The study, published in JAMA Network Open, examined outcomes among patients treated between 2023 and 2026. The analysis considered survival, liver function before and after treatment, and the risk of kidney injury. Early clinical studies supporting the Food and Drug Administration’s 2023 clearance of the procedure had reported encouraging technical effectiveness and safety in carefully selected patients, but the new review was designed to assess how histotripsy performed in broader clinical practice.

Histotripsy is a noninvasive treatment that uses focused sound waves to create air bubbles within diseased liver tissue. The bubbles destroy cancer cells, and the procedure is typically performed on an outpatient basis without a hospital stay. The approach is intended to treat liver tumors directly, without the incision required by surgery. The new findings indicate that the procedure itself was generally well tolerated: laboratory toxicity and procedural complications occurred at low rates, while liver function and kidney-injury outcomes were assessed as markers of treatment-related safety.

However, nearly 70% of the treatments in the analysis were performed in patients with metastatic cancer involving the liver, including some patients with pancreatic cancer. The researchers said this distribution raises questions about which patients with metastatic disease are most likely to benefit from a therapy directed specifically at liver tumors. They also emphasized that advanced cancer and overall disease burden may have contributed to the observed mortality, although the study cannot establish whether histotripsy caused any of the deaths. “That does not mean histotripsy caused those deaths,” said Allan Tsung, a surgical oncologist and chair of UVA Health’s Department of Surgery. “What it does tell us is that we need to better understand which patients are most likely to live long enough and have the right type of cancer to meaningfully benefit from this treatment.”

The authors said the timing of histotripsy therefore deserves careful consideration, especially for people with advanced disease and limited life expectancy. A procedure can be technically safe and still provide limited benefit if a patient’s cancer is too advanced for a liver-directed treatment to alter the broader course of illness. Tsung described the study’s broader implication in practical terms: the next question is not simply whether histotripsy can be performed, but when it should be performed and for whom. The analysis was observational and did not determine that the procedure caused the deaths or establish that histotripsy improved survival. Instead, it provides a real-world safety snapshot and identifies patient selection and treatment timing as priorities for future evaluation. The research team included Olivia Sears, Elio R. Bitar, Kaelyn C. Cummins, Natalie Blatz, Maclean Cook, Daniel Sheeran and Tsung; the report noted that Sheeran had served on HistoSonics’ Prior Medical Advisory Board.

Subject of Research: Real-world safety and patient-selection outcomes of noninvasive histotripsy for liver tumors

Article Title: Review reveals real-world results of new, incisionless liver cancer treatment

Article References: Review reveals real-world results of new, incisionless liver cancer treatment. Original publication (Bibliographic details unavailable.)

Image Credits: AI Generated

DOI: Not provided

Keywords: histotripsy, liver cancer, focused ultrasound, real-world evidence, metastatic disease, patient selection, treatment safety, clinical outcomes, Review, reveals, real-world, results

The study focused on the right globus pallidus interna, a deep structure that is part of a circuit involved in movement, thought and emotion. Previous work led by study author Wei Qi and colleagues had linked problems in this circuit to delusions and to the degree of patients’ responses to medication. Unlike approaches that require implanted devices or surgical access, transcranial ultrasound stimulation uses gentle, focused sound waves to alter activity in selected brain regions. The researchers proposed that targeting the globus pallidus interna might offer a way to test—and potentially modulate—the circuitry underlying psychotic symptoms. This was the first study to apply the technique to schizophrenia symptoms, according to the research team, and its results should be viewed as an early clinical test rather than proof of therapeutic benefit.

Each participant received one active session and one sham session, allowing investigators to compare responses within the same individuals while limiting differences caused by separate groups. The active procedure and sham condition were administered one week apart in random order. Neither the participants nor the members of the research team who assessed symptoms knew which condition they were receiving. During the sham session, the ultrasound device was positioned on the head and switched on, but a mechanism inside it blocked the sound waves from reaching the brain. This design was intended to preserve the sensory and procedural experience of treatment while isolating the biological effect of stimulation. The study was classified as a randomized controlled clinical trial, although its size and format identify it as a pilot investigation.

MRI scans were used to guide placement of the ultrasound device and identify the right globus pallidus interna. The researchers then applied ultrasound for 10 minutes in alternating 30-second stimulation and 30-second rest cycles. The targeted structure lies deep within the brain and ordinarily would be difficult to reach with non-invasive methods that offer precise spatial targeting. Focused ultrasound can be directed to a small area, giving the team a way to test the function of a defined neural circuit. In this study, the goal was not simply to expose the brain to sound but to determine whether stimulation of the selected region was associated with a change in delusions and whether the procedure could be tolerated under blinded conditions.

Symptoms were evaluated before treatment, during treatment and for up to seven days after each session. The assessment included a series of rating scales covering delusions, hallucinations, thinking, memory and side effects. The principal signal appeared in the delusion ratings: the average score decreased by 1.2 points following the active ultrasound session, whereas it rose by an average of 0.4 points after the sham procedure. The study team characterized the active-treatment change as modest but clear and reported that the difference between the two conditions persisted for as long as a week, which was the end of the observation period. The article did not provide uncertainty estimates such as confidence intervals for the score changes, so the precision and variability of the effect could not be evaluated from the supplied report alone.

The procedure was generally well tolerated. Side effects—including fatigue, headache and brief increases in psychotic symptoms—were described as mild and short-lived. Their frequency did not differ between active and sham sessions, meaning the report did not show a side-effect burden unique to the ultrasound intervention. This safety finding is important in a pilot psychiatric study involving people with serious symptoms despite medication treatment, but it should not be interpreted as evidence that ultrasound is broadly risk-free. Ten participants were too few to detect uncommon adverse events, and the maximum follow-up lasted only seven days after each session. Larger and longer studies would be needed to characterize both tolerability and durability more reliably.

Shy Shoham, the study’s co-senior author and a professor of neuroscience and ophthalmology at NYU Grossman School of Medicine, said the work demonstrates the unusual targeting possibilities offered by focused ultrasound. Other emerging approaches can modulate brain circuits, but ultrasound can be focused on very small regions that influence thinking and behavior. That spatial precision is central to the investigators’ strategy: rather than stimulating a large portion of the brain, they aimed at a structure selected because of evidence connecting it to delusions and medication response. Donald Goff, the study’s senior author, said the results also show that focused ultrasound can be used to examine circuits relevant to psychiatric illness. The experiment therefore combined a potential treatment mechanism with a probe of brain function.

