Ultrasonic Deep Brain Stimulation During Anesthetic Sedation
Phase: PHASE2
Conditions: Mental Function
Sponsor: University of Michigan

Ultrasonic Deep Brain Stimulation During 
Anesthetic Sedation 
 
NCT05495945 
 
Date of IRB Approval: August 22, 2023 
 
 

Ultrasonic Deep Brain Stimulation during Anesthetic Sedation 
Dr. Zirui Huang and Dr. Anthony G. Hudetz 
General Goal 
The goal of this study is to understand the neural basis of human consciousness and its 
modulation by anesthetic agents supported by Departmental Research Funds. The fundamental 
question is how the state and contents of consciousness are intertwined in the brain. As previously 
defined [1], state distinguishes the conditions or levels of being aware of anything at all from that 
being completely oblivious such as in general anesthesia or coma. Contents of consciousness 
refers to what one is aware of at a particular moment vs. what is outside of immediate awareness. 
Our central hypothesis is that state and contents are linked by a cooperation between the anterior 
forebrain mesocircuit and macroscale cortical networks, and that this cooperation is controlled by 
a few key brain areas (Fig. 1). To investigate, we will combine pharmacologic, psychologic and 
noninvasive brain stimulation approaches. We will alter the state of consciousness by propofol in 
healthy volunteers, and assess the contents of consciousness by applying a near-threshold 
perceptual task with Signal Detection Theory (SDT) metrics. Task-related brain activity will be 
assessed by simultaneous fMRI. We will also apply transcranial low-intensity focused ultrasound 
pulsation (LIFUP) to stimulate specific brain regions and assess their causal involvement in the 
control of conscious state and contents. From a basic science perspective, this work will help 
understand the neural basis of consciousness, which is one of the most fundamental unsolved 
problems of neuroscience. From a clinical perspective, the work will facilitate better understanding 
of the neural mechanism of the anesthetics’ sedative-hypnotic effects, which is a prerequisite for 
future enhancements of clinical anesthesiology. 
 
Fig. 1. Schematic illustration of the central hypothesis. The state and contents of consciousness are linked 
by a cooperation between the anterior forebrain mesocircuit and the macroscale cortical networks, 
controlled by a few key brain areas. The central thalamus (CT) controls the state of consciousness. The 
anterior insula cortex (AIC) gates conscious contents and regulates brain network switches between dorsal 
attention (associated with external awareness) and default mode (associated with internal awareness) 

