A proof of concept 'phase zero' study of neurodevelopment using brain organoid models with Vis/near-infrared spectroscopy and electrophysiology

Sci Rep. 2020 Dec 2;10(1):20987. doi: 10.1038/s41598-020-77929-8.

Abstract

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 development, 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 with studying 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 (chi-square (2, N = 10) = 20, p = 4.5400e-05), and spectral exponent between 30-50 Hz (chi-square (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 (chi-square (3, N = 10) = 25.44, p = 1.2492e-05), spectral exponent between 1 and 20 Hz (chi-square (3, N = 16) = 43.5, p = 1.9273e-09) and 30-50 Hz (chi-square (3, N = 16) = 23.47, p = 3.2148e-05) in 34 days old CO from schizophrenia (SCZ) patients iPSC. We present the feasibility of a multimodal approach, combining electrophysiology and broadband Vis-NIR spectroscopy, to monitor neurodevelopment in brain organoid models that can complement traditional drug design approaches to test clinically meaningful hypotheses.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acetylcarnitine / pharmacology
  • Brain / cytology
  • Brain / drug effects
  • Brain / growth & development*
  • Brain / physiology
  • Case-Control Studies
  • Cell Line
  • Choline / pharmacology
  • Electron Transport Complex IV / metabolism
  • Electrophysiology
  • Female
  • Humans
  • Induced Pluripotent Stem Cells / cytology
  • Induced Pluripotent Stem Cells / metabolism
  • Male
  • Mitochondria / metabolism
  • Organoids / drug effects
  • Organoids / growth & development*
  • Organoids / physiology
  • Proof of Concept Study
  • Schizophrenia / metabolism
  • Spectroscopy, Near-Infrared
  • Thioctic Acid / pharmacology
  • Ubiquinone / analogs & derivatives
  • Ubiquinone / pharmacology

Substances

  • Ubiquinone
  • Acetylcarnitine
  • Thioctic Acid
  • Electron Transport Complex IV
  • idebenone
  • Choline