Resting-state Functional Connectivity MRI Research Articles

High-resolution functional connectivity of the default mode network in young adults with down syndrome.

Studies of resting-state functional connectivity MRI in Alzheimer's disease suggest that disease stage plays a role in functional changes of the default mode network. Individuals with the genetic disorder Down syndrome show an increased incidence of early-onset Alzheimer's-type dementia, along with early and nearly universal neuropathologic changes of Alzheimer's disease. The present study examined high-resolution functional connectivity of the default mode network in 11 young adults with Down syndrome that showed no measurable symptoms of dementia and 11 age- and sex-matched neurotypical controls. We focused on within-network connectivity of the default mode network, measured from both anterior and posterior aspects of the cingulate cortex. Sixty-eight percent of connections to the posterior cingulate and 26% to the anterior cingulate showed reduced strength in the group with Down syndrome (p < 0.01). The Down syndrome group showed increased connectivity strength from the anterior cingulate to the bilateral inferior frontal gyri and right putamen (p < 0.005). In an exploratory analysis, connectivity in the group with Down syndrome showed regional relationships to plasma measures of inflammatory markers and t-tau. In non-demented adults with Down syndrome, functional connectivity within the default mode network may be analogous to changes reported in preclinical Alzheimer's disease, and warrants further investigation as a measure of dementia risk.

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.

Effects of bifrontal transcranial direct current stimulation on brain glutamate levels and resting state connectivity: multimodal MRI data for the cathodal stimulation site

Transcranial direct current stimulation (tDCS) over prefrontal cortex (PFC) regions is currently proposed as therapeutic intervention for major depression and other psychiatric disorders. The in-depth mechanistic understanding of this bipolar and non-focal stimulation technique is still incomplete. In a pilot study, we investigated the effects of bifrontal stimulation on brain metabolite levels and resting state connectivity under the cathode using multiparametric MRI techniques and computational tDCS modeling. Within a double-blind cross-over design, 20 subjects (12 women, 23.7 ± 2 years) were randomized to active tDCS with standard bifrontal montage with the anode over the left dorsolateral prefrontal cortex (DLPFC) and the cathode over the right DLPFC. Magnetic resonance spectroscopy (MRS) was acquired before, during, and after prefrontal tDCS to quantify glutamate (Glu), Glu + glutamine (Glx) and gamma aminobutyric acid (GABA) concentration in these areas. Resting-state functional connectivity MRI (rsfcMRI) was acquired before and after the stimulation. The individual distribution of tDCS induced electric fields (efields) within the MRS voxel was computationally modelled using SimNIBS 2.0. There were no significant changes of Glu, Glx and GABA levels across conditions but marked differences in the course of Glu levels between female and male participants were observed. Further investigation yielded a significantly stronger Glu reduction after active compared to sham stimulation in female participants, but not in male participants. For rsfcMRI neither significant changes nor correlations with MRS data were observed. Exploratory analyses of the effect of efield intensity distribution on Glu changes showed distinct effects in different efield groups. Our findings are limited by the small sample size, but correspond to previously published results of cathodal tDCS. Future studies should address gender and efield intensity as moderators of tDCS induced effects.

O2.2. EVALUATION OF THE RELATIONSHIP BETWEEN GLUTAMATE AND BRAIN CONNECTIVITY IN ANTIPSYCHOTIC-NAïVE FIRST EPISODE PATIENTS – A COMBINED MAGNETIC RESONANCE SPECTROSCOPY AND RESTING STATE FUNCTIONAL CONNECTIVITY MRI STUDY

