Objective: Exhaustion of Serotonin (5-hydroxytryptamine, 5-HT) is a typical cause of the depression disorder’s development and progression, including depression-like behaviors. Transcranial ultrasound stimulation (TUS) is an emerging non-invasive neuromodulation technique treating various neurodegenerative diseases. This study aims to investigate whether TUS ameliorates depression-like behaviors by restoring 5-HT levels. Methods: The depression model mice are established by chronic restraint stress (CRS). Ultrasound waves (FF = 1.1MHz, PRF = 1000 Hz, TBD = 0.5 ms, SD = 1 s, ISI = 1 s, and DC = 50%) were delivered into the dorsal raphe nucleus (DRN) for 30 min per day for two weeks. Depression-like behavior changes are evaluated with the sucrose preference and tail suspension tests. Liquid chromatography-mass spectrometry is performed to quantitatively detect the concentration of 5-HT in the DRN to explore its potential mechanism. The effectiveness and safety of TUS assessed by c-Fos immunofluorescence and hematoxylin and eosin (HE) staining, respectively. Results: Three weeks after CRS, 22 depressive mice models were screened by sucrose preference index (SPI). After two weeks of ultrasound stimulation of the DRN (DRN-TUS) in depressive mice, the SPI was increased (p = 0.1527) and the tail suspension immobility duration was significantly decreased (p = 0.0038) compared with the non-stimulated group. In addition, TUS significantly enhances the c-Fos (p = 0.05) positive cells’ expression and the 5-HT level (p = 0.0079) in the DRN. Importantly, HE staining shows no brain tissue damage. Conclusion: These results indicate that DRN-TUS has safely and effectively improved depression-like behaviors including anhedonia and hopelessness, potentially by reversing the depletion of 5-TH. Significance: TUS may provide a new perspective on depression therapy, possibly through restoring monoamine levels.

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Objective: Ultrasound neuromodulation has become an emerging method for the therapy of neurodegenerative and psychiatric diseases. The phased array ultrasonic transducer enables multi-target ultrasound neuromodulation in small animals, but the relatively large size and mass and the thick cables of the array limit the free movement of small animals. Furthermore, spatial interference may occur during multi-target ultrasound brain stimulation with multiple micro transducers. Approach: In this study, we developed a miniature power ultrasound transducer and used the virtual source time inversion method and 3-D printing technology to design, optimize, and manufacture the acoustic holographic lens to construct a multi-target ultrasound neuromodulation system for free-moving mice. The feasibility of the system was verified by in vitro transcranial ultrasound field measurements, in vivo dual-target blood-brain barrier opening experiments, and in vivo dual-target ultrasound neuromodulation experiments. Main results: The developed miniature transducer has a diameter of 4.0 mm, a center frequency of 1.1 MHz, and a weight of 1.25 g. The developed miniature acoustic holographic lens had a weight of 0.019 g to generate dual-focus transcranial ultrasound. The ultrasonic field measurements’ results showed that the bifocal’s horizontal distance was 3.0 mm, the -6 dB focal spot width in the x-direction was 2.5 and 2.25 mm, and 2.12 and 2.24 mm in the y-direction. Finally, the in vivo experimental results showed that the system could achieve dual-target blood-brain barrier opening and ultrasound neuromodulation in freely-moving mice. Significance: The ultrasonic neuromodulation system based on a miniature single-element transducer and the miniature acoustic holographic lens could achieve dual-target neuromodulation in awake small animals, which is expected to be applied to the research of non-invasive dual-target ultrasonic treatment of brain diseases in awake small animals.

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Objective. Monoamine dysfunction has been implicated as a pathophysiological basis of several mental disorders, including anxiety and depression. Transcranial ultrasound stimulation (TUS) is a noninvasive nerve stimulation technic showing great potential in treating depression/anxiety disorders. This study aims to investigate whether TUS can ameliorate depression with anxiety in mice by regulating brain monoamine levels. Approach. Mice received repeated subcutaneous injections of corticosterone (CORT, 20 mg/kg) for 3 weeks to produce depression- and anxiety-like behaviors. Ultrasound stimulated the dorsal lateral nucleus (DRN) for 30 minutes daily for 3 weeks without interruption of CORT injection. Behavioral phenotypes of depression and anxiety were estimated by sucrose preference test (SPT), tail suspension test (TST), and elevated plus-maze test (EPM). Liquid chromatography-mass spectrometry was used to quantify brain levels of serotonin (5-HT), norepinephrine (NE), and dopamine (DA). Western blotting was performed to detect brain-derived neurotrophic factor (BDNF) levels in hippocampal. Main results. TUS of DRN significantly ameliorated the depression-like behaviors in SPT (p = 0.0004) and TST (p = 0.0003) as well as anxiety-like behaviors in EPM (open arm entry frequencies, p < 0.05). Moreover, TUS increased c-Fos-positive cell expression (p = 0.0127) and induced no tissue damage. LC-MS results showed TUS of DRN resulted in a non-significant increase in the 5-HT levels and a significant decrease in the NE levels, but did not affect the levels of DA and BDNF. Significance. These results suggest TUS of DRN has safely and effectively ameliorated CORT-induced depression- and anxiety-like behaviors, possibly by restoring brain levels of 5-HT and NE. TUS may be a safe and effective technique for remedying depression and anxiety comorbidity.