Neuromodulation accompanying focused ultrasound-induced blood-brain barrier opening.
Authors: Chu PC, Liu HL, Lai HY, Lin CY, Tsai HC, Pei YC
Burst-mode focused ultrasound (FUS) induces microbubble cavitation in the vasculature and temporarily disrupts the blood-brain barrier (BBB) to enable therapeutic agent delivery. However, it remains unclear whether FUS-induced BBB opening is accompanied by neuromodulation. Here we characterized the functional effects of FUS-induced BBB opening by measuring changes in somatosensory evoked potentials (SSEPs) and blood-oxygen-level dependent (BOLD) responses. Rats underwent burst-mode FUS (mechanical index (MI) of 0.3, 0.55 or 0.8) to the forelimb region in the left primary somatosensory cortex to induce BBB opening. Longitudinal measurements were followed for up to 1 week to characterize the temporal dynamics of neuromodulation. We observed that 0.8-MI FUS profoundly suppressed SSEP amplitude and prolonged latency, and this effect lasted 7 days. 0.55-MI FUS resulted in minimal and short-term suppression of SSEP for less than 60 minutes and didn't affect latency. BOLD responses were also suppressed in an MI-dependent manner, mirroring the effect on SSEPs. Furthermore, repetitive delivery of 0.55-MI FUS every 3 days elicited no accumulative effects on SSEPs or tissue integrity. This is the first evidence that FUS-induced BBB opening is accompanied by reversible changes in neuron responses, and may provide valuable insight toward the development of FUS-induced BBB opening for clinical applications.
Introduction
Purpose
Transcranial ultrasound stimulation
Study Objective
To determine whether burst-mode focused ultrasound–induced blood–brain barrier opening produces neuromodulatory effects by characterizing changes in somatosensory evoked potentials and BOLD responses in rats.
Animal model / Human subject
Rat (Rattus norvegicus), Sprague-Dawley strain, adult (weight 250–300 g; age not specified), male
Disease model
Healthy
Targeted brain region(s)
Primary Somatosensory Cortex, Forelimb Region (S1Fl)
Target coordinates
AP +1 mm; ML -4 mm; DV 1–2 mm under skull (center of focal zone, over left S1FL)
Outcomes and Safety
Summary of Outcomes
Burst-mode FUS (400 kHz) produced MI-dependent neuromodulation accompanying BBB opening: 0.55-MI and 0.8-MI both opened the BBB and suppressed SSEPs and BOLD signals (0.55-MI caused short-lived suppression <60 min with no RBC extravasation and no cumulative effects after repeated treatments, while 0.8-MI caused more extensive BBB opening with RBC extravasation and profound SSEP suppression and latency prolongation lasting ≥7 days); 0.3-MI did not open the BBB or alter SSEPs, and 0.8-MI without microbubbles produced no BBB opening or neuromodulation.
Duration of biological effect
7 days
Safety-related matter
High-intensity (0.8-MI) FUS-induced BBB opening produced red blood cell extravasation and prolonged suppression of SSEPs/BOLD responses lasting up to 7 days, indicating tissue insult; by contrast, 0.55-MI FUS (within the safe range) caused only transient neuromodulation (<60 min) without RBC extravasation, and repetitive 0.55-MI treatments every 3 days produced no cumulative functional or histological adverse effects.
Brain Region
Ultrasound Parameters
Ultrasound instrument
FUS instrument consisting of a function generator (33120A; Agilent, Palo Alto, CA, USA), RF power amplifier (150A100B; Amplifier Research, Souderton, PA, USA) and a focused ultrasound transducer (IMASONIC, Besançon, France; diameter = 60 mm, radius of curvature = 80 mm, frequency = 400 kHz, electric-to-acoustic efficiency = 70%)
FUS Frequency
400 kHz
FUS Pressure
0.35 Mpa
FUS Mode
pulsed
Pulse duration
10 ms
Duration of a single FUS session
120 s (2 minutes)
Focal Characteristics
Focal depth: 1–2 mm under the skull; Focal length: 80 mm (radius of curvature); Aperture size: 60 mm (diameter)
Treatment frequency
multiple sessions
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