Abnormal Induced Neural Oscillations in 16p11.2 Deletions and Duplications

Background: Rare genetic copy number variations (CNVs), specifically the recurrent ≈600 kb (BP4-BP5) 16p11.2 deletion and duplication, are known to contribute to a range of neurodevelopmental disorders, including autism spectrum disorders, language delay, and intellectual disability. Here, we examined changes in oscillatory activity derived from magnetoencephalographic imaging (MEG-I) in a large cohort of individuals recruited as part of the Simons VIP project (Simons VIP Consortium, Neuron 2013 73:1063-1067).

Objectives: We hypothesized that gene dosage in this interval is critical for the development of abnormal neural oscillatory networks in the brain that in turn are associated with behavioral phenotypes.

Methods: Data were acquired using 275-channel whole-head biomagnetometers (CTF; Vancouver, BC) installed at UCSF and CHOP.  During MEG recording, participants engaged three tasks: 1) an auditory discrimination task of spoken words into semantic categories - living or non-living ; 2) a visual discrimination task differentiating between faces and patterns; 3) a picture naming task in which the subject responded by overtly naming the  object on a picture. Tomographic reconstructions of oscillatory activity across the alpha, beta, gamma and high-gamma frequency bands were stimulus and response-locked and generated using an adaptive spatial filtering technique implemented in Nutmeg (nutmeg.berkeley.edu).  For the picture naming task, we also compute laterality index (LI) from oscillatory activity in the left and right frontal and temporal hemispheres to evaluate language dominance.

Results: Induced high gamma activity was reduced bilaterally in auditory cortex for 16p11.2 deletion child participants only relative to their control group, in response to auditory stimuli occurring at ~100 ms post-stimulus onset. Induced high gamma activity was also reduced in the right fusiform cortex in 16p11.2 child deletion participants, in response to faces. In the picture naming task, while typically developing adults (mean age = 32.6) and children (mean age = 11.3) exhibited left-hemisphere dominance (LI>0.1 in 70% adults and 69% children), 54% of 16p11.2 child deletion carriers exhibited right-hemispheric or bilateral patterns of activity. LI was significantly lower in the 16p11.2 deletion group (p=0.0035) when compared to matched controls. Importantly, LI (or the degree of leftward laterality) in deletion carriers was positively correlated with non-word repetition (CTOPP) scores (r=0.53) – a test of phonological processing. Interestingly, in 16p11.2 adult duplication carriers, only 20% were right-hemispheric dominant, and laterality patterns were comparable to controls.

Conclusions: These results suggest pervasive abnormalities in induced neural oscillations across multiple sensory cortices in participants with 16p11.2 deletions. These findings also indicate that one versus two copies of gene(s) at 16p11.2 alter hemispheric specialization of language.