Future Directions of MR-guided Focused Ultrasound.

MR-guided focused ultrasound (MRgFUS) allows for the incisionless treatment of intracranial lesions in an outpatient setting. While this is currently approved for the surgical treatment of essential tremor and Parkinson's disease, advancements in imaging and ultrasound technology are allowing for the expansion of treatment indications to other intracranial diseases. In addition, these advancements are also making MRgFUS treatments easier, safer, and more efficacious.

Identification of the Vulnerability of Atherosclerotic Plaques by a Photoacoustic/Ultrasonic Dual-Modal cRGD Nanomolecular Probe.

Objective: To explore the feasibility of using cRGD-GNR-PFP-NPs to assess plaque vulnerability in an atherosclerotic plaque mouse model by dual-modal photoacoustic/ultrasonic imaging. Methods: A nanomolecular probe containing gold nanorods (GNRs) and perfluoropentane (PFP) coated with the cyclic Arg-Gly-Asp (cRGD) peptide were prepared by double emulsion solvent evaporation and carbodiimide methods. The morphology, particle size, potential, cRGD conjugation and absorption features of the nanomolecular probe were characterized, along with its in vitro phase transformation and photoacoustic/ultrasonic dual-modal imaging properties. In vivo fluorescence imaging was used to determine the distribution of cRGD-GNR-PFP-NPs in vivo in apolipoprotein E-deficient (ApoE-/-) atherosclerotic plaque model mice, the optimal imaging time was determined, and photoacoustic/ultrasonic dual-modal molecular imaging of integrin αvß3 expressed in atherosclerotic plaques was performed. Pathological assessments verified the imaging results in terms of integrin αvß3 expression and plaque vulnerability. Results: cRGD-GNR-PFP-NPs were spherical with an appropriate particle size (average of approximately 258.03±6.75 nm), a uniform dispersion, and a potential of approximately -9.36±0.53 mV. The probe had a characteristic absorption peak at 780~790 nm, and the surface conjugation of the cRGD peptide reached 92.79%. cRGD-GNR-PFP-NPs were very stable in the non-excited state but very easily underwent phase transformation under low-intensity focused ultrasound (LIFU) and had excellent photoacoustic/ultrasonic dual-modal imaging capability. Mice fed a high-fat diet for 20 weeks had obvious hyperlipidemia with larger, more vulnerable plaques. These plaques could be specifically targeted by cRGD-GNR-PFP-NPs as determined by in vivo fluorescence imaging, and the enrichment of nanomolecular probe increased with the increasing of plaque vulnerability; the photoacoustic/ultrasound signals of the plaques in the high-fat group were stronger. The pathological assessments were in good agreement with the cRGD-GNR-PFP-NPs plaque accumulation, integrin αvß3 expression and plaque vulnerability results. Conclusion: A phase variant photoacoustic/ultrasonic dual-modal cRGD nanomolecular probe was successfully prepared and can be used to identify plaque vulnerability safely and effectively.

A Comprehensive Review of Low-Intensity Focused Ultrasound Parameters and Applications in Neurologic and Psychiatric Disorders.

OBJECTIVES: Low-intensity focused ultrasound (LIFU) is gaining increased interest as a potential therapeutic modality for a range of neuropsychiatric diseases. Current neuromodulation modalities often require a choice between high spatial fidelity or invasiveness. LIFU is unique in this regard because it provides high spatial acuity of both superficial and deep neural structures while remaining noninvasive. This new form of noninvasive brain stimulation may provide exciting potential treatment options for a variety of neuropsychiatric disorders involving aberrant neurocircuitry within deep brain structures, including pain and substance use disorders. Furthermore, LIFU is compatible with noninvasive neuroimaging techniques, such as functional magnetic resonance imaging and electroencephalography, making it a useful tool for more precise clinical neuroscience research to further understand the central nervous system. MATERIALS AND METHODS: In this study, we provide a review of the most recent LIFU literature covering three key domains: 1) the history of focused ultrasound technology, comparing it with other forms of neuromodulation, 2) the parameters and most up-to-date proposed mechanisms of LIFU, and finally, 3) a consolidation of the current literature to date surrounding the clinical research that has used LIFU for the modification or amelioration of several neuropsychiatric conditions. RESULTS: The impact of LIFU including poststroke motor changes, pain, mood disorders, disorders of consciousness, dementia, and substance abuse is discussed. CONCLUSIONS: Although still in its infancy, LIFU is a promising tool that has the potential to change the way we approach and treat neuropsychiatric disorders. In this quickly evolving field, this review serves as a snapshot of the current understanding of LIFU in neuropsychiatric research.

