Early brain development in infants at high risk for autism spectrum disorder.

Brain enlargement has been observed in children with autism spectrum disorder (ASD), but the timing of this phenomenon, and the relationship between ASD and the appearance of behavioural symptoms, are unknown. Retrospective head circumference and longitudinal brain volume studies of two-year olds followed up at four years of age have provided evidence that increased brain volume may emerge early in development. Studies of infants at high familial risk of autism can provide insight into the early development of autism and have shown that characteristic social deficits in ASD emerge during the latter part of the first and in the second year of life. These observations suggest that prospective brain-imaging studies of infants at high familial risk of ASD might identify early postnatal changes in brain volume that occur before an ASD diagnosis. In this prospective neuroimaging study of 106 infants at high familial risk of ASD and 42 low-risk infants, we show that hyperexpansion of the cortical surface area between 6 and 12 months of age precedes brain volume overgrowth observed between 12 and 24 months in 15 high-risk infants who were diagnosed with autism at 24 months. Brain volume overgrowth was linked to the emergence and severity of autistic social deficits. A deep-learning algorithm that primarily uses surface area information from magnetic resonance imaging of the brain of 6-12-month-old individuals predicted the diagnosis of autism in individual high-risk children at 24 months (with a positive predictive value of 81% and a sensitivity of 88%). These findings demonstrate that early brain changes occur during the period in which autistic behaviours are first emerging.

Exploring Individual Brain Variability during Development based on Patterns of Maturational Coupling of Cortical Thickness: A Longitudinal MRI Study.

Structural covariance has recently emerged as a tool to study brain connectivity in health and disease. The main assumption behind the phenomenon of structural covariance is that changes in brain structure during development occur in a coordinated fashion. However, no study has yet explored the correlation of structural brain changes within individuals across development. Here, we used longitudinal magnetic resonance imaging scans from 141 normally developing children and adolescents (scanned 3 times) to introduce a novel subject-based maturational coupling approach. For each subject, maturational coupling was defined as similarity in the trajectory of cortical thickness (across the time points) between any two cortical regions. Our approach largely captured features seen in population-based structural covariance, and confirmed strong maturational coupling between homologous and near-neighbor cortical regions. Stronger maturational coupling among several homologous regions was observed for females compared to males, possibly indicating greater interhemispheric connectivity in females. Developmental changes in maturational coupling within the default-mode network (DMN) aligned with developmental changes in structural and functional DMN connectivity. Our findings indicate that patterns of maturational coupling within individuals may provide mechanistic explanation for the phenomenon of structural covariance, and allow investigation of individual brain variability with respect to cognition and disease vulnerability.

Selective memory retrieval of auditory what and auditory where involves the ventrolateral prefrontal cortex.

There is evidence from the visual, verbal, and tactile memory domains that the midventrolateral prefrontal cortex plays a critical role in the top-down modulation of activity within posterior cortical areas for the selective retrieval of specific aspects of a memorized experience, a functional process often referred to as active controlled retrieval. In the present functional neuroimaging study, we explore the neural bases of active retrieval for auditory nonverbal information, about which almost nothing is known. Human participants were scanned with functional magnetic resonance imaging (fMRI) in a task in which they were presented with short melodies from different locations in a simulated virtual acoustic environment within the scanner and were then instructed to retrieve selectively either the particular melody presented or its location. There were significant activity increases specifically within the midventrolateral prefrontal region during the selective retrieval of nonverbal auditory information. During the selective retrieval of information from auditory memory, the right midventrolateral prefrontal region increased its interaction with the auditory temporal region and the inferior parietal lobule in the right hemisphere. These findings provide evidence that the midventrolateral prefrontal cortical region interacts with specific posterior cortical areas in the human cerebral cortex for the selective retrieval of object and location features of an auditory memory experience.

Evaluating accuracy of striatal, pallidal, and thalamic segmentation methods: Comparing automated approaches to manual delineation.

