Schematic overview of the specificity of brain perturbation techniques.

Brain perturbation techniques vary in the precision of the spatial and temporal effects that can be elicited, on logarithmic (log10) scales. This includes transcranial Focused Ultrasound Stimulation (TUS), in green. Some approaches with cellular specificity are shown that are currently primarily in use with nonhuman animals as models (optogenetics, infrared neuromodulation, chemogenetics and genetic manipulation). Figure modified with permission from P.C. Klink, from (Klink et al., 2021).

Low-intensity Transcranial Ultrasound Stimulation for Neuromodulation in Humans.

(A, B, C) Example focal TUS targeting of a human motor cortex using k-plan software (BrainBox, Inc.) (D) TUS simulation software uses an input set of parameters (e.g., pulse duration, PD, sonication duration, pulse repetition frequency, PRF, transducer properties and fundamental frequency (FF), intensity in water (ISSPA), to simulate and calculate the approximate TUS intensity in the target brain region using the participant’s MRI and CT scans if available, or template human brain and CT scans. Simulation software will also generate the complete set of minimal parameters for reporting.

Transcranial focused ultrasound stimulation (TUS) key parameters.

Shown are the abbreviations and measurement value definitions for the key TUS parameters.

Recommendations for TUS parameters.

Currently, there are no established and universally recognized guidelines for the safe application of TUS. Nevertheless, FDA guidelines exist for diagnostic ultrasound, and as such much of the TUS literature has taken these limits into consideration. These are summarized in the table above, see Box 1 for a description of these parameters. The International Transcranial Ultrasonic Stimulation Safety and Standards (iTRUSST) consortium has recently established recommendations based on existing guidelines for diagnostic ultrasound from regulatory bodies such as the Food and Drug Administration (FDA), the British Medical Ultrasound Society (BMUS) and the American Institute of Ultrasound in Medicine (AIUM). In brief the MI should be below 1.9 and temperature rise in soft tissue below 2 degrees Celsius (https://arxiv.org/abs/2311.05359). Importantly, those recommendations should be considered in parallel to individualized simulations to further reduce the risk of adverse bioeffects.

Net enhancement versus suppression hypotheses.

Summarized hypotheses on how net enhancement or suppression could be biased with TUS parameters.

Meta-analysis selection and inclusion criteria using the PRISMA recommended approach.

Selection and inclusion criteria for the meta-analysis, with resulting sample sizes for the meta-analysis.

Human ‘online’ effect TUS studies categorized by probable enhancement or suppression.

Summarized are the TUS parameters reported in human studies focusing on inducing online effects and their reported neurobiological effects summarized by likely excitatory or inhibitory effects. Independently confirmed effects cite the independent assessment source.

Meta-analysis effects relative to NICE model predictions.

(A) Online effects meta-analysis based on the studies in Table 1, segregated by probable enhancement versus suppression. Light blue line shows the NICE model boundary between suppression and enhancement (potential net excitation). Blue circles are human studies reporting probable enhancement, red circles probable suppression. Index numbers correspond to studies numbered in Table 1. (B) Same format and analysis approach showing the “offline” effects studies in Table 2 with stars. Index numbers correspond to studies numbered in Table 2. (C) Combined figure with online (Table 1) and offline (Table 2) studies. Same symbol and color use as in A-B. (D) Additional hypothesized parameters like pulse repetition frequency (PRF) can be plotted in multi-dimensional spaces as shown.

Human ‘offline’ effect TUS studies categorized by probable enhancement or suppression.

Summarized are the TUS parameters used in human studies focusing on inducing longer lasting or ‘offline’ effects.

Box plots of meta-analysis results for the key TUS parameters.

Shown are boxplots for each of the TUS parameters of interest segregated by probable enhancement or suppression (data from Tables 1 and 2). Plots show TUS parameters: Pulse Repetition Frequency (PRF), Duty Cycle, Sonication Duration, ISPPA. These are shown separately for Online effects (A) and Offline effects (B). The logistic regression only showed a significant effect for Duty Cycle, but we recognize that the results are underpowered at this stage. (C) Shows results for ISPTA, the potential ultrasound ‘dose’ parameter that integrates ISPPA and DC. This is shown for online (left panel), offline (middle panel) effects, and for ISPPA in the brain for both offline and online effects combined (right panel)