Care of individuals with neurodevelopmental disorders is undergoing a transformative change. With advances in genetics and neuroscience, we are moving from being a field of observation and description alone to developing mechanism-based treatments and even prevention. However, several mechanism-based studies in genetically defined neurodevelopmental disorders (NDDs) such as Fragile X, Tuberous Sclerosis and Rett Syndrome have failed to reach the predefined efficacy endpoints despite promise in animal models. Given this recent history of failed clinical trials, there is an urgent need to develop and validate biomarkers in order to accelerate progress in future trials. These are needed to track drug effects on brain systems directly in order to solidify translational models, establish effect on the target organ (brain), determine whether there are subgroups of patients more likely to respond to a novel treatment, and potentially to optimize dosing. Some of the biomarkers include electrophysiological (e.g., EEG, MEG, event related potentials), functional (e.g., eye tracking, pupillometry, transcranial magnetic stimulation (TMS), neurocognitive measures, continuous monitoring/wearable sensors), imaging (structural and functional) and molecular biomarkers.

There are several challenges for validating novel biomarkers for NDDs. First, many potential biomarkers change with development; thus, it will be critical to understand the developmental trajectories of these measures to apply them in a trials context. Second, the neurodevelopmental disorders under consideration are primarily rare genetic diseases. Therefore, limited patient populations will likely require multi-site clinical biomarker studies, which increases the need for rigorous data/acquisition standards, portability, feasibility, and reproducibility across sites. Third, there is a need to understand the fundamental biology underlying these markers and how these biomarkers correlate with disease onset, severity and/or response to treatment, and how similar these mechanisms and effects are to those in animal models. Multi-disciplinary efforts that encompass investigators with basic neuroscience, genetics, imaging, electrophysiology, data science and clinical trial expertise may be necessary to overcome these challenges.

In this Research Topic, we will highlight basic, translational and clinical research studies that investigate a broad range of biomarkers with potential utility for translational drug development programs for neurodevelopmental disorders across the life span.

Keywords: autism, clinical trials, EEG, MRI, imaging

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