Transcranial ultrasound stimulation has previously been explored for anxiety, depression and obsessive-compulsive disorder, as well as for thinking and memory problems in people with Alzheimer’s and Parkinson’s diseases. Those earlier investigations established the technique as an experimental tool for influencing selected brain areas, but they do not supply evidence for treating delusions in schizophrenia. The present pilot involved a distinct population and target, and it tested only a single active session. The observed reduction cannot yet be separated fully from ordinary symptom fluctuation, expectancy, placebo response or other influences, despite the use of a sham procedure and blinded symptom ratings. A larger trial with more participants, repeated stimulation and follow-up beyond one week would be needed to determine whether the effect is reproducible and clinically meaningful.

Researchers from the psychiatry and biomedical engineering teams plan to enroll more patients and test repeated ultrasound sessions over longer periods. They also intend to use more advanced brain imaging to verify that the ultrasound is reaching the intended globus pallidus interna and to adjust stimulation intensity for individual participants. Those steps address two central challenges in translating the result: confirming that the targeted structure receives the intended dose and determining whether repeated treatment produces more durable effects. The team has said further work is required before targeted ultrasound could supplement—or potentially replace—standard medicines for schizophrenia. That possibility remains speculative; the present evidence comes from a short, small sham-controlled crossover pilot, not from a trial demonstrating replacement of established care.

The work was funded by the Doris Duke Foundation Fund to Retain Clinical Scientists, the Brain & Behavior Research Foundation and the Max G. Schlapp Mental Hygiene Fund. The results were led by Wei Qi, a clinical assistant professor in NYU Langone’s Department of Psychiatry, together with Shoham, Goff and colleagues from the medical school’s psychiatry and engineering programs. The report was slated for publication in npj Acoustics on October 20, 2026, under the title “Transcranial ultrasound stimulation of the right globus pallidus interna in schizophrenia: A randomized, sham-controlled pilot study.” For now, the most defensible conclusion is that a carefully targeted, single ultrasound session was safe in this small group and coincided with a modest improvement in delusions that was not observed after sham stimulation. Whether that signal can become a reliable psychiatric treatment will depend on larger, longer and more technically verified studies.

Subject of Research: A sham-controlled pilot trial of focused ultrasound targeting the right globus pallidus interna in schizophrenia and schizoaffective disorder

Article Title: Gentle brain ultrasound may help ease delusions in schizophrenia

Article References: Gentle brain ultrasound may help ease delusions in schizophrenia. Original publication (Bibliographic details unavailable.)

Image Credits: AI Generated

DOI: Not provided

Keywords: transcranial ultrasound, schizophrenia, delusions, schizoaffective disorder, focused ultrasound, globus pallidus interna, brain stimulation, randomized crossover trial, psychosis, non-invasive neuromodulation, Gentle, brain

The survey’s methodology deserves attention because mapping professional roles across borders is not straightforward. The researchers combined three complementary approaches: systematic searches of the scientific literature, direct examination of national health organizations’ websites, and direct correspondence with local health authorities. This triangulation matters because formal regulations, professional society guidelines, and actual bedside practice can diverge considerably. A country may have no written rule about who may operate a TMS device, yet in practice only physicians perform the procedure; conversely, a regulation may exist on paper but be poorly enforced. By contacting authorities directly, the authors could capture practices that would otherwise remain invisible to a purely bibliographic search, though the approach also means that the completeness of the picture depends on how responsive each national body was to inquiry.

The consistency found for EEG and MRI is not accidental. Both technologies share a structural feature that makes role division comparatively easy: the recording or acquisition phase is separable in time from the interpretation phase. An EEG technologist can attach electrodes, calibrate amplifiers, and record a tracing that is stored for later review, and an MRI radiographer can position the patient, select sequences, and archive the images without making any diagnostic judgment. The interpretation, in turn, requires medical training because it carries diagnostic and therapeutic consequences. This temporal and cognitive separation maps naturally onto a technician-physician division, and international bodies such as the International Federation of Clinical Neurophysiology and the American College of Radiology have codified it in their recommendations. The survey’s finding that this pattern holds across most of the 26 countries suggests that these recommendations have been widely absorbed into national practice, even where formal national protocols are absent.

The clinical stakes of this division are considerable. In EEG, the distinction between a technically adequate recording and an interpretable one depends on details such as electrode impedance, artifact recognition, and activation procedures, which is why trained technologists matter. But the reading itself, particularly the identification of interictal epileptiform discharges or the recognition of non-convulsive status epilepticus, demands subspecialty expertise, and misreading can lead to either missed seizures or inappropriate treatment with antiseizure medications. Similarly, in MRI, the technologist’s role in sequence selection and image quality directly determines whether the radiologist can detect subtle pathology such as early demyelinating lesions or small ischemic foci. The survey’s confirmation that neurologists and radiologists respectively hold interpretive authority for EEG and MRI therefore reflects a division of labor that has direct consequences for diagnostic accuracy.

Transcranial Doppler stands out in the survey because it resists this clean separation. Unlike EEG and MRI, TCD is an interactive, real-time examination: the operator must find acoustic windows through the temporal bone or other thin regions of the skull, adjust insonation angles, and track vessels dynamically, and the diagnostic conclusion often emerges during the examination itself rather than afterward. The result is heavily operator-dependent, which is why professional guidelines such as those from the American Institute of Ultrasound in Medicine permit performance by either trained sonographers or physicians, but the survey found that in most countries physicians both perform and interpret the study. This is particularly evident in applications such as detecting vasospasm after subarachnoid hemorrhage, where serial bedside examinations track changing flow velocities and findings must be acted upon immediately, or in sickle cell disease, where elevated flow velocities in the middle cerebral artery guide transfusion decisions that prevent stroke in children. In these settings, the delay inherent in a two-stage perform-then-interpret workflow could be clinically harmful, which plausibly explains why the physician-performed model dominates.

