Differences in regional brain structure in toddlers with autism are related to future language outcomes.

Language and social symptoms improve with age in some autistic toddlers, but not in others, and such outcome differences are not clearly predictable from clinical scores alone. Here we aim to identify early-age brain alterations in autism that are prognostic of future language ability. Leveraging 372 longitudinal structural MRI scans from 166 autistic toddlers and 109 typical toddlers and controlling for brain size, we find that, compared to typical toddlers, autistic toddlers show differentially larger or thicker temporal and fusiform regions; smaller or thinner inferior frontal lobe and midline structures; larger callosal subregion volume; and smaller cerebellum. Most differences are replicated in an independent cohort of 75 toddlers. These brain alterations improve accuracy for predicting language outcome at 6-month follow-up beyond intake clinical and demographic variables. Temporal, fusiform, and inferior frontal alterations are related to autism symptom severity and cognitive impairments at early intake ages. Among autistic toddlers, brain alterations in social, language and face processing areas enhance the prediction of the child's future language ability.

Language, Social, and Face Regions Are Affected in Toddlers with Autism and Predictive of Language Outcome.

Identifying prognostic early brain alterations is crucial for autism spectrum disorder (ASD). Leveraging structural MRI data from 166 ASD and 109 typical developing (TD) toddlers and controlling for brain size, we found that, compared to TD, ASD toddlers showed larger or thicker lateral temporal regions; smaller or thinner frontal lobe and midline structures; larger callosal subregion volume; and smaller cerebellum. Most of these differences were replicated in an independent cohort of 38 ASD and 37 TD toddlers. Moreover, the identified brain alterations were related to ASD symptom severity and cognitive impairments at intake, and, remarkably, they improved the accuracy for predicting later language outcome beyond intake clinical and demographic variables. In summary, brain regions involved in language, social, and face processing were altered in ASD toddlers. These early-age brain alterations may be the result of dysregulation in multiple neural processes and stages and are promising prognostic biomarkers for future language ability.

Increased insula response to interoceptive attention following mindfulness training is associated with increased body trusting among patients with depression.

Interoceptive dysfunction is often present in anxiety and depression. We investigated the effects of an 8-week intervention, Mindfulness Training for Primary Care (MTPC), on brain mechanisms of interoceptive attention among patients with anxiety and/or depression. We hypothesized that fMRI brain response to interoception in the insula, a region known for interoceptive processing, would increase following the MTPC intervention, and that such increases would be associated with post-intervention changes in self-reported measures of interoceptive awareness. Adults (n = 28) with anxiety and/or depression completed baseline and post-intervention fMRI visits, including a task in which they alternated between focusing on their heartbeat (interoception (INT)) and a control visual attention task (exteroception (EXT)). Following MTPC, we observed increased evoked fMRI response (relative to baseline) in left anterior insula during the INT-EXT task contrast (z > 3.1, p < 0.001 corrected). In patients with moderate-to-severe depression as defined by the Patient Reported Outcomes Measurement Information System (PROMIS), increased post-intervention insula response was associated with increased Body Trusting, a subscale of the Multidimensional Assessment of Interoceptive Awareness (z > 3.1, p = 0.007 corrected). This study demonstrates that patients with mood disorders may respond differentially to mindfulness-based treatment depending on depression severity, and that among those who are more depressed, increased trusting in one's own body sensations and experiencing the body as a safe place to attend to may be necessary components of positive responses to mindfulness-based interventions.

The Effects of Combined Respiratory-Gated Auricular Vagal Afferent Nerve Stimulation and Mindfulness Meditation for Chronic Low Back Pain: A Pilot Study.

