for developing depression as adolescents. Here, we investigated longitudinally whether resting-state functional connectivity (RSFC) could predict the onset of MDD. In this pilot study, we followed a group of never-depressed children with familial risk for MDD and a group of age-matched controls without familial risk who had undergone an MRI study at 8-14 years of age. Participants were reassessed 3-4 years later with diagnostic interviews. We first investigated group differences in RSFC from regions in the emotion regulation, cognitive control, and default mode networks in the children who later developed MDD (converted), the children who did not develop MDD (nonconverted), and the control group. We then built a prediction model based on baseline RSFC that was independent of the group differences to classify the individuals who later developed MDD. Compared with the nonconverted group, the converted group exhibited hypoconnectivity between subgenual anterior cingulate cortex (sgACC) and inferior parietal lobule (IPL) and between left and right dorsolateral prefrontal cortices. The nonconverted group exhibited higher sgACC-IPL connectivity than did both the converted and control groups, suggesting a possible resilience factor to MDD. Classification between converted and nonconverted individuals based on baseline RSFC yielded high predictive accuracy with high sensitivity and specificity that was superior to classification based on baseline clinical rating scales. Intrinsic brain connectivity measured in healthy children with familial risk for depression has the potential to predict MDD onset, and it can be a useful neuromarker in early identification of children for preventive treatment.

A Comparison of Static and Dynamic Functional Connectivities for Identifying Subjects and Biological Sex Using Intrinsic Individual Brain Connectivity

Functional magnetic resonance imaging has revealed correlated activities in brain regions even in the absence of a task. Initial studies assumed this resting-state functional connectivity (FC) to be stationary in nature, but recent studies have modeled these activities as a dynamic network. Dynamic spatiotemporal models better model the brain activities, but are computationally more involved. A comparison of static and dynamic FCs was made to quantitatively study their efficacies in identifying intrinsic individual connectivity patterns using data from the Human Connectome Project. Results show that the intrinsic individual brain connectivity pattern can be used as a ‘fingerprint’ to distinguish among and identify subjects and is more accurately captured with partial correlation and assuming static FC. It was also seen that the intrinsic individual brain connectivity patterns were invariant over a few months. Additionally, biological sex identification was successfully performed using the intrinsic individual connectivity patterns, and group averages of male and female FC matrices. Edge consistency, edge variability and differential power measures were used to identify the major resting-state networks involved in identifying subjects and their sex.

Recreational use of GHB is associated with alterations of resting state functional connectivity of the central executive and default mode networks.

Gamma‐hydroxybutyrate acid (GHB) is a recreational drug with a high addictive potential. Severe side effects such as GHB‐induced coma are common and linked to increased emergency room attendances. Task‐based functional‐imaging studies have revealed an association between the regular use of GHB and multiple GHB‐induced comas, and altered neurocognitive function. However the effects of multiple GHB‐induced comas and regular GHB‐use on intrinsic brain connectivity during rest remain unknown. The study population consisted of 23 GHB‐users with ≥4 GHB‐induced comas (GHB‐Coma), 22 GHB‐users who never experienced a GHB‐induced coma (GHB‐NoComa) and 24 polydrug users who never used GHB (No‐GHB). Resting‐state scans were collected to assess resting‐state functional‐connectivity within and between the default mode network (DMN), the bilateral central executive network (CEN) and the salience network (SN). The GHB‐NoComa group showed decreased rsFC of the right CEN with a region in the anterior cingulate cortex (p FWE = 0.048) and decreased rsFC between the right CEN and the DMN (p FWE = 0.048) when compared with the No‐GHB group. These results suggest that regular GHB‐use is associated with decreased rsFC within the right CEN and between the right CEN and the DMN. The presence of multiple GHB‐induced comas is not associated with (additional) alterations in rsFC.

Exploring Characteristic Alteration of the White Matter Functional Networks at Rest in Children with Attention-Deficit/Hyperactivity Disorder

Background: Previous studies mapping intrinsic brain connectivity have facilitated the neuropathological model of attention-deficit/hyperactivity disorder (ADHD) which encompasses a number of different large-scale networks. However, these studies have traditionally focused on the functional connectivity within grey matter regions, ignoring the critical role played by white matter in supporting brain functions. This study aimed to investigate the characteristic alterations of activity and connectivity within white matter functional networks in children with ADHD. Methods: K-means clustering was performed on the white matter resting-state fMRI data to identify white matter functional networks for a total of ninety-nine drug-naive children with ADHD and typically developing controls. Intrinsic activity in each network and functional connectivity between each network were assessed as well as the associations between network activity and ADHD clinical symptoms. Outcomes: Eight distinct white matter functional networks were identified. DMN, SMN, DAN and VAN showed lower spontaneous neural activity in children with ADHD. In particular, the DMN and SMN mainly showed increased connectivity with other networks while the DAN and VAN had more decreased connectivity. Interpretation: This study for the first time uncovered the feature of intrinsic functional organization of white matter networks in children with ADHD. Our findings demonstrated that the abnormal white matter network activity and connectivity in DMN, SMN, DAN and VAN share similar characteristic changes with those of grey matter, which suggests abnormal white matter network interactions that encode neural activity may underlie ADHD neuropathology. Funding Statement: This study was supported by the National Natural Science Foundation (Grant No. 81671669) and Science and Technology Project of Sichuan Province (Grant No. 2017JQ0001). Declaration of Interests: The authors stated: None declared. Ethics Approval Statement: The Ethics Committee of the First Affiliated Hospital of Wenzhou Medical University approved the study. All participants and their parents were fully informed about the purpose and procedures of this study, and written informed consent was obtained from the parents.

Oxytocin receptor agonist reduces perinatal brain damage by targeting microglia.

Prematurity and fetal growth restriction (FGR) are frequent conditions associated with adverse neurocognitive outcomes. We have previously identified early deregulation of genes controlling neuroinflammation as a putative mechanism linking FGR and abnormal trajectory of the developing brain. While the oxytocin system was also found to be impaired following adverse perinatal events, its role in the modulation of neuroinflammation in the developing brain is still unknown. We used a double-hit rat model of perinatal brain injury induced by gestational low protein diet (LPD) and potentiated by postnatal injections of subliminal doses of interleukin-1β (IL1β) and a zebrafish model of neuroinflammation. Effects of the treatment with carbetocin, a selective, long lasting, and brain diffusible oxytocin receptor agonist, have been assessed using a combination of histological, molecular, and functional tools in vivo and in vitro. In the double-hit model, white matter inflammation, deficient myelination, and behavioral deficits have been observed and the oxytocin system was impaired. Early postnatal supplementation with carbetocin alleviated microglial activation at both transcriptional and cellular levels and provided long-term neuroprotection. The central anti-inflammatory effects of carbetocin have been shown in vivo in rat pups and in a zebrafish model of early-life neuroinflammation and reproduced in vitro on stimulated sorted primary microglial cell cultures from rats subjected to LPD. Carbetocin treatment was associated with beneficial effects on myelination, long-term intrinsic brain connectivity and behavior. Targeting oxytocin signaling in the developing brain may be an effective approach to prevent neuroinflammation - induced brain damage of perinatal origin.