Multi-modal transducer-waveguide construct coupled to a medical needle.

Annually, more than 16 × 109 medical needles are consumed worldwide. However, the functions of the medical needle are still limited mainly to cutting and delivering material to or from a target site. Ultrasound combined with a hypodermic needle could add value to many medical applications, for example, by reducing the penetration force needed during the intervention, adding precision by limiting the needle deflection upon insertion into soft tissues, and even improving tissue collection in fine-needle biopsy applications. In this study, we develop a waveguide construct able to operate a longitudinal-flexural conversion of a wave when transmitted from a Langevin transducer to a conventional medical needle, while maintaining high electric-to-acoustic power efficiency. The optimization of the waveguide structure was realized in silico using the finite element method followed by prototyping the construct and characterizing it experimentally. The experiments conducted at low electrical power consumption (under 5 W) show a 30 kHz flexural needle tip displacement up to 200 µm and 73% electric-to-acoustic power efficiency. This, associated with a small sized transducer, could facilitate the design of ultrasonic medical needles, enabling portability, batterization, and improved electrical safety, for applications such as biopsy, drug and gene delivery, and minimally invasive interventions.

Focused ultrasound transiently increases membrane conductance in isolated crayfish axon.

We report a novel phenomenon produced by focused ultrasound (US) that may be important for understanding its effects on cell membranes. When a US burst (2.1 MHz, 1-mm focal diameter, 0.1-1 MPa) was focused on a motor axon of the crayfish neuromuscular junction, it consistently produced a fast hyperpolarization, which was followed or superseded by subthreshold depolarizations or action potentials in a stochastic manner. The depolarization persisted in the presence of voltage-gated channel blockers [1 µM TTX ( INa), 50 µM ZD7288 ( Ih), and 200 µM 4-aminopyridine ( IK)] and typically started shortly after the onset of a 5-ms US burst, with a mean latency of 3.35 ± 0.53 ms (SE). The duration and amplitude of depolarizations averaged 2.13 ± 0.87 s and 10.1 ± 2.09 mV, with a maximum of 200 s and 60 mV, respectively. The US-induced depolarization was always associated with a decrease in membrane resistance. By measuring membrane potential and resistance during the US-induced depolarization, the reversal potential of US-induced conductance ( gus) was estimated to be -8.4 ± 2.3 mV, suggesting a nonselective conductance. The increase in gus was 10-100 times larger than the leak conductance; thus it could significantly influence neuronal activity. This change in conductance may be due to stimulation of mechanoreceptors. Alternatively, US may perturb the lateral motion of phospholipids and produce nanopores, which then increase gus. These results may be important for understanding mechanisms underlying US-mediated modulation of neuronal activity and brain function. NEW & NOTEWORTHY We report a specific increase in membrane conductance produced by ultrasound (US) on neuronal membrane. When a 5-ms US tone burst was focused on a crayfish motor axon, it stochastically triggered either depolarization or a spike train. The depolarization was up to 60 mV in amplitude and 200 s in duration and therefore could significantly influence neuronal activity. Depolarization was still evoked by US burst in the presence of Na+ and Ca2+ channel blockers and had a reversal potential of -8.4 ± 2.3 mV, suggesting a nonselective permeability. US can be applied noninvasively in the form of a focused beam to deep brain areas through the skull and has been shown to modulate brain activity. Understanding the depolarization reported here should be helpful for improving the use of US for noninvasive modulation and stimulation in brain-related disease.

Ultrasound-Enhanced Fine-Needle Biopsy Improves Yield in Human Epithelial and Lymphoid Tissue.

