Biology subjects

Ash, R. T.

Publications and source records attributed to Ash, R. T..

11 recordsLinked to original sources

bioRxiv2026

Dose-dependent ultrasound neuromodulation of the human brain

Transcranial ultrasound stimulation (TUS) can noninvasively modulate deep brain structures, but the relationship between delivered dose and neuromodulatory response remains poorly characterized in humans. Here, we show that ultrasound-induced tissue displacement measured in vivo predicts local and downstream functional neuromodulation. In 24 healthy adults, we combined magnetic resonance acoustic radiation force imaging (MR-ARFI) with concurrent TUS-fMRI in a double-blind, counterbalanced, within-subject design. Relative to active control stimulation, targeting the lateral geniculate nucleus (LGN) increased visually evoked BOLD responses in the LGN and ipsilateral primary visual cortex, localized to the retinotopic projection zone of the stimulated LGN site. Displacement predicted effect magnitude in both regions across participants and covaried with voxelwise responses within participants. Simulated in situ intensity showed no significant association with displacement or neuromodulatory response. These findings link in vivo mechanical displacement to functional modulation of a human thalamocortical circuit, providing an empirical basis for individualized dosing in causal neuroscience and clinical intervention.

neuroscience↗

bioRxiv2026

Psychophysical validation of calibrated white-noise and tuned-noise auditory masks for transcranial focused ultrasound

Auditory confounds have proven to be a major hurdle in the elucidation of veridical neuromodulation effects with transcranial ultrasound stimulation (TUS). Auditory noise masks are an essential method to reduce the audibility of TUS and have shown promise in several studies. Here we describe a novel approach for design, calibration, and psychometric validation of auditory noise masks to reduce the perceptibility of TUS. White noise masks and spectrum-tuned masks matched to a TUS protocol that generates highly salient auditory costimulation (487.5 Hz pulse repetition frequency, 10% duty cycle, 68 W/cm2 pulse-peak average intensity, 500 kHz acoustic frequency) were generated, and dB(A) levels were calibrated with an artificial ear. The masker levels needed to reduce TUS detection performance in a two-interval forced choice task were determined with an adaptive QUEST+ staircase in 20 neurotypical participants. Detection performance of this highly salient TUS protocol was driven to near chance performance (<55%) in 17/20 participants with white-noise and 18/20 participants with spectrum-tuned noise. However, high masker levels approaching safety limits were needed to render TUS inaudible for the majority of participants, indicating the need for formal masker calibration for these TUS settings. Additionally, against expectation the spectrum-tuned masker did not significantly outperform the white-noise masker, suggesting that perceptibility of TUS auditory costimulation does not lawfully follow the sound expected from its pulse envelope and the known spectrum of human hearing.

neuroscience↗

bioRxiv2026

Effects of transcranial focused ultrasound stimulation to human lateral geniculate nucleus on visual perception and steady-state visual evoked potentials

Transcranial ultrasound stimulation (TUS) is an emerging tool to non-invasively modulate neural activity in deep brain areas. A key need in accelerating TUS into cognitive neuroscience and neuropsychiatry is to better understand how different sonication parameters relate to neuromodulatory effects. Here we assess the role of pulse repetition frequency (PRF), a key TUS parameter thought to determine the relative contribution of molecular displacement and acoustic radiation force effects on neural tissue using the human subcortical visual pathway as a testbed. We combined frequency-tagged steady-state visual evoked potential (SSVEP) measures of contrast-response with contrast increment detection psychophysics as neural and behavioral readouts of visual pathway function. We used structural MRIs and acoustic simulations to target the lateral geniculate nucleus (LGN). Concurrent with visual stimulus presentation, the left LGN or a more superficial control site were stimulated with a neuronavigated depth-steerable 4-element TUS transducer at a range of PRFs with 68 W/cm2 free-water ISPPA, and a 10% duty cycle. An effective white-noise auditory mask blinded participants to stimulation conditions. Recordings from 25 neurotypical participants failed to detect any impact of TUS on SSVEP response amplitude, SSVEP response latency, or perceptual behavior. Analysis of simulations generated from the measured transducer positions grant reasonably high confidence that the LGN was within the TUS focus in most participants, with no correlation between targeting accuracy and changes in activity during TUS. Our results provide a cautionary note about the effect size of neuronavigated TUS for online causal manipulations in cognitive and clinical neuroscience.

neuroscience↗

bioRxiv2025

Spatial Attention and Session Day Independently Modulate Human Visual Cortical Plasticity

