According to the Centers for Disease Control and Prevention (CDC), traumatic brain injury (TBI) is the leading cause of loss of consciousness, long-term disability, and death in children and young adults (age 1 to 44). Currently, there are no United States Food and Drug Administration (FDA) approved pharmacological treatments for post-TBI regeneration and recovery, particularly related to permanent disability and level of consciousness. In some cases, long-term disorders of consciousness (DoC) exist, including the vegetative state/unresponsive wakefulness syndrome (VS/UWS) characterized by the exhibition of reflexive behaviors only or a minimally conscious state (MCS) with few purposeful movements and reflexive behaviors. Electroceuticals, including non-invasive brain stimulation (NIBS), vagus nerve stimulation (VNS), and deep brain stimulation (DBS) have proved efficacious in some patients with TBI and DoC. In this review, we examine how electroceuticals have improved our understanding of the neuroanatomy of consciousness. However, the level of improvements in general arousal or basic bodily and visual pursuit that constitute clinically meaningful recovery on the Coma Recovery Scale-Revised (CRS-R) remain undefined. Nevertheless, these advancements demonstrate the importance of the vagal nerve, thalamus, reticular activating system, and cortico-striatal-thalamic-cortical loop in the process of consciousness recovery.

In the central nervous system, the neuropeptide oxytocin stimulates neural networks that regulate social behaviors, including social attachment, aggression, and complex social cognition. Perturbations in oxytocin and/or oxytocin receptor expression results in social behavioral deficits and are associated with a number of psychopathologies including autism spectrum disorder, schizophrenia, anxiety, and depression. In rodent models of autism spectrum disorder, oxytocin is effective at improving social behavior. However, limited translatability between animal models and human physiology has hindered successful translation of these findings into human therapeutics. Oxytocin variant-induced cellular signaling pathways and G-protein coupling have largely been investigated in HEK and CHO heterologous expression systems; however, cellular context is crucial, and these profiles likely differ from intact neurons. This project assessed oxytocin variants in in vitro human-derived neuron-like SH-SY5Y cells that endogenously express the oxytocin receptor. Results demonstrated that the naturally occurring oxytocin variants Leu⁸-OT, Pro⁸-OT and Val³-Pro⁸-OT activated intracellular signaling pathways and promoted neuronal differentiation-associated responses, including calcium mobilization, membrane hyperpolarization, and neurite outgrowth in a concentration-dependent manner. Knowledge of how oxytocin variants alter cellular structure and function has the potential to both identify mechanisms that produce social dysfunction and to inform the development of therapeutic agents.