The situation for transcranial magnetic stimulation is more layered because the technology serves two distinct purposes. Single-pulse TMS, used diagnostically to elicit motor evoked potentials and assess corticospinal tract integrity and cortical excitability, is a neurophysiological test in the tradition of EEG, and the survey found that it is either performed by physicians directly or performed by technicians under physician presence, with interpretation reserved for physicians. Repetitive TMS, by contrast, is a therapeutic intervention whose effects depend on stimulation frequency: frequencies below one hertz tend to reduce cortical excitability, while frequencies above five hertz tend to increase it. The therapeutic applications span treatment-resistant major depressive disorder, post-stroke motor rehabilitation, neuropathic pain, and obsessive-compulsive disorder. The survey found that where information was available, therapeutic rTMS is delivered by physicians, typically neurologists or psychiatrists, which aligns with the fact that the prescribing decision, the selection of stimulation parameters, and the monitoring of psychiatric or neurological response all require medical judgment.

The IFCN framework for TMS roles is worth unpacking because it represents the most developed international attempt to structure this workforce. Under these guidelines, technicians conduct sessions, monitor patient safety and comfort, and administer standardized assessments such as depression rating scales; physicians determine appropriateness, prescribe protocols, and supervise; and scientists, usually principal investigators, design studies and oversee implementation in research contexts. This three-tier model resembles the division of labor in other procedural fields, such as anesthesia or interventional cardiology, where delegated performance under medical supervision is standard. Yet the survey’s central finding is that this framework, despite existing in international recommendations, has not been translated into national guidelines in most of the countries examined. The gap between international recommendation and national regulation means that in many jurisdictions the question of who may legally perform or interpret TMS is governed by general medical device or professional practice rules rather than by modality-specific standards.

Focused ultrasound presents an even starker regulatory vacuum, compounded by the fact that the term covers interventions of very different risk profiles. High-intensity focused ultrasound, above roughly 200 watts per square centimeter, produces permanent thermal lesions and is functionally a surgical technique; it has received regulatory approval for thalamotomy in essential tremor and tremor-dominant Parkinson’s disease, and for treatments outside the brain such as uterine fibroids and bone metastases. Medium-intensity applications can transiently open the blood-brain barrier to enable drug delivery, an approach being explored in neurodegenerative diseases. Low-intensity focused ultrasound, below 100 watts per square centimeter, modulates neural activity through mechanical effects on cell membranes and ion channels without destroying tissue, and early-phase pilot trials have explored its neuromodulatory potential in drug-resistant epilepsy. The survey found that where therapeutic use is established, it is performed by physicians, including surgeons for the ablative applications, but the absence of local guidelines for the newer, non-ablative applications means that practice is likely to be improvised as the technology spreads.

The economic dimension of these role assignments should not be overlooked. The authors note that the costs of these technologies are determined not only by equipment and infrastructure but also by the specialized staff required to operate and interpret them. When a modality requires a physician for every session, as TCD largely does, the cost per procedure and the scalability of the service are constrained by physician availability. When delegation to technicians is permitted, as in EEG and MRI, services can be scaled more economically. This has direct implications for accessibility: rTMS, which requires 20 to 30 daily sessions per treatment course and trained personnel, remains of limited availability in many countries precisely because the staffing model is expensive. How countries resolve the question of who may perform stimulation procedures will therefore shape not only patient safety but also whether these therapies reach the patients who could benefit from them.

The survey’s call for standardized national protocols rests on a straightforward premise: that patient safety and diagnostic accuracy should not depend on geography. For EEG and MRI, the international convergence on a technician-performs, physician-interprets model suggests that standardization is achievable when the technology’s demands are well understood and professional consensus has had decades to mature. For TMS and FUS, technologies whose clinical roles are still expanding and whose risk profiles range from non-invasive neuromodulation to permanent ablation, the absence of national guidance leaves both practitioners and patients in an uncertain position. The survey provides the baseline map against which future regulatory developments in these countries can be measured.

Subject of Research: International survey of professional roles in performing and interpreting EEG, MRI, TCD, TMS and focused ultrasound procedures

Article Title: Roles in brain stimulation, recording and interpreting neuroimaging data: a systematic survey of 26 countries on current practices in EEG, MRI, TCD, TMS and FUS

Article References: Valizada, V., Sesseljuson, L. D., Nardone, R., Thomschewski, A., Trinka, E., & Höller, Y. (2026). Roles in brain stimulation, recording and interpreting neuroimaging data: a systematic survey of 26 countries on current practices in EEG, MRI, TCD, TMS and FUS. Frontiers in Medical Technology, 8, Article 1917621. https://doi.org/10.3389/fmedt.2026.1917621

Image Credits: AI Generated

DOI: 10.3389/fmedt.2026.1917621

Keywords: EEG, MRI, transcranial magnetic stimulation, focused ultrasound, transcranial Doppler, neurotechnology, clinical guidelines, health professionals, brain stimulation, neuroimaging, patient safety, health policy

The study, published in Frontiers in Acoustics by Sam Bleker and colleagues at HAWK University of Applied Sciences and Arts, the University Medical Center Göttingen, and the Medical Laser Center Lübeck, is notable less for a single dramatic number than for the unusual rigor of its temporal accounting. Rather than simply measuring how much tracer crossed a barrier after ultrasound exposure, the team measured transport during the sixty-second sonication window and again in the nine minutes that followed, treating these intervals as fundamentally different biological events. That distinction, they argue, has been missing from much of the in vitro literature.

The experimental system was deliberately reductionist. Human cerebral microvascular endothelial cells, the hCMEC/D3 line widely used as a workhorse model of the blood-brain barrier, were grown on ThinCert permeable inserts for six days until they formed continuous monolayers. Lucifer Yellow, a small hydrophilic fluorescent dye that normally crosses such barriers only slowly through paracellular routes, was placed in the donor compartment above the cells. The researchers then applied continuous-wave focused ultrasound at 1.2 megahertz and 80 volts peak-to-peak for exactly sixty seconds, with no microbubbles, no pulse modulation, and no amplitude ramping.

