This letter was written in response to the case report mentioned above (Link here) and submitted to the editor of Brain Stimulation.

Dear Editor,

I am writing to express my concerns regarding the recent case report presenting a “brain injury during focused ultrasound neuromodulation for substance use disorder” (1). As a reviewer, I stated that I could not support publication of this manuscript in its current form, as its lack of transparency appeared more harmful to the field than informative. Now that it has been published, I feel responsible for making these concerns public.

My primary issue with the manuscript is the refusal from the authors and manufacturer to disclose the basic acoustic amplitude metrics, specifically, the acoustic intensity (free-field or in situ) and the Mechanical Index (MI), on the grounds that these are “proprietary”. While this may be a corporate policy, omitting such crucial metrics in a scientific paper is not defensible and could mislead readers. My second and third concerns are that the MI is portrayed as irrelevant to participant safety, and that the risk mitigation strategy relies on cavitation-based mechanisms. These positions are particularly problematic, as they are inconsistent with the current biophysical understanding and safety framework that guide low-intensity ultrasound neuromodulation (2). I expand on these issues in the following sections.

Acoustic amplitude parameters are fundamental to safety assessments in low-intensity ultrasound neuromodulation (3–5) and arguably determine whether the term “low-intensity” can be applied altogether. The MI is essential for deriving any understanding of cavitation risk (6). Withholding this information prevents the community from evaluating how the injury happened and developing appropriate safety standards. It also sets a concerning precedent for industry-academia collaborations. Treating these key operating parameters as confidential business information is incompatible with scientific and ethical responsibility. Moreover, the financial value of such parameters seems dubious given the harm that is now evident.

It is timely that expert consensus recommendations on non-significant risk thresholds for preventing inertial cavitation in human ultrasound neuromodulation have now been published (3), clarifying that we simply do not know what happens above a MI or transcranial MI (MItc) of 1.9. Researchers and manufacturers who choose to operate above these non-significant risk limits do so knowingly at increased risk. With this case report, the authors explicitly acknowledge exceeding the MI limit of 1.9 according to their previous dose-escalation study (7) but do not specify by how much. Notably, their dose-escalation study provides some intensity values from which MI can be derived, but this level of transparency is absent in the present report. Although the authors state that their goal is to inform the community about safety and to “advance patient safety,” they are withholding the very information needed to do so.

Equally concerning is their rationale for continuing to use the same protocol in future patients. The authors state that their risk mitigation strategy “is not about the MI but rather about monitoring the acoustic feedback (cavitation) in real time and linking it to power adjustment”.

This rationale is problematic in at least three ways: 1) It dismisses MI as a biosafety limit. 2) It does not prevent cavitation but instead accepts it will occur and relies on real-time monitoring to stop treatment before harm. Thus, any software inaccuracies would result in tissue damage. Such dependence on software, rather than on conservative biophysical limits, seems an unacceptable safety risk. 3) This definition appears incompatible with efforts to leverage neuromodulation mechanisms that operate primarily through mechanical forces (e.g., acoustic radiation force, particle displacement) independent of bubble nucleation (2). Protocols that expect or depend on cavitation to achieve bioeffects seem fundamentally different; they exploit cavitation-based bioeffects and should be classified, described, and regulated as cavitation protocols, not neuromodulation protocols.

The paper also fails to provide evidence that the incident led to substantive safety improvements. They claim that the device now includes “enhanced acoustic feedback monitoring” and “stricter halting criteria” yet provide no supporting data. No information is offered regarding what triggered the original cavitation event, what technical modifications were made, or how these changes were validated (if validated at all) before further human use. Without empirical evidence, such assurances remain unsupported.

The manuscript has more issues. 1) It introduces speculative explanations that distract from the primary safety issue: the hypothesis that the injury may have resulted from CO₂ accumulation due to patient’s somnolence seems conjectural and unsubstantiated. 2) Methodological details are missing according to standardized reporting guidelines (8). 3) No information on skull geometry (aside an uninformative picture) clarifies the likelihood of standing wave formation near bone / air interfaces. 4) Acoustic feedback data; critical to substantiating the claim of inertial cavitation; are not shown. 5) The timing of the MRI abnormalities relative to stopping the sonication is ambiguous. Basically, no data is shared.

