Higher-order functional brain networks and anterior cingulate glutamate + glutamine (Glx) in antipsychotic-naïve first episode psychosis patients.

Human connectome studies have provided abundant data consistent with the hypothesis that functional dysconnectivity is predominant in psychosis spectrum disorders. Converging lines of evidence also suggest an interaction between dorsal anterior cingulate cortex (dACC) cortical glutamate with higher-order functional brain networks (FC) such as the default mode (DMN), dorsal attention (DAN), and executive control networks (ECN) in healthy controls (HC) and this mechanism may be impaired in psychosis. Data from 70 antipsychotic-medication naïve first-episode psychosis (FEP) and 52 HC were analyzed. 3T Proton magnetic resonance spectroscopy (1H-MRS) data were acquired from a voxel in the dACC and assessed correlations (positive FC) and anticorrelations (negative FC) of the DMN, DAN, and ECN. We then performed regressions to assess associations between glutamate + glutamine (Glx) with positive and negative FC of these same networks and compared them between groups. We found alterations in positive and negative FC in all networks (HC > FEP). A relationship between dACC Glx and positive and negative FC was found in both groups, but when comparing these relationships between groups, we found contrasting associations between these variables in FEP patients compared to HC. We demonstrated that both positive and negative FC in three higher-order resting state networks are already altered in antipsychotic-naïve FEP, underscoring the importance of also considering anticorrelations for optimal characterization of large-scale functional brain networks as these represent biological processes as well. Our data also adds to the growing body of evidence supporting the role of dACC cortical Glx as a mechanism underlying alterations in functional brain network connectivity. Overall, the implications for these findings are imperative as this particular mechanism may differ in untreated or chronic psychotic patients; therefore, understanding this mechanism prior to treatment could better inform clinicians.Clinical trial registration: Trajectories of Treatment Response as Window into the Heterogeneity of Psychosis: A Longitudinal Multimodal Imaging Study, NCT03442101 . Glutamate, Brain Connectivity and Duration of Untreated Psychosis (DUP), NCT02034253 .

Higher-Order Intrinsic Brain Network Trajectories After Antipsychotic Treatment in Medication-Naïve Patients With First-Episode Psychosis.

BACKGROUND: Intrinsic brain network connectivity is already altered in first-episode psychosis (FEP), but the longitudinal trajectories of network connectivity, especially in response to antipsychotic treatment, remain poorly understood. The goal of this study was to investigate how antipsychotic medications affect higher-order intrinsic brain network connectivity in FEP. METHODS: Data from 87 antipsychotic medication-naïve patients with FEP and 87 healthy control participants were used. Medication-naïve patients received antipsychotic treatment for 16 weeks. Resting-state functional connectivity (FC) of the default mode, salience, dorsal attention, and executive control networks were assessed prior to treatment and at 6 and 16 weeks after treatment. We evaluated baseline and FC changes using linear mixed models to test group × time interactions within each network. Associations between FC changes after 16 weeks and response to treatment were also evaluated. RESULTS: Prior to treatment, significant group differences in all networks were found. However, significant trajectory changes in FC were found only in the default mode and executive control networks. Changes in FC in these networks were associated with treatment response. Several sensitivity analyses showed a consistent normalization of executive control network FC in response to antipsychotic treatment. CONCLUSIONS: Here, we found that alterations in intrinsic brain network FC were not only alleviated with antipsychotic treatment, but the extent of this normalization was also associated with the degree of reduction in symptom severity. Taken together, our data suggest modulation of intrinsic brain network connectivity (mainly frontoparietal connectivity) as a mechanism underlying antipsychotic treatment response in FEP.

Hippocampal Hyperconnectivity to the Visual Cortex Predicts Treatment Response.