BackgroundSchizophrenia is thought to be a disorder of brain dysconnectivity. An imbalance between cortical excitation/inhibition is also implicated, but the link between these abnormalities remains unclear. The present study used resting state functional connectivity MRI (rs-fcMRI) and magnetic resonance spectroscopy (MRS) to investigate how measurements of glutamate + glutamine (Glx) in the anterior cingulate cortex (ACC) relate to rs-fcMRI in medication-naïve first episode psychosis (FEP) subjects compared to healthy controls (HC). Based on our previous findings, we hypothesized that in HC would show correlations between Glx and rs-fMRI in the salience and default mode network, but these relationships would be altered in FEP.MethodsData from 53 HC (age = 24.70 ±6.23, 34M/19F) and 60 FEP (age = 24.08 ±6.29, 38M/22F) were analyzed. To obtain MRS data, a voxel was placed in the ACC (PRESS, TR/TE = 2000/80ms). Metabolite concentrations were quantified with respect to internal water using the AMARES algorithm in jMRUI. rs-fMRI data were processed using a standard preprocessing pipeline in the CONN toolbox. BOLD signal from a priori brain regions of interest from posterior cingulate cortex (default mode network, DMN), anterior cingulate cortex (salience network, SN), and right posterior parietal cortex (central executive network, CEN) were extracted and correlated with the rest of the brain to measure functional connectivity (FC). Group analyses were performed on Glx, FC, and Glx-FC interactions while controlling for age, gender, and motion when applicable. FC and Glx-FC analyses were performed using small volume correction [(p < 0.01, threshold-free cluster enhancement corrected (TFCE)].ResultsNo significant between-group differences were found in Glx concentration in the ACC [F(1, 108) = 0.34, p = 0.56], but reduced FC was found on each network in FEP compared to HC (pTFCE corrected). Group Glx-FC interactions were found in the form of positive correlations between Glx and FC in DMN and SN in the HC group, but not in FEP; and negative correlations in CEN in HC, but not in FEP.DiscussionWhile we did not find significant group differences in ACC Glx measurements, ACC Glx modulated FC differentially in FEP and HC. Positive correlations between Glx and FC were found in the SN and DMN, suggesting long range modulation of the two networks in HC, but not in FEP. Additionally, negative correlations between Glx and FC were found in CEN in HC, but not in FEP. Overall, these results suggest that even in the absence of group differences in Glx concentration, the long-range modulation of these 3 networks by ACC Glx is altered in FEP.

Increased intrinsic default-mode network activity as a compensatory mechanism in aMCI: a resting-state functional connectivity MRI study.

Numerous studies have investigated the differences in the mean functional connectivity (FC) strength between amnestic mild cognitive impairment (aMCI) patients and normal subjects using resting-state functional magnetic resonance imaging. However, whether the mean FC is increased, decreased or unchanged in aMCI patients compared to normal controls remains unclear. Two factors might lead to inconsistent results: the determination of regions of interest and the reliability of the FC.We explored differences in FC and the degree centrality (Dc) constructed by the bootstrap method, between and within networks (default-mode network (DN), frontoparietal control network (CN), dorsal attention network (AN)), and resulting from a hierarchical-clustering algorithm.The mean FC within the DN and CN was significantly increased (P < 0.05, uncorrected) in patients. Significant increases (P < 0.05, uncorrected) in the mean FC were found in patients between DN and CN and between DN and AN. Five pairs of FC (false discovery rate corrected) and the Dc of six regions (Bonferroni corrected) displayed a significant increase in patients. Lower cognitive ability was significantly associated with a greater increase in the Dc of the left superior temporal sulcus.Our results demonstrate that the early dysfunctions in aMCI disease are mainly compensatory impairments.

Resting-state functional MRI connectivity impact on epilepsy surgery plan and surgical candidacy: prospective clinical work.

