Notes:
low-intensity, low-frequency ultrasound (LILFU)
By transmitting US waveforms through hippocampal slice cultures and ex vivo mouse brains, we determined LILFU is capable of remotely and noninvasively exciting neurons and network activity. Our results illustrate that LILFU can stimulate electrical activity in neurons by activating voltage-gated sodium channels, as well as voltage-gated calcium channels. The LILFU-induced changes in neuronal activity were sufficient to trigger SNARE-mediated exocytosis and synaptic transmission in hippocampal circuits. Because LILFU can stimulate electrical activity and calcium signaling in neurons as well as central synaptic transmission we conclude US provides a powerful tool for remotely modulating brain circuit activity.
*Transcranial ultrasonography of the basilar artery has been shown to trigger auditory sensations in human subjects Other studies have reported similar observations in animals during delivery of transcranial US and at least one underlying mechanism is thought to involve the direct stimulation of auditory nerve fibers by US
*The frequency of US we chose for the construction of LILFU waveforms (0.44–0.67 MHz) represents a range where optimal gains have been previously reported between transcranial US transmission and brain absorption. Based on modeling data of transmission and attenuation coefficients, as well as experimental data examining the transmission of US through ex vivo human skulls, the optimal gain for the transcranial US transmission and brain absorption is between 0.60 and 0.70 MHz [25], [26]. Based on our observations and the findings of others, it is likely that LILFU fields can be transmitted through skulls into the intact brain for gross neurostimulation purposes similar to methods using rTMS. In order to achieve targeted neurostimulation however, it will be necessary to focus LILFU fields.
*It is possible to focus US fields using a variety of approaches. Pulsed US (<1 MHz) can be focused through human skulls to points within 1 mm of intended loci using phased US transducer arrays [6], [8], [59]. Based on observations reported in studies designed to investigate US field focusing through human skulls [6], [8], [59], US may be able to confer a spatial resolution similar to those achieved by currently implemented neuromodulation strategies such as vagal nerve stimulation and DBS, which have been shown to possess high therapeutic value [1], [60].