Characterizing the acoustic field proved to be its own challenge, and the team approached it with unusual candor. Using a calibrated PVDF hydrophone, they scanned frequencies from 0.1 to 2.0 megahertz and found that 1.2 megahertz produced the highest mean peak rarefactional pressure at the focal distance of 5.0 millimeters from the lens apex. Because direct measurement at the biological exposure voltage was not performed, they scaled pressures from the 100-volt calibration condition by a factor of 0.8, arriving at an estimated peak rarefactional focal pressure of 0.838 plus or minus 0.054 megapascals. The authors are explicit that this number describes the calibration geometry, not the actual pressure at the cell layer inside the well-and-insert system, where reflections, standing waves, and lateral spread can substantially reshape the field.

The central result was unambiguous in direction. Across eight independent paired experiments, each comparing an ultrasound-exposed monolayer with an unexposed control from the same culture preparation, the mean control-adjusted increase in Lucifer Yellow accumulation during the exposure interval was 0.283 nanomoles, with a 95 percent confidence interval of 0.185 to 0.380 nanomoles. All eight experiments showed the effect in the same direction, and the standardized effect size, Cohen’s dz of 2.43, was exceptionally large. After Holm correction for multiple comparisons, the p-value was 0.000475. Leave-one-experiment-out analyses confirmed that no single pair drove the result.

What happened next was equally informative. During the nine minutes after the ultrasound was switched off, the additional control-adjusted accumulation was only 0.035 nanomoles, with a confidence interval spanning zero and a Holm-adjusted p-value of 0.555. In other words, the transport enhancement was essentially confined to the period of active insonification. The cumulative difference at ten minutes remained positive, but the authors caution that this largely reflects tracer that crossed during exposure, not continued leakage afterward. They also stress that the absence of detectable post-exposure accumulation does not prove the barrier had fully recovered, since no formal equivalence test or later functional measurement was performed.

The viability data add a layer of caution. In five separate paired experiments, the team stained monolayers immediately after exposure with Calcein-AM and ethidium homodimer-1, standard live-dead indicators, and quantified four image-derived metrics using condition-independent segmentation thresholds. The results were mixed: some experiments showed apparent increases in certain metrics, others showed decreases, and no reproducible ultrasound-associated direction emerged. Standardized effect sizes were small, and the authors explicitly warn that these findings cannot establish biological safety or the absence of delayed or spatially heterogeneous injury, particularly given the small sample size and the lack of a deliberately damaged positive control.

Perhaps the most intriguing and least settled observation came from the cell-free experiments. In a preliminary session conducted before the cellular series, three paired comparisons of ultrasound-exposed and unexposed cell-free inserts, inserts coated with Matrigel but lacking cells, showed no comparable positive response during the exposure interval. All three paired differences were negative. This hints that the transport enhancement in the cellular experiments may depend on the presence of living endothelial cells rather than on ultrasound-driven convection through the membrane alone. But the authors are careful: because all three cell-free pairs came from a single session, they cannot reliably quantify or exclude non-cellular contributions, and independent replication would be needed to separate endothelial, membrane, and fluid-system effects.

What mechanism could explain the response? The authors decline to commit. Acoustic radiation force, oscillatory deformation of the cells, fluid motion, or local shear stress could activate mechanosensitive signaling pathways, alter cortical actin tension, or transiently reorganize cell-cell junctions. Membrane permeabilization or vesicular transport cannot be ruled out either. A thermal contribution is also possible, since the sixty-second continuous-wave exposure was delivered without temperature monitoring, and the liquids were not degassed. The absence of visible bubbles during exposure does not exclude microscopic cavitation, and no passive cavitation detection was performed. The study therefore establishes that something happened during insonification, but not precisely what.

The broader context makes the work more than a laboratory curiosity. Focused ultrasound combined with intravenously administered microbubbles has already progressed from preclinical studies to early clinical trials for temporarily opening the blood-brain barrier in conditions such as Alzheimer’s disease and amyotrophic lateral sclerosis. Rodent studies have also demonstrated targeted and reversible opening of the blood-retinal barrier. But those approaches depend on circulating microbubbles, which introduce their own variability and safety considerations. Demonstrating that continuous-wave focused ultrasound can modulate tracer transport across a human endothelial monolayer without any added bubbles suggests that a simpler, bubble-free paradigm might deserve closer investigation, at least under controlled in vitro conditions.

The authors are equally clear about the limits of generalization. The hCMEC/D3 line, while human and reproducible, exhibits lower electrical resistance and higher paracellular permeability than primary or stem-cell-derived barrier models, and it lacks the pericytes, glial interactions, basement membrane, and hemodynamic environment of a real neurovascular barrier. The cells are of cerebral, not retinal, origin, so the findings cannot be assumed to translate directly to the blood-retinal barrier, even though the two share fundamental endothelial features. The study also did not measure transendothelial electrical resistance or junctional protein organization, leaving baseline barrier tightness and post-exposure recovery uncharacterized by orthogonal measures.

What the study does deliver is a methodological template. By treating the paired experiment as the biological unit, correcting cumulative transport calculations for both decreasing compartment volume and tracer removed during repeated sampling, and analyzing exposure and post-exposure intervals separately, the researchers have built a framework that other groups can adopt to disentangle when, not just whether, ultrasound affects endothelial transport. Future work, they suggest, should include randomized well positions, applicator-coupled sham controls, direct acoustic characterization near the monolayer, temperature monitoring, cavitation detection, time-resolved electrical resistance measurements, and replication in human retinal microvascular endothelial cells and more complex multicellular barrier models.

For now, the finding stands as a carefully bounded but genuinely novel observation: a short burst of continuous-wave focused ultrasound, delivered without microbubbles, measurably and reproducibly increased the passage of a small hydrophilic tracer across a human brain endothelial monolayer, and it did so predominantly while the sound was on. Whether that transient window of enhanced transport can be harnessed for drug delivery to the brain or retina, and whether it can be achieved without collateral cellular stress, remains an open and compelling question for the field.