OBJECTIVE: Respiratory-gated Auricular Vagal Afferent Nerve stimulation (RAVANS) is a safe nonpharmacological approach to managing chronic pain. The purpose of the current study was to examine (1) the feasibility and acceptability of RAVANS, combined with mindful meditation (MM) for chronic low back pain (CLBP), (2) the potential synergy of MM+RAVANS on improving pain, and (3) possible moderators of the influence of MM+RAVANS on pain. DESIGN: Pilot feasibility and acceptability study. SETTING: Pain management center at large academic medical center. SUBJECTS: Nineteen adults with CLBP and previous MM training. METHODS: Participants attended two sessions during which they completed quantitative sensory testing (QST), rated pain severity, and completed a MM+stimulation session. Participants received RAVANS during one visit and sham stimulation during the other, randomized in order. Following intervention, participants repeated QST. RESULTS: MM+RAVANS was well tolerated, acceptable, and feasible to provide relief for CLBP. Both MM+stimulation sessions resulted in improved back pain severity, punctate pain ratings, and pressure pain threshold. Individuals with greater negative affect showed greater back pain improvement from MM+RAVANS while those with greater mindfulness showed greater back pain improvement from MM+sham. CONCLUSIONS: Results suggest that for CLBP patients with prior MM training, the analgesic effects of MM may have overshadowed effects of RAVANS given the brief single session MM+RAVANS intervention. However, those with greater negative affect may benefit from combined MM+RAVANS.

Default mode-visual network hypoconnectivity in an autism subtype with pronounced social visual engagement difficulties.

Social visual engagement difficulties are hallmark early signs of autism (ASD) and are easily quantified using eye tracking methods. However, it is unclear how these difficulties are linked to atypical early functional brain organization in ASD. With resting state fMRI data in a large sample of ASD toddlers and other non-ASD comparison groups, we find ASD-related functional hypoconnnectivity between 'social brain' circuitry such as the default mode network (DMN) and visual and attention networks. An eye tracking-identified ASD subtype with pronounced early social visual engagement difficulties (GeoPref ASD) is characterized by marked DMN-occipito-temporal cortex (OTC) hypoconnectivity. Increased DMN-OTC hypoconnectivity is also related to increased severity of social-communication difficulties, but only in GeoPref ASD. Early and pronounced social-visual circuit hypoconnectivity is a key underlying neurobiological feature describing GeoPref ASD and may be critical for future social-communicative development and represent new treatment targets for early intervention in these individuals.

Quitting starts in the brain: a randomized controlled trial of app-based mindfulness shows decreases in neural responses to smoking cues that predict reductions in smoking.

Current treatments for smoking yield suboptimal outcomes, partly because of an inability to reduce cue-induced smoking. Mindfulness training (MT) has shown preliminary efficacy for smoking cessation, yet its neurobiological target remains unknown. Our prior work with nonsmokers indicates that MT reduces posterior cingulate cortex (PCC) activity. In individuals who smoke, the PCC, consistently a main hub of the "default mode network," activates in response to smoking cues. In this randomized controlled trial, we tested the effects of app-delivered MT on PCC reactivity to smoking cues and whether individual differences in MT-mediated PCC changes predicted smoking outcomes. Smoking cue-induced PCC reactivity was measured using functional magnetic resonance imaging at baseline and 1 month after receiving smartphone app-based MT (n = 33) vs. an active control (National Cancer Institute's QuitGuide, n = 34). Whether individual differences in treatment-related changes in PCC activity predicted smoking behavior was assessed. The MT group demonstrated a significant correlation between a reduction in PCC reactivity to smoking cues and a decline in cigarette consumption (r = 0.39, p = 0.02). No association was found in the control group (r = 0.08, p = 0.65). No effects of group alone were found in PCC or cigarette reduction. Post hoc analysis revealed this association is sex specific (women, r = 0.49, p = 0.03; men: r = -0.08, p = 0.79). This initial report indicates that MT specifically reduces smoking cue-induced PCC activity in a subject-specific manner, and the reduction in PCC activity predicts a concurrent decline in smoking. These findings link the hypothesized behavioral effects of MT for smoking to neural mechanisms particularly in women. This lays the groundwork for identifying individuals who may benefit from targeted digital therapeutic treatments such as smartphone-based MT, yielding improved clinical outcomes.

From research to clinic: A sensor reduction method for high-density EEG neurofeedback systems.