Progress in Noninvasive Low-Intensity Focused Ultrasound Neuromodulation.

Low-intensity focused ultrasound represents groundbreaking medical advancements, characterized by its noninvasive feature, safety, precision, and broad neuromodulatory capabilities. This technology operates through mechanisms, for example, acoustic radiation force, cavitation, and thermal effects. Notably, with the evolution of medical technology, ultrasound neuromodulation has been gradually applied in treating central nervous system diseases, especially stroke. Furthermore, burgeoning research areas such as sonogenetics and nanotechnology show promising potential. Despite the benefit of low-intensity focused ultrasound the precise biophysical mechanism of ultrasound neuromodulation still need further exploration. This review discusses the recent and ongoing developments of low-intensity focused ultrasound for neurological regulation, covering the underlying rationale to current utility and the challenges that impede its further development and broader adoption of this promising alternative to noninvasive therapy.

Model-based navigation of transcranial focused ultrasound neuromodulation in humans: Application to targeting the amygdala and thalamus.

BACKGROUND: Transcranial focused ultrasound (tFUS) neuromodulation has shown promise in animals but is challenging to translate to humans because of the thicker skull that heavily scatters ultrasound waves. OBJECTIVE: We develop and disseminate a model-based navigation (MBN) tool for acoustic dose delivery in the presence of skull aberrations that is easy to use by non-specialists. METHODS: We pre-compute acoustic beams for thousands of virtual transducer locations on the scalp of the subject under study. We use the hybrid angular spectrum solver mSOUND, which runs in ∼4 s per solve per CPU yielding pre-computation times under 1 h for scalp meshes with up to 4000 faces and a parallelization factor of 5. We combine this pre-computed set of beam solutions with optical tracking, thus allowing real-time display of the tFUS beam as the operator freely navigates the transducer around the subject' scalp. We assess the impact of MBN versus line-of-sight targeting (LOST) positioning in simulations of 13 subjects. RESULTS: Our navigation tool has a display refresh rate of ∼10 Hz. In our simulations, MBN increased the acoustic dose in the thalamus and amygdala by 8-67 % compared to LOST and avoided complete target misses that affected 10-20 % of LOST cases. MBN also yielded a lower variability of the deposited dose across subjects than LOST. CONCLUSIONS: MBN may yield greater and more consistent (less variable) ultrasound dose deposition than transducer placement with line-of-sight targeting, and thus could become a helpful tool to improve the efficacy of tFUS neuromodulation.

Low-intensity focused ultrasound to the posterior insula reduces temporal summation of pain.

BACKGROUND: The insula and dorsal anterior cingulate cortex (dACC) are core brain regions involved in pain processing and central sensitization, a shared mechanism across various chronic pain conditions. Methods to modulate these regions may serve to reduce central sensitization, though it is unclear which target may be most efficacious for different measures of central sensitization. OBJECTIVE/HYPOTHESIS: Investigate the effect of low-intensity focused ultrasound (LIFU) to the anterior insula (AI), posterior insula (PI), or dACC on conditioned pain modulation (CPM) and temporal summation of pain (TSP). METHODS: N = 16 volunteers underwent TSP and CPM pain tasks pre/post a 10 min LIFU intervention to either the AI, PI, dACC or Sham stimulation. Pain ratings were collected pre/post LIFU. RESULTS: Only LIFU to the PI significantly attenuated pain ratings during the TSP protocol. No effects were found for the CPM task for any of the LIFU targets. LIFU pressure modulated group means but did not affect overall group differences. CONCLUSIONS: LIFU to the PI reduced temporal summation of pain. This may, in part, be due to dosing (pressure) of LIFU. Inhibition of the PI with LIFU may be a future potential therapy in chronic pain populations demonstrating central sensitization. The minimal effective dose of LIFU for efficacious neuromodulation will help to translate LIFU for therapeutic options.

