Subcortical-cortical white matter connectivity in adults with autism spectrum disorder and schizophrenia patients.

Autism spectrum disorder (ASD) and schizophrenia (SZ) are neuropsychiatric disorders that overlap in symptoms associated with social-cognitive impairment. Alterations of the cingulate cortex, subcortical, medial-temporal, and orbitofrontal structures are frequently reported in both disorders. In this study, we examined white-matter connectivity between these structures in adults with ASD and SZ patients compared with their respective neurotypical controls and indirectly with each other, using probabilistic and local DTI tractography. This exploratory study utilized publicly available neuroimaging databases, of adults with ASD (ABIDE II; n = 28) and SZ (COBRE; n = 38), age-gender matched neurotypicals (NT) and associated phenotypic data. Tractography was performed using Freesurfer and MRtrix software, and diffusion metrics of white-matter tracts between cingulate-, orbitofrontal- cortices, subcortical structures, parahippocampal, entorhinal cortex were assessed. In ASD, atypical diffusivity parameters were found in the isthmus cingulate and parahippocampal connectivity to subcortical and rostral-anterior cingulate, which were also associated with IQ and social skills (SRS). In contrast, atypical diffusivity parameters were observed between the medial-orbitofrontal cortex and subcortical structures in SZ, and were associated with executive function (i.e., IQ, processing speed) and emotional regulation. Overall, the results suggest that defects in the isthmus cingulate, medial-orbitofrontal, and striato-limbic white matter connectivity may help unravel the neural underpinnings of executive and social-emotional dysfunction at the core of neuropsychiatric disorders.

Predictive models demonstrate age-dependent association of subcortical volumes and cognitive measures.

Whether brain matter volume is correlated with cognitive functioning and higher intelligence is controversial. We explored this relationship by analysis of data collected on 193 healthy young and older adults through the "Leipzig Study for Mind-Body-Emotion Interactions" (LEMON) study. Our analysis involved four cognitive measures: fluid intelligence, crystallized intelligence, cognitive flexibility, and working memory. Brain subregion volumes were determined by magnetic resonance imaging. We normalized each subregion volume to the estimated total intracranial volume and conducted training simulations to compare the predictive power of normalized volumes of large regions of the brain (i.e., gray matter, cortical white matter, and cerebrospinal fluid), normalized subcortical volumes, and combined normalized volumes of large brain regions and normalized subcortical volumes. Statistical tests showed significant differences in the performance accuracy and feature importance of the subregion volumes in predicting cognitive skills for young and older adults. Random forest feature selection analysis showed that cortical white matter was the key feature in predicting fluid intelligence in both young and older adults. In young adults, crystallized intelligence was best predicted by caudate nucleus, thalamus, pallidum, and nucleus accumbens volumes, whereas putamen, amygdala, nucleus accumbens, and hippocampus volumes were selected for older adults. Cognitive flexibility was best predicted by the caudate, nucleus accumbens, and hippocampus in young adults and caudate and amygdala in older adults. Finally, working memory was best predicted by the putamen, pallidum, and nucleus accumbens in the younger group, whereas amygdala and hippocampus volumes were predictive in the older group. Thus, machine learning predictive models demonstrated an age-dependent association between subcortical volumes and cognitive measures. These approaches may be useful in predicting the likelihood of age-related cognitive decline and in testing of approaches for targeted improvement of cognitive functioning in older adults.

Longitudinal PET studies of mGluR5 in FXS using an FMR1 knockout mouse model.

