Ryan Ash, M.D., Ph.D.

Instructor, Stanford University

SFARI Bridge to Independence Fellow

Ryan Thomas Ash is an instructor in the Department of Psychiatry and Behavioral Sciences at Stanford University. He studied cortical circuit dysfunction in autism while completing his M.D./Ph.D. at the Baylor University College of Medicine and postdoc at Harvard Medical School, where he was mentored by Stelios Smirnakis and Huda Zoghbi. Ash found evidence for abnormally increased stability of cortical circuits in the MECP2 duplication syndrome mouse model of autism, first at the level of synaptic connections during his doctorate, and then at the level of neuronal population activity during his postdoc. This work suggests that increased neural circuit stability could contribute to behavioral inflexibility in patients with autism. He then completed the research track psychiatry residency program and T32 Biobehavioral Research Fellowship at Stanford University. He has a K08 Career Development Award to investigate how attentional state regulates the neuroplasticity induced by repetitive transcranial magnetic stimulation. He was awarded the 2022 Brain & Behavior Research Foundation (BBRF) Young Investigator Award to develop in-human applications of ultrasound stimulation in the visual system and fear regulation circuit. As a SFARI Bridge to Independence Fellow,he hopes to integrate ultrasound neuromodulation and noninvasive electrophysiology to implement closed-loop noninvasive deep brain stimulation as a tool to modulate behavioral flexibility-related circuits in autism.

Project: Noninvasive focal closed-loop deep brain neuromodulation with transcranial ultrasound and source-localized electroencephalography for the treatment of behavioral inflexibility in autism

The debilitating behavioral rigidity and insistence on sameness in autism are hypothesized to arise from dysfunction in excitatory-inhibitory balance of corticostriatal-thalamic circuits. The goal of this proposal is to develop a noninvasive closed-loop method to focally upregulate or downregulate neural activity in deep brain areas as a novel brain stimulation therapy for autism. I will combine two emerging technologies for noninvasive stimulation and recording in the human central nervous system: transcranial ultrasound stimulation (TUS) and high-density MRI-source-localized electroencephalography (source-EEG). TUS is a promising novel method to focally modulate deep brain circuits via the focusing of steerable ultrasound waves through the scalp and skull. Source-EEG harnesses computational and hardware advances to enable targeted human electrophysiology at 1–2 cm spatial resolution, providing a tool to quantify the neurophysiological effect of TUS and update stimulation parameters in real time. This closed-loop neuromodulation system will be implemented to test the hypothesis that normalization of corticostriatal circuit homeostasis will ameliorate behavioral inflexibility in autism. This work could lead to the first neural-circuit-level treatment for behavioral inflexibility in autism, that is more targeted than medications with fewer side effects, avoids invasive neurosurgery, and augments the efficacy of occupational therapy, the standard-of-care for behavioral inflexibility.

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