# ITRUSST Consensus on Standardised Reporting for Transcranial Ultrasound
Stimulation

Eleanor Martin  Department of Medical Physics and Biomedical Engineering,
University College London, London, U.K  Wellcome/EPSRC Centre for
Interventional and Surgical Sciences,
University College London, London, UK  Jean-François Aubry  Physics for
Medicine Paris, Inserm U1273, ESPCI Paris, CNRS UMR8063,
PSL University, Paris, France  Mark Schafer  School of Biomedical Engineering,
Science and Health Systems,
Drexel University, Philadelphia, PA USA  Lennart Verhagen  Donders Institute
for Brain, Cognition and Behaviour,
Radboud University, 6525 GD Nijmegen, the Netherlands  Bradley Treeby
Department of Medical Physics and Biomedical Engineering,
University College London, London, U.K  Kim Butts Pauly  Department of
Radiology,
Stanford University, Stanford, CA, USA * These authors contributed equally.
Corresponding Author: Kim Butts Pauly<EMAIL_ADDRESS>
(Feb 2024)

###### Abstract

As transcranial ultrasound stimulation (TUS) advances as a precise, non-
invasive neuromodulatory method, there is a need for consistent reporting
standards to enable comparison and reproducibility across studies. To this
end, the International Transcranial Ultrasonic Stimulation Safety and
Standards Consortium (ITRUSST) formed a subcommittee of experts across several
domains to review and suggest standardised reporting parameters for low
intensity TUS, resulting in the guide presented here. The scope of the guide
is limited to reporting the ultrasound aspects of a study. The guide and
supplementary material provide a simple checklist covering the reporting of:
(1) the transducer and drive system, (2) the drive system settings, (3) the
free field acoustic parameters, (4) the pulse timing parameters, (5) _in situ_
estimates of exposure parameters in the brain, and (6) intensity parameters.
Detailed explanations for each of the parameters, including discussions on
assumptions, measurements, and calculations, are also provided.

##  1 Introduction

Transcranial ultrasound stimulation (TUS) is a non-invasive neuromodulation
technique that employs focused ultrasound waves to modulate neuronal activity
within the brain. TUS offers a promising avenue for therapeutic and research
applications due to its spatial precision and ability to target deep neural
structures. As the field transitions to more widespread human studies, the
time is upon us to standardize the reporting of such studies to aid
understanding and reproducibility.

To this end, the International Transcranial Ultrasonic Stimulation Safety and
Standards Consortium (ITRUSST) formed a subcommittee to review and suggest
standardised reporting parameters for low intensity TUS, with multiple
presentations to the ITRUSST group and multiple opportunities for feedback,
resulting in the guide presented here. Similar guidelines have been produced
for other analogous techniques and applications [1, 2].

This guide focuses on the ultrasound aspects of TUS experiments. It does not
discuss reporting of additional elements such as EEG, fMRI, or behavioral
readouts, which are important, but outside the scope of this work. It does not
seek to establish safety values or thresholds, which are addressed in a
separate ITRUSST consensus on TUS safety [3]. While this guide endeavors to
align with existing international standards related to diagnostic ultrasound
imaging and focused ultrasound transducers, it may diverge from these
standards when necessary. An important additional note is that we make the
assumption that the ultrasound fields that this guide applies to are linear.
Our rationale for doing so is provided in Sec. A of the Supplementary
Material.

This guide is structured as follows. In Section 2, we discuss reporting of the
transducer and drive system, and the free field acoustic pressure amplitude
and spatial characteristics of the focal region, as measured by a hydrophone
in free field in a water bath. These measurements, performed under
standardised conditions, serve as a baseline for comparison between studies
independent from the specific configuration of use during TUS studies. In
Section 3, we discuss the pulse timing parameters. Next, in Section 4, we
discuss the reporting of exposure parameters, which describe the acoustic
field inside the individual brain, after accounting for the skull bone, brain
tissue, and any other acoustic distortions. Further details and a summary
checklist of all required reporting parameters are provided in the
Supplementary Material, Sections A-F.

##  2 System and Free Field Acoustic Pressure Parameters

System parameters describe the type and geometry of the transducer, and the
signal chain or system used to drive the transducer in order to generate the
acoustic field. The free field acoustic pressure parameters provide a
description of the generated ultrasound field under reference conditions. The
term ‘free field’ refers to the field generated when a transducer is radiating
continuously [4] (or with the comparatively long pulses used in TUS studies)
into water without any obstruction by reflectors, scatterers, or aberrators.
See Sec. B for details of how this is implemented during measurements.

Reporting free field acoustic parameters allows comparison of the transducer
output at the chosen output level and focal settings under standardised
conditions, serving as a baseline for comparison between studies. In this
guide, the term output level refers to the amplitude of the acoustic pressure
output, which is governed by settings on the drive system such as voltage,
power or intensity. The focal position setting refers to the position of the
focal region where this can be steered to different positions. It may be fixed
for a particular transducer, or set by the operator, for example, by selecting
a distance setting, or by setting the relative phases applied to the
transducer elements. The free field parameters described in this section
should be reported at the output and focal settings used during exposure of
participants during studies.

###  2.1 Transducer and Drive System

####  2.1.1 Transducer Description

A description of the ultrasound transducer should be given, including the
manufacturer and model number, and the operating frequency of the transducer.
For spherically focussing transducers, the geometry is described by the radius
of curvature and aperture diameter (see Fig. 1). In some cases, the exact
geometry may not be known, for example, if the transducer construction
includes a lens or permanently attached coupling medium, in which case, any
other information such as the nominal position of the focus relative to the
transducer face should be reported. For multi-element transducers, the number
of elements and information about their shape, size, and positions should be
given if available. The exact size and position of elements may not be
available for commercial transducers, so a brief description accompanied by
the model number is sufficient. Any other features of the transducer such as
permanently attached coupling media, or lenses should be described, including
a description of the material, its thickness and shape/geometry, and
properties of the material such as the sound speed, density and attenuation
coefficient where known.

####  2.1.2 Drive System Description

The input signal used to drive the transducer may be generated by an
integrated drive system, or using a signal generator and RF amplifier. All
components of the system, including manufacturer and model numbers and any
external electrical impedance matching networks used to couple the drive
signal to the transducer should be reported.

####  2.1.3 Drive System Settings

All drive system settings used during studies should be described, including
the operating frequency, output level settings (e.g. displayed electrical
power, focal intensity, voltage etc.), and for multielement transducers, focal
distance or position settings applied. The method of coupling the transducer
to the participant forms part of the _in situ_ acoustic transmission path, so
the materials and methods used should be described.

Figure 1: Schematics of example transducers, geometric and field parameters,
for information. (A) common transducer configurations including attached
coupling media or internal lenses. The external transducer surface plane,
$Z_{ex}$ which may be coincident with the front surface of the transducer
housing often serves as the reference plane, $Z_{ref}$ from which distances
are measured. For some transducers, e.g. complex multi-element devices,
$Z_{ref}$ may intersect with the centre of the surface on which the elements
sit. (B) Aperture diameter, D, and radius of curvature, R, are used to
describe the geometry of focusing transducers. (C) Free field pressure
parameters shown with respect to the reference plane. $Z_{sp}$ is the axial
position of the location of spatial-peak pressure relative to the reference
plane $Z_{ref}$; $Z_{c}$ is the axial position of the centre of the -3dB focal
region relative to the reference plane.

