Low‐intensity pulsed ultrasound ameliorates depression‐like behaviors in a rat model of chronic unpredictable stress

Abstract

Introduction There is an unmet need for better nonpharmaceutical treatments for depression. Low‐intensity pulsed ultrasound (LIPUS) is a novel type of neuromodulation that could be helpful for depressed patients. Objective The goal of this study was to investigate the feasibility and potential mechanisms of LIPUS in the treatment of depression. Methods Chronic unpredictable stress (CUS) was used to generate rats with depression‐like features that were treated with four weeks of LIPUS stimulation of the ventromedial prefrontal cortex. Depression‐like behaviors were assessed with the sucrose preference, forced swim, and open field tests. BDNF/mTORC1 signaling was examined by Western blot to investigate this potential molecular mechanism. The safety of LIPUS was evaluated using hematoxylin‐eosin and Nissl staining. Results Four weeks of LIPUS stimulation significantly increased sucrose preference and reduced forced swim immobility time in CUS rats. LIPUS also partially reversed the molecular effects of CUS that included decreased levels of BDNF, phosphorylated tyrosine receptor kinase B (TrkB), extracellular signal‐regulated kinase (ERK), mammalian target of rapamycin complex 1 (mTORC1), and S6 kinase (S6K). Moreover, histological staining revealed no gross tissue damage. Conclusions Chronic LIPUS stimulation can effectively and safely improve depression‐like behaviors in CUS rats. The underlying mechanisms may be related to enhancement of BDNF/ERK/mTORC1 signaling pathways in the prefrontal cortex (PFC). LIPUS is a promising noninvasive neuromodulation tool that merits further study as a potential treatment for depression.

Neuroinflammation mechanisms of neuromodulation therapies for anxiety and depression

“…LIFUS can normalize the expression of not only inflammatory cytokines (NF-κB, TNF-α, IL-1β) but also downstream signaling proteins such as COX-2 and NF-κB [ 124 ]. In animal studies, LIPUS stimulation of the vmPFC or left PFC improved the rat’s anxiety-depression-like behavior [ 125 , 126 ]. In human studies, Sanguinetti et al found that TUS (2 MHz, 15 s) in the right inferior frontal gyrus increased positive mood for 15–30 min in healthy subjects [ 127 ].…”

Animal models for the study of depressive disorder

“…It was also shown that chronic, uncontrollable stress contributes to the impairment of the brain stimulation reward system 76 . Therefore, these reports suggest that the chronic stress animal model can be used to study depressive neuropathology, 77 and several studies used this model for the test of therapeutic targets to treat the depressive disorder 78,79 …”

“…76 Therefore, these reports suggest that the chronic stress animal model can be used to study depressive neuropathology, 77 and several studies used this model for the test of therapeutic targets to treat the depressive disorder. 78,79 In the mouse model of chronic mild stress, the mice are subjected to unpredictable mild psychosocial stressors for 9 weeks (Figure 2A). 80 From the transcriptome data, many genes showed marked expression changes in brain region including the prefrontal cortex and hippocampus, in chronic mild stress animal models (Table S2).…”

Non-invasive transcranial ultrasound stimulation for neuromodulation

“…Additionally, by using chemically deafened mice, it was shown that TUS could decrease the beta band power independent of auditory confound (Wang et al, 2020). To explore the feasibility and potential mechanisms of TUS in depression, ultrasound was applied to the ventromedial prefrontal cortex (vmPFC) of rats and mice with depression-like features (Legrand et al, 2019;Zhang et al, 2021). The chronic unpredictable stress model was used to generate depression-like behaviors, and the vmPFC was chosen because of its role in emotion regulation.…”