diff --git a/.pre-commit-config.yaml b/.pre-commit-config.yaml index bdd42be8..f4540145 100644 --- a/.pre-commit-config.yaml +++ b/.pre-commit-config.yaml @@ -62,7 +62,7 @@ repos: rev: "v2.2.6" hooks: - id: codespell - exclude: .*\.ipynb # exclude notebooks because images are sometimes captured in spell check + exclude: ^(.*\.ipynb|literature_library\.md)$ # exclude notebooks because images are sometimes captured in spell check, exclude literature_library.md because author names are flagged as typos - repo: https://github.com/shellcheck-py/shellcheck-py rev: "v0.10.0.1" diff --git a/literature_library.md b/literature_library.md new file mode 100644 index 00000000..b8be9814 --- /dev/null +++ b/literature_library.md @@ -0,0 +1,215 @@ +# Literature Library + +This table collects papers from 2023–2025 that are relevant to the Openwater +literature library. Its scope includes peer-reviewed work related to +Open-LIFU[^LIFU] and adjacent focused-ultrasound research. + +The goal is to make it easier to compare work across application areas, +measurement approaches, biological or physical targets, dosing and parameter +choices, outcomes, and study types, while giving prospective contributors a +credible map of the field. + +To suggest an addition, please open a PR with a new row in the table. Include a +citation in APA or similar format, indication, sonication target, key +dose/parameter details, primary outcome, sample size, open-access link where +available, and short notes explaining why the paper is relevant. + +| Citation | Indication | Sonication Target | Key Dose/Parameter Details | Primary Outcome | Sample Size | Open-Access Link | PubMed Link | +| ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- | ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- | ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- | ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- | ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ | -------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- | --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- | ----------------------------------------- | +| Bawiec, C. R., Hollender, P. J., Ornellas, S. B., Schachtner, J. N., Dahill-Fuchel, J. F., Konecky, S. D., & Allen, J. J. B. (2025). A Wearable, Steerable, Transcranial Low-Intensity Focused Ultrasound System. Journal of ultrasound in medicine : official journal of the American Institute of Ultrasound in Medicine, 44(2), 239–261. https://doi.org/10.1002/jum.16600 | Safety/usability and technical validation of a wearable steerable LIFU neuromodulation system for anterior brain targets; not a therapeutic indication | Left amPFC[^amPFC] / left Brodmann Area 10 | Custom 400 kHz 128-element array; 10 min ultrasound delivery targeting left amPFC/Brodmann area 10. Phase 1.1: N=9, single focus, PNP[^PNP] 510 kPa, MI[^MI] 0.8, ISPTA[^ISPTA] 435 mW/cm². Phase 1.2: N=6, multi-focus, PNP 650 kPa, MI 1.03, ISPTA <450 mW/cm². Phase 1.3: N=5, multi-focus, PNP 820 kPa, MI 1.3, ISPTA <675 mW/cm². | Simulations and hydrophone readings agreed within <5%; safe steering range encompassed 1.8 × 2.5 × 2 cm at ~5 cm depth; no adverse effects on qualitative assessments; no SWI[^SWI] evidence of damage; all participants tolerated treatment. | 20 healthy volunteers with some degree of repetitive negative thinking | https://onlinelibrary.wiley.com/doi/10.1002/jum.16600 | https://pubmed.ncbi.nlm.nih.gov/39449176/ | +| Schachtner, J. N., Dahill-Fuchel, J. F., Allen, K. E., Bawiec, C. R., Hollender, P. J., Ornellas, S. B., Konecky, S. D., Achrol, A. S., & Allen, J. J. B. (2025). Transcranial focused ultrasound targeting the default mode network for the treatment of depression. Frontiers in psychiatry, 16, 1451828. https://doi.org/10.3389/fpsyt.2025.1451828 | MDE[^MDE]/depression with clinically significant repetitive negative thought | Left amPFC, a major hub of the DMN[^DMN] | Up to 11 tFUS[^tFUS] sessions over up to 3 weeks; 10 min/session; 128-element Openwater array; 400 kHz acoustic frequency; 5 ms pulse duration; 10 Hz PRR[^PRR]; max ISPTA 670 mW/cm²; PNP 820 kPa | Depression symptoms and repetitive negative thought significantly decreased; 60% met BDI-II[^BDI-II] response criteria, 45% met HDRS[^HDRS] response criteria, and 35% met remission criteria on both BDI-II and HDRS | 20 enrolled; 2 discontinued/withdrew after week 1; dropout was not due to AEs[^AEs] | https://www.frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2025.1451828/full | https://pubmed.ncbi.nlm.nih.gov/40256163/ | +| Favilla, C. G., Carter, S., Hartl, B., Gitlevich, R., Mullen, M. T., Yodh, A. G., Baker, W. B., & Konecky, S. (2024). Validation of the Openwater wearable optical system: cerebral hemodynamic monitoring during a breath-hold maneuver. Neurophotonics, 11(1), 015008. https://doi.org/10.1117/1.NPh.11.1.015008 | Validation of non-invasive bedside cerebral hemodynamic monitoring during breath-hold–induced CBF[^CBF] increase in healthy adults; not a therapeutic indication | Module positioned on the left lateral aspect of the forehead, overlying the lateral frontal lobe | Openwater wearable headset + concurrent TCD[^TCD] during breath-hold. Optical system used 785 nm near-infrared laser pulses, 250 μs pulse duration, 400 μJ pulse energy, 40 Hz pulse rate, 36 mm source-detector separation, 1% duty cycle, 1.6 W peak power per channel; 30 s baseline then 30 s breath-hold, repeated after 2 min rest if needed. | Beat-to-beat optical relative blood flow agreed strongly with TCD CBF velocity: R=0.79, mixed-effects slope 0.87 (95% CI[^CI] 0.83–0.92). Optical relative blood volume also correlated with TCD CBFv[^CBFv]: R=0.72, slope 0.18. | 25 healthy adults completed monitoring; 2 excluded for poor TCD quality; 23 included in final analysis | https://www.spiedigitallibrary.org/journals/neurophotonics/volume-11/issue-01/015008/Validation-of-the-Openwater-wearable-optical-system--cerebral-hemodynamic/10.1117/1.NPh.11.1.015008.full | https://pubmed.ncbi.nlm.nih.gov/38464864/ | +| Favilla, C. G., Baird, G. L., Grama, K., Konecky, S., Carter, S., Smith, W., Gitlevich, R., Lebron-Cruz, A., Yodh, A. G., & McTaggart, R. A. (2025). Portable cerebral blood flow monitor to detect large vessel occlusion in patients with suspected stroke. Journal of neurointerventional surgery, 17(4), 388–393. https://doi.org/10.1136/jnis-2024-021536 | Acute stroke; detection of anterior circulation LVO[^LVO] | N/A[^NA] | Openwater portable optical blood-flow monitor; 70-second bedside scan; speckle-contrast