The authors' goal was to prospectively quantify the impact of resting-state functional MRI (rs-fMRI) on pediatric epilepsy surgery planning. Fifty-one consecutive patients (3 months to 20 years old) with intractable epilepsy underwent rs-fMRI for presurgical evaluation. The team reviewed the following available diagnostic data: video-electroencephalography (n = 51), structural MRI (n = 51), FDG-PET (n = 42), magnetoencephalography (n = 5), and neuropsychological testing (n = 51) results to formulate an initial surgery plan blinded to the rs-fMRI findings. Subsequent to this discussion, the connectivity results were revealed and final recommendations were established. Changes between pre- and post-rs-fMRI treatment plans were determined, and changes in surgery recommendation were compared using McNemar's test. Resting-state fMRI was successfully performed in 50 (98%) of 51 cases and changed the seizure onset zone localization in 44 (88%) of 50 patients. The connectivity results prompted 6 additional studies, eliminated the ordering of 11 further diagnostic studies, and changed the intracranial monitoring plan in 10 cases. The connectivity results significantly altered surgery planning with the addition of 13 surgeries, but it did not eliminate planned surgeries (p = 0.003). Among the 38 epilepsy surgeries performed, the final surgical approach changed due to rs-fMRI findings in 22 cases (58%), including 8 (28%) of 29 in which extraoperative direct electrical stimulation mapping was averted. This study demonstrates the impact of rs-fMRI connectivity results on the decision-making for pediatric epilepsy surgery by providing new information about the location of eloquent cortex and the seizure onset zone. Additionally, connectivity results may increase the proportion of patients considered eligible for surgery while optimizing the need for further testing.

Heterogeneity of executive function revealed by a functional random forest approach across ADHD and ASD.

Those with autism spectrum disorder (ASD) and/or attention-deficit-hyperactivity disorder (ADHD) exhibit symptoms of hyperactivity and inattention, causing significant hardships for families and society. A potential mechanism involved in these conditions is atypical executive function (EF). Inconsistent findings highlight that EF features may be shared or distinct across ADHD and ASD. With ADHD and ASD each also being heterogeneous, we hypothesized that there may be nested subgroups across disorders with shared or unique underlying mechanisms. Participants (N=130) included adolescents aged 7-16 with ASD (n=64) and ADHD (n=66). Typically developing (TD) participants (n=28) were included for a comparative secondary sub-group analysis. Parents completed the K-SADS and youth completed an extended battery of executive and other cognitive measures. A two stage hybrid machine learning tool called functional random forest (FRF) was applied as a classification approach and then subsequently to subgroup identification. We input 43 EF variables to the classification step, a supervised random forest procedure in which the features estimated either hyperactive or inattentive ADHD symptoms per model. The FRF then produced proximity matrices and identified optimal subgroups via the infomap algorithm (a type of community detection derived from graph theory). Resting state functional connectivity MRI (rs-fMRI) was used to evaluate the neurobiological validity of the resulting subgroups. Both hyperactive (Mean absolute error (MAE)=0.72, Null model MAE=0.8826, (t(58)=-4.9, p<.001) and inattentive (MAE=0.7, Null model MAE=0.85, t(58)=-4.4, p<.001) symptoms were predicted better than chance by the EF features selected. Subgroup identification was robust (Hyperactive: Q=0.2356, p<.001; Inattentive: Q=0.2350, p<.001). Two subgroups representing severe and mild symptomology were identified for each symptom domain. Neuroimaging data revealed that the subgroups and TD participants significantly differed within and between multiple functional brain networks, but no consistent "severity" patterns of over or under connectivity were observed between subgroups and TD. The FRF estimated hyperactive/inattentive symptoms and identified 2 distinct subgroups per model, revealing distinct neurocognitive profiles of Severe and Mild EF performance per model. Differences in functional connectivity between subgroups did not appear to follow a severity pattern based on symptom expression, suggesting a more complex mechanistic interaction that cannot be attributed to symptom presentation alone.