networks. The dorsolateral prefrontal cortex (DLPFC) within the lateral frontoparietal network has a flexible 
cooperation with the dorsal attention and default mode networks, and it initiates brain-wide global 
broadcasting of contents that leads to reportable conscious experience known as access consciousness. 
Macroscale brain networks unfold along a hierarchical cortical organization from unimodal to transmodal 
regions. The CT, AIC and DLPFC are target areas with LIFUP. Abbreviations: medial prefrontal cortex 
(MPFC), posterior cingulate cortex (PCC), posterior parietal cortex (PPC), frontal eye field (FEF), superior 
parietal lobe (SPL), anterior cingulate cortex (ACC). 
Rationale and Hypothesis 
Investigations into the state and contents of consciousness have traditionally progressed 
independently. However, we previously proposed that the state and contents of consciousness 
are fundamentally linked, and they can be neither studied nor understood in isolation from each 
other [2]. Thus, a gap of knowledge exists, mainly due to the lack of systematic investigations into 
both aspects of consciousness with the same experimental setup. The research proposed here 
is designed to overcome this gap by discovering the neural linkages between state and contents 
of consciousness. Our general hypothesis is that the relationship between state and contents of 
consciousness rests on the functional interaction of brain systems between meso- and 
macroscales. At mesoscale, the “anterior forebrain mesocircuit” hypothesis [3–5] encapsulates 
the role of central thalamic (CT) neurons and their frontostriatal connections in determining the 
state of consciousness. The mesocircuit also incorporates acceding projections from brainstem 
arousal nuclei and cooperates with the frontoparietal cortical network to generate conscious 
experience [5]. At macroscale, the contents of consciousness are thought to be determined 
through a hierarchical cortical organization along a cortical gradient from unimodal to transmodal 
areas [6]. Prior studies suggest the involvement of specific brain regions; particularly that of the 
AIC which gates conscious access of sensory information [7] by controlling the balance of activity 
between the default-mode and dorsal attention networks that correspond to internal and external 
awareness, respectively [8,9]. In addition, the DLPFC is thought to initiate brain-wide global 
broadcasting of contents to generate reportable conscious experience known as access 
consciousness [10–12]. 
In this study, we aim to determine how conscious contents are degraded during anesthetic 
modification of the conscious state, and to disentangle the causal roles of specific brain areas in 
state-content interaction through a perturbational approach. We hypothesize that suppressing the 
state of consciousness will diminish the quality of conscious contents and that this will be 
associated with functional alterations in three key brain areas: CT, AIC and DLPFC. We also 
hypothesize that stimulating the three areas will lead to differential perceptual outcomes (e.g., a 
change in subjective perceptual criterion alone, detection sensitivity alone, or both). 
To test the hypotheses, we will (1) administer propofol to reduce the state of consciousness 
(moderate sedation), (2) perform near-threshold perceptual task to assess the contents of 
consciousness, (3) apply transcranial low-intensity focused ultrasound pulsation (LIFUP) to 
noninvasively stimulate the CT, AIC and DLPFC, and (4) perform functional magnetic resonance 
imaging (fMRI) to measure the related brain process during baseline, sedation, and 
sedation+LIFUP. We will measure the quality of conscious contents by two orthogonal quantities, 
criterion (c) and sensitivity (d’) derived from the Signal Detection Theory. Here c captures the 
tendency of a subject to report subjective recognition of a target stimulus regardless of whether 
the target is present or absent, whereas d’ captures the ability of a subject to distinguish between 
target present and absent trials.  
We anticipate that suppressing the conscious state will decrease both c and d’, indicating more 
conservative responses and reduced stimulus differentiation, while c and d’ are differentially 
affected by the activity of DLPFC and AIC. Furthermore, neither c nor d’ alone but their product 
will be associated with the activity of the CT, thus implying a putative mechanism for state-content 

relationship by the functional interaction of brain areas CT for controlling state, and AIC and 
DLPFC for gating and broadcasting, respectively, the conscious contents. We also anticipate that 
stimulating the DLPFC and AIC will differentially change c and d’. Stimulating the CT will positively 
shift c and substantially increase d’, thereby restoring perceptual performance to the awake 
baseline level. This will be associated with an increase of task-related activity in the DLPFC and 
AIC. If so, this would disentangle the causal roles of CT, AIC and DLPFC on perceptual outcomes. 
Number of Subjects, Recruitment and Informed Consent 
Statistical power analysis (see below) requires a group of 25 subjects. We plan to enroll 100 
evaluable subjects randomly assign into four groups; we intend to enroll 150 subjects to account 
for unevaluable participants. See experimental design details below. Healthy participants will be 
recruited by listing on UMClinicalStudies.org and by postings at area colleges and community 
groups in Ann Arbor. Interested volunteers will call the phone number of a designated recruiter 
for an initial phone screening. The initial phone screening will consist of questionnaires related to 
medical history, demographic information, handedness, inclusion and exclusion criteria and 
procedure standard MRI screening questionnaire. If interested, the participant will complete the 
questionnaires, which will be reviewed by the study team. The health status will be confirmed by 
the attending anesthesiologist before the study on site. Once eligibility is confirmed by the study 
team, the one-time research study session will be scheduled.  Participants will screened for 
COVID-19 prior to entry into the hospital per hospital guidelines. A standard face mask will be 
provided upon hospital entry if participants do not have one. 
All participants will give written informed consent according to institutional guidelines prior to any 
testing. The Principal Investigators or their designee will obtain consent using a written consent 
form approved by the Institutional Review Boards of the University of Michigan Medical School 
(IRBMED). It will contain detailed information regarding the purpose, risks and benefits of 
participating. Copies of the signed consent form will be given to the subjects; the original consent 
will remain with the study team. Subjects will be compensated for their involvement.  
Inclusion and Exclusion Criteria 
Volunteers are screened using a medical history and demographics questionnaire.  
Inclusion criteria. The subject population will consist of healthy study subjects with ASA-1 status. 
The participants’ health status will be assessed by the attending anesthesiologist prior to inclusion 
in the study. The participants will be right-handed adults between the ages of 18 and 40 with a 
body mass index (BMI) less than 30. All subjects will be English speakers.  
Exclusion criteria. Participants will be excluded if they have any medical contraindication to MRI 
scanning; are unable to undergo MRI scanning because of possible pregnancy or currently 
breastfeeding, BMI>30, metallic substances in the body, claustrophobia, anxiety, or 
cardiopulmonary disease; or have an intracranial structural abnormality on T1-weighted MRI 
scans. Potential subjects will be excluded if they have a history of allergy to propofol, eggs or egg 
products, soybean or soybean products, neurological, cardiovascular, or pulmonary illness; 
significant head injury with loss of consciousness; learning disability or other developmental 
disorder; sleep apnea or any severe snoring history; gastroesophageal reflux disease (GERD) or 
heartburn; pancreatitis or a history of pancreatitis, or sensory/motor loss sufficient to interfere with 
performance of the study. Participants with tattoos in the head or neck region will be excluded 
from study; other tattoos are subject to determination by investigators based on their assessment 
regarding participant safety. To eliminate aspiration risk subjects will also be excluded if they have 
had recent food or liquid intake (within 8 hours). Subjects will be excluded if they have a history 
of drug use, have a positive drug screen, are unwilling to abstain from alcohol for 24 hours prior 
to dosing, or have a current history of nicotine use. Women will be required to take a pregnancy 

