Focal, remote-controlled, chronic chemical modulation of brain microstructures

Khalil B. Ramadi, Canan Dagdeviren, Kevin C. Spencer, Pauline Joe, Max Cotler, Erin Rousseau, Carlos Nunez-Lopez, Ann M. Graybiel, Robert Langer, Michael J. Cima

    Research output: Contribution to journalArticle

    Abstract

    Direct delivery of fluid to brain parenchyma is critical in both research and clinical settings. This is usually accomplished through acutely inserted cannulas. This technique, however, results in backflow and significant dispersion away from the infusion site, offering little spatial or temporal control in delivering fluid. We present an implantable, MRI-compatible, remotely controlled drug delivery system for minimally invasive interfacing with brain microstructures in freely moving animals. We show that infusions through acutely inserted needles target a region more than twofold larger than that of identical infusions through chronically implanted probes due to reflux and backflow. We characterize the dynamics of in vivo infusions using positron emission tomography techniques. Volumes as small as 167 nL of copper-64 and fludeoxyglucose labeled agents are quantified. We further demonstrate the importance of precise drug volume dosing to neural structures to elicit behavioral effects reliably. Selective modulation of the substantia nigra, a critical node in basal ganglia circuitry, via muscimol infusion induces behavioral changes in a volume-dependent manner, even when the total dose remains constant. Chronic device viability is confirmed up to 1-y implantation in rats. This technology could potentially enable precise investigation of neurological disease pathology in preclinical models, and more efficacious treatment in human patients.

    Original languageEnglish (US)
    Pages (from-to)7254-7259
    Number of pages6
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume115
    Issue number28
    DOIs
    StatePublished - Jul 10 2018

    Keywords

    • Brain
    • Drug delivery
    • Neural implant
    • PET
    • Substantia nigra

    ASJC Scopus subject areas

    • General

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  • Cite this

    Ramadi, K. B., Dagdeviren, C., Spencer, K. C., Joe, P., Cotler, M., Rousseau, E., Nunez-Lopez, C., Graybiel, A. M., Langer, R., & Cima, M. J. (2018). Focal, remote-controlled, chronic chemical modulation of brain microstructures. Proceedings of the National Academy of Sciences of the United States of America, 115(28), 7254-7259. https://doi.org/10.1073/pnas.1804372115