Focused ultrasound modulates region-specific brain activity

Seung-Schik Yoo, Alexander Bystritsky, Jong-Hwan Lee, Yongzhi Zhang, Krisztina Fischer, Byoung-Kyong Min, Nathan J. McDannold, Alvaro Pascual-Leone, Ferenc A. Jolesz

NeuroImage 2011, 56, 1267-1275 · 10.1016/j.neuroimage.2011.02.058

large animalhealthyfmrieeg megemg mepother mribehaviourhistology molecular

Abstract

We demonstrated the in vivo feasibility of using focused ultrasound (FUS) to transiently modulate (through either stimulation or suppression) the function of regional brain tissue in rabbits. FUS was delivered in a train of pulses at low acoustic energy, far below the cavitation threshold, to the animal's somatomotor and visual areas, as guided by anatomical and functional information from magnetic resonance imaging (MRI). The temporary alterations in the brain function affected by the sonication were characterized by both electrophysiological recordings and functional brain mapping achieved through the use of functional MRI (fMRI). The modulatory effects were bimodal, whereby the brain activity could either be stimulated or selectively suppressed. Histological analysis of the excised brain tissue after the sonication demonstrated that the FUS did not elicit any tissue damages. Unlike transcranial magnetic stimulation, FUS can be applied to deep structures in the brain with greater spatial precision. Transient modulation of brain function using image-guided and anatomically-targeted FUS would enable the investigation of functional connectivity between brain regions and will eventually lead to a better understanding of localized brain functions. It is anticipated that the use of this technology will have an impact on brain research and may offer novel therapeutic interventions in various neurological conditions and psychiatric disorders.

Abstract via europepmc.

Speciesrabbit

Subjects19 animals

Sessions per subjectnot reported

Randomisedyes

Blindingnot reported

Sham / controlnone

Auditory controlnot reported

Readout timingboth

Anaesthesianot reported

Readoutsfmri, eeg meg, emg mep, other mri, behaviour, histology molecular — Visual evoked potentials (VEP; p30 component) via subdermal EEG electrodes; forelimb subdermal EMG electrodes with visual inspection of forepaw movement; MR thermometry (water proton resonant frequency); Trypan Blue and gadolinium contrast-enhanced MRI for blood-brain-barrier integrity; H&E, TUNEL and vanadium acid fuchsin (VAF) histology

Direction of effectbidirectionalFUS to the somatomotor area increased BOLD signal and elicited forepaw EMG/motor responses (excitatory), while FUS to the visual cortex during light stimulation suppressed the p30 VEP component and reduced visually evoked BOLD responses (inhibitory); the modulatory effects were explicitly described as bimodal, depending on the tone-burst duration and PRF used.

Adverse eventsnone observedMR thermometry showed no measurable temperature change during sonication except a slight rise (~0.7 C, still <0.8 C) at a much higher intensity (23 W/cm2 Isppa) and longer duration (27 s); no BBB disruption was found by Trypan Blue injection or gadolinium contrast-enhanced MRI; histological analysis (H&E, TUNEL, VAF) showed no tissue damage, apoptosis or ischemia in any animal across survival times up to 6 weeks; the peak negative pressure used (0.38 MPa at 6.4 W/cm2 Isppa) corresponded to a mechanical index of 0.5, below the FDA diagnostic limit of 1.9.

Exposures

Exposure 1: Sonication of primary somatomotor area (excitatory parameter testing, forepaw EMG, BOLD fMRI)

Target: primary motor cortex — “somatomotor area (motor cortex)”
Device: custom-built

Pulse timing
Waveform	pulsed
Fundamental frequency (kHz)	690	✓✓✓
Pulse duration (ms)	0.05, 0.5, 10, 50swept	✓✓✓
Pulse repetition frequency (Hz)	10, 20, 100, 1,000swept	✓✓✓
Duty cycle (%)	not reported
Sonication duration (s)	0.5, 1, 1.5, 2swept	✓✓✓

Pressure and intensity, by domain
Free-field pressure (kPa)	not reported
Free-field Isppa (W/cm²)	not reported
Free-field Ispta (W/cm²)	1.6, 6.3swept	✓✓✓
In-situ estimate	deratingsingle value
In-situ pressure (kPa)	380	✓✓✓⚑
In-situ Isppa (W/cm²)	3.3, 6.4, 9.5, 12.6swept	✓?
In-situ Ispta (W/cm²)	1.6, 6.3swept	✓?⚑