Fragile X syndrome (FXS) is a monogenic disorder characterized by intellectual disability and behavioral challenges. It is caused by aberrant methylation of the fragile X mental retardation 1 (FMR1) gene. Given the failure of clinical trials in FXS and growing evidence of a role of metabotropic glutamate subtype 5 receptors (mGluR5) in the pathophysiology of the disorder, we investigated mGluR5 function in FMR1 Knockout (FMR1-KO) mice and age- and sex-matched control mice using longitudinal positron emission tomography (PET) imaging to better understand the disorder. The studies were repeated at four time points to examine age- and disease-induced changes in mGluR5 availability using 3-fluoro-[18F]5-(2-pyridinylethynyl)benzonitrile ([18F]FPEB). We found that the binding potential (BP) of [18F]FPEB was significantly lower in the KO mice in mGluR5-implicated brain areas including striatum, cortex, hippocampus, thalamus, and olfactory bulb. The BP also changed with age, regardless of disorder status, increasing in early adulthood in male but not in female mice before decreasing later in both sexes. The difference in mGluR5 availability between the FMR1-KO and control mice and the change in BP in the KO mice as a function of age and sex illustrate the nature of the disorder and its progression, providing mechanistic insights for treatment design.

Subcortical Brain Morphometry Differences between Adults with Autism Spectrum Disorder and Schizophrenia.

Autism spectrum disorder (ASD) and schizophrenia (SZ) are neuropsychiatric disorders that overlap in symptoms associated with social-cognitive impairment. Subcortical structures play a significant role in cognitive and social-emotional behaviors and their abnormalities are associated with neuropsychiatric conditions. This exploratory study utilized ABIDE II/COBRE MRI and corresponding phenotypic datasets to compare subcortical volumes of adults with ASD (n = 29), SZ (n = 51) and age and gender matched neurotypicals (NT). We examined the association between subcortical volumes and select behavioral measures to determine whether core symptomatology of disorders could be explained by subcortical association patterns. We observed volume differences in ASD (viz., left pallidum, left thalamus, left accumbens, right amygdala) but not in SZ compared to their respective NT controls, reflecting morphometric changes specific to one of the disorder groups. However, left hippocampus and amygdala volumes were implicated in both disorders. A disorder-specific negative correlation (r = -0.39, p = 0.038) was found between left-amygdala and scores on the Social Responsiveness Scale (SRS) Social-Cognition in ASD, and a positive association (r = 0.29, p = 0.039) between full scale IQ (FIQ) and right caudate in SZ. Significant correlations between behavior measures and subcortical volumes were observed in NT groups (ASD-NT range; r = -0.53 to -0.52, p = 0.002 to 0.004, SZ-NT range; r = -0.41 to -0.32, p = 0.007 to 0.021) that were non-significant in the disorder groups. The overlap of subcortical volumes implicated in ASD and SZ may reflect common neurological mechanisms. Furthermore, the difference in correlation patterns between disorder and NT groups may suggest dysfunctional connectivity with cascading effects unique to each disorder and a potential role for IQ in mediating behavior and brain circuits.

Abnormal Brain Oscillations in Developmental Disorders: Application of Resting State EEG and MEG in Autism Spectrum Disorder and Fragile X Syndrome.

Autism Spectrum Disorder (ASD) and Fragile X Syndrome (FXS) are neurodevelopmental disorders with similar clinical and behavior symptoms and partially overlapping and yet distinct neurobiological origins. It is therefore important to distinguish these disorders from each other as well as from typical development. Examining disruptions in functional connectivity often characteristic of neurodevelopment disorders may be one approach to doing so. This review focuses on EEG and MEG studies of resting state in ASD and FXS, a neuroimaging paradigm frequently used with difficult-to-test populations. It compares the brain regions and frequency bands that appear to be impacted, either in power or connectivity, in each disorder; as well as how these abnormalities may result in the observed symptoms. It argues that the findings in these studies are inconsistent and do not fit neatly into existing models of ASD and FXS, then highlights the gaps in the literature and recommends future avenues of inquiry.

In vivo imaging of mGlu5 receptor expression in humans with Fragile X Syndrome towards development of a potential biomarker.

