@article{f6dc59d1e4a4468f8e80a4a523cb20e2,
title = "Focal, remote-controlled, chronic chemical modulation of brain microstructures",
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.",
keywords = "Brain, Drug delivery, Neural implant, PET, Substantia nigra",
author = "Ramadi, {Khalil B.} and Canan Dagdeviren and Spencer, {Kevin C.} and Pauline Joe and Max Cotler and Erin Rousseau and Carlos Nunez-Lopez and Graybiel, {Ann M.} and Robert Langer and Cima, {Michael J.}",
note = "Funding Information: We thank Preksha Bhagchandani and Cathy Choi for their technical support during device fabrication. We thank Howard Mak of the Animal Imaging Core Facility at the Koch Institute for Integrative Cancer Research for his assistance with PET imaging. We acknowledge the facilities at the Center for Nanoscale Systems at Harvard University and the Massachusetts Institute of Technology Microsystems Technology Laboratories. This work is supported by the US National Institutes of Health, National Institute of Biomedical Imaging and Bioengineering (R01 EB016101 to R.L., A.M.G., and M.J.C.) and in part by the National Cancer Institute (P30-CA14051 to the Koch Institute Core). Funding Information: ACKNOWLEDGMENTS. We thank Preksha Bhagchandani and Cathy Choi for their technical support during device fabrication. We thank Howard Mak of the Animal Imaging Core Facility at the Koch Institute for Integrative Cancer Research for his assistance with PET imaging. We acknowledge the facilities at the Center for Nanoscale Systems at Harvard University and the Massachusetts Institute of Technology Microsystems Technology Laboratories. This work is supported by the US National Institutes of Health, National Institute of Biomedical Imaging and Bioengineering (R01 EB016101 to R.L., A.M.G., and M.J.C.) and in part by the National Cancer Institute (P30-CA14051 to the Koch Institute Core).",
year = "2018",
month = jul,
day = "10",
doi = "10.1073/pnas.1804372115",
language = "English (US)",
volume = "115",
pages = "7254--7259",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "28",
}