Accurate automated quantification of subcortical structures is a greatly pursued endeavour in neuroimaging. In an effort to establish the validity and reliability of these methods in defining the striatum, globus pallidus, and thalamus, we investigated differences in volumetry between manual delineation and automated segmentations derived by widely used FreeSurfer and FSL packages, and a more recent segmentation method, the MAGeT-Brain algorithm. In a first set of experiments, the basal ganglia and thalamus of thirty subjects (15 first episode psychosis [FEP], 15 controls) were manually defined and compared to the labels generated by the three automated methods. Our results suggest that all methods overestimate volumes compared to the manually derived "gold standard", with the least pronounced differences produced using MAGeT. The least between-method variability was noted for the striatum, whereas marked differences between manual segmentation and MAGeT compared to FreeSurfer and FSL emerged for the globus pallidus and thalamus. Correlations between manual segmentation and automated methods were strongest for MAGeT (range: 0.51 to 0.92; p<0.01, corrected), whereas FreeSurfer and FSL showed moderate to strong Pearson correlations (range 0.44-0.86; p<0.05, corrected), with the exception of FreeSurfer pallidal (r=0.31, p=0.10) and FSL thalamic segmentations (r=0.37, p=0.051). Bland-Altman plots highlighted a tendency for greater volumetric differences between manual labels and automated methods at the lower end of the distribution (i.e. smaller structures), which was most prominent for bilateral thalamus across automated pipelines, and left globus pallidus for FSL. We then went on to examine volume and shape of the basal ganglia structures using automated techniques in 135 FEP patients and 88 controls. The striatum and globus pallidus were significantly larger in FEP patients compared to controls bilaterally, irrespective of the method used. MAGeT-Brain was more sensitive to shape-based group differences, and uncovered widespread surface expansions in the striatum and globus pallidus bilaterally in FEP patients compared to controls, and surface contractions in bilateral thalamus (FDR-corrected). By contrast, after using a recommended cluster-wise thresholding method, FSL only detected differences in the right ventral striatum (FEP>Control) and one cluster of the left thalamus (Control>FEP). These results suggest that different automated pipelines segment subcortical structures with varying degrees of variability compared to manual methods, with particularly pronounced differences found with FreeSurfer and FSL for the globus pallidus and thalamus.

Cortical Thickness Abnormalities in Autism Spectrum Disorders Through Late Childhood, Adolescence, and Adulthood: A Large-Scale MRI Study.

Neuroimaging studies in autism spectrum disorders (ASDs) have provided inconsistent evidence of cortical abnormality. This is probably due to the small sample sizes used in most studies, and important differences in sample characteristics, particularly age, as well as to the heterogeneity of the disorder. To address these issues, we assessed abnormalities in ASD within the Autism Brain Imaging Data Exchange data set, which comprises data from approximately 1100 individuals (~6-55 years). A subset of these data that met stringent quality control and inclusion criteria (560 male subjects; 266 ASD; age = 6-35 years) were used to compute age-specific differences in cortical thickness in ASD and the relationship of any such differences to symptom severity of ASD. Our results show widespread increased cortical thickness in ASD, primarily left lateralized, from 6 years onwards, with differences diminishing during adulthood. The severity of symptoms related to social affect and communication correlated with these cortical abnormalities. These results are consistent with the conjecture that developmental patterns of cortical thickness abnormalities reflect delayed cortical maturation and highlight the dynamic nature of morphological abnormalities in ASD.

Joint Attention and Brain Functional Connectivity in Infants and Toddlers.

Initiating joint attention (IJA), the behavioral instigation of coordinated focus of 2 people on an object, emerges over the first 2 years of life and supports social-communicative functioning related to the healthy development of aspects of language, empathy, and theory of mind. Deficits in IJA provide strong early indicators for autism spectrum disorder, and therapies targeting joint attention have shown tremendous promise. However, the brain systems underlying IJA in early childhood are poorly understood, due in part to significant methodological challenges in imaging localized brain function that supports social behaviors during the first 2 years of life. Herein, we show that the functional organization of the brain is intimately related to the emergence of IJA using functional connectivity magnetic resonance imaging and dimensional behavioral assessments in a large semilongitudinal cohort of infants and toddlers. In particular, though functional connections spanning the brain are involved in IJA, the strongest brain-behavior associations cluster within connections between a small subset of functional brain networks; namely between the visual network and dorsal attention network and between the visual network and posterior cingulate aspects of the default mode network. These observations mark the earliest known description of how functional brain systems underlie a burgeoning fundamental social behavior, may help improve the design of targeted therapies for neurodevelopmental disorders, and, more generally, elucidate physiological mechanisms essential to healthy social behavior development.