Fragile X Syndrome (FXS) is a neurodevelopmental disorder caused by silencing of the Fragile X Mental Retardation (FMR1) gene. The resulting loss of Fragile X Mental Retardation Protein (FMRP) leads to excessive glutamate signaling via metabotropic glutamate subtype 5 receptors (mGluR5) which has been implicated in the pathogenesis of the disorder. In the present study we used the radioligand 3-[18F]fluoro-5-(2-pyridinylethynyl)benzonitrile ([18F]FPEB) in simultaneous PET-MR imaging of males with FXS and age- and gender-matched controls to assess the availability of mGlu5 receptors in relevant brain areas. Patients with FXS showed lower [18F]FPEB binding potential (p < 0.01), reflecting reduced mGluR5 availability, than the healthy controls throughout the brain, with significant group differences in insula, anterior cingulate, parahippocampal, inferior temporal and olfactory cortices, regions associated with deficits in inhibition, memory, and visuospatial processes characteristic of the disorder. The results are among the first to provide in vivo evidence of decreased availability of mGluR5 in the brain in individuals with FXS than in healthy controls. The consistent results across the subjects, despite the tremendous challenges with neuroimaging this population, highlight the robustness of the protocol and support for its use in drug occupancy studies; extending our radiotracer development and application efforts from mice to humans.

Assessment of speech and fine motor coordination in children with autism spectrum disorder.

Autism Spectrum Disorder (ASD) is a developmental disorder characterized by difficulty in communication, which includes a high incidence of speech production errors. We hypothesize that these errors are partly due to underlying deficits in motor coordination and control, which are also manifested in degraded fine motor control of facial expressions and purposeful hand movements. In this pilot study, we computed correlations of acoustic, video, and handwriting time-series derived from five children with ASD and five children with neurotypical development during speech and handwriting tasks. These correlations and eigenvalues derived from the correlations act as a proxy for motor coordination across articulatory, laryngeal, and respiratory speech production systems and for fine motor skills. We utilized features derived from these correlations to discriminate between children with and without ASD. Eigenvalues derived from these correlations highlighted differences in complexity of coordination across speech subsystems and during handwriting, and helped discriminate between the two subject groups. These results suggest differences in coupling within speech production and fine motor skill systems in children with ASD. Our long-term goal is to create a platform assessing motor coordination in children with ASD in order to track progress from speech and motor interventions administered by clinicians.

Sex Differences in White Matter Pathways Related to Language Ability.

Evidence from functional imaging studies points to a role for gender in language ability. However, recent studies suggest that sex differences in the neural basis of language are still unclear, reflecting a complex interaction between sex and language ability. We used diffusion weighted magnetic resonance imaging and global probabilistic tractography to investigate white matter (WM) pathways between 32 male and 35 age- and IQ-matched female adult participants in relation to their verbal abilities. Males showed higher fractional anisotropy (FA) in the left anterior thalamic radiations (ATR), right cingulum-angular bundle, right corticospinal tract, bilateral superior longitudinal fasciculus-temporal terminations, bilateral uncinate fasciculus (UNC), and corpus callosum-forceps minor when compared with the female group. In contrast, females showed higher radial diffusivity (RD) in the left ATR and left UNC when compared to the male group. The relationship between WM metrics and verbal ability also differed across the two groups: a negative correlation between verbal comprehension index (VCI) and FA as well as axial diffusivity (AD) in left cingulum-cingulate gyrus (CCG) supracallosal bundle in males but not in females; a negative correlation between verbal IQ (VIQ) and FA in the right corticospinal tract (CST), and a positive correlation between VCI and RD in corpus callosum-forceps minor in the female but not in the male group. A direct comparison of these correlation coefficients yielded significant differences between the groups for the VCI-AD and VIQ -FA associations. The findings may reflect sex differences in WM related to language ability.

Overview of MEG.