test prior to participation to ensure a negative result. The pre-scan drug screen and pregnancy 
test will be paid for by the study. 
 
Participants will be compensated $200 for completing the one-time fMRI scanning visit.  
Participants who have shaved or no hair, or those willing to shave the left side of their temple will 
be compensated an additional $75. 
 
Methods and Procedures 
Imaging 
Noninvasive functional magnetic resonance imaging will be performed in the Philips 3T (MR2) 
Research MRI (standard 32-channel transmit/receive head coil) at the University of Michigan 
Health System, University Hospital, Department of Radiology.  
 1) SPGR high-resolution images. T1 weighted spoiled gradient recalled echo (SPGR) images 
will be acquired for high spatial resolution of anatomical images with parameters: 170 sagittal 
slices, 1.0mm thickness (no gap), TR=8.1s, TE=3.7ms, flip angle=8o, FOV=24cm, image matrix 
256×256. 
 2) Functional MRI images. A gradient-echo EPI pulse sequence will be employed to acquire 
functional images over the whole brain with parameters: 28 slices, TR/TE=800/25ms (multiband 
fMRI acquisition), slice thickness=4mm, in-plane resolution=3.4×3.4mm; MB factor=4; field of 
view (FOV)=220mm, flip angle=76°, image matrix: 64×64. The imaging protocols and data 
acquisition will be completed within 2.5 hours scanning session for each subject.  
Anesthesia 
Anesthetic agents. In both experiments, propofol will be applied because it has been the most 
widely-used agent in human fMRI studies of anesthetic effects in brain activity [13–16] and we 
have considerable experience in this field [7,17–21]. The advantage of propofol is that it exerts 
minimal effects on cerebral and systemic hemodynamics [22,23] and therefore does not confound 
the fMRI results. Propofol suppresses neuronal activity mainly through an enhancement of GABA-
A receptor-mediated inhibition thus modulating widespread targets across the brain. 
Anesthetic administration and monitoring. Both experiments will be performed by the 
attending anesthesiologists. Sedation will be achieved by target-controlled IV infusion of propofol. 
The IV line will be placed after application of a local anesthetic. Nasal cannula will be used for 
supplemental O2 and CO2 sampling. Spontaneous respiration, end-tidal CO2, heart rate, and 
electrocardiogram will be continuously monitored during the experiment. Noninvasive arterial 
pressure will be measured with magnetic resonance (MR)-compatible automatic monitor. Post 
anesthesia care will consist of checking vital signs for 1 hour by the nursing staff. A wheelchair 
will be provided to assist the participant if needed. All anesthesia equipment, supplies, and drugs 
will be provided by anesthesiologists from the University of Michigan Health System. 
LIFUP Method 
We 
will 
utilize 
the 
BrainSonix 
BXPulsar 
1002 
LIFUP 
System 
(BrainSonix 
Inc. 
http://www.brainsonix.com/). FDA has determined that our proposed clinical investigation is a 
nonsignificant risk (NSR) device study because it does not meet the definition of a significant risk 
(SR) device under 21 CFR 812.3(m) of the investigational device exemptions (IDE) regulation (21 
CFR 812). An IDE application is not required to be submitted to, or approved by, FDA for a NSR 
study. This device contains a single-element, air-backed, spherical section ultrasound transducer 
with 61 mm diameter and 80 mm focal depth. The transducer is mounted in a plastic housing filled 

