Search

Introduction: Opioid use disorder (OUD) is a serious and persistent problem in the United States with limited non-pharmacological treatment options, especially for the concomitant sleep disorders experienced by most individuals with addiction. While new, non-invasive interventions such as low-intensity focused ultrasound (LIFU) have shown promise in targeting the brain regions impacted throughout addiction and recovery, the devices used are not amenable to outpatient treatment in their current form factor and cannot be used at night during sleep. To bridge this gap and provide a much-needed treatment option for repeated, at-home use, we developed a wearable LIFU device out-of-clinic use. Methods: This study evaluated the feasibility and acceptability of the portable treatment device among individuals recovering from OUD in an unsupervised, at-home setting. 31 subjects were recruited from a Baltimore, Maryland (USA) outpatient treatment facility and, along with a separate group of 14 healthy controls (HC), were asked to wear a prototype EEG-only (non-LIFU) device for 7 consecutive nights to assess their willingness and adherence to nightly use. Participants used a smartphone application, TrialKit (ePRO), to self-report nightly sleep data (e.g. duration, quality, possible disturbances, and device comfort). Results: Of the 31 OUD participants recruited, 30 (97%) successfully completed the at-home study, and the majority responded that they would participate in future studies using the head wearable device (OUD, 87%; HC, 71%). OUD participants were statistically more likely than HCs to respond that they would consider using the device in the future to help them sleep (OUD, 70%; HC, 29%). Despite some participants facing technological issues (e.g. lack of reliable phone access or cellular data plans), the OUD group demonstrated high study compliance on par with the healthy control group. Discussion: Participant's daily ePRO and exit interview results established that at-home use of advanced treatment technology is feasible in a population group challenged with recovering from OUD. Even more so, numerous participants noted strong willingness to participate in future LIFU-enabled intervention studies to address their persistent sleep issues during recovery. [ABSTRACT FROM AUTHOR]

Objective. To evaluate the feasibility of transspine focused ultrasound using simulation-based phase corrections from a CT-derived ray acoustics model. Approach. Bilateral transspine focusing was performed in ex vivo human vertebrae with a spine-specific ultrasound array. Ray acoustics-derived phase correction was compared to geometric focusing and a hydrophone-corrected gold standard. Planar hydrophone scans were recorded in the spinal canal and three metrics were calculated: target pressure, coronal and sagittal focal shift, and coronal and sagittal Sørensen–Dice similarity to the free-field. Post hoc analysis was performed in silico to assess the impact of windows between vertebrae on focal shift. Main results. Hydrophone correction reduced mean sagittal plane shift from 1.74 ± 0.82 mm to 1.40 ± 0.82 mm and mean coronal plane shift from 1.07 ± 0.63 mm to 0.54 ± 0.49 mm. Ray acoustics correction reduced mean sagittal plane and coronal plane shift to 1.63 ± 0.83 mm and 0.83 ± 0.60 mm, respectively. Hydrophone correction increased mean sagittal similarity from 0.48 ± 0.22 to 0.68 ± 0.19 and mean coronal similarity from 0.48 ± 0.23 to 0.70 ± 0.19. Ray acoustics correction increased mean sagittal and coronal similarity to 0.53 ± 0.25 and 0.55 ± 0.26, respectively. Target pressure was relatively unchanged across beamforming methods. In silico analysis found that, for some targets, unoccluded paths may have increased focal shift. Significance. Gold standard phase correction significantly reduced coronal shift and significantly increased sagittal and coronal Sørensen–Dice similarity (p < 0.05). Ray acoustics-derived phase correction reduced sagittal and coronal shift and increased sagittal and coronal similarity but did not achieve statistical significance. Across beamforming methods, mean focal shift was comparable to MRI resolution, suggesting that transspine focusing is possible with minimal correction in favourable targets. Future work will explore the mitigation of acoustic windows with anti-focus control points. [ABSTRACT FROM AUTHOR]

Systemic delivery of adeno-associated virus (AAV) vectors targeting the central nervous system has the potential to solve many neurodevelopmental disorders, yet it is made difficult by the filtering effect of the blood-brain barrier and systemic complications. To overcome this limitation, we attempted to inject a Venus-expressing, oligodendrocyte-selective AAV9 viral vector in the ventricles together with lipid microbubbles and subjected them to focused ultrasound (FUS); the resulting mechanical stimulation on the brain ventricles is able to open small, temporary gaps from which vector particles can leak and spread. Our findings indicate that FUS can increase viral vector diffusion across both the anteroposterior and left-right axes without influencing cell tropism; significant effects were found with 60 and 90 s exposure time, but no effects were observed with longer intervals. Taken together, these results highlight a new strategy for the safe and effective delivery of viral vectors and offer new perspectives for the development and application of gene therapies for central nervous system diseases. [ABSTRACT FROM AUTHOR]

Background: Growing demand for facial rejuvenation drives advancements in these therapies, including laser, radiofrequency, and focused ultrasound, alongside thermal stimulation adjuncts. These methods, known for stimulating collagen regeneration, skin tightening, and lifting, have gained popularity due to their minimal side effects, low trauma, and high safety, demonstrating favorable outcomes in clinical practice. Objective: We sought to assess the efficacy of ultrasound skin tightening for brow lift within the scope of a procedure addressing facial sagging across the entire face. Our aim was to explore a noninvasive method capable of effectively enhancing mild to moderate brow ptosis by tightening and lifting the skin in the upper facial region. Methods: This was a rater‐blinded, prospective cohort study. The upper facial region of the participants was treated with the new device, micro‐focused ultrasound (MFU), in model D3.0/D2.0/M3.0. Outcomes of brow lift were measured in comparison of pretreatment and posttreatment photographs and three‐dimensional (3D) vector analysis. Results: A total of 42 participants (37 females) were enrolled, with 2 participants withdrawing from the trial, resulting in 40 subjects who completed 180‐day‐follow‐up and evaluation. 35 (87.5%) were deemed to have clinically significant brow elevation by two blinded assessors (experienced clinicians) at 180‐day posttreatment (p < 0.01). The mean change in brow height after 90‐day was 2.16 ± 0.63 mm at the frontal position (straight‐ahead gaze) (p < 0.01). The 3D vector analysis reveals varying magnitudes of vector displacement in the upward and outward directions of the skin on the frontal region above the eyebrows. Conclusion: Focused ultrasound appears to be a safe and effective method for upper facial skin rejuvenation. A single focused ultrasound treatment on the forehead and temple areas resulted in an average brow elevation of 2.1 mm. [ABSTRACT FROM AUTHOR]

Low-boiling point perfluorocarbon nanodroplets (NDs) are valued as effective sonosensitive agents, encapsulating a liquid perfluorocarbon that would instantaneously vaporize at body temperature without the NDs shell. Those NDs have been explored for both therapeutic and diagnostic purposes. Here, phospholipid-shelled nanodroplets containing octafluoropropane (C 3 F 8) or decafluorobutane (C 4 F 10) formed by condensation of microbubbles were thoroughly characterized before blood-brain (BBB) permeabilization. Transmission electron microscopy (TEM) and cryo-TEM were employed to confirm droplet formation while providing high-resolution insights into the droplet surface and lipid arrangement assessed from electron density observation after condensation. The vaporization threshold of NDs was determined with a high-speed camera, and the frequency signal emitted by the freshly vaporized bubbles was analyzed using cavitation detection. C 3 F 8 NDs exhibited vaporization at 0.3 MPa (f 0 = 1.5 MHz, 50 cycles), and emitted signals at 2 f 0 and 1.5 f 0 from 0.45 MPa onwards (f 0 = 1.5 MHz, 50 cycles), while broadband noise was measured starting from 0.55 MPa. NDs with the higher boiling point C 4 F 10 vaporized at 1.15 MPa and emitted signals at 2 f 0 from 0.65 MPa and 1.5 f 0 from 0.9 MPa, while broadband noise was detected starting from 0.95 MPa. Both ND formulations were used to permeabilize the BBB in healthy mice using tailored ultrasound sequences, allowing for the identification of optimal applications for each NDs type. C 3 F 8 NDs proved suitable and safe for permeabilizing a large area, potentially the entire brain, at low acoustic pressure. Meanwhile, C 4 F 10 droplets facilitated very localized (400 μm isotropic) permeabilization at higher pressure. This study prompts a closer examination of the structural rearrangements occurring during the condensation of microbubbles into NDs and highlights the potential to tailor solutions for different brain pathologies by choosing the composition of the NDs and adjusting the ultrasound sequence. [Display omitted] [ABSTRACT FROM AUTHOR]

Low-intensity histotripsy (LIH) is a novel and safe technique for tissue ablation. This study aimed to explore the effects of LIH on canine prostate tissue and identify the degree of acute injury to the gland. We constructed and evaluated two types of acoustically responsive droplet (ARD) emulsions using either perfluoropentane (PFP) with a lipid shell or perfluoromethyl-cyclopentane (PFMCP) with lauromacrogol (L) injection. Twenty beagles were assigned to four experimental groups: ultrasound (US) + PFP (n = 6), US + PFMCP-L (n = 6), PFMCP-L (n = 5) and PFP (n = 3). The ARDs were injected transcutaneously and transabdominally into normal canine prostates under US-guided imaging. Subsequently, focused therapeutic US was employed to induce acoustic droplet vaporization and bubble cloud cavitation. The mechanical damage to canine prostate tissue was evaluated using gross and histological examination. Gross specimens showed that the injured area was dark brown. Hematoxylin and eosin-stained tissue sections of the damage zone showed significant cavity formation and interstitial edema. The total tissue damage scores in the US + PFP group were compared to those of the other three experimental groups. No statistically significant differences were observed in the extent of tissue damage and total scores among the US + PFMCP-L, PFMCP-L and PFP groups. We achieved significant mechanical tissue damage in the canine prostate using PFP ARD-based LIH that proved to be superior to that using PFMCP ARDs with LIH. [ABSTRACT FROM AUTHOR]

