Biology subjects

Pauly, K. B.

Publications and source records attributed to Pauly, K. B..

8 recordsLinked to original sources

bioRxiv2026

Ultrasonic local anesthetic uncaging enables noninvasive, targeted, and transient knock-out of brain function

Noninvasive, spatially localized brain inhibition would enable precise neural circuit interrogation, mapping, and treatment. We previously presented SonoRopi, an acoustically activatable liposomal formulation of ropivacaine, and demonstrated its utility for targeted peripheral nerve anesthesia. Here, we extend SonoRopi to localized brain anesthesia following intravenous administration and transcranial focused ultrasound application. Ultrasonic uncaging of SonoRopi releases ropivacaine, which crosses the intact blood-brain barrier to anesthetize the sonicated region. SonoRopi uncaging in mouse primary visual cortex suppressed visually evoked cortical activity for one hour, while uncaging in rat somatosensory hindlimb cortex produced lateralized, reversible hindlimb sensory anesthesia. Off-target control sonication preserved function in both paradigms. No acute histologic injury or open-field behavioral abnormalities were detected following this intervention. SonoRopi thereby enables noninvasive, spatially targeted, reversible brain inhibition with physiologic and behavioral efficacy in two rodent species.

bioengineering↗

bioRxiv2026

MR-ARFI and Beyond: Characterizing the Temporal Dynamics of Acoustic Radiation Force in Human Brain

Purpose: Magnetic Resonance Acoustic Radiation Force Imaging (MR-ARFI) encodes focused ultrasound (FUS)-induced tissue displacements to MR phase shifts. Because these phase shifts are small, optimizing displacement sensitivity and minimizing motion artifacts requires characterization of the temporal dynamics of acoustic radiation force (ARF). Beyond sequence design, such characterization enables MR-ARFI to serve as a probe of brain viscoelastic behavior and can inform the design of therapeutic ultrasound pulsing schemes by quantifying how rapidly tissue deforms and relaxes. Methods: We developed a dynamic model assuming a gamma-variate impulse response for ARF(t), with time constant ({tau}) to be estimated. A single-shot spin echo ARFI acquisition with a bipolar motion encoding gradient (MEG) was implemented, incorporating retrospective corrections for head motion and physiological noise. A 500 kHz FUS pulse was applied in on/off blocks while systematically varying the timing between the MEG and sonication. The resulting phase time series were fit to the model to estimate time constant in five human participants. To assess sensitivity to tissue stiffness, {tau} was additionally measured in two customized gelatin phantoms of differing stiffness, characterized independently by MR elastography (MRE). Results: The average measured time constant in human participants was {tau} 3.7 {+/-} 0.27 ms. Comparing the two phantoms, the stiffer phantom exhibited a shorter {tau} (3.0-3.5 ms) than the softer phantom (4.0-4.5 ms), which tracked the MRE-derived Kelvin-Voigt viscoelastic time constants. In addition, the peak ARFI displacement was lower in the stiffer phantom (0.17 vs 0.74 m for the less stiff phantom), and a broader displacement focal spot size (FWHM 22 mm vs 15 mm). Conclusion: This time series approach with motion and physiological noise corrections validates an MR-based technique capable of characterizing the brain's temporal response to sonication-induced mechanical forces, providing a foundation for optimizing the design of ultrasound pulsing schemes for ARFI, as well as for future studies of brain biomechanics.

bioengineering↗

bioRxiv2026

Noninvasive Diagnostic Ultrasound-Guided Focused Ultrasound Enables Selective, Reversible Inhibition of Peripheral Nociceptive Fibers and Prevents Acute Pain

BackgroundAcute postoperative pain remains a major clinical therapeutic challenge. Current peripheral nerve blockade (PNB) techniques are effective for some patients but are limited by invasiveness, short duration, reliance on highly trained providers, and off-target motor and sensory effects. Focused ultrasound (FUS) is a novel neuromodulatory technology with the potential to achieve noninvasive, selective, reversible, and prolonged inhibition of peripheral nociceptive fibers to prevent and treat acute pain. We hypothesized that noninvasive transcutaneous targeting of the rat sciatic nerve using co-aligned diagnostic ultrasound (dUS) and FUS transducers could produce selective and reversible inhibition of nociceptive pain behaviors while preserving motor and non-nociceptive sensory functions. MethodsIn an in vivo rat hindpaw incisional (HPI) pain model, using a novel, transcutaneous dUS-guided FUS system, the sciatic nerve was located with dUS, and FUS energy was applied to it just prior to hindpaw incision. FUS parameters were iteratively adjusted to achieve reversible, selective inhibition of nociceptive behaviors without changing motor and non-pain sensory behaviors. Animals were randomized into six groups: No Intervention (Control), HPI Only (Disease Control), Sham FUS, FUS Only, FUS+HPI (Intervention), and LA+HPI (Positive Control). Primary outcomes were changes in nociceptive sensory functions, assessed by thermal and mechanical sensitivity. Secondary outcomes were changes in non-nociceptive sensory and motor functions, assessed by hindpaw flexion and extension reflexes. ResultsCompared with the HPI Only group, the FUS+HPI group demonstrated (1) significant attenuation of hindpaw thermal hypersensitivity from day 0 - week 5.0 and week 8.0 - 16.0 (p < 0.05-0.001); (2) significant attenuation of mechanical hypersensitivity from day 0 until week 4.0 (p < 0.05-0.001); (3) no significant attenuation of flexion; and (4) no significant attenuation of extension. ConclusionsTranscutaneous dUS-guided FUS enables selective, reversible inhibition of A{delta} and C nociceptive fiber mediated behaviors while sparing A motor and A{beta} sensory behaviors. FUS-induced PNB prevented both acute and persistent pain behaviors. These findings support FUS as a promising noninvasive peripheral nerve blockade strategy for acute pain management.