Noninvasive Monitoring of Tissue Temperature Changes Induced by Focused Ultrasound Exposure using Sparse Expression of Ultrasonic Radio Frequency Echo Signals.

Background: Noninvasive therapies such as focused ultrasound were developed to be used for cancer therapies, vessel bleeding, and drug delivery. The main purpose of focused ultrasound therapy is to affect regions of interest (ROI) of tissues without any injuries to surrounding tissues. In this regard, an appropriate monitoring method is required to control the treatment. Methods: This study is aimed to develop a noninvasive monitoring technique of focused ultrasound (US) treatment using sparse representation of US radio frequency (RF) echo signals. To this end, reasonable results in temperature change estimation in the tissue under focused US radiation were obtained by utilizing algorithms related to sparse optimization as orthogonal matching pursuit (OMP) and accompanying Shannon's entropy. Consequently, ex vivo tissue experimental tests yielded two datasets, including low-intensity focused US (LIFU) and high-intensity focused US (HIFU) data. The proposed processing method analyzed the ultrasonic RF echo signal and expressed it as a sparse signal and calculated the entropy of each frame. Results: The results indicated that the suggested approach could noninvasively estimate temperature changes between 37°C and 47°C during LIFU therapy. In addition, it represented temperature changes during HIFU ablation at various powers, ranging from 10 to 130 W. The normalized mean square error of the proposed method is 0.28, approximately 2.15 on previous related methods. Conclusion: These results demonstrated that this novel proposed approach, including the combination of sparsity and Shanoon's entropy, is more feasible and effective in temperature change estimation than its predecessors.

A noval noninvasive targeted therapy for osteosarcoma: the combination of LIFU and ultrasound-magnetic-mediated SPIO/TP53/PLGA nanobubble.

Purpose: Osteosarcoma (OS) is the most common type of primary malignant bone tumor. Transducing a functional TP53 gene can effectively inhibit OS cell activity. Poly lactic acid-glycolic acid (PLGA) nanobubbles (NBs) mediated by focused ultrasound (US) can introduce exogenous genes into target cells in animal models, but this technique relies on the passive free diffusion of agents across the body. The inclusion of superparamagnetic iron oxide (SPIO) in microbubbles allows for magnetic-based tissue localization. A low-intensity-focused ultrasound (LIFU) instrument was developed at our institute, and different intensities of LIFU can either disrupt the NBs (RLI-LIFU) or exert cytocidal effects on the target tissues (RHI-LIFU). Based on these data, we performed US-magnetic-mediated TP53-NB destruction and investigated its ability to inhibit OS growth when combined with LIFU both in vitro and in vivo. Methods: Several SPIO/TP53/PLGA (STP) NB variants were prepared and characterized. For the in vitro experiments, HOS and MG63 cells were randomly assigned into five treatment groups. Cell proliferation and the expression of TP53 were detected by CCK8, qRT-PCR and Western blotting, respectively. In vivo, tumor-bearing nude mice were randomly assigned into seven treatment groups. The iron distribution of Perls' Prussian blue-stained tissue sections was determined by optical microscopy. TUNEL-DAPI was performed to examine apoptosis. TP53 expression was detected by qRT-PCR and immunohistochemistry. Results: SPIO/TP53/PLGA NBs with a particle size of approximately 200 nm were prepared successfully. For in vitro experiments, ultrasound-targeted transfection of TP53 overexpression in OS cells and efficient inhibition of OS proliferation have been demonstrated. Furthermore, in a tumor-bearing nude mouse model, RLI-LIFU-magnetic-mediated SPIO/TP53/PLGA NBs increased the transfection efficiency of the TP53 plasmid, resulting in apoptosis. Adding RHI-LIFU to the treatment regimen significantly increased the apoptosis of OS cells in vivo. Conclusion: Combining LIFU and US-magnetic-mediated SPIO/TP53/PLGA NB destruction is potentially a novel noninvasive and targeted therapy for OS.