The MNI data-sharing and processing ecosystem.

Neuroimaging has been facing a data deluge characterized by the exponential growth of both raw and processed data. As a result, mining the massive quantities of digital data collected in these studies offers unprecedented opportunities and has become paramount for today's research. As the neuroimaging community enters the world of "Big Data", there has been a concerted push for enhanced sharing initiatives, whether within a multisite study, across studies, or federated and shared publicly. This article will focus on the database and processing ecosystem developed at the Montreal Neurological Institute (MNI) to support multicenter data acquisition both nationally and internationally, create database repositories, facilitate data-sharing initiatives, and leverage existing software toolkits for large-scale data processing.

Left mid-ventrolateral prefrontal cortex: underlying principles of function.

There is a growing body of evidence indicating that the mid-ventrolateral prefrontal cortex in the left hemisphere is involved in some aspect of controlled verbal memory retrieval. Its precise role, however, remains unclear. We tested the hypothesis that when stimuli in memory are related to each other in multiple ways, and therefore familiarity, strong constant stimulus-stimulus links or contextual cues are not sufficient for successful retrieval, control processing emanating from the mid-ventrolateral prefrontal cortex is required to disambiguate and select the appropriate information among memory traces. We refer to this type of retrieval as active retrieval to distinguish it from automatic retrieval which depends on the simple reactivation of memory traces. Normal human subjects were scanned with functional magnetic resonance imaging while they performed three memory tasks that varied in their demands on active retrieval of verbal information. As the demands on active retrieval increased, there was an increase in the activity within the mid-ventrolateral prefrontal cortex, bilaterally, but with more prominent activity in the left hemisphere. These activity increases correlated with activity in the posterior temporal region which, in the left hemisphere, is involved in language processing. No significant activity increases were observed in any other prefrontal region. Furthermore, for the retrieval of well-learned verbally cued conditional motor associations, there were no activity increases in the mid-ventrolateral prefrontal cortex. The present findings provide strong support for the hypothesis that the mid-ventrolateral prefrontal cortex, particularly in the left hemisphere, plays a major role in the active retrieval of information from verbal memory.

Preoperative functional magnetic resonance imaging assessment of higher-order cognitive function in patients undergoing surgery for brain tumors.

OBJECT: Resection of brain tumors has been shown to increase patient survival. The extent of the possible resection, however, depends on whether the tumor has invaded brain regions important for motor, sensory, or cognitive processes and whether the brain tissue surrounding the tumor maintains its functional role. The goal of the present study was to develop new pre- and intraoperative tools to specifically assess the function of the rostral part of the dorsal premotor cortex (PMdr) in 4 patients with brain tumors close to this region. METHODS: Using functional magnetic resonance (fMR) imaging and a task developed to assess accurate selection between competing responses based on conditional rules, the authors preoperatively assessed the function of the PMdr in 4 patients with brain tumors close to this region. In 1 patient, the authors developed an intraoperative procedure to assess performance on the task during the tumor resection. RESULTS: Preoperative fMR imaging data showed specific activity increases in the vicinity of the tumors, that is, in the PMdr. As confirmed by postoperative structural MR imaging, the extent of the tumor resection was optimal and the functional region within the PMdr was preserved. Furthermore, patients exhibited no postoperative deficits during task performance, demonstrating that the function was preserved. Intraoperative behavioral results demonstrated that the cognitive processes underlying performance on the task remained intact throughout the tumor resection. CONCLUSIONS: These findings suggest that preoperative fMR imaging, together with intraoperative behavioral evaluation, may be a useful paradigm to assist neurosurgeons in preserving cognitive function in patients with brain tumors.

Waiting to retrieve: possible implications for brain function.