cerebral blood-flow waveforms | Openwater classification detected LVO with 79% sensitivity, 84% specificity, and AUROC[^AUROC] 0.82, outperforming RACE[^RACE] and LAMS[^LAMS] prehospital stroke scales | 135 patients | https://pmc.ncbi.nlm.nih.gov/articles/PMC11415534/ | https://pubmed.ncbi.nlm.nih.gov/38514189/ | +| Rasouli, R., Hartl, B., & Konecky, S. D. (2025). Low-intensity ultrasound lysis of amyloid microclots in a lab-on-chip model. Frontiers in bioengineering and biotechnology, 13, 1604447. https://doi.org/10.3389/fbioe.2025.1604447 | Preclinical/in vitro model relevant to Long COVID[^COVID] and amyloid-associated coagulopathies | Amyloid microclots in a lab-on-chip model | Low-intensity ultrasound at 150, 300, 500 kHz, and 1 MHz; MI maintained at 0.3; PNP: 150 kHz = 0.11 MPa, 300 kHz = 0.16 MPa, 500 kHz = 0.21 MPa, 1 MHz = 0.30 MPa; US[^US], MB[^MB]+US, rtPA[^rtPA]+US, and MB+rtPA+US conditions evaluated in vitro. | Strongest effect at 150 kHz with up to ~3-fold reduction in clot size and large-clot number, with microbubbles further enhancing lysis at several frequencies | In vitro study; n=3 biologically independent samples per experimental group (except Figure 2 in the paper n=2); three non-overlapping microscopic fields of view per replicate. | https://www.frontiersin.org/journals/bioengineering-and-biotechnology/articles/10.3389/fbioe.2025.1604447/full | https://pubmed.ncbi.nlm.nih.gov/40661336/ | +| Barksdale, B. R., Enten, L., DeMarco, A., Kline, R., Doss, M. K., Nemeroff, C. B., & Fonzo, G. A. (2025). Low-intensity transcranial focused ultrasound amygdala neuromodulation: a double-blind sham-controlled target engagement study and unblinded single-arm clinical trial. Molecular psychiatry, 30(10), 4497–4511. https://doi.org/10.1038/s41380-025-03033-w | Mood, anxiety, and trauma-related disorders | Left amygdala | Daily repetitive tFUS, 5 days/week for 3 weeks. Device: Brainsonix Pulsar 1002. Parameters: 10 Hz PRF[^PRF], 5% duty cycle, 5 ms pulse width, derated ISPPA[^ISPPA] 14.4 W/cm², derated ISPTA 719.91 mW/cm², derated instantaneous peak pressure 0.64 MPa, 10 min total in 10 sets of 30 s on/off blocks. | Active vs sham tFUS/fMRI[^fMRI] reduced left amygdala BOLD[^BOLD] signal and modulated interconnected limbic/prefrontal circuitry. In the unblinded rtFUS[^rtFUS] trial, MASQ-GD[^MASQ-GD] decreased from 26.79±6.41 to 21.10±7.02, F(1,25)=12.89, p=0.001, Cohen’s d=0.77. rtFUS was feasible/well tolerated with no serious AEs or AEs requiring medical intervention; task-based amygdala activation to emotional stimuli was attenuated post-treatment. | 52 enrolled: 29 MATRD[^MATRD] patients and 23 healthy controls. 47 completed both tFUS/fMRI scans: 25 MATRD and 22 controls. 24 MATRD patients initiated daily rtFUS; 21 completed all 15 sessions | https://www.nature.com/articles/s41380-025-03033-w | https://pubmed.ncbi.nlm.nih.gov/40275098/ | +| Oh, J., Ryu, J. S., Kim, J., Kim, S., Jeong, H. S., Kim, K. R., Kim, H. C., Yoo, S. S., & Seok, J. H. (2024). Effect of Low-Intensity Transcranial Focused Ultrasound Stimulation in Patients With Major Depressive Disorder: A Randomized, Double-Blind, Sham-Controlled Clinical Trial. Psychiatry investigation, 21(8), 885–896. https://doi.org/10.30773/pi.2024.0016 | MDD[^MDD] | Left DLPFC[^DLPFC] subregion | Six sessions over 2 weeks, 20 min/session, 3 sessions/week. Device: NS-US100, Neurosona, 250 kHz. FUS[^FUS] focus FWHM[^FWHM]: 8.5 mm diameter × 51 mm length; focus center 30 mm from transducer exit plane. Reported output: incident ISPPA 3 W/cm², PNP 300 kPa; 1 ms tone burst at 50% duty cycle for 300 ms, delivered every 6 s for 20 min. With 55% pressure derating, estimated in-situ pressure ~135 kPa, MI 0.27, with reported in-situ acoustic intensity 600 mW/cm² and corresponding spatial-peak temporal-average intensity 300 mW/cm². | Verum MADRS[^MADRS] decreased from 28.5±8.4 at baseline to 16.8±6.8 end-treatment and 14.8±7.2 follow-up; sham decreased from 29.2±8.3 to 25.7±9.0 and 24.8±9.3. Group x session interaction: F1,21=9.0, p=0.003. Sessions were well tolerated without reported undesirable effects | 26 participants, 23 were analyzed | https://psychiatryinvestigation.org/journal/view.php?doi=10.30773/pi.2024.0016 | https://pubmed.ncbi.nlm.nih.gov/39111747/ | +| Mahdavi, K. D., Jordan, S. E., Jordan, K. G., Rindner, E. S., Haroon, J. M., Habelhah, B., Becerra, S. A., Surya, J. R., Venkatraman, V., Zielinski, M. A., Spivak, N. M., Bystritsky, A., & Kuhn, T. P. (2023). A pilot study of low-intensity focused ultrasound for treatment-resistant generalized anxiety disorder. Journal of psychiatric research, 168, 125–132. https://doi.org/10.1016/j.jpsychires.2023.10.039 | Treatment-resistant GAD[^GAD] | Centromedial nucleus of the right amygdala | Brainsonix Pulsar 1002. Eight weekly 10-min sessions. Parameters: 650 kHz fundamental frequency, 5 ms pulse width, 5% duty cycle, PRF 10 Hz, ISPPA.3[^ISPPA3] 14.39 W/cm², ISPTA.3[^ISPTA3] 719.73 mW/cm², MI 0.75, PNP 0.61 MPa. Administration: 30 s on / 30 s off for 10 min. | tFUS significantly reduced anxiety: HAM-A[^HAM-A] W=−3.69, p<0.001, pre-post Δ −12.64±12.51; BAI[^BAI] W=−3.94, p<0.001, Δ −12.88±10.42. Sixteen participants (64%) reported PGI-I[^PGI-I] >2, 15 (60%) had >30% HAM-A reduction, and 8 (32%) met remission threshold HAM-A <14. No adverse events were reported. | 25 patients | https://www.sciencedirect.com/science/article/pii/S0022395623004776?via%3Dihub | https://pubmed.ncbi.nlm.nih.gov/39491902/ | +| Riis, T., Feldman, D., Losser, A., Mickey, B., & Kubanek, J. (2024). Device for Multifocal Delivery of Ultrasound Into Deep Brain Regions in Humans. IEEE transactions on bio-medical engineering, 71(2), 660–668. https://doi.org/10.1109/TBME.2023.3313987 | Device validation/proof-of-concept neuromodulation study in two patients with severe TRD[^TRD]; not a clinical efficacy trial | Electronically steered deep-brain targets including SGC[^SGC] and ventral striatum | Device: two phased arrays, operated at 650 kHz. Mood-session parameters: 30 ms ON periods at 650 kHz, estimated 1.0 MPa peak pressure, MI 1.2, ISPPA 31 W/cm², followed by 4 s OFF, duty cycle 0.75%, ISPTA 0.233 W/cm²; sonication duration 60–180 s | Device achieved flexible targeting and reproducible MRI[^MRI]-free positioning; relative targeting-position error 1.64 ± 0.66 mm. In 2 TRD patients, SGC stimulation ≥60 s significantly improved depression ratings (p=0.0012) and anxiety ratings (p=0.0051); sham had no significant effect; no adverse effects