Subject of Research: Focused ultrasound modulation of tracer transport across human cerebral endothelial monolayers in vitro

Article Title: Focused ultrasound increases Lucifer Yellow transport across hCMEC/D3 endothelial monolayers

Article References: Bleker, S., Redeker, K.-E. M., Meußler, G., Brinkmann, R., Brockmöller, J., & Russmann, C. (2026). Focused ultrasound increases Lucifer Yellow transport across hCMEC/D3 endothelial monolayers. Frontiers in Acoustics, 4, Article 1968185. https://doi.org/10.3389/facou.2026.1968185

Image Credits: AI Generated

DOI: 10.3389/facou.2026.1968185

Keywords: focused ultrasound, blood-brain barrier, hCMEC/D3, endothelial monolayer, Lucifer Yellow, drug delivery, microbubbles, in vitro model, acoustic bioeffects, blood-retinal barrier, paracellular transport, continuous-wave ultrasound

The review, led by Madeline I. Foo of Johns Hopkins Hospital and Alissa Hendricks-Wenger of Mayo Clinic Florida, together with colleagues including Eli Vlaisavljevich of Virginia Tech, one of the technique’s pioneering engineers, searched PubMed and SCOPUS for studies of histotripsy ablation of parenchymal tissues in vivo. From an initial pool of 1,270 publications identified on June 22, 2026, the team applied strict inclusion criteria: the work had to use histotripsy for in vivo ablation of parenchymal tissue, be peer-reviewed, and have full text available in English. Conference abstracts, preprints, reviews, and studies targeting non-parenchymal structures such as phantoms, abscesses, or thromboses were excluded. The final analysis included 141 studies, of which 114 were pre-clinical and 27 were clinical reports. Most animal work involved healthy tissue in murine or porcine models, while the clinical literature concentrated overwhelmingly on hepatic malignancies, with 25 of the 27 clinical studies focused on the liver. Assuming no overlaps beyond those identified, the clinical experience could encompass a maximum of roughly 607 unique patients, a reminder of how early the human evidence base still is.

The authors performed a formal meta-analysis only on clinical cohort studies of hepatic ablation, synthesizing the remaining findings qualitatively and grading severity with the Society of Interventional Radiology adverse event classification. The pooled numbers tell a broadly reassuring story with important caveats. The screen-failure rate, meaning patients deemed appropriate on clinical criteria who ultimately did not receive treatment, was 49 percent, reflecting how carefully candidates are still being selected. The overall incidence of serious adverse events, grade 3 or higher on the SIR scale, was 6 percent. The two most common serious complications were thrombotic events and acute kidney injury, each with a pooled incidence of roughly 4 to 6 percent. Pain, by contrast, was infrequently and inconsistently reported, but where it was measured, most patients experienced only mild to moderate discomfort with minimal analgesic requirements, and in a canine osteosarcoma limb-sparing trial, treated animals actually improved their weight-bearing on the treated limb over follow-up.

What makes the review particularly valuable is its attention to mechanism-specific risks. Because histotripsy works by mechanical fractionation rather than thermal coagulation, it creates injury patterns that thermal ablation does not. The rapid liquefaction of tissue releases intracellular electrolytes and macromolecules into the circulation, a process that may contribute to local and systemic injury. Cavitation events occur with a probabilistic distribution, which means that even an adequate-appearing treatment can leave viable cells behind, generate debris particles measuring up to 54 micrometers, small enough to act as embolic agents, and theoretically liberate tumor cell clusters that could disseminate. The review also distinguishes injuries along the ultrasound beam path: pre-focal damage between the transducer and the focus, post-focal injury deep to the treatment zone, and unintended effects within the prescribed treatment volume itself.

Some of the most sobering findings come from the pre-clinical literature. Three bowel perforations occurred in a murine study using a custom 1 MHz transducer with high treatment parameters and wide margins that encompassed bowel. In porcine pancreatic ablation with the Edison clinical system, two grade 3 events were reported, including septic peritonitis requiring euthanasia and gastrointestinal obstruction, with poor ultrasound visualization from overlying bowel gas associated with bowel damage in three of nine swine. Pulmonary injury appeared in a porcine study of transcostal hepatic treatment, where four of five subjects showed magnetic resonance evidence of right lower lobe lung injury, though no pneumothoraxes developed. A chronic rodent study found that mice developed alveolar septal rupture and pulmonary hemorrhage because the acoustic channel was long relative to their small bodies, an injury absent when the same protocol was applied to rats, underscoring how body size and acoustic-window geometry shape beam-path risk. Urinary tract studies reported rectoprostatic fistulas and urethral perforation in a canine prostate model, while a porcine ureter study showed only low-grade, reversible urothelial injury.

Clinically, the pattern of serious events differs in instructive ways. Gastrointestinal and pulmonary adverse events have so far appeared only in animals, while vascular injuries, acute kidney injuries, and disease progression have emerged only in humans. Acute kidney injury following hepatic histotripsy has become a recognized systemic complication: in a five-center review of 146 procedures, nine patients developed AKI, including two grade 5 events, and additional cases have surfaced in case reports and the FDA’s MAUDE registry. Vascular complications have included bleeding requiring embolization and transfusion, hepatic pseudoaneurysms within the treatment zone, and hemorrhagic shock, with one death on postoperative day 28 from fulminant hepatic failure in a vascular-injury series. Portal and hepatic vein thrombosis has emerged as one of the most common clinically significant events, with central tumor location and overlapping treatment zones identified as key risk factors, findings that align with pre-clinical work linking thrombosis to cavitation-induced endothelial injury. Notably, three anticoagulated large-animal studies found no significant hemorrhage after hepatic, renal, or prostate treatment, and pre-clinical work suggests prophylactic low-dose heparin can mitigate thrombotic risk without increasing bleeding.

Perhaps the most scientifically provocative section of the review concerns tumor biology. Across 41 publications with at least one week of follow-up, the majority of clinical and all veterinary studies reported stable or progressive systemic disease acutely, which is expected given the advanced stage of most treated patients. But five clinical reports described fourteen patients in whom untreated tumors regressed on follow-up imaging, sometimes with concordant decreases in tumor markers, a phenomenon consistent with the abscopal effect, in which local treatment sparks systemic immune activity against cancer elsewhere. Two pre-clinical studies support the idea that histotripsy can elicit statistically significant systemic tumor inhibition through immune-mediated mechanisms, likely because mechanical fractionation releases tumor antigens in a form the immune system can process. Against this hopeful backdrop stands a single clinical case report of hyperprogression: a patient with recurrent cholangiocarcinoma developed hyperacute, extensive metastatic disease within three months of treatment, with roughly fifty lesions appearing in the retroperitoneum and subcutaneous fat in an atypical pattern. Causality cannot be established from one case, and no animal study showed an acute increase in systemic disease burden compared with controls, but the authors argue it highlights the need for long-term oncologic surveillance and mechanistic investigation.