Protocol, in the paper’s words

A range of sonication parameters was tested under electrophysiological monitoring at the motor area: acoustic intensities (3.3, 6.4, 9.5 and 12.6 W/cm2 Isppa), tone-burst durations (TBD; 0.05, 0.5, 10 and 50 msec), pulse repetition frequencies (PRF; 10, 20, 100 and 1000 Hz), and sonication durations (0.5, 1, 1.5 and 2 s, set via the number of tone bursts, NTB). FUS given at TBD=50 msec, PRF=10 Hz and Isppa=12.6 W/cm2 (Ispta=6.3 W/cm2) for a duration equal to or greater than 1 s elicited detectable forepaw motor activity (n=4), while positive BOLD activation of the motor area was observed at a lower intensity of Isppa=3.3 W/cm2 (Ispta=1.6 W/cm2). A separate BOLD-dynamics experiment (n=4) delivered three 1-s sonications (TBD=50 msec, PRF=10 Hz) per fMRI run at Isppa=3.3 and 6.4 W/cm2.

Exposure 2: Sonication of visual cortex (suppression of VEP and visually evoked BOLD signal)

Target: primary visual cortex — “visual cortex/visual areas”
Device: custom-built

Pulse timing
Waveform	pulsed
Fundamental frequency (kHz)	690	✓✓✓
Pulse duration (ms)	0.5	✓✓✓
Pulse repetition frequency (Hz)	10, 20, 100, 1,000swept	✓✓✓
Duty cycle (%)	5	✓✓✓
Sonication duration (s)	9	✓✓✓

Pressure and intensity, by domain
Free-field pressure (kPa)	not reported
Free-field Isppa (W/cm²)	3.3, 6.4, 9.5swept	✓✓✓
Free-field Ispta (W/cm²)	not reported
In-situ estimate	deratingsingle value
In-situ pressure (kPa)	not reported
In-situ Isppa (W/cm²)	3.3, 6.4, 9.5swept	✓?
In-situ Ispta (W/cm²)	0.16	✓?

Protocol, in the paper’s words

Combinations of different PRFs (10, 20, 100 and 1000 Hz) and intensities (3.3, 6.4 and 9.5 W/cm2 Isppa) were explored at a fixed TBD of 0.5 msec to find parameters suppressing the p30 VEP component; sonication was delivered to the visual areas for 18 s total (9 s to each hemisphere) without light stimulation. The effective suppressive parameter set used for VEP (n=6) and fMRI (n=10) experiments was TBD=0.5 msec, PRF=100 Hz and AI=3.3 W/cm2 Isppa (Ispta=160 mW/cm2; 5% duty cycle), delivered as 9-s-long sonications to the unilateral visual cortex under fMRI monitoring, once every 2 min across 7 fMRI sessions.

Flags from extraction

n_subjects — 19 rabbits underwent craniotomy but 'all of the animals, except for one, recovered fully from the craniotomy and underwent the subsequent sonication experiments'; 19 (enrolled) is recorded, not the 18 that were actually sonicated.
exposures[0].in_situ.ispta_w_cm2 — List combines two values from two adjacent but distinct sentences (Ispta=1.6 W/cm2 at Isppa=3.3, and Ispta=6.3 W/cm2 at Isppa=12.6); the quoted sentence documents only the 6.3 W/cm2 value, the 1.6 W/cm2 value is quoted verbatim in the protocol_description.
exposures[0].in_situ.pressure_kpa — The 0.38 MPa peak negative pressure value is given generically in the methods (tied to Isppa=6.4 W/cm2) before the motor- and visual-cortex experiments are described separately; applied here as the only explicit pressure value in the paper.
anaesthesia — Anaesthesia (ketamine/xylazine) is explicitly stated only for the craniotomy procedure two weeks before sonication; the paper does not explicitly restate whether animals were anaesthetised during the sonication/imaging sessions themselves.
sham_type — The paper compares sonicated sites to an unsonicated control site/hemisphere within the same animals, but does not describe delivering any sham acoustic stimulus; recorded as none.
exposures[*].in_situ.method — Classified as 'derating' because the pressure amplitude at the focus was estimated by correcting the water-bath-calibrated output for attenuation through 5 mm of neural tissue (skull was removed by craniotomy, so no skull correction is involved).