These structural findings suggest abnormal brain developmental processes early in the clinical course of autism. Research currently is underway to better elucidate mechanisms underlying these structural abnormalities and their longitudinal progression.

We are performing whole genome sequencing (WGS) of families with Autism Spectrum Disorder (ASD) to build a resource, named MSSNG, to enable the sub-categorization of phenotypes and underlying genetic factors involved. Here, we report WGS of 5,205 samples from families with ASD, accompanied by clinical information, creating a database accessible in a cloud platform, and through an internet portal with controlled access. We found an average of 73.8 de novo single nucleotide variants and 12.6 de novo insertion/deletions (indels) or copy number variations (CNVs) per ASD subject. We identified 18 new candidate ASD-risk genes such as MED13 and PHF3, and found that participants bearing mutations in susceptibility genes had significantly lower adaptive ability (p=6×10−4). In 294/2,620 (11.2%) of ASD cases, a molecular basis could be determined and 7.2% of these carried CNV/chromosomal abnormalities, emphasizing the importance of detecting all forms of genetic variation as diagnostic and therapeutic targets in ASD.

Summary Brain enlargement has been observed in children with Autism Spectrum Disorder (ASD), but the timing of this phenomenon and its relationship to the appearance of behavioral symptoms is unknown. Retrospective head circumference and longitudinal brain volume studies of 2 year olds followed up at age 4 years, have provided evidence that increased brain volume may emerge early in development.1, 2 Studies of infants at high familial risk for autism can provide insight into the early development of autism and have found that characteristic social deficits in ASD emerge during the latter part of the first and in the second year of life3,4. These observations suggest that prospective brain imaging studies of infants at high familial risk for ASD might identify early post-natal changes in brain volume occurring before the emergence of 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 cortical surface area hyper-expansion between 6-12 months of age precedes brain volume overgrowth observed between 12-24 months in the 15 high-risk infants diagnosed with autism at 24 months. Brain volume overgrowth was linked to the emergence and severity of autistic social deficits. A deep learning algorithm primarily using surface area information from brain MRI at 6 and 12 months of age predicted the diagnosis of autism in individual high-risk children at 24 months (with a positive predictive value of 81%, sensitivity of 88%). These findings demonstrate that early brain changes unfold during the period in which autistic behaviors are first emerging.

OBJECTIVE Evidence from prospective high-risk infant studies 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. This is the first neuroimaging study to prospectively examine white matter fiber tract organization during this interval in infants who develop autism spectrum disorder (ASD) by 24 months. METHOD Participants included 92 infant siblings from an ongoing imaging study of autism. All participants had diffusion tensor imaging at 6 months and behavioral assessments at 24 months, with a majority contributing additional imaging data at either or both 12 and 24 months. At 24 months, 28 infants met criteria for ASD; 64 infants did not. Microstructural properties of white-matter fiber tracts reported to be associated with ASD or related behaviors were characterized by fractional anisotropy (FA) and radial and axial diffusivity. RESULTS FA trajectories differed significantly between infants who did versus did not develop ASD for 12 of 15 fiber tracts. Development for most fiber tracts in infants with ASD was characterized by elevated FA at 6 months followed by slower developmental change overtime relative to infants without ASD. Thus, by 24 months of age, lower FA values were evident for those with ASD. CONCLUSION These results suggest that the aberrant development of white matter pathways 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.

There has been significant advancement in various aspects of scientific knowledge concerning the role of cerebellum in the etiopathogenesis of autism. In the current consensus paper, we will observe the diversity of opinions regarding the involvement of this important site in the pathology of autism. Recent emergent findings in literature related to cerebellar involvement in autism are discussed, including: cerebellar pathology, cerebellar imaging and symptom expression in autism, cerebellar genetics, cerebellar immune function, oxidative stress and mitochondrial dysfunction, GABAergic and glutamatergic systems, cholinergic, dopaminergic, serotonergic, and oxytocin related changes in autism, motor control and cognitive deficits, cerebellar coordination of movements and cognition, gene-environment interactions, therapeutics in autism and relevant animal models of autism. Points of consensus include presence of abnormal cerebellar anatomy, abnormal neurotransmitter systems, oxidative stress, cerebellar motor and cognitive deficits, and neuroinflammation in subjects with autism. Undefined areas or areas requiring further investigation include lack of treatment options for core symptoms of autism, vermal hypoplasia and other vermal abnormalities as a consistent feature of autism, mechanisms underlying cerebellar contributions to cognition, and unknown mechanisms underlying neuroinflammation.