or structural MRI changes were reported | 2 patients | https://pmc.ncbi.nlm.nih.gov/articles/PMC10803076/ | https://pubmed.ncbi.nlm.nih.gov/37695955/ | +| Riis, T. S., Feldman, D. A., Vonesh, L. C., Brown, J. R., Solzbacher, D., Kubanek, J., & Mickey, B. J. (2023). Durable effects of deep brain ultrasonic neuromodulation on major depression: a case report. Journal of medical case reports, 17(1), 449. https://doi.org/10.1186/s13256-023-04194-4 | Single-patient case report in severe treatment-resistant, non-psychotic recurrent MDD | Posterior SCC[^SCC], anterior SCC, and pregenual cingulate | Diadem array; 650 kHz continuous-wave pulses; 30 ms ON every 4 s (0.8% duty cycle); estimated target peak pressure 1.0 MPa; each of 3 SCC-associated targets sonicated 10 times in randomized order, with individual epochs averaging 2 min (range 20–180 s) and 30 epochs spanning 64 min; kept below FDA[^FDA] Track 3 limits (peak intensity <190 W/cm²; time-averaged intensity <720 mW/cm²) | HDRS-6[^HDRS-6] decreased from 11 to 0 the day after stimulation, with remission maintained for 44 days at last assessment; fMRI showed decreased BOLD activity at SCC target during focused stimulation but not sham; no treatment-related side effects or MRI anomalies reported | 1 patient | https://link.springer.com/article/10.1186/s13256-023-04194-4 | https://pubmed.ncbi.nlm.nih.gov/37891643/ | +| Mahoney, J. J., Haut, M. W., Carpenter, J., Ranjan, M., Thompson-Lake, D. G. Y., Marton, J. L., Zheng, W., Berry, J. H., Tirumalai, P., Mears, A., D'Haese, P., Finomore, V. S., Hodder, S. L., & Rezai, A. R. (2023). Low-intensity focused ultrasound targeting the nucleus accumbens as a potential treatment for substance use disorder: safety and feasibility clinical trial. Frontiers in psychiatry, 14, 1211566. https://doi.org/10.3389/fpsyt.2023.1211566 | SUD[^SUD] / OUD[^OUD] with histories of excessive non-opioid substance use | Bilateral NAc[^NAc] | MR-guided LIFU with ExAblate Neuro Type 2; 220 kHz. Protocol: 10 min sham first, then 20 min active LIFU total: 10 min left NAc, then 10 min right NAc. First 2 participants received 60 W lower dose; next 2 received 90 W enhanced dose. Table parameters: lower/enhanced dose intensity ~55/~80 W/cm², energy ~120/~180 J/min, repetition time 5/10 s, pulse duration on/off 100/900 ms, duty cycle 3.3% | No safety concerns were present during treatment or follow-up; no unexpected LIFU-related adverse events and no serious adverse events; MRI showed no edema, hemorrhage, or notable structural change. Secondary craving signal: 60 W produced minimal acute craving changes, while 90 W attenuated cue-induced craving for participants’ primary substances and reduced daily craving ratings in the two enhanced-dose participant | 4 participants | https://www.frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2023.1211566/full | https://pubmed.ncbi.nlm.nih.gov/37779628/ | +| Huang, Z., Charalambous, C. C., Chen, M., Kim, T., Sokhadze, E., Song, A., Jung, S. H., Shekhar, S., Feld, J. A., Jiang, X., & Feng, W. (2025). Low intensity focused ultrasound stimulation in stroke: A phase I safety & feasibility trial. Brain stimulation, 18(1), 179–187. https://doi.org/10.1016/j.brs.2025.01.015 | Stroke patients with motor impairment; inclusion included first-ever ischemic or hemorrhagic stroke >1 month prior, unilateral limb weakness, and TMS[^TMS]-elicitable MEPs[^MEP] in the paretic APB[^APB] | Ipsilesional motor cortex | Phase I 3+3 intensity escalation of estimated in-vivo transcranial ISPPA: 0, 1, 2, 4, 6, and 8 W/cm². One 12-min LIFUS[^LIFUS] session during 3 blocks of MSL[^MSL] using the affected hand. Device/protocol: custom 500 kHz single-element focused transducer, 30 mm focal depth; 100 cycles of 500 kHz per pulse; 1000 Hz PRF; 200 μs tone burst duration; 20% duty cycle; 500 ms sonication duration; 8 W/cm2 ISPPA; 533 mW/cm2 averaged ISPTA; pressure 0.49 MPa. | ISPPA escalated to 8 W/cm² without meeting stopping rules: no 2nd-degree scalp burn, seizure, visible DWI[^DWI] lesion, major ADC[^ADC] reduction, or discontinuation. One participant at 8 W/cm² had a mild first-degree scalp burn/pain that resolved the next day. HIGH intensity group had more ≥20% MSL improvement than LOW group, 6/9 vs 0/9, p=0.009; corticospinal excitability change was directionally higher but not significant, 7/9 vs 5/9, p=0.62. | 18 patients | https://www.brainstimjrnl.com/article/S1935-861X(25)00017-8/fulltext | https://pubmed.ncbi.nlm.nih.gov/39842609/ | +| Bubrick, E. J., McDannold, N. J., Orozco, J., Mariano, T. Y., Rigolo, L., Golby, A. J., Tie, Y., & White, P. J. (2024). Transcranial ultrasound neuromodulation for epilepsy: A pilot safety trial. Brain stimulation, 17(1), 7–9. https://doi.org/10.1016/j.brs.2023.11.013 | Drug-resistant epilepsy | Anterior hippocampus; four targets 4 mm apart sonicated sequentially through the ipsilateral temporal acoustic window | 6 sessions over 3 weeks (2/week); 140-s sonications per target; f0=548 kHz, PRF=500 Hz, duty cycle 18–50%, pulse/pulse-train repetition period 7 s; ISPTA=0.50–1.1 W/cm² and PNP=0.14–0.42 MPa, reported as free-field values | No AEs/side effects were reported and no structural MRI changes; one subject had a typical seizure during the first session with unclear association, after which duty cycle was reduced to 18.3%; exploratory seizure reduction averaged ~50%, with 5/6 showing significant reductions | 6 adult patients | https://www.brainstimjrnl.com/article/S1935-861X(23)01956-3/fulltext | https://pubmed.ncbi.nlm.nih.gov/38070706/ | +| Samuel, N., Ding, M. Y. R., Sarica, C., Darmani, G., Harmsen, I. E., Grippe, T., Chen, X., Yang, A., Nasrkhani, N., Zeng, K., Chen, R., & Lozano, A. M. (2023). Accelerated Transcranial Ultrasound Neuromodulation in Parkinson's Disease: A Pilot Study. Movement disorders : official journal of the Movement Disorder Society, 38(12), 2209–2216. https://doi.org/10.1002/mds.29622 | PD[^PD-disease] in the OFF-medication state; participants had PD ≥1 year | Bilateral M1[^M1] | Three a-tbTUS[^a-tbTUS] sonications delivered to bilateral M1s at 30-min intervals. Device: custom two-element annular array, 0.5 MHz fundamental frequency, 38 mm diameter, 30 mm sonication depth. Each theta-burst TUS[^TUS] train: 80 s, PRF 5 Hz, pulse duration 20 ms, ultrasonic stimulus duration 200 ms, duty cycle 10%, 400 pulses; ultrasound power 20 W. Estimated target ISPPA 2.26 W/cm² and ISPTA 0.23 W/cm² | No moderate or severe AEs were reported; 4/10 reported temporary fatigue. MEP amplitude