Magnetoencephalography (MEG) is a method to study electrical activity in the human brain by recording the neuromagnetic field outside the head. MEG, like electroencephalography (EEG), provides an excellent, millisecond-scale time resolution, and allows the estimation of the spatial distribution of the underlying activity, in favorable cases with a localization accuracy of a few millimeters. To detect the weak neuromagnetic signals, superconducting sensors, magnetically shielded rooms, and advanced signal processing techniques are used. The analysis and interpretation of MEG data typically involves comparisons between subject groups and experimental conditions using various spatial, temporal, and spectral measures of cortical activity and connectivity. The application of MEG to cognitive neuroscience studies is illustrated with studies of spoken language processing in subjects with normal and impaired reading ability. The mapping of spatiotemporal patterns of activity within networks of cortical areas can provide useful information about the functional architecture of the brain related to sensory and cognitive processing, including language, memory, attention, and perception.

A brain network model for depression: From symptom understanding to disease intervention.

Understanding the neural substrates of depression is crucial for diagnosis and treatment. Here, we review recent studies of functional and effective connectivity in depression, in terms of functional integration in the brain. Findings from these studies, including our own, point to the involvement of at least four networks in patients with depression. Elevated connectivity of a ventral limbic affective network appears to be associated with excessive negative mood (dysphoria) in the patients; decreased connectivity of a frontal-striatal reward network has been suggested to account for loss of interest, motivation, and pleasure (anhedonia); enhanced default mode network connectivity seems to be associated with depressive rumination; and diminished connectivity of a dorsal cognitive control network is thought to underlie cognitive deficits especially ineffective top-down control of negative thoughts and emotions in depressed patients. Moreover, the restoration of connectivity of these networks-and corresponding symptom improvement-following antidepressant treatment (including medication, psychotherapy, and brain stimulation techniques) serves as evidence for the crucial role of these networks in the pathophysiology of depression.

Sex Differences in the Default Mode Network with Regard to Autism Spectrum Traits: A Resting State fMRI Study.

Autism spectrum traits exist on a continuum and are more common in males than in females, but the basis for this sex difference is unclear. To this end, the present study draws on the extreme male brain theory, investigating the relationship between sex difference and the default mode network (DMN), both known to be associated with autism spectrum traits. Resting-state functional magnetic resonance imaging (MRI) was carried out in 42 females (mean age ± standard deviation, 22.4 ± 4.2 years) and 43 males (mean age ± standard deviation, 23.8 ± 3.9 years) with typical development. Using a combination of different analyses (viz., independent component analysis (ICA), fractional amplitude of low-frequency fluctuation (fALFF), regional homogeneity (ReHo), and seed-based analyses), we examined sex differences in the DMN and the relationship to autism spectrum traits as measured by autism-spectrum quotient (AQ) scores. We found significant differences between female and male subjects in DMN brain regions, with seed-based analysis revealing a significant negative correlation between default-mode resting state functional connectivity of the anterior medial prefrontal cortex seed (aMPFC) and AQ scores in males. However, there were no relationships between DMN sex differences and autism spectrum traits in females. Our findings may provide important insight into the skewed balance of functional connectivity in males compared to females that could serve as a potential biomarker of the degree of autism spectrum traits in line with the extreme male brain theory.

Speech and Language Impairments in Autism: Insights from Behavior and Neuroimaging.

A failure to develop language is one of the earliest signs of autism. The ability to identify the neural signature of this deficit in very young children has become increasingly important, given that the presence of speech before five years of age is the strongest predictor for better outcomes in autism. This review consolidates what is known about verbal and preverbal precursors of language development as a framework for examining behavioral and brain anomalies related to speech and language in autism spectrum disorders. Relating the disruptions in the speech network to the social deficits observed will provide promising targets for behavioral and pharmacological interventions in ASD.

Gamma phase locking modulated by phonological contrast during auditory comprehension in reading disability.

