Abstract
Pharmacological options for neurodevelopmental disorders are limited to symptom suppressing agents that do not target underlying pathophysiological mechanisms. Studies on specific genetic disorders causing neurodevelopmental disorders have elucidated pathophysiological mechanisms to develop more rational treatments. Here, we present our concerted multi-level strategy ‘BRAINMODEL’, focusing on excitation/inhibition ratio homeostasis across different levels of neuroscientific interrogation. The aim is to develop personalized treatment strategies by linking iPSC-based models and novel EEG measurements to patient report outcome measures in individual patients. We focus our strategy on chromatin- and SNAREopathies as examples of severe genetic neurodevelopmental disorders with an unmet need for rational interventions.
Highlights
We could use long-range temporal correlations (LRTC) to estimate excitatory and inhibitory inputs (E/I) ratios leading to a functional E/I measure (Figure 4E–G)
We have recently investigated how sensory reactivity problems, recently added as a core domain element for ASD in the DSM, may extend into problematic behavior or affective dysregulation and how disturbed E/I ratio homeostasis may be translated into clinical readout measures [63]
This resulted in the Patient Reported Outcome Measures (PROMs) for the repeated and reliable measurement of patient-relevant consequences of sensory reactivity alterations [63] that we developed by following the FDA steps for PROM for clinical trials [66,67]
Summary
There is a need for mechanism-based therapeutic options to remedy the life-long suffering of patients and caregivers often associated with NDDs. The identification of risk genes for NDDs provides new starting points for mechanismbased therapies. We put forward that induced stem-cell stem-cell (iPSC)-based modelsnew provide new opportunities for translatability of E/Itoratios (iPSC)-based models provide opportunities for translatability of E/I ratios netto network activity homeostasis as proposed by BRAINMODEL. This project is conducted work activity homeostasis as proposed by BRAINMODEL. E/I targeting treatments through the linkingthe iPSC-based models, EEG data, develop personalized through linking iPSC-based models, and assessments patients with formswith of genetic.
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