SCIDOT-44. CREATING CAUSAL CAPABILITIES IN FUNCTIONAL BRAIN MAPPING USING A CED APPROACH

Abstract INTRODUCTION The spatial and temporal resolution limits of functional MRI (fMRI) brain mapping provide primarily correlative information on brain connectivity. Determining how one region causally modulates and mediates activity in other regions remains difficult with fMRI. We demonstrate a simple means to add causality in resting state functional connectivity MRI (rs-fcMRI) using techniques developed first for convection-enhanced delivery (CED) of therapeutics. Here we use CED to guide and monitor pharmacologic alteration of a local brain region in anaesthetized Rhesus monkeys while monitoring rs-fcMRI signal changes. METHODS Pre-surgical MRI was used to determine skull locations for craniotomies for installation of NavigusTMbrain ports in two untrained monkeys slated for euthanasia. The ports were aligned in real–time to provide trajectories aimed at the central nucleus of the amygdala (CeA). Fused silica catheters were then inserted into the CeA where 24 mg of muscimol (inhibitory agent) was infused in 24 ml of buffered solution under pressure over 12 minutes, first on the right side and then on the left side. rs-fcMRI studies were done for 45 minutes before and after the unilateral infusion and then after the bilateral infusion. RESULTS Catheters were successfully aligned and inserted into the CeA targets with sub-mm accuracy. T2-weighted imaging detected the enhanced T2 from the infusion’s buffer. Pre-infusion rs-fcMRI provides results consistent with prior studies, which have shown that the CeA is most strongly connected to the contralateral CeA. This connectivity was significantly reduced following both unilateral and bilateral injections of muscimol into the CeA, demonstrating the effectiveness of the muscimol infusions. Conditional Grainger Causality (CGC) analysis shows unexpected new connectivity after the unilateral infusion. Upon the bilateral infusion, global effective connectivity in the region is reduced. CONCLUSION Expected and unexpected changes in resting state functional connectivity resulted from unilateral and bilateral infusions of inhibitory agents.

Longitudinal degradation of the default/salience network axis in symptomatic individuals with elevated amyloid burden.

Resting-state functional connectivity MRI (rs-fcMRI) is a non-invasive imaging technique that has come into increasing use to understand disrupted neural network function in neuropsychiatric disease. However, despite extensive study over the past 15 years, the development of rs-fcMRI as a biomarker has been impeded by a lack of reliable longitudinal rs-fcMRI measures. Here we focus on longitudinal change along the Alzheimer's disease (AD) trajectory and demonstrate the utility of Template Based Rotation (TBR) in detecting differential longitudinal rs-fcMRI change between higher and lower amyloid burden individuals with mildly impaired cognition. Specifically, we examine a small (N = 24), but densely sampled (~5 observations over ~3 years), cohort of symptomatic individuals with serial rs-fcMRI imaging and PiB-PET imaging for β-amyloid pathology. We observed longitudinal decline of the Default Mode and Salience network axis (DMN/SAL) among impaired individuals with high amyloid burden. No other networks showed differential change in high vs. low amyloid individuals over time. The standardized effect size of AD related DMN/SAL change is comparable to the standardized effect size of amyloid-related change on the mini-mental state exam (MMSE) and hippocampal volume (HV). Last, we show that the AD-related change in DMN/SAL connectivity is almost completely independent of change on MMSE or HV, suggesting that rs-fcMRI is sensitive to an aspect of AD progression that is not captured by these other measures. Together these analyses demonstrate that longitudinal rs-fcMRI using TBR can capture disease-relevant network disruption in a clinical population.

Increased Functional Connectivity Within Intrinsic Neural Networks in Chronic Stroke Following Treatment with Red/Near-Infrared Transcranial Photobiomodulation: Case Series with Improved Naming in Aphasia.