Tamoxifen is the most used agent to treat estrogen receptor-positive (ER+) breast cancer (BC). While it decreases the risk of cancer recurrence by 50%, many patients develop resistance to this treatment, culminating in highly aggressive disease. Tamoxifen resistance comes from the repression of ER transcriptional activity that switches the cancer cells to proliferation via nonhormonal signaling pathways. Here, we evaluate a potential strategy to overcome tamoxifen resistance by focused ultrasound (FUS), a noninvasive approach for the mechanical excitation of cancer cells. Resistant and nonresistant ER+ BC cells and xenografts from patients with ER+ BC were treated with tamoxifen, FUS or their combination. The apoptosis, proliferation rate, gene expression and activity of estrogen receptor, and morphological changes were measured in treated cells and tissues. FUS caused the mechanical disruption of tamoxifen-resistant BC cells that in turn led to the upregulation of ERα-encoding gene expression and long-term re-sensitization of the cells to tamoxifen. Patient-derived xenografts treated with Tamoxifen and FUS demonstrated a significant reduction in tumor viability and proliferation and a strong structural damage to tumor cells and extracellular matrix. FUS can improve ER+ BC treatment by re-sensitizing the cancer cells to tamoxifen. [ABSTRACT FROM AUTHOR]

This study explores the feasibility of using low-intensity focused ultrasound (LIFU) to induce rotational sensations in the human semicircular canal (SCC) through the acoustic streaming effect. Existing vestibular stimulation methods, such as galvanic vestibular stimulation (GVS), caloric vestibular stimulation (CVS), and magnetic vestibular stimulation (MVS), face limitations in spatial and temporal resolution, with unclear mechanisms. This study investigates whether LIFU can overcome these limitations by modulating endolymph motion within SCC. A 3D finite element model was constructed to simulate the effects of LIFU-induced acoustic streaming on SCC (particularly the endolymph), with thermal effects evaluated to ensure safety. Fluid–structure interaction (FSI) was used to analyze the relationship between endolymph flow and cupula deformation. By adjusting the focal point of the ultrasound transducer, we were able to alter fluid flow pattern, which resulted in variations in cupula displacement. The results demonstrated that LIFU successfully induces fluid motion in SCC without exceeding thermal safety limits (<1 °C), suggesting its potential for controlling rotational sensations, with cupula displacement exceeding 1 μm. This novel approach enhances the understanding of LIFU's thermal and neuromodulatory effects on the vestibular system, and thereby offers promising implications for future therapeutic applications. [ABSTRACT FROM AUTHOR]

Various preclinical and clinical studies have demonstrated the neuromodulatory and ablative effects of focused ultrasound (FUS). However, the safety and efficacy of FUS in clinical settings for treating epilepsy have not been well established. This study aims to provide a systematic review of all preclinical and clinical studies that have used FUS for the treatment of epilepsy. A systematic search was conducted using Scopus, Web of Science, PubMed, and Embase databases. All preclinical and clinical studies reporting outcomes of FUS in the treatment of epilepsy were included in the systematic review. Random-effect meta-analysis was performed to determine safety in clinical studies and seizure activity reduction in preclinical studies. A total of 24 articles were included in the study. Meta-analysis demonstrated that adverse events occurred in 13% (95% CI = 2–57%) of patients with epilepsy who underwent FUS. The frequency of adverse events was higher with the use of FUS for lesioning (36%, 95% CI = 4–88%) in comparison to neuromodulation (5%, 95% CI = 0–71%), although this difference was not significant (P = 0.31). Three-level meta-analysis in preclinical studies demonstrated a reduced spike rate in neuromodulating FUS compared to the control group (P = 0.02). According to this systematic review and meta-analysis, FUS can be considered a safe and feasible approach for treating epileptic seizures, especially in drug-resistant patients. While the efficacy of FUS has been demonstrated in several preclinical studies, further research is necessary to confirm its effectiveness in clinical practice and to determine the adverse events. [ABSTRACT FROM AUTHOR]

Transcranial focused ultrasound has been studied for non-invasive and localized treatment of many brain diseases. The biggest challenge for focusing ultrasound onto the brain is the skull, which attenuates ultrasound and changes its propagation direction, leading to pressure drop, focus shift, and defocusing. We presented an optimization algorithm which automatically found the optimal location for placing a single-element focused transducer. At this optimal location, the focus shift was in an acceptable range and the ultrasound was tightly focused. The algorithm simulated the beam profiles of placing the transducer at different locations and compared the results. Locations with a normalized peak-negative pressure (PNP) above threshold were first found. Then, the optimal location was identified as the location with the smallest focal volume. The optimal location found in this study had a normalized PNP of 0.966 and a focal volume of 6.8% smaller than without the skull. A Zeta navigation system was used to automatically place the transducer and track the error caused by movement. These results demonstrated that the algorithm could find the optimal transducer location to avoid large focus shift and defocusing. With the Zeta navigation system, our algorithm can help to make transcranial focused ultrasound treatment safer and more successful. [ABSTRACT FROM AUTHOR]

• Low-intensity focused ultrasound (LIFU) can target insular and cingulate cortex subregions. • Modulation of the anterior and posterior insula differentially decreased the heartbeat evoked potential (HEP). • The effects on the HEP were partially explained by LIFU pressure. The heartbeat evoked potential (HEP) is a brain response time-locked to the heartbeat and a potential marker of interoceptive processing that may be generated in the insula and dorsal anterior cingulate cortex (dACC). Low-intensity focused ultrasound (LIFU) can selectively modulate sub-regions of the insula and dACC to better understand their contributions to the HEP. Healthy participants (n = 16) received stereotaxically targeted LIFU to the anterior insula (AI), posterior insula (PI), dACC, or Sham at rest during continuous electroencephalography (EEG) and electrocardiography (ECG) recording on separate days. Primary outcome was HEP amplitudes. Relationships between LIFU pressure and HEP changes and effects of LIFU on heart rate and heart rate variability (HRV) were also explored. Relative to sham, LIFU to the PI, but not AI or dACC, decreased HEP amplitudes; PI effects were partially explained by increased LIFU pressure. LIFU did not affect heart rate or HRV. These results demonstrate the ability to modulate HEP amplitudes via non-invasive targeting of key interoceptive brain regions. Our findings have implications for the causal role of these areas in bottom-up heart-brain communication that could guide future work investigating the HEP as a marker of interoceptive processing in healthy and clinical populations. [ABSTRACT FROM AUTHOR]

Background Objective Methods Results Conclusion No clinical trials have been reported on the use of focused ultrasound (FUS) for treating cervical dystonia.We aimed to confirm the efficacy and safety of FUS pallidothalamic tractotomy for cervical dystonia.This was a prospective, open‐label, non‐controlled pilot study. The primary outcome was defined as a change in the score for the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) from baseline to 6 months after FUS pallidothalamic tractotomy. The secondary outcomes included a change in the neck scale for the Burke‐Fahn‐Marsden Dystonia Rating Scale (BFMDRS), mood scales including Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), Apathy Evaluating Scale (AES), and adverse events. Patients were assessed for TWSTRS, BFMDRS, and adverse events at baseline, 1 week, 1 month, 3 months, and 6 months after treatment. BDI, BAI, and AES were assessed at baseline and 6 months after treatment.Ten patients were enrolled in this study. The mean age of onset of dystonia was 51.6 ± 10.2 years. The TWSTRS at 6 months (29.9 ± 16.0, range: 3–55) was significantly improved by 43.4% (P < 0.001) from baseline. The BFMDRS‐Neck scales at 6 months (4.2 ± 2.8) were significantly improved by 38.2% (P < 0.001) from baseline. The BDI, BAI, and AES at 6 months were improved by 23.2%, 10.9%, and 30.3%, respectively from baseline. Reduced hand dexterity in three patients and weight gain in two patients were confirmed at the last evaluation.This study suggests that FUS pallidothalamic tractotomy may be an effective treatment option for patients with cervical dystonia. © 2024 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Purpose: Brain tumors, particularly glioblastoma multiforme (GBM), present significant prognostic challenges despite multimodal therapies, including surgical resection, chemotherapy, and radiotherapy. One major obstacle is the limited drug delivery across the blood–brain barrier (BBB). Focused ultrasound (FUS) combined with systemically administered microbubbles has emerged as a non-invasive, targeted, and reversible approach to transiently open the BBB, thus enhancing drug delivery. This review examines clinical trials employing BBB opening techniques to optimise pharmacotherapy for brain tumors, evaluates current challenges, and proposes directions for further research. Methods: A systematic literature search was conducted in PubMed and ClinicalTrials.gov up to November 2023, searching for "ultrasound" AND "brain tumor". The search yielded 1446 results. After screening by title and abstract, followed by full-text screening (n = 48), 35 studies were included in the analysis. Results: Our analysis includes data from 11 published studies and 24 ongoing trials. The predominant focus of these studies is on glioma, including GMB and astrocytoma. One paper investigated brain metastasis from breast cancer. Evidence indicates that FUS facilitates BBB opening and enhances drug uptake following sonication. Exploration of FUS in the pediatric population is limited, with no published studies and only three ongoing trials dedicated to this demographic. Conclusion: FUS is a promising strategy to safely disrupt the BBB, enabling precise and non-invasive lesion targeting, and enhance drug delivery. However, pharmacokinetic studies are required to quantitatively assess improvements in drug uptake. Most studies are phase I clinical trials, and long-term follow-up investigating patient outcomes is essential to evaluate the clinical benefit of this treatment approach. Further studies involving diverse populations and pathologies will be beneficial. [ABSTRACT FROM AUTHOR]