increased after active sonication, 1.08±0.22 mV to 1.72±0.67 mV, and active MEP ratio was higher than sham, 1.58±0.5 vs 0.90±0.20, p<0.01. No statistically significant MDS-UPDRS-III[^MDS-UPDRS-III] change with active or sham | 10 patients | https://movementdisorders.onlinelibrary.wiley.com/doi/10.1002/mds.29622 | https://pubmed.ncbi.nlm.nih.gov/37811802/ | +| Shin, D. H., Son, S., & Kim, E. Y. (2023). Low-Energy Transcranial Navigation-Guided Focused Ultrasound for Neuropathic Pain: An Exploratory Study. Brain sciences, 13(10), 1433. https://doi.org/10.3390/brainsci13101433 | Uncontrolled/intractable chronic neuropathic pain | Bilateral ACC[^ACC] | Treatment 3 times/week for 2 weeks. Low-energy FUS: 250 kHz, spatial-peak temporal-average intensity <0.72 W/cm², tone burst duration 5–10 ms, 50–70% duty cycle, total stimulation time including rests ≤30 min; MI kept ≤1.9 / in situ peak rarefaction pressure <0.95 MPa. | Current pain improved from median 10.0 to 7.0 at 4 weeks (p=0.021); average pain from 8.5 to 6.0 (p=0.027); maximum pain from 10.0 to 8.0 (p=0.008); BPI[^BPI] daily-life interference improved from 59.00±11.66 to 51.91±9.18 (p=0.021), but subjective pain-relieving-effect percentage did not significantly change (p=0.429) | 12 registered; 11 final analyzed after 1 withdrawal | https://www.mdpi.com/2076-3425/13/10/1433 | https://pubmed.ncbi.nlm.nih.gov/37891801/ | +| Zhai, Z., Ren, L., Song, Z., Xiang, Q., Zhuo, K., Zhang, S., Li, X., Zhang, Y., Jiao, X., Tong, S., Sun, J., & Liu, D. (2023). The efficacy of low-intensity transcranial ultrasound stimulation on negative symptoms in schizophrenia: A double-blind, randomized sham-controlled study. Brain stimulation, 16(3), 790–792. https://doi.org/10.1016/j.brs.2023.04.021 | Schizophrenia patients with predominantly negative syndrome | Left DLPFC | Double-blind randomized sham-controlled rTUS[^rTUS]; active or sham rTUS over left DLPFC on workdays for 3 consecutive weeks (15 sessions). Transducer: V391-SU immersion-type focused ultrasound transducer, 3.8 cm focal length, 500 kHz fundamental frequency. Excitatory protocol: 15-min session; 500 ms sonication blocks every 8 s; 500 µs tone-burst duration; PRF 100 Hz (1/PRF=10 ms); ISPPA=8.086 W/cm²; ISPTA=0.404 W/cm². | SANS[^SANS] interaction F=16.965, p<0.001, partial η²=0.414; active rTUS reduced SANS, sham did not. PANSS[^PANSS] total showed a similar interaction, and CPT[^CPT] improved; no serious AEs. | 32 participants randomized; 26 completed | https://www.brainstimjrnl.com/article/S1935-861X(23)01765-5/fulltext | https://pubmed.ncbi.nlm.nih.gov/37121354/ | +| Chou, T., Deckersbach, T., Guerin, B., Sretavan Wong, K., Borron, B. M., Kanabar, A., Hayden, A. N., Long, M. P., Daneshzand, M., Pace-Schott, E. F., & Dougherty, D. D. (2024). Transcranial focused ultrasound of the amygdala modulates fear network activation and connectivity. Brain stimulation, 17(2), 312–320. https://doi.org/10.1016/j.brs.2024.03.004 | Mechanistic fear/anxiety-circuit target-engagement study in healthy adults; not a clinical treatment study | Left amygdala | Active tFUS: 20 min of 30 s on / 30 s off blocks; PRF = 10 Hz, PW[^PW] = 5 ms, DC[^DC] = 5%, derated ISPPA = 14.4 W/cm2, derated ISPTA = 0.72 W/cm2, fundamental frequency = 0.65 MHz) | Active vs sham left-amygdala tFUS decreased amygdala BOLD activation during the fear task, F(1,25)=4.86, p=0.04; lowered hippocampal and dACC[^dACC] activation; and the amygdala-activation decrease correlated with decreased subjective anxiety (r=0.62, p=0.03). No group effect on SCR[^SCR] changes. Resting-state effects included decreased amygdala-insula and amygdala-hippocampal connectivity and increased amygdala-vmPFC[^vmPFC] connectivity. | 30 healthy individuals | https://www.brainstimjrnl.com/article/S1935-861X(24)00040-8/fulltext | https://pubmed.ncbi.nlm.nih.gov/38447773/ | +| Peng, X., Connolly, D. J., Sutton, F., Robinson, J., Baker-Vogel, B., Short, E. B., & Badran, B. W. (2024). Non-invasive suppression of the human nucleus accumbens (NAc) with transcranial focused ultrasound (tFUS) modulates the reward network: a pilot study. Frontiers in human neuroscience, 18, 1359396. https://doi.org/10.3389/fnhum.2024.1359396 | Mechanistic reward-network target-engagement study in healthy adults | Left NAc | 20 min total active/sham tFUS targeting left NAc: two 10-min runs. Fundamental frequency = 650 kHz, Pulse repetition frequency = 10 Hz, Pulse width = 5 ms, Duty cycle = 5%, Sonication duration = 30 s, ISPTA.0 = 995 mW/cm2, ISPTA.3 = 719 mW/cm2, Peak rarefactional pressure = 0.72 MPa. | Feasible/safe with no AEs; active tFUS reduced activity in anterior bilateral NAc / left posterior NAc versus sham, though uncorrected; active group showed increased NAc–mPFC[^mPFC] functional connectivity after tFUS (t = 2.850, p = 0.046), not seen in sham. | 10 healthy participants | https://www.frontiersin.org/journals/human-neuroscience/articles/10.3389/fnhum.2024.1359396/full | https://pubmed.ncbi.nlm.nih.gov/38628972/ | +| Yaakub, S. N., White, T. A., Roberts, J., Martin, E., Verhagen, L., Stagg, C. J., Hall, S., & Fouragnan, E. F. (2023). Transcranial focused ultrasound-mediated neurochemical and functional connectivity changes in deep cortical regions in humans. Nature communications, 14(1), 5318. https://doi.org/10.1038/s41467-023-40998-0 | Mechanistic neuromodulation study; whether theta-burst TUS induces changes in GABA[^GABA], glutamate and functional connectivity; not a therapeutic indication | Left dACC and left PCC[^PCC] | NeuroFUS four-element 64 mm transducer; 500 kHz center frequency. Theta-burst TUS: pulse duration 20 ms, pulse repetition interval 200 ms, total duration 80 s, 400 pulses; free-field ISPPA 33.8 W/cm². Transcranial simulations kept exposure below FDA diagnostic ultrasound limits; simulated in situ values were approximately 0.66/0.65 MPa max pressure, MI 0.95/0.93, ISPPA 15.07/14.47 W/cm², ISPTA 1507/1447 mW/cm² for dACC/PCC. | PCC TUS selectively reduced GABA+[^GABAplus]/water in the PCC voxel versus sham, with session main effect F(2,55)=4.66, p=0.013; PCC TUS vs sham p=0.017. No significant GABA change was found in dACC, and no significant Glx[^Glx] differences were found. Functional connectivity increased after TUS of both regions, with larger effects later, around 46 min post-TUS; effects lasted at least ~50 min. | 24 healthy adults | https://www.nature.com/articles/s41467-023-40998-0 | https://pubmed.ncbi.nlm.nih.gov/37658076/ | +| Legon, W., Strohman, A., In, A., & Payne, B. (2024). Noninvasive