###  2.2 Free Field Acoustic Parameters

####  2.2.1 Parameters To Report

The free field acoustic pressure field parameters are illustrated in Fig. 1.
Table 1.1 shows the quantities to be reported which includes spatial peak
pressure amplitude, focal dimensions, and location. An explanation of how to
calculate focal dimensions from the axial pressure profile is given in Sec.
B.8. Two illustrative reporting examples are provided in Table 1.1, and
annotated example axial pressure profiles are shown in Fig. B.2.

The amplitude of the spatial-peak acoustic pressure should be reported at each
of the output level settings, and all quantities should be reported for each
of the focal position settings used during studies, where practical. This will
provide a reference spatial-peak pressure in water for each study exposure.
For multi-element array devices where steering and aberration correction are
performed, the focal position and amplitude may vary between participants and
target locations. Therefore, reporting of free field parameters for each
condition may not be useful. Instead information about the pressure amplitude
and size of the focal region over the focal steering range utilised during the
study should be reported. See Sec. C for recommendations for reporting average
or ranges of parameters.

A
Transducer and Drive System Parameters
Manufacturer, Model Number Centre Frequency Radius of Curvature Aperture
Diameter Number Elements Element Distribution Transducer TX1, Manufacturer 1
250 kHz 64 mm 64 mm 2 Spherical cap, annular array, equal area Matching
Electrical impedance matching network, Manufacturer 1 Integrated drive system
2-channel drive system, Manufacturer 1

Drive System Settings
Operating Frequency Output level Setting Focal Position Setting Experiment 1-4
270 kHz 4.78 W Phases: 0, 66.3º

Free Field Pressure Parameters
Spatial Peak Pressure Amplitude Axial Position Spatial Peak Pressure Position
of Centre of Axial -3dB Pressure Axial -3dB Size Lateral -3dB Size Axial -6dB
Size Lateral -6dB Size Experiment 1-4 700 kPa 43 mm 48 mm 30 mm 5 mm 48.7 mm 7
mm Notes: Reference plane is coincident with the centre of the radiating
surface

B
Transducer and Drive System Parameters
Manufacturer, Model Number Centre Frequency Radius of Curvature Aperture
Diameter Number Elements Element Distribution Transducer TX2, Manufacturer 2
650 kHz 80 mm 61 mm 1 Spherical cap Integrated drive system Ultrasound driving
systems, Manufacturer 2

Drive System Settings
Operating Frequency Output level Setting Focal Position Setting Experiment 1
650 kHz $p_{r}$ = 0.72 MPa fixed

Free Field Pressure Parameters
Spatial Peak Pressure Amplitude Axial Position Spatial Peak Pressure Position
of Centre of Axial -3dB Pressure Axial -3dB Size Lateral -3dB Size Axial -6dB
Size Lateral -6dB Size Experiment 1 720 kPa 80 mm 30 mm 5 mm Notes: Reference
plane is coincident with the outer surface of the transducer housing

Table 1: Table 1.1: Transducer and drive system description, drive system
settings, and free-field pressure parameters adapted from Johnstone et al [5]
and Badran et al. [6].

####  2.2.2 Methods of Obtaining Free Field Pressure Parameters

The free field pressure parameters can be obtained by investigators in one of
several ways, for example, directly from acoustic field measurements using a
hydrophone in a water bath, from a test report provided by the manufacturer or
other calibration/characterisation provider, or via a combination of
simulation and measurement. In any case, the source and/or method used to
obtain the field parameters should be reported, and where measurement or
simulation were used, the procedures should be described, as well as the
equipment used (including hydrophone type and element size, and calibration
parameters). Further guidance can be found in Sec. B.

For those performing their own measurements to determine the free field
acoustic pressure parameters, it is recommended that information on
measurement best practice be sought from hydrophone measurement standards [7,
8, 4] with additional help from the literature (e.g. [9, 10, 11]). While a
full description is out of scope of this document, some further details and
discussion are provided in Sec. B. Similarly, where simulation is used to
obtain some or all of the field parameters, the literature should be consulted
for methods and best practice.

####  2.2.3 Spatial-Peak Pressure at Study Output Levels

The free field spatial-peak pressure amplitude at each of the study output
level settings and focal position settings may be obtained either directly
from a measurement with the transducer operated at the study output level and
focal setting, or by scaling a measurement made with the same focal setting,
but at a different output level. Typically, a lower output level can be used
for free field measurements than would be used to obtain a similar pressure
amplitude in the brain after propagation through the skull. Measurements with
sufficient signal to noise ratio can be made, while reducing the possibility
of causing damage to the hydrophone (especially at the lowest frequencies).
This is discussed in more detail in Sec. B.

####  2.2.4 Defining the Spatial Location of Reported Free Field Pressure
Parameters

The spatial location of the spatial-peak pressure amplitude can be defined
relative to a variety of different reference locations, for example the
radiating surface or the external transducer surface plane, also known as the
exit plane (see Fig. 1). In some cases the full construction of the transducer
or the distance from the radiating surface to the outer surface of any
permanently attached or integrated lens or coupling medium may not be known.
In this case, a useful reference location would be the outer surface of these
layers, the external transducer surface plane. The chosen reference plane
location should be reported along with the parameters.

####  2.2.5 Uncertainty on Free-Field Acoustic Parameters

All hydrophone measurements have an associated measurement uncertainty which
arises from a combination of systematic and random uncertainties. One major
source of systematic uncertainty is hydrophone sensitivity, which can be up to
20% depending on frequency, and calibration method. Additionally, uncertainty
on pressure measurements will propagate to derived quantities. Understanding
of uncertainty on pressure measurements is essential when reporting and
comparing measurements. Further discussion of this can be found in Sec B.3.

##  3 Pulse Timing Parameters

Typical pulse timing parameters are laid out in Figure 2.The period refers to
the duration of one cycle of the operating frequency $f_{0}$. A pulse is a
single continuous sonication and has a duration referred to as the pulse
duration (PD). If the pulse is repeated, the pulse repetition interval (PRI)
is the time between successive pulses. The pulse repetition frequency is given
by $PRF=\frac{1}{PRI}$.

Figure 2: Figure 2. Schematics of two ultrasound pressure waveforms. A
rectangular ramp shape is used in A, while a Tukey window on the pressure
waveform is used in B. The pressure amplitude is shown as $p$, while the peak
negative pressure is shown as $p_{r}$; these should be the same when operating
at low pressures within the linear regime. The duration of a single cycle of
the operating frequency is the period (T). A single continuous sonication is a
pulse with a duration of pulse duration (PD). Pulses are often repeated in a
pulse train. The time between two pulses in a pulse train is the pulse
repetition interval (PRI) and is equal to 1 divided by the pulse repetition
frequency (PRF). The pulse train has a duration which is the pulse train
duration. The pulse train can be repeated, and if so has a structure similar
to the pulse, as laid out in Tables 2.1-2.3. In this figure, the operating
frequency $f_{0}$ is lower than typically used in order to aid visualization.