Objective: To examine effects of four different transcranial, red/near-infrared (NIR), light-emitting diode (tLED) protocols on naming ability in persons with aphasia (PWA) due to left hemisphere (LH) stroke. This is the first study to report beneficial effects from tLED therapy in chronic stroke, and parallel changes on functional magnetic resonance imaging (fMRI). Materials and methods: Six PWA, 2-18 years poststroke, in whom 18 tLED treatments were applied (3 × /week, 6 weeks) using LED cluster heads: 500 mW, red (633 nm) and NIR (870 nm), 22.48 cm2, 22.2 mW/cm2. Results: After Protocol A with bilateral LED placements, including midline, at scalp vertex over left and right supplementary motor areas (L and R SMAs), picture naming was not improved. P1 underwent pre-/postovert, picture-naming task-fMRI scans; P2 could not. After Protocol A, P1 showed increased activation in LH and right hemisphere, including L and R SMAs. After Protocol B with LEDs only on ipsilesional, LH side, naming ability significantly improved for P1 and P2; the fMRI scans for P1 then showed activation only on the ipsilesional LH side. After Protocol C with LED placements on ipsilesional LH side, plus one midline placement over mesial prefrontal cortex (mPFC) at front hairline, a cortical node of the default mode network (DMN), P3 and P4 had only moderate/poor response, and no increase in functional connectivity on resting-state functional-connectivity MRI. After Protocol D, however, with LED placements on ipsilesional LH side, plus over two midline nodes of DMN, mPFC, and precuneus (high parietal) simultaneously, P5 and P6 each had good response with significant increase in functional connectivity within DMN, p < 0.0005; salience network, p < 0.0005; and central executive network, p < 0.05. Conclusions: NIR photons can affect surface brain cortex areas subjacent to where LEDs are applied on the scalp. Improved naming ability was present with optimal Protocol D. Transcranial photobiomodulation may be an additional noninvasive therapy for stroke.

Pediatric postoperative cerebellar cognitive affective syndrome follows outflow pathway lesions.

To evaluate lesion location after pediatric cerebellar tumor resection in relation to the development of severe cognitive and affective disturbances, or cerebellar cognitive affective syndrome (CCAS). The postsurgical lesion location of 195 pediatric patients with cerebellar tumors was mapped onto a template brain. Individuals with CCAS were matched to 2 participants without CCAS by sex, age, and lesion volume. Lesion analyses included both a hypothesis-driven evaluation of the cerebellar outflow pathway (deep nuclei and superior cerebellar peduncles) and data-driven multivariate lesion symptom mapping. Lesion-associated networks were evaluated by comparing connectivity patterns between the lesion location of cases with and those without CCAS with resting-state functional connectivity MRI data from large normative adult and pediatric cohorts. CCAS was present in 48 of 195 participants (24.6%) and was strongly associated with cerebellar outflow tract lesions (p < 0.0001). Lesion symptom mapping also highlighted the cerebellar outflow pathway, with peak findings in the fastigial nuclei extending into the inferior vermis. Lesion network mapping revealed that the cerebellar region most associated with CCAS was functionally connected to the thalamic mediodorsal nucleus, among other sites, and that higher connectivity between lesion location and the mediodorsal nucleus predicts CCAS occurrence (p < 0.01). A secondary analysis of 27 participants with mutism revealed similar localization of lesions and lesion-associated networks. Lesions of the cerebellar outflow pathway and inferior vermis are associated with major cognitive and affective disturbances after pediatric cerebellar tumor resection, and disrupted communication between the cerebellum and the thalamic mediodorsal nucleus may be important.

The role of the hippocampus in the semantic variant of primary progressive aphasia: A resting-state fcMRI study.

The goal of the study was to determine whether the semantic variant of primary progressive aphasia (svPPA) affects the intrinsic connectivity network anchored to left and right anterior hippocampus, but spares the posterior hippocampus. A resting-state functional connectivity MRI (rs-fcMRI) study was conducted in a group of patients with svPPA and in controls, using a seed-to-voxel approach. In comparison to controls, massively reduced connectivity was found in the anterior hippocampus, mainly the left one, for svPPA patients but not in the left or right posterior hippocampus. In svPPA, the anterior hippocampus showed reduced functional connectivity with regions implicated in the semantic memory network. Significant correlation was also found between the functional connectivity strength of the left anterior hippocampus and the ventromedial cortex, and performance in semantic tasks. These findings indicate that the functional disconnection of the anterior hippocampus may be a promising in vivo biomarker of svPPA and illustrate the role of this hippocampal subregion in the semantic memory system.

