Targeted, noninvasive blockade of cortical neuronal activity.
Authors: McDannold N, Zhang Y, Power C, Arvanitis CD, Vykhodtseva N, Livingstone M
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.
Introduction
Purpose
Drug delivery with BBB opening
Study Objective
To demonstrate that focused ultrasound–induced temporary disruption of the blood–brain barrier can enable focal, noninvasive delivery of GABA to suppress neural activity in targeted brain regions.
Animal model / Human subject
Rattus norvegicus (Sprague Dawley), age not reported (weight 262–433 g), male
Disease model
healthy
MRI or image guidance method
MRI-guided FUS
Targeted brain region(s)
Somatosensory Cortex
Target coordinates
AP: 2 mm posterior to bregma (AP = -2 mm); ML: 2 mm lateral to the right (ML = +2 mm); DV: not specified
Cargo name and characteristics
GABA (gamma-aminobutyric acid
Route of administration
Intravenous (tail vein catheter)
Outcomes and Safety
Summary of Outcomes
Focused ultrasound disruption of the blood–brain barrier allowed intravenously administered GABA to enter targeted rat cortex and produce a dose-dependent, reversible suppression of somatosensory-evoked potentials.
Duration of biological effect
1.5–3.5 hours
Safety-related matter
No adverse effects were reported, but the authors note uncertainty about possible neuromodulatory effects from the sonications or BBB disruption, that the BBB remained open for hours, and that systems exist for precise, safe transcranial focusing in humans.
Brain Region
Ultrasound Parameters
Ultrasound instrument
function generator (33220A, Agilent) and amplifier (240L, E&I)
FUS Frequency
690 kHz
FUS Intensity
Not reported (no W/cm2 values provided in the paper)
FUS Pressure
Not reported in the provided text
FUS Mode
pulsed
Pulse duration
10 ms
Duration of a single FUS session
Approximately 19–28 minutes (10 sonications × 60 s each = 10 min active sonication, plus nine 1–2 min inter-sonication intervals = 9–18 min, total ≈19–28 min)
Focal Characteristics
8 cm (3T transducer); 3 cm (7T transducer)
Treatment frequency
single session
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