There is evidence that the mid-ventrolateral prefrontal cortex is involved in control processing necessary for the active retrieval of mnemonic information when retrieval cannot be triggered automatically by unique/constant associations within memory. We hypothesized that this process is initiated as soon as an instructional cue to retrieve a particular aspect of an encoded stimulus is presented prior to the appearance of the test stimulus that prompts the subjects' response. To test this hypothesis, we provided the subjects with a delay period following the presentation of the instructional cue. Across delays, the subjects took longer to respond during the active retrieval compared with the automatic retrieval trials. Importantly, for both trial types, delays of up to 300 ms improved the subjects' reaction times during the test period by an average of 101 ms. Retrieval mechanisms, therefore, are initiated early during the post-instruction delay period prior to the presentation of the test stimulus needed for the decision.

Local morphology predicts functional organization of the dorsal premotor region in the human brain.

A confusing picture of the functional organization of the dorsal premotor region of the human brain emerged when functional neuroimaging studies that either examined visuomotor hand conditional activity or attempted to localize the human frontal eye field reported activity increases at the same general location, namely the junction of the superior precentral sulcus with the superior frontal sulcus. The present functional magnetic resonance imaging study examined visuomotor hand conditional activity and the locus of the frontal eye field as defined by a standard task, on a subject-by-subject basis, to clarify their location and reveal relationships between the pattern of local morphology and functional activity. The results demonstrate that visuomotor hand conditional activity and the frontal eye field lie within distinct parts of the superior precentral sulcus, revealing an organization of the human premotor cortex consistent with that observed in experimental studies in the monkey.

The Emergence of Network Inefficiencies in Infants With Autism Spectrum Disorder.

BACKGROUND: Autism spectrum disorder (ASD) is a developmental disorder defined by behavioral features that emerge during the first years of life. Research indicates that abnormalities in brain connectivity are associated with these behavioral features. However, the inclusion of individuals past the age of onset of the defining behaviors complicates interpretation of the observed abnormalities: they may be cascade effects of earlier neuropathology and behavioral abnormalities. Our recent study of network efficiency in a cohort of 24-month-olds at high and low familial risk for ASD reduced this confound; we reported reduced network efficiencies in toddlers classified with ASD. The current study maps the emergence of these inefficiencies in the first year of life. METHODS: This study uses data from 260 infants at 6 and 12 months of age, including 116 infants with longitudinal data. As in our earlier study, we use diffusion data to obtain measures of the length and strength of connections between brain regions to compute network efficiency. We assess group differences in efficiency within linear mixed-effects models determined by the Akaike information criterion. RESULTS: Inefficiencies in high-risk infants later classified with ASD were detected from 6 months onward in regions involved in low-level sensory processing. In addition, within the high-risk infants, these inefficiencies predicted 24-month symptom severity. CONCLUSIONS: These results suggest that infants with ASD, even before 6 months of age, have deficits in connectivity related to low-level processing, which contribute to a developmental cascade affecting brain organization and eventually higher-level cognitive processes and social behavior.

Emerging Executive Functioning and Motor Development in Infants at High and Low Risk for Autism Spectrum Disorder.

Existing evidence suggests executive functioning (EF) deficits may be present in children with autism spectrum disorder (ASD) by 3 years of age. It is less clear when, prior to 3 years, EF deficits may emerge and how EF unfold over time. The contribution of motor skill difficulties to poorer EF in children with ASD has not been systematically studied. We investigated the developmental trajectory of EF in infants at high and low familial risk for ASD (HR and LR) and the potential associations between motor skills, diagnostic group, and EF performance. Participants included 186 HR and 76 LR infants. EF (A-not-B), motor skills (Fine and Gross Motor), and cognitive ability were directly assessed at 12 months and 24 months of age. Participants were directly evaluated for ASD at 24 months using DSM-IV-TR criteria and categorized as HR-ASD, HR-Negative, and LR-Negative. HR-ASD and HR-Negative siblings demonstrated less improvement in EF over time compared to the LR-Negative group. Motor skills were associated with group and EF performance at 12 months. No group differences were found at 12 months, but at 24 months, the HR-ASD and HR-Negative groups performed worse than the LR-Negative group overall after controlling for visual reception and maternal education. On reversal trials, the HR-ASD group performed worse than the LR-Negative group. Motor skills were associated with group and EF performance on reversal trials at 24 months. Findings suggest that HR siblings demonstrate altered EF development and that motor skills may play an important role in this process.

Cyberinfrastructure for Open Science at the Montreal Neurological Institute.

