Focused ultrasound modulates region-specific brain activity

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.

Fig. 1

Diagram of the experimental apparatus. The ultrasound transducer was mounted on the 3-axis positioning stage and submerged into degassed water. The computer-controlled operation of a function generator produced electrical signals that actuated the ultrasound transducer after being amplified by a linear radiofrequency amplifier. A power meter was used to monitor the power input to the brain.

Fig. 2

(A) Three-dimensional acoustic intensity profile at the focal plane perpendicular to the sonication path (left inset, two-dimensional profile). The right inset shows the sonication profile along the sonication path (arrows) as detected in the MRI of a silicon gel after continuous sonication for 2 min at an acoustic intensity of 50 W/cm² (I_sppa). Bars indicate 2 mm. All values were normalized at the peak. (B) Illustration of sonication pulsing schemes. TBD indicates tone-burst-duration; PRF, pulse repetition frequency; AI, acoustic intensity; NTB, number of tone bursts.

Fig. 3

(A) Experimental setup of a rabbit with subdermal electrodes positioned in the left forepaw for motion recording (see arrow). Upon sonication, forepaw movement was observed (B and C; arrow indicates movement). (D) An example of forepaw motion recording from an animal. The signal averaged across four repeated excitations (with standard error) recorded upon the completion of 1 s-long sonication in the motor cortex (E) and away from the motor cortex (F) (n = 4).

Fig. 4

(A and B) fMRI activation maps showing selective FUS-mediated activation of the somatomotor area in the right cerebral hemisphere (visualized using a threshold of p<0.005). Spatial orientation is illustrated in the cartoon (inset). The crosshairs on the fMRI map indicate the location of the sonication focus. (C) FUS-mediated BOLD signal time course (percentage BOLD signal change) from the sonication focus (n = 4; with standard error) for two different acoustic intensities (3.3 and 6.4 W/cm² I_sppa). The BOLD signal from the unsonicated control site is shown in green line. The gray bar indicates the timing of the sonication.

Fig. 5

(A) VEP recordings from an animal. The pre-sonication baseline VEP activity is shown as a black dotted line. VEP after the application of FUS to the visual areas is shown as a solid red line, and the recovery of VEP 10 min after the sonication, is shown as a solid blue line. The gray arrow indicates the timing of visual stimulation. (B) Changes in the magnitude of the p30 component, normalized with respect to the pre-sonication level (n = 6; with standard error). * indicates a significant difference from the pre-sonication level (paired t-test; p<0.05).

Fig. 6

(A) Changes in the fMRI map of visual activity (thresholded at p<0.005) from before (top row) and after sonication (middle row), along with the map showing recovery of presonicated activity (bottom row). (B) The suppression of group-averaged (n = 10) BOLD signal upon the application of FUS and its recovery (noted “FUS+/V+”; * indicates a significant reduction at p<0.05). The unsonicated sites (FUS−/V+) did not show any reductions in BOLD contrast level. The sonication alone did not elicit any BOLD signal from the sonicated site (“FUS+/V−”). x-axis labels: pre indicates pre-sonication; FUS, during sonication; post 1 through 5, post-sonication periods.

Fig. 7

Tissue temperature measured using MR thermometry from the sonication locus (red line) and the control non-sonicated site (green line) (n = 7; shown with standard error). The sonication duration is shown by a black bar. The black solid line indicates that a slight temperature rise (less than 0.8 °C) was detected when higher acoustic intensity (I_sppa = 23 W/cm²) was given at the same pulsing scheme (i.e., TBD = 0.5 msec and PRF = 100 Hz; I_spta = 1.15 W/cm²).

Fig. 8

Histological examination of the sonicated rabbit brain. H&E stained tissue section at magnification (A) 4× and (B) 20×. Sonication did not cause any visible minor or major vascular damage. Magnified (20×) view of (C) TUNEL and (D) VAF stained sections of the rabbit's brain (black bars, 150 μm). No TUNEL positive, apoptotic cells are present. No major ischemic alteration, like acidophilic cells, were found in the VAF stained sections.