Bimodal distribution of tone-matching deficits indicates discrete pathophysiological entities within the syndrome of schizophrenia

To date, no measures are available that permit differentiation of discrete, clinically distinct subtypes of schizophrenia (SZ) with potential differential underlying pathophysiologies. Over recent years, there has been increasing recognition that SZ is heterogeneously associated with deficits in early auditory processing (EAP), as demonstrated using clinically applicable tasks such as tone-matching task (TMT). Here, we pooled TMT performances across 310 SZ individuals and 219 healthy controls (HC), along with clinical, cognitive, and resting-state functional-connectivity MRI (rsFC-MRI) measures. In addition, TMT was measured in a group of 24 patients at symptomatic clinical high risk (CHR) for SZ and 24 age-matched HC (age range 7–27 years). We provide the first demonstration that the EAP deficits are bimodally distributed across SZ subjects (P < 0.0001 vs. unimodal distribution), with one group showing entirely unimpaired TMT performance (SZ-EAP+), and a second showing an extremely large TMT impairment (SZ-EAP−), relative to both controls (d = 2.1) and SZ-EAP+ patients (d = 3.4). The SZ-EAP− group predominated among samples drawn from inpatient sites, showed higher levels of cognitive symptoms (PANSS), worse social cognition and a differential deficit in neurocognition (MATRICS battery), and reduced functional capacity. rsFC-MRI analyses showed significant reduction in SZ-EAP− relative to controls between subcortical and cortical auditory regions. As opposed to SZ, CHR patients showed intact EAP function. In HC age-matched to CHR, EAP ability was shown to increase across the age range of vulnerability preceding SZ onset. These results indicate that EAP measure segregates between discrete SZ subgroups. As TMT can be readily implemented within routine clinical settings, its use may be critical to account for the heterogeneity of clinical outcomes currently observed across SZ patients, as well as for pre-clinical detection and efficacious treatment selection.

Spatiotemporal Empirical Mode Decomposition of Resting-State fMRI Signals: Application to Global Signal Regression.

Resting-state functional connectivity MRI (rs-fcMRI) is a common method for mapping functional brain networks. However, estimation of these networks is affected by the presence of a common global systemic noise, or global signal (GS). Previous studies have shown that the common preprocessing steps of removing the GS may create spurious correlations between brain regions. In this paper, we decompose fMRI signals into 5 spatial and 3 temporal intrinsic mode functions (SIMF and TIMF, respectively) by means of the empirical mode decomposition (EMD), which is an adaptive data-driven method widely used to analyze non-linear and non-stationary phenomena. For each SIMF, functional connectivity matrices were computed by means of Pearson correlation between TIMFs of different brain areas. Thus, instead of a single connectivity matrix, we obtained 5 × 3 = 15 functional connectivity matrices. Given the high correlation and global efficiency values of the connectivity matrices related to the low spatial maps (SIMF3, SIMF4, and SIMF5), our results suggest that these maps can be considered as spatial global signal masks. Thus, by summing up the first two SIMFs extracted from the fMRI signals, we have automatically excluded the GS which is now voxel-specific. We compared the performance of our method with the conventional GS regression and to the results when the GS was not removed. While the correlation pattern identified by the other methods suffers from a low level of precision in identifying the correct brain network connectivity, our approach demonstrated expected connectivity patterns for the default mode network and task-positive network.

Modulation of the spontaneous hemodynamic response function across levels of consciousness

Functional imaging research has already contributed with several results to the study of neural correlates of consciousness. Apart from task-related activation derived in fMRI, PET based glucose metabolism rate or cerebral blood flow account for a considerable proportion of the study of brain activity under different levels of consciousness. Resting state functional connectivity MRI is playing a crucial role to explore the consciousness related functional integration, successfully complementing PET, another widely used neuroimaging technique. Here, spontaneous hemodynamic response is introduced to characterize resting state brain activity giving information on the local metabolism (neurovascular coupling), and useful to improve the time-resolved activity and connectivity measures based on BOLD fMRI. This voxel-wise measure is then used to investigate the loss of consciousness under Propofol anesthesia and unresponsive wakefulness syndrome. Changes in the hemodynamic response in precuneus and posterior cingulate are found to be a common principle underlying loss of consciousness in both conditions. The thalamus appears to be less obviously modulated by Propofol, compared with frontoparietal regions. However, a significant increase in spontaneous thalamic hemodynamic response was found in patients in unresponsive wakefulness syndrome compared with healthy controls. Our results ultimately show that anesthesia- or pathology-induced neurovascular coupling could be tracked by modulated spontaneous hemodynamic response derived from resting state fMRI.