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↗

bioRxiv2023

DLG1 functions upstream of SDCCAG3 and IFT20 to control targeting of polycystin-2 to the primary cilium

Polarized vesicular trafficking directs specific receptors and ion channels to cilia, but the underlying mechanisms are poorly understood. Here we describe a role for DLG1, a core component of the Scribble polarity complex, in regulating ciliary protein trafficking in kidney epithelial cells. Conditional knockout of Dlg1 in mouse kidney caused ciliary elongation and cystogenesis, and cell-based proximity labelling proteomics and fluorescence microscopy showed alterations in the ciliary proteome upon loss of DLG1. Specifically, the retromer-associated protein SDCCAG3, IFT20 and polycystin-2 (PC2) were reduced in cilia of DLG1 deficient cells compared to control cells. This phenotype was recapitulated in vivo and rescuable by re-expression of wildtype DLG1, but not a Congenital Anomalies of the Kidney and Urinary Tract (CAKUT)-associated DLG1 variant, p.T489R. Finally, biochemical approaches and Alpha Fold modelling suggested that SDCCAG3 and IFT20 form a complex that associates, at least indirectly, with DLG1. Our work identifies a key role for DLG1 in regulating ciliary protein composition and suggests that ciliary dysfunction of the p.T489R DLG1 variant may contribute to CAKUT.

cell biology↗

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↗

bioRxiv2018

Transcranial ultrasound selectively biases decision-making in primates

Transcranial focused ultrasound has the promise to evolve into a transformative noninvasive way to modulate activity of neuronal circuits deep in the brain. The approach may enable systematic and causal mapping of how individual brain circuits are involved in specific behaviors and behavioral disorders. Previous studies demonstrated neuromodulatory potential, but the effect polarity, size, and spatial specificity have been difficult to assess. Here, we engaged non-human primates (macaca mulatta) in an established task that provides a well defined framework to characterize the neuromodulatory effects. In this task, subjects decide whether to look at a right or a left target, guided by one the targets appearing first. Previous studies showed that excitation/inhibition of oculomotor circuits leads to contralateral/ipsilateral biases in this choice behavior. We found that brief, low-intensity ultrasound stimuli (300 ms, 0.6 MPa, 270 kHz) delivered to the animals left/right frontal eye fields bias the animals decisions to the right/left visual hemifield. The effect was modest, about on the order of that produced when injecting moderate amounts of potent neuromodulatory drugs into the same regions in this task. The polarity of the effects suggested a neuronal excitation within the stimulated regions. No effects were observed when we applied the same stimuli to control brain regions not involved in oculomotor target selection. Together, using an established paradigm, we found that transcranial ultrasound is capable of modulating neurons to the extent of biasing choice behavior of non-human primates. A demonstration of tangible, double-dissociated effects on behavior of primates constitutes a critical step toward applying this noninvasive neuromodulation method in investigations of how specific neural circuits are involved in specific behaviors or disease signs.

neuroscience↗

bioRxiv2017

Physical mechanisms of ultrasonic neurostimulation of the retina

Focused ultrasound has been shown to be effective at stimulating neurons in vivo, ex vivo and in vitro preparations. Ultrasonic neuromodulation is the only non-invasive method of stimulation that could reach deep in the brain with high spatial-temporal resolution, and thus has potential for use in clinical applications and basic studies of the nervous system. Understanding the physical mechanism by which energy in a high acoustic frequency wave is delivered to stimulate neurons will be important to optimize this technology. Two primary candidates for a physical mechanism are radiation force, the delivery of momentum by the acoustic wave, and cavitation, oscillating gas bubbles. We imaged the isolated salamander retina during ultrasonic stimuli that drive ganglion cell activity and observed micron scale displacements consistent with radiation force. We recorded ganglion cell spiking activity with a planar multielectrode array and changed the acoustic carrier frequency across a broad range (0.5 - 43 MHz), finding that increased stimulation occurs at higher acoustic frequencies, a result that is consistent with radiation force but not cavitation. A quantitative radiation force model can explain retinal responses, and could potentially explain previous in vivo results in the mouse, suggesting a new hypothesis to be tested in vivo. Finally, we found that neural activity was strongly modulated by the distance between the transducer and the electrode array showing the influence of standing waves on the response. We conclude that radiation force is the physical mechanism underlying ultrasonic neurostimulation in the ex vivo retina, and that the control of standing waves is a new potential method to modulate these effects.

neuroscience↗