The basal ganglia are involved in motor control and action selection, and their impairment manifests in movement disorders such as Parkinson's disease (PD) and dystonia, among others. The complex neuronal circuitry of the basal ganglia is located deep inside the brain and presents significant treatment challenges. Conventional treatment strategies, such as invasive surgeries and medications, may have limited effectiveness and may result in considerable side effects. Non-invasive ultrasound (US) treatment approaches are becoming increasingly recognized for their therapeutic potential for reversibly permeabilizing the blood-brain barrier (BBB), targeting therapeutic delivery deep into the brain, and neuromodulation. Studies conducted on animals and early clinical trials using ultrasound as a therapeutic modality have demonstrated promising outcomes for controlling symptom severity while preserving neural tissue. These results could improve the quality of life for patients living with basal ganglia impairments. This review article explores the therapeutic frontiers of ultrasound technology, describing the brain mechanisms that are triggered and engaged by ultrasound. We demonstrate that this cutting-edge method could transform the way neurological disorders associated with the basal ganglia are managed, opening the door to less invasive and more effective treatments. [ABSTRACT FROM AUTHOR]

Low-intensity transcranial focused ultrasound stimulation (TUS) is a novel technique for noninvasive brain stimulation (NIBS). TUS delivered in a theta (5 Hz) burst pattern (tbTUS) induces plasticity in the human primary motor cortex (M1) for 30–60 min, showing promise for therapeutic development. Metaplasticity refers to activity-dependent changes in neural functions governing synaptic plasticity; depotentiation is the reversal of long-term potentiation (LTP) by a subsequent protocol with no effect alone. Metaplasticity can enhance plasticity induction and clinical efficacy of NIBS protocols. In our study, we compared four NIBS protocol combinations to investigate metaplasticity on tbTUS in humans of either sex. We delivered four interventions: (1) sham continuous theta burst stimulation with 150 pulses (cTBS150) followed by real tbTUS (tbTUS only), (2) real cTBS150 followed by sham tbTUS (cTBS only), (3) real cTBS150 followed by real tbTUS (metaplasticity), and (4) real tbTUS followed by real cTBS150 (depotentiation). We measured motor-evoked potential amplitude, short-interval intracortical inhibition, long-interval intracortical inhibition, intracortical facilitation (ICF), and short-interval intracortical facilitation before and up to 90 min after plasticity intervention. Plasticity effects lasted at least 60 min longer when tbTUS was primed with cTBS150 compared with tbTUS alone. Plasticity was abolished when cTBS150 was delivered after tbTUS. cTBS150 alone had no significant effect. No changes in M1 intracortical circuits were observed. Plasticity induction by tbTUS can be modified in manners consistent with homeostatic metaplasticity and depotentiation. This substantiates evidence that tbTUS induces LTP-like processes and suggests that metaplasticity can be harnessed in the therapeutic development of TUS. [ABSTRACT FROM AUTHOR]

Objective: Brain tumors represent some of the most treatment refractory cancers, and there is a clinical need for additional treatments for these tumors. Domesticated dogs are the only other mammalian species which commonly develop spontaneous brain tumors, making them an ideal model for investigating novel therapies. Histotripsy is a non-thermal ultrasonic ablation method that emulsifies tissue through acoustic cavitation. The primary objectives of this prospective study were to assess the feasibility and safety of histotripsy to ablate naturally occurring canine brain tumors. Secondary endpoints included characterization of magnetic resonance imaging (MRI) responses to histotripsy treatment, and exploratory immunogenomic tumor response analyses. Methods: The study design utilized a treat and resect paradigm, where tumors were approached using craniotomy, partially ablated with histotripsy delivered through the cranial defect, imaged with MRI, and then resected. Dogs were evaluated with clinical, brain MRI, immunopathologic, and genomic examinations before treatment, intraoperatively, and 1, 14, and 42 days post-treatment. Here we report the results of the three dogs with meningiomas, all of which were treated with a custom eight element 1 MHz histotripsy transducer at a pulse repetition frequency of 100 Hz and a treatment dosage of 400 pulses/point. Results: Histotripsy was successfully delivered to all dogs, resulting in histopathologic evidence of ablations that were sharply demarcated from untreated tumor, with measured treatments approximating planned volumes in 2/3 dogs. One dog experienced an adverse event consisting of transient cerebral edema that was possibly attributable to histotripsy. Histotripsy ablations could be grossly visualized and identified on MRI, with features consistent with hemorrhage and necrosis. Significant expression or upregulation of the damage associated molecular pattern HMGB1, cytokine-cytokine receptor interaction, and NF-κb signaling pathways were observed in histotripsy treated tumors. Conclusion: Ablation of canine meningiomas with histotripsy through an open cranial window was feasible and clinically well tolerated. [ABSTRACT FROM AUTHOR]

Focused ultrasound can non-invasively modulate neural activity, but whether effective stimulation parameters generalize across brain regions and cell types remains unknown. We used focused ultrasound coupled with fiber photometry to identify optimal neuromodulation parameters for four different arousal centers of the brain in an effort to yield overt changes in behavior. Applying coordinate descent, we found that optimal parameters for excitation or inhibition are highly distinct, the effects of which are generally conserved across brain regions and cell types. Optimized stimulations induced clear, target-specific behavioral effects, whereas non-optimized protocols of equivalent energy resulted in substantially less or no change in behavior. These outcomes were independent of auditory confounds and, contrary to expectation, accompanied by a cyclooxygenase-dependent and prolonged reduction in local blood flow and temperature with brain-region-specific scaling. These findings demonstrate that carefully tuned and targeted ultrasound can exhibit powerful effects on complex behavior and physiology. [Display omitted] • Optimal ultrasound neuromodulation parameters generalize across neuronal cell types • Distinct parameters for excitation and inhibition are identified • Targeted stimulation induces site-specific behavioral changes • COX2-dependent vasoconstriction and brain cooling occur with excitatory protocols The field of focused ultrasound (FUS) neuromodulation is undergoing rapid growth but is limited by our understanding of effective waveform parameters and cell-type effects. Murphy et al. combine deep-brain optical readouts with FUS technology to uncover waveforms for inducing powerful, bidirectional neuromodulation across a collection of therapeutically important brain cell types. [ABSTRACT FROM AUTHOR]

This study investigated the high‐intensity focused ultrasound (HIFU)‐mediated propulsion of mesoporous silica nanoparticles (MSNs) and microspheres (MSMs). Nanoparticles are heavily sought as vehicles for drug delivery, but their transport through tissue is often restricted. Here, MSNs and MSMs are hydrophobically modified and coated with phospholipids to facilitate inertial cavitation to promote propulsion under HIFU. Modified nanoparticles show significantly enhanced cavitation and propulsion, achieving a maximum displacement of 250 µm (≈2500 body length) and speed of ≈1600 µm s−1 (16 000 body length s−1), compared to unmodified nanoparticles (2 µm, 20 body length, 60 µm s−1, 600 body length). In contrast, microparticles demonstrate comparable cavitation responses. Modified microparticles reached a maximum speed of 4000 µm s−1 (800 body length s−1) and displacement of 230 µm (46 body length), and unmodified microparticles achieved 2000 µm s−1 (400 body length s−1) and 75 µm (15 body length). In all HIFU‐responsive samples, displacement and speed decreased with successive pulses, implying that particles fatigue with continued pulsing. Analyses of particle trajectories and rotational diffusion times suggest that cavitation occurs uniformly on particle surfaces rather than at specific sites. These principles are important for the design of future drug‐delivery vehicles capable of ultrasound‐triggered motion. [ABSTRACT FROM AUTHOR]