Stimulus-specific response potentiation (SSRP) is a noninvasive form of cortical neuroplasticity elicited by repeated presentation of high-contrast visual stimuli. Analogous to long-term potentiation, SSRP has been proposed to exhibit input specificity, with potentiation confined to neural populations driven by the induction stimulus. In rodent models, SSRP effects accumulate across days; however, it remains unclear whether selective attention influences the magnitude or specificity of potentiation in humans. Here, we examined whether covert spatial attention modulates SSRP strength using high-density electroencephalography (EEG) in neurotypical adults. An established SSRP paradigm was modified to include an attention task during induction. Pre- and post-induction amplitudes were measured using frequency-tagged (6 and 7.5 reversals/s) bilateral hemifield contrast-sweep checkerboard steady-state visual evoked potentials (SSVEPs). The 10-minute, high-contrast, 2 Hz sign-reversing induction stimulus was presented exclusively to the left hemifield, with the right serving as control. Across two experimental sessions, participants attended either toward or away from the potentiated hemifield during induction. SSRP produced increased post-induction amplitudes in both hemifields, challenging the notion of strict input specificity. Potentiation was significantly greater on the second session day, independent of attention condition. Notably, attention enhanced SSRP in naive but not experienced observers, reflecting a significant interaction between attention and session day. Together, these findings suggest that (1) human SSRP may not be strictly stimulus-specific, (2) attention modestly enhances SSRP during initial exposure, and (3) repeated induction produces a robust plasticity effect that occludes attentional modulation.

neuroscience↗

bioRxiv2024

Optimization of MR-ARFI for Human Transcranial Focused Ultrasound

Magnetic resonance acoustic radiation force imaging (MR-ARFI) is an exceptionally promising technique to non-invasively confirm targeting accuracy and estimate exposure of low-intensity transcranial focused ultrasound stimulation. MR-ARFI uses magnetic field motion encoding gradients to visualize the MR phase changes generated by microscopic displacements at the ultrasound focus. Implementing MR-ARFI in the human central nervous system has been hindered by 1) phase distortion caused by subject motion, and 2) insufficient signal-to-noise ratio at low (<1.0 MPa) ultrasound pressures. The purpose of this study was to optimize human MR-ARFI to allow reduced ultrasound exposure while at the same time being robust to bulk and physiological motion. We demonstrate that a time series of single-shot spiral acquisitions, while triggering ultrasound on and off in blocks, provides ARFI maps that with correction are largely immune to bulk and pulsatile brain motion. Furthermore, the time series approach allows for a reduction in ultrasound exposure per slice while improving motion robustness with reduced scan time. The focused ultrasound beam can be visualized in an 80 second scan with our protocol, enabling iteration for image-guided targeting. We demonstrated robust ARFI signals at the expected target in 4 participants. Our results provide persuasive proof-of-principle that MR-ARFI can be used as a tool to guide ultrasound-based precision neural circuit therapeutics.

biophysics↗

bioRxiv2022

Stability of steady-state visual evoked potential contrast response functions

A repeated measure of neural activity that is stable over time when unperturbed is needed to be able to meaningfully measure neuroplastic changes in the brain. With sensory-evoked potentials in particular, repeated presentation of stimuli can generate neuroplasticity by itself under certain conditions. We assessed the repeated-measure within-day and across-day stability of the steady-state visual-evoked potential (ssVEP), a high signal-to-noise electrophysiological readout of neural activity in human visual cortex, in preparation for studies of visual cortical neuroplasticity. Steady-state VEP contrast-sweep responses were measured daily for 4 days (four 20-trial blocks per day, 22 participants). Response amplitudes were stable in individual participants, with measured across-block and across-day coefficients of variation (CV= SD / Mean) of 12{+/-}1% and 19{+/-}2%, respectively. No consistent changes in response amplitude were observed either across blocks or across days. We conclude that contrast-sweep steady-state VEPs provide a stable human neurophysiological measure well-suited for repeated-measures studies.

neuroscience↗

bioRxiv2022

Increased reliability of visually-evoked activity in area V1 of the MECP2-duplication mouse model of autism

Atypical sensory processing is now thought to be a core feature of the autism spectrum. Influential theories have proposed that both increased and decreased neural response reliability within sensory systems could underlie altered sensory processing in autism. Here, 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. Increased response reliability was due in part to decreased response amplitude, decreased fluctuations in endogenous activity, and decreased neuronal coupling to endogenous activity. Similarly to what was observed neuronally, the optokinetic reflex occurred more reliably at low contrasts in mutant mice compared to controls. Retinal responses did not explain our observations. These data suggest that the circuit mechanisms for convolution of sensory-evoked and endogenous signal and noise may be altered in this form of syndromic autism.

neuroscience↗

bioRxiv2021

Transcranial Focused Ultrasound Neuromodulation of the Thalamic Visual Pathway in a Large Animal Model