In Tables 2.1-2.3 we suggest a table reporting structure. In the rare case of
only a single continuous pulse, only the first line of a table need be
provided, with the pulse duration, and if a ramp is used, the pulse ramp
duration and the pulse ramp shape. The pulse repetition interval is not
applicable. When the pulse is repeated, the PRI/PRF are entered in the first
line, and the second line provides information on the pulse train including
the pulse train duration, the pulse train ramp duration, and the pulse train
ramp shape.

The examples chosen from the literature illustrate a number of variations in
TUS pulse parameters in order to illustrate increasing levels of patterning,
as well as rectangular and ramped waveforms. While figures are helpful and
illustrative, we feel that tables of the pulse parameters would be most clear.

|  |  _Duration |  _Ramp Duration |  _Ramp Shape |  _Repetition Interval/ Frequency |  Notes
---|---|---|---|---|---|---
A |  Pulse_ |  2 s |  0 |  rectangular |  4 ms/250 Hz |
|  Pulse Train_ |  0.3 s |  0 |  rectangular |  |
B |  Pulse_ |  3.25 ms |  1 ms |  Tukey on Pressure |  4 ms/250 Hz |
|  Pulse Train_ |  0.3 s |  0 |  rectangular |  |  A 1s 250Hz square wave auditory mask was delivered using cicumaural headphones. The mask was synchronised to start 100 ms before the onset of TUS pulse trains.
Table 2: Table 2.1: Pulse timing parameters from two experiments in Johnstone
_et al._ [5]. The A stimulation is experiment 1, condition A2 and the B
stimulation is experiment 4, condition A2. In both cases, the first line
contains the pulse characteristics and the second line contains the pulse
train characteristics.

A number of phrases are commonly used to refer to ultrasound pulse trains. We
recommend avoiding ambiguous phrases while retaining clear conventions of the
community. The use of the word “burst” is ambiguous as it has different
meanings in different contexts. For example, in diagnostic ultrasound, burst
refers to a single long pulse, while on function generators and in TMS, burst
is often used to refer to pulse trains. We suggest avoiding the use of the
word “burst” to remove this ambiguity and instead to use the terms “pulse” and
“pulse trains.”

The phrase “repetitive TUS” (rTUS) is conventionally used to refer to pulse
trains intended to elicit cumulative or delayed effects, as opposed to only
acute effects. The distinction between acute and delayed effects is critical
for study design (‘online’ vs. ‘offline’ designs), the underlying
neurophysiology (acute modulatory vs. early-phase plasticity mechanisms), and
the safety assessment. Distinguishing characteristics of an rTUS protocol, for
example, the pulse repetition frequency, can be included in the label, as in
the phrase ‘10 Hz rTUS’. It is recommended to avoid using unique labels when
an (extended) rTUS label is also appropriate. By definition, all rTUS
protocols include at least the pulse and pulse train timing parameters, as in
the 5 Hz rTUS example A of Table 2.2. Patterned rTUS protocols are a subset of
rTUS where the pulse trains are repeated in a pattern and, thus, include more
than two rows, as in the patterned rTUS example B of Table 2.2.

|  |  _Duration |  _Ramp Duration |  _Ramp Shape |  _Repetition Interval/ Frequency |  Notes
---|---|---|---|---|---|---
A |  Pulse_ |  20 ms |  0 |  rectangular |  200 ms/5 Hz |
|  Pulse Train_ |  80 ms |  0 |  rectangular |  |
B |  Pulse_ |  0.32 ms |  0 |  rectangular |  1 ms/1 kHz |
|  Pulse Train_ |  500 ms |  0 |  rectangular |  1.6 s/0.625 Hz |
|  Pulse Train Repeat_ |  80 s |  0 |  rectangular |  |
Table 3: Table 2.2. Pulse timing parameters for the two stimulations from Zeng _et al._ [12]. A was a single pulse train repeated every 200 ms for 80 s. B consisted of a short pulse train repeated every 1.6 s, again for a total time of 80 s. This is an example of patterned repetitive TUS.  |  _Duration |  _Ramp Duration |  _Ramp Shape |  _Repetition Interval/ Frequency |  Notes
---|---|---|---|---|---
Pulse_ |  0.5 ms |  0 |  rectangular |  1 ms/1 kHz |
Pulse Train_ |  0.3 s |  0 |  rectangular |  1 s/1 Hz |
Pulse Train Repeat_ |  30 s |  0 |  rectangular |  60 s/0.017 Hz |  TUS and Light+TUS conditions were interleaved with Light Only and No Stimulus conditions
Repeat 2_ |  40 min |  0 |  rectangular |  |
Table 4: Table 2.3. Pulse timing parameters from Gaur _et al._ [13] and
Mohammadjavadi _et al._ [14]. Pulse trains had two levels of repetitions.

For rectangular pulses in a single pulse train, duty cycle (DC) is defined as
the percentage of time that a pulse is on,

$DC=\frac{PD}{PRI}100\%.$ (1)

Duty cycle can be optionally reported since it can be easily derived from the
timing tables and is only defined for rectangular pulses. However, if
provided, we recommend referring to it in a particular way. The rTUS
stimulation protocol of Table 2.2A has a single duty cycle of 10%. In this
case, the overall DC is equal to the $DC_{\text{pulse train}}$. However, when
rTUS is patterned, such as in the stimulation of Table 2.2B, it would be
clearer to refer to the duty cycle of each level of patterning, such as
$DC_{\text{pulse train}}$ and $DC_{\text{pulse train repeat}}$. The overall
$DC$ is then the product of each $DC$. For the patterned rTUS stimulation in
Table 2.2B, $DC_{\text{pulse train}}=32\%,$ $DC_{\text{pulse train
repeat}}=31.25\%$, and the product is the overall duty cycle, $DC=10\%.$

Note, our definition of the pulse duration differs slightly from the
diagnostic ultrasound definition, which defines it as “1.25 times the interval
between the time when the time integral of the square of the instantaneous
acoustic pressure reaches 10% and 90% of its final value” [7]. This difference
is negligible for long pulses.

While the community is only starting to embrace ramping as a means to reduce
the auditory confound [5, 15, 16], it is likely that this will continue and
potentially become a source of confusion unless reported in a standardised
way. The shape and duration of the ramp must be reported as already described,
as well as whether that shape is applied to the pressure (voltage) waveform or
the intensity (power) waveform. In Table 2.1, we specify how ramping is
applied in Johnstone _et al._ [5].

It is likely that the field will continue to evolve in ways that we cannot now
anticipate. The table structure allows for evolution by adding columns or rows
as needed.

##  4 Derived Parameters: _In Situ_ Estimates of Exposure Parameters

Exposure parameters describe the properties of the acoustic field inside the
individual brain, after accounting for the skull bone, brain tissue, and any
other acoustic distortions. The exact ultrasound exposure is generally
difficult to directly measure _in vivo_. Instead, exposure parameters are
typically estimated using knowledge of the free field parameters along with a
derating procedure, simulations, or in-direct measurements. Here, _in situ_
estimate is used as a general term to describe the procedure used to calculate
the exposure parameters, i.e., the _in vivo_ or _in situ_ properties of the
acoustic field. The recommended _in situ_ parameters are provided here, with
examples provided in Sec D.