Introduction: Coaxial 3D bioprinting has advanced the formation of tissue constructs that recapitulate key architectures and biophysical parameters for in-vitro disease modeling and tissue-engineered therapies. Controlling gene expression within these structures is critical for modulating cell signaling and probing cell behavior. However, current transfection strategies are limited in spatiotemporal control because dense 3D scaffolds hinder diffusion of traditional vectors. To address this, we developed a coaxial extrusion 3D bioprinting technique using ultrasound-responsive gene delivery bioinks. These bioink materials incorporate echogenic microbubble gene delivery particles that upon ultrasound exposure can sonoporate cells within the construct, facilitating controllable transfection. Methods: Phospholipid-coated gas-core microbubbles were electrostatically coupled to reporter transgene plasmid payloads and incorporated into cell-laden alginate bioinks at varying particle concentrations. These bioinks were loaded into the coaxial nozzle core for extrusion bioprinting with CaCl2 crosslinker in the outer sheath. Resulting bioprints were exposed to 2.25 MHz focused ultrasound and evaluated for microbubble activation and subsequent DNA delivery and transgene expression. Results: Coaxial printing parameters were established that preserved the stability of ultrasound-responsive gene delivery particles for at least 48 h in bioprinted alginate filaments while maintaining high cell viability. Successful sonoporation of embedded cells resulted in DNA delivery and robust ultrasound-controlled transgene expression. The number of transfected cells was modulated by varying the number of focused ultrasound pulses applied. The size region over which DNA was delivered was modulated by varying the concentration of microbubbles in the printed filaments. Conclusions: Our results present a successful coaxial 3D bioprinting technique designed to facilitate ultrasound-controlled gene delivery. This platform enables remote, spatiotemporally-defined genetic manipulation in coaxially bioprinted tissue constructs with important applications for disease modeling and regenerative medicine. [ABSTRACT FROM AUTHOR]

Background/Objectives: Focused ultrasound (FUS) and microbubble (MB) exposure is a promising technique for targeted drug delivery to the brain; however, refinement of protocols suitable for large-volume treatments in a clinical setting remains underexplored. Methods: Here, the impacts of various sonication parameters on blood–brain barrier (BBB) permeability enhancement and tissue damage were explored in rabbits using a clinical-prototype hemispherical phased array developed in-house, with real-time 3D MB cavitation imaging for exposure calibration. Initial experiments revealed that continuous manual agitation of MBs during infusion resulted in greater gadolinium (Gd) extravasation compared to gravity drip infusion. Subsequent experiments used low-dose MB infusion with continuous agitation and a low burst repetition frequency (0.2 Hz) to mimic conditions amenable to long-duration clinical treatments. Results: Key sonication parameters—target level (proportional to peak negative pressure), number of bursts, and burst length—significantly affected BBB permeability enhancement, with all parameters displaying a positive relationship with relative Gd contrast enhancement (p < 0.01). Even at high levels of BBB permeability enhancement, tissue damage was minimal, with low occurrences of hypointensities on T2*-weighted MRI. When accounting for relative Gd contrast enhancement, burst length had a significant impact on red blood cell extravasation detected in histological sections, with 1 ms bursts producing significantly greater levels compared to 10 ms bursts (p = 0.03), potentially due to the higher pressure levels required to generate equal levels of BBB permeability enhancement. Additionally, albumin and IgG extravasation correlated strongly with relative Gd contrast enhancement across sonication parameters, suggesting that protein extravasation can be predicted from non-invasive imaging. Conclusions: These findings contribute to the development of safer and more effective clinical protocols for FUS + MB exposure, potentially improving the efficacy of the approach. [ABSTRACT FROM AUTHOR]

Background: Focused ultrasound therapy has been widely used for the treatment of various diseases, employing different types of transducers. The focused ultrasound pressure fields inevitably exhibit nonlinear effects, which can influence the ablation region. However, the nonlinear effects exhibit noticeable variations across different applications. The characterization of the nonlinear pressure fields of ultrasound is important for the effective implementation of focused ultrasound therapy. Purpose: The traditional angular spectrum method (ASM) was extended to accurately and efficiently simulate the propagation of weakly nonlinear ultrasound in heterogeneous mediums of clinical model. The nonlinear effects were further analyzed in relationship to the transducer parameters that are different in various applications. Methods: The pressure fields were simulated using the extended ASM, incorporating calculations for phase aberration in the frequency domain and magnitude compensation in the spatial domain to account for heterogeneous acoustic impedance mismatch. Validation was performed by comparison to k‐Wave simulation results using two simplified clinical models, an abdominal soft tissue and a transcranial skull model. The nonlinear effects were then analyzed in relation to the transducer parameters of f‐number and effective source area based on the same acoustic output power. The analysis of nonlinear effects was conducted under both homogeneous medium and the clinical models. Results: The simulation results demonstrated a maximum error of 3.93% in the calculated harmonic pressure of the abdominal model, and a maximum error of 4.89% within the transcranial model when comparing the extended ASM simulation results to those obtained from k‐Wave simulations. The characterization of the nonlinear effects reveals a strong correlation with the transducer parameters. Specifically, the results indicate that the nonlinear effects intensify with an increase in the effective source area and f‐number, under the same acoustic output power of the transducer. However, the clinical model also showed an influence on the nonlinear effects in relation to the f‐number. Conclusion: The extended ASM was demonstrated as an accurate and efficient simulation tool, and the simulation results provide a reference for evaluating the intensity of nonlinear effects in various transducer designs. [ABSTRACT FROM AUTHOR]

To systematically review and conduct a meta-analysis to evaluate the safety and efficacy of the unilateral focused ultrasound (FUS) pallidotomy on motor complications in Parkinson's disease (PD) patients. A comprehensive search strategy was implemented through August 15, 2023, and updated on February 13, 2024, across six databases, identifying studies relevant to unilateral focused ultrasound pallidotomy and PD. Eligibility criteria included observational studies, clinical trials, and case series reporting on the impact of the intervention on motor complications in PD patients. The screening and data extraction were done by two independent reviewers. Risk of bias assessment utilized appropriate tools for different study designs. Statistical analysis involved narrative synthesis and meta-analysis. Subgroup analyses and leave-one-out analyses were performed. Five studies were included in our study, involving 112 PD patients undergoing FUS pallidotomy. UPDRS-II analysis revealed a significant improvement from baseline (mean difference (MD): -3.205, 95% CI: -4.501, -1.909, P < 0.001). UPDRS-III overall change was significant (MD: -10.177, 95% CI: [-12.748, -7.606], P < 0.001). UPDRS-IV showed a significant change from baseline (MD: -5.069, 95% CI: [-5.915, -4.224], P < 0.001). UDysRS demonstrated a significant overall improvement (MD: -18.895, 95% CI: [-26.973, -10.818], P < 0.001). The effect of FUS pallidotomy on motor complications in PD patients was effective, with a significant decrease in the UPDRS and UDysRS, reflecting improvement. The incidence of adverse events (headaches, pin-site pain, difficulty walking, and sonication-related head pain) of the FUS pallidotomy was not statistically significant, indicating its safety. [ABSTRACT FROM AUTHOR]

Interventional procedures for the recanalization of blood vessels to treat deep vein thrombosis carry a high risk of vessel wall injuries or hemorrhaging. Focused ultrasound (FUS) has been used to non-invasively break down blood clots that occlude the vessels in both in vitro and in vivo studies. Previous studies have either used thrombolytic drugs or ultrasound contrast agents (e.g., microbubbles) in combination with FUS. Several studies have applied very high peak-negativepressures (PNP) during FUS treatment to achieve successful thrombolysis without the use of contrast agents. In the current study, we demonstrated that cavitation activity could be significantly enhanced by placing a nitinol wire, whose surface was roughed by laser etching, in the focal region of a FUS field. We demonstrated in vitro in a mock thrombosis that the thrombolysis efficacy of a 500 kHz FUS transducer was significantly enhanced using a surface-etched nitinol wire as compared to an unetched nitinol wire, whereas FUS-alone at the same pressure level did not result in any thrombolysis. These results suggest that a surface modified nitinol catheter exposed to FUS can result in intense cavitation activities leading to enhanced thrombolysis without the use of additional pharmacological or contrast agents. [ABSTRACT FROM AUTHOR]

Despite aggressive therapy, approximately 50% of patients with neuroblastoma (NB) fail to respond, and survivors endure lifelong toxicities. Sonopermeation increases drug uptake via cell bilayer disruption through focused ultrasound and microbubbles (MBs)—gas-filled, sound sensitive lipid spheres. MB response to a given ultrasound pulse (cavitation) varies according to MB size. We asked whether size-sorted MBs (SSMB) 4 to 5 µm in diameter will more consistently and predictably enhance doxorubicin uptake, compared with polydisperse MBs (PMB, 0.5–10 µm in diameter), thereby increasing drug delivery to NB xenografts. Human NB cells were implanted into the left kidney of nude mice and grown for 5 to 6 wk. Mice received sonopermeation alongside either PMB or SSMB at low (0.6 MPa) or high (2 MPa) negative pressures. Some mice also received different chemotherapy agents (doxorubicin, etoposide or cyclophosphamide). Circulating tumor cells were assessed by flow cytometry 1 h after treatment. Survival was assessed for up to 21 d, a subset of mice was euthanized 24 h after treatment for histological assessment of apoptosis, vascular lumen size and tight junctions. Tumors treated with SSMB and high pressure showed synergy with liposomal doxorubicin (L-DOX) owing to increased vascular lumen and disruption of tight junctions, resulting in drug uptake, apoptosis, lack of tumor growth and increased survival. We found no difference in the numbers of circulating tumor cells. Sonopermeation with SSMB at 2 MPa synergizes with L-DOX delivery, increasing apoptosis, perfusion and vascular permeability, suggesting that SSMB sonopermeation at high pressure is promising for NB-targeted treatment, especially in combination with L-DOX. [ABSTRACT FROM AUTHOR]