The review is candid about the limitations of the evidence it synthesizes. Histotripsy data span fewer than two decades, dominated by pre-clinical models with highly variable transducers and acoustic parameters, while clinical data cover only about six years and consist almost entirely of single-arm trials, feasibility studies, case series, and case reports. Multiple publications derive from overlapping cohorts, so the number of papers overrepresents the breadth of independent experience. The predominance of early-adopter centers and investigator-industry collaborations introduces potential publication and reporting bias, and learning-curve effects may inflate apparent adverse event rates while incomplete ascertainment, such as omitting laboratory tests needed to detect kidney injury, may lower them. Strikingly, the review found that pre-clinical studies routinely specified therapeutic parameters such as mechanism, transducer frequency, and acoustic delivery, while clinical studies often did not, with no clear reporting of the Edison system’s acoustic parameters, making it difficult to extrapolate animal safety data to human treatments.

The authors close with practical guidance and a call for rigor. Non-target injury is best minimized through careful patient selection, pretreatment planning, a clear acoustic window, continuous bubble-cloud visualization, respiratory management, precise transducer alignment, and therapy pauses when needed, with particular avoidance of susceptible structures such as lung and bowel. Standardized post-procedure imaging protocols should prospectively evaluate for thrombotic and embolic events, and clinical systems must report their therapeutic parameters in line with the established ablation reporting lexicon. The overall verdict is measured: early data suggest an acceptable acute safety profile in select settings, and most studies reported few adverse events, but the serious exceptions, thromboses, vascular injuries, kidney injuries, and the single hyperprogression case, form a framework for mechanism-specific vigilance. As histotripsy expands beyond subcostal liver targets toward pancreas, kidney, prostate, and extremity tumors, the review’s central message is that open adverse event reporting and rigorous, longer-term follow-up must keep pace with the technology’s undeniable appeal, ensuring that enthusiasm for a genuinely noninvasive cancer therapy is matched by equally rigorous science.

Subject of Research: Safety and adverse events of histotripsy, a cavitation-based focused ultrasound ablation technique, across pre-clinical and clinical studies

Article Title: Understanding histotripsy ablation safety: a systematic review of pre-clinical and clinical adverse events

Article References: Foo, M. I., Uzoukwu, C., Morhard, R., Falk, K. L., Wood, B. J., Frey, G., Ziemlewicz, T. J., Vlaisavljevich, E., Toskich, B. B., & Hendricks-Wenger, A. (2026). Understanding histotripsy ablation safety: a systematic review of pre-clinical and clinical adverse events. CVIR Oncology, 2(1), Article 33. https://doi.org/10.1007/s44343-026-00062-2

Image Credits: AI Generated

DOI: 10.1007/s44343-026-00062-2

Keywords: histotripsy, focused ultrasound, cavitation, tumor ablation, adverse events, liver cancer, thrombosis, acute kidney injury, abscopal effect, systematic review, interventional radiology, patient safety

The technology at the heart of the award is remarkable in its simplicity and its audacity. Histotripsy uses focused ultrasound waves, delivered from outside the body, to create microscopic bubbles in targeted tissue. These bubbles form and collapse in rapid cycles, generating mechanical forces that liquefy and destroy the targeted cells with millimeter precision, all without a single incision. Unlike thermal ablation methods that burn or freeze tissue, histotripsy destroys tumors mechanically, sparing surrounding blood vessels, nerves and healthy structures and producing few side effects. Patients typically recover quickly because there is no surgical wound to heal. Since the technique received authorization from the U.S. Food and Drug Administration for the treatment of liver tumors in 2023, it has moved rapidly from the laboratory into clinics around the world, offering a glimpse of what noninvasive cancer care might look like in the decades ahead.

The commercial engine behind that clinical expansion is HistoSonics, a University of Michigan startup that Xu and a small group of U-M engineers and doctors founded in 2009 to translate the laboratory discovery into a viable medical platform. The company’s trajectory illustrates how long the road from basic discovery to patient benefit can be, and how unlikely that road looks at its start. By June of this year, HistoSonics had reached a valuation of $3.75 billion and now employs roughly 500 people, with offices in Ann Arbor and corporate headquarters in Minnesota. More than 130 of the company’s treatment systems have been installed around the world, and those systems have already been used to treat more than 5,000 patients. For a technology that early-stage investors once dismissed as too speculative to fund, those numbers represent an extraordinary vindication.

Xu is emphatic that none of it would have happened without sustained federal support. In the years before histotripsy could attract private capital, funding from the National Institutes of Health and the U.S. Department of Defense carried the research through its most uncertain phase, she explained. The early research and development of such a new, disruptive technology was viewed as too high a risk for investors and companies, such that funding from industry or investors could not be secured early on, Xu said. The initial research on histotripsy, as well as its early development for the treatment of cancer, brain diseases and cardiovascular diseases, was largely funded by the NIH. Government funding, she said, was the only way to establish a solid research foundation and advance the technology until it was ready for commercialization, allowing a small academic team to pursue a question that no one else was willing to underwrite.

That message resonates deeply with the mission of the Golden Goose Awards, which were first awarded in 2012 specifically to counter the narrative of wasteful federal spending on science. The awards deliberately spotlight research projects whose initial goals may have sounded obscure, odd or even frivolous, but which went on to produce discoveries of enormous practical value. Sudip Parikh, chief executive officer of AAAS and executive publisher of the Science family of journals, framed the award in exactly those terms. Part of the nation’s scientific and economic leadership starts with giving researchers the freedom to follow promising ideas, even when no one knows exactly where they will lead, Parikh said. This year’s Golden Goose awardees, he argued, demonstrate why that freedom matters.