###  4.1 Estimated _In Situ_ Pressure Amplitude

The skull bone has very different acoustic material properties (sound speed,
density, and attenuation) to the surrounding soft tissues. As ultrasound
traverses the skull, these differences cause the waves to become distorted and
lose energy. Brain tissue also has a higher attenuation coefficient compared
to water. Consequently, the acoustic focus inside the brain will generally
have a much lower intensity (sometimes by a factor of 10 [17]). In some cases,
the shape and position of the focus can also become distorted. To complicate
matters, the shape and properties of the skull vary significantly both within
and between subjects. The same system and pulse timing parameters can
therefore generate very different acoustic fields in the brain depending on
the subject and the position of the transducer. An estimate of _in situ_
pressure amplitude should thus be reported. Several different approaches for
obtaining this are outlined below. In all cases, the method used should be
reported, along with details of any calculations, parameters, and assumptions.

  1. (a)

Simulating the intracranial ultrasound field. Simulations are increasingly
used to calculate the ultrasound and temperature fields inside the skull and
brain. The material properties for the simulations might be based on
individualised images for each subject or a CT or MR template image.

If using simulations to calculate the exposure parameters, the following
should be reported:

     * •

Details of the simulation tool.

     * •

Details of how the acoustic and thermal material properties are assigned.

     * •

How the transducer modelling and positioning was performed within the
simulation.

     * •

Details of relevant simulation input parameters, program settings including
mesh or grid parameters, and processing steps.

An excellent reference to follow is the _Reporting of Computational Modeling
Studies in Medical Device Submissions_ FDA guidance document [18]. Examples
from the literature can be found in e.g., [19] and [20].

  2. (b)

Derating. The simplest approach to calculating exposure parameters is to
derate the pressure by applying acoustic attenuation coefficients to the free
field parameters. Skull and frequency-specific acoustic attenuation
coefficients can be included to give an estimate of attenuation by the skull
under different conditions [21].

If using attenuation factors to calculate the _in situ_ exposure parameters,
the following should be reported:

     * •

The individual acoustic attenuation coefficients in dB.(MHz.cm)-1 or dB.cm-1
(for example, for skull, scalp and brain), and the values used for frequency
and distance.

     * •

The total attenuation applied in dB.

If experimental measurements are used to determine derating factors, for
example using a sample of human skulls, the methods, assumptions, and
variability should be reported [3].

  3. (c)

Measuring the effect of the intracranial ultrasound field. In some cases,
indirect measurement of the physical effects of the ultrasound field on the
brain can be made. For example, a temperature rise induced by the absorption
of ultrasound energy could be measured using MR thermometry. Similarly, for
some beam shapes, the bulk displacement induced by an acoustic radiation force
could be measured using MR-ARFI. With some restrictions, these measurements
could be correlated with the ultrasound exposure parameters in the brain [22].

If using measurements to calculate the exposure parameters, the following
should be reported:

     * •

Details of the measured quantity and the measurement method.

     * •

Details of how the exposure parameters are calculated from the measured
quantity.

In principle, all of the spatial acoustic parameters described in Section 2
could be reported after accounting for the skull and brain. In particular, if
using simulations to calculate exposure parameters, it is possible to extract
the focal characteristics as well as pressure values at the spatial-peak and
target locations [23]. As a minimum we recommend the following parameters are
reported: (1) the _in situ_ estimate for the spatial-peak pressure amplitude
and its location, and (2) the _in situ_ estimate for the pressure amplitude at
the target, if it is known and different from the spatial-peak pressure
amplitude. The former values are related to safety, the latter values are
related to the study efficacy.

###  4.2 Estimate of _In Situ_ Mechanical Index

For diagnostic ultrasound imaging, the mechanical index ($MI$) provides a
standardised indicator related to the potential for mechanical bioeffects,
specifically cavitation. In lieu of a safety standard specifically related to
TUS, $MI$ is also often reported in TUS studies in relation to regulatory
limits given in the FDA guidance document [24]. A detailed discussion can be
found in [25]. The _in situ_ estimate of mechanical index is easily derived
from the _in situ_ estimate of spatial-peak pressure.

The mechanical index is formally defined as

$MI=\frac{p_{r,.3}}{\sqrt{f_{0}}},$ (2)

where $p_{r,.3}$ is the peak-rarefactional pressure in MPa derated using an
attenuation coefficient of 0.3 dB cm-1 MHz-1, and $f_{0}$ is the operating
frequency in MHz (note units). This index and derating factor is intended to
apply to ultrasound propagating in soft tissue. Note, in this expression,
$p_{r}$ is used, as this is the formal definition of MI. Assuming operation in
the linear regime, the peak positive and negative pressures are equal, and
equal to the pressure amplitude, i.e., $p_{r}=p$, as used in elsewhere in this
guide.

In TUS applications where ultrasound propagates through the skull, a more
suitable derating factor may be used to define an alternative index, specific
to this application, called the $MI_{tc}$, where the subscript “tc” refers to
transcranial applications:

$MI_{tc}=\frac{p_{r,\alpha}}{\sqrt{f_{0}}}.$ (3)

In this case, the method used to calculate the _in situ_ or derated peak-
rarefactional pressure $p_{r,\alpha}$ (for example, a simulation) should be
reported. If derating a free field value, $\alpha$, the attenuation
coefficient, insertion loss of the skull, and any methods and parameters used
for calculation should be reported. If modeling indicates that the target
pressure is lower than the peak pressure, then the MI for both the spatial-
peak and the target should be given.

###  4.3 Thermal Metrics

At least one of the following metrics should be reported.

  1. (a)

Temperature Rise

In some cases, it may be possible to directly measure the temperature rise in
soft tissue due to the applied TUS (for example, using MR thermometry or
thermocouples), or to estimate the temperature rise in soft tissue using a
thermal simulation. If reporting the temperature rise in soft tissue, the
measurement or simulation method should be described as discussed in Sec. 4.1.

  2. (b)

Thermal Index  For diagnostic ultrasound imaging, the thermal index ($TI$)
provides a standardised indicator related to the potential for thermal
bioeffects. $TI$ is a unitless quantity intended to indicate a potential
temperature rise in degrees celsius, but doesn’t directly correlate to tissue
heating.111From 60601-2-37 [26]: “The TI gives a relative indication of the
potential for temperature increase at a specific point along the ultrasound
beam. The reason for the term “relative” is that the assumed conditions for
heating in tissue are complex such that any single index or model cannot be
expected to give the actual increase in temperature for all possible
conditions and tissue types. Thus, for a particular beamshape, a TI of 2
represents a higher temperature rise than a TI of 1, but does not necessarily
represent a rise of $2^{\circ}C$.” In lieu of a safety standard specifically
related to TUS, it is also often reported in TUS studies in relation to limits
given in the FDA guidance document [24] as evidence of safety. Detailed
discussions of these parameters can be found in [25]. Following IEC 62359
[25], the relevant thermal index is the bone-at-surface or cranial $TI$
($TIC$), which is calculated as

$TIC=\frac{W}{40D}.$ (4)

Here, $W$ is the time-averaged acoustic power of the transducer in free field
in mW, and $D$ is the equivalent aperture diameter of the transducer in cm.
For transducers in direct contact with the scalp, the equivalent aperture
diameter would be taken to be the nominal aperture diameter of the transducer.
However, when TUS transducers are applied with some stand off (such as a
coupling pad) between the transducer surface and the scalp, the equivalent
aperture diameter should be taken as the beam diameter at the scalp. This can
be estimated from the distance between the transducer surface and the scalp,
and the geometry of the transducer. Therefore, the transducer to scalp
distance should be reported. If reporting TIC, the values for $W$ and $D$ (and
the methods used to measure or calculate them) should also be reported.