This retrospective study aimed to investigate the efficacy and safety of focused ultrasound (FU) treatment for high-risk human papillomavirus (HR-HPV) infection-related cervical intraepithelial neoplasia grade 2 (CIN2) in nulligravidae under 35 y old, while also assessing pregnancy outcomes post-treatment. Nulligravid patients aged 18–35 y with histologically confirmed CIN2 and HR-HPV infection were included in the study. We collected demographics, pertinent medical history, HPV genotypes and cervical length at baseline. Follow-up evaluations were conducted at 6- and 12-mo intervals post-treatment to assess histopathological response, HPV infection clearance and adverse events related to treatment. A total of 31 eligible patients were recruited and underwent FU treatment. At the 6-mo follow-up, complete pathologic response was observed in 22 out of 31 patients (70.96%), while partial response was seen in eight out of 31 patients (25.80%). The average duration from pathological diagnosis to achieving either a complete response or partial response after treatment was 214.36 ± 24.31 (186–270) d. The baseline remission rate for HPV was 35.48% at 6 mo, increasing to 71.49% at 12 mo. Moderate lower abdominal pain and increased vaginal discharge were the most frequent adverse events. Among the patients desiring pregnancy, the successful pregnancy rate was 57.14%, resulting in eight deliveries. FU demonstrated a favorable safety profile and efficacy in nulliparous females under 35 y old with CIN2, and its benefits for fertility warrant further investigation. [ABSTRACT FROM AUTHOR]

Elastography images tissue mechanical responses and infers the underlying properties to aid diagnosis and treatment response monitoring. The estimation of absolute or relative tumor properties may vary with dimensions even when the mechanical properties remain constant. Harmonic motion imaging (HMI) uses amplitude-modulated (AM) focused ultrasound to interrogate the targeted tissue's viscoelastic properties. In this study, effects of AM frequencies on HMI were investigated in terms of inclusion relative stiffness and size estimation. AM frequencies from 200 to 600 Hz in steps of 100 Hz were considered using a 5.3-kPa phantom with cylindrical inclusions (Young's modulus: 22, 31, 44, 56 kPa, and diameter: 4.8, 8.1, 13.6, 19.8 mm) to optimize the performance of HMI in characterizing tumors with the same mechanical properties and of different dimensions. Consistent displacement ratios (DRs) (17.5% variation) of the inclusion to background were obtained with 200-Hz AM for breast-tumor-mimicking inclusions albeit a suboptimal inclusion size estimation obtained. 400-Hz was otherwise used for small and low-contrast inclusions (4.8 mm, 22 or 31 kPa). A linear relationship (R2 = 0.9043) was found between the inverse DR at these frequencies and the Young's modulus ratio. 400 Hz obtained the most accurate inclusion size estimation with an overall estimation error on the lateral dimension of 0.5 mm. In vivo imaging of breast cancer patients (n = 5) was performed at 200 or 400 Hz. The results presented herein indicate that the HMI AM frequency could be optimized adaptively in cases of different applications, i.e., at 200 or 400 Hz, depending on whether aimed for consistent DR measurement for tumor response assessment or tumor margin delineation for surgical planning. HMI may thus be capable of predicting the pathologic endpoint of tumors in response to neoadjuvant chemotherapy (NACT) as early as 3 weeks into treatment. [ABSTRACT FROM AUTHOR]

Ultrasound is well-perceived for its diagnostic application. Meanwhile, ultrasound, especially focused ultrasound (FUS), has also demonstrated therapeutic capabilities, such as thermal tissue ablation, hyperthermia, and mechanical tissue ablation, making it a viable therapeutic approach for cancer treatment. Cancer immunotherapy is an emerging cancer treatment approach that boosts the immune system to fight cancer, and it has also exhibited enhanced effectiveness in treating previously considered untreatable conditions. Currently, cancer immunotherapy is regarded as one of the four pillars of cancer treatment because it has fewer adverse effects than radiation and chemotherapy. In recent years, the unique capabilities of FUS in ablating tumors, regulating the immune system, and enhancing anti-tumor responses have resulted in a new field of research known as FUS-induced/assisted cancer immunotherapy. In this work, we provide a comprehensive overview of this new research field by introducing the basics of focused ultrasound and cancer immunotherapy and providing the state-of-the-art applications of FUS in cancer immunotherapy: the mechanisms and preclinical and clinical studies. This review aims to offer the scientific community a reliable reference to the exciting field of FUS-induced/assisted cancer immunotherapy, hoping to foster the further development of related technology and expand its medical applications. [ABSTRACT FROM AUTHOR]

Over the past decade, focused ultrasound (FUS) has emerged as a promising therapeutic modality for various medical conditions. However, the exponential growth in the published literature on FUS therapies has made the literature review process increasingly time-consuming, inefficient, and error-prone. Machine learning approaches offer a promising solution to address these challenges. Therefore, the purpose of our study is to (1) explore and compare machine learning techniques for the text classification of scientific abstracts, and (2) integrate these machine learning techniques into the conventional literature review process. A classified dataset of 3588 scientific abstracts related and unrelated to FUS therapies sourced from the PubMed database was used to train various traditional machine learning and deep learning models. The fine-tuned Bio-ClinicalBERT (Bidirectional Encoder Representations from Transformers) model, which we named FusBERT, had comparatively optimal performance metrics with an accuracy of 0.91, a precision of 0.85, a recall of 0.99, and an F1 of 0.91. FusBERT was then successfully integrated into the literature review process. Ultimately, the integration of this model into the literature review pipeline will reduce the number of irrelevant manuscripts that the clinical team must screen, facilitating efficient access to emerging findings in the field.

Non-invasive ultrasound neuromodulation has experienced exponential growth in the neuroscientific literature, recently also including clinical studies and applications. However, clinical recommendations for the secure and effective application of ultrasound neuromodulation in pathological brains are currently lacking. Here, clinical experts with neuroscientific expertise in clinical brain stimulation and ultrasound neuromodulation present initial clinical recommendations for ultrasound neuromodulation with relevance for all ultrasound neuromodulation techniques. The recommendations start with methodological safety issues focusing on technical issues to avoid harm to the brain. This is followed by clinical safety issues focusing on important factors concerning pathological situations.

Abstract Microbubbles (MBs) combined with focused ultrasound (FUS) has emerged as a promising noninvasive technique to permeabilize the blood–brain barrier (BBB) for drug delivery into the brain. However, the safety and biological consequences of BBB opening (BBBO) remain incompletely understood. This study aims to investigate the effects of two parameters mediating BBBO: microbubble volume dose (MVD) and mechanical index (MI). High-resolution MRI-guided FUS was employed in mouse brains to assess BBBO by manipulating these two parameters. Afterward, the sterile inflammatory response (SIR) was studied 6 h post-FUS treatment. Results demonstrated that both MVD and MI significantly influenced the extent of BBBO, with higher MVD and MI leading to increased permeability. Moreover, RNA sequencing revealed upregulation of major inflammatory pathways and immune cell infiltration after BBBO, indicating the presence and extent of SIR. Gene set enrichment analysis identified 12 gene sets associated with inflammatory responses that were significantly upregulated at higher MVD or MI. A therapeutic window was established between therapeutically relevant BBBO and the onset of SIR, providing operating regimes to avoid damage from stimulation of the NFκB pathway via TNFɑ signaling to apoptosis. These results contribute to the optimization and standardization of BBB opening parameters for safe and effective drug delivery to the brain and further elucidate the underlying molecular mechanisms driving sterile inflammation.

Background: Intra-axial brain tumors persist as significant clinical challenges. Aggressive surgical resection carries risk of morbidity, and the blood-brain barrier (BBB) prevents optimal pharmacological interventions. There is a clear clinical demand for innovative and less invasive therapeutic strategies for patients, especially those that can augment established treatment protocols. Focused ultrasound (FUS) has emerged as a promising approach to manage brain tumors. Sonodynamic therapy (SDT), a subset of FUS, utilizes sonosensitizers activated by ultrasound waves to generate reactive oxygen species (ROS) and induce tumor cell death. Objective: This review explores the historical evolution and rationale behind SDT, focusing on its mechanisms of action and potential applications in brain tumor management. Method: A systematic review was conducted using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Results: Preclinical studies have demonstrated the efficacy of various sonosensitizers, including 5-aminolevulinic acid (5-ALA), fluorescein, porphyrin derivatives, and nanoparticles, in conjunction with FUS for targeted tumor therapy and BBB disruption. Clinical trials have shown promising results in terms of safety and efficacy, although further research is needed to fully understand the potential adverse effects and optimize treatment protocols. Challenges such as skull thickness affecting FUS penetration, and the kinetics of BBB opening require careful consideration for the successful implementation of SDT in clinical practice. Future directions include comparative studies of different sonosensitizers, optimization of FUS parameters, and exploration of SDT's immunomodulatory effects. Conclusion: SDT represents a promising frontier in the treatment of aggressive brain tumors, offering hope for improved patient outcomes. [ABSTRACT FROM AUTHOR]