BACKGROUND: Converging lines of evidence point to hippocampal dysfunction in psychosis spectrum disorders, including altered functional connectivity. Evidence also suggests that antipsychotic medications can modulate hippocampal dysfunction. The goal of this project was to identify patterns of hippocampal connectivity predictive of response to antipsychotic treatment in 2 cohorts of patients with a psychosis spectrum disorder, one medication-naïve and the other one unmedicated. HYPOTHESIS: We hypothesized that we would identify reliable patterns of hippocampal connectivity in the 2 cohorts that were predictive of treatment response and that medications would modulate abnormal hippocampal connectivity after 6 weeks of treatment. STUDY DESIGN: We used a prospective design to collect resting-state fMRI scans prior to antipsychotic treatment and after 6 weeks of treatment with risperidone, a commonly used antipsychotic medication, in both cohorts. We enrolled 44 medication-naïve first-episode psychosis patients (FEP) and 39 unmedicated patients with schizophrenia (SZ). STUDY RESULTS: In both patient cohorts, we observed a similar pattern where greater hippocampal connectivity to regions of the occipital cortex was predictive of treatment response. Lower hippocampal connectivity of the frontal pole, orbitofrontal cortex, subcallosal area, and medial prefrontal cortex was predictive of treatment response in unmedicated SZ, but not in the medication-naïve cohort. Furthermore, greater reduction in hippocampal connectivity to the visual cortex with treatment was associated with better clinical response. CONCLUSIONS: Our results suggest that greater connectivity between the hippocampus and occipital cortex is not only predictive of better treatment response, but that antipsychotic medications have a modulatory effect by reducing hyperconnectivity.

Dorsal striatial hypoconnectivity predicts antipsychotic medication treatment response in first-episode psychosis and unmedicated patients with schizophrenia.

INTRODUCTION: The dorsal striatum, comprised of the caudate and putamen, is implicated in the pathophysiology of psychosis spectrum disorders. Given the high concentration of dopamine receptors in the striatum, striatal dopamine imbalance is a likely cause in cortico-striatal dysconnectivity. There is great interest in understanding the relationship between striatal abnormalities in psychosis and antipsychotic treatment response, but few studies have considered differential involvement of the caudate and putamen. This study's goals were twofold. First, identify patterns of dorsal striatal dysconnectivity for the caudate and putamen separately in patients with a psychosis spectrum disorder; second, determine if these dysconnectivity patterns were predictive of treatment response. METHODS: Using resting state functional connectivity, we evaluated dorsal striatal connectivity using separate bilateral caudate and putamen seed regions in two cohorts of subjects: a cohort of 71 medication-naïve first episode psychosis patients and a cohort of 42 unmedicated patients with schizophrenia (along with matched controls). Patient and control connectivity maps were contrasted for each cohort. After receiving 6 weeks of risperidone treatment, patients' clinical response was calculated. We used regression analyses to determine the relationship between baseline dysconnectivity and treatment response. RESULTS: This dysconnectivity was also predictive of treatment response in both cohorts. DISCUSSION: These findings suggest that the caudate may be more of a driving factor than the putamen in early cortico-striatal dysconnectivity.

Contrasting Frontoparietal Network Connectivity in Antipsychotic Medication-Naive First-Episode Psychosis Patients Who Do and Do Not Display Features of the Deficit Syndrome.

BACKGROUND: The deficit syndrome is a clinical subtype of schizophrenia that is characterized by enduring negative symptoms. Several lines of evidence point to frontoparietal involvement, but the frontoparietal control network (FPCN) and its subsystems (FPCNA and FPCNB) proposed by Yeo et al. have not been systematically characterized at rest in patients with the deficit syndrome. METHODS: We used resting-state fMRI to investigate the FPCN and its subnetworks in 72 healthy controls and 65 antipsychotic medication-naive, first-episode psychosis patients (22 displayed deficit syndrome features, 43 did not). To assess whole-brain FPCN connectivity, we used the right posterior parietal cortex as the seed region. We then performed region of interest analyses in FPCN subsystems. RESULTS: We found that patterns of FPCN dysconnectivity to the whole brain differed in patients who displayed deficit syndrome features compared with those who did not. Examining the FPCN on a more granular level revealed reduced within-FPCN(A) connectivity only in patients displaying deficit features. FPCNB connectivity did not differ between patient groups. DISCUSSION: Here, we describe a neurobiological signature of aberrant FPCN connectivity in antipsychotic-naive, first-episode patients who display clinical features of the deficit syndrome. Importantly, frontoparietal subnetwork connectivity differentiated subgroups, where the FPCNA is selectively involved in patients with deficit features. Our findings add to the growing body of literature supporting a neurobiological distinction between two clinical subtypes of schizophrenia, which has the potential to be leveraged for patient stratification in clinical trials and the development of novel treatments.