Children with specific reading impairment may have subtle deficits in speech perception related to difficulties in phonological processing. The aim of this study was to examine brain oscillatory activity related to phonological processing in the context of auditory sentence comprehension using magnetoencephalography to better understand these deficits. Good and poor readers, 16-18 years of age, were tested on speech perception of sentence-terminal incongruent words that were phonologically manipulated to be similar or dissimilar to corresponding congruent target words. Functional coupling between regions was measured using phase-locking values (PLVs). Gamma-band (30-45 Hz) PLV between auditory cortex and superior temporal sulcus in the right hemisphere was differentially modulated in the two groups by the degree of phonological contrast between the congruent and the incongruent target words in the latency range associated with semantic processing. Specifically, the PLV was larger in the phonologically similar than in the phonologically dissimilar condition in the good readers. This pattern was reversed in the poor readers, whose lower PLV in the phonologically similar condition may be indicative of the impaired phonological coding abilities of the group, and consequent vulnerability under perceptually demanding conditions. Overall, the results support the role of gamma oscillations in spoken language processing.

White matter integrity and pictorial reasoning in high-functioning children with autism.

The current study investigated the neurobiological role of white matter in visuospatial versus linguistic processing abilities in autism using diffusion tensor imaging. We examined differences in white matter integrity between high-functioning children with autism (HFA) and typically developing controls (CTRL), in relation to the groups' response times (RT) on a pictorial reasoning task under three conditions: visuospatial, V, semantic, S, and V+S, a hybrid condition allowing language use to facilitate visuospatial transformations. Diffusion-weighted images were collected from HFA and CTRL participants, matched on age and IQ, and significance maps were computed for group differences in fractional anisotropy (FA) and in RT-FA association for each condition. Typically developing children showed increased FA within frontal white matter and the superior longitudinal fasciculus (SLF). HFA showed increased FA within peripheral white matter, including the ventral temporal lobe. Additionally, RT-FA relationships in the semantic condition (S) implicated white matter near the STG and in the SLF within the temporal and frontal lobes to a greater extent in CTRL. Performance in visuospatial reasoning (V, V+S), in comparison, was related to peripheral parietal and superior precentral white matter in HFA, but to the SLF, callosal, and frontal white matter in CTRL. Our results appear to support a preferential use of linguistically-mediated pathways in reasoning by typically developing children, whereas autistic cognition may rely more on visuospatial processing networks.

Neuroimaging of the functional and structural networks underlying visuospatial vs. linguistic reasoning in high-functioning autism.

High-functioning individuals with autism have been found to favor visuospatial processing in the face of typically poor language abilities. We aimed to examine the neurobiological basis of this difference using functional magnetic resonance imaging and diffusion tensor imaging. We compared 12 children with high functioning autism (HFA) to 12 age- and IQ-matched typically developing controls (CTRL) on a pictorial reasoning paradigm under three conditions: V, requiring visuospatial processing; S, requiring language (i.e., semantic) processing; and V+S, a hybrid condition in which language use could facilitate visuospatial transformations. Activated areas in the brain were chosen as endpoints for probabilistic diffusion tractography to examine tract integrity (FA) within the structural network underlying the activation patterns. The two groups showed similar networks, with linguistic processing activating inferior frontal, superior and middle temporal, ventral visual, and temporo-parietal areas, whereas visuospatial processing activated occipital and inferior parietal cortices. However, HFA appeared to activate occipito-parietal and ventral temporal areas, whereas CTRL relied more on frontal and temporal language regions. The increased reliance on visuospatial abilities in HFA was supported by intact connections between the inferior parietal and the ventral temporal ROIs. In contrast, the inferior frontal region showed reduced connectivity to ventral temporal and middle temporal areas in this group, reflecting impaired activation of frontal language areas in autism. The HFA group's engagement of posterior brain regions along with its weak connections to frontal language areas suggest support for a reliance on visual mediation in autism, even in tasks of higher cognition.

Cognitive differences in pictorial reasoning between high-functioning autism and Asperger's syndrome.

