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Noninvasive transcranial stimulation of rat abducens nerve by focused ultrasound.

ABSTRACT: Nonpharmacologic and nonsurgical transcranial modulation of the nerve function may provide new opportunities in evaluation and treatment of cranial nerve diseases. This study investigates the possibility of using low-intensity transcranial focused ultrasound (FUS) to selectively stimulate the rat abducens nerve located above the base of the skull. FUS (frequencies of 350 kHz and 650 kHz) operating in a pulsed mode was applied to the abducens nerve of Sprague-Dawley rats under stereotactic guidance. The abductive eyeball movement ipsilateral to the side of sonication was observed at 350 kHz, using the 0.36-msec tone burst duration (TBD), 1.5-kHz pulse repetition frequency (PRF), and the overall sonication duration of 200 msec. Histologic and behavioral monitoring showed no signs of disruption in the blood brain barrier (BBB), as well as no damage to the nerves and adjacent brain tissue resulting from the sonication. As a novel functional neuro-modulatory modality, the pulsed application of FUS has potential for diagnostic and therapeutic applications in diseases of the peripheral nervous system.

SUBMITTER: Kim H

PROVIDER: S-EPMC3428140 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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Noninvasive transcranial stimulation of rat abducens nerve by focused ultrasound.

Kim Hyungmin H Taghados Seyed Javid SJ Fischer Krisztina K Maeng Lee-So LS Park Shinsuk S Yoo Seung-Schik SS

Ultrasound in medicine & biology 20120703 9

Nonpharmacologic and nonsurgical transcranial modulation of the nerve function may provide new opportunities in evaluation and treatment of cranial nerve diseases. This study investigates the possibility of using low-intensity transcranial focused ultrasound (FUS) to selectively stimulate the rat abducens nerve located above the base of the skull. FUS (frequencies of 350 kHz and 650 kHz) operating in a pulsed mode was applied to the abducens nerve of Sprague-Dawley rats under stereotactic guidan ...[more]

PMID: 22763009

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Project description:Transcranial focused ultrasound (tFUS) neuromodulation provides a promising emerging non-invasive therapy for the treatment of neurological disorders. Many studies have demonstrated the ability of tFUS to elicit transient changes in neural responses. However, the ability of tFUS to induce sustained changes need to be carefully examined. In this study, we use the long-term potentiation/long term depression (LTP/LTD) model in the rat hippocampus, the medial perforant path (mPP) to dentate gyrus (DG) pathway, to explore whether tFUS is capable of encoding frequency specific information to induce plasticity. Single-element focused transducers were used for tFUS stimulation with ultrasound fundamental frequency of 0.5 MHz and nominal focal distance of 38 mm tFUS stimulation is directed to mPP. Measurement of synaptic connectivity is achieved through the slope of field excitatory post synaptic potentials (fEPSPs), which are elicited using bipolar electrical stimulation electrodes and recorded at DG using extracellular electrodes to quantify degree of plasticity. We applied pulsed tFUS stimulation with total duration of 5 min, with 5 levels of pulse repetition frequencies each administered at 50 Hz sonication frequency at the mPP. Baseline fEPSP is recorded 10 min prior, and 30+ minutes after tFUS administration. In N = 16 adult wildtype rats, we observed sustained depression of fEPSP slope after 5 min of tFUS focused at the presynaptic field mPP. Across all PRFs, no significant difference in maximum fEPSP slope change was observed, average tFUS induced depression level was observed at 19.6%. When compared to low frequency electrical stimulation (LFS) of 1 Hz delivered to the mPP, the sustained changes induced by tFUS stimulation show no statistical difference to LFS for up to 24 min after tFUS stimulation. When both the maximum depression effects and the duration of sustained effects are both taken into account, PRF 3 kHz can induce significantly larger effects than other PRFs tested. tFUS stimulation is measured with a spatial-peak pressure amplitude of 99 kPa, translating to an estimation of 0.43 °C temperature increase when assuming no loss of heat. The results suggest the ability of tFUS to encode sustained changes in synaptic connectivity through mechanism which are unlikely to involve thermal changes.