The blood-brain barrier (BBB) stands as a critical guardian separating the central nervous system (CNS) from the systemic circulation. This comprehensive review explores the anatomical and functional components of the BBB and its association with the neurovascular unit (NVU), emphasizing its role in synaptic signaling and shielding the CNS from neurotoxic elements. Detailed discussions encompass MRI techniques like dynamic contrast enhancement (DCE) and arterial spin labeling (ASL) MRI, illuminating their significance in assessing BBB integrity and permeability. Various models and pharmacokinetic parameters utilized in imaging analysis offer insights into barrier permeability, aiding in the evaluation of neurodegenerative illnesses such as Alzheimer's, Parkinson's, and multiple sclerosis. Additionally, the study investigates the distinct characteristics of imaging protocols and their impact on BBB evaluation. Highlighting physiological conditions, the analysis discerns regional disparities in BBB permeability, shedding light on diverse microvascular architectures in healthy subjects. Conversely, in pathological states like Alzheimer's, Parkinson's, and multiple sclerosis, BBB dysfunction leads to a cascade of events facilitating the entry of harmful substances, exacerbating neurodegeneration. Imaging studies have unveiled distinct alterations in BBB permeability and perfusion, providing crucial insights into disease progression, notably preceding structural changes in Alzheimer's and indicating localized disruptions in multiple sclerosis. This comprehensive exploration underscores the pivotal role of the BBB in maintaining CNS health and its intricate involvement in the pathogenesis of neurodegenerative disorders. While imaging techniques serve as promising tools for BBB assessment, further research is warranted to refine their diagnostic precision and differentiation abilities across neurological conditions. [ABSTRACT FROM AUTHOR]

Over the past decade, focused ultrasound (FUS) has emerged as a promising therapeutic modality for various medical conditions. However, the exponential growth in the published literature on FUS therapies has made the literature review process increasingly time-consuming, inefficient, and error-prone. Machine learning approaches offer a promising solution to address these challenges. Therefore, the purpose of our study is to (1) explore and compare machine learning techniques for the text classification of scientific abstracts, and (2) integrate these machine learning techniques into the conventional literature review process. A classified dataset of 3588 scientific abstracts related and unrelated to FUS therapies sourced from the PubMed database was used to train various traditional machine learning and deep learning models. The fine-tuned Bio-ClinicalBERT (Bidirectional Encoder Representations from Transformers) model, which we named FusBERT, had comparatively optimal performance metrics with an accuracy of 0.91, a precision of 0.85, a recall of 0.99, and an F1 of 0.91. FusBERT was then successfully integrated into the literature review process. Ultimately, the integration of this model into the literature review pipeline will reduce the number of irrelevant manuscripts that the clinical team must screen, facilitating efficient access to emerging findings in the field. [ABSTRACT FROM AUTHOR]

Introduction: Focused ultrasound (FUS) pallidotomy is a promising new therapy for Parkinson's disease (PD). The efficacy, motor outcomes, and side effects of FUS pallidotomy compared to radiofrequency (RF) pallidotomy are unknown. Methods: We performed a systematic review of the outcomes and side effect profiles of FUS versus RF pallidotomy in patients with PD. Results: Across four RF reports and one FUS report, putative contralateral UPDRS III scores were not significantly different following RF versus FUS pallidotomy. Across 18 RF and 2 FUS reports, the mean failure rate was 14% following RF pallidotomy versus 24% following FUS pallidotomy. Across 25 RF and 3 FUS reports, cognitive deficit was significantly more prevalent following RF pallidotomy (p = 0.004). Conclusion: At present, limited data and heterogeneity in outcome reporting challenges comparisons of FUS and RF pallidotomy efficacy and safety. Available evidence suggests FUS pallidotomy may have broadly similar efficacy and a lower risk of cognitive impairment relative to RF pallidotomy. Standardized reporting of post-lesion outcomes in future studies would improve power and rule out potential confounders of these results. [ABSTRACT FROM AUTHOR]

Introduction: Alzheimer's disease, a progressive neurodegenerative disorder, is marked by beta-amyloid plaque accumulation and cognitive decline. The limited efficacy and significant side effects of anti-amyloid monoclonal antibody therapies have prompted exploration into innovative treatments like focused ultrasound therapy. Focused ultrasound shows promise as a noninvasive technique for disrupting the blood-brain barrier, potentially enhancing drug delivery directly to the brain and improving the penetration of existing therapeutic agents. Methods: This systematic review was conducted using PubMed and Embase databases, focusing on studies published in the last ten years that examined the use of low-intensity focused ultrasound for blood-brain barrier disruption in Alzheimer's disease. The search strategy encompassed terms related to Alzheimer's disease, focused ultrasound, and the blood-brain barrier. Studies were selected based on predefined inclusion and exclusion criteria. The quality of included studies was assessed using the Oxford Centre for Evidence-Based Medicine Levels of Evidence framework. Results: Twelve studies were analyzed, the results of which suggested that low intensity focused ultrasound when combined with microbubbles may safely and transiently disrupt the blood-brain barrier. These studies, primarily early-phase and observational, highlight the potential feasibility of focused ultrasound in facilitating drug delivery to the brain for the treatment of Alzheimer's disease. Notably, one study reported positive impacts on cognitive tests, suggesting potential direct therapeutic effects of focused ultrasound beyond blood-brain barrier disruption. Conclusion: The results of the included studies indicate the use of focused ultrasound in Alzheimer's disease treatment might be safe and effective in transiently opening the blood-brain barrier. Although current evidence is promising, further research is needed to establish generalizability. Future studies should also aim to further elucidate the mechanisms of action of low-intensity focused ultrasound as well as microbubbles for blood-brain barrier opening and explore potential clinical benefits beyond blood-brain barrier opening such as impacts on cognitive outcomes. Future studies should also aim for greater participant diversity to ensure findings are applicable across the full spectrum of Alzheimer's disease patients. [ABSTRACT FROM AUTHOR]

Alzheimer's disease is characterized by progressive impairment of neuronal functions culminating in neuronal loss and dementia. A universal feature of dementia is protein aggregation, a process by which a monomer forms intermediate oligomeric assembly states and filaments that develop into end-stage hallmark lesions. In Alzheimer's disease, this is exemplified by extracellular amyloid-β (Aβ) plaques which have been placed upstream of tau, found in intracellular neurofibrillary tangles and dystrophic neurites. This implies causality that can be modeled as a linear activation cascade. When Aβ load is reduced, for example, in response to an anti-Aβ immunotherapy, cognitive functions improve in plaque-forming mice. They also deteriorate less in clinical trial cohorts although real-world clinical benefits remain to be demonstrated. Given the existence of aged humans with unimpaired cognition despite a high plaque load, the central role of Aβ has been challenged. A counter argument has been that clinical symptoms would eventually develop if these aged individuals were to live long enough. Alternatively, intrinsic mechanisms that protect the brain in the presence of pathology may exist. In fact, Aβ toxicity can be abolished by either reducing or manipulating tau (through which Aβ signals), at least in preclinical models. In addition to manipulating steps in this linear pathocascade model, mechanisms of restoring brain reserve can also counteract Aβ toxicity. Low-intensity ultrasound is a neuromodulatory modality that can improve cognitive functions in Aβ-depositing mice without the need for removing Aβ. Together, this highlights a dissociation of Aβ and cognition, with important implications for therapeutic interventions. [ABSTRACT FROM AUTHOR]

Background: Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disorder with minimally effective treatment options. An important hurdle in ALS drug development is the non-invasive therapeutic access to the motor cortex currently limited by the presence of the blood-brain barrier (BBB). Focused ultrasound and microbubble (FUS+ MB) treatment is an emerging technology that was successfully used in ALS patients to temporarily open the cortical BBB. However, FUS+ MB-mediated drug delivery across ALS patients' BBB has not yet been reported. Similarly, the effects of FUS+ MB on human ALS BBB cells remain unexplored. Methods: Here we established the first FUS+ MB-compatible, fully-human ALS patient-cell-derived BBB model based on induced brain endothelial-like cells (iBECs) to study anti-TDP-43 antibody delivery and FUS+ MB bioeffects in vitro. Results: Generated ALS iBECs recapitulated disease-specific hallmarks of BBB pathology, including reduced BBB integrity and permeability, and TDP-43 proteinopathy. The results also identified differences between sporadic ALS and familial (C9orf72 expansion carrying) ALS iBECs reflecting patient heterogeneity associated with disease subgroups. Studies in these models revealed successful ALS iBEC monolayer opening in vitro with no adverse cellular effects of FUS+ MB as reflected by lactate dehydrogenase (LDH) release viability assay and the lack of visible monolayer damage or morphology change in FUS+ MB treated cells. This was accompanied by the molecular bioeffects of FUS+ MB in ALS iBECs including changes in expression of tight and adherens junction markers, and drug transporter and inflammatory mediators, with sporadic and C9orf72 ALS iBECs generating transient specific responses. Additionally, we demonstrated an effective increase in the delivery of anti-TDP-43 antibody with FUS+ MB in C9orf72 (2.7-fold) and sporadic (1.9-fold) ALS iBECs providing the first proof-of-concept evidence that FUS+ MB can be used to enhance the permeability of large molecule therapeutics across the BBB in a human ALS in vitro model. Conclusions: Together, this study describes the first characterisation of cellular and molecular responses of ALS iBECs to FUS+ MB and provides a fully-human platform for FUS+ MB-mediated drug delivery screening on an ALS BBB in vitro model. [ABSTRACT FROM AUTHOR]

