Macrocephalic Individuals with Autism Have Increased White Matter Whereas Normocephalic Individuals with Autism Exhibit Preserved Volumes

Background: A large variety of neuroanatomical abnormalities have been reported in the autism research literature.  Two consistently reported abnormalities include larger head sizes (macrocephaly) and abnormal brain volumes, especially increases in white matter volume.  While these anomalies may represent key pathological features of the disorder, the relationship between macrocephaly and brain volume remains unclear.

Objectives: The present study was conducted to assess the relationship between groups of macrocephalic individuals with autism (MacA), normocephalic individuals with autism (NorA), and typically developing controls without macrocephaly (TDC).

Methods: All participants were right-handed boys (N = 48) who were participants in the Simons Simplex Collection project.  The MacA group consisted of individuals with autism with a head circumference greater than the 97th percentile for age and gender (mean age = 11.3 ±3.4 years).  The NorA group consisted of normocephalic individuals with autism (mean age = 10.0 ±3.7 years).  The TDC group consisted of normocephalic, non-affected siblings of individuals with autism (mean age = 15.0 ±2.0 years).  Notably, the broad autism phenotype was absent in all TDC individuals.  MRI scanning was performed at 3-Tesla.  In conjunction with a standard single-channel head coil, high-resolution, whole-brain structural MRI for study of neuroanatomy was performed with a sagittal 1-cubic mm Magnetization Prepared Rapid Gradient Echo (MPRAGE) sequence.  Structural MRI data was processed and analyzed using the FreeSurfer image analysis suite which consists of automated tools for reconstruction of the brain from high-resolution MRI data, facilitating the accurate and precise quantification of regional white matter volumes.  Subcortical gray matter (subGM) as well as left and right hemisphere cortical gray (corGM) and total white matter (totWM) volumes were measured directly by the FreeSurfer program with manual correction as needed.  These volumes were entered into the Statistical Package for the Social Sciences (SPSS), and comparisons of volumes between groups were conducted using multivariate analysis of covariance (MANCOVA).  The protected Fisher's Least Significant Difference (LSD) test was implemented to address multiple comparisons.

Results: MANCOVA was performed controlling for age, cognitive functioning, and intracranial volume and revealed significant group differences in left and right totWM only.  When MacA was compared to NorA and TDC on left totWM, significant volumetric increases were observed (p = 0.010 and 0.015, respectively).  Significant volumetric increases were also noted when MacA was compared to NorA and TDC on right totWM (p = 0.016 and 0.008, respectively).  While not reaching statistical significance, the NorA group exhibited smaller left and right totWM when compared to the TDC group.

Conclusions: This study supports neuroanatomical differences in the pathobiology of autism between macrocephalic and normocephalic individuals with the disorder.  Individuals with autism and macrocephaly may have increased white matter volume, whereas affected normocephalic individuals may have preserved white matter volume.  These data suggest a biological basis for the observation that individuals with both autism and macrocephaly are more severely affected by the developmental disability.