Abstract

Here we describe a novel method to noninvasively modulate targeted brain areas through the temporary disruption of the blood-brain barrier (BBB) via focused ultrasound, enabling focal delivery of a neuroactive substance. Ultrasound was used to locally disrupt the BBB in rat somatosensory cortex, and intravenous administration of GABA then produced a dose-dependent suppression of somatosensory-evoked potentials in response to electrical stimulation of the sciatic nerve. No suppression was observed 1–5 days afterwards or in control animals where the BBB was not disrupted. This method has several advantages over existing techniques: it is noninvasive; it is repeatable via additional GABA injections; multiple brain regions can be affected simultaneously; suppression magnitude can be titrated by GABA dose; and the method can be used with freely behaving subjects. We anticipate that the application of neuroactive substances in this way will be a useful tool for noninvasively mapping brain function, and potentially for surgical planning or novel therapies.

Highlights

  • GABA is released from inhibitory nerve terminals and bound to receptors distributed on post-synaptic cell membranes[6]

  • GABA’s actions in the synaptic cleft are terminated by its reuptake by either pre-synaptic neurons or nearby glial cells via specific and high-affinity transporters that are believed to be the major mechanism for reducing its concentration in the extracellular fluid[7]

  • Efflux from the brain to the bloodstream has been identified as a mechanism that removes extracellular GABA8

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Summary

Introduction

BBB disruption in the targeted region was evident in MRI as signal enhancement after administration of Gd-DTPA, an MRI contrast agent with a molecular weight of 938 Da that does not normally extravasate into the brain. Administration of GABA resulted in a dose-dependent suppression of SSEP signals. A linear relationship was observed between SSEP magnitude suppression and GABA dose.

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Conclusion
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