What is the Functional Difference Between Sagittal With Metopic and Isolated Sagittal Craniosynotosis?

The purpose of this study is to understand the neurological differences between patients born with combined sagittal and metopic craniosynostosis (SMc) and isolated sagittal craniosynostosis (ISc) by studying aberrations in functional brain connectivity and white matter microstructure, before surgery, utilizing functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI). The authors collected DTI and resting-state (ie, no sedation and asleep) functional connectivity MRI data in 10 infant patients preoperatively: 5 in the SMc group (4.3 ± 1 months) and 5 in the ISc group (4.8 ± 1.1 months). Resting state fMRI imaging and DTI data were acquired using a 3-T Siemens Trio MRI system (Erlangen, Germany) while the infant patients slept. fMRI data were corrected for movement using SPM, underwent cerebrospinal fluid and white matter signal regression and further analyzed with BioImageSuite. For the DTI data, 3 diffusion runs were averaged, processed utilizing FMRIB Software Library, and analyzed statistically using BioImageSuite. Comparing the SMc versus ISc groups, SMc demonstrated that there was increased connectivity, statistically significant differences, in neural networks between children with sagittal synostosis alone versus those with sagittal with metopic synostosis, in the right BA 31 and BA 23 (corresponding to the posterior cingulate cortex (PCC) (P < 0.001). Analysis of the DTI revealed increased fractional anisotropy (normal maturation of white tracts) in the SMc group in the cingulum compared to the ISc group (P < 0.05). Differences in the functional networks include increased connectivity right frontoparietal network (RFPN) in ISc and increased connectivity in the primary visual network (V1) in SMc (P < 0.001). The SMc had increased connectivity as measured by fMR in the PCC, an area associated with attention deficit hyperactivity disorder. The DTI analysis demonstrated an increase in fractional anisotropy of the cingulum in the SMc group, a white matter tract projecting from the cingulate cortex; connections of the limbic (emotional regulation) system are instrumental. In SMc, increase of connectivity in the PCC correlates with an increase in maturation of the cingulum compared to ISc. There is increased connectivity of the RFPN network in the ISc and increased connectivity of the V1 network in the SMc patients. The SMc group has increased connectivity in the PCC, the original seed of the DMN network, and decreased connectivity to the RFPN network. The pattern of increased connectivity in the area of the DMN and decreased connectivity in the RFPN network is similar to the trend when comparing ADHD patients to normal controls. SMc has more similar functional network connectivity to ADHD as compared to ISc.

Autism-associated Nf1 deficiency disrupts corticocortical and corticostriatal functional connectivity in human and mouse

Children with the autosomal dominant single gene disorder, neurofibromatosis type 1 (NF1), display multiple structural and functional changes in the central nervous system, resulting in neuropsychological cognitive abnormalities. Here we assessed the pathological functional organization that may underlie the behavioral impairments in NF1 using resting-state functional connectivity MRI. Coherent spontaneous fluctuations in the fMRI signal across the entire brain were used to interrogate the pattern of functional organization of corticocortical and corticostriatal networks in both NF1 pediatric patients and mice with a heterozygous mutation in the Nf1 gene (Nf1+/−). Children with NF1 demonstrated abnormal organization of cortical association networks and altered posterior-anterior functional connectivity in the default network. Examining the contribution of the striatum revealed that corticostriatal functional connectivity was altered. NF1 children demonstrated reduced functional connectivity between striatum and the frontoparietal network and increased striatal functional connectivity with the limbic network. Awake passive mouse functional connectivity MRI in Nf1+/− mice similarly revealed reduced posterior-anterior connectivity along the cingulate cortex as well as disrupted corticostriatal connectivity. The striatum of Nf1+/− mice showed increased functional connectivity to somatomotor and frontal cortices and decreased functional connectivity to the auditory cortex. Collectively, these results demonstrate similar alterations across species, suggesting that NF1 pathogenesis is linked to striatal dysfunction and disrupted corticocortical connectivity in the default network.

