Model-based investigation of elasticity and spectral exponent from atomic force microscopy and electrophysiology in normal versus Schizophrenia human cerebral organoids

The physiological origin of the aperiodic signal present in the electrophysiological recordings, called l/f neural noise, is unknown; nevertheless, it has been associated with health and disease. The power spectrum slope, $-\alpha$ in $1/\mathrm{f}^{\alpha}$ , has been postulated to be related to the dynamic balance between excitation (E) and inhibition (I). Our study found that human cerebral organoids grown from induced pluripotent stem cells (iPSCs) from Schizophrenia patients (SCZ) showed structural changes associated with altered elasticity compared to that of the normal cerebral organoids. Furthermore, mitochondrial drugs modulated the elasticity in SCZ that was found related to the changes in the spectral exponent. Therefore, we developed an electro-mechanical model that related the microtubular-actin tensegrity structure to the elasticity and the $1/\mathrm f^\alpha$ noise. Model-based analysis showed that a decrease in the number and length of the constitutive elements in the tensegrity structure decreased its elasticity and made the spectral exponent more negative while thermal white noise will make $\alpha=0$ .. Based on the microtubularactin model and the cross-talk in structural (elasticity) and functional (electrophysiology) response, aberrant mitochondrial dynamics in SCZ are postulated to be related to the deficits in mitochondrial-cytoskeletal interactions for long-range transport of mitochondria to support synaptic activity for E/I balance. Clinical Relevance—Our experimental data and modeling present a structure-function relationship between mechanical elasticity and electrophysiology of human cerebral organoids that differentiated SCZ patients from normal controls.