with deionized, de-gassed water and sealed with a thin polyethylene membrane permeable to 
ultrasound. The transducer will be coupled to the scalp of the participant using a 3D-printed 
transducer holder that allows for sonication to occur in conjunction with ultrasonic standoff pads 
and ultrasound gel. The LIFUP system operates at a fundamental frequency of 650 kHz. Following 
the previous work [24,25], we plan to administer a pulse repetition frequency of 100 Hz and pulse 
width of 0.5 ms. A total of 30 sonications will be administered, with a derated spatial-peak 
temporal-average intensity (Ispta) of 720 mW/cm2, each lasting 30 s, separated by 30 s pause 
intervals. Sonication will be administered in a 3 Tesla Philips scanner at University of Michigan 
Hospital. Using a rapid structural MRI sequence, the perpendicular will be adjusted along the 
apex of the transducer’s concavity directly targeting a region of interest. We will utilize a 
neuronavigation system (Brainsight Navigation system, Brainbox Ltd, https://brainbox-
neuro.com/products/brainsight-tms-navigation) to ensure precise targeting and positioning of the 
transducer. At the target location, the estimated peak pressure will be 0.71 MPa, and the 
ultrasound beam width will be 5 mm. The estimated targeting accuracy (uncertainty) at the desired 
location is ±2.5 mm.  
Experimental Design 
Three 30-min sessions will be conducted including wakeful baseline, moderate sedation, and the 
application of LIFUP under moderate sedation (sedation+LIFUP) with an effect-site 
concentrations of 1.5 μg/ml (Fig. 2). Moderate sedation will be achieved by IV infusion of propofol 
to achieve effect-site concentrations of 1.5 μg/ml. Infusion rate will be manually controlled. An 
initial bolus dose and subsequent infusion rate for each participant will be pre-determined based 
on a pharmacokinetic model [26] developed for target-controlled propofol infusion and 
implemented in software (STANPUMP [27]). A 5-min equilibration period between baseline and 
moderate sedation will be included. After sedation+LIFUP session, the infusion will be terminated 
allowing for spontaneous recovery of consciousness. A random group assignment will be applied 
in four groups of participants receiving LIFUP with sham control, or in the DLPFC, AIC, or CT, 
respectively. 
 
Fig. 2. Concept, design and anticipated outcomes. In the hypothetical brain process (top left) visual 

information propagates through ventral (V1/V2-->VOTC) and dorsal (V1/V2-->MTG-->PPC) pathways. The 
AIC receives inputs from the VOTC and prioritizes the inputs before sending them to the DLPFC for global 
broadcasting. The activities of DLPFC and AIC are hypothetically associated with two orthogonal SDT 
quantities, criterion (c) and sensitivity (d’). Given the wiring of the mesocircuit and thalamocortical loops 
(e.g., DLPFC-CT, and AIC-CT), the CT is hypothetically associated with the product of c and d’. 
Experimental design (bottom left) includes three fMRI sessions: wakeful baseline, moderate sedation, and 
LIFUP under moderate sedation. Participants will be assigned at random to four groups: those receiving 
LIFUP to DLPFC, AIC, CT or sham control. Anticipated effects are illustrated (right). Abbreviations: early 
visual cortex (V1/V2), ventral occipitotemporal cortex (VOTC), middle temporal gyrus (MTG), posterior 
parietal cortex (PCC). 
Visual task. Participants will be asked to lay in the scanner, pay attention on the screen, and 
complete an image recognition task. All stimuli will be programmed using E-Prime (Psychology 
Software Tools, Pittsburgh, PA) and delivered via a visual presentation system designed for an 
MRI environment. Stimuli will be presented at the threshold of subjective recognition. An adaptive 
thresholding procedure will be conducted whereby image contrast will be titrated to reach a 50% 
subjective recognition rate for each subject. Stimuli will include two common visual object 
categories: faces and houses. Participants’ task is to report the category (“F” or “H”) of an image 
presented and their recognition experience (“Yes” or “No”) (Fig. 3). Specifically, they will be 
instructed to report the object category regardless of their recognition experience and, in cases 
of unrecognized images, to make a genuine guess (two-alternative choice discrimination). Then, 
they will be instructed to report whether they see an object, such that even if the object appears 
unclear or noisy, they should respond “yes”, but if they see nothing or only low-level features, 
such as cloud-like abstract patterns, they should respond “no”.  
 
