Transcranial focused ultrasound as a possible treatment for major depression. Tsai Shih-Jen Medical hypotheses Antidepressants are currently used as initial therapies for major depressive disorder (MDD). However, despite the remarkable increase in medications validated as effective in MDD, treatments are still plagued by inadequate responses in part of MDD patients. For MDD with inadequate responses to medications, brain stimulation methods such as electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), vagus nerve stimulation (VNS), and deep brain stimulation (DBS) have been used as alternative strategies for treatment of depression, although each of these modalities has an indication for MDD treatment resistance and suffers from a limitation or weakness. Thus, development of new strategies based on novel theories of MDD may help to develop faster and more effective treatments for MDD. Recent studies have suggested that decreased brain brain-derived neurotrophic factor (BDNF) may be involved in the pathogenesis of MDD. Moreover, increasing brain BDNF and adult hippocampal neurogenesis have been implicated in some of the therapeutic mechanisms of antidepressants. Transcranial focused ultrasound (tFUS), a novel technique to deliver highly focused acoustic energy to a small brain region, has been used for targeted drug delivery by increasing blood-brain barrier permeability, and it can noninvasively focally modulate human cortical function. Recent animal studies have demonstrated that tFUS stimulation can increase BDNF and neurogenesis in mice. Furthermore, the increase blood-brain barrier (BBB) permeability may increase delivery of serum BDNF to the brain. From the above evidence, tFUS can increase brain BDNF levels and neurogenesis in the hippocampus, suggesting it could be an alternative strategy for the treatment of MDD. Further investigations into the frequency and duration of tFUS stimulation are needed to verify the efficacy of this intervention in depressive disorders. 10.1016/j.mehy.2015.01.030

Safety and efficacy of repetitive stimulation of the left dorsolateral prefrontal cortex using transcranial focused ultrasound in treatment-resistant depressed patients: A non-inferiority randomized controlled trial protocol. Asian journal of psychiatry BACKGROUND:About 30% of patients diagnosed with major depressive disorder fail with the mainstream pharmacological treatment. Patients who do not achieve clinical remission of symptoms, even with two different antidepressants, are classified with treatment-resistant depression (TDR). This condition imposes an additional burden with increased Disability Adjusted Life Years. Therefore, complementary treatments, such as neuromodulation, are necessary. The transcranial focused ultrasound (tFUS) has emerged in the past few years as a reliable method for non-invasive neuromodulation in humans and may help treat TRD. This study aims to propose a research protocol for a non-inferiority randomized clinical trial of TDR with tFUS. METHODS:Patients with documented TRD will be screened upon entering the TRD outpatient clinic at UFMG (Brazil). One hundred patients without a clinical history of other psychiatric illness, anatomical abnormalities on magnetic resonance imaging (MRI), or treatment with electroconvulsive therapy will be invited to participate. Patients will be randomized (1:1) into two groups: 1) treatment with a previously established protocol of transcranial magnetic stimulation; and 2) treatment with a similar protocol using the stimulation. Besides regular consultations in the outpatient clinic, both groups will attend 7 protocolled spaced days of brain stimulation targeted at the left dorsolateral prefrontal cortex. They will also be submitted to 4 sessions of image studies (2 MRIs, 2 positron-emission tomography), 3 of neuropsychological assessments (at baseline, 1 week and 2 months after treatment), the Montgomery-Åsberg Depression Rating Scale to analyze the severity of depressive symptoms. DISCUSSION:This clinical trial intends to verify the safety and clinical efficacy of tFUS stimulation of the dorsolateral prefrontal cortex of patients with TRD, compared with a previously established neuromodulation method. 10.1016/j.ajp.2024.103994

Influence of behavioral state on the neuromodulatory effect of low-intensity transcranial ultrasound stimulation on hippocampal CA1 in mouse. Wang Xingran,Zhang Yiyao,Zhang Kaiqing,Yuan Yi NeuroImage In process of brain stimulation, the influence of any external stimulus depends on the features of the stimulus and the initial state of the brain. Understanding the state-dependence of brain stimulation is very important. However, it remains unclear whether neural activity induced by ultrasound stimulation is modulated by the behavioral state. We used low-intensity focused ultrasound to stimulate the hippocampal CA1 regions of mice with different behavioral states (anesthesia, awake, and running) and recorded the neural activity in the target area before and after stimulation. We found the following: (1) there were different spike firing rates and response delays computed as the time to reach peak for all behavioral states; (2) the behavioral state significantly modulates the spike firing rate linearly increased with an increase in ultrasound intensity under different behavioral states; (3) the mean power of local field potential induced by TUS significantly increased under anesthesia and awake states; (4) ultrasound stimulation enhanced phase-locking between spike and ripple oscillation under anesthesia state. These results suggest that ultrasound stimulation-induced neural activity is modulated by the behavioral state. Our study has great potential benefits for the application of ultrasound stimulation in neuroscience. 10.1016/j.neuroimage.2021.118441

Transcranial focused ultrasound induces sustained synaptic plasticity in rat hippocampus. Brain stimulation 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. 10.1016/j.brs.2022.01.015

Transcranial focused ultrasound of the amygdala modulates fear network activation and connectivity. Brain stimulation BACKGROUND:Current noninvasive brain stimulation methods are incapable of directly modulating subcortical brain regions critically involved in psychiatric disorders. Transcranial Focused Ultrasound (tFUS) is a newer form of noninvasive stimulation that could modulate the amygdala, a subcortical region implicated in fear. OBJECTIVE:We investigated the effects of active and sham tFUS of the amygdala on fear circuit activation, skin conductance responses (SCR), and self-reported anxiety during a fear-inducing task. We also investigated amygdala tFUS' effects on amygdala-fear circuit resting-state functional connectivity. METHODS:Thirty healthy individuals were randomized in this double-blinded study to active or sham tFUS of the left amygdala. We collected fMRI scans, SCR, and self-reported anxiety during a fear-inducing task (participants viewed red or green circles which indicated the risk of receiving an aversive stimulus), as well as resting-state scans, before and after tFUS. RESULTS:Compared to sham tFUS, active tFUS was associated with decreased (pre to post tFUS) blood-oxygen-level-dependent fMRI activation in the amygdala (F(1,25) = 4.86, p = 0.04, η = 0.16) during the fear task, and lower hippocampal (F(1,27) = 4.41, p = 0.05, η = 0.14), and dorsal anterior cingulate cortex (F(1,27) = 6.26, p = 0.02; η = 0.19) activation during the post tFUS fear task. The decrease in amygdala activation was correlated with decreased subjective anxiety (r = 0.62, p = 0.03). There was no group effect in SCR changes from pre to post tFUS (F(1,23) = 0.85, p = 0.37). The active tFUS group also showed decreased amygdala-insula (F(1,28) = 4.98, p = 0.03) and amygdala-hippocampal (F(1,28) = 7.14, p = 0.01) rsFC, and increased amygdala-ventromedial prefrontal cortex (F(1,28) = 3.52, p = 0.05) resting-state functional connectivity. CONCLUSIONS:tFUS can change functional connectivity and brain region activation associated with decreased anxiety. Future studies should investigate tFUS' therapeutic potential for individuals with clinical levels of anxiety. 10.1016/j.brs.2024.03.004