  3. (c)

Thermal Dose

The extent of biological changes in tissue resulting from thermal exposure is
correlated with the amount of energy absorbed in tissue. However, for thermal
energy, it is the temperature to which the tissue is raised, and the duration
of the heating that plays the predominant biological role. Sapareto and Dewey
[27] defined a ‘thermal isoeffective dose’ in terms of cumulative equivalent
minutes (CEM) at $43^{\circ}C$ which allows conversion of any temperature-time
(T-t) combination to the equivalent time for which the reference temperature
of $43^{\circ}C$ must be applied to obtain the same level of thermal damage,
given by

$CEM=\int_{t=0}^{t=final}{R^{(43-T)}dt},$ (5)

where $R=0.5$ for $T\geq 43^{\circ}$ and $R=0.25$ for $T<43^{\circ}$. This
formula accounts for tissue thermotolerance (e.g. mediated by heat-shock
proteins) which occurs during exposure at mild hyperthermic temperatures.

###  4.4 Spatial-Peak Pulse-Average Intensity

Acoustic intensity is a measure of the flow of energy from one point in an
acoustic medium to another. The instantaneous acoustic intensity is a vector
quantity (it depends on direction) and is given by the product of the acoustic
pressure and acoustic particle velocity. For a plane wave, the pressure and
particle velocity are related by the characteristic acoustic impedance of the
medium (the product of sound speed and density). While plane wave expressions
have only limited validity and cannot generally be applied throughout a
focused acoustic field [7], they are often used to calculate the spatial-peak
intensity in a focused field, where the wave is approximately plane.

Under this assumption, the instantaneous intensity in the direction of the
plane wave can be calculated by

$I_{\mathrm{sp}}(t)=\frac{p_{\mathrm{sp}}(t)^{2}}{Z}.$ (6)

Here, $p_{\mathrm{sp}}(t)$ is the time varying acoustic pressure at the
location of the spatial-peak, and $Z$ is the characteristic acoustic impedance
of the medium, which is approximately $1.5\times 10^{6}$ Rayls for soft
tissue. For a harmonically-varying acoustic wave, assuming that the pulse
duration is an integer multiple of the acoustic period (or otherwise long
compared to the acoustic period), the intensity time-averaged over the pulse
duration (generally called the pulse average intensity) can be calculated
using

$I_{\mathrm{sppa}}=\frac{1}{PD~{}Z}\int_{0}^{PD}{p_{\mathrm{sp}}(t)^{2}dt},$
(7)

which, for long pulses without ramping, reduces to

$I_{\mathrm{sppa}}=\frac{p_{\mathrm{sp}}^{2}}{2Z},$ (8)

where $p_{\mathrm{sp}}$ is the spatial-peak pressure amplitude (the amplitude
of the sinusoidal pressure signal at the location of the spatial-peak). The
$I_{\mathrm{sppa}}$ should be easily derivable by the reader from the
estimated _in situ_ pressure and timing, and is therefore an optional
reporting parameter. If reporting intensity values, the characteristic
acoustic impedance $Z$ used for the calculation must be reported.

###  4.5 Spatial-Peak Time-Average Intensities

The intensity time-averaged over the pulse train or pulse train repetition
interval (generally called the time average intensity) can be calculated by

$I_{\mathrm{spta}}=\frac{1}{T~{}Z}\int_{0}^{T}{p_{\mathrm{sp}}(t)^{2}dt},$ (9)

where $T$ is the time period over which the average is taken. In the case of a
pulse train without ramping, this reduces to

$I_{\mathrm{\text{spta, pulse train}}}=DC_{\text{pulse
train}}\;I_{\mathrm{sppa}}.$ (10)

Intensity parameters are widely reported in TUS studies. However, as mentioned
above, it is important to note that in general, acoustic intensity is a vector
quantity. Thus, intensity values calculated in this manner should always be
reported alongside (not instead of) acoustic pressure values.

The pulse timing parameters used in TUS frequently include intermittent
pulsing, often with different repetition intervals at different pulse levels
(see Sec. 3). This causes ambiguity in the definition of time-averaged
intensity, specifically regarding which time period should be used for
averaging. Clearly, if 5 second pulse trains are administered every hour,
taking the time-average over the latter period does not give a meaningful
quantity.

Ultimately, the maximum continuous length of time where no TUS is administered
included in the $I_{\mathrm{spta}}$ calculation should be determined based on
knowledge of characteristic diffusion times relevant to TUS. However, this is
still a topic of active research, thus a recommendation cannot yet be made.
For standardised reporting, our current recommendation is therefore to report
the time period over which the average is taken. This can be done succinctly
using the pulse level nomenclature introduced in Sec. 3, e.g. $I_{\text{spta,
pulse train}}$ and $I_{\text{spta, pulse train repeat}}$.

###  4.6 Neuromodulation Dose Parameters

For TUS, the precise mechanisms through which ultrasound affects brain
function are only just beginning to be understood. This means it is not yet
possible to define or adopt appropriate dose parameters [28].

##  5 Summary

In this paper, we have suggested a minimal set of reporting guidelines for TUS
parameters. In the supplementary material, we provide more details on how to
obtain free field measurements. We provide some examples of how to estimate
_In Situ_ Parameters. We briefly list other aspects of the TUS experiment that
fall outside of the scope of this paper but are also important in fully
describing a study. We also provide a checklist of parameters to be reported.

## Acknowledgements

EM was supported by a UKRI Future Leaders Fellowship (MR/T019166/1), by the
EIC Pathfinder project CITRUS (Grant Agreement No. 101071008) funded by the EU
Horizon Europe research and innovation programme, and by the Wellcome/EPSRC
Centre for Interventional and Surgical Sciences (WEISS) (203145Z/16/Z). JFA is
supported by the Focused Ultrasound Foundation Center of Excellence program
(Physics for Medicine Paris). L.V. is supported by the Dutch Research Council
(NWO) with a VIDI fellowship (18919). BET was supported in part by the
Engineering and Physical Sciences Research Council (EPSRC), UK, and the EIC
Pathfinder project CITRUS (Grant Agreement No. 101071008) funded by the EU
Horizon Europe research and innovation programme. KBP was funded by NIH R01
NS112152, NIH RF1 MH116977, NIH R01 MH131684.

## Declaration of Interests

EM has acted as a consultant for BrainBox Ltd. JFA holds 5 patents on
transcranial ultrasound and had research support from Insightec within the
last 3 years. MS is a consultant to Brainsonix Corp., co-inventor on several
patents in tFUS, and is a member of the US Technical Advisory Group to the IEC
responsible for diagnostic ultrasound output regulation. BET is a developer of
and holds a financial interest in the commercially available k-Plan treatment
planning software. LV is a member of the scientific board of the Brainbox
Initiative. KBP has acted as a consultant for Attune Neurosciences and has had
research support from MR Instruments and General Electric within the last 3
years.