Consensus review on strategies to improve delivery across the blood-brain barrier including focused ultrasound.

Drug delivery to the central nervous system (CNS) has been a major challenge for CNS tumors due to the impermeability of the blood-brain barrier (BBB). There has been a multitude of techniques aimed at overcoming the BBB obstacle aimed at utilizing natural transport mechanisms or bypassing the BBB which we review here. Another approach that has generated recent interest in the recently published literature is to use new technologies (Laser Interstitial Thermal Therapy, LITT; or Low-Intensity Focused Ultrasound, LIFU) to temporarily increase BBB permeability. This review overviews the advantages, disadvantages, and major advances of each method. LIFU has been a major area of research to allow for chemotherapeutics to cross the BBB which has a particular emphasis in this review. While most of the advances remain in animal studies, there are an increasing number of translational clinical trials that will have results in the next few years.

LIFU/MMP-2 dual-responsive release of repurposed drug disulfiram from nanodroplets for inhibiting vasculogenic mimicry and lung metastasis in triple-negative breast cancer.

BACKGROUND: Vasculogenic mimicry (VM), when microvascular channels are formed by cancer cells independent of endothelial cells, often occurs in deep hypoxic areas of tumors and contributes to the aggressiveness and metastasis of triple-negative breast cancer (TNBC) cells. However, well-developed VM inhibitors exhibit inadequate efficacy due to their low drug utilization rate and limited deep penetration. Thus, a cost-effective VM inhibition strategy needs to be designed for TNBC treatment. RESULTS: Herein, we designed a low-intensity focused ultrasound (LIFU) and matrix metalloproteinase-2 (MMP-2) dual-responsive nanoplatform termed PFP@PDM-PEG for the cost-effective and efficient utilization of the drug disulfiram (DSF) as a VM inhibitor. The PFP@PDM-PEG nanodroplets effectively penetrated tumors and exhibited substantial accumulation facilitated by PEG deshielding in a LIFU-mediated and MMP-2-sensitive manner. Furthermore, upon exposure to LIFU irradiation, DSF was released controllably under ultrasound imaging guidance. This secure and controllable dual-response DSF delivery platform reduced VM formation by inhibiting COL1/pro-MMP-2 activity, thereby significantly inhibiting tumor progression and metastasis. CONCLUSIONS: Considering the safety of the raw materials, controlled treatment process, and reliable repurposing of DSF, this dual-responsive nanoplatform represents a novel and effective VM-based therapeutic strategy for TNBC in clinical settings.

Noninvasive intervention by transcranial ultrasound stimulation: Modulation of neural circuits and its clinical perspectives.

Low-intensity focused transcranial ultrasound stimulation (TUS) is an emerging noninvasive technique capable of stimulating both the cerebral cortex and deep brain structures with high spatial precision. This method is recognized for its potential to comprehensively perturb various brain regions, enabling the modulation of neural circuits, in a manner not achievable through conventional magnetic or electrical brain stimulation techniques. The underlying mechanisms of neuromodulation are based on a phenomenon where mechanical waves of ultrasound kinetically interact with neurons, specifically affecting neuronal membranes and mechanosensitive channels. This interaction induces alterations in the excitability of neurons within the stimulated region. In this review, we briefly present the fundamental principles of ultrasound physics and the physiological mechanisms of TUS neuromodulation. We explain the experimental apparatus and procedures for TUS in humans. Due to the focality, the integration of various methods, including magnetic resonance imaging and magnetic resonance-guided neuronavigation systems, is important to perform TUS experiments for precise targeting. We then review the current state of the literature on TUS neuromodulation, with a particular focus on human subjects, targeting both the cerebral cortex and deep subcortical structures. Finally, we outline future perspectives of TUS in clinical applications in psychiatric and neurological fields.

Low-intensity focused ultrasound modulation of the paraventricular nucleus to prevent myocardial infarction-induced ventricular arrhythmia.