Background: Atherosclerosis is a condition in which an adhesive substance called plaque accumulates over time inside the arteries. Plaque buildup results in the constriction of arteries, causing a shortage of blood supply to tissues and organs. Removing atherosclerotic plaques controls the development of acute ischemic stroke and heart diseases. It remains imperative for positive patient outcomes. Purpose: This study sought to develop a minimally invasive technique for removing arterial plaques by applying focused ultrasound (FUS) energy on the metal surface of a nitinol catheter wire to induce inertial cavitation. The induced cavitation can deplete plaque mechanically inside the arteries, leading towards improved recanalization of blood vessels. Methods: The enhanced cavitation effect induced by combining FUS with a metal catheter was first verified by exposing agar phantom gels with or without a 0.9‐mm diameter nitinol wire to an acoustic field produced by a 0.5‐MHz FUS transducer. The phenomenon was further confirmed in pork belly fat samples with or without a 3‐mm diameter nitinol catheter wire. Cavitation was monitored by detecting the peaks of emitted ultrasound signals from the samples using a passive cavitation detector (PCD). Cavitation threshold values were determined by observing the jump in the peak amplitude of signals received by the PCD when the applied FUS peak negative pressure (PNP) increased. To simulate arterial plaque removal, FUS with or without a catheter was used to remove tissues from pork belly fat samples and the lipid cores of human atherosclerotic plaque samples using 2500‐cycle FUS bursts at 10% duty cycle and a burst repetition rate of 20 Hz. Treatment outcomes were quantified by subtracting the weight of samples before treatment from the weight of samples after treatment. All measurements were repeated 5 times (n = 5) unless otherwise indicated, and paired t‐tests were used to compare the means of two groups. A p‐value of <0.05 will be considered significant. Results: Our results showed that with a nitinol wire, the cavitation threshold in agar phantoms was reduced to 2.6 MPa from 4.3 MPa PNP when there was no nitinol wire in the focal region of FUS. For pork belly fat samples, cavitation threshold values were 1.0 and 2.0 MPa PNP, with and without a catheter wire, respectively. Pork belly fat tissues and lipid cores of atherosclerotic plaques were depleted at the interface between a catheter and the samples at 2 and 4 MPa FUS PNP, respectively. The results showed that with a catheter wire in the focal region of a 3‐min FUS treatment session, 24.7 and 25.6 mg of lipid tissues were removed from pork belly fat and human atherosclerotic samples, respectively. In contrast, the FUS‐only group showed no reduction in sample weight. The differences between FUS‐only and FUS‐plus‐catheter groups were statistically significant (p < 0.001 for the treatment on pork belly samples, and p < 0.01 for the treatment on human atherosclerotic samples). Conclusion: This study demonstrated the feasibility of catheter‐assisted FUS therapy for removing atherosclerotic plaques. [ABSTRACT FROM AUTHOR]

• Neuromodulation techniques have a therapeutic potential in movement disorders. • Techniques of invasive and non-invasive brain stimulation, spinal cord stimulation, and focused ultrasound are reviewed. • Botulinum toxin injections can benefit from electromyography to accurately identify the muscles to treat. In this review, different aspects of the use of clinical neurophysiology techniques for the treatment of movement disorders are addressed. First of all, these techniques can be used to guide neuromodulation techniques or to perform therapeutic neuromodulation as such. Neuromodulation includes invasive techniques based on the surgical implantation of electrodes and a pulse generator, such as deep brain stimulation (DBS) or spinal cord stimulation (SCS) on the one hand, and non-invasive techniques aimed at modulating or even lesioning neural structures by transcranial application. Movement disorders are one of the main areas of indication for the various neuromodulation techniques. This review focuses on the following techniques: DBS, repetitive transcranial magnetic stimulation (rTMS), low-intensity transcranial electrical stimulation, including transcranial direct current stimulation (tDCS) and transcranial alternating current stimulation (tACS), and focused ultrasound (FUS), including high-intensity magnetic resonance-guided FUS (MRgFUS), and pulsed mode low-intensity transcranial FUS stimulation (TUS). The main clinical conditions in which neuromodulation has proven its efficacy are Parkinson's disease, dystonia, and essential tremor, mainly using DBS or MRgFUS. There is also some evidence for Tourette syndrome (DBS), Huntington's disease (DBS), cerebellar ataxia (tDCS), and axial signs (SCS) and depression (rTMS) in PD. The development of non-invasive transcranial neuromodulation techniques is limited by the short-term clinical impact of these techniques, especially rTMS, in the context of very chronic diseases. However, at-home use (tDCS) or current advances in the design of closed-loop stimulation (tACS) may open new perspectives for the application of these techniques in patients, favored by their easier use and lower rate of adverse effects compared to invasive or lesioning methods. Finally, this review summarizes the evidence for keeping the use of electromyography to optimize the identification of muscles to be treated with botulinum toxin injection, which is indicated and widely performed for the treatment of various movement disorders. [ABSTRACT FROM AUTHOR]

Introduction: Focused ultrasound (FUS) is an innovative and emerging technology for the treatment of adult and pediatric brain tumors and illustrates the intersection of various specialized fields, including neurosurgery, neuro-oncology, radiation oncology, and biomedical engineering. Objective: The authors provide a comprehensive overview of the application and implications of FUS in treating pediatric brain tumors, with a special focus on pediatric low-grade gliomas (pLGGs) and the evolving landscape of this technology and its clinical utility. Methods: The fundamental principles of FUS include its ability to induce thermal ablation or enhance drug delivery through transient blood-brain barrier (BBB) disruption, emphasizing the adaptability of high-intensity focused ultrasound (HIFU) and low-intensity focused ultrasound (LIFU) applications. Results: Several ongoing clinical trials explore the potential of FUS in offering alternative therapeutic strategies for pathologies where conventional treatments fall short, specifically centrally-located benign CNS tumors and diffuse intrinsic pontine glioma (DIPG). A case illustration involving the use of HIFU for pilocytic astrocytoma is presented. Conclusion: Discussions regarding future applications of FUS for the treatment of gliomas include improved drug delivery, immunomodulation, radiosensitization, and other technological advancements. [ABSTRACT FROM AUTHOR]

This review delves into the innovative technology of Blood-Brain Barrier (BBB) opening with low-intensity focused ultrasound in combination with microbubbles (LIFU-MB), a promising therapeutic modality aimed at enhancing drug delivery to the central nervous system (CNS). The BBB's selective permeability, while crucial for neuroprotection, significantly hampers the efficacy of pharmacological treatments for CNS disorders. LIFU-MB emerges as a non-invasive and localized method to transiently increase BBB permeability, facilitating the delivery of therapeutic molecules. Here, we review the procedural stages of LIFU-MB interventions, including planning and preparation, sonication, evaluation, and delivery, highlighting the technological diversity and methodological challenges encountered in current clinical applications. With an emphasis on safety and efficacy, we discuss the crucial aspects of ultrasound delivery, microbubble administration, acoustic feedback monitoring and assessment of BBB permeability. Finally, we explore the critical choices for effective BBB opening with LIFU-MB, focusing on selecting therapeutic agents, optimizing delivery methods, and timing for delivery. Overcoming existing barriers to integrate this technology into clinical practice could potentially revolutionize CNS drug delivery and treatment paradigms in the near future. [Display omitted] [ABSTRACT FROM AUTHOR]

We report our experience disrupting the blood-brain barrier (BBB) to improve drug delivery in glioblastoma patients receiving temozolomide chemotherapy. The goals of this retrospective analysis were to compare MRI-based measures of BBB disruption and vascular damage to the exposure levels, acoustic emissions data, and acoustic simulations. We also simulated the cavitation detectors. Monthly BBB disruption (BBBD) was performed using a 220 kHz hemispherical phased array focused ultrasound system (Exablate Neuro, InSightec) and Definity microbubbles (Lantheus) over 38 sessions in nine patients. Exposure levels were actively controlled via the cavitation dose obtained by monitoring subharmonic acoustic emissions. The acoustic field and sensitivity profile of the cavitation detection system were simulated. Exposure levels and cavitation metrics were compared to the level of BBBD evident in contrast-enhanced MRI and to hypointense regions in T2*-weighted MRI. Our treatment strategy evolved from using a relatively high cavitation dose goal to a lower goal and longer sonication duration and ultimately resulted in BBBD across the treatment volume with minimal petechiae. Subsonication-level feedback control of the exposure using acoustic emissions also improved consistency. Simulations of the acoustic field suggest that reflections and standing waves appear when the focus is placed near the skull, but their effects can be mitigated with aberration correction. Simulating the cavitation detectors suggest variations in the sensitivity profile across the treatment volume and between patients. A correlation was observed with the cavitation dose, BBBD and petechial hemorrhage in 8/9 patients, but substantial variability was evident. Analysis of the cavitation spectra found that most bursts did not contain wideband emissions, a signature of inertial cavitation, but biggest contribution to the cavitation dose – the metric used to control the procedure – came from bursts with wideband emissions. Using a low subharmonic cavitation dose with a longer duration resulted in BBBD with minimal petechiae. The correlation between cavitation dose and outcomes demonstrates the benefits of feedback control based on acoustic emissions, although more work is needed to reduce variability. Acoustic simulations could improve focusing near the skull and inform our analysis of acoustic emissions. Monitoring additional frequency bands and improving the sensitivity of the cavitation detection could provide signatures of microbubble activity associated with BBB disruption that were undetected here and could improve our ability to achieve BBB disruption without vascular damage. A hemispherical ultrasound phased array was used to disrupt the BBB in glioblastoma patients. Left: targeted and disrupted volumes. Right: treatment plan and post-ultrasound contrast-enhanced MRI. [Display omitted] • We used focused ultrasound to disrupt the blood-brain barrier in glioma patients. • We found parameters that produced effective disruption with minimal side effects. • We demonstrated the potential utility of acoustic modeling of the treatments. • We show how acoustic emissions were related to the disruption and vascular damage. [ABSTRACT FROM AUTHOR]