OBJECTIVE: To accurately deliver a source-estimated neurofeedback (NF) signal developed on a 128-sensors EEG system on a reduced 32-sensors EEG system. METHODS: A linearly constrained minimum variance beamformer algorithm was used to select the 64 sensors which contributed most highly to the source signal. Monte Carlo-based sampling was then used to randomly generate a large set of reduced 32-sensors montages from the 64 beamformer-selected sensors. The reduced montages were then tested for their ability to reproduce the 128-sensors NF. The high-performing montages were then pooled and analyzed by a k-means clustering machine learning algorithm to produce an optimized reduced 32-sensors montage. RESULTS: Nearly 4500 high-performing montages were discovered from the Monte Carlo sampling. After statistically analyzing this pool of high performing montages, a set of refined 32-sensors montages was generated that could reproduce the 128-sensors NF with greater than 80% accuracy for 72% of the test population. CONCLUSION: Our Monte Carlo reduction method was used to create reliable reduced-sensors montages which could be used to deliver accurate NF in clinical settings. SIGNIFICANCE: A translational pathway is now available by which high-density EEG-based NF measures can be delivered using clinically accessible low-density EEG systems.

Positive effects of neurofeedback on autism symptoms correlate with brain activation during imitation and observation.

Autism has been characterized by atypical task-related brain activation and functional connections, coinciding with deficits in sociocommunicative abilities. However, evidence of the brain's experience-dependent plasticity suggests that abnormal activity patterns may be reversed with treatment. In particular, neurofeedback training (NFT), an intervention based on operant conditioning resulting in self-regulation of brain electrical oscillations, has shown increasing promise in addressing abnormalities in brain function and behavior. We examined the effects of ≥ 20 h of sensorimotor mu-rhythm-based NFT in children with high-functioning autism spectrum disorders (ASD) and a matched control group of typically developing children (ages 8-17). During a functional magnetic resonance imaging imitation and observation task, the ASD group showed increased activation in regions of the human mirror neuron system following the NFT, as part of a significant interaction between group (ASD vs. controls) and training (pre- vs. post-training). These changes were positively correlated with behavioral improvements in the ASD participants, indicating that mu-rhythm NFT may be beneficial to individuals with ASD.

Behavioral and Neurochemical Phenotyping of Mice Incapable of Homer1a Induction.

Immediate early and constitutively expressed products of the Homer1 gene regulate the functional assembly of post-synaptic density proteins at glutamatergic synapses to influence excitatory neurotransmission and synaptic plasticity. Earlier studies of Homer1 gene knock-out (KO) mice indicated active, but distinct, roles for IEG and constitutively expressed Homer1 gene products in regulating cognitive, emotional, motivational and sensorimotor processing, as well as behavioral and neurochemical sensitivity to cocaine. More recent characterization of transgenic mice engineered to prevent generation of the IEG form (a.k.a Homer1a KO) pose a critical role for Homer1a in cocaine-induced behavioral and neurochemical sensitization of relevance to drug addiction and related neuropsychiatric disorders. Here, we extend our characterization of the Homer1a KO mouse and report a modest pro-depressant phenotype, but no deleterious effects of the KO upon spatial learning/memory, prepulse inhibition, or cocaine-induced place-conditioning. As we reported previously, Homer1a KO mice did not develop cocaine-induced behavioral or neurochemical sensitization within the nucleus accumbens; however, virus-mediated Homer1a over-expression within the nucleus accumbens reversed the sensitization phenotype of KO mice. We also report several neurochemical abnormalities within the nucleus accumbens of Homer1a KO mice that include: elevated basal dopamine and reduced basal glutamate content, Group1 mGluR agonist-induced glutamate release and high K+-stimulated release of dopamine and glutamate within this region. Many of the neurochemical anomalies exhibited by Homer1a KO mice are recapitulated upon deletion of the entire Homer1 gene; however, Homer1 deletion did not affect NAC dopamine or alter K+-stimulated neurotransmitter release within this region. These data show that the selective deletion of Homer1a produces a behavioral and neurochemical phenotype that is distinguishable from that produced by deletion of the entire Homer1 gene. Moreover, the data indicate a specific role for Homer1a in regulating cocaine-induced behavioral and neurochemical sensitization of potential relevance to the psychotogenic properties of this drug.

Network organization is globally atypical in autism: A graph theory study of intrinsic functional connectivity.

