Kahn, J. | Search bioRxiv

bioRxiv2025

A wireless, 60-channel, AI-enabled neurostimulation platform

ObjectiveClosed-loop neuromodulatory therapies require devices that can both decode ongoing brain states and deliver multi-site stimulation. MethodsWe describe the Smart Neurostimulation System (SNS), a cranially mounted implant with 60 configurable recording/stimulation channels, inductive power, and onboard spectral-feature classification. In three freely-moving sheep we streamed local-field potentials and conducted two parameter sweep experiments. ResultsCross-validated movement classifiers achieved an average AUC > 0.95. Increasing stimulation amplitude and frequency produced post-stimulation elevations in -band (8-12 Hz) and{gamma} -band (78-82 Hz) power at most target locations. ConclusionThe SNS unifies high-density sensing, real-time brain state decoding, and programmable closed-loop stimulation in a single device, demonstrating behavioral-state prediction and parameter-dependent neuromodulation in vivo. SignificanceThese findings establish a preclinical foundation for biomarker-guided stimulation targeting distributed cortical networks underlying memory and cognition. HighlightsO_LIWireless 60-channel implant enables simultaneous sensing and stimulation C_LIO_LIvine study demonstrates reliable classification of movement and stimulation-related modulation of spectral activity C_LIO_LIThe SNS represents a platform for biomarker-guided neuromodulation therapies C_LI

neuroscience↗

bioRxiv2024

Identification of Small Molecule Inhibitors of PPM1D Using a Novel Drug Discovery Platform

Protein phosphatase, Mg2+/Mn2+ dependent 1D (PPM1D), is a serine/threonine phosphatase that is recurrently activated in cancer, regulates the DNA damage response (DDR), and suppresses the activation of p53. Consistent with its oncogenic properties, genetic loss or pharmacologic inhibition of PPM1D impairs tumor growth and sensitizes cancer cells to cytotoxic therapies in a wide range of preclinical models. Given the therapeutic potential of targeting PPM1D specifically and the DDR and p53 pathway more generally, we sought to deepen our biological understanding of PPM1D as a drug target and determine how PPM1D inhibition differs from other therapeutic approaches to activate the DDR. We performed a high throughput screen to identify new allosteric inhibitors of PPM1D, then generated and optimized a suite of enzymatic, cell-based, and in vivo pharmacokinetic and pharmacodynamic assays to drive medicinal chemistry efforts and to further interrogate the biology of PPM1D. Importantly, this drug discovery platform can be readily adapted to broadly study the DDR and p53. We identified compounds distinct from previously reported allosteric inhibitors and showed in vivo on-target activity. Our data suggest that the biological effects of inhibiting PPM1D are distinct from inhibitors of the MDM2-p53 interaction and standard cytotoxic chemotherapies. These differences also highlight the potential therapeutic contexts in which targeting PPM1D would be most valuable. Therefore, our studies have identified a series of new PPM1D inhibitors, generated a suite of in vitro and in vivo assays that can be broadly used to interrogate the DDR, and provided important new insights into PPM1D as a drug target.

cancer biology↗