BACKGROUND: Our previous study showed that light-emitting diode modulation of the hypothalamic paraventricular nucleus (PVN), which is the control center of the sympathetic nervous system, might attenuate neuroinflammation in the PVN and prevent ventricular arrhythmias (VAs) after myocardial infarction (MI). Low-intensity focused ultrasound (LIFU) has deeper penetration than does light-emitting diode, while its effect on the PVN has not been reported. OBJECTIVE: This study aimed to explore the effect of LIFU modulation of the PVN on the inducibility of post-MI VAs. METHODS: Fifty-four Sprague-Dawley rats were randomly divided into acute control (n = 12, 22.22%), acute MI (AMI, n = 12, 22.22%), AMI + LIFU (n = 12, 22.22%), chronic control (n = 6, 11.11%), chronic MI (CMI, n = 6, 11.11%), and CMI + LIFU (n = 6, 11.11%) groups. MI was induced by left anterior artery ligation, and electrocardiographic recording for 0.5 hours after MI and programmed electrophysiological stimulation were used to test the vulnerability of VAs. Peripheral sympathetic neural activity was assessed by measuring left stellate ganglion neural activity. Finally, hearts and brains were extracted for Western blotting and histopathological analysis, respectively. RESULTS: Compared with the AMI group, AMI-induced VAs (P < .05) and left stellate ganglion neural activity (P < .05) were significantly attenuated in the AMI + LIFU group. In addition, LIFU resulted in a significant reduction of microglial activation in the PVN and expression of inflammatory cytokines in the peri-ischemic myocardium. In the CMI + LIFU group, there was no obvious tissue damage in the brain. CONCLUSION: LIFU modulation of the PVN may prevent the incidence of post-MI VAs by attenuating MI-induced sympathetic neural activation and inflammatory response.

Accelerated Transcranial Ultrasound Neuromodulation in Parkinson's Disease: A Pilot Study.

OBJECTIVE: Low-intensity transcranial focused ultrasound (TUS) is a novel method for neuromodulation. We aimed to study the feasibility of stimulating the bilateral primary motor cortices (M1) with accelerated theta-burst TUS (a-tbTUS) on neurophysiologic and clinical outcomes in Parkinson's disease (PD). METHODS: Patients were randomly assigned to receive active or sham a-tbTUS for the first visit and the alternate condition on the second visit, at least 10 days apart. a-tbTUS was administered in three consecutive sonications at 30-minute intervals. We used an accelerated protocol to produce an additive effect of stimulation. Patients were studied in the OFF-medication state. Transcranial magnetic stimulation (TMS)-elicited motor-evoked potentials (MEPs) were used to assess motor cortical excitability before and after TUS. Clinical outcomes after a-tbTUS administration were assessed using the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS)-III. RESULTS: A total of 20 visits were conducted in 10 PD patients. Compared to the baseline, TMS-elicited MEP amplitudes significantly increased following active but not sham sonication (P = 0.0057). MEP amplitudes were also higher following a-tbTUS than sham sonication (P = 0.0064). There were no statistically significant changes in MDS-UPDRS-III scores with active or sham a-tbTUS. CONCLUSIONS: a-tbTUS increases motor cortex excitability and is a feasible non-invasive neuromodulation strategy in PD. Future studies should determine optimal dosing parameters and the durability of neurophysiologic and clinical outcomes in PD patients. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Focused Ultrasound, an Emerging Tool for Atherosclerosis Treatment: A Comprehensive Review.

Focused ultrasound (FUS) has emerged as a promising noninvasive therapeutic modality for treating atherosclerotic arterial disease. High-intensity focused ultrasound (HIFU), a noninvasive and precise modality that generates high temperatures at specific target sites within tissues, has shown promising results in reducing plaque burden and improving vascular function. While low-intensity focused ultrasound (LIFU) operates at lower energy levels, promoting mild hyperthermia and stimulating tissue repair processes. This review article provides an overview of the current state of HIFU and LIFU in treating atherosclerosis. It focuses primarily on the therapeutic potential of HIFU due to its higher penetration and ability to achieve atheroma disruption. The review summarizes findings from animal models and human trials, covering the effects of FUS on arterial plaque and arterial wall thrombolysis in carotid, coronary and peripheral arteries. This review also highlights the potential benefits of focused ultrasound, including its noninvasiveness, precise targeting, and real-time monitoring capabilities, making it an attractive approach for the treatment of atherosclerosis and emphasizes the need for further investigations to optimize FUS parameters and advance its clinical application in managing atherosclerotic arterial disease.