BackgroundNeuromodulation of deep brain structures via transcranial ultrasound stimulation (TUS) is a promising, but still elusive approach to non-invasive treatment of brain disorders. ObjectiveThe purpose of this study was to determine whether MR-guided TUS of the lateral geniculate nucleus (LGN) can modulate visual evoked potentials (VEPs) and cortical brain oscillations in a large animal model. MethodsThe lateral geniculate nucleus (LGN) on one side was identified with T2-weighted MRI in sheep (all male, n=9). MR acoustic radiation force imaging (MR-ARFI) was used to confirm a tight sonication focus. Electroencephalographic (EEG) signals were recorded, and the visual evoked potential (VEP) peak-to-peak amplitude (N70 and P100) was calculated for each trial. Time-frequency spectral analysis was performed to elucidate the effect of TUS on cortical brain dynamics. ResultsThe VEP peak-to-peak amplitude was reversibly suppressed relative to baseline during TUS. Dynamic spectral analysis demonstrated a change in cortical oscillations when TUS is paired with visual sensory input, but not when TUS is applied by itself. ConclusionTUS non-invasively delivered to LGN can neuromodulate visual activity and oscillatory dynamics in large mammalian brains.

neuroscience↗

bioRxiv2019

Contribution of Apical and Basal Dendrites of L2/3 Pyramidal Neurons to Orientation Encoding in Mouse V1

Pyramidal neurons integrate synaptic inputs from basal and apical dendrites to generate stimulus-specific responses. It has been proposed that feed-forward inputs to basal dendrites drive a neurons stimulus preference, while feedback inputs to apical dendrites sharpen selectivity. However, how a neurons dendritic domains relate to its functional selectivity has not been demonstrated experimentally. We performed 2-photon dendritic micro-dissection on layer-2/3 pyramidal neurons in mouse primary visual cortex. We found that removing the apical dendritic tuft did not alter orientation-tuning. Furthermore, orientation-tuning curves were remarkably robust to the removal of basal dendrites: ablation of 2-3 basal dendrites was needed to cause a small shift in orientation preference, without significantly altering tuning width. Computational modeling corroborated our results and put limits on how orientation preferences among basal dendrites differ in order to reproduce the post-ablation data. In conclusion, neuronal orientation-tuning appears remarkably robust to loss of dendritic input.

neuroscience↗

bioRxiv2017

Increased axonal bouton stability during learning in the mouse model of MECP2 duplication syndrome

MECP2-duplication syndrome is an X-linked form of syndromic autism caused by genomic duplication of the region encoding Methyl-CpG-binding protein 2. Mice overexpressing MECP2 demonstrate altered patterns of learning and memory, including enhanced motor learning. Previous work associated this enhanced motor learning to abnormally increased stability of dendritic spine clusters formed in the apical tuft of corticospinal, area M1, neurons during rotarod training. In the current study, we measure the structural plasticity of axonal boutons in Layer 5 (L5) pyramidal neuron projections to layer 1 of area M1 during motor learning. In wild-type mice we find that during rotarod training, bouton formation rate changes minimally, if at all, while bouton elimination rate doubles. Notably, the observed upregulation in bouton elimination with learning is absent in MECP2-duplication mice. This result provides further evidence of imbalance between structural stability and plasticity in this form of syndromic autism. Furthermore, the observation that axonal bouton elimination doubles with motor learning in wild-type animals contrasts with the increase of dendritic spine consolidation observed in corticospinal neurons at the same layer. This dissociation suggests that different area M1 microcircuits may manifest different patterns of structural synaptic plasticity during motor learning.\n\nSIGNIFICANCE STATEMENTAbnormal balance between synaptic stability and plasticity is a feature of several autism spectrum disorders, often corroborated by in vivo studies of dendritic spine turnover. Here we provide the first evidence that abnormally increased stability of axonal boutons, the presynaptic component of excitatory synapses, occurs during motor learning in the MECP2 duplication syndrome mouse model of autism. In contrast, in normal controls, axonal bouton elimination in L5 pyramidal neuron projections to layer 1 of area M1 doubles with motor learning. The fact that axonal projection boutons get eliminated, while corticospinal dendritic spines get consolidated with motor learning in layer 1 of area M1, suggests that structural plasticity manifestations differ across different M1 microcircuits.

neuroscience↗

bioRxiv2017

Excessive ERK-dependent synaptic clustering with enhanced motor learning in the MECP2 duplication syndrome mouse model of autism

Autism-associated genetic mutations may produce altered learning abilities by perturbing the balance between stability and plasticity of synaptic connections in the brain. Here we report an increase in the stabilization of dendritic spines formed during repetitive motor learning in the mouse model of MECP2-duplication syndrome, a high-penetrance form of syndromic autism. This increased stabilization is mediated entirely by spines that form cooperatively in clusters. The number of clusters formed and stabilized predicts the mutants enhanced motor learning and memory phenotype, reminiscent of savant-like behaviors occasionally associated with autism.\n\nThe ERK signaling pathway, which promotes cooperative plasticity between spines, was found to be hyperactive in MECP2-duplication motor cortex specifically after training. Inhibition of ERK signaling normalizes clustered spine stabilization and rescues motor learning behavior in mutants. We conclude that learning-associated dendritic spine clustering stabilized by hyperactive ERK signaling drives abnormal motor learning and memory consolidation in this model of syndromic autism.

neuroscience↗