neuromodulation of subregions of the human insula differentially affect pain processing and heart-rate variability: a within-subjects pseudo-randomized trial. Pain, 165(7), 1625–1641. https://doi.org/10.1097/j.pain.0000000000003171 | Mechanistic pain-processing and autonomic-reactivity study using transient contact-heat pain in healthy volunteers | Left AI[^AI] (dorsal anterior short gyrus) and left PI[^PI] (dorsal anterior longus gyrus) | Sonic Concepts H-281 single-element 500 kHz transducer; active diameter 45 mm; focal depth 38 mm from exit plane. Waveform: 1.0 s duration, 1 kHz PRF, 360 ms pulse width, 36% duty cycle, time-locked 200 ms before CHEP[^CHEP] stimulus; free-field peak negative pressure 400 kPa or 3.5 W/cm² ISPPA. | Only PI significantly reduced pain ratings versus sham in the primary pain-rating analysis (pain main effect F(2,44)=4.29, p=0.019; post hoc PI vs sham). Both AI and PI reduced CHEP N1/P1 peak-to-peak amplitude versus sham (F(2,44)=8.19, p=0.009; post hoc sham vs AI and sham vs PI). Only AI increased HRV[^HRV] as indexed by SDNN[^SDNN] (F(2,44)=3.75, p=0.03; AI vs sham). | 23 healthy volunteers | https://journals.lww.com/pain/fulltext/2024/07000/noninvasive_neuromodulation_of_subregions_of_the.21.aspx | https://pubmed.ncbi.nlm.nih.gov/38314779/ | +| Zhang, T., Guo, B., Zuo, Z., Long, X., Hu, S., Li, S., Su, X., Wang, Y., & Liu, C. (2023). Excitatory-inhibitory modulation of transcranial focus ultrasound stimulation on human motor cortex. CNS neuroscience & therapeutics, 29(12), 3829–3841. https://doi.org/10.1111/cns.14303 | Neuromodulation study on M1 excitability and GABA/Glx-related intracortical mechanisms | Left M1, hand motor area | GreenValley BrainTech focused transducer; 0.5 MHz, diameter 48 mm, focal length ~30 mm. Two 5-min parameter sets: etFUS[^etFUS]: TBD[^TBD] 200 μs, PRP[^PRP] 0.5 ms, SD[^SD-param] 500 ms, SP[^SP] 2 s, PRF 2000 Hz, DC 40%. itFUS[^itFUS]: TBD 400 μs, PRP 20 ms, SD 500 ms, SP 2 s, PRF 50 Hz, DC 2%. Acoustic beam FWHM 4.58 × 4.58 mm laterally, axial peak 28.8 mm; ISPPA 0.6156–2.4624 W/cm², ISPTA 3.078–12.312 mW/cm². | etFUS increased M1 excitability and reduced SICI[^SICI] and LICI[^LICI]. itFUS suppressed M1 excitability, increased SICI and LICI, and reduced ICF[^ICF]. Seven daily etFUS sessions decreased GABA by 6.32%, increased Glx by 12.40%, and lowered GABA/Glx; itFUS increased GABA by 18.59%, decreased Glx by 0.35%, and significantly increased GABA/Glx. | 12 healthy volunteers; 10 completed Experiment 1; 9 completed paired-pulse TMS and MRS[^MRS] Experiments 2–3 | https://onlinelibrary.wiley.com/doi/10.1111/cns.14303 | https://pubmed.ncbi.nlm.nih.gov/37309308/ | +| Shamli Oghli, Y., Grippe, T., Arora, T., Hoque, T., Darmani, G., & Chen, R. (2023). Mechanisms of theta burst transcranial ultrasound induced plasticity in the human motor cortex. Brain stimulation, 16(4), 1135–1143. https://doi.org/10.1016/j.brs.2023.07.056 | tbTUS[^tbTUS]-induced motor-cortex plasticity; not a therapeutic indication | Left M1 FDI[^FDI] hotspot | 5 visits. At each visit, participants received one oral drug or placebo followed after 2.5 h by tbTUS. tbTUS: 500 kHz annular array, sonication depth 30 mm, 80 s sonication, 20 ms tone burst duration, 5 Hz PRF, 10% duty cycle, 20 W intensity. Free-water values: ISPPA 11.73 W/cm², ISPTA 1.17 W/cm²; estimated brain-target ISPPA 2.93 W/cm², ISPTA 0.29 W/cm²; focal width at half maximum 8 mm. | Under placebo, tbTUS increased MEP amplitudes up to 60 min; tbTUS plasticity effects were reduced by the study drugs compared with placebo. Authors interpret the results as consistent with NMDA[^NMDA]-dependent LTP[^LTP]-like plasticity and mechanosensitive voltage-gated Na⁺/Ca²⁺ channel involvement, but also note a possible non-specific excitatory/inhibitory imbalance explanation | 16 right-handed healthy adults enrolled; 14 completed/analyzed after 2 dropouts | https://www.brainstimjrnl.com/article/S1935-861X(23)01870-3/fulltext | https://pubmed.ncbi.nlm.nih.gov/37524296/ | +| Kim, H. C., Lee, W., Weisholtz, D. S., & Yoo, S. S. (2023). Transcranial focused ultrasound stimulation of cortical and thalamic somatosensory areas in human. PloS one, 18(7), e0288654. https://doi.org/10.1371/journal.pone.0288654 | Healthy-volunteer target-engagement/safety study of somatosensory-circuit FUS; not a therapeutic study | Right S1[^S1] hand representation for the non-dominant/left hand and right VPL[^VPL] | Two sessions ~1 week apart (S1 then VPL); 250 kHz fundamental frequency; 200 ms sonications; PD[^PD-duration] 0.5, 1, or 2 ms at 70% duty cycle; PRF 1,400/700/350 Hz; 4 s ISI[^ISI]; 80 trials per PD condition plus passive sham; session ~21 min. Free-water ISPPA: 14.7 W/cm² (S1) and 9.1 W/cm² (VPL). Estimated in situ ISPPA: 4.1±2.3 W/cm² (S1) and 3.4±1.1 W/cm² (VPL); in situ ISPTA: 2.9±1.6 and 2.4±0.8 W/cm²; MI: 0.7±0.2 and 0.6±0.1 | FUS evoked EEG[^EEG] potentials in all FUS completers, but not all participants perceived tactile hand sensations; 0.5 ms PD produced more distinctive ipsilateral FEP[^FEP] features than 1 or 2 ms; thalamic/VPL stimulation increased rsFC[^rsFC] in sensorimotor and sensory-integration networks for >1 h; no adverse/unintended findings on neurological evaluation, EEG, or MRI. | 8 healthy adults completed the FUS segment; separate AEP[^AEP] control segment n=8 | https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0288654 | https://pubmed.ncbi.nlm.nih.gov/37478086/ | +| Fine, J. M., Mysore, A. S., Fini, M. E., Tyler, W. J., & Santello, M. (2023). Transcranial focused ultrasound to human rIFG improves response inhibition through modulation of the P300 onset latency. eLife, 12, e86190. https://doi.org/10.7554/eLife.86190 | Mechanistic healthy-volunteer response-inhibition/Stop-Signal task study with EEG; not a therapeutic study | Right pars opercularis / rIFG[^rIFG]; controls were ipsilateral S1 active stimulation and sham near the right temple | Single-element 0.5 MHz transducer, 30 mm focal depth, lateral spatial resolution 4.5 mm, axial spatial resolution 18 mm, PRF 1.0 kHz, 24% duty cycle, 500 ms tFUS time-locked to Go or Stop signal. Simulation caveat: transcranial-without-silicone estimates were Pmax[^Pmax] 0.54 MPa, ISPPA 10.01 W/cm², ISPTA 2.40 W/cm²; with silicone puck/acoustic gel estimates were Pmax 0.52–0.53 MPa, ISPPA 9.37–9.82 W/cm², ISPTA 2.25–2.35 W/cm² | tFUS improved stopping only when applied to rIFG simultaneously with the Stop signal. Stimulation of the rIFG with tFUS