‘Phase Zero’ clinical study platform combining broadband Vis/near-infrared spectroscopy and electrophysiology to study human brain organoid models of neurodevelopmental disorders

Homeostatic control of neuronal excitability by modulation of synaptic inhibition (I) and excitation (E) of the principal neurons is important during brain maturation. The fundamental features of in-utero brain developmental, including local synaptic E-I ratio and bioenergetics, can be modeled by cerebral organoids (CO) that have exhibited highly regular nested oscillatory network events. Therefore, we evaluated a ‘Phase Zero’ clinical study platform combining broadband Vis/near-infrared(NIR) spectroscopy and electrophysiology to study E-I ratio based on the spectral exponent of local field potentials and bioenergetics based on the activity of mitochondrial Cytochrome-C Oxidase (CCO). We found a significant effect of the age of the healthy controls iPSC CO from 23 days to 3 months on the CCO activity (χ 2 (2,N=10)=20,p=4.5400e-05), and spectral exponent between 30–50Hz (χ 2 (2,N=16)=13.88,p=0.001). Also, a significant effect of drugs, choline (CHO), idebenone (IDB), R-alpha-lipoic acid plus acetyl-L-carnitine (LCLA), was found on the CCO activity (χ 2 (3,N=10)=25.44,p = 1.2492e-05), spectral exponent between 1–20Hz (χ 2 (3,N=16)=43.5,p=1.9273e-09) and 30–50Hz (χ 2 (3,N=16)=23.47, p=3.2148e-05) in 34 days old CO from schizophrenia (SCZ) patients iPSC. We present a multidimensional approach combining electrophysiology and Vis-NIR spectroscopy to complement traditional drug design approaches that can advance the system towards a normative parameter space.