MRI Study of Minor Physical Anomaly in Childhood Autism Implicates Aberrant Neurodevelopment in Infancy

Abstract

BackgroundMPAs (minor physical anomalies) frequently occur in neurodevelopmental disorders because both face and brain are derived from neuroectoderm in the first trimester. Conventionally, MPAs are measured by evaluation of external appearance. Using MRI can help overcome inherent observer bias, facilitate multi-centre data acquisition, and explore how MPAs relate to brain dysmorphology in the same individual. Optical MPAs exhibit a tightly synchronized trajectory through fetal, postnatal and adult life. As head size enlarges with age, inter-orbital distance increases, and is mostly completed before age 3 years. We hypothesized that optical MPAs might afford a retrospective ‘window’ to early neurodevelopment; specifically, inter-orbital distance increase may represent a biomarker for early brain dysmaturation in autism.MethodsWe recruited 91 children aged 7–16; 36 with an autism spectrum disorder and 55 age- and gender-matched typically developing controls. All children had normal IQ. Inter-orbital distance was measured on T1-weighted MRI scans. This value was entered into a voxel-by-voxel linear regression analysis with grey matter segmented from a bimodal MRI data-set. Age and total brain tissue volume were entered as covariates.ResultsIntra-class coefficient for measurement of the inter-orbital distance was 0.95. Inter-orbital distance was significantly increased in the autism group (p = 0.03, 2-tailed). The autism group showed a significant relationship between inter-orbital distance grey matter volume of bilateral amygdalae extending to the unci and inferior temporal poles.ConclusionsGreater inter-orbital distance in the autism group compared with healthy controls is consistent with infant head size expansion in autism. Inter-orbital distance positively correlated with volume of medial temporal lobe structures, suggesting a link to “social brain” dysmorphology in the autism group. We suggest these data support the role of optical MPAs as a “fossil record” of early aberrant neurodevelopment, and potential biomarker for brain dysmaturation in autism.

A trend toward smaller optical angles and medial‐ocular distance in schizophrenia spectrum, but not in bipolar and major depressive disorders

“…In this study, after further controlling for the skull length and width, a trend toward a smaller medial‐orbital distance and optical angle were detected in patients with SCZ and their relatives, with similar patterns in individuals with SPD, showing gradient differences when compared to non‐SPD controls. In contrast to other findings showing hypertelorism in other developmental disorders (Cheung et al, ; Cohen, ), our finding of the opposite suggests that early developmental insults in SCZ‐spectrum disorders may occur under a different causal mechanism and/or at a different developmental stage.…”

“…Five craniofacial MPA items were included in this study because they were objectively measurable on T1‐weighted images with a clear definition. First, medial ocular distance was taken as the medial inter‐ocular distance, which is similar to the measurement described in an MRI study of autism (Cheung et al, ). In brief, on the mid‐sagittal view, the axial slice with the appearance of nasal bone was selected (see Figure A).…”

“…In order to address this issue, magnetic resonance imaging (MRI) has been adopted to examine the craniofacial MPA items, which might be more relevant than MPAs in other regions, such as the limbs (Compton et al, ; Trixler, Tényi, Csábi, & Szabó, ). For example, Boyes, Whalley, Lawrie, Johnstone, and Best () used MRI to assess binocular diameter in patients with SCZ‐spectrum disorders, and others have used MRI to quantify inter‐orbital and inter‐pupillary distance in autism‐spectrum disorders (Cheung et al, ; Hardan, Keshavan, Sreedhar, Vemulapalli, & Minshew, ). Therefore, compared to conventional inspections, MRI‐based measurements may provide a new reliable and valid option for craniofacial MPA evaluations.…”

Head circumference and brain size in autism spectrum disorder: A systematic review and meta-analysis

“…At the end of this process, 44 studies were selected, each assessing patients with idiopathic autism (i.e., DSM-IV diagnoses of either Autistic Disorder, Asperger's Disorder or Pervasive Developmental Disorder Not Otherwise Specified, PDD-NOS) and controls (Piven et al, 1995;Aylward et al, 1999;Haznedar et al, 2000;Hardan et al, 2000;Courchesne et al, 2001;Pierce and Couchesne, 2001;Aylward et al, 2002;Carper et al, 2002;McAlonan et al, 2002;Rojas et al, 2002;Sparks et al, 2002;Hardan et al, 2003;Herbert et al, 2003;Tsatsanis et al, 2003;Akshoomoff et al, 2004;Kates et al, 2004;Palmen et al, 2004;Schumann et al, 2004;Palmen et al, 2005;Vidal et al, 2006;Bloss and Courchesne, 2007;Girgis et al, 2007;Mostofsky et al, 2007;Tate et al, 2007;Cleavinger et al, 2008;Hardan et al, 2008;Freitag et al, 2009;Hallahan et al, 2009;Hardan et al, 2009;Scott et al, 2009;Bigler et al, 2010;Griebling et al, 2010;Jou et al, 2010aJou et al, , 2010bSchumann et al, 2010;Tamura et al, 2010;Tepest et al, 2010;Cheung et al, 2011;Hong et al, 2011;Calderoni et al, 2012;Greimel et al, 2012;…”

Investigating facial phenotype in autism spectrum conditions: The importance of a hypothesis driven approach

“…Using the Waldrop scale, Walker [] reported increased incidence of hypertelorism among 74 individuals with ASC relative to TD controls. More recent studies using the Waldrop Scale [Ozgen et al, ] or MRI [Cheung et al, ] measurements have also found significantly increased inner inter‐canthal and inter‐orbital distances in ASC groups relative to TD controls. However, several studies have identified significantly reduced mean inter‐canthal distance in children with ASC [Aldridge et al, ], and a relationship between smaller mean inter‐orbital distance in ASC and low IQ [Hardan, Keshavan, Sreedhar, Vemulapalli, & Minshew, ].…”