Data sharing is becoming more of a requirement as technologies mature and as global research and communications diversify. As a result, researchers are looking for practical solutions, not only to enhance scientific collaborations, but also to acquire larger amounts of data, and to access specialized datasets. In many cases, the realities of data acquisition present a significant burden, therefore gaining access to public datasets allows for more robust analyses and broadly enriched data exploration. To answer this demand, the Montreal Neurological Institute has announced its commitment to Open Science, harnessing the power of making both clinical and research data available to the world (Owens, 2016a,b). As such, the LORIS and CBRAIN (Das et al., 2016) platforms have been tasked with the technical challenges specific to the institutional-level implementation of open data sharing, including: Comprehensive linking of multimodal data (phenotypic, clinical, neuroimaging, biobanking, and genomics, etc.)Secure database encryption, specifically designed for institutional and multi-project data sharing, ensuring subject confidentiality (using multi-tiered identifiers).Querying capabilities with multiple levels of single study and institutional permissions, allowing public data sharing for all consented and de-identified subject data.Configurable pipelines and flags to facilitate acquisition and analysis, as well as access to High Performance Computing clusters for rapid data processing and sharing of software tools.Robust Workflows and Quality Control mechanisms ensuring transparency and consistency in best practices.Long term storage (and web access) of data, reducing loss of institutional data assets.Enhanced web-based visualization of imaging, genomic, and phenotypic data, allowing for real-time viewing and manipulation of data from anywhere in the world.Numerous modules for data filtering, summary statistics, and personalized and configurable dashboards. Implementing the vision of Open Science at the Montreal Neurological Institute will be a concerted undertaking that seeks to facilitate data sharing for the global research community. Our goal is to utilize the years of experience in multi-site collaborative research infrastructure to implement the technical requirements to achieve this level of public data sharing in a practical yet robust manner, in support of accelerating scientific discovery.

Behavioral, cognitive, and adaptive development in infants with autism spectrum disorder in the first 2 years of life.

BACKGROUND: To delineate the early progression of autism spectrum disorder (ASD) symptoms, this study investigated developmental characteristics of infants at high familial risk for ASD (HR), and infants at low risk (LR). METHODS: Participants included 210 HR and 98 LR infants across 4 sites with comparable behavioral data at age 6, 12, and 24 months assessed in the domains of cognitive development (Mullen Scales of Early Learning), adaptive skills (Vineland Adaptive Behavioral Scales), and early behavioral features of ASD (Autism Observation Scale for Infants). Participants evaluated according to the DSM-IV-TR criteria at 24 months and categorized as ASD-positive or ASD-negative were further stratified by empirically derived cutoff scores using the Autism Diagnostic Observation Schedule yielding four groups: HR-ASD-High, HR-ASD-Moderate (HR-ASD-Mod), HR-ASD-Negative (HR-Neg), and LR-ASD-Negative (LR-Neg). RESULTS: The four groups demonstrated different developmental trajectories that became increasingly distinct from 6 to 24 months across all domains. At 6 months, the HR-ASD-High group demonstrated less advanced Gross Motor and Visual Reception skills compared with the LR-Neg group. By 12 months, the HR-ASD-High group demonstrated increased behavioral features of ASD and decreased cognitive and adaptive functioning compared to the HR-Neg and LR-Neg groups. By 24 months, both the HR-ASD-High and HR-ASD-Moderate groups demonstrated differences from the LR- and HR-Neg groups in all domains. CONCLUSIONS: These findings reveal atypical sensorimotor development at 6 months of age which is associated with ASD at 24 months in the most severely affected group of infants. Sensorimotor differences precede the unfolding of cognitive and adaptive deficits and behavioral features of autism across the 6- to 24-month interval. The less severely affected group demonstrates later symptom onset, in the second year of life, with initial differences in the social-communication domain.

Accurate age classification of 6 and 12 month-old infants based on resting-state functional connectivity magnetic resonance imaging data.