Fig. 3. Visual task design. During each 30-min session, participants will complete an image recognition 
task. Stimuli (faces, houses, and scrambled images) will be presented at the threshold of subjective 
recognition. Participants’ task is to report the category (“F” or “H”) of the image presented and their 
recognition experience (“Yes” or “No”). 
The stimulus set will include real and scrambled images, where the scrambled images will be 
created by phase-shuffling a randomly chosen real image from each category to preserve 
category specific low-level image features [28]. Because scrambled images do not include an 
object stimulus, they are used as “catch trials” to determine the subjects’ baseline tendency to 
give positive responses to a question about their recognition experience. Each object category 
will include four unique real images and one scrambled image. Each image will be repeated 10 
times (i.e., trials) for each 30-min session. The pre-stimulus interval will vary randomly from trial 
to trial between 4 and 8 seconds to prevent stimulus timing predictability. The stimuli will be 
presented in a randomized order to prevent category predictability. 

Primary Outcome Measure:  Blood Oxygen Level Dependent (BOLD) response to visual stimuli 
(timeframe: baseline to 90 minutes). 
Secondary Outcome Measure: Perceptual criterion (c) and sensitivity (d’) derived from the 
Signal Detection Theory (SDT) (timeframe: baseline to 90 minutes). 
Data Analysis and Statistics 
For each 30-min session, we will calculate SDT metrics of sensitivity (d’) and criterion (c) using 
subjective reports of recognition as “yes” or ”no”. The d’ indicates the ability to discriminate 
between real and scrambled images. It is computed by subtracting the z-transformed False 
Alarms Rate (FAR) from the z-transformed Hit Rate (HR): d’ = Z(HR) - Z(FAR)), where Z is an 
inverse normal cumulative distribution function. The c represents the tendency to make “yes” 
reports to indicate recognition, regardless of whether the stimulus is a real or a scrambled image, 
which is computed as: c = 0.5 x (Z(HR)+Z(FAR)). We will also calculate percent of correct 
responses as an operational measure of two alternative-forced-choice sensitivity using subjective 
category reports, i.e., responses to the first question: “Face” or “House”. 
For fMRI data, preprocessing steps will be implemented in AFNI (http://afni.nimh.nih.gov/afni). 1) 
Slice timing correction; 2) Rigid head motion correction/realignment within and across runs; 
frame-wise displacement (FD) of head motion was calculated using frame-wise Euclidean Norm 
(square root of the sum squares) of the six-dimension motion derivatives. A frame and its each 
previous frame will be tagged as zeros (ones, otherwise) if the given frame’s derivative value has 
a Euclidean Norm above FD=0.5 mm; 3) Coregistration with high-resolution anatomical images; 
4) Spatial normalization into Talairach stereotactic space and resampling to 3 × 3 × 3 mm3; 5) 
using AFNI’s function 3dTproject, the time-censored data will be high-pass filtered above 0.008 
Hz. Undesired components (e.g., physiological estimates, motion parameters) will be removed 
via linear regression. The latter include linear and nonlinear drift, time series of head motion, its 
temporal derivative, and mean time series from the white matter and cerebrospinal fluid; 6) Spatial 
smoothing with 6 mm full-width at half-maximum isotropic Gaussian kernel; 7) The time-course 
per voxel of each run will be normalized to zero mean and unit variance, accounting for differences 
in variance of non-neural origin (e.g., distance from head coil).  
We will calculate the average BOLD activity (across the trials with real images) in the regions of 
interest including the CT, AIC, and DLPFC. For a given measurement, repeated-measures 
ANOVA plus post-hoc tests will be performed at the group level. Inter-subject multivariate linear 
regression analyses will be performed with SDT metrics as dependent variables and average 
BOLD activity as independent variables. Statistical significance will be defined at FDR-corrected 
α < 0.05. 
Anticipated Results and Interpretation 
We expect to observe a decrease of both c and d’ during sedation, indicating more conservative 
responses and reduced stimulus differentiation. This would suggest that suppressing the state of 
consciousness diminishes the quality of conscious content. We also expect to find an overall 
reduction of average BOLD activity across all examined regions, i.e., in CT (state control), AIC 
(content gating) and DLPFC (content broadcasting). Furthermore, the change of c (baseline vs. 
sedation) may be associated with the change of DLPFC's average BOLD activity, and the change 
of d’ may be associated with the change of AIC’s average BOLD activity. The change of c × d’ 
may be associated with the change of CT’s average BOLD activity. Because the activity of CT 
supervenes on the activity of DLPFC and AIC, the state (CT) and contents (DLPFC/AIC) are 
altered together in sedation. If found, the results would suggest a neural mechanism for the 
linkage between state and contents. We also anticipate that the LIFUP stimulation in DLPFC 
during sedation will increase c without changing d’ and increase the average BOLD activity in the 