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## Supplementary Material

##  Appendix A Linearity Assumption

We make the assumption that the ultrasound fields that this guide applies to
are linear. Our rationale for assuming so is that the pressure values
currently under investigation for the vast majority of transcranial ultrasound
stimulation studies are low enough to be in the linear regime.

We note that linearity means that all or almost all of the energy is at the
operating frequency, with minimal energy contained in the harmonics. Energy
transferred to harmonic frequencies during nonlinear propagation of ultrasound
results in an asymmetric pressure waveform, where the peak positive pressure
becomes greater than the peak negative pressure. To verify linearity, the
difference between the two pressure values can be examined . This can (and
should) be checked by examining the frequency spectrum of the measured
pressure waveforms and ensuring that e.g. the amplitude of the second harmonic
is $\lesssim$5% of the amplitude of the fundamental frequency, or the
difference between the peak positive and peak negative pressures is not more
than $\sim 10$%.

In our measurements, for a focused ultrasound transducer with a 64 mm radius
of curvature and 64 mm aperture diameter operating in water at 500 kHz, the
peak positive and negative pressure differ by $>$10% (indicating that the
field is still quasi-linear) only when the pressure amplitude is $>$2 MPa.
This corresponds to a Mechanical Index (MI) of $>$2.5. For the same transducer
operating at 250 kHz, the peak positive and peak negative pressure differ by
$>$10% only when the pressure amplitude is $>$3 MPa, for which the MI is 6.

When the field is linear, the size and position of the focal region for a
given focal setting can be considered to remain constant between output
levels. In addition, this assumption simplifies the calculation of several
derived parameters in Section 4. For avoidance of doubt, throughout the guide,
the term _pressure amplitude_ will be used to describe the amplitude of a
sinusoidally varying pressure signal in steady-state under linear conditions,
where the pressure amplitude is equal to the peak positive and negative
pressures, and half the peak-to-peak pressure (see Fig. 2, Fig. B.1 for
further details).

##  Appendix B Measurement of Free Field Acoustic Pressure Parameters

###  B.1 Guidance on Performing Measurements of Acoustic Pressure

Measurements of acoustic pressure fields are often made using a hydrophone
scanned through the field using an automated scanning tank filled with
deionised and degassed water. Measurement procedures and the choice of
suitable sensors (usually hydrophones) and scanning equipment is specified in
detail in international standards for the measurement of medical ultrasonic
fields [7], with further specific definitions and measurement methods
specifically for focusing transducers specified in [8]. Other sources of
guidance and examples of good practice for hydrophone measurements of acoustic
pressure fields can be found in the literature [9, 11, 10], and may be more
accessible to readers of this document. Important factors to consider in order
to reduce uncertainty in measurement include choice of hydrophone, alignment
procedures, spatial sampling, and signal acquisition and processing.

###  B.2 Choice of Hydrophone

Measurements require a suitable sensor which has adequate sensitivity while
minimising the effects of spatial averaging, is stable over time, and for the
purposes of acquiring absolute pressure measurements, has a calibrated
sensitivity (frequency dependent or at least at the frequency of interest). In
general, the diameter or width of the hydrophone sensitive element should be
less than one quarter of the wavelength of the acoustic field at the frequency
of interest. In practice, at the low frequencies ($<$ 1 MHz) often employed in
TUS, the effective size of the hydrophone sensitive area can be significantly
larger than the nominal size, increasing the effects of spatial averaging. For
example, at 500 kHz, the wavelength of sound in water is $\sim$3 mm, so a
hydrophone element diameter of less than 0.75 mm should be used. A hydrophone
with a nominal element diameter of 0.5 mm may be suitable, although it should
be noted that the effective element size may be significantly larger so it is
strongly advised to choose a smaller element size [11, 29]. If spatial
averaging is unavoidable and likely to be significant, corrections may be
applied to the pressure measurements to compensate [30].

Most commercially available hydrophones can be expected to maintain stable
sensitivity provided they are handled carefully and well maintained (i.e. the
sensitive element should not be touched, they should not be exposed to
pressures above the range of safe operation, they should be rinsed with DI
water after use in tap water or other liquids to avoid build up of deposits on
the element surface), and in most cases a soaking period of at least an hour
should be allowed before measurements are made. Calibrated sensitivity at the
frequency of interest traceable to international pressure standards can
usually be provided by the hydrophone manufacturer, or obtained directly from
a national measurement institute. Calibration at frequencies below 1 MHz may
have to be specifically requested.

###  B.3 Uncertainty on Hydrophone Measurements

All hydrophone calibrations have an uncertainty which varies with frequency,
and calibration method. Hydrophone calibrations obtained from a national
measurement institute (NMI) such as the National Physical Laboratory in the UK
have a typical uncertainty of 9% in the range 250 kHz to 1 MHz. The
uncertainty on hydrophone calibrations obtained from hydrophone manufacturers
is typically approximately double that associated with NMI calibrations, up to
20% or more.

Other sources of systematic uncertainty include spatial averaging, which can
become significant for large hydrophones in focused fields. Random uncertainty
also arises from various sources including positioning, alignment and
electrical fluctuations in amplifiers and source impedance. Despite the
relatively high uncertainties, it has been demonstrated that reproducibility
and repeatability of pressure measurements can be within 10% [11]. It should
also be noted that the uncertainty on pressure measurements will propagate to
derived quantities. As intensity is proportional to the square of pressure,
this results in a doubling of the uncertainty from pressure to intensity.

When comparing multiple pressure measurements of the same field, for example
where sequential measurements are performed at intervals, or measurements are
obtained from different sources, agreement is demonstrated if two measurements
differ by less than the uncertainty on the measurements. Where multiple
measurements agree to within the uncertainty, then an average value can be
reported. If the difference is larger, it may indicate some change in
performance of the device or error in the measurement process.

###  B.4 Signal Parameters and Acquisition

To achieve free field conditions under which the effect of reflections and
interference are suppressed during measurements, the pulse parameters used for
measurement of free field pressure parameters are usually different from those
used during the study itself. The pulse length and timing of the signal
waveform acquisition is chosen so that the measured field represents the field
that would exist if the transducer was radiating into water continuously or
with the comparatively long pulses used in TUS studies [4] . These timing
conditions together with a water bath of sufficient volume or with a suitable
absorbing lining ensures that interference from acoustic reflections is
reduced or eliminated.

These quasi steady state conditions are achieved in a time window which starts
after sound emitted from all parts of the transducer has reached all
measurement locations, with additional time to allow for the ring-up time of
the transducer, and ends before reflections from the measurement equipment
reach the hydrophone (e.g. sound which is reflected from the hydrophone back
to the source and then back to the hydrophone). The pulse duration should be
chosen to be long enough to include some or all of this period and to ensure
that there is a period of the waveform which has a consistent amplitude. The
pulse duration should be short enough to avoid overlap of electrical pick up
from transducer drive voltage with the acquisition window, and reflections
from other parts of the measurement set up. Most transducers have a ring up
time of at least a few cycles at the beginning of the pulse. This is the
length of time it takes for the pulse amplitude to reach a steady value.
Depending on the bandwidth of the transducer, this varies from a few cycles to
10s of cycles. Measurements of pressure amplitude should be made using part of
the waveform which occurs after this period (see Fig. B.1).