Human large-scale functional brain networks are hypothesized to undergo significant changes over development. Little is known about these functional architectural changes, particularly during the second half of the first year of life. We used multivariate pattern classification of resting-state functional connectivity magnetic resonance imaging (fcMRI) data obtained in an on-going, multi-site, longitudinal study of brain and behavioral development to explore whether fcMRI data contained information sufficient to classify infant age. Analyses carefully account for the effects of fcMRI motion artifact. Support vector machines (SVMs) classified 6 versus 12 month-old infants (128 datasets) above chance based on fcMRI data alone. Results demonstrate significant changes in measures of brain functional organization that coincide with a special period of dramatic change in infant motor, cognitive, and social development. Explorations of the most different correlations used for SVM lead to two different interpretations about functional connections that support 6 versus 12-month age categorization.

Differences in white matter fiber tract development present from 6 to 24 months in infants with autism.

OBJECTIVE: Evidence from prospective studies of high-risk infants suggests that early symptoms of autism usually emerge late in the first or early in the second year of life after a period of relatively typical development. The authors prospectively examined white matter fiber tract organization from 6 to 24 months in high-risk infants who developed autism spectrum disorders (ASDs) by 24 months. METHOD: The participants were 92 high-risk infant siblings from an ongoing imaging study of autism. All participants had diffusion tensor imaging at 6 months and behavioral assessments at 24 months; a majority contributed additional imaging data at 12 and/or 24 months. At 24 months, 28 infants met criteria for ASDs and 64 infants did not. Microstructural properties of white matter fiber tracts reported to be associated with ASDs or related behaviors were characterized by fractional anisotropy and radial and axial diffusivity. RESULTS: The fractional anisotropy trajectories for 12 of 15 fiber tracts differed significantly between the infants who developed ASDs and those who did not. Development for most fiber tracts in the infants with ASDs was characterized by higher fractional anisotropy values at 6 months followed by slower change over time relative to infants without ASDs. Thus, by 24 months of age, those with ASDs had lower values. CONCLUSIONS: These results suggest that aberrant development of white matter pathways may precede the manifestation of autistic symptoms in the first year of life. Longitudinal data are critical to characterizing the dynamic age-related brain and behavior changes underlying this neurodevelopmental disorder.

Ventrolateral prefrontal cortex and tactile memory disambiguation in the human brain.

Tactile sensory information is first channeled from the primary somatosensory cortex on the postcentral gyrus to the parietal opercular region (i.e., the secondary somatosensory cortex) and the rostral inferior parietal lobule and, from there, to the prefrontal cortex, with which bidirectional connections exist. Although we know that tactile memory signals can be found in the prefrontal cortex, the contribution of the different prefrontal areas to tactile memory remains unclear. The present functional MRI study shows that a specific part of the prefrontal cortex in the human brain, namely the midventrolateral prefrontal region (cytoarchitectonic areas 47/12 and 45), is involved in active controlled retrieval processing necessary for the disambiguation of vibrotactile information in short-term memory. Furthermore, we demonstrate that this particular part of the prefrontal cortex interacts functionally with the secondary somatosensory areas in the parietal operculum and the rostral inferior parietal lobule during controlled processing for the retrieval of specific tactile information.

The mid-ventrolateral prefrontal cortex: insights into its role in memory retrieval.

Although it is widely known that the prefrontal cortex plays a role in memory, the specific contribution of particular prefrontal regions in mnemonic functions remains controversial. The present investigation examined whether the mid-ventrolateral prefrontal cortex is selectively involved in active memory retrieval in situations in which mnemonic traces are embedded in ambiguous relations and automatic recollection cannot lead to successful retrieval. Thirteen subjects participated in this event-related functional magnetic resonance imaging experiment. Throughout the scanning session, trials belonging to an experimental and a control condition were administered in a pseudorandom fashion. During the encoding phase of any particular trial, subjects were presented with a stimulus-complex that was a combination of a face and a spatial location on the screen. In the experimental active retrieval condition, a question cue following the encoding phase instructed the subjects to retrieve selectively one of the two aspects of the encoded stimulus-complex, i.e. the face or the location. In the control condition, the question cue that followed the encoding phase instructed the subjects simply to recall the initially presented stimulus-complex, so as to be able to make a decision during the test phase based on simple stimulus familiarity. The comparison of the signal obtained during the retrieval phase of these two conditions yielded an increase in activity selective to the right mid-ventrolateral prefrontal region. These results therefore establish a specific link between the mid-ventrolateral prefrontal cortex and active retrieval mechanisms.