DLPFC. Stimulation of the AIC will increase d’ without changing c, possibly through an 
enhancement of salience/attentional process offsetting the general inhibitory effect of propofol. 
Importantly, stimulation of the CT is expected to substantially increase both d’ and c, arguably 
restoring perceptual performance to baseline level. This may be accompanied by an overall 
increase of average BOLD activity along the entire visual processing pathway. 
Power Analysis 
For an fMRI study of cognitive function, Desmond and Glover [29] reported that about 25 subjects 
are necessary to achieve 80% power for a 0.5% increase of activity. We also conducted power 
analysis based on our previous study with graded sedation of propofol [30]. The average Cohen’s 
d as a measure of the effect size was 0.56. For 80% power and α=0.05, N=24 human subjects 
will be needed. The obtained subject number is also very close to the suggested optimal group 
size for reliable statistics in functional MRI studies [31]. We plan for a minimum of 25 subjects per 
group. 
Biological Variables 
We will recruit participants of both sexes with various ethnic/racial backgrounds, aiming for 
diversity and equal representation. The age range will be limited to 18-40 years in order to limit 
age-dependent variation in anesthetic requirement for sedation and for participant safety. 
Human Studies and Safety Profile related to LIFUP 
The first human application of the LIFUP technique targeted the primary somatosensory cortex of 
healthy volunteers in a sham-controlled study [32]. Subsequently, low-intensity ultrasonic 
thalamic stimulation was successfully applied to facilitate the emergence of a patient from 
minimally conscious state after acute brain injury [25]. This was followed up by the recent report 
on the same subject [24] and ongoing clinical trial for thalamic low-intensity focused ultrasound 
modulation 
of 
consciousness 
following 
in 
brain 
injury 
(Nct02522429; 
https://clinicaltrials.gov/ct2/show/NCT02522429). 
LIFUP has important advantages over formerly applied interventions that makes it a highly 
promising clinical tool. Compared to existing magnetic or electric noninvasive brain stimulation, 
LIFUP provides superior spatial resolution on the millimeter scale as well as the capability to target 
sub-cortical structures non-invasively. Because of LIFUP’ high spatial resolution and ability to 
stimulate at depth, it is also of particular interest to pair with concurrent magnetic resonance 
imaging (MRI) that helps both precise targeting and readout of the stimulation effects. 
The biophysical mechanism of LIFUP is not fully understood; several mechanisms including 
mechanically induced changes in membrane capacitance, cavitation events, and mechanical 
sensitivity of voltage-gated ion channels [33,34] have been proposed. Currently, the ion channel 
modulation theory seems to be most plausible [33,35]. Although a few studies reported inhibitory 
effects of LIFUP on visual-evoked potentials in animals [36,37] and somatosensory-evoked 
potentials in humans [32], the majority of LIFUP studies have reported motor or sensory effects 
consistent with neural excitation (a recent review by [38]). 
The application of LIFUP over 0.5–5 min has been shown to produce persistent neuromodulatory 
effects, lasting from a few minutes to several hours. For example, excitation-like effects and 
changes in functional connectivity lasting for over an hour were reported in nonhuman primates 
and human subjects. Stimulation of the amygdala and supplementary motor area in nonhuman 
primates affected circuit connectivity, resulting in a change in coupling of fMRI activity between 
the LIFUP target and other brain areas [39,40]. LIFUP stimulation of the frontal eye field of 
macaques for 100 ms immediately before a visual cue shifted the bias of a choice task in favor of 