Microbubbles (MBs) combined with focused ultrasound (FUS) has emerged as a promising noninvasive technique to permeabilize the blood–brain barrier (BBB) for drug delivery into the brain. However, the safety and biological consequences of BBB opening (BBBO) remain incompletely understood. This study aims to investigate the effects of two parameters mediating BBBO: microbubble volume dose (MVD) and mechanical index (MI). High-resolution MRI-guided FUS was employed in mouse brains to assess BBBO by manipulating these two parameters. Afterward, the sterile inflammatory response (SIR) was studied 6 h post-FUS treatment. Results demonstrated that both MVD and MI significantly influenced the extent of BBBO, with higher MVD and MI leading to increased permeability. Moreover, RNA sequencing revealed upregulation of major inflammatory pathways and immune cell infiltration after BBBO, indicating the presence and extent of SIR. Gene set enrichment analysis identified 12 gene sets associated with inflammatory responses that were significantly upregulated at higher MVD or MI. A therapeutic window was established between therapeutically relevant BBBO and the onset of SIR, providing operating regimes to avoid damage from stimulation of the NFκB pathway via TNFɑ signaling to apoptosis. These results contribute to the optimization and standardization of BBB opening parameters for safe and effective drug delivery to the brain and further elucidate the underlying molecular mechanisms driving sterile inflammation. [ABSTRACT FROM AUTHOR]

RNA-based therapeutics, including siRNA, have obtained recognition in recent years due to their potential to treat various chronic and rare diseases. However, there are still limitations to lipid-based drug delivery systems in the clinical use of RNA therapeutics due to the need for optimization in the design and the preparation process. In this study, we propose adaptive focused ultrasound (AFU) as a drug loading technique to protect RNA from degradation by encapsulating small RNA in nanoliposomes, which we term nanoplexes. The AFU method is non-invasive and isothermal, as nanoplexes are produced without direct contact with any external materials while maintaining precise temperature control according to the desired settings. The controllability of sample treatments can be effectively modulated, allowing for a wide range of ultrasound intensities to be applied. Importantly, the absence of co-solvents in the process eliminates the need for additional substances, thereby minimizing the potential for cross-contaminations. Since AFU is a non-invasive method, the entire process can be conducted under sterile conditions. A minimal volume (300 μL) is required for this process, and the treatment is speedy (10 min in this study). Our in vitro experiments with silencer CD44 siRNA, which performs as a model therapeutic drug in different mammalian cell lines, showed encouraging results (knockdown > 80%). To quantify gene silencing efficacy, we employed quantitative polymerase chain reaction (qPCR). Additionally, cryo-electron microscopy (cryo-EM) and atomic force microscopy (AFM) techniques were employed to capture images of nanoplexes. These images revealed the presence of individual nanoparticles measuring approximately 100–200 nm in contrast with the random distribution of clustered complexes observed in ultrasound-untreated samples of liposome nanoparticles and siRNA. AFU holds great potential as a standardized liposome processing and loading method because its process is fast, sterile, and does not require additional solvents. [ABSTRACT FROM AUTHOR]

Background and objectives: Magnetic Resonance-guided Focused Ultrasound (MRgFUS) is an emerging technique for the treatment of severe, medication-refractory tremor syndromes. We here report motor and non-motor outcomes 6 and 12 months after unilateral MRgFUS thalamotomy in tremor-dominant Parkinson's disease (tdPD). Methods: 25 patients with tdPD underwent neuropsychological evaluation including standardized questionnaires of disability, quality of life (QoL), mood, anxiety, apathy, sleep disturbances, and cognition at baseline, 6 and 12 months after MRgFUS. Motor outcome was evaluated using the Clinical Rating Scale for Tremor (CRST) and Movement Disorder Society–Unified Parkinson's Disease Rating Scale (MDS-UPDRS). In addition, side effects and QoL of family caregivers were assessed. Results: 12 months after MRgFUS significant improvements were evident in the tremor subscores. Patients with concomitant rest and postural tremor showed better tremor outcomes compared to patients with predominant rest tremor. There were no differences in the non-motor assessments. No cognitive decline was observed. Side effects were mostly transient (54%) and classified as mild (62%). No changes in the caregivers' QoL could be observed. Conclusion: We found no changes in mood, anxiety, apathy, sleep, cognition or persistent worsening of gait disturbances after unilateral MRgFUS thalamotomy in tdPD. Concomitant postural tremors responded better to treatment than predominant rest tremors. [ABSTRACT FROM AUTHOR]

Background: MR‐guided focused ultrasound (FUS) thermoablation is an established therapy for movement disorders. FUS candidates must meet a predefined threshold of skull density ratio (SDR), a parameter that accounts for the efficiency in reaching ablative temperatures. Randomized sham‐controlled trials to provide definitive therapeutic evidence employ pure randomization of subjects into active treatment or control arms. The latter design has several general limitations. Objective: To demonstrate that SDR values are not associated with clinically and demographically relevant variables in patients with Parkinson's disease (PD). This in turn would allow using SDR as an arm‐allocation parameter, separating patients who will receive active FUS treatment and best medical management treatment (BMT). Methods: We studied a cohort of 215 PD patients who were candidates for FUS subthalamotomy to determine if the SDR was correlated with demographic or clinical variables that could introduce bias for group allocation in a controlled trial. Results: SDR was unassociated with age, gender, and clinical motor features nor with levodopa daily dose in our cohort of PD patients. A negative association with age was found for the female subgroup. Conclusions: Our results show that in a PD population considered for FUS subthalamotomy treatment, the SDR may be a valid group‐allocation parameter. This could be considered as the basis for a controlled study comparing FUS subthalamotomy vs BMT. [ABSTRACT FROM AUTHOR]

This article examines the impact of magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy on caregiver burden in individuals with essential tremor (ET). The study included 18 patients with medication-refractory ET and their caregivers. The results showed that MRgFUS thalamotomy not only reduced the need for caregiver assistance with daily tasks but also decreased caregiver burden. However, there was no significant change in ET-specific caregiver burden. The study suggests that caregiver burden in ET may be more influenced by caregivers' perception of patients' distress rather than solely by tremor severity. Further research with larger sample sizes and longer follow-up durations is needed to explore these findings. [Extracted from the article]

Non-invasive ultrasound neuromodulation has experienced exponential growth in the neuroscientific literature, recently also including clinical studies and applications. However, clinical recommendations for the secure and effective application of ultrasound neuromodulation in pathological brains are currently lacking. Here, clinical experts with neuroscientific expertise in clinical brain stimulation and ultrasound neuromodulation present initial clinical recommendations for ultrasound neuromodulation with relevance for all ultrasound neuromodulation techniques. The recommendations start with methodological safety issues focusing on technical issues to avoid harm to the brain. This is followed by clinical safety issues focusing on important factors concerning pathological situations. • First Clinical Expert Recommendations for Ultrasound Neuromodulation as a new Brain Therapy. [ABSTRACT FROM AUTHOR]

Introduction: Essential tremor (ET) and Parkinson’s Disease (PD) are debilitating neurodegenerative disorders characterized by tremor as a predominant symptom, significantly impacting patients’ quality of life. Magnetic Resonanceguided Focused Ultrasound (MRgFUS) Thalamotomy is an innovative therapeutic option for the treatment of unilateral medically refractory tremor with fewer adverse effects compared to traditional surgical interventions. A recent CE approval allows appropriate patients to have their second side treated. Objective: The objective of this systematic review was to analyze available current knowledge about the use of MRgFUS for the treatment of bilateral ET and PD related tremor, to identify the effectiveness and the risks associated with bilateral treatment. Methods: Eligible studies were identified by searching published studies in PubMed and Scopus databases from May 2014 to January 2024 and by identifying ongoing studies registered on the clinicaltrials.gov website. Data were summarized by considering the following information topics: the number of patients involved, the selected lesion target, the assessment tool used to evaluate clinical changes, the observed improvement, the reported side effects, and the time interval between the two treatments. The study was registered in PROSPERO (ID: CRD42024513178). Results: Nine studies were eligible for this review, 7 for ET and 2 for PD. The involved population included a variable number of patients, ranging from 1 to 11 subjects for ET and from 10 to 15 subjects for PD. The main lesional targets were the ventral intermediate nucleus of the thalamus, the pallidothalamic tract and the cerebellothalamic tract bilaterally. All studies investigated the tremor relief through the Clinical Rating Scale for Tremor (CRST) in patients with ET, and through the Unified Parkinson’s Disease Rating Scale (UPDRS) in patients with PD. A variable degree of improvement was observed, with all patients expressing overall satisfaction with the bilateral treatment. Adverse events were mild and transient, primarily involving gait disturbances, dysarthria, and ataxia. A standardized protocol for administering the two consecutive treatments was not identifiable; typically, the timing of the second treatment was delayed by at least 6 months. Conclusion: Available evidence supports the effectiveness and safety of staged bilateral MRgFUS treatments for ET and PD-related tremor. [ABSTRACT FROM AUTHOR]