enhanced inhibitory control, reflected by shorter stopping times that corresponded with earlier N200/P300 onset latencies. P300 amplitude changed across groups but did not track behavior. | 63 healthy adults randomized; 5 excluded from EEG analyses for recording/noise issues. | https://elifesciences.org/articles/86190 | https://pubmed.ncbi.nlm.nih.gov/38117053/ | +| Ziebell, P., Rodrigues, J., Forster, A., Sanguinetti, J. L., Allen, J. J., & Hewig, J. (2023). Inhibition of midfrontal theta with transcranial ultrasound explains greater approach versus withdrawal behavior in humans. Brain stimulation, 16(5), 1278–1288. https://doi.org/10.1016/j.brs.2023.08.011 | Motivational conflicts regarding whether participants execute approach versus withdrawal behavior; not a therapeutic indication | Right PFC[^PFC] | Device: Neurotrek U+ prototype. Parameters for current study: 0.500 MHz, peak negative pressure 1.09 MPa, ISPPA 40 W/cm², ISPTA 199 mW/cm², pulse length 125 μs, PRF 40 Hz, duty cycle 0.50%, total sonication time 120 s, MI 1.54, TIC[^TIC] 1.66. | TUS significantly decreased conflict-related MFT[^MFT] vs sham, F(1,151)=6.199, p=0.014, ηp²=0.039, Cohen’s d=0.20. Behavioral link: for the ambiguous conflict condition, greater TUS-induced MFT inhibition explained greater approach behavior, β=0.205, p=0.011, and less withdrawal behavior, β=−0.211, p=0.009. Subjective mood hypothesis was not supported; no TUS-specific mood change was found. | 152 healthy students | https://www.brainstimjrnl.com/article/S1935-861X(23)01887-9/fulltext | https://pubmed.ncbi.nlm.nih.gov/37611659/ | +| Kosnoff, J., Yu, K., Liu, C., & He, B. (2024). Transcranial focused ultrasound to V5 enhances human visual motion brain-computer interface by modulating feature-based attention. Nature communications, 15(1), 4382. https://doi.org/10.1038/s41467-024-48576-8 | Enhancement of human visual motion BCI[^BCI] performance; not a therapeutic indication | Left V5[^V5] / middle temporal complex; spatial-control condition used the geometric periphery of V5 near inferior temporal gyrus | 128-element random-array H275 tFUS transducer. Estimated peak-to-peak pressure 0.2 MPa; ~2 mm focal diameter and length; 700 kHz fundamental frequency; 140 cycles/pulse; PN[^PN] 1500; PRF 3 kHz; 200 μs pulse duration; 500 ms sonication; first sonication starts 100 ms before first BCI stimulation. Ex vivo estimates: derated ISPTA.3 101 mW/cm² and ISPPA.3 0.168 W/cm². | tFUS to geometric center of V5 reduced error versus non-modulated, decoupled-sham, and V5-periphery control conditions: tFUS-GC[^tFUS-GC] mean error 13.3±18.4% vs non-modulated 15.5±18.7%, decoupled-sham 16.9±20.8%, and tFUS-GP[^tFUS-GP] 17.0±18.2%; ANOVA[^ANOVA] p<0.001 | 25 healthy human subjects. tFUS-GC 356 trials/25 subjects; non-modulated 351 trials/25 subjects; decoupled-sham 268 trials/19 subjects; tFUS-GP 214 trials/16 subjects. | https://www.nature.com/articles/s41467-024-48576-8 | https://pubmed.ncbi.nlm.nih.gov/38862476/ | +| Rezai, A. R., D'Haese, P. F., Finomore, V., Carpenter, J., Ranjan, M., Wilhelmsen, K., Mehta, R. I., Wang, P., Najib, U., Vieira Ligo Teixeira, C., Arsiwala, T., Tarabishy, A., Tirumalai, P., Claassen, D. O., Hodder, S., & Haut, M. W. (2024). Ultrasound Blood-Brain Barrier Opening and Aducanumab in Alzheimer's Disease. The New England journal of medicine, 390(1), 55–62. https://doi.org/10.1056/NEJMoa2308719 | MCI[^MCI] due to AD[^AD] or mild AD dementia; FUS-mediated BBB[^BBB] opening to enhance aducanumab delivery/amyloid reduction | Selected Aβ[^A-beta]-positive regions in one hemisphere; homologous contralateral regions served as controls. Participant 1: up to 10 ml right frontal lobe; Participant 2: up to 20 ml left frontal/parietal lobes; Participant 3: up to 40 ml left frontal, parietal, temporal lobes and hippocampus. | ExAblate-Neuro-Type2 MRI-guided FUS system with >1000 ultrasound sources. Six monthly aducanumab infusions were paired with FUS BBB opening initiated 2 h after each infusion; aducanumab escalation was 1 mg/kg for 2 months, 3 mg/kg for 2 months, then 6 mg/kg for 2 months. Follow-up phase used monthly 10 mg/kg aducanumab without FUS. Targeted BBB-opening volumes were capped at 10, 20, and 40 ml for participants 1–3. | BBB opening occurred in all targeted regions and closed within 24–48 h. At 26 weeks, Aβ centiloid reductions were greater in FUS-treated regions than contralateral untreated homologous regions: 107.5, 87.6, and 158.1 centiloids greater reductions in participants 1–3, respectively. No ARIA[^ARIA] were observed; AEs were mainly headaches, and the trial was not powered to detect clinical cognitive benefit. | 3 participants | https://www.nejm.org/doi/10.1056/NEJMoa2308719?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed | https://pubmed.ncbi.nlm.nih.gov/38169490/ | +| Yuan, J., Xu, L., Chien, C. Y., Yang, Y., Yue, Y., Fadera, S., Stark, A. H., Schwetye, K. E., Nazeri, A., Desai, R., Athiraman, U., Chaudhuri, A. A., Chen, H., & Leuthardt, E. C. (2023). First-in-human prospective trial of sonobiopsy in high-grade glioma patients using neuronavigation-guided focused ultrasound. NPJ precision oncology, 7(1), 92. https://doi.org/10.1038/s41698-023-00448-y | High-grade glioma; sonobiopsy for noninvasive enrichment/detection of circulating tumor biomarkers, not tumor treatment | Tumor location within the glioma | 15 concentric-ring FUS transducer, 650 kHz center frequency, 65 mm aperture, 65 mm focal distance, axial/lateral FWHM 20/3.0 mm. FUS parameters: PRF 1 Hz, pulse duration 10 ms, treatment duration 3 min. Definity microbubbles 10 µL/kg IV[^IV] were administered 15 s after FUS began. Acoustic output was adjusted to in situ MI 0.4–0.7 and kept below 0.8. | Abstract reports the 1.6-fold cfDNA[^cfDNA], 1.9-fold patient-specific ctDNA[^ctDNA], and 5.6-fold TERT[^TERT] ctDNA maximum enrichments plus transcriptome findings; Results report no significant vital-sign fluctuations/AEs, no hemorrhage or histologic tissue damage, and 34/17,982 DEGs[^DEGs] with only two upregulated immune-pathway genes. | 5 patients | https://www.nature.com/articles/s41698-023-00448-y | https://pubmed.ncbi.nlm.nih.gov/37717084/ | +| Chen, K. T., Huang, C. Y., Pai, P. C., Yang, W. C., Tseng, C. K., Tsai, H. C., Li, J. C., Chuang, C. C., Hsu, P. W., Lee, C. C., Toh, C. H., Liu, H. L., & Wei, K. C. (2023). Focused ultrasound combined with radiotherapy for malignant brain tumor: a preclinical and clinical study. Journal of neuro-oncology, 165(3), 