Male Brain Phenotype Linked to Autism Risk, Even in Girls

Pauline Anderson

February 13, 2017

A new study may help explain why autism spectrum disorder (ASD) affects up to five times more males than females. The answer may lie in cortical thickness in various regions of the brain.

Researchers found that the brains of females with autism had features of cortical thickness that more closely resembled characteristics of the male brain phenotype.

The findings highlight the importance of considering neurobiological information, along with environmental and genetic factors, when determining risk for ASD, said lead author Christine Ecker, PhD, Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Goethe University, Frankfurt am Main, Germany.

"Just because someone has XX or XY chromosomes doesn't mean they have a particular risk for ASD; you need to also take into account the actual phenotype or the neurobiology associated with being male or female," said Dr Ecker. "Only by looking at the phenotype rather than just biological sex can you come up with a risk score that is more accurate."

Dr Christine Ecker

The study was published online February 8 in JAMA Psychiatry.

The analysis included 98 high-functioning right-handed adults with confirmed ASD (49 men and 49 women; mean age, about 27 years) and 98 matched "neurotypical" control persons.

The authors used MRI scans of the participants' brains and a sophisticated statistical approach to establish how cortical thickness varies across neurotypical male and female patients.

Machine Learning

This approach involved what Dr Ecker described as a "machine learning method," in which a computer algorithm finds a pattern in cortical thickness data that can distinguish males from females.

She and her colleagues were interested in cortical thickness because, although the male brain is larger in volume than the female brain, the cortex in the female brain tends to be thicker. This increase in thickness might represent a protective mechanism.

The authors report that their CT-driven probabilistic classifier predicted biological sex at an accuracy of 71.4% in neurotypical control persons. This, they say, was significantly higher than would be expected to have occurred by chance.

In total, 68.1% of biologically female participants were correctly allocated to the category of phenotypic female person, and 74.5% of biological male participants were correctly allocated to the category of phenotypic male individuals.

The researchers then used their model to investigate the probability that males and females with ASD exhibited the more male-typic or female-typic normative patterns. They found that the vast majority (79.6%) of women with ASD were allocated to the category of phenotypic male individuals.

No such differences were seen in male individuals with ASD who were correctly allocated to the male category.

The study showed "that biological female individuals with male neuroanatomical features were 6.5 times more likely to have ASD than biological female individuals with a characteristically female neuroanatomy," the authors write.

The analysis showed that the women with ASD were more significantly different from female control persons than the men with ASD were in comparison with male control persons. "This indicates that the pathology is more significant in females," said Dr Ecker.

However, she noted that female patients with ASD were not more severely impaired in terms of autistic symptoms than male patients. "Maybe females with ASD have to have a larger degree of brain abnormality to have the same level of symptoms."

Brain Mosaic

The new findings fit well with the concept of the brain being a "mosaic" of regions, "each of relative maleness or femaleness, resulting in significant interindividual variability both within and between sexes," say the authors.

They believe their probabilistic classification approach "holds promise" for future investigations into the neurobiologic mechanisms that underpin risk and resilience for conditions that differ in prevalence with respect to the sexes.

But their study examined only the statistical associations between normative sex-related phenotypic diversity and ASD probability. Future studies should examine the causal mechanisms of this association, said Dr Ecker.

"We don't know whether females with autism are born having a brain with features that look a bit more like the male brain and therefore are more vulnerable towards ASD, or alternatively, whether ASD causes the female brain to look a little bit more male-like."

Researchers are developing software to eventually be used in the office setting that will incorporate phenotype information to help clinicians identify ASD, said Dr Ecker.

Important Step

In an accompanying editorial, Larry Cahill, PhD, Department of Neurobiology and Behavior, University of California, Irvine, says the new study "represents an important new step" in recognizing sex influences as fundamental to understanding both normal and abnormal brain function.

Dr Cahill points out that the brain "mosaic" concept discussed by the study's authors dates back to an article by Richard E. Whalen, MD, published in 1974. In that study, Dr Whalen proposed that the the influences that the two sexes have on the brain do not lie on a continuum, with male and female influences lying on opposite ends. Rather, male and female brains are both subject to masculinizing and feminizing sex influences.

That both males and females with a male-typic cortical thickness pattern appear to be more likely to have ASD does not mean that there are no sex-specific mechanisms at work in ASD, Dr Cahill writes. In fact, he notes that the authors report that variability in cortical thickness in several brain regions – including the parahippocampal and the entorhinal cortex – distinguished between low- and high-risk women, but not men.

Dr Cahill also stresses that it remains to be seen "whether and how the new findings will generalize to other measures of brain anatomy."

This study was supported by a grant from the Autism Imaging Multicenter Study Consortium, funded by Medical Research Council United Kingdom, and by the European Union–Autism Imaging Multicentre Study Consortium, supported by the Innovative Medicines Initiative Joint Undertaking. Additional support to individual investigators is listed in the article. Dr Ecker and Dr Cahill report no relevant financial relationships.

JAMA Psychiatry. Published online February 8, 2017. Full text, Editorial

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