Abstract
Biological treatment development for syndromal neuropsychiatric conditions such as autism has seen slow progress for decades. Speeding drug discovery may result from the judicious development and application of biomarker measures of brain function to select patients for clinical trials, to confirm target engagement and to optimize drug dose. For neurodevelopmental disorders, electrophysiology (EEG) offers considerable promise because of its ability to monitor brain activity with high temporal resolution and its more ready application for pediatric populations relative to MRI. Here, we discuss conceptual/definitional issues related to biomarker development, discuss practical implementation issues, and suggest preliminary guidelines for validating EEG approaches as biomarkers with a context of use in neurodevelopmental disorder drug development.
Highlights
Pressing needs in clinical care and concerns about low-yield clinical trials in neurodevelopmental disabilities (NDD) have increased enthusiasm for brain-based biomarkers, with particular additional challenges in neurodevelopmental disorders (NDD) (Sahin et al, 2018)
The last few decades have made clear that there is poor correspondence across levels of analyses in behaviorally defined NDD (“degeneracy”): patients with a particular genotype may have a range of behavioral phenotypes as in Fragile X syndrome (FXS), and a single behaviorally defined diagnosis [e.g., autism spectrum disorder (ASD)] may be caused by a range of genetic alterations (e.g., Angelman, tuberous sclerosis, FXS, multiple risk loci)
A generalized tonic-clonic seizure (GTC) may result either from seizure activity arising in the brain all at once, or seizure activity arising from one spot in the brain and spreading quickly across the brain; different medications are effective for each type
Summary
Pressing needs in clinical care and concerns about low-yield clinical trials in neurodevelopmental disabilities (NDD) have increased enthusiasm for brain-based biomarkers, with particular additional challenges in neurodevelopmental disorders (NDD) (Sahin et al, 2018). The current push for biomarker development in the realm of brain disorders follows on the heels of several wellknown failures in clinical trials in genetically more homogeneous disorders (Berry-Kravis et al, 2012; Hagerman et al, 2018). While there is high enthusiasm for biomarkers for NDDs, the field is just at the beginning of establishing utility of biomarkers for guiding selection of therapies and the patients most likely to benefit in clinical trials. The aims of this paper are to help guide early-phase efforts in this area by providing a conceptual framework for planning biomarker validation research, suggestions for early phase investigation strategy and an early framework of thresholds for determining successful reliability/validation, and to explore issues specific to the use of EEG
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