Low intensity focused ultrasound: a new prospect for the treatment of Parkinson's disease.

Background: As a chronic and progressive neurodegenerative disease, Parkinson's disease (PD) still lacks effective and safe targeted drug therapy. Low-intensity focused ultrasound (LIFU), a new method to stimulate the brain and open the blood-brain barrier (BBB), has been widely concerned by PD researchers due to its non-invasive characteristics.Methods: PubMed was searched for the past 10 years using the terms 'focused ultrasound', 'transcranial ultrasound', 'pulse ultrasound', and 'Parkinson's disease'. Relevant citations were selected from the authors' references. After excluding articles describing high-intensity focused ultrasound or non-Parkinson's disease applications, we found more than 100 full-text analyses for pooled analysis.Results: Current preclinical studies have shown that LIFU could improve PD motor symptoms by regulating microglia activation, increasing neurotrophic factors, reducing oxidative stress, and promoting nerve repair and regeneration, while LIFU combined with microbubbles (MBs) can promote drugs to cross the BBB, which may become a new direction of PD treatment. Therefore, finding an efficient drug carrier system is the top priority of applying LIFU with MBs to deliver drugs.Conclusions: This article aims to review neuro-modulatory effect of LIFU and the possible biophysical mechanism in the treatment of PD, summarize the latest progress in delivering vehicles with MBs, and discuss its advantages and limitations.

Neuro-modulatory effects of LIFU at the cellular or molecular level.Opening the BBB through the combination of LIFU and MBs.Biophysical mechanism of LIFU.

Immunotherapy Approaches in Isocitrate-Dehydrogenase-Mutant Low-Grade Glioma.

Low-grade gliomas (LGGs) are slow-growing tumors in the central nervous system (CNS). Patients characteristically show the onset of seizures or neurological deficits due to the predominant LGG location in high-functional brain areas. As a molecular hallmark, LGGs display mutations in the isocitrate dehydrogenase (IDH) enzymes, resulting in an altered cellular energy metabolism and the production of the oncometabolite D-2-hydroxyglutarate. Despite the remarkable progress in improving the extent of resection and adjuvant radiotherapy and chemotherapy, LGG remains incurable, and secondary malignant transformation is often observed. Therefore, novel therapeutic approaches are urgently needed. In recent years, immunotherapeutic strategies have led to tremendous success in various cancer types, but the effect of immunotherapy against glioma has been limited due to several challenges, such as tumor heterogeneity and the immunologically "cold" tumor microenvironment. Nevertheless, recent preclinical and clinical findings from immunotherapy trials are encouraging and offer a glimmer of hope for treating IDH-mutant LGG patients. Here, we aim to review the lessons learned from trials involving vaccines, T-cell therapies, and IDH-mutant inhibitors and discuss future approaches to enhance the efficacy of immunotherapies in IDH-mutant LGG.

A Bibliometric Analysis for Low-Intensity Ultrasound Study Over the Past Three Decades.

Low-intensity ultrasound (LI-US) is a non-invasive stimulation technique that has emerged in recent years and has been shown to have positive effects on neuromodulation, fracture healing, inflammation improvement, and metabolic regulation. This study reports the conclusions of a bibliometric analysis of LI-US. Input data for the period between 1995 and 2022, including 7209 related articles in the field of LI-US, were collected from the core library of the Web of Science (WOS) database. Using these data, a set of bibliometric indicators was obtained to gain knowledge on different aspects: global production, research areas, and sources analysis, contributions of countries and institutions, author analysis, citation analysis, and keyword analysis. This study combined the data analysis capabilities provided by the WOS database, making use of two bibliometric software tools: R software and VOS viewer to achieve analysis and data exploration visualization, and predicted the further development trends of LI-US. It turns out that the United States and China are co-leaders while Zhang ZG is the most significant author in LI-US. In the future, the hot spots of LI-US will continue to focus on parameter research, mechanism discussion, safety regulations, and neuromodulation applications.

