A growing body of evidence from genetic and cell studies indicates that autism spectrum disorders (ASDs) result from abnormalities in how neurons connect to each other to establish brain circuitry. Striking MRI images taken at Children’s Hospital Boston, published in the January Academic Radiology, now strengthen this case visually.
Children’s neurologist-neuroscientist Mustafa Sahin, Simon Warfield, director of the hospital’s Computational Radiology Laboratory, and Jurriaan Peters compared brain organization in 29 healthy subjects with that in 40 patients with tuberous sclerosis, a rare genetic syndrome 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.
The panels above (click to enlarge) are advanced MRI images from the corpus callosum, showing bundles of nerve fibers, or axons. The leftmost images are from a healthy subject; the middle images from an age-matched patient with tuberous sclerosis (TS); the right images from a patient with both TS and autism. They represent a relatively new MRI technique called Diffusion Tensor Imaging, which traces the pathways of nerve fibers by measuring the diffusion of water in the brain.
The images exemplify a general trend: While the 29 healthy subjects’ axons followed well-defined directions in organized bundles, axons of the 12 patients with both TS and ASDs tended not to orient together in common directions, referred to in computational terms as having lower fractional anisotropy. Patients with TS alone – like the middle one above — showed only slight axon disorganization compared to controls.
The study also revealed defects in myelin — the fatty, insulating coating that helps nerve fibers conduct signals and that makes up the brain’s white matter. In general, compared with controls, patients with TS had greater water diffusion out of (perpendicular to) the axons, indicating that their myelin coating and white matter was compromised. This diffusivity was greatest in patients with both TS and ASDs.
These studies in the corpus callosum, which acts as a highway transferring signals between the brain’s left and right cerebral hemispheres, add to previous human imaging studies by Sahin and Warfield showing similar differences in the tracts that carry information from the thalamus to the visual cortex (below). They’re also 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 cognition.
The findings also jive with Sahin’s data from mouse models of TS. The animals’ neurons grew multiple axons (where they should grow just one), causing too many connections being made. Axons originating in the retina has less myelination, failed to land in the right places in the brain and didn’t respond to navigation cues.
And here’s the real power of studying autism-related genetic disorders like TS. Sahin’s lab showed in their mice that the defects in neurons and axons arise from a biological pathway that can actually be reversed, using the drug rapamycin.
So now, Sahin is enrolling patients in a clinical trial to test whether Afinitor (a rapamycin-like drug) can improve measures of cognition and autism in children and young adults with TS. And that’s a great example of a genetic disorder leading the way toward drug treatment to improve a cognitive/behavioral condition – guided by neuroimaging findings.
“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. Recent advances are revealing nuances in brain development that aren’t readily seen on conventional imaging, he adds.
“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,” says Sahin. “This may have implications for autism in patients without tuberous sclerosis as well.”