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Autism and other neurodevelopmental disorders often aren\u2019t diagnosed until a child is a few years of age, when behavioral interventions and speech\/occupational therapy become less effective. But new research this week in PNAS<\/i><\/a> suggests that two simple, quantifiable measures \u2014 spontaneous fluctuations in pupil dilation or heart rate \u2014 could enable much earlier diagnosis of Rett syndrome and possibly other disorders with autism-like features. <\/p>\n The study, led by Boston Children\u2019s Hospital neuroscientist Michela Fagiolini, PhD<\/a>, and postdoctoral fellow Pietro Artoni, PhD, unveils a machine-learning algorithm that can spot abnormalities in pupil dilation that are predictive of autism spectrum disorder (ASD) in mouse models. It further shows that the algorithm can accurately detect if a girl has Rett syndrome, a genetic disorder that impairs cognitive, sensory, motor, and autonomic function, as well as autism-like behaviors.<\/p>\n Fagiolini and colleagues hope this system could provide an early warning signal not just for Rett syndrome but for ASD in general. In the future, they believe it could also be used to monitor patients\u2019 responses to treatments; currently, a clinical trial is testing the drug ketamine for Rett syndrome, and a gene therapy trial is planned. <\/p>\n \u201cWe want to have some readout of what\u2019s going on in the brain that is quantitative, objective, and sensitive to subtle changes,\u201d says Fagiolini. \u201cMore broadly, we are lacking biomarkers that are reflective of brain activity, easy to quantify, and not biased. A machine could measure a biomarker and not be affected by subjective interpretations of how a patient is doing.\u201d<\/p>\n <\/strong><\/p>\n Fagiolini and Artoni, in close collaboration with Takao Hensch, PhD<\/a>, and Charles Nelson, PhD<\/a>, at Boston Children\u2019s, began with the idea that people on the autism spectrum have altered behavioral states. Prior evidence indicates that the brain\u2019s cholinergic circuits, which are involved in arousal, are especially perturbed, and that altered arousal affects both spontaneous pupil dilation\/constriction and heart rate.<\/p>\n Fagiolini\u2019s team, supported by the IRCN at Boston Children\u2019s F.M. Kirby Neurobiology Center, set out to measure pupil fluctuations in several mouse models of ASD, including mice with the mutations causing Rett syndrome or CDKL5 disorder, as well as BTBR mice. Spontaneous pupil dilation and constriction were altered even before the animals began showing ASD-like symptoms, the team found. <\/p>\n Moreover, in mice lacking MeCP2<\/i>, the gene mutated in Rett syndrome, restoring a normal copy of the gene, in cholinergic brain circuits only, prevented the onset of pupillary abnormalities as well as behavioral symptoms.<\/p>\n <\/strong><\/p>\n To systematically link the observed arousal changes to the cholinergic system, the team took advantage of an earlier discovery by Hensch: mice lacking the LYNX1 protein exhibit enhanced cholinergic signaling. Based on about 60 hours of observation of these mice, the investigators \u201ctrained\u201d a deep learning algorithm to recognize abnormal pupillary patterns. The same algorithm accurately estimated cholinergic dysfunction in the BTBR, CDKL5, and MeCP2-deficient mice.<\/p>\n \"Pupil dilation and heart rate fluctuate in a similar way because they are proxies of autonomic arousal \u2014 the \u2018fight or flight\u2019 response.\"<\/i><\/span><\/p>\n The team then brought this algorithm to 35 young girls with Rett syndrome and 40 typically developing controls. Instead of measuring the girls\u2019 pupils (as patients may fidget), they used heart rate fluctuations as the measure of arousal. The algorithm nonetheless successfully identified the girls with Rett, with an accuracy of 80 percent in the first and second year of life. <\/p>\n \u201cThese two biomarkers fluctuate in a similar way because they are proxies of the activity of autonomic arousal,\u201d says Artoni. \u201cIt is the so-called \u2018fight or flight response.\u201d <\/p>\n Autonomic arousal, a property of the brain that is strongly preserved across different species, is a robust indicator of an altered developmental trajectory, Fagiolini and Artoni found.<\/p>\n <\/strong><\/p>\n![\"\"](\"http:\/\/ircn.jp\/wp-content\/uploads\/2019\/07\/Michela_Fagiolini.jpg\")
Altered arousal in autism<\/span><\/h2>\n
Predicting Rett syndrome in girls<\/span><\/h2>\n
Biomarkers for babies?<\/span><\/h2>\n
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