Hippocampal Dysconnectivity and Altered Glutamatergic Modulation of the Default Mode Network: A Combined Resting-State Connectivity and Magnetic Resonance Spectroscopy Study in Schizophrenia.

BACKGROUND: Converging lines of evidence point to hippocampal dysfunction in schizophrenia. It is thought that hippocampal dysfunction spreads across hippocampal subfields and to cortical regions by way of long-range efferent projections. Importantly, abnormalities in the excitation/inhibition balance could impair the long-range modulation of neural networks. The goal of this project was twofold. First, we sought to identify replicable patterns of hippocampal dysconnectivity in patients with a psychosis spectrum disorder. Second, we aimed to investigate a putative link between glutamatergic metabolism and hippocampal connectivity alterations. METHODS: We evaluated resting-state hippocampal functional connectivity alterations in two cohorts of patients with a psychosis spectrum disorder. The first cohort consisted of 55 medication-naïve patients with first-episode psychosis and 41 matched healthy control subjects, and the second cohort consisted of 42 unmedicated patients with schizophrenia and 41 matched control subjects. We also acquired measurements of glutamate + glutamine in the left hippocampus using magnetic resonance spectroscopy for 42 patients with first-episode psychosis and 37 healthy control subjects from our first cohort. RESULTS: We observed a pattern of hippocampal functional hypoconnectivity to regions of the default mode network and hyperconnectivity to the lateral occipital cortex in both cohorts. We also show that in healthy control subjects, greater hippocampal glutamate + glutamine levels predicted greater hippocampal functional connectivity to the anterior default mode network. Furthermore, this relationship was reversed in medication-naïve subjects with first-episode psychosis. CONCLUSIONS: These results suggest that an alteration in the relationship between glutamate and functional connectivity may disrupt the dynamic of major neural networks.

Salience network glutamate and brain connectivity in medication-naïve first episode patients - A multimodal magnetic resonance spectroscopy and resting state functional connectivity MRI study.

BACKGROUND: Salience network (SN) connectivity is altered in schizophrenia, but the pathophysiological origin remains poorly understood. The goal of this multimodal neuroimaging study was to investigate the role of glutamatergic metabolism as putative mechanism underlying SN dysconnectivity in first episode psychosis (FEP) subjects. METHODS: We measured glutamate + glutamine (Glx) in the dorsal anterior cingulate cortex (dACC) from 70 antipsychotic-naïve FEP subjects and 52 healthy controls (HC). The dACC was then used as seed to define positive and negative resting state functional connectivity (FC) of the SN. We used multiple regression analyses to test main effects and group interactions of Glx and FC associations. RESULTS: dACC Glx levels did not differ between groups. Positive FC was significantly reduced in FEP compared to HC, and no group differences were found in negative FC. Group interactions of Glx-FC associations were found within the SN for positive FC, and in parietal cortices for negative FC. In HC, higher Glx levels predicted greater positive FC in the dACC and insula, and greater negative FC of the lateral parietal cortex. These relationships were weaker or absent in FEP. CONCLUSIONS: Here, we found that positive FC in the SN is already altered in medication-naïve FEP, underscoring the importance of considering both correlations and anticorrelations for characterization of pathology. Our data demonstrate that Glx and functional connectivity work differently in FEP than in HC, pointing to a possible mechanism underlying dysconnectivity in psychosis.

Structural and Functional Default Mode Network Connectivity and Antipsychotic Treatment Response in Medication-Naïve First Episode Psychosis Patients.

INTRODUCTION: Only a few studies have comprehensively characterized default mode network (DMN) pathology on a structural and functional level, and definite conclusions cannot be drawn due to antipsychotic medication exposure and illness chronicity. The objective of this study was to characterize DMN pathology in medication-naïve first episode psychosis (FEP) patients, and determine if DMN structural and functional connectivity (FC) have potential utility as a predictor for subsequent antipsychotic treatment response. METHODS: Diffusion imaging and resting state FC data from 42 controls and 52 FEP were analyzed. Patients then received 16 weeks of antipsychotic treatment. Using region of interest analyses, we quantified FC of the DMN and structural integrity of the white matter tracts supporting DMN function. We then did linear regressions between DMN structural and FC indices and antipsychotic treatment response. RESULTS: We detected reduced DMN fractional anisotropy and axial diffusivity in FEP compared to controls. No DMN FC abnormalities nor correlations between DMN structural and FC were found. Finally, DMN fractional anisotropy and radial diffusivity were associated with response to treatment. CONCLUSION: Our study highlights the critical role of the DMN in the pathophysiology suggesting that axonal damage may already be present in FEP patients. We also demonstrated that DMN pathology is clinically relevant, as greater structural DMN alterations were associated with a less favorable clinical response to antipsychotic medications.