OBJECTIVE: Needle biopsy is a common technique used to obtain cell and tissue samples for diagnostics. Currently, two biopsy methods are widely used: (i) fine-needle aspiration biopsy (FNAB) and (ii) core needle biopsy (CNB). However, these methods have limitations. Recently, we developed ultrasound-enhanced fine-needle aspiration biopsy (USeFNAB), which employs a needle that flexurally oscillates at an ultrasonic frequency of ∼32 kHz. The needle motion contributes to increased tissue collection while preserving cells and tissue constructs for pathological assessment. Previously, USeFNAB has been investigated only in ex vivo animal tissue. The present study was aimed at determining the feasibility of using USeFNAB in human epithelial and lymphoid tissue. METHODS: Needle biopsy samples were acquired using FNAB, CNB and USeFNAB on ex vivo human tonsils (N = 10). The tissue yield and quality were quantified by weight measurement and blinded pathologists' assessments. The biopsy methods were then compared. RESULTS: The results revealed sample mass increases of, on average, 2.3- and 5.4-fold with USeFNAB compared with the state-of-the-art FNAB and CNB, respectively. The quality of tissue fragments collected by USeFNAB was equivalent to that collected by the state-of-the-art methods in terms of morphology and immunohistochemical stainings made from cell blocks as judged by pathologists. CONCLUSION: Our study indicates that USeFNAB is a promising method that could improve tissue yield to ensure sufficient material for ancillary histochemical and molecular studies for diagnostic pathology, thereby potentially increasing diagnostic accuracy.

Magnetic resonance imaging (MRI)-guided transurethral ultrasound therapy of the prostate: a preclinical study with radiological and pathological correlation using customised MRI-based moulds.

OBJECTIVE: To characterise the feasibility and safety of a novel transurethral ultrasound (US)-therapy device combined with real-time multi-plane magnetic resonance imaging (MRI)-based temperature monitoring and temperature feedback control, to enable spatiotemporally precise regional ablation of simulated prostate gland lesions in a preclinical canine model. To correlate ablation volumes measured with intra-procedural cumulative thermal damage estimates, post-procedural MRI, and histopathology. MATERIALS AND METHODS: Three dogs were treated with three targeted ablations each, using a prototype MRI-guided transurethral US-therapy system (Philips Healthcare, Vantaa, Finland). MRI provided images for treatment planning, guidance, real-time multi-planar thermometry, as well as post-treatment evaluation of efficacy. After treatment, specimens underwent histopathological analysis to determine the extent of necrosis and cell viability. Statistical analyses (Pearson's correlation, Student's t-test) were used to evaluate the correlation between ablation volumes measured with intra-procedural cumulative thermal damage estimates, post-procedural MRI, and histopathology. RESULTS: MRI combined with a transurethral US-therapy device enabled multi-planar temperature monitoring at the target as well as in surrounding tissues, allowing for safe, targeted, and controlled ablations of prescribed lesions. Ablated volumes measured by cumulative thermal dose positively correlated with volumes determined by histopathological analysis (r(2) 0.83, P < 0.001). Post-procedural contrast-enhanced and diffusion-weighted MRI showed a positive correlation with non-viable areas on histopathological analysis (r(2) 0.89, P < 0.001, and r(2) 0.91, P = 0.003, respectively). Additionally, there was a positive correlation between ablated volumes according to cumulative thermal dose and volumes identified on post-procedural contrast-enhanced MRI (r(2) 0.77, P < 0.01). There was no difference in mean ablation volumes assessed with the various analysis methods (P > 0.05, Student's t-test). CONCLUSIONS: MRI-guided transurethral US therapy enabled safe and targeted ablations of prescribed lesions in a preclinical canine prostate model. Ablation volumes were reliably predicted by intra- and post-procedural imaging. Clinical studies are needed to confirm the feasibility, safety, oncological control, and functional outcomes of this therapy in patients in whom focal therapy is indicated.

Ultrasound-Induced Membrane Hyperpolarization in Motor Axons and Muscle Fibers of the Crayfish Neuromuscular Junction.