BACKGROUND: Despite abundant evidence of brain network anomalies in autism spectrum disorder (ASD), findings have varied from broad functional underconnectivity to broad overconnectivity. Rather than pursuing overly simplifying general hypotheses ('under' vs. 'over'), we tested the hypothesis of atypical network distribution in ASD (i.e., participation of unusual loci in distributed functional networks). METHODS: We used a selective high-quality data subset from the ABIDE datashare (including 111 ASD and 174 typically developing [TD] participants) and several graph theory metrics. Resting state functional MRI data were preprocessed and analyzed for detection of low-frequency intrinsic signal correlations. Groups were tightly matched for available demographics and head motion. RESULTS: As hypothesized, the Rand Index (reflecting how similar network organization was to a normative set of networks) was significantly lower in ASD than TD participants. This was accounted for by globally reduced cohesion and density, but increased dispersion of networks. While differences in hub architecture did not survive correction, rich club connectivity (among the hubs) was increased in the ASD group. CONCLUSIONS: Our findings support the model of reduced network integration (connectivity with networks) and differentiation (or segregation; based on connectivity outside network boundaries) in ASD. While the findings applied at the global level, they were not equally robust across all networks and in one case (greater cohesion within ventral attention network in ASD) even reversed.

Resting State Functional Connectivity MRI among Spectral MEG Current Sources in Children on the Autism Spectrum.

Social and communicative impairments are among the core symptoms of autism spectrum disorders (ASD), and a great deal of evidence supports the notion that these impairments are associated with aberrant functioning and connectivity of various cortical networks. The present study explored the links between sources of MEG amplitude in various frequency bands and functional connectivity MRI in the resting state. The goal of combining these modalities was to use sources of neural oscillatory activity, measured with MEG, as functionally relevant seed regions for a more traditional pairwise fMRI connectivity analysis. We performed a seed-based connectivity analysis on resting state fMRI data, using seed regions derived from frequency-specific amplitude sources in resting state MEG data in the same nine subjects with ASD (10-17 years of age). We then compared fMRI connectivity among these MEG-source-derived regions between participants with autism and typically developing, age-matched controls. We used a source modeling technique designed for MEG data to detect significant amplitude sources in six frequency bands: delta (2-4 Hz), theta (4-8 Hz), alpha (8-12 Hz), beta (12-30 Hz), low gamma (30-60 Hz), and high gamma (60-120 Hz). MEG-derived source maps for each participant were co-registered in standard MNI space, and group-level source maps were obtained for each frequency. For each frequency band, the 10 largest clusters resulting from these t-tests were used as regions of interest (ROIs) for the fMRI functional connectivity analysis. Pairwise BOLD signal correlations were obtained between each pair of these ROIs for each frequency band. Each pairwise correlation was compared between the ASD and TD groups using t-tests. We also constrained these pairwise correlations to known network structures, resulting in a follow-up set of correlation matrices specific to each network we considered. Frequency-specific MEG sources had distinct patterns of fMRI resting state functional connectivity in the ASD group, but perhaps the most significant was a finding of hypoconnectivity between many sources of low and high gamma activity. These novel findings suggest that in ASD there are differences in functionally defined networks as shown in previous fMRI studies, as well as between sets of regions defined by magnetoencephalographic neural oscillatory activity.

Underconnected, But Not Broken? Dynamic Functional Connectivity MRI Shows Underconnectivity in Autism Is Linked to Increased Intra-Individual Variability Across Time.

Autism spectrum disorder (ASD) is characterized by core sociocommunicative impairments. Atypical intrinsic functional connectivity (iFC) has been reported in numerous studies of ASD. A majority of findings has indicated long-distance underconnectivity. However, fMRI studies have thus far exclusively examined static iFC across several minutes of scanning. We examined temporal variability of iFC, using sliding window analyses in selected high-quality (low-motion) consortium datasets from 76 ASD and 76 matched typically developing (TD) participants (Study 1) and in-house data from 32 ASD and 32 TD participants. Mean iFC and standard deviation of the sliding window correlation (SD-iFC) were computed for regions of interest (ROIs) from default mode and salience networks, as well as amygdala and thalamus. In both studies, ROI pairings with significant underconnectivity (ASD

Patterns of Atypical Functional Connectivity and Behavioral Links in Autism Differ Between Default, Salience, and Executive Networks.