Corpus callosum size and homotopic connectivity in Autism spectrum disorder.

By examining how morphology of the corpus callosum (CC) in autism spectrum disorder (ASD) may affect functional communication across hemispheres, we hope to provide new insights into the structure-function relationship in the brain. We used a sample of 94 participants from the Autism Brain Imaging Data Exchange (ABIDE) database (55 typically-developing (TD) and 39 with ASD). The CC was segmented into five sub-regions (anterior, mid-anterior, central, mid-posterior, posterior) using FreeSurfer software, which were further examined for group differences. The total volume and specific sub-region volumes of the CC, and interhemispheric (homotopic) functional connectivity were calculated, along with the relationship between volume and connectivity. These measures were correlated with social ability assessed by the Social Responsiveness Scale (SRS). The central sub-region of CC was significantly smaller in ASD, although there was no group difference in total CC volume. ASD participants also showed stronger homotopic connectivity in the superior frontal gyrus. SRS scores were negatively correlated with the CC central sub-region volumes in ASD. The findings of this study add to the body of research showing morphological differences in the CC in ASD as well as connectivity differences. The absence of a significant relationship between structure and homotopic functional connectivity aligns with previous findings.

"Unrest while Resting"? Brain entropy in autism spectrum disorder.

Biological systems typically exhibit complex behavior with nonlinear dynamic properties. Nonlinear signal processing techniques such as sample entropy is a novel approach to characterize the temporal dynamics of brain connectivity. Estimating entropy is especially important in clinical populations such as autism spectrum disorder (ASD) as differences in entropy may signal functional alterations in the brain. Considering the models of disrupted brain network connectivity in ASD, sample entropy would provide a novel direction to understand brain organization. Resting state fMRI data from 45 high-functioning children with ASD and 45 age-and-IQ-matched typically developing (TD) children were obtained from the Autism Brain Imaging Data Exchange (ABIDE-II) database. Data were preprocessed using the CONN toolbox. Sample entropy was then calculated using the complexity toolbox, in a whole-brain voxelwise manner as well as in regions of interests (ROIs) based methods. ASD participants demonstrated significantly increased entropy in left angular gyrus, superior parietal lobule, and right inferior temporal gyrus; and reduced sample entropy in superior frontal gyrus compared to TD participants. Positive correlations of average entropy in clusters of significant group differences scores across all subjects were found. Finally, ROI analysis revealed a main effect of lobes. Differences in entropy between the ASD and TD groups suggests that entropy may provide another important index of brain dysfunction in clinical populations like ASD. Further, the relationship between increased entropy and ASD symptoms in our study underscores the role of optimal brain synchronization in cognitive and behavioral functions.

Duration of Untreated Psychosis Correlates With Brain Connectivity and Morphology in Medication-Naïve Patients With First-Episode Psychosis.

BACKGROUND: In the United States, the average duration of untreated psychosis (DUP) is 21 months, and it remains unknown how longer DUP may affect brain functioning in antipsychotic-naïve patients with first-episode psychosis. The objective was to determine the effects of DUP on functional connectivity and brain morphology measured with resting-state functional and structural magnetic resonance imaging. METHODS: Medication-naïve patients with first-episode psychosis were referred from various clinical settings. After accounting for exclusion criteria, attrition, and data quality, final analyses included 55 patients (35 male and 20 female; mean age, 24.18 years). Patients with first-episode psychosis were subjected to a 16-week trial of risperidone, a commonly used antipsychotic drug. Treatment response was calculated as change in the psychosis subscale of the Brief Psychiatric Rating Scale between baseline and 16 weeks. Resting-state functional connectivity magnetic resonance imaging and brain morphology (surface area and cortical thickness) were assessed. RESULTS: Longer DUP was associated with worse treatment response and reduced functional connectivity-more specifically in the default, salience, and executive networks. Moreover, longer DUP was associated with reduced surface area in the salience and executive networks and with increased cortical thickness in the default mode and salience networks. When the functional connectivity of the default mode network was added as a mediator, the relationship between DUP and treatment response was no longer significant. CONCLUSIONS: These data suggest that several neurobiological alterations in the form of reduced functional connectivity and surface area and increased cortical thickness underpin the effect of prolonged DUP.