Figure B.1: Example focal waveforms measured at the position of spatial-peak
pressure under free field conditions. The region within the red dashed box is
the transducer ring up period before the waveform reaches a steady amplitude.
The region within the green dotted box shows the steady part of the waveform
which should be used to calculate the pressure amplitude, denoted as $p$. The
figure on the left shows a measurement from a transducer with a broad
bandwidth (short ring-up time), and on the right a transducer with a narrow
bandwidth (long ring-up time).

Voltage signals from the hydrophone are usually acquired using an
oscilloscope. The temporal sample rate should be sufficient to accurately
represent the waveforms, with a recommended sample rate of at least 20 times
the ultrasound frequency of interest [31]. The oscilloscope should be
triggered using the trigger output from the drive system. This should provide
a stable acquisition and provide the delay time between emission of the pulse
from the transducer, and arrival of the acoustic signal at the hydrophone.
This can be used to calculate the axial position of the hydrophone relative to
the transducer, given knowledge of the sound speed of water at the measurement
temperature. It is recommended that this axial position calculation is
performed at the focus of the field where the arrival time of the pulse can be
most easily determined.

###  B.5 Alignment and Spatial Sampling

It is recommended that hydrophone measurements of the spatial distribution of
acoustic pressure are performed in deionised and degassed water of known
temperature, using an automated scanning tank with which the hydrophone can be
positioned reproducibly to within 0.05 mm along three orthogonal directions.
Following a rough alignment by eye, the hydrophone should be aligned to the
beam axis by alternately scanning along the two lateral directions through the
centre of the -6 dB focal region until the position of the centre is
consistent to within approximately 100 $\mu$m. Finding the midpoint using the
centre of mass of the -6 dB region rather than the peak value is recommended,
since it is less susceptible to noise and fluctuations.

The transducer may be mounted in a fixed geometry using a mount that ensures
that the beam axis is aligned with the parallel tank scanning axis, this
should be verified. It is recommended that before acquiring pressure profile
measurements, the hydrophone should be aligned to the spatial peak pressure,
to ensure that all line measurements pass through that through the focus.
Where the transducer mount geometry is not fixed and adjustment of the angular
position is possible, the transducer beam axis should be aligned with the
parallel scanning axis. This can be achieved by aligning the hydrophone with
the beam axis at two axial distances to determine any angular offset, and
correcting the angular tilt and rotation of the transducer accordingly.
Alternatively, where scans can be performed along arbitrary directions, the
scan coordinates should follow the beam axis.

Measurements of the field should be made with adequate spatial sampling, of
less than half a wavelength or finer in order to accurately capture spatial
features and peak pressure values. Rather than acquiring point measurements,
it is recommended that orthogonal line scans are acquired along lines which
pass through the location of the spatial-peak pressure. Once the hydrophone is
aligned with the transducer beam axis, an axial line scan should be performed
to identify the axial position of the spatial-peak pressure.

The axial position relative to the transducer can be estimated using the time
of flight of the acoustic signal. However, there may be some error in this
distance where there are e.g. time delays between the trigger signal and
generation of the acoustic output due to the system electronics. Additionally,
where the transducer construction includes lenses or coupling media, the
measurement coordinates are often defined relative to a reference plane which
is not the origin of the acoustic signal. In this case, a physical measurement
of the reference plane to hydrophone distance should be made. This can be done
using e.g. a force sensor, dummy hydrophone, or offset block.

###  B.6 Signal Processing

Hydrophones output a voltage signal which must be converted to pressure using
the known hydrophone sensitivity. Some signal processing steps should be taken
to ensure that errors are not introduced during this conversion. For linear
fields, the peak negative pressure, peak positive pressure and the pressure
amplitude can be expected to be equivalent. Peak negative pressure is usually
given as a quantity linked to mechanical effects. The values can be obtained
by several methods, but it is recommended that a method is chosen which
reduces the impact of noise and fluctuation of the signal amplitude throughout
the acquisition window.

For quasi steady state signals, the pressure amplitude can be acquired by
performing a fast Fourier transform (FFT) on a measured waveform which has
been trimmed to include a whole number of cycles from a steady part of the
waveform, then extracting the magnitude of the FFT at the frequency of
interest. The length (number of samples) in the voltage signal should be large
enough to provide adequate sampling in frequency space so that the amplitude
at the frequency of interest can be obtained. Alternatively, the minimum value
of each cycle from a steady part of the acquired waveform can be obtained and
averaged. The peak negative voltage or voltage amplitude can then be converted
to pressure by dividing by the hydrophone sensitivity at the frequency of
interest given in units of V/Pa, or by deconvolution of the hydrophone
response from the voltage waveform.

###  B.7 Scaling Spatial-Peak Pressure Measurements by Drive Level

The free field spatial-peak pressure amplitude at each of the study output
level settings should be reported. The pressure can be obtained either
directly from a measurement with the transducer operated at the study output
level and focal setting, but in practice, it may be simpler and more practical
to establish a scaling from the measurement output level, or the output level
given in the manufacturer’s test report, to the study output level(s) for a
given focal setting.

While the acoustic pressure field is linear, the output pressure of most
systems is expected to scale linearly with the voltage applied to the
transducer. So for example, focal pressure amplitude should scale linearly
with drive voltage amplitude. Correspondingly, if the output setting used is
power or intensity, since this is proportional to pressure squared, the
spatial-peak pressure should scale linearly with the square root of the power
or intensity setting. It is assumed that at the range of output levels used
for TUS, the location and volume of the focal region will remain constant
provided no changes are made to the focal settings.

The relationship between output level setting and spatial-peak pressure should
be verified if possible by making several measurements of the spatial-peak
pressure at different output level settings for a given focal setting. A line
fitted to the measurement points can then be used to obtain the pressure for
any output level setting later used in studies. Note that if the focal
position setting is changed, a different scaling is needed.

###  B.8 Decibels and Focal Size Quantities

Figure B.2: Axial profiles of normalised pressure amplitude (top) and
corresponding normalised intensity (bottom), showing the -3 dB and -6 dB axial
focal lengths which correspond to different fractional thresholds in pressure
and intensity.

In acoustics, decibels are used to describe the loudness of sound on a
logarithmic scale, as the range of pressure amplitudes in the human audible
range is large, similarly for the range of pressure amplitudes in the
transmitted and received pulses in ultrasound imaging. When used in ultrasound
field characterisation, they are often used to describe a change or difference
in pressure or intensity. These differences in units of decibels [dB] are
calculated from the log to the base 10 of the ratio of the pressure or
intensity at the point of interest, $p$, to the reference pressure or
intensity, $p_{ref}$:

$10\ \log_{10}\left(\frac{I}{I_{ref}}\right)=10\
\log_{10}\left(\frac{p^{2}}{p^{2}_{ref}}\right)=20\
\log_{10}\left(\frac{p}{p_{ref}}\right)\ [dB]$ (11)

In the context of determining focal length and width values, the reference
pressure or intensity is the spatial-peak value. The same focal length value
can be calculated from either the pressure or intensity profiles in terms of
dB, with the appropriate fractional threshold (see Fig. B.2). The full width
half maximum of the intensity profile is the -3 dB region, but in terms of
pressure, this -3 dB region corresponds to the region over which the pressure
exceeds 70% of the maximum value. Note that these quantities are useful for
comparison of fields in water or for looking at focal distortion in situ, for
example, but since they are relative quantities, they do not indicate the
region of potential effect, since this is likely to correspond to an absolute
pressure threshold.