535–545. https://doi.org/10.1007/s11060-023-04517-x | FUS-mediated BBB opening as an adjunct to re-RT[^RT] in recurrent malignant high-grade glioma | Preclinical: implanted GL261 glioma in mouse brain/striatum. Clinical: recurrent tumor ROIs[^ROI] selected to encompass T1-enhancing and/or T2 high-signal tumor regions | Preclinical FUS: 500 kHz, 0.4–0.56 MI, 1% duty cycle, 1 s burst period, 120 s exposure, SonoVue 7 µL/mouse. Clinical: NaviFUS with SonoVue 0.1 mL/kg; designed peak energy limit 0.68 MI, observed FUS energy 0.53–0.61 MI across 24 sessions. | Primary outcome: Preclinical mouse GBM[^GBM] model: RT-FUS (2 Gy) prolonged survival versus RT 2 Gy and control and improved tumor control. Clinical interim open-label pilot: 6 recurrent malignant high-grade glioma patients completed 24 RT-FUS treatments; no FUS-related AEs, but 1/6 had re-RT-related grade 3 radiation necrosis. ORR[^ORR] was 16.7% (1 partial response) and median PFS[^PFS] was 97.5 days; clinical efficacy was descriptive/not conclusive. | Preclinical: 23 mice. Clinical: 6 patients | | https://pubmed.ncbi.nlm.nih.gov/38060066/ | +| Arrieta, V. A., Gould, A., Kim, K. S., Habashy, K. J., Dmello, C., Vázquez-Cervantes, G. I., Palacín-Aliana, I., McManus, G., Amidei, C., Gomez, C., Dhiantravan, S., Chen, L., Zhang, D. Y., Saganty, R., Cholak, M. E., Pandey, S., McCord, M., McCortney, K., Castro, B., Ward, R., … Sonabend, A. M. (2024). Ultrasound-mediated delivery of doxorubicin to the brain results in immune modulation and improved responses to PD-1 blockade in gliomas. Nature communications, 15(1), 4698. https://doi.org/10.1038/s41467-024-48326-w | Recurrent GBM; LIPU[^LIPU]/MB-mediated BBB opening to enhance delivery of DOX[^DOX] and anti-PD-1[^PD1]/pembrolizumab | Tumor and peritumoral brain covered by SonoCloud-9 emitters | Human EAP[^EAP]: SonoCloud-9 implanted from prior recurrent-GBM trial; SC9[^SC9] activated with 10 µL/kg IV DEFINITY; pembrolizumab 200 mg before sonication; liposomal DOX 30 mg after sonication; induction low-dose liposomal DOX alone followed 10–14 days later by DOX+aPD-1[^aPD1] and subsequent DOX+aPD-1 cycles. Mouse LIPU/MB parameters: preclinical Sonocloud device; 100 µL Lumason MB; 60 s sonication using 1 MHz, 25,000-cycle bursts, 1 Hz PRF, 0.3 MPa | LIPU/MB increased DOX 2-fold in human sonicated peritumoral brain samples at 48 h and 3.92-fold in mouse brain; increased aPD-1/pembrolizumab ~2-fold in human sonicated peritumoral brain (2 patients) and nivolumab 6.3/6.6-fold in mouse brain at 1/4 h; DOX+aPD-1 delivered with LIPU/MB upregulated MHC[^MHC] I/II and IFN-γ[^IFN-gamma] immune phenotypes and improved long-term survival in glioma-bearing mice. Human clinical efficacy was not established | 4 patients; Preclinical sample sizes varied by experiment | https://www.nature.com/articles/s41467-024-48326-w | https://pubmed.ncbi.nlm.nih.gov/38844770/ | +| Krishna, V., Fishman, P. S., Eisenberg, H. M., Kaplitt, M., Baltuch, G., Chang, J. W., Chang, W. C., Martinez Fernandez, R., Del Alamo, M., Halpern, C. H., Ghanouni, P., Eleopra, R., Cosgrove, R., Guridi, J., Gwinn, R., Khemani, P., Lozano, A. M., McDannold, N., Fasano, A., Constantinescu, M., … Elias, W. J. (2023). Trial of Globus Pallidus Focused Ultrasound Ablation in Parkinson's Disease. The New England journal of medicine, 388(8), 683–693. https://doi.org/10.1056/NEJMoa2202721 | Medication-refractory idiopathic PD with dyskinesias or motor fluctuations and off-medication motor impairment | Unilateral GPi[^GPi], opposite the patient’s dominant or more impaired body side | Mean number of sonications 12.9 (SD[^SD-stat]: 4.8, range: 6-25); maximum energy delivered was 21.2 kilojoules (SD: 9.8, range: 5.7-36.1), yielding a maximal temperature of 54.3 degrees Celsius (SD: 2.6, range: 43-61) | Response at 3 months, defined as ≥3-point improvement in treated-side MDS-UPDRS-III off-medication or UDysRS[^UDysRS] on-medication, without clinically meaningful worsening. Response occurred in 45/65 active-treatment patients (69%) vs 7/22 sham patients (32%); difference 37 percentage points, 95% CI 15–60, P=0.003 | 94 randomized: 69 active treatment, 25 sham. Primary-outcome assessment completed by 65 active and 22 sham patients | https://www.nejm.org/doi/10.1056/NEJMoa2202721?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed | https://pubmed.ncbi.nlm.nih.gov/36812432/ | +| Jiang, S., Wu, X., Yang, F., Rommelfanger, N. J., & Hong, G. (2023). Activation of mechanoluminescent nanotransducers by focused ultrasound enables light delivery to deep-seated tissue in vivo. Nature protocols, 18(12), 3787–3820. https://doi.org/10.1038/s41596-023-00895-8 | Non-invasive deep-tissue light delivery platform for optogenetics, fluorescence imaging, photoactivatable genome editing, and related light-gated applications; not a therapeutic indication | Application-defined vascularized deep tissue; representative in vivo demonstration uses mouse brain regions for sono-optogenetic neuromodulation | Representative FUS setup: 1.5 MHz transducer, 38.2 mm diameter, 1.0 mm lateral focal spot, max transducer input power 50 W. Representative first FUS pulse train: 5 min, 25% amplitude, 200 ms pulse duration, 800 ms delay. | DeLight achieves localized light emission in deep tissue from systemically delivered MLNTs[^MLNTs] gated by FUS, with sub-millimeter spatial resolution and millisecond response times in vascularized organs of living mice. Representative demonstrations include non-invasive sono-optogenetic neuromodulation in live mice without craniotomy or brain implants | N/A; protocol/platform paper | https://pmc.ncbi.nlm.nih.gov/articles/PMC11405139/ | https://pubmed.ncbi.nlm.nih.gov/37914782/ | + +## Review Papers + +| Citation | PubMed Link | +| -------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- | ----------------------------------------- | +| Cox, S. S., Connolly, D. J., Peng, X., & Badran, B. W. (2025). A Comprehensive Review of Low-Intensity Focused Ultrasound Parameters and Applications in Neurologic and Psychiatric Disorders. Neuromodulation : journal of the International Neuromodulation Society, 28(1), 1–15. https://doi.org/10.1016/j.neurom.2024.07.008 | https://pubmed.ncbi.nlm.nih.gov/39230530/ | +| Zhong, Y. X., Liao, J. C., Liu, X., Tian, H., Deng, L. R., & Long, L. (2023). Low intensity focused ultrasound: a new prospect for the treatment of Parkinson's disease. Annals of medicine, 55(2), 2251145. https://doi.org/10.1080/07853890.2023.2251145 | https://pubmed.ncbi.nlm.nih.gov/37634059/ | +| Lee, K., Park, T. Y., Lee, W., & Kim, H. (2024). A review of functional neuromodulation in humans using low-intensity transcranial focused ultrasound. Biomedical engineering letters, 14(3), 407–438. https://doi.org/10.1007/s13534-024-00369-0 | https://pubmed.ncbi.nlm.nih.gov/38645585/ | +| Martínez-Fernández, R., Paschen, S., Del Álamo, M., Rodríguez-Rojas, R., Pineda-Pardo, J. A., Blesa, J., Kaplitt, M. G., Deuschl, G., & Obeso, J. A. (2025). Focused ultrasound therapy for movement disorders. The Lancet. Neurology, 24(8), 698–712. https://doi.org/10.1016/S1474-4422(25)00210-8 | https://pubmed.ncbi.nlm.nih.gov/40683278/ | + +[^LIFU]: Low-intensity focused ultrasound. +[^amPFC]: Anterior medial prefrontal cortex. +[^PNP]: Peak negative pressure. +[^MI]: Mechanical index. +[^ISPTA]: Spatial-peak temporal-average intensity. +[^SWI]: Susceptibility-weighted imaging. +[^MDE]: Major depressive episode. +[^DMN]: Default mode network. +[^tFUS]: Transcranial focused ultrasound. +[^PRR]: Pulse repetition rate. +[^BDI-II]: Beck Depression Inventory-II. +[^HDRS-6]: Six-item Hamilton Depression Rating Scale. +[^HDRS]: Hamilton Depression Rating Scale. +[^AEs]: Adverse events. +[^CBF]: Cerebral blood flow. +[^TCD]: Transcranial Doppler. +[^CI]: Confidence interval. +[^CBFv]: Cerebral blood-flow velocity. +[^NA]: Not applicable. +[^LVO]: Large vessel occlusion. +[^AUROC]: Area under the receiver operating characteristic curve. +[^RACE]: Rapid Arterial oCclusion Evaluation. +[^LAMS]: Los Angeles Motor Scale. +[^COVID]: Coronavirus disease. +[^US]: Ultrasound. +[^MB]: Microbubbles. +[^rtPA]: Recombinant tissue plasminogen activator. +[^PRF]: Pulse repetition frequency. +[^ISPPA]: Spatial-peak pulse-average intensity. +[^fMRI]: Functional magnetic resonance imaging. +[^BOLD]: Blood-oxygen-level-dependent. +[^rtFUS]: Repetitive transcranial focused ultrasound. +[^MASQ-GD]: Mood and Anxiety Symptom Questionnaire-General Distress. +[^MATRD]: Mood, anxiety, and trauma-related disorders. +[^MDD]: Major depressive disorder. +[^FUS]: Focused ultrasound. +[^FWHM]: Full width at half maximum. +[^MADRS]: Montgomery-Åsberg Depression Rating Scale. +[^DLPFC]: Dorsolateral prefrontal cortex. +[^GAD]: Generalized anxiety disorder. +[^ISPPA3]: + Derated spatial-peak pulse-average intensity, as reported by the source + paper. + +[^ISPTA3]: + Derated spatial-peak temporal-average intensity, as reported by the source + paper. + +[^HAM-A]: Hamilton Anxiety Rating Scale. +[^BAI]: Beck Anxiety Inventory. +[^PGI-I]: Patient Global Impression of Improvement. +[^TRD]: Treatment-resistant depression. +[^SGC]: Subgenual cingulate cortex. +[^MRI]: Magnetic resonance imaging. +[^SCC]: Subcallosal cingulate cortex. +[^FDA]: U.S. Food and Drug Administration. +[^NAc]: Nucleus accumbens. +[^SUD]: Substance use disorder. +[^OUD]: Opioid use disorder. +[^DWI]: Diffusion-weighted imaging. +[^ADC]: Apparent diffusion coefficient. +[^LIFUS]: Low-intensity focused ultrasound stimulation. +[^TMS]: Transcranial magnetic stimulation. +[^MEP]: Motor-evoked potential. +[^APB]: Abductor pollicis brevis. +[^MSL]: Motor sequence learning. +[^PD-disease]: Parkinson’s disease. +[^a-tbTUS]: Accelerated theta-burst transcranial ultrasound stimulation. +[^tbTUS]: Theta-burst transcranial ultrasound stimulation. +[^M1]: Primary motor cortex. +[^FDI]: First dorsal interosseous. +[^MDS-UPDRS-III]: + Movement Disorder Society-sponsored revision of the Unified Parkinson’s + Disease Rating Scale Part III. + +[^ACC]: Anterior cingulate cortex. +[^BPI]: Brief Pain Inventory. +[^rTUS]: Repetitive transcranial ultrasound stimulation. +[^SANS]: Scale for the Assessment of Negative Symptoms. +[^PANSS]: Positive and Negative Syndrome Scale. +[^CPT]: Continuous Performance Test. +[^PW]: Pulse width. +[^DC]: Duty cycle. +[^SCR]: Skin conductance response. +[^dACC]: Dorsal anterior cingulate cortex. +[^vmPFC]: Ventromedial prefrontal cortex. +[^PCC]: Posterior cingulate cortex. +[^TUS]: Transcranial ultrasound stimulation. +[^GABAplus]: GABA plus co-edited macromolecules. +[^GABA]: Gamma-aminobutyric acid. +[^Glx]: Combined glutamate/glutamine signal. +[^MRS]: Magnetic resonance spectroscopy. +[^rsFC]: Resting-state functional connectivity. +[^AI]: Anterior insula. +[^PI]: Posterior insula. +[^CHEP]: Contact heat-evoked potential. +[^HRV]: Heart-rate variability. +[^SDNN]: Standard deviation of normal-to-normal intervals. +[^ICF]: Intracortical facilitation. +[^SICI]: Short-interval intracortical inhibition. +[^LICI]: Long-interval intracortical inhibition. +[^etFUS]: Excitatory transcranial focused ultrasound stimulation. +[^itFUS]: Inhibitory transcranial focused ultrasound stimulation. +[^TBD]: Tone-burst duration. +[^PRP]: Pulse repetition period. +[^SD-param]: Sonication duration. +[^SP]: Sonication period. +[^NMDA]: N-methyl-D-aspartate. +[^LTP]: Long-term potentiation. +[^FEP]: FUS-evoked potential. +[^S1]: Primary somatosensory cortex. +[^VPL]: Ventral posterolateral nucleus. +[^EEG]: Electroencephalography. +[^AEP]: Auditory evoked potential. +[^rIFG]: Right inferior frontal gyrus. +[^Pmax]: Maximum pressure. +[^PFC]: Prefrontal cortex. +[^MFT]: Midfrontal theta. +[^TIC]: Thermal index for cranial bone. +[^BCI]: Brain-computer interface. +[^V5]: Visual area V5 / middle temporal complex. +[^PN]: Pulse number. +[^tFUS-GC]: Transcranial focused ultrasound at the geometric center. +[^tFUS-GP]: Transcranial focused ultrasound at the geometric periphery. +[^ANOVA]: Analysis of variance. +[^MCI]: Mild cognitive impairment. +[^AD]: Alzheimer’s disease. +[^A-beta]: Amyloid beta. +[^BBB]: Blood-brain barrier. +[^ARIA]: Amyloid-related imaging abnormalities. +[^cfDNA]: Cell-free DNA. +[^ctDNA]: Circulating tumor DNA. +[^TERT]: Telomerase reverse transcriptase. +[^DEGs]: Differentially expressed genes. +[^IV]: Intravenous. +[^ROI]: Region of interest. +[^RT]: Radiotherapy. +[^GBM]: Glioblastoma. +[^ORR]: Objective response rate. +[^PFS]: Progression-free survival. +[^LIPU]: Low-intensity pulsed ultrasound. +[^PD1]: Programmed cell death protein 1. +[^DOX]: Doxorubicin. +[^EAP]: Expanded access program. +[^SC9]: SonoCloud-9. +[^aPD1]: Anti-PD-1 antibody. +[^MHC]: Major histocompatibility complex. +[^IFN-gamma]: Interferon gamma. +[^GPi]: Internal segment of the globus pallidus. +[^SD-stat]: Standard deviation. +[^UDysRS]: Unified Dyskinesia Rating Scale. +[^MLNTs]: Mechanoluminescent nanotransducers. +[^mPFC]: Medial prefrontal cortex. +[^PD-duration]: Pulse duration. +[^ISI]: Interstimulus interval.