Hyperconnectivity of social brain networks in autism during action-intention judgment.

Deficits in social communication in autism spectrum disorder (ASD) have been documented using neuroimaging techniques such as functional MRI over the past decade. More recently, functional connectivity MRI has revealed altered connectivity in face processing, mentalizing, and mirroring brain networks, networks involved in the social brain in ASD. However, to our knowledge, previous studies have not examined these three networks concurrently. The purpose of the current study was to investigate the functional connectivity of the face processing, mentalizing, and mirroring networks (within each network and across networks) in ASD during an action-intention task in which participants were asked to determine the means and intention of a model's actions. We examined: a) within-network connectivity of each network using an ROI-to-ROI analysis; b) connectivity of each network hub to the rest of the brain using a seed-to-voxel analysis; c) the between-network connectivity of each network hub using ROI-to-ROI analysis; and d) brain-behavior relationships by correlating autism symptoms with brain connectivity. Task-fMRI data were used from 21 participants with ASD and 20 typically developing participants. The ASD group consistently showed significantly greater connectivity between networks and between hub regions to the rest of the brain. Hyperconnectivity in ASD may entail more and widespread resource utilization for accomplishing action-intention judgment.

Aberrant "deep connectivity" in autism: A cortico-subcortical functional connectivity magnetic resonance imaging study.

The number of studies examining functional brain networks in Autism Spectrum Disorder (ASD) has risen over the last decade and has characterized ASD as a disorder of altered brain connectivity. However, these studies have focused largely on cortical structures, and only a few studies have examined cortico-subcortical connectivity in regions like thalamus and basal ganglia in ASD. The goal of this study was to characterize the functional connectivity between cortex and subcortical regions in ASD using the Autism Brain Imaging Data Exchange (ABIDE-II). Resting-state functional magnetic resonance imaging data were used from 168 typically developing (TD) and 138 ASD participants across different sites from the ABIDE II dataset. Functional connectivity of basal ganglia and thalamus to unimodal and supramodal networks was examined in this study. Overconnectivity (ASD > TD) was found between unimodal (except for medial visual network) and subcortical regions, and underconnectivity (TD > ASD) was found between supramodal (except for default mode and dorsal attention networks) and subcortical regions; positive correlations between ASD phenotype and unimodal-subcortical connectivity were found and negative ones with supramodal-subcortical connectivity. These findings suggest that brain networks heavily involved in sensory processing had higher connectivity with subcortical regions, whereas those involved in higher-order thinking showed decreased connectivity in ASD. In addition, brain-behavior correlations indicated a relationship between ASD phenotype and connectivity. Thus, differences in cortico-subcortical connectivity may have a significant impact on basic and higher-order cognitive processes in ASD. Autism Res 2019, 12: 384-400 © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: This study focused on examining the functional connectivity (synchronization of brain activity across regions) of two types of brain networks (unimodal and supramodal) with subcortical areas (thalamus and basal ganglia) in children, adolescents, and adults with autism spectrum disorder (ASD) and how this relates to ASD phenotype. ASD participants showed overconnectivity in unimodal networks and underconnectivity in supramodal networks. These findings provide new insights into cortico-subcortical connections between basic sensory and high-order cognitive processes.

A Longitudinal Multimodal Neuroimaging Study to Examine Relationships Between Resting State Glutamate and Task Related BOLD Response in Schizophrenia.

