Neurodevelopmental disorders (NDDs) significantly impact both patients and their caregivers, resulting in substantial suffering. The heterogeneity of these disorders ranges from mild developmental delays to severe conditions such as epilepsy and autism. Unfortunately, current treatments are predominantly symptomatic, often relying on medications that merely suppress symptoms, with varying efficacy even within the same disorder.

To expedite therapy development, we need a fresh perspective that embraces this clinical diversity. This approach can pave the way for mechanism-based therapies that are applicable across a wide range of NDDs, as they are not tied to any specific disorder. We propose that energy metabolism could act as a unifying mechanism with therapeutic implications for various NDDs. This is especially pertinent when considering the effects of environmental stressors, such as inflammation, which can disrupt the balance between excitatory and inhibitory inputs in neuronal networks during critical postnatal stages.

Our hypothesis centers on the notion that both genetic and environmental factors may lead to underlying disturbances in energy metabolism - processes that are meticulously regulated in the brain. Disruptions caused by gene mutations or environmental insults can adversely affect neuronal health and function. By leveraging quantitative EEG, we aim to track metabolic changes in NDDs, thus enhancing our understanding of their heterogeneity. We have developed advanced markers of excitation/inhibition (E/I) balance, which we have successfully implemented in precision trials. Furthermore, we are innovating methods to directly link EEG findings to measures of energy expenditure. In this context, we are also testing novel energy-boosting therapies, utilizing ecological measures of fatigue and sensory reactivity to assess their efficacy.

Through comprehensive investigation of energy metabolism at both clinical (using EEG) and preclinical levels (with pluripotent stem cell models), we strive to gather deeper insights into NDD heterogeneity. Our research endeavors aim to generate substantial preclinical evidence that will inform future personalized treatment strategies. With the combined expertise of our NDD brain energy group, we are committed to maximizing potential benefits for patients and improving their quality of life.