Non-invasive neuromodulation of sub-regions of the human insula differentially affect pain processing and heart-rate variability.

The insula is a portion of the cerebral cortex folded deep within the lateral sulcus covered by the overlying opercula of the inferior frontal lobe and superior portion of the temporal lobe. The insula has been parsed into sub-regions based upon cytoarchitectonics and structural and functional connectivity with multiple lines of evidence supporting specific roles for each of these sub-regions in pain processing and interoception. In the past, causal interrogation of the insula was only possible in patients with surgically implanted electrodes. Here, we leverage the high spatial resolution combined with the deep penetration depth of low-intensity focused ultrasound (LIFU) to non-surgically modulate either the anterior insula (AI) or posterior insula (PI) in humans for effect on subjective pain ratings, electroencephalographic (EEG) contact head evoked potentials (CHEPs) and time-frequency power as well as autonomic measures including heart-rate variability (HRV) and electrodermal response (EDR). N = 23 healthy volunteers received brief noxious heat pain stimuli to the dorsum of their right hand during continuous heart-rate, EDR and EEG recording. LIFU was delivered to either the AI (anterior short gyrus), PI (posterior longus gyrus) or under an inert sham condition time-locked to the heat stimulus. Results demonstrate that single-element 500 kHz LIFU is capable of individually targeting specific gyri of the insula. LIFU to both AI and PI similarly reduced perceived pain ratings but had differential effects on EEG activity. LIFU to PI affected earlier EEG amplitudes around 300 milliseconds whereas LIFU to AI affected EEG amplitudes around 500 milliseconds. In addition, only LIFU to the AI affected HRV as indexed by an increase in standard deviation of N-N intervals (SDNN) and mean HRV low frequency power. There was no effect of LIFU to either AI or PI on EDR or blood pressure. Taken together, LIFU looks to be an effective method to individually target sub-regions of the insula in humans for site-specific effects on brain biomarkers of pain processing and autonomic reactivity that translates to reduced perceived pain to a transient heat stimulus. These data have implications for the treatment of chronic pain and several neuropsychological diseases like anxiety, depression and addiction that all demonstrate abnormal activity in the insula concomitant with dysregulated autonomic function.

Investigating the impact of skull vibrations on motor responses to focused ultrasound neuromodulation in small rodents and methods to mitigate them.

Objective. Focused ultrasound (FUS) neuromodulation non-invasively alters brain activity, likely via acoustic radiation force with dynamics of the pulse repetition frequency (PRF). PRF impacts neuromodulation as well as indirect auditory activation, a confound linked to skull vibrations. This study aimed to minimize these vibrations, by adjusting and randomizing PRF, and determine their impact on FUS-induced motor activity. We hypothesized that: the skull would vibrate most at a specific PRF; randomizing PRF would reduce skull vibrations without affecting motor responses; and FUS would yield motor activity while actuator-induced skull vibrations would not.Approach. Three objectives were studied in parallel using C57Bl/6 mice (n= number of mice used per objective). First, skull vibration amplitude, measured as a percentage of maximum amplitude per treatment, was recorded via contact microphone over a range of PRFs to assess the PRF-dependency of skull vibrations (n= 19). Vibrations were then compared between random and fixed PRFs (n= 15). Lastly, motor responses were compared between fixed 1.5 kHz PRF FUS, random PRF FUS, air-puff stimulation, sham stimulation, and vibration induction via piezoelectric actuator (n= 30).Main Results.The study found amplitude peaked at 1.51 kHz (88.1 ± 11.5%), significantly higher than at 0.54 kHz (75.5 ± 15.1%;p= 0.0149). Random PRF reduced amplitude by 4.2% (p= 0.0181). Motor response rates to actuator-induced skull vibrations at the PRF (5.73 ± 6.96%) and its third harmonic (22.9 ± 22.7%) were not significantly different than sham (14.1 ± 11.6%), but lower than FUS (70.2 ± 16.3%;p< 0.0001).Significance. Based on these results, PRF near 0.5 kHz may best avoid skull vibrations, while random PRF could be utilized to slightly reduce vibration amplitude. The results also suggested that skull vibrations likely do not significantly impact motor responses to FUS neuromodulation.