Targeted, noninvasive neuromodulation of the brain of an otherwise awake subject could revolutionize both basic and clinical neuroscience. Toward this goal, we have developed nanoparticles that allow noninvasive uncaging of a neuromodulatory drug, in this case the small molecule anesthetic propofol, upon the application of focused ultrasound. These nanoparticles are composed of biodegradable and biocompatible constituents and are activated using sonication parameters that are readily achievable by current clinical transcranial focused ultrasound systems. These particles are potent enough that their activation can silence seizures in an acute rat seizure model. Notably, there is no evidence of brain parenchymal damage or blood-brain barrier opening with their use. Further development of these particles promises noninvasive, focal, and image-guided clinical neuromodulation along a variety of pharmacological axes.

No abstract

Non-invasive gene delivery across the blood-spinal cord barrier (BSCB) remains a challenge for treatment of spinal cord injury or disease. Here, we demonstrate the use of magnetic resonance imaging-guided focused ultrasound (MRIgFUS) to mediate non-surgical gene delivery to the spinal cord, using self-complementary adeno-associated virus serotype 9 (scAAV9). scAAV9 encoding green fluorescent protein (GFP) was injected intravenously in rats. MRIgFUS allows for transient, targeted permeabilization of the BSCB through the interaction of FUS with systemically-injected Definity® lipid-shelled microbubbles. scAAV9-GFP was delivered at 3 dosages: 4×108, 2×109, and 7×109 vector genomes per gram (VG/g). Viral delivery at 2×109 and 7×109 VG/g leads to robust GFP expression in the targeted length and side of the spinal cord. At a dose of 2×109 VG/g, GFP expression was found in 36% of oligodendrocytes, and in 87% of neurons in FUS-treated areas. FUS applications to the spinal cord could address a long-term goal of gene therapy: delivering vectors from the circulation to diseased areas in a noninvasive manner.

Fibroids were successfully targeted and treated from a single transducer position to acceptable extents and without causing damage in the near- or far-field. Compared to clinical systems, treatment rates were good. The proposed treatment paradigm is a promising alternative to existing systems and warrants further investigation.

Sparse arrays are widely used in diagnostic ultrasound for their strong performance and relative technical simplicity. This simulation study assessed the efficacy of phased arrays of varied sparseness for thermal surgery, especially with regard to power consumption and near-field heating. It employs a linear ultrasound propagation model and a semi-analytical solution to the Pennes' bioheat transfer equation. The basic design had 4912 cylindrical transducers (500 kHz) arranged on a flat 12 cm disk (1.5 mm spacing). This array was compared to randomly-thinned sparse arrays with 75%, 50% and 25% populations. Temperature elevations of 60 and 70 °C were induced in sonication times of 5-20 s, at foci spanning depths of 50-150 mm and radii of 0-60 mm. The sparse arrays produced nearly indistinguishable focal patterns but, averaged across the foci, required 132%, 200% and 393% of the power of the full array, respectively, applied through fewer transducer elements. Comparable results were found at 1 MHz from equivalent arrays. Simulated lesions were formed (thermal dose ⩾ 240 equivalent minutes at 43 °C (T(43))) and 'transition' and 'unsafe' regions (both defined as 5 min < T(43) < 240 min) were identified, the former immediately surrounding the lesion and the latter anywhere else. At a depth of 100 mm, sparse arrays were found to produce comparable lesions to the full array at the focus, but 'unsafe', over-heated near-field regions after some ablated lesion volume: about 12 mL for the 25% array, around 100 mL for the 50% array, while the 75% and full arrays produced 150 mL lesions safely.

No abstract

Flat, λ/2-spaced phased arrays for therapeutic ultrasound were examined in silico and in vitro. All arrays were made by combining modules made of 64 square elements with 1.5 mm inter-element spacing along both major axes. The arrays were designed to accommodate integrated, co-aligned diagnostic transducers for targeting and monitoring. Six arrays of 1024 elements (16 modules) and four arrays of 6144 elements (96 modules) were modelled and compared according to metrics such as peak pressure amplitude, focal size, ability to be electronically-steered far off-axis and grating lobe amplitude. Two 1024 element prototypes were built and measured in vitro, producing over 100 W of acoustic power. In both cases, the simulation model of the pressure amplitude field was in good agreement with values measured by hydrophone. Using one of the arrays, it was shown that the peak pressure amplitude dropped by only 24% and 25% of the on-axis peak pressure amplitude when steered to the edge of the array (40 mm) at depths of 30 mm and 50 mm. For the 6144 element arrays studied in in silico only, similarly high steerability was found: even when steered 100 mm off-axis, the pressure amplitude decrease at the focus was less than 20%, while the maximum pressure grating lobe was only 20%. Thermal simulations indicate that the modules produce more than enough acoustic power to perform rapid ablations at physiologically relevant depths and steering angles. Arrays such as proposed and tested in this study have enormous potential: their high electronic steerability suggests that they will be able to perform ablations of large volumes without the need for any mechanical translation.

Effective preclinical research is a vital component in the development of MRI-guided focused ultrasound (MRgFUS) and its translation to clinic. In this review, we seek to outline the challenges at hand for effective preclinical research, survey different solutions, and underline best practices. Furthermore, we summarize efforts to build and characterize dedicated preclinical MRgFUS equipment, including lab prototypes and available commercial products. Finally, we discuss constraints and considerations specific to using clinical MRgFUS equipment in preclinical research. Specifically, we examine additional hardware that has been used to adapt clinical MRgFUS equipment to better position, constrain, and image preclinical subjects, as well as software solutions that have been used to extend the potential and capabilities of clinical devices.