We investigated linguistic and visuospatial processing during pictorial reasoning in high-functioning autism (HFA), Asperger's syndrome (ASP), and age and IQ-matched typically developing participants (CTRL), using three conditions designed to differentially engage linguistic mediation or visuospatial processing (visuospatial, V; semantic, S; visuospatial + semantic, V + S). The three groups did not differ in accuracy, but showed different response time profiles. ASP and CTRL participants were fastest on V + S, amenable to both linguistic and nonlinguistic mediation, whereas HFA participants were equally fast on V and V + S, where visuospatial strategies were available, and slowest on S. HFA participants appeared to favor visuospatial over linguistic mediation. The results support the use of linguistic versus visuospatial tasks for characterizing subtypes on the autism spectrum.

Auditory word perception in sentence context in reading-disabled children.

Reading difficulties seem to be related to a phonological deficit that has its origin in poor speech perception. As such, disabled readers may use contextual cues to compensate for their weak speech perception abilities. We compared good and poor readers, 7-13 years old, on auditory perception of words varying in phonological contrast, in congruent versus incongruent sentence contexts. Both groups did worse in the phonologically similar than in the phonologically dissimilar incongruent condition. Magnetoencephalography revealed differential activation between the groups as a function of phonological contrast in left superior temporal gyrus between 200 and 300 ms, suggesting that poor readers may have processed phonologically similar incongruent stimuli as congruent. The results are consistent with a phonological account of reading disability.

Head movements of children in MEG: quantification, effects on source estimation, and compensation.

Head movements during magnetoencephalography (MEG) recordings may lead to inaccurate localization of brain activity. This can be particularly problematic for studies with children. We quantified head movements in 8- to 12-year-old children performing a cognitive task and examined how the movements affected source estimation. Each child was presented auditory word stimuli in five 4-min runs. The mean change in the MEG sensor locations during the experiment ranged from 3 to 26mm across subjects. The variation in the head position was largest in the up-down direction. The mean localization error in equivalent current dipole (ECD) simulations was 12mm for runs with the most head movement, with the frontal cortex appearing to be most prone to errors due to head movements. In addition, we examined the effect of head movements on two types of source estimates, ECDs and minimum-norm estimates (MNE), for an auditory evoked response. Application of a recently introduced signal space separation (SSS) method to compensate for the head movements was found to increase the goodness-of-fit of the ECDs, reduce the spatial confidence intervals of the ECDs, and enhance the peak amplitude in the MNE. These results are indicative of the SSS method being able to compensate for the spatial smoothing of the signals caused by head movements. Overall, the results suggest that MEG source estimates are relatively robust against head movements in children, and that confounds due to head movements can be successfully dealt with in MEG studies of developmental cognition.

Effects of phonological contrast on auditory word discrimination in children with and without reading disability: a magnetoencephalography (MEG) study.

Poor readers perform worse than their normal reading peers on a variety of speech perception tasks, which may be linked to their phonological processing abilities. The purpose of the study was to compare the brain activation patterns of normal and impaired readers on speech perception to better understand the phonological basis in reading disability. Whole-head magnetoencephalography (MEG) was recorded as good and poor readers, 7-13 years of age, performed an auditory word discrimination task. We used an auditory oddball paradigm in which the 'deviant' stimuli (/bat/, /kat/, /rat/) differed in the degree of phonological contrast (one versus three features) from a repeated standard word (/pat/). Both good and poor readers responded more slowly to deviants that were phonologically similar compared to deviants that were phonologically dissimilar to the standard word. Source analysis of the MEG data using minimum norm estimation (MNE) showed that compared to good readers, poor readers had reduced left-hemisphere activation to the most demanding phonological condition reflecting their difficulties with phonological processing. Furthermore, unlike good readers, poor readers did not show differences in activation as a function of the degree of phonological contrast. These results are consistent with a phonological account of reading disability.