Autism spectrum disorder (ASD) is characterized by atypical brain network organization, but findings have been inconsistent. While methodological and maturational factors have been considered, the network specificity of connectivity abnormalities remains incompletely understood. We investigated intrinsic functional connectivity (iFC) for four "core" functional networks-default-mode (DMN), salience (SN), and left (lECN) and right executive control (rECN). Resting-state functional MRI data from 75 children and adolescents (37 ASD, 38 typically developing [TD]) were included. Functional connectivity within and between networks was analyzed for regions of interest (ROIs) and whole brain, compared between groups, and correlated with behavioral scores. ROI analyses showed overconnectivity (ASD > TD), especially between DMN and ECN. Whole-brain results were mixed. While predominant overconnectivity was found for DMN (posterior cingulate seed) and rECN (right inferior parietal seed), predominant underconnectivity was found for SN (right anterior insula seed) and lECN (left inferior parietal seed). In the ASD group, reduced SN integrity was associated with sensory and sociocommunicative symptoms. In conclusion, atypical connectivity in ASD is network-specific, ranging from extensive overconnectivity (DMN, rECN) to extensive underconnectivity (SN, lECN). Links between iFC and behavior differed between groups. Core symptomatology in the ASD group was predominantly related to connectivity within the salience network.

Regional specificity of aberrant thalamocortical connectivity in autism.

Preliminary evidence suggests aberrant (mostly reduced) thalamocortical (TC) connectivity in autism spectrum disorder (ASD), but despite the crucial role of thalamus in sensorimotor functions and its extensive connectivity with cerebral cortex, relevant evidence remains limited. We performed a comprehensive investigation of region-specific TC connectivity in ASD. Resting-state functional MRI and diffusion tensor imaging (DTI) data were acquired for 60 children and adolescents with ASD (ages 7-17 years) and 45 age, sex, and IQ-matched typically developing (TD) participants. We examined intrinsic functional connectivity (iFC) and anatomical connectivity (probabilistic tractography) with thalamus, using 68 unilateral cerebral cortical regions of interest (ROIs). For frontal and parietal lobes, iFC was atypically reduced in the ASD group for supramodal association cortices, but was increased for cingulate gyri and motor cortex. Temporal iFC was characterized by overconnectivity for auditory cortices, but underconnectivity for amygdalae. Occipital iFC was broadly reduced in the ASD group. DTI indices (such as increased radial diffusion) for regions with group differences in iFC further indicated compromised anatomical connectivity, especially for frontal ROIs, in the ASD group. Our findings highlight the regional specificity of aberrant TC connectivity in ASD. Their overall pattern can be largely accounted for by functional overconnectivity with limbic and sensorimotor regions, but underconnectivity with supramodal association cortices. This could be related to comparatively early maturation of limbic and sensorimotor regions in the context of early overgrowth in ASD, at the expense of TC connectivity with later maturing cortical regions.

Reduced integration and differentiation of the imitation network in autism: A combined functional connectivity magnetic resonance imaging and diffusion-weighted imaging study.

OBJECTIVE: Converging evidence indicates that brain abnormalities in autism spectrum disorder (ASD) involve atypical network connectivity, but few studies have integrated functional with structural connectivity measures. This multimodal investigation examined functional and structural connectivity of the imitation network in children and adolescents with ASD, and its links with clinical symptoms. METHODS: Resting state functional magnetic resonance imaging and diffusion-weighted imaging were performed in 35 participants with ASD and 35 typically developing controls, aged 8 to 17 years, matched for age, gender, intelligence quotient, and head motion. RESULTS: Within-network analyses revealed overall reduced functional connectivity (FC) between distributed imitation regions in the ASD group. Whole brain analyses showed that underconnectivity in ASD occurred exclusively in regions belonging to the imitation network, whereas overconnectivity was observed between imitation nodes and extraneous regions. Structurally, reduced fractional anisotropy and increased mean diffusivity were found in white matter tracts directly connecting key imitation regions with atypical FC in ASD. These differences in microstructural organization of white matter correlated with weaker FC and greater ASD symptomatology. INTERPRETATION: Findings demonstrate atypical connectivity of the brain network supporting imitation in ASD, characterized by a highly specific pattern. This pattern of underconnectivity within, but overconnectivity outside the functional network is in contrast with typical development and suggests reduced network integration and differentiation in ASD. Our findings also indicate that atypical connectivity of the imitation network may contribute to ASD clinical symptoms, highlighting the role of this fundamental social cognition ability in the pathophysiology of ASD.