Previous studies have observed impairments in both brain function and neurometabolite levels in schizophrenia. In this study, we investigated the relationship between brain activity and neurochemistry in off-medication patients with schizophrenia and if this relationship is altered following antipsychotic medication by combining proton magnetic resonance spectroscopy (1H-MRS) with functional magnetic resonance imaging (fMRI). We used single voxel MRS acquired in the bilateral dorsal anterior cingulate cortex (ACC) and fMRI during performance of a Stroop color-naming task in 22 patients with schizophrenia (SZ), initially off-medication and after a 6-week course of risperidone, and 20 matched healthy controls (HC) twice, 6 weeks apart. We observed a significant decrease in ACC glutamate + glutamine (Glx)/Creatine (Cr) levels in medicated SZ patients compared to HC but not compared to their off-medication baseline. In off-medication SZ, the relationship between ACC Glx/Cr levels and the blood oxygen level-dependent (BOLD) response in regions of the salience network (SN) and posterior default mode network (DMN) was opposite than of HC. After 6 weeks, the relationship between Glx and the BOLD response was still opposite between the groups; however for both groups the direction of the relationship changed from baseline to week 6. These results suggest a mechanism whereby alterations in the relationship between cortical glutamate and BOLD response is disrupting the modulation of major neural networks subserving cognitive processes, potentially affecting cognition. While these relationships appear to normalize with treatment in patients, the interpretations of the results are confounded by significant group differences in Glx levels, as well as the variability of the relationship between Glx and BOLD response in HC over time, which may be driven by factors including habituation to task or scanner environment.

Action simulation and mirroring in children with autism spectrum disorders.

Mental imitation, perhaps a precursor to motor imitation, involves visual perspective-taking and motor imagery. Research on mental imitation in autism spectrum disorders (ASD) has been rather limited compared to that on motor imitation. The main objective of this fMRI study is to determine the differences in brain responses underlying mirroring and mentalizing networks during mental imitation in children and adolescents with ASD. Thirteen high-functioning children and adolescents with ASD and 15 age-and- IQ-matched typically developing (TD) control participants took part in this fMRI study. In the MRI scanner, participants were shown cartoon pictures of people performing everyday actions (Transitive actions: e.g., ironing clothes but with the hand missing; and Intransitive actions: e.g., clapping hands with the palms missing) and were asked to identify which hand or palm orientation would best fit the gap. The main findings are: 1) both groups performed equally while processing transitive and intransitive actions; 2) both tasks yielded activation in the bilateral inferior frontal gyrus (IFG) and inferior parietal lobule (IPL) in ASD and TD groups; 3) Increased activation was seen in ASD children, relative to TD, in left ventral premotor and right middle temporal gyrus during intransitive actions; and 4) ASD symptom severity positively correlated with activation in left parietal, right middle temporal, and right premotor regions across all subjects. Overall, our findings suggest that regions mediating mirroring may be recruiting more brain resources in ASD and may have implications for understanding social movement through modeling.

From word reading to multisentence comprehension: Improvements in brain activity in children with autism after reading intervention.

BACKGROUND: Children with ASD show a unique reading profile characterized by decoding abilities equivalent to verbal abilities, but with lower comprehension skills. Neuroimaging studies have found recruitment of regions primarily associated with visual processing (e.g., fusiform gyrus and medial parietal cortex), but reduced activation in frontal and temporal regions, when reading in adults with ASD. The purpose of this study was to assess neural changes associated with an intense reading intervention program in children with ASD using three fMRI tasks of reading. METHODS: 25 children with ASD were randomly assigned to a treatment (ASD-EXP) or waitlist group (ASD-WLC). Children participated in a reading intervention program (4-hour sessions per day, 5 days a week for 10 weeks). We utilized three tasks: word, sentence, and multisentence processing, each with differential demands of reading comprehension. fMRI data were acquired at each of two scanning sessions 10-weeks apart. RESULTS: Across tasks, post-intervention results revealed that the ASD-EXP group showed greater activation in bilateral precentral gyrus and the postcentral gyrus, visual processing regions (e.g., occipital cortex, fusiform gyrus), and frontal regions. In the word task, left thalamus and the right angular gyrus (AG) activation was unique to the ASD-EXP group post-intervention. Sentence tasks showed differential activation of core language areas (e.g., IFG, IPL) post-intervention. CONCLUSIONS: Our results provide evidence for differential recruitment of brain regions based on task demands in children with ASD, and support the potential of targeted interventions to alter brain activation in response to positive gains in treatment. Children with ASD have a different reading profile from other reading disorders that needs to be specifically targeted in interventions.

Changes in intrinsic local connectivity after reading intervention in children with autism.

