Effects of Noninvasive Brain Stimulation on the Developing Brain - Abstract The brain is structured by experiences through a process called neuroplasticity. Neuroplasticity is highest in early life, during the phase of rapid brain growth. During this growth spurt period, the brain is also exceedingly vulnerable to toxicity of environmental influences. Hypoxia, trauma, infections, medications that influence activity levels of neuronal networks can trigger cell death, and impair the formation of new cells (neurogenesis) and neuronal connections. This period in humans expands from the third trimester of pregnancy to the 3rd year of life. Noninvasive brain stimulation (NIBS), in particular transcranial direct current (tDCS) stimulation, is increasingly being used to promote neuroplasticity and repair in the human brain. tDCS has been used in clinical trials in adults and children. Substantial benefits have been demonstrated in the treatment of neurologic and psychiatric disorders in different age groups. tDCS is considered safe and well tolerated. Utilization of NIBS interventions in infancy and early childhood may bear the greatest potential for improving neurologic and neurocognitive outcomes, given the enormous ability of the brain to reorganize at that stage. But, we do not know whether tDCS can be safely administered to infants and young children. Research in animal models on the potential toxic effect of NIBS on very young brains, in particular during the brain growth spurt period, has been very limited. Thus, there are justified concerns that modulation of brain activity at that stage might be harmful. These concerns pose ethical barriers to clinical trials utilizing tDCS and other NIBS interventions in infancy and early childhood. Consequently, there is a great need for preclinical research in appropriate animal models that will explore toxic thresholds of NIBS in developing brains. Here we propose to investigate the nature of and the thresholds for neurotoxic, gliotoxic, and neuroinflammatory effects of tDCS in developing guinea pigs. We will use guinea pigs at ages 1-30 days, which is considered the age equivalent of 10-30-month-old humans. We hypothesize that (a) tDCS will cause dose-dependent toxicity and neuroinflammation in infant guinea pig brains and (b) thresholds for neurotoxic and neuroinflammatory responses to tDCS will increase as the brain matures. To address these hypotheses, we will first expose 1-day- old guinea pigs to 5 serial daily sessions of tDCS at different current intensities and will computationally model generated electrical fields using head and brain models generated from MR- and micro-CT images. To identify toxic thresholds at this age, we will analyze the brains for signs of cell death, alterations of dendritic morphology and inflammation at different stimulation current intensities. We will then investigate toxic thresholds of tDCS at different ages. For that, we will perform experiments on 15 and 30-day-old guinea pigs. Using computational modeling at each age, we will be able to determine whether and how the vulnerability of brain tissue to comparable electrical fields changes as the animals mature. These studies will generate valuable knowledge which will help define tDCS doses that are safe to use in infants and young children.