Improved data acquisition and processing strategies for blood oxygenatlon level-dependent (BOlO)-conlrast funcllona1 magnetie resonaneo imaging (fMRI), wllich enhance the functional eontrast-to-nolse ratio (CNR) by sampllng multiple echo limes In a single shot, are descrlbed. The dependence of Ihe CNR on Ti, Ihe image encoding time, and Ihe number of samplod oeho titnes are Investigated for exponentia1 fitting, echo summation, welghled echo summation, and averaglng of corrolalion maps oblainod at different echo limes. The mothod is validated In vlvo using visual stimulation and turbo proton echoplanar speelroseopie imaging (turbo-PEPSI), a new single-shot multi-slice MR spoclroscoplc Imaging teehnlque, whlch acqulres up 10 12 consocutive ochoplanar images wlth echo limes ranging from 1210213 msec. Quantitative Ti-mapplng slgnificanUy increasos Ihe measured extent of aetivatJon and the mean correlalion coefficient compared wilh convenlional echoplanar imaging. The sensltlvity gain with echo summation, wllicll is compulationally efficiet:'lt provides similar sensitivity as fitting. For all data processing methods sensltivlty is optimum wh on echo limes IIp 10 3.2 T 2 are sampled. This molhodology has implications for comparing functional sonsitivity at different magnetie field strengths and between braln regions with different magnetic field inhomogeneitics.

Gray matter lactate and Glx elevations in medication-free BD patients suggest a shift in energy redox state from oxidative phosphorylation toward glycolysis. The possibility of mitochondrial alterations underlying these findings is discussed and may provide a theoretical framework for future targeted treatment interventions.

The autism spectrum disorder (ASD) is among the most devastating disorders of childhood in terms of prevalence, morbidity, outcome, impact on the family, and cost to society. According to recent epidemiological data, ϳ1 child in 166 is affected with ASD, a considerable increase compared with estimates compiled 15-20 years ago (Fombonne, 2003a,b). Although at one time considered an emotional disturbance resulting from early attachment experiences (Bettelheim, 1967), ASD is now recognized as a disorder of prenatal and postnatal brain development. Although ASD is primarily a genetic disorder involving multiple genes, insights into underlying mechanisms will require a multidisciplinary approach. Assessment of the earliest clinical signs and symptoms and the functional and structural networks by neuroimaging and neuropathology can be used to identify the underlying brain regions, neural networks, and cellular systems. In turn, the efforts of human and animal geneticists and neuroscientists are needed to define molecular and protein signaling pathways that mediate normal as well as abnormal development of language, social interaction, and cognitive and motor routines. In this review, we focus on several issues: the earliest manifestations of ASD, reported abnormalities of brain growth, functional neural networks, and neuropathology. We also consider the possible etiological factors and the challenges of creating animal models for this uniquely human behavioral disorder. Autism spectrum disorder: phenotypes and clinical diagnosisASD comprises several different disorders as defined by deficits in social behaviors and interactions. These deficits prevent the development of normal interpersonal relationships of affected patients with their parents, siblings, and other children. Deficits in nonverbal communication include reduced eye contact, facial expression, and body gestures (American Psychiatric Association, 1994). These disorders include prototypic autistic disorder, Asperger syndrome, and pervasive developmental disorder-not otherwise specified (PDD-NOS). Autistic disorder has three core symptom domains: deficits in communication, abnormal social interactions, and restrictive and/or repetitive interests and behaviors. Autistic disorder is typically noticed in the first or second year of life. The manifestations include delay or abnormality in language and play, repetitive behaviors, such as spinning things or lining up small objects, or unusual interests such as preoccupations with stop signs or ceiling fans. Asperger syndrome also involves social symptoms but language development and non-