T14. Predicting Cognitive Behavioral Therapy Treatment Outcome Using Neural Markers of Maladaptive Self-Focused Attention

Maladaptive self-focused attention (SFA) is a bias toward internal thoughts that may predict poor cognitive-behavioral therapy (CBT) response. In this study, we used resting state functional connectivity MRI to test whether maladaptive SFA maps onto hyperconnectivity within the default mode network (DMN), an intrinsic brain network mediating internally-directed mentation, and whether DMN hyperconnectivity predicts worse CBT response.

3046 Reduced structural and functional connectivity in infants with prenatal opioid exposure

OBJECTIVES/SPECIFIC AIMS:. This study aims to understand the effects of prenatal opioid exposure on structural and functional connectivity in the neonatal brain. Our central hypothesis is that infants with prenatal opioid exposure will have decreased structural and functional connectivity as compared to non-exposed controls. Our overarching goal is to improve neurodevelopmental and behavioral outcomes in infants with prenatal opioid exposure. METHODS/STUDY POPULATION:. Infants with prenatal opioid exposure were recruited from 2 birth hospitals in our area. Control infants were recruited from the larger community. Infants underwent MRI between 4-6 weeks of age in the Cincinnati Children’s Hospital Imaging Research Center. MRI sequences included 3D structural T1 and T2-weighted imaging, resting state functional connectivity MRI, and multi-shell DTI (36 directions at b=800 and 68 directions at b=2000). Tract-based spatial statistics (TBSS) was used to identify differences in fractional anisotropy (a measure of white matter integrity) between groups. Group independent component analysis was used to identify differences in resting-state networks between groups RESULTS/ANTICIPATED RESULTS:. There were 5 subjects enrolled in the study with evaluable imaging, 3 infants with prenatal opioid exposure and 2 unexposed controls. Structural MRI was normal in all cases. Infants with prenatal opioid exposure had reduced structural connectivity as measured by fractional anisotropy (FA) in the genu and splenium of the corpus callosum as compared with controls. The orange/red color represents areas in which the FA of the opioid-exposed group was lower than controls and green represents the white matter skeleton common to both groups. Infants with prenatal opioid exposure also had significantly reduced within-network functional connectivity strength (z-transformed partial correlation coefficient 0.358 vs 0.199, p = 0.03) in the sensorimotor network as compared with controls. DISCUSSION/SIGNIFICANCE OF IMPACT:. In this small pilot study, both structural and functional connectivity were reduced in opioid-exposed infants compared with controls. This data suggests that differences in structural and functional connectivity may underlie the later developmental and behavioral problems seen in opioid-exposed children. These findings must be validated in a larger population with correction for confounding factors such as maternal education

Fourth finger dependence of high-functioning autism spectrum disorder in multi-digit force coordination

A number of studies have reported that the digit ratio 2D:4D (length of the second finger divided by length of the fourth finger) is smaller (longer fourth digit) in autism spectrum disorder (ASD) than in typically developed (TD) controls. Because form and function are closely related in biological systems, we hypothesized that the 4D dominance occurs in not only finger morphology but also physical performance in ASD. Individuals with ASD and TD controls participated in a multi-digit force-producing task. Individuals with ASD showed a significant 4D dependence compared to TD controls in the task. We found a significant correlation between 4D dependence and scores of the standard diagnostic instrument across individuals with ASD. Our analysis of functional connectivity in resting-state functional MRI suggests that connectivity between the visual cortex and the cerebellum contributes to the 4D dependence. Collectively, these results extend the 2D:4D ratio beyond being a morphological marker to being involved in motor functions in the form of 4D dependence in a multi-digit force task.