Biological neuronal cells communicate using neurochemistry and electrical signals. The same phenomena also allow us to probe and manipulate neuronal systems and communicate with them. Neuronal system malfunctions cause a multitude of symptoms and functional deficiencies that can be assessed and sometimes alleviated by electrical stimulation. Our working hypothesis is that real-time closed-loop full-duplex measurement and stimulation paradigms can provide more in-depth insight into neuronal networks and enhance our capability to control diseases of the nervous system. In this study, we review extracellular electrical stimulation methods used in in vivo, in vitro, and in silico neuroscience research and in the clinic (excluding methods mainly aimed at neuronal growth and other similar effects) and highlight the potential of closed-loop measurement and stimulation systems. A multitude of electrical stimulation and measurement-based methods are widely used in research and the clinic. Closed-loop methods have been proposed, and some are used in the clinic. However, closed-loop systems utilizing more complex measurement analysis and adaptive stimulation systems, such as artificial intelligence systems connected to biological neuronal systems, do not yet exist. Our review promotes the research and development of intelligent paradigms aimed at meaningful communications between neuronal and information and communications technology systems, “dialogical paradigms,” which have the potential to take neuroscience and clinical methods to a new level.

"Regenerative medicine is a promising branch of health science that aims at restoring the physiological function of organs of the human body by rebuilding or replacing the affected areas when canonical treatments have failed. Despite encouraging results, repairing a dysfunctional brain is one of the hardest challenges in health research.

HERMES pursues the long-term vision of healing disabling brain disorders by means of brain tissue transplants, a reality that is only possible to date for other organs of the human body.

The HERMES consortium is joining their efforts to establish a new paradigm in regenerative medicine, aiming at overcoming the biological uncertainty inherent to it. This paradigm is named enhanced regenerative medicine and it is rooted in the establishment of biohybrid neuronics (neural electronics), that is the symbiotic integration of bioengineered brain tissue, neuromorphic microelectronics and artificial intelligence."

HERMES is funded from the European Union's Horizon 2020 Research and Innovation Programme under grant agreement No. 824164.

This chapter provides an overview of the current stage of human in vitro functional neuronal cultures, their biological application areas, and modalities to analyze their behavior. During the last 10 years, this research area has changed from being practically non-existent to one that is facing high expectations. Here, we present a case study as a comprehensive short history of this process based on extensive studies conducted at NeuroGroup (University of Tampere) and Computational Biophysics and Imaging Group (Tampere University of Technology), ranging from the differentiation and culturing of human pluripotent stem cell (hPSC)-derived neuronal networks to their electrophysiological analysis. After an introduction to neuronal differentiation in hPSCs, we review our work on their functionality and approaches for extending cultures from 2D to 3D systems. Thereafter, we discuss our target applications in neuronal developmental modeling, toxicology, drug screening, and disease modeling. The development of signal analysis methods was required due to the unique functional and developmental properties of hPSC-derived neuronal cells and networks, which separate them from their much-used rodent counterparts. Accordingly, a line of microelectrode array (MEA) signal analysis methods was developed. This work included the development of action potential spike detection methods, entropy-based methods and additional methods for burst detection and quantification, joint analysis of spikes and bursts to analyze the spike waveform compositions of bursts, assessment methods for network synchronization, and computational simulations of synapses and neuronal networks.