Cerebro-cerebellar Resting-State Functional Connectivity in Children and Adolescents with Autism Spectrum Disorder.

BACKGROUND: The cerebellum plays important roles in sensori-motor and supramodal cognitive functions. Cellular, volumetric, and functional abnormalities of the cerebellum have been found in autism spectrum disorders (ASD), but no comprehensive investigation of cerebro-cerebellar connectivity in ASD is available. METHODS: We used resting-state functional connectivity magnetic resonance imaging in 56 children and adolescents (28 subjects with ASD, 28 typically developing subjects) 8-17 years old. Partial and total correlation analyses were performed for unilateral regions of interest (ROIs), distinguished in two broad domains as sensori-motor (premotor/primary motor, somatosensory, superior temporal, and occipital) and supramodal (prefrontal, posterior parietal, and inferior and middle temporal). RESULTS: There were three main findings: 1) Total correlation analyses showed predominant cerebro-cerebellar functional overconnectivity in the ASD group; 2) partial correlation analyses that emphasized domain specificity (sensori-motor vs. supramodal) indicated a pattern of robustly increased connectivity in the ASD group (compared with the typically developing group) for sensori-motor ROIs but predominantly reduced connectivity for supramodal ROIs; and 3) this atypical pattern of connectivity was supported by significantly increased noncanonical connections (between sensori-motor cerebral and supramodal cerebellar ROIs and vice versa) in the ASD group. CONCLUSIONS: Our findings indicate that sensori-motor intrinsic functional connectivity is atypically increased in ASD, at the expense of connectivity supporting cerebellar participation in supramodal cognition.

Impact of methodological variables on functional connectivity findings in autism spectrum disorders.

Growing evidence suggests that Autism Spectrum Disorder (ASD) involves abnormalities of multiple functional networks. Neuroimaging studies of ASD have therefore increasingly focused on connectivity. Many functional connectivity (fcMRI) studies have reported network underconnectivity in children and adults with ASD. However, there are notable inconsistencies, with some studies reporting overconnectivity. A previous literature survey suggested that a few methodological factors play a crucial role in differential fcMRI outcomes. Using three ASD data sets (two task-related, one resting state) from 54 ASD and 51 typically developing (TD) participants (ages 9-18 years), we examined the impact of four methodological factors: type of pipeline (co-activation vs. intrinsic analysis, related to temporal filtering and removal of task-related effects), seed selection, field of view (whole brain vs. limited ROIs), and dataset. Significant effects were found for type of pipeline, field of view, and dataset. Notably, for each dataset results ranging from robust underconnectivity to robust overconnectivity were detected, depending on the type of pipeline, with intrinsic fcMRI analyses (low bandpass filter and task regressor) predominantly yielding overconnectivity in ASD, but co-activation analyses (no low bandpass filter or task removal) mostly generating underconnectivity findings. These results suggest that methodological variables have dramatic impact on group differences reported in fcMRI studies. Improved awareness of their implications appears indispensible in fcMRI studies when inferences about "underconnectivity" or "overconnectivity" in ASD are made. In the absence of a gold standard for functional connectivity, the combination of different methodological approaches promises a more comprehensive understanding of connectivity in ASD.

A prolyl-isomerase mediates dopamine-dependent plasticity and cocaine motor sensitization.

Synaptic plasticity induced by cocaine and other drugs underlies addiction. Here we elucidate molecular events at synapses that cause this plasticity and the resulting behavioral response to cocaine in mice. In response to D1-dopamine-receptor signaling that is induced by drug administration, the glutamate-receptor protein metabotropic glutamate receptor 5 (mGluR5) is phosphorylated by microtubule-associated protein kinase (MAPK), which we show potentiates Pin1-mediated prolyl-isomerization of mGluR5 in instances where the product of an activity-dependent gene, Homer1a, is present to enable Pin1-mGluR5 interaction. These biochemical events potentiate N-methyl-D-aspartate receptor (NMDAR)-mediated currents that underlie synaptic plasticity and cocaine-evoked motor sensitization as tested in mice with relevant mutations. The findings elucidate how a coincidence of signals from the nucleus and the synapse can render mGluR5 accessible to activation with consequences for drug-induced dopamine responses and point to depotentiation at corticostriatal synapses as a possible therapeutic target for treating addiction.