OBJECTIVE: Focused ultrasound (FUS) can modulate neuronal activity by depolarization or hyperpolarization. Although FUS-evoked depolarization has been studied extensively, the mechanisms underlying FUS-evoked hyperpolarization (FUSH) have received little attention. In the study described here, we developed a procedure using FUS to selectively hyperpolarize motor axons in crayfish. As a previous study had reported that these axons express mechano- and thermosensitive two-pore domain potassium (K2P) channels, we tested the hypothesis that K2P channels underlie FUSH. METHODS: Intracellular recordings from a motor axon and a muscle fiber were obtained simultaneously from the crayfish opener neuromuscular preparation. FUSH was examined while K2P channel activities were modulated by varying temperature or by K2P channel blockers. RESULTS: FUSH in the axons did not exhibit a coherent temperature dependence, consistent with predicted K2P channel behavior, although changes in the resting membrane potential of the same axons indicated well-behaved K2P channel temperature dependence. The same conclusion was supported by pharmacological data; namely, FUSH was not suppressed by K2P channel blockers. Comparison between the FUS-evoked responses recorded in motor axons and muscle fibers revealed that the latter exhibited very little FUSH, indicating that the FUSH was specific to the axons. CONCLUSION: It is not likely that K2P channels are the underlying mechanism for FUSH in motor axons. Alternative mechanisms such as sonophore and axon-specific potassium channels were considered. Although the sonophore hypothesis could account for electrophysiological features of axonal recordings, it is not consistent with the lack of FUSH in muscle fibers. An axon-specific and mechanosensitive potassium channel is also a possible explanation.

Tumour hyperthermia and ablation in rats using a clinical MR-HIFU system equipped with a dedicated small animal set-up.

PURPOSE: We report on the design, performance, and specifications of a dedicated set-up for the treatment of rats on a clinical magnetic resonance high intensity focused ultrasound (MR-HIFU) system. MATERIALS AND METHODS: The small animal HIFU-compatible 4-channel MR receiver volume coil and animal support were designed as add-on to a clinical 3T Philips Sonalleve MR-HIFU system. Prolonged hyperthermia (T ≈ 42°C, 15 min) and thermal ablation (T = 65°C) was performed in vivo on subcutaneous rat tumours using 1.44 MHz acoustic frequency. The direct treatment effect was assessed with T(2)-weighted imaging and dynamic contrast enhanced (DCE-) MRI as well as histology. RESULTS: The developed HIFU-compatible coil provided an image quality that was comparable to conventional small animal volume coils (i.e. without acoustic window), and a SNR increase by a factor of 10 as compared to the coil set-up used for clinical MR-HIFU therapy. The use of an animal support minimised far field heating and allowed precise regulation of the animal body core temperature, which varied <1°C during treatment. CONCLUSIONS: The results demonstrated that, by using a designated set-up, both controlled hyperthermia and thermal ablation treatment of malignant tumours in rodents can be performed on a clinical MR-HIFU system. This approach provides all the advantages of clinical MR-HIFU, such as volumetric heating, temperature feedback control and a clinical software interface for use in rodent treatment. The use of a clinical system moreover facilitates a rapid translation of the developed protocols into the clinic.

Effects of Osmolarity on Ultrasound-Induced Membrane Depolarization in Isolated Crayfish Motor Axon.

We have previously identified a novel non-selective membrane conductance (gUS) opened by focused ultrasound (FUS) in crayfish motor axons. In the work described here, we studied gUS properties further by comparing FUS-evoked depolarization (FUSD) in control and hypotonic saline with 75% of control osmolarity. The FUS was a train of 20 FUS bursts (2.1 MHz and 50 µs per burst) delivered at 1 kHz. The amplitude, onset latency, frequency of occurrence and duration of FUSD were compared in a 15-min time window before and after switching to hypotonic saline. Significant increases were observed for amplitude (p < 0.001) and frequency of occurrence (p < 0.01) while the onset latency exhibited a significant decrease (p < 0.001). FUSD duration did not significantly differ. These results support predictions based on our hypothesis that gUS is mediated by opening of nanopores in the lipid bilayer and that stretching of axonal membrane caused by swelling at low osmolarity should increase the probability of nanopore formation under FUS. The FUSD parameters, in addition, exhibited time-dependent trends when the window of observation was expanded to 45 min in each saline. The statistical significance of amplitude and duration differed between 15- and 45-min time windows, indicating the presence of adaptive responses of axonal membrane to osmotic manipulation.

Direct Activation of Cortical Neurons in the Primary Somatosensory Cortex of the Rat in Vivo Using Focused Ultrasound.

