Ryan Ash, MD, PhD

Preprint investigating the empirical limitations of computational platforms used to simulate low-intensity focused ultrasound delivery in human subjects.

We optimized MR acoustic radiation force imaging (MR-ARFI) for human transcranial focused ultrasound applications, demonstrating improved methods for measuring the in situ focus location and intensity in individual human participants to guide and validate FUS targeting.

We targeted transcranial ultrasound stimulation (TUS) to the lateral geniculate nucleus (visual thalamus) in sheep. Light-flash EEG visual evoked potentials were reversibly suppressed by TUS; MR-ARFI confirmed targeting and predicted the suppressive effect, establishing a translational pipeline for human subcortical FUS neuromodulation.

We measured the plasticity-inducing effect of repetitive contrast-reversal-sweep steady-state visual-evoked potential (ssVEP) stimuli. No significant neuroplastic changes were observed, but steady-state VEP contrast-sweep responses showed high within-participant stability (CV 15–25%), well suited for repeated-measures longitudinal studies.

We report evidence for abnormally increased reliability of visual-evoked responses in layer 2/3 neurons of adult primary visual cortex in the MECP2-duplication syndrome animal model of autism, suggesting that increased neural circuit stability contributes to behavioral inflexibility in autism.

We found that trametinib, an MEK inhibitor, reversed both the abnormal stabilization of dendritic spine clusters and the enhanced motor learning phenotype in MECP2-duplication mice, identifying Ras-MAPK signaling as a therapeutic target for the excessive circuit stability that may drive behavioral inflexibility in autism.

We report excessive formation and abnormal stabilization of clustered dendritic spines in cortical neurons of MECP2-duplication syndrome mice. This synaptic phenotype provides a structural circuit mechanism for the behavioral rigidity characteristic of this autism model, paralleling human MECP2 duplication syndrome.

During motor learning, axonal boutons in primary motor cortex showed abnormally increased stability in MECP2-duplication mice compared to wild-type, suggesting that excessive synaptic stabilization—not just abnormal formation—is a core circuit mechanism for behavioral inflexibility in autism.

MeCP2 deficiency impairs the flexibility of motor cortical circuits during motor skill learning. The proportion of speed-selective neurons and their population synchronization failed to undergo the adaptive changes observed in wild-type mice with training, establishing circuit-level biomarkers for motor regression in Rett syndrome.

Intensive motor training improved rotarod coordination and reduced anxiety-like behavior in symptomatic Mecp2-null Rett syndrome mice, despite persistent impairments in motor circuit functional connectivity. Results suggest behaviorally-driven compensatory plasticity can partially overcome circuit dysfunction.

Both loss (Rett syndrome) and gain (MECP2 duplication) of MeCP2 cause convergent hippocampal circuit dysfunction, characterized by elevated excitatory-inhibitory ratios and impaired theta oscillations. Deep brain stimulation of the hippocampal circuit rescued these abnormalities, suggesting a unifying circuit pathophysiology.

Two-photon calcium imaging of apical and basal dendritic compartments in V1 revealed that apical dendrites are more sharply orientation-tuned than basal dendrites, demonstrating compartmentalized computation in cortical pyramidal neurons and the distinct roles of feedforward versus feedback inputs.

A Rac1 GEF/GAP complex (Tiam1 and β-PIX) dynamically balances excitatory synapse formation and maturation during brain development. Disruption of this balance causes abnormal dendritic spine morphology and impairs synaptic plasticity, revealing a molecular mechanism for excitatory synapse development relevant to autism.

In MECP2-duplication mice, cortical neurons show excessive dendritic arborization, increased spine density, and abnormal spine dynamics with reduced turnover. These structural phenotypes establish synaptic connectivity abnormalities as core pathological features of this autism model.

Neonatal viral injection achieves controllable genetic mosaicism across brain regions, enabling sparse cell-type-specific labeling and manipulation of neuronal circuits in vivo with high efficiency. This method has become a widely used tool for in vivo circuit visualization and optogenetic manipulation.