Quantitative 3D Reconstructions of the Human Superior Olive Complex are Consistent with Auditory Dysfunction in Autism Spectrum Disorder

Abstract

Beyond the characteristic social, communication and behavioral aberrations associated with autism spectrum disorder (ASD), the vast majority of subjects with this condition have some degree of auditory dysfunction. The auditory deficits range from complete deafness to hypersensitivity but typically include difficulty listening to speech in the presence of background noise. Clinical testing of brainstem evoked potentials and stapedial reflexes in children and adults with ASD reveal lower thresholds but slower conduction times and right‐left ear asymmetries. Previous studies on post‐mortem brain specimens from our lab revealed drastic and consistent hypoplasia and dysmorphology in the auditory brainstem. The most drastic alterations were found in the medial superior olive (MSO), the largest and most prominent component of the superior olivary complex (SOC). Our morphological studies have shown that in subjects with ASD, there are significantly fewer neurons in the MSO and surviving neurons are smaller, more round and have an abnormal orientation. Based on these results, we hypothesized that the SOC in subjects with ASD not only includes fewer neurons but that these nuclei occupy significantly less brain volume and demonstrate abnormal nuclear contours. We investigated this hypothesis by obtaining donated brain tissue from an age‐matched series of subjects with ASD or no known neurological diagnosis (neurotypical; NT) through Autism BrainNet. Free‐floating tissue sections were mounted onto glass slides, stained for Nissl substance with Giemsa and sealed under coverslips. 3D volume renderings of the SOC nuclei were created in Amira. Subjects in this study include two NT subjects (ages 4 and 8, both female) and four age‐matched subjects with ASD (ages 2–11 years of age, all male). At autopsy, there was no difference in total brain weight between NT and ASD subjects (p=.42). Our 3D reconstructions reveal a drastic reduction in the total volume of the SOC in subjects with ASD (control = 6.8 mm3, ASD = 2.23 mm3; p<.005). In fact, all SOC nuclei were significantly smaller in ASD subjects expect for the ventral nucleus of the trapezoid body (p=.922). Together, these results support the brainstem as a core site of pathology in ASD and are consistent with previous clinical evaluations of hearing in subjects with ASD.Support or Funding InformationAutism BrainNet