We address the recent controversy over whether focused ultrasound (FUS) activates cortical neurons directly or indirectly by initially activating auditory pathways. We obtained two types of evidence that FUS can directly activate cortical neurons. The depth profile of the local field potential (LFP) in the barrel cortex of the rat in vivo indicated a generator was located within the cortical gray matter. The onset and peak latencies of the initial component p1 were 3.2 ± 0.25 ms (mean ± standard error of the mean) and 7.6 ± 0.12 ms, respectively, for the direct cortical response (DCR), 6.8 ± 0.40 and 14.3 ± 0.54 ms for the FUS-evoked LFP (4 MHz, 3.2 MPa, 50 or 300 µs/pulse, 1-20 pulses at 1 kHz) and 6.9 ± 0.51 and 15.8 ± 0.94 ms for the LFP evoked by 1-ms deflection of the C2 whisker projecting to the same area. The peak latency of the FUS p1 was statistically (t-test) longer than the DCR, but shorter than the whisker p1 at p < 0.005.

Volumetric HIFU ablation under 3D guidance of rapid MRI thermometry.

A volumetric sonication method is proposed that produces volume ablations by steering the focal point along a predetermined trajectory consisting of multiple concentric outward-moving circles. This method was tested in vivo on pig thigh muscle (32 ablations in nine animals). Trajectory diameters were 4, 12, and 16 mm with sonication duration depending on the trajectory size and ranging from 20 to 73 s. Despite the larger trajectories requiring more energy to reach necrosis within the desired volume, the ablated volume per unit applied energy increased with trajectory size, indicating improved treatment efficiency for larger trajectories. The higher amounts of energy required for the larger trajectories also increased the risk of off-focus heating, especially along the beam axis in the near field. To avoid related adverse effects, rapid volumetric multiplane MR thermometry was introduced for simultaneous monitoring of the temperature and thermal dose evolution along the beam axis and in the near field, as well as in the target region with a total coverage of six slices acquired every 3 s. An excellent correlation was observed between the thermal dose and both the nonperfused (R=0.929 for the diameter and R=0.964 for the length) and oedematous (R=0.913 for the diameter and R=0.939 for the length) volumes as seen in contrast-enhanced T1-weighted difference images and T2-weighted postsonication images, respectively. Histology confirmed the presence of a homogeneous necrosis inside the heated volumes. These results show that volumetric high-intensity focused ultrasound (HIFU) sonication allows for efficiently creating large thermal lesions while reducing treatment duration and also that the rapid multiplane MR thermometry improves the safety of the therapeutic procedure by monitoring temperature evolution both inside as well as outside the targeted volume.

A study of the use of Overhauser enhancement to assist with needle and catheter placement during interventional MRI.

The practicability of using Overhauser enhancement of saline in interventional MRI was investigated. Saline was used as a means of marking the path taken by a fluid-filled cavity, similar to that formed by a needle, catheter, or cannula during interventional MRI procedures. A prototype device was designed and constructed for saturation and propulsion of 0.6 ml of doped liquid. The pertinent Overhauser parameters, such as the obtainable enhancement factor, were measured. Signal enhancement in excess of 10 was demonstrated in practice by acquiring images showing an enhancement of fluid in a catheter tube.

Automatic segmentation for detecting uterine fibroid regions treated with MR-guided high intensity focused ultrasound (MR-HIFU).

PURPOSE: Up to 25% of women suffer from uterine fibroids (UF) that cause infertility, pain, and discomfort. MR-guided high intensity focused ultrasound (MR-HIFU) is an emerging technique for noninvasive, computer-guided thermal ablation of UFs. The volume of induced necrosis is a predictor of the success of the treatment. However, accurate volume assessment by hand can be time consuming, and quick tools produce biased results. Therefore, fast and reliable tools are required in order to estimate the technical treatment outcome during the therapy event so as to predict symptom relief. METHODS: A novel technique has been developed for the segmentation and volume assessment of the treated region. Conventional algorithms typically require user interaction ora priori knowledge of the target. The developed algorithm exploits the treatment plan, the coordinates of the intended ablation, for fully automatic segmentation with no user input. RESULTS: A good similarity to an expert-segmented manual reference was achieved (Dice similarity coefficient = 0.880 ± 0.074). The average automatic segmentation time was 1.6 ± 0.7 min per patient against an order of tens of minutes when done manually. CONCLUSIONS: The results suggest that the segmentation algorithm developed, requiring no user-input, provides a feasible and practical approach for the automatic evaluation of the boundary and volume of the HIFU-treated region.