Functional Lateralization of the Cerebral Cortex in 16p11.2 Deletion and Duplication Carriers

Background: Deletion or duplication of the ~600 kb BP4-BP5 interval at 16p11.2 is associated with a wide range of cognitive deficits and neuropsychiatric disorders, including autism spectrum disorders (ASD), language delay, and intellectual disability. These associated behavioral phenotypes can also relate to atypical functional lateralization of the cerebral cortex. Deletion and duplication carriers have widespread differences in gray and white matter volume. They also differ in the white matter microstructure.

Objectives: Given the association between the 16p11.2 copy number variant (CNV) and ASD, and language or intellectual deficits, we investigated how functional asymmetry of the cerebral cortex is affected in CNV carriers and how it relates to IQ and language ability.

Methods: Two cohorts of CNV carriers (children with deletions: n = 26, 8 – 16 years old; adults with duplications: n = 23, 18 – 62 years old) were compared to two samples of age-matched controls (children: n = 45; adults: n = 58). The preprocessing of the resting-state BOLD images and calculation of the mean left and right laterality indices followed the pipeline outlined in Liu et al. (2009). An independent sample of 100 healthy individuals was used to determine highly lateralized functional connections in the cerebral cortex. These left- and right-lateralized connections were used to calculate mean left and right laterality indices for each participant, respectively.

Results: The deletion carriers were less left- and right-lateralized than age-matched controls, although after controlling for age, sex, handedness, imaging site, and micromovements, only the right-lateralized differences remained significant (left: t = -1.75, p = 0.09; right: t = 2.44, p = 0.02). Group differences were not found in the adult duplication participants (left: t = 0.08, p = 0.93; right: t = 0.31, p = 0.76). Across all children, full scale IQ and language ability were positively correlated with the degree of left lateralization (IQ: b = 0.005, p = 0.004; language: b = 0.003, p = 0.05), although after controlling for the group effects only full scale IQ’s relationship with left lateralization remained (IQ: b = 0.004, p = 0.03; language: b = 0.002, p = 0.34). In other words, as left lateralization increased in the children, IQ increased. A relationship was not found between full scale IQ and right lateralization (b = 0.0008, p = 0.59) or language ability and right lateralization (b = 0.0007, p = 0.62) in the children samples. Also, there was no relationship found between lateralization and full scale IQ (left: b = 0.002, p = 0.39; right: b = -0.003, p= 0.09) in the adult samples.

Conclusions: Functional lateralization of the cerebral cortex is affected when a single copy of the 16p11.2 CNV is present but not when three copies are present. The pattern of decreased lateralization matches previously reported findings in ASD. Group differences in laterality overlap with IQ and language ability, with the relationship between IQ and lateralization in the left hemisphere remaining even after accounting for group differences.