Trigeminal Nerve Stimulation for Prenatal Alcohol Exposure

ABSTRACT/SUMMARY Prenatal alcohol exposure (PAE) is a severe, life-long neurodevelopmental disorder. It afflicts hundreds of thousands of children in the US and worldwide. The highly distressing, disruptive, and disabling behavioral symptoms of PAE include inattention, hyperactivity, and executive dysfunction, symptoms that overlap with

those of attention deficit hyperactivity disorder (ADHD). In ADHD, these symptoms are treated routinely with stimulant medications. But children with PAE often fail to respond to stimulants, or to any therapy. There has long been, therefore, a pressing need for new treatments for PAE. This R61/R33 proposal is about one

prospective way to meet that need. Recently, it was demonstrated at UCLA that trigeminal nerve stimulation (TNS) is safe and effective in treating pediatric ADHD. TNS is a low-current neurostimulatory therapy that is noninvasive, minimal-risk, and now FDA-cleared. Given the similarities PAE has with ADHD, there is a very

good (though not 100%) chance that PAE would respond to TNS as well. But, to our knowledge, TNS has never been tested systematically in children with PAE. Here we propose the first clinical trial of TNS for PAE. The R61 (pilot) phase will determine whether TNS is feasible for PAE: Do children with PAE comply with the

TNS procedure? Does TNS have any any serious side effects in these children? Is there an indication that TNS relieves symptoms of PAE? If the pilot shows feasibility, as we expect it will, in the ensuing R33 phase we will conduct a formal double-blind sham-controlled randomized clinical trial to determine rigorously whether

TNS is truly efficacious for PAE. If it is, the impact could be enormous. TNS could bring much needed relief to children with PAE and their families everywhere. Our proposal will furthermore address the need to understand the brain mechanisms by which TNS works, which are underexplored and largely unknown. The few studies

done to date point to three major candidate brain regions where TNS may exercise its therapeutic effects. All three are regions where we, in prior work, detected differences between children with PAE and typically

developing children in tissue properties (“endpoints”) measured using multiple different varieties (“modalities”) of brain MRI. These findings raise our confidence that TNS will be effective for PAE, i.e., if the brain regions that produce PAE symptoms are the same as those acted upon by TNS, maybe TNS will quell those

symptoms. In both phases of this clinical trial we will measure the same endpoints with the same modalities of brain MRI in children with PAE before and after TNS treatment. We will determine whether these endpoints are changed by TNS (target engagement) and/or predict TNS clinical response (prognostic marker) in individual

patients in the three candidate regions or elsewhere in the brain. If successful, this proposal will help meet a long-standing urgent need for novel treatments for PAE and will help clarify the currently mysterious brain mechanisms of an emerging pediatric neurostimulatory therapy.