###  B.9 Obtaining Pressure Quantities from Manufacturer’s Report

It is expected that the manufacturer should provide some conversion between
the setting used to control the output level and the spatial-peak pressure for
at least a subset of focal settings. It may not be possible to obtain all
required parameters for all possible focal settings from the manufacturers
report, but all parameters that can be obtained should be reported. For
example, if the position setting refers to the centre of the focal region
rather than the location of the spatial-peak pressure, then it may not be
possible to report both for every focal setting used. The difference between
these positions will vary depending on the transducer parameters and focal
settings, it may be as much as 10 or 20 mm.

##  Appendix C Reporting Average Parameters

In some cases where a study includes a large number of participants, each with
personalised ultrasound parameters, it could be impractical to report the free
field parameters, drive system settings, and estimated _in situ_ exposure
parameters under each condition used. In this situation, it is appropriate to
report the mean, minimum and maximum values.

In the simplest case, the same drive system settings and free field pressure
parameters may be applied for all participants, but individualised _in situ_
exposure parameters obtained from simulations using the participants anatomy.
In this case, it is reasonable to report the mean, minimum and maximum of the
estimated _in situ_ exposure parameters across all participants.

In another the case, the drive system settings may be adjusted with aim of
delivering the same ultrasound pressure to the same brain region across
subjects. In this case, the range of drive system settings used should be
reported. The mean, minimum and maximum of the free field spatial-peak
pressure amplitude and size of the focal volume should be reported, and the
range of the positions of the free field spatial-peak pressure amplitude.

Where an array transducer is used with steering and aberration correction to
obtain the same _in situ_ spatial-peak pressure amplitude across subjects,
free field measurements made under the exact conditions are not relevant and
would be impractical to perform for every condition. In this case,
measurements of the free field pressure parameters should be made at the
geometric focus or central position, and over the steering range employed
during the study. Free field spatial-peak pressure amplitudes and size of the
focal volume measured across the steering range relative to the geometric
focus or central position will illustrate the steering and focusing
performance of the array. The range of drive system settings used should also
be reported. The range of _in situ_ size of the focal volume obtained from
simulations used to perform the aberration correction should be reported,
since these may vary depending on position and skull anatomy.

##  Appendix D Example Estimates of _In Situ_ Parameters

###  D.1 Estimated _In Situ_ Pressure Amplitude

This example adapted from Deffieux 2013 [16] reports attenuation from only
skull in the following way: “ _The pressure amplitude at focus was set to 0.6
MPa, as measured in free water with a heterodyne interferometer. Skull
transmission was estimated on a clean and degassed primate skull specimen
(Macaca mulatta skull) at seven different locations and was found to be 58% ±
8% (derating factor of -4.7 dB). This allowed us to estimate the derated
spatial-peak pressure at 0.35 MPa in the brain of the monkeys._ ”

###  D.2 Estimate of _In Situ_ Mechanical Index

The following example calculation uses values taken from Johnstone et al. [5]:
“ _The $MI$ was 0.44, calculated as follows. The spatial-peak pressure
amplitude measured in water was 700 kPa. Assuming a constant derating factor
of -9.8 dB (the average insertion loss of the skull at 270 kHz measured in
[17]), the derated spatial-peak pressure amplitude was 230 kPa. The operating
frequency was 270 kHz. The $MI_{\text{tc}}$ is then 0.23 / sqrt(0.27) = 0.44._

###  D.3 Thermal Metrics

The following example calculation uses values taken from Johnstone et al. [5]:
“ _The TIC was 0.48, calculated as follows. The electrical power was 4.8 W.
Assuming a nominal electrical efficiency of 85%, this gives an acoustic power
of 4.1 W. The minimum pulse train repetition interval was 5 seconds, giving an
overall duty cycle of 3% (150 ms on every 5 s). This gives a time-averaged
power of 0.12 W. The nominal aperture diameter was 64 mm. The TIC is then
(1000 * 4.8 * 0.85 * 0.03) / (40 * 6.4) = 0.48 ._ ”

##  Appendix E Additional Experimental Reporting

There are many other aspects to the TUS experiment that critically impact the
experiment and should be reported. Due to the large number of different
measurement conditions, equipment, and experimental setups, it is not possible
to be prescriptive about how these should be reported. Here, we briefly list
other aspects of the TUS experiment that fall outside of the scope of this
paper but are also important in fully describing a study.

  * •

Hair preparation

  * •

Subject positioning (e.g., sitting or lying) and fixation (e.g., chin rest)

  * •

Transducer alignment and fixation

  * •

Neuronavigation equipment and procedure

  * •

Auditory perception

  * •

Masking and earplugs

  * •

Sham conditions and blinding

  * •

Environmental conditions (e.g., background noise and light levels)

  * •

Additional measurement equipment

  * •

Subject experience, side effects, and adverse events

  * •

Any safety and electromagnetic compatibility tests performed

##  Appendix F Checklist

Report these parameters for all devices and settings used. Further details for
each parameter are given in the referenced section.

### Transducer and Drive System Description

  * $\square$

Transducer manufacturer and model number (Sec. 2.1.1)

  * $\square$

Transducer centre frequency (Sec. 2.1.1)

  * $\square$

Transducer geometry (e.g., radius of curvature and aperture diameter) (Sec.
2.1.1)

  * $\square$

Drive system components, including manufacturer and model number (e.g., signal
generator and amplifier or integrated driving system) (Sec. 2.1.2)

### Drive System Settings (Sec. 2.1.3)

  * $\square$

Operating frequency

  * $\square$

Output level settings

  * $\square$

Focal position settings

  * $\square$

Description of transducer coupling method

### Free Field Acoustic Parameters (Sec. 2.2.1)

  * $\square$

Reference position for measurements

  * $\square$

Spatial-peak pressure amplitude

  * $\square$

Position of spatial-peak pressure amplitude (relative to reference position)

  * $\square$

Size of focal volume (-3 dB and -6 dB axial lengths and lateral widths)

  * $\square$

Position of centre of focal volume (centre of -3 dB relative to reference
position)

  * $\square$

Description of how free field parameters were obtained

### Pulse Timing Parameters (Sec. 3)

  * $\square$

Pulse timing table

###  _In Situ_ Estimates of Exposure Parameters

  * $\square$

Estimated _in situ_ spatial-peak pressure amplitude (Sec. 4.1)

  * $\square$

Estimated _in situ_ pressure amplitude at the target (Sec. 4.1)

  * $\square$

Estimated _in situ_ mechanical index (Sec. 4.2)

  * $\square$

One of the following thermal metrics: temperature rise, thermal index, or
thermal dose (Sec. 4.3)

  * $\square$

Description of how _in situ_ estimates were obtained (Sec. 4.1)

### Intensity Parameters (Optional)

  * $\square$

Spatial-peak pulse-average intensity (Sec. 4.4)

  * $\square$

Spatial-peak time-average intensities (Sec. 4.5)

  * $\square$

The acoustic impedance used for the conversion (Sec. 4.4)