Structural deviations of the posterior fossa and the cerebellum and their cognitive links in a neurodevelopmental deletion syndrome.

High-impact genetic variants associated with neurodevelopmental disorders provide biologically-defined entry points for mechanistic investigation. The 3q29 deletion (3q29Del) is one such variant, conferring a 40-100-fold increased risk for schizophrenia, as well as high risk for autism and intellectual disability. However, the mechanisms leading to neurodevelopmental disability remain largely unknown. Here, we report the first in vivo quantitative neuroimaging study in individuals with 3q29Del (N = 24) and neurotypical controls (N = 1608) using structural MRI. Given prior radiology reports of posterior fossa abnormalities in 3q29Del, we focused our investigation on the cerebellum and its tissue-types and lobules. Additionally, we compared the prevalence of cystic/cyst-like malformations of the posterior fossa between 3q29Del and controls and examined the association between neuroanatomical findings and quantitative traits to probe gene-brain-behavior relationships. 3q29Del participants had smaller cerebellar cortex volumes than controls, before and after correction for intracranial volume (ICV). An anterior-posterior gradient emerged in finer grained lobule-based and voxel-wise analyses. 3q29Del participants also had larger cerebellar white matter volumes than controls following ICV-correction and displayed elevated rates of posterior fossa arachnoid cysts and mega cisterna magna findings independent of cerebellar volume. Cerebellar white matter and subregional gray matter volumes were associated with visual-perception and visual-motor integration skills as well as IQ, while cystic/cyst-like malformations yielded no behavioral link. In summary, we find that abnormal development of cerebellar structures may represent neuroimaging-based biomarkers of cognitive and sensorimotor function in 3q29Del, adding to the growing evidence identifying cerebellar pathology as an intersection point between syndromic and idiopathic forms of neurodevelopmental disabilities.

Dissociable Cognitive Systems for Recognizing Places and Navigating through Them: Developmental and Neuropsychological Evidence.

Recent neural evidence suggests that the human brain contains dissociable systems for "scene categorization" (i.e., recognizing a place as a particular kind of place, for example, a kitchen), including the parahippocampal place area, and "visually guided navigation" (e.g., finding our way through a kitchen, not running into the kitchen walls or banging into the kitchen table), including the occipital place area. However, converging behavioral data - for instance, whether scene categorization and visually guided navigation abilities develop along different timelines and whether there is differential breakdown under neurologic deficit - would provide even stronger support for this two-scene-systems hypothesis. Thus, here we tested scene categorization and visually guided navigation abilities in 131 typically developing children between 4 and 9 years of age, as well as 46 adults with Williams syndrome, a developmental disorder with known impairment on "action" tasks, yet relative sparing on "perception" tasks, in object processing. We found that (1) visually guided navigation is later to develop than scene categorization, and (2) Williams syndrome adults are impaired in visually guided navigation, but not scene categorization, relative to mental age-matched children. Together, these findings provide the first developmental and neuropsychological evidence for dissociable cognitive systems for recognizing places and navigating through them.SIGNIFICANCE STATEMENT Two decades ago, Milner and Goodale showed us that identifying objects and manipulating them involve distinct cognitive and neural systems. Recent neural evidence suggests that the same may be true of our interactions with our environment: identifying places and navigating through them are dissociable systems. Here we provide converging behavioral evidence supporting this two-scene-systems hypothesis - finding both differential development and breakdown of "scene categorization" and "visually guided navigation." This finding suggests that the division of labor between perception and action systems is a general organizing principle for the visual system, not just a principle of the object processing system in particular.

Autism spectrum disorder symptom expression in individuals with 3q29 deletion syndrome.

BACKGROUND: The 1.6 Mb 3q29 deletion is associated with neurodevelopmental and neuropsychiatric phenotypes, including a 19-fold increased risk for autism spectrum disorder (ASD). Previous work by our team identified elevated social disability in this population via parent-report questionnaires. However, clinical features of ASD in this population have not been explored in detail. METHODS: Thirty-one individuals with 3q29 deletion syndrome (3q29del, 61.3% male) were evaluated using two gold-standard clinical ASD evaluations: the Autism Diagnostic Observation Schedule, Second Edition (ADOS-2), and the Autism Diagnostic Interview, Revised (ADI-R). Four matched comparators for each subject were ascertained from the National Database for Autism Research. Item-level scores on the ADOS-2 and ADI-R were compared between subjects with 3q29del and matched comparators. RESULTS: Subjects with 3q29del and no ASD (3q29del-ASD) had greater evidence of social disability compared to typically developing (TD) comparison subjects across the ADOS-2. Subjects with 3q29del and ASD (3q29del + ASD) were largely indistinguishable from non-syndromic ASD (nsASD) subjects on the ADOS-2. 3q29del + ASD performed significantly better on social communication on the ADI-R than nsASD (3q29 + ASD mean = 11.36; nsASD mean = 15.70; p = 0.01), and this was driven by reduced deficits in nonverbal communication (3q29 + ASD mean = 1.73; nsASD mean = 3.63; p = 0.03). 3q29del + ASD reported significantly later age at the first two-word phrase compared to nsASD (3q29del + ASD mean = 43.89 months; nsASD mean = 37.86 months; p = 0.01). However, speech delay was not related to improved nonverbal communication in 3q29del + ASD. LIMITATIONS: There were not enough TD comparators with ADI-R data in NDAR to include in the present analysis. Additionally, our relatively small sample size made it difficult to assess race and ethnicity effects. CONCLUSIONS: 3q29del is associated with significant social disability, irrespective of ASD diagnosis. 3q29del + ASD have similar levels of social disability to nsASD, while 3q29del-ASD have significantly increased social disability compared to TD individuals. However, social communication is reasonably well preserved in 3q29del + ASD relative to nsASD. It is critical that verbal ability and social disability be examined separately in this population to ensure equal access to ASD and social skills evaluations and services.

Late Development of Navigationally Relevant Motion Processing in the Occipital Place Area.

Human adults flawlessly and effortlessly navigate boundaries and obstacles in the immediately visible environment, a process we refer to as "visually guided navigation." Neuroimaging work in adults suggests this ability involves the occipital place area (OPA) [1, 2]-a scene-selective region in the dorsal stream that selectively represents information necessary for visually guided navigation [3-9]. Despite progress in understanding the neural basis of visually guided navigation, however, little is known about how this system develops. Is navigationally relevant information processing present in the first few years of life? Or does this information processing only develop after many years of experience? Although a handful of studies have found selective responses to scenes (relative to objects) in OPA in childhood [10-13], no study has explored how more specific navigationally relevant information processing emerges in this region. Here, we do just that by measuring OPA responses to first-person perspective motion information-a proxy for the visual experience of actually navigating the immediate environment-using fMRI in 5- and 8-year-old children. We found that, although OPA already responded more to scenes than objects by age 5, responses to first-person perspective motion were not yet detectable at this same age and rather only emerged by age 8. This protracted development was specific to first-person perspective motion through scenes, not motion on faces or objects, and was not found in other scene-selective regions (the parahippocampal place area or retrosplenial complex) or a motion-selective region (MT). These findings therefore suggest that navigationally relevant information processing in OPA undergoes prolonged development across childhood.