Mitral valve coaptation and its relationship to late diastolic flow: A color Doppler and vector flow map echocardiographic study in normal subjects.

BACKGROUND: Three competing theories about the mechanism of mitral coaptation in normal subjects were evaluated by color Doppler and vector flow mapping (VFM): (1) beginning of ventricular (LV) ejection, (2) "breaking of the jet" of diastolic LV inflow, and (3) returning diastolic vortices impacting the leaflets on their LV surfaces. METHODS AND RESULTS: We analyzed 80 color Doppler frames and 320 VFM measurements. In all 20 normal subjects, coaptation occurred before LV ejection, 78±16 ms before onset. On color Doppler frames the larger anterior, and smaller posterior vortices circle back and, in all cases, strike the ventricular surfaces of the leaflets. On the first closing-begins frame, for the first time, vortex velocity normal to the ventricular surface of the anterior leaflet (AML) is greater than that in the mitral orifice, and the angle of attack of LV vortical flow onto the AML is twice as high as the angle of flow onto the valve in orifice. Thus, at the moment coaptation begins, vortical flow strikes the mitral leaflet with higher velocity, and higher angle of attack than orifice flow, and thus with greater force. According to the "breaking of the jet" theory, one would expect to see de novo LV flow perpendicular to the leaflets beginning after transmitral flow terminates. Instead, the returning continuous LV vortical flow that impacts the valve builds continuously after the P-wave. CONCLUSIONS: Late diastolic vortices strike the ventricular surfaces of the mitral leaflets and contribute to valve coaptation, permitted by concomitant decline in transmitral flow.

Non-invasive peripheral nerve stimulation via focused ultrasound in vivo.

Focused ultrasound (FUS) has been employed on a wide range of clinical applications to safely and non-invasively achieve desired effects that have previously required invasive and lengthy procedures with conventional methods. Conventional electrical neuromodulation therapies that are applied to the peripheral nervous system (PNS) are invasive and/or non-specific. Recently, focused ultrasound has demonstrated the ability to modulate the central nervous system and ex vivo peripheral neurons. Here, for the first time, noninvasive stimulation of the sciatic nerve eliciting a physiological response in vivo is demonstrated with FUS. FUS was applied on the sciatic nerve in mice with simultaneous electromyography (EMG) on the tibialis anterior muscle. EMG signals were detected during or directly after ultrasound stimulation along with observable muscle contraction of the hind limb. Transecting the sciatic nerve downstream of FUS stimulation eliminated EMG activity during FUS stimulation. Peak-to-peak EMG response amplitudes and latency were found to be comparable to conventional electrical stimulation methods. Histology along with behavioral and thermal testing did not indicate damage to the nerve or surrounding regions. The findings presented herein demonstrate that FUS can serve as a targeted, safe and non-invasive alternative to conventional peripheral nervous system stimulation to treat peripheral neuropathic diseases in the clinic.

Focused ultrasound-enhanced intranasal brain delivery of brain-derived neurotrophic factor.

The objective of this study was to unveil the potential mechanism of focused ultrasound (FUS)-enhanced intranasal (IN) brain drug delivery and assess its feasibility in the delivery of therapeutic molecules. Delivery outcomes of fluorescently-labeled dextrans to mouse brains by IN administration either before or after FUS sonication were compared to evaluate whether FUS enhances IN delivery by active pumping or passive diffusion. Fluorescence imaging of brain slices found that IN administration followed by FUS sonication achieved significantly higher delivery than IN administration only, while pre-treatment by FUS sonication followed by IN administration was not significantly different from IN administration only. Brain-derived neurotrophic factor (BDNF), a promising neurotrophic factor for the treatment of many central nervous system diseases, was delivered by IN followed by FUS to demonstrate the feasibility of this technique and compared with the established FUS technique where drugs are injected intravenously. Immunohistochemistry staining of BDNF revealed that FUS-enhanced IN delivery achieved similar locally enhanced delivery as the established FUS technique. This study suggested that FUS enhances IN brain drug delivery by FUS-induced active pumping of the drug and demonstrated that FUS-enhanced IN delivery is a promising technique for noninvasive and localized delivery of therapeutic molecules to the brain.