More broadly, this situation exposes a systemic problem at the intersection of academic research, clinical experimentation, and proprietary technology. If fundamental safety parameters are treated as intellectual property, the research community loses its capacity for independent evaluation and control. The credibility of the entire field depends on openness about basic exposure metrics. Without it, even well-intentioned studies risk damaging public trust and regulatory confidence. I acknowledge the complexity of academic–industry collaborations and accept that manufacturers may protect certain engineering details. However, amplitude parameters such as MI and acoustic intensity should not be commercial secrets and regulatory or ethics bodies should require such information in safety-critical contexts.

I hope future dissemination from the same group will disclose the necessary amplitude metrics and procedural details. This case marks a pivotal moment for the community. The field stands at the frontier of transformative possibilities, holding immense promise for neuroscience and psychiatry (9–11). That promise comes with the duty to uphold the highest standards of rigor, transparency, and participant safety. When adverse events occur, our collective integrity in confronting them determines the credibility of the entire discipline. To advance responsibly, we must insist on full disclosure of the parameters that define biological safety. Anything less leaves both science and patients unprotected.

Sincerely

Elsa Fouragnan, PhD

Professor of Neuroscience

Director of the Brain Research Imaging Center

University of Plymouth, UK

Acknowledgement:

Elsa Fouragnan is funded by a UKRI FLF (MR/Y034368/1), a BBSRC (BB/Y001494/1), a Neuromod+ grant (EP/W035057/1) and an ARIA grant (SCNI-PR01-P15).

Reference:

1.         Rezai A, Ranjan M, Bhagwat A, Arsiwala T, Carpenter J, Schafer M, et al. Brain Injury During Focused Ultrasound Neuromodulation for Substance Use Disorder. Brain Stimul Basic Transl Clin Res Neuromodulation [Internet]. 2025 Oct 31 [cited 2025 Nov 1];0(0). Available from: https://www.brainstimjrnl.com/article/S1935-861X(25)00358-4/fulltext

2.         Nandi T, Kop BR, Naftchi-Ardebili K, Stagg CJ, Pauly KB, Verhagen L. Biophysical effects and neuromodulatory dose of transcranial ultrasonic stimulation. Brain Stimulat. 2025 May 1;18(3):659–64.

3.         Aubry JF, Attali D, Schafer ME, Fouragnan E, Caskey CF, Chen R, et al. ITRUSST consensus on biophysical safety for transcranial ultrasound stimulation. Brain Stimulat. 2025 Nov 1;18(6):1896–905.

4.         Blackmore J, Shrivastava S, Sallet J, Butler CR, Cleveland RO. Ultrasound Neuromodulation: A Review of Results, Mechanisms and Safety. Ultrasound Med Biol. 2019 July 1;45(7):1509–36.

5.         Pasquinelli C, Hanson LG, Siebner HR, Lee HJ, Thielscher A. Safety of transcranial focused ultrasound stimulation: A systematic review of the state of knowledge from both human and animal studies. Brain Stimulat. 2019 Dec;12(6):1367–80.

6.         Ahmadi F, McLoughlin IV, Chauhan S, ter-Haar G. Bio-effects and safety of low-intensity, low-frequency ultrasonic exposure. Prog Biophys Mol Biol. 2012 Apr 1;108(3):119–38.

7.         Mahoney JJ, Haut MW, Carpenter J, Ranjan M, Thompson-Lake DGY, Marton JL, et al. Low-intensity focused ultrasound targeting the nucleus accumbens as a potential treatment for substance use disorder: safety and feasibility clinical trial. Front Psychiatry [Internet]. 2023 Sept 15 [cited 2024 May 14];14. Available from: https://www.frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2023.1211566/full

8.         Martin E, Aubry JF, Schafer M, Verhagen L, Treeby B, Pauly KB. ITRUSST consensus on standardised reporting for transcranial ultrasound stimulation. Brain Stimulat. 2024;17(3):607–15.

9.         Arulpragasam AR, van ’t Wout-Frank M, Barredo J, Faucher CR, Greenberg BD, Philip NS. Low Intensity Focused Ultrasound for Non-invasive and Reversible Deep Brain Neuromodulation-A Paradigm Shift in Psychiatric Research. Front Psychiatry. 2022;13:825802.

10.       Darmani G, Bergmann TO, Butts Pauly K, Caskey CF, de Lecea L, Fomenko A, et al. Non-invasive transcranial ultrasound stimulation for neuromodulation. Clin Neurophysiol. 2022 Mar 1;135:51–73.

11.       Murphy K, Fouragnan E. The future of transcranial ultrasound as a precision brain interface. PLOS Biol. 2024 Oct 29;22(10):e3002884.