Parikh’s argument extends beyond any single discovery to the structure of the scientific enterprise itself. Some of the most consequential discoveries, he noted, began with questions whose value was far from obvious at the outset, and sustained federal investment ensures that scientists can keep asking those questions and pursuing unexpected discoveries that make people healthier, safer and more competitive. Histotripsy is a case study in that principle at work. The fundamental physics of bubble dynamics in tissue had no obvious commercial endpoint when Xu and her colleagues began their work, and had the research been judged solely on near-term market potential, it would almost certainly have died in its infancy. Instead, federal grants allowed a long arc of exploratory science to unfold at its own pace, eventually producing a platform that now treats thousands of patients annually.

Xu’s ambitions for the technology extend far beyond the liver tumors for which it is currently authorized. Even though histotripsy is currently FDA-approved to treat tumors in the liver, she describes it as a platform technology that can be used to treat many diseases, including a wide range of cancer types, with tumors in the kidney, pancreas, breast, prostate, thyroid, skin and sarcoma among the potential targets. Beyond oncology, she sees applications in brain diseases such as hemorrhagic stroke, brain tumors and epilepsy. Perhaps most intriguingly, she points to the possibility of combining histotripsy with cancer drugs and immunotherapy to treat some advanced cancer types that currently have no cure, since mechanically disrupting a tumor may help therapeutic agents reach and attack cancer cells more effectively. Each of these directions remains under active investigation, and none is yet an approved use of the technology.

To accelerate that expansion, Xu directs the University of Michigan Histotripsy Center, a first-of-its-kind research institution that launched earlier this month with roughly $10 million in support. The center’s explicit mission is to rapidly discover more cancers and other diseases that may be treatable with focused ultrasound, shortening the path from laboratory hypothesis to clinical trial. By concentrating expertise in ultrasound physics, biomedical engineering, immunology and clinical medicine under one roof, the center aims to systematically map the boundaries of what mechanical tissue ablation can achieve. If the history of histotripsy is any guide, some of the questions pursued there will sound improbable today, and some of them will prove to matter enormously.

Xu shares this year’s Golden Goose Award with two other groups of researchers whose unlikely-seeming projects produced outsized benefits. One team’s work led to NASA’s Black Marble program, which can track power outages in real time from space, giving responders and utilities an unprecedented view of infrastructure failures during disasters. The other honoree is University of Chicago physicist Sidney Nagel, whose investigations into the physics behind complex everyday phenomena have led to improvements in medical diagnostics, inkjet printing and industrial processes. Taken together, the 2026 cohort of awardees reads like a catalog of research directions that a cost-benefit analysis would once have cut: sound waves that shred tumors, satellites that see blacked-out cities, and the slow-motion physics of a coffee drop.

For Xu, the recognition is also a statement about the ecosystem that makes such science possible. She and the University of Michigan hold a financial interest in HistoSonics, a disclosure that underscores how federal seed funding helped create not only a medical technology but a thriving company and hundreds of jobs in Michigan and Minnesota. The larger lesson, she suggests, is that patience is a form of investment. A therapy that destroys tumors with sound, without surgery and with few side effects, was never an overnight success; it was a federally funded question that stubborn researchers kept asking until the answer changed what medicine can do. As more than 5,000 patients can now attest, the questions least obvious in value at the outset are sometimes the ones most worth funding.

Subject of Research: Noninvasive focused ultrasound cancer treatment and federal funding of exploratory biomedical research

Article Title: U-M's Zhen Xu wins Golden Goose Award for development of noninvasive cancer treatment

Article References: U-M's Zhen Xu wins Golden Goose Award for development of noninvasive cancer treatment. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: histotripsy, Zhen Xu, Golden Goose Award, focused ultrasound, HistoSonics, cancer treatment, noninvasive surgery, University of Michigan, AAAS, NIH funding, FDA authorization, medical ultrasound

The central idea behind the study is neuromodulation, the deliberate adjustment of nerve activity to change the function of an organ. For the heart, the relevant nerves belong to the autonomic nervous system, the network that operates largely outside conscious control. Sympathetic branches act like an accelerator, speeding the heart when the body demands more oxygen, while parasympathetic branches act as a brake, slowing it during rest and recovery. Clinicians have long known that adjusting this balance can treat rhythm disorders, but the tools available to do so have been crude, invasive, or both. Focused ultrasound offers a way to deliver energy to a precisely defined volume of tissue deep inside the body, stimulating or suppressing neural structures without any incision.

Ultrasound neuromodulation has attracted growing interest over the past decade because sound waves interact with tissue in ways that electrodes cannot. An ultrasound transducer can focus acoustic energy at a target millimeters across, several centimeters beneath the skin, while leaving intervening tissue essentially untouched. The mechanical and thermal effects of the focused beam can alter the excitability of nerve fibers, changing how likely they are to fire action potentials. Depending on the acoustic parameters chosen, the same technology can excite or inhibit neural activity, giving researchers a reversible dial for nervous system function rather than a simple on-off switch.

What distinguishes the new work is the emphasis on image guidance. Delivering energy to the region around the heart is technically demanding because the target moves constantly with each heartbeat and shifts with every breath. The researchers integrated their ultrasound system with imaging that allowed them to track and compensate for this motion, keeping the acoustic focus locked on the intended neural target as the body moved. This kind of closed-loop control is widely regarded as essential if ultrasound neuromodulation is ever to leave the laboratory, because even small targeting errors could disperse the acoustic energy to unintended structures or miss the nerve tissue altogether.

The reported outcome is that this image-guided stimulation could regulate heart rate. By directing focused ultrasound at cardiac neural targets, the team demonstrated that the technique could influence the pace of the heartbeat in a controlled fashion, adjusting the balance between the nerves that accelerate the heart and those that slow it. Regulation, rather than simple stimulation, is the crucial claim. A clinically useful therapy would need to raise or lower heart rate on demand, or damp pathological overactivity, and the study presents its approach as capable of that kind of bidirectional control.

The technical machinery required for this achievement is considerable. High-intensity focused ultrasound systems of the kind used for ablating tumors deliver enough energy to destroy tissue, but neuromodulation typically operates at far lower intensities, below thresholds that would cause lasting damage. The acoustic parameters, including frequency, pulse duration, and repetition rate, determine whether the beam primarily excites nerve fibers, suppresses them, or produces transient heating that changes their behavior. Finding parameter sets that reliably modulate cardiac nerves without harming the surrounding myocardium is one of the field’s central challenges, and the published work contributes data toward that goal.

