Modulation of brain function by targeted delivery of GABA through the disrupted blood-brain barrier.
Authors: Todd N, Zhang Y, Power C, Becerra L, Borsook D, Livingstone M, McDannold N
The technology of transcranial focused ultrasound (FUS) enables a novel approach to neuromodulation, a tool for selective manipulation of brain function to be used in neurobiology research and with potential applications in clinical treatment. The method uses transcranial focused ultrasound to non-invasively open the blood-brain barrier (BBB) in a localized region such that a systemically injected neurotransmitter chemical can be delivered to the targeted brain site. The approach modulates the chemical signaling that occurs in and between neurons, making it complimentary to most other neuromodulation techniques that affect the electrical properties of neuronal activity. Here, we report delivering the inhibitory neurotransmitter GABA to the right somatosensory cortex of the rat brain during bilateral hind paw electrical stimulation and measure the inhibition of activation using functional MRI (fMRI). In a 2 × 2 factorial design, we evaluated conditions of BBB Closed vs BBB Open and No GABA vs GABA. Results from fMRI measurements of the blood oxygen level-dependent (BOLD) signal show: 1) intravenous GABA injection without FUS-mediated BBB opening does not have an effect on the BOLD response; 2) FUS-mediated BBB opening alone significantly alters the BOLD signal response to the stimulus, both in amplitude and shape of the time course; 3) the combination of FUS-mediated BBB opening and GABA injection further reduces the peak amplitude and spatial extent of the BOLD signal response to the stimulus. The data support the thesis that FUS-mediated opening of the BBB can be used to achieve non-invasive delivery of neuroactive substances for targeted manipulation of brain function.
Introduction
Purpose
Drug delivery with BBB opening
Study Objective
To determine whether transcranial focused ultrasound-mediated opening of the blood–brain barrier enables targeted delivery of the inhibitory neurotransmitter GABA to the rat somatosensory cortex and consequent modulation of neural activity measured by fMRI.
Animal model / Human subject
Rat; strain: None; age: None; sex: None
Disease model
Healthy
Targeted brain region(s)
Somatosensory Cortex
Cargo name and characteristics
GABA (gamma-aminobutyric acid) — small-molecule inhibitory neurotransmitter, systemically injected for targeted delivery after FUS-mediated BBB opening
Route of administration
intravenous
Outcomes and Safety
Summary of Outcomes
FUS-mediated BBB opening enabled delivery of intravenous GABA to the right somatosensory cortex and, when combined with GABA, further reduced the peak amplitude and spatial extent of the stimulus-evoked BOLD response; FUS alone also significantly altered BOLD amplitude and time-course, while IV GABA without BBB opening had no effect. Successful FUS parameter: FUS-mediated BBB opening (BBB Open) compared with BBB Closed.
Safety-related matter
The paper does not report any safety concerns or adverse effects; no adverse events were mentioned. It does note that FUS-mediated BBB opening alone significantly altered the BOLD response, but no adverse safety outcomes were described.
Brain Region
Ultrasound Parameters
Focal Characteristics
focal depth: None; focal length: None; aperture size: None
Treatment frequency
single
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