Autism May Involve Disordered White Matter in the Brain

ScienceDaily (Dec. 5, 2011) It's still unclear what's different in the brains of people with autism spectrum disorders (ASDs), but evidence from genetic and cell studies points to abnormalities in how brain cells (neurons) connect to each other. A study at Children's Hospital Boston now provides visual evidence associating autism with a disorganized structure of brain connections, as well as defects in myelin -- the fatty, insulating coating that helps nerve fibers conduct signals and that makes up the brain's white matter. Researchers led by Mustafa Sahin, MD, PhD, of the Department of Neurology, Simon Warfield, PhD, director of the Computational Radiology Laboratory, and first author Jurriaan Peters, MD, of both departments at Children's, used advanced magnetic resonance imaging (MRI) to image the brains of 40 patients (infants to age 25) with tuberous sclerosis complex and 29 age-matched, healthy controls. Tuberous sclerosis is a rare genetic condition often associated with cognitive and behavioral deficits, including ASDs about 50 percent of the time. "Patients with tuberous sclerosis can be diagnosed at birth or potentially before birth, because of cardiac tumors that are visible on ultrasound, giving us the opportunity to understand the circuitry of the brain at an early age," explains Sahin. "Our ultimate goal is to use imaging in infancy to find which tuberous sclerosis patients are at high risk for autism so we can intervene early. This may have implications for autism in patients without tuberous sclerosis as well." The team used a relatively new MRI technique called Diffusion Tensor Imaging to trace the pathways of nerve fibers by measuring the diffusion of water in the brain. In the January issue of the journal Academic Radiology, they report findings in the corpus callosum, the brain's largest white-matter structure that acts as a highway transferring signals between the left and right cerebral hemispheres. Of the 40 patients with tuberous sclerosis, 24 had clinically significant developmental delays or intellectual disability, and 12 had ASDs. ASDs were diagnosed clinically by a pediatric neurologist, and, in most cases, by the Autism Diagnostic Observation Schedule (ADOS). In general, compared with controls, patients with tuberous sclerosis had higher radial diffusivity values, a measure of water diffusion out of (perpendicular to) the nerve fibers (axons). Radial diffusivity is an indirect measure of how well insulated the axons are: Having higher radial diffusivity means axons are poorly insulated with myelin, suggesting abnormalities in the white matter (which is partly made up of myelin. Patients with both tuberous sclerosis and ASDs not only had increased radial diffusivity -- compared with both non-ASD patients and controls -- but they also had clearly disorganized axon pathways. As shown in the images, axons in the control subjects followed well-defined directions in organized bundles (left panels), while the ASD patients' axons (right panels) tended not to orient together in common directions (referred to in the paper as having lower fractional anisotropy). Tuberous sclerosis patients without ASDs (middle panels) showed only slight disorganization compared to controls. "This study shows that we can use diffusion tensor imaging to differentiate tuberous patients with autism from those without autism," says Sahin. "Our advances in imaging and in image analysis are enabling us to identify and quantitatively characterize alterations in brain development that are not readily visible in conventional imaging,'' adds Warfield. The findings add to previous human imaging studies by Sahin and Warfield showing similar differences in the brain's visual cortex, and are consistent with brain MRIs in older, high-functioning individuals with ASDs, showing abnormalities in connectivity in the corpus callosum and in areas of brain involved in language and social skills. The findings are also consistent with studies in Sahin's lab using mouse models of tuberous sclerosis. The neurons in these mice grew multiple axons (normal neurons grow just one), causing too many connections being made, and axons originating in the retina failed to land in the right places in the brain and did not respond to navigation cues. Additional studies showed that the axons in these mice had less myelination, identified the biochemical pathway causing these defects, known as the mTOR pathway, and showed that the pathway and the myelination defects could be reversed in mice with the mTOR-inhibiting drug rapamycin. Armed with these data, Sahin has launched a Phase II clinical trial of a rapamycin-like drug called Afinitor® (everolimus; formerly RAD001), sponsored by Novartis, the Tuberous Sclerosis Alliance and Autism Speaks. The trial will enroll 50 patients with TSC to test whether Afinitor improves neurocognition, autism, seizures and sleep disorders. "Specifically modulating neurocognition with a small molecule is only starting to be done," says Sahin. "Ultimately, imaging will play a crucial role in identifying who may benefit from treatment, and in seeing the changes in the brain in response to treatment," says Warfield.

Biomarker for Autism Discovered

ScienceDaily (July 12, 2011) — Siblings of people with autism show a similar pattern of brain activity to that seen in people with autism when looking at emotional facial expressions. Researchers at the University of Cambridge identified the reduced activity in a part of the brain associated with empathy and argue it may be a 'biomarker' for a familial risk of autism.

Dr Michael Spencer, who led the study from the University's Autism Research Centre, said: "The findings provide a springboard to investigate what specific genes are associated with this biomarker. The brain's response to facial emotion could be a fundamental building block in causing autism and its associated difficulties."

The Medical Research Council funded study is published on the 12th of July, in the journal Translational Psychiatry.

Previous research has found that people with autism often struggle to read people's emotions and that their brains process emotional facial expressions differently to people without autism. However, this is the first time scientists have found siblings of individuals with autism have a similar reduction in brain activity when viewing others' emotions.

In one of the largest functional MRI (fMRI) studies
of autism ever conducted, the researchers studied 40 families who had both a teenager with autism and a sibling without autism. Additionally, they recruited 40 teenagers with no family history of autism. The 120 participants were given fMRI scans while viewing a series of photographs of faces which were either neutral or expressing an emotion such as happiness. By comparing the brain's activity when viewing a happy verses a neutral face, the scientists were able to observe the areas within the brain that respond to this emotion.

Despite the fact that the siblings of those with autism did not have a diagnosis of autism or Asperger syndrome, they had decreased activity in various areas of the brain (including those associated with empathy, understanding others' emotions and processing information from faces) compared to those with no family history of autism. The scans of those with autism revealed that the same areas of the brain as their siblings were also underactive, but to a greater degree. (These brain regions included the temporal poles, the superior temporal sulcus, the superior frontal gyrus, the dorsomedial prefrontal cortex and the fusiform face area.)

Because the siblings without autism and the controls differed only in terms of the siblings having a family history of autism, the brain activity differences can be attributed to the same genes that give the sibling their genetic risk for autism.

Explaining why only one of the siblings might develop autism when both have the same biomarker, Dr Spencer said: "It is likely that in the sibling who develops autism additional as yet unknown steps -- such as further genetic, brain structure or function differences -- take place to cause autism."

It is known that in a family where one child already has autism, the chances of a subsequent child developing autism are at least 20 times higher than in the general population. The reason for the enhanced risk, and the reason why two siblings can be so differently affected, are key unresolved questions in the field of autism research, and Dr Spencer's group's findings begin to shed light on these fundamental questions.

Professor Chris Kennard, chairman of the Medical Research Council funding board for the research, said: "This is the first time that a brain response to different human facial emotions has been shown to have similarities in people with autism and their unaffected brothers and sisters. Innovative research like this improves our fundamental understanding of how autism is passed through generations affecting some and not others. This is an important contribution to the Medical Research Council's strategy to use sophisticated techniques to uncover underpinning brain processes, to understand predispositions for disease, and to target treatments to the subtypes of complex disorders such as autism."