Preventing PMS Regressions Through Non-Invasive Neuromodulation

Phelan-McDermid Syndrome (PMS) is a rare genetic disorder most often caused by mutations or deletions in the SHANK3 gene. It is associated with developmental delays, intellectual disability, motor difficulties, and frequent loss of previously acquired skills. Many individuals with PMS also go on to develop serious neuropsychiatric conditions, such as catatonia, psychosis, or bipolar disorder, during adolescence or early adulthood. The SHANK3 gene plays a key role in maintaining healthy brain connections and supporting brain plasticity, which may help explain the wide range of symptoms seen in PMS. Currently, there is no cure for PMS. Existing treatments focus on managing symptoms with therapies and medications. Recent research has begun exploring transcranial direct current stimulation (tDCS), a non-invasive method that uses gentle electrical currents to influence brain activity and boost brain plasticity. Preliminary results from our previous Seed grant showed that a single tDCS session targeting the sensory cortex can temporarily change how the brain responds to touch in a mouse model of PMS. This project builds on those findings by applying tDCS during early development, a period when the brain is especially flexible and responsive to change. Our goal is to test whether early treatment can lead to more lasting improvements in brain function and lower the risk of both developmental regression and future psychiatric symptoms. To this aim, we will use advanced brain imaging, behavioral assessments, and neural circuit analysis in a PMS mouse model. With the proposed study, we will uncover the therapeutic potential of non-invasive cortical manipulation in PMS by understanding the mechanisms leading to behavioral recovery. Because tDCS is safe, painless, and well-tolerated—even in children—this research could lay the groundwork for quickly translating non-invasive brain stimulation into a promising new therapy for PMS.