Most of the existing behavioral and cognitive intervention programs in autism spectrum disorders (ASD) have not been tested at the neurobiological level, thus falling short of finding quantifiable neurobiological changes underlying behavioral improvement. The current study takes a translational neuroimaging approach to test the impact of a structured visual imagery-based reading intervention on improving reading comprehension and assessing its underlying local neural circuitry. Behavioral and resting state functional MRI (rs-fMRI) data were collected from children with ASD who were randomly assigned to an Experimental group (ASD-EXP; n=14) and a Wait-list control group (ASD-WLC; n=14). Participants went through an established reading intervention training program (Visualizing and Verbalizing for language comprehension and thinking or V/V; 4-h per day, 10-weeks, 200h of face-to-face instruction). Local functional connectivity was examined using a connection density approach from graph theory focusing on brain areas considered part of the Reading Network. The main results are as follows: (I) the ASD-EXP group showed significant improvement, compared to the ASD-WLC group, in their reading comprehension ability evidenced from change in comprehension scores; (II) the ASD-EXP group showed increased local brain connectivity in Reading Network regions compared to the ASD-WLC group post-intervention; (III) intervention-related changes in local brain connectivity were observed in the ASD-EXP from pre to post-intervention; and (IV) improvement in language comprehension significantly predicted changes in local connectivity. The findings of this study provide novel insights into brain plasticity in children with developmental disorders using targeted intervention programs.

"Decoding versus comprehension": Brain responses underlying reading comprehension in children with autism.

Despite intact decoding ability, deficits in reading comprehension are relatively common in children with autism spectrum disorders (ASD). However, few neuroimaging studies have tested the neural bases of this specific profile of reading deficit in ASD. This fMRI study examined activation and synchronization of the brain's reading network in children with ASD with specific reading comprehension deficits during a word similarities task. Thirteen typically developing children and 18 children with ASD performed the task in the MRI scanner. No statistically significant group differences in functional activation were observed; however, children with ASD showed decreased functional connectivity between the left inferior frontal gyrus (LIFG) and the left inferior occipital gyrus (LIOG). In addition, reading comprehension ability significantly positively predicted functional connectivity between the LIFG and left thalamus (LTHAL) among all subjects. The results of this study provide evidence for altered recruitment of reading-related neural resources in ASD children and suggest specific weaknesses in top-down modulation of semantic processing.

The Action Imitation network and motor imitation in children and adolescents with autism.

While deficits in imitation had been reported in children with autism spectrum disorder (ASD), its exact nature remains unclear. A dysfunction in mirroring mechanisms (through action imitation) has been proposed by some studies to explain this, although some recent evidence points against this hypothesis. The current study used behavior and functional MRI to examine the integrated functioning of the regions that are considered part of the Action Imitation network (AIN) in children and adolescents with ASD during a motor imitation task. Fourteen ASD and 15 age-and-IQ-matched typically developing (TD) children were asked to imitate a series of hand gestures in the MRI scanner. Intact performance on imitation (accurate imitation of hand gestures outside the scanner) in both ASD and TD groups was accompanied by significantly lower activity in ASD participants, relative to TD, in right angular gyrus, precentral gyrus, and left middle cingulate. In addition, autism traits were found to be significantly correlated with activation in the right angular gyrus. Overall, the findings of this study support the role of AIN in imitation and a potential difference in the recruitment of this network in ASD children.

Task-Dependent Changes in Frontal-Parietal Activation and Connectivity During Visual Search.

Visual search is an important skill in navigating and locating objects (a target) among distractors in our environment. Efficient and faster target detection involves reciprocal interaction between a viewer's attentional resources as well as salient target characteristics. The neural correlates of visual search have been extensively investigated over the last decades, suggesting the involvement of a frontal-parietal network comprising the frontal eye fields (FEFs) and intraparietal sulcus (IPS). In addition, activity and connectivity of these network changes as the visual search become complex and more demanding. The current functional magnetic resonance imaging study examined the modulation of the frontal-parietal network in response to cognitive demand in 22 healthy adult participants. In addition to brain activity, changes in functional connectivity and effective connectivity in this network were examined in response to easy and difficult visual search. Results revealed significantly increased activation in FEF, IPS, and supplementary motor area, more so in difficult search than in easy search. Functional and effective connectivity analyses showed enhanced connectivity in the frontal-parietal network during difficult search and enhanced information transfer from left to right hemisphere during the difficult search process. Our overall findings suggest that cognitive demand significantly increases brain resources across all three measures of brain processing. In sum, we found that goal-directed visual search engages a network of frontal-parietal areas that are modulated in relation to cognitive demand.