Project description:BackgroundLow-intensity transcranial focused ultrasound (tFUS) has emerged as a new non-invasive modality of brain stimulation with the potential for high spatial selectivity and penetration depth. Anesthesia is typically applied in animal-based tFUS brain stimulation models; however, the type and depth of anesthesia are known to introduce variability in responsiveness to the stimulation. Therefore, the ability to conduct sonication experiments on awake small animals, such as rats, is warranted to avoid confounding effects of anesthesia.ResultsWe developed a miniature tFUS headgear, operating at 600 kHz, which can be attached to the skull of Sprague-Dawley rats through an implanted pedestal, allowing the ultrasound to be transcranially delivered to motor cortical areas of unanesthetized freely-moving rats. Video recordings were obtained to monitor physical responses from the rat during acoustic brain stimulation. The stimulation elicited body movements from various areas, such as the tail, limbs, and whiskers. Movement of the head, including chewing behavior, was also observed. When compared to the light ketamine/xylazine and isoflurane anesthetic conditions, the response rate increased while the latency to stimulation decreased in the awake condition. The individual variability in response rates was smaller during the awake condition compared to the anesthetic conditions. Our analysis of latency distribution of responses also suggested possible presence of acoustic startle responses mixed with stimulation-related physical movement. Post-tFUS monitoring of animal behaviors and histological analysis performed on the brain did not reveal any abnormalities after the repeated tFUS sessions.ConclusionsThe wearable miniature tFUS configuration allowed for the stimulation of motor cortical areas in rats and elicited sonication-related movements under both awake and anesthetized conditions. The awake condition yielded diverse physical responses compared to those reported in existing literatures. The ability to conduct an experiment in freely-moving awake animals can be gainfully used to investigate the effects of acoustic neuromodulation free from the confounding effects of anesthesia, thus, may serve as a translational platform to large animals and humans.

Project description:Focused ultrasound is a promising therapeutic technique, as it involves the focusing of an ultrasonic beam with sufficient acoustic energy into a target brain region with high precision. Low-intensity ultrasound transmission by a single-element transducer is mostly established for neuromodulation applications and blood-brain barrier disruption for drug delivery. However, transducer positioning errors can occur without fine control over the sonication, which can affect repeatability and lead to reliability problems. The objective of this study was to determine whether the target brain region would be stable under small displacement (0.5 mm) of the transducer based on numerical simulations. Computed-tomography-derived three-dimensional models of a rat head were constructed to investigate the effects of transducer displacement in the caudate putamen (CP) and thalamus (TH). Using three different frequencies (1.1, 0.69, and 0.25 MHz), the transducer was displaced by 0.5 mm in each of the following six directions: superior, interior, anterior, posterior, left, and right. The maximum value of the intracranial pressure field was calculated, and the targeting errors were determined by the full-width-at-half-maximum (FWHM) overlap between the free water space (FWHMwater) and transcranial transmission (FWHMbase). When the transducer was positioned directly above the target region, a clear distinction between the target regions was observed, resulting in 88.3%, 81.5%, and 84.5% FWHMwater for the CP and 65.6%, 76.3%, and 64.4% FWHMwater for the TH at 1.1, 0.69, and 0.25 MHz, respectively. Small transducer displacements induced both enhancement and reduction of the peak pressure and targeting errors, compared with when the transducer was displaced in water. Small transducer displacement to the left resulted in the lowest stability, with 34.8% and 55.0% targeting accuracy (FWHMwater) at 1.1 and 0.69 MHz in the TH, respectively. In addition, the maximum pressure was reduced by up to 11% by the transducer displacement. This work provides the targeting errors induced by transducer displacements through a preclinical study and recommends that attention be paid to determining the initial sonication foci in the transverse plane in the cases of small animals.

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Noninvasive transcranial stimulation of rat abducens nerve by focused ultrasound.

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Noninvasive transcranial stimulation of rat abducens nerve by focused ultrasound.

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