Why does this matter for medicine? Disturbances of heart rate and rhythm are among the most common and lethal problems in clinical cardiology. Abnormally fast rhythms, abnormally slow rhythms, and chaotic fibrillation all arise from malfunctions in the heart’s electrical control system, and the autonomic nerves that supply the heart are deeply implicated in many of these conditions. Catheter ablation, in which a physician threads wires into the heart and burns small areas of tissue, is effective for some disorders but is invasive and carries procedural risk. Drugs can modulate autonomic tone but act throughout the body, producing side effects far from the heart. A noninvasive, focal, and reversible method for adjusting cardiac nerve activity would fill a genuine gap in the therapeutic arsenal.

The study also speaks to a broader trend in bioelectronic medicine, a field built on the idea that many diseases can be treated by adjusting the electrical signals carried by nerves rather than by delivering chemicals. Researchers have implanted electrodes on the vagus nerve to treat epilepsy and inflammatory conditions, and others have explored stimulation of the carotid sinus and spinal cord for cardiovascular indications. Ultrasound offers these same possibilities from outside the body, which would eliminate implantation surgery and infection risk. The heart, with its well-mapped autonomic innervation and its easily monitored output, is a natural proving ground for the concept, because heart rate itself provides an immediate, continuous readout of whether the neuromodulation is working.

As with any early-stage study, important questions remain before patients could benefit. The durability of the effect, the precise neural structures targeted, the safety margins for repeated sessions, and the translation of results across species are all matters that will require further investigation. The team’s own account presents the work as a demonstration of feasibility: that image guidance can keep a focused ultrasound beam on a moving cardiac target, and that the resulting neuromodulation is sufficient to regulate heart rate. Scaling from demonstration to therapy will demand larger and longer studies, refinement of the targeting algorithms, and careful assessment of any off-target effects on neighboring tissue.

Nevertheless, the publication marks a noteworthy step for a technology that many researchers hope will reshape how medicine interacts with the nervous system. The combination of focused ultrasound with real-time imaging transforms neuromodulation from a procedure requiring precision hardware implanted inside the body into something closer to an examination: the patient lies still, the imaging system tracks the target, and the acoustic beam delivers its influence without a single incision. If subsequent studies confirm and extend these results, the day may come when clinicians tune the heart’s rhythm the way this study did, with sound alone, guided by images, and reversed the moment the therapy ends.

The physics underlying this approach rewards a closer look, because it explains both the promise and the difficulty of the method. Ultrasound waves at the megahertz frequencies typically used for neuromodulation travel through soft tissue at roughly fifteen hundred meters per second and can be steered by phasing the emissions of hundreds of individual elements on a transducer array. Each element fires with a slightly different delay, so that the wavefronts arrive simultaneously at a chosen point, constructive interference concentrates the acoustic pressure there, and tissue elsewhere receives comparatively little energy. This electronic steering means the focus can be repositioned in milliseconds purely by changing the timing signals, a property that pairs naturally with the fast feedback demanded by a beating heart.

The choice of neural target is equally consequential. The heart’s autonomic control is organized around ganglionated plexi, clusters of neurons embedded in the epicardial fat pads near the pulmonary veins, the superior vena cava, and the atria. These microganglia act as local integration centers, relaying and processing signals from the vagus nerve and the sympathetic chain before they reach the cardiac conduction system. Cardiac surgeons and electrophysiologists have known for decades that disturbing these clusters alters atrial rhythm tendencies, which is precisely why they represent attractive targets for noninvasive modulation. Delivering acoustic energy to such small structures, however, requires submillimeter accuracy sustained over many cardiac cycles.

Motion compensation of this kind borrows heavily from techniques developed in radiation oncology, where tumor-tracking linear accelerators adjust beam delivery to a patient’s respiratory cycle. The cardiac problem is harder still, because the heart moves faster than the lungs and exhibits beat-to-beat variability. A successful tracking system must therefore anticipate where the target will be when each acoustic pulse arrives, rather than simply following its past position, and any latency in the imaging chain must be accounted for in the control algorithm.

Safety considerations extend beyond the avoidance of thermal injury. Regulatory frameworks for medical ultrasound, built around indices that estimate heating and the potential for cavitation, will need to be interpreted carefully for a therapy whose intended effect is functional rather than destructive. Repeated exposure of the same neural tissue raises questions about cumulative changes in nerve excitability, and the possibility that acoustic energy scattered by ribs or lung tissue could stimulate unintended structures deserves systematic study. The chest wall itself presents an acoustic obstacle, since bone reflects and absorbs ultrasound strongly, so coupling of the beam through an intercostal window is a practical constraint on positioning.

The experimental logic of using heart rate as an endpoint also deserves emphasis. Unlike modulation of deeper brain circuits, where effects must be inferred indirectly, cardiac neuromodulation produces a continuous, quantitative, beat-by-beat readout that can be captured with noninvasive electrocardiography. This tight feedback loop makes the heart an ideal model system for validating the principles of image-guided acoustic neuromodulation generally, and lessons learned here may well inform applications to the peripheral and central nervous system, where comparable targeting and monitoring challenges await solutions.

Subject of Research: Noninvasive image-guided focused ultrasound neuromodulation of cardiac autonomic nerves to regulate heart rate

Article Title: Image-guided cardiac focused ultrasound neuromodulation regulates heart rate

Article References: Piao, X., Wei, Y., Yao, X., Xu, Z., Pan, J.-J., Hu, P., & Cheng, B. (2026). Image-guided cardiac focused ultrasound neuromodulation regulates heart rate. Communications Engineering. https://doi.org/10.1038/s44172-026-00774-6

Image Credits: AI Generated

DOI: 10.1038/s44172-026-00774-6

Keywords: focused ultrasound, neuromodulation, heart rate, autonomic nervous system, image guidance, cardiology, bioelectronic medicine, ultrasound therapy, cardiac nerves, noninvasive stimulation, Image-guided, cardiac