Toward a Cognitive Neural Prosthesis Using Focused Ultrasound.
Authors: Downs ME, Teichert T, Buch A, Karakatsani ME, Sierra C, Chen S, Konofagou EE, Ferrera VP
Non-invasive brain stimulation using focused ultrasound has many potential applications as a research and clinical tool, including its incorporation as either an extracorporeal or implantable neural prosthetic. To this end, we investigated the effect of focused ultrasound (FUS) combined with systemically administered microbubbles on visual-motor decision-making behavior in monkeys. We applied FUS to the putamen in one hemisphere to open the blood-brain barrier (BBB), and then tested behavioral performance 3-4 h later. On days when the monkeys were treated with FUS, their decisions were faster and more accurate than days without sonication. The performance improvement suggested both a shift in the decision criterion and an enhancement of the use of sensory evidence in the decision process. FUS also interacted with the effect of a low dose of haloperidol. The findings indicate that a two-minute application of FUS can have a sustained impact on performance of complex cognitive tasks, and may increase the efficacy of psychoactive medications. The results lend further support to the idea that the dorsal striatum plays an integral role in evidence- and reward-based decision-making, and provide motivation for incorporating FUS into cognitive neural prosthetic devices.
Introduction
Purpose
Drug delivery with BBB opening
Study Objective
To determine whether focused ultrasound with systemically administered microbubbles applied to the putamen alters visual-motor decision-making performance and interacts with low-dose haloperidol in rhesus monkeys.
Animal model / Human subject
Macaca mulatta (rhesus macaque; strain not specified) — 2 adult males, ages 9 and 20 years (weights 5.5 and 9.5 kg); Macaca fascicularis (cynomolgus macaque; strain not specified) — 2 adult males, ages 14 and 18 years (weights 5.3 and 5.6 kg)
Disease model
healthy
MRI or image guidance method
Stereotactic positioning
Targeted brain region(s)
Putamen
Cargo name and characteristics
Haloperidol
Route of administration
Intravenous and intramuscular
Outcomes and Safety
Summary of Outcomes
A two-minute focused ultrasound application with systemic microbubbles targeted unilaterally to the putamen (opening the BBB) produced sustained improvements in monkeys' visual-motor decision-making—faster and more accurate choices (especially with the contralateral hand) when tested 3–4 hours after sonication—and altered the behavioral effects of low-dose haloperidol.
Duration of biological effect
3–4 hours
Safety-related matter
No damage was detected in this study (no hyper- or hypo-intense voxels on T2‑ and susceptibility‑weighted MRI) and all BBB openings were confined to the targeted putamen; prior work by the authors indicates repeated FUS with microbubbles is non‑traumatic when acoustic pressures remain within a safe range. However, sonication interacted with haloperidol to reduce decision accuracy, anesthesia (ketamine) produced transient slowing, and other studies have reported sustained changes in neurophysiological signals (e.g., decreased SSEP/BOLD) at higher acoustic pressures, indicating potential parameter‑dependent adverse effects.
Brain Region
Ultrasound Parameters
Ultrasound instrument
Single-element transducer H-107 Sonic Concepts, WA, USA
FUS Frequency
500 kHz
FUS Pressure
0.4 MPa
FUS Mode
pulsed
Pulse duration
10 ms
Duration of a single FUS session
120 s (2 minutes)
Focal Characteristics
not provided
Treatment frequency
multiple sessions
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