the corresponding contralateral side [41]. The forgoing evidence supports the feasibility and 
potential effectiveness of LIFUP to modulate circuitry of interest. 
LIFUP has been shown to be a safe and effective method to modulate human brain activity, when 
the stimulation parameters and protocol follow the available guidelines [38,42,43]. The majority 
of studies with ultrasound have reported no adverse events or evidence of anatomical damage 
[32,44–47]. Mild and moderate symptoms were reported such as neck pain, sleepiness, muscle 
twitches, itchiness, and headache [48,49]. An in-depth survey of the safety of ultrasound for 
human neuromodulation did not find any evidence of serious events in a large cohort of 
participants [50]. Specifically, 64/120 participants (53%) responded to follow-up questionnaire, 
and none of them experienced serious adverse effects. 7/64 reported mild to moderate symptoms 
(e.g., neck pain, problems with attention, muscle twitches and anxiety), that were perceived as 
‘possibly’ or ‘probably’ related to participation in LIFUP experiments. The most common unrelated 
symptoms included sleepiness and neck pain. There were initial transient reports of mild neck 
pain, scalp tingling and headache that were extinguished upon follow-up. No new symptoms were 
reported upon follow up out to 1 month [50]. In addition, no studies have shown LIFUP induced 
tissue damage in the absence of heating, unless they utilized contrast agents to enhance 
cavitation effects [34]. Finally, the LIFUP appears to be safe even at intensities several times 
higher than the FDA limit for diagnostic ultrasound (720 mW/cm2) [51]. 
Potential Risks related to MRI Scanning 
There are no known risks associated with magnetic resonance imaging, as long as technical 
parameters remain within FDA guidelines. A licensed MR technologist is instructed in these 
guidelines and performs all machine manipulations. Complete histories, physical examinations 
and stringent medical guidelines exclude many potential subjects before they enter the study, 
thereby further minimizing risks. A crash cart is always present and regular safety drills are 
performed by the medical and experimental staff to prepare for any untoward effects. 
MRI Static Magnetic Fields: FDA guidelines for clinical product scanners limit the main magnetic 
field to 3 Tesla. Our studies will be performed on a standard, clinical 3 T Philips scanner. A 
substantial body of literature exits that supports the safety of field strengths up to 7 T. There are 
no known risks of exposure to 3 or 7 T fields for MR imaging. 
Among the reported biological effects of exposure to strong static magnetic fields are the 
following: 1) Dizziness (with nausea) or stimulation of the sensory nerves in the soft palate has 
been reported as a result of the subject’s head being moved while in the magnet. 2) Rapid eye 
movement has been reported (at 4 and 7 T) to cause magnetophosphene effects. First described 
in 1896, these flickering light sensations are similar to visual phenomena caused by direct electric 
current passage across the head or retina. 
Radiofrequency (rf) Magnetic Fields: Radiofrequency energy burns are the result of high electric 
fluxes in the immediate vicinity of the patient. All MRI systems create some rf electric fields 
incidental to the production of the intended rf magnetic fields. The potential causes are 
malfunctions in the rf coil switching circuitry, improper use of the surface coils, design flaws in 
some clinical MRI system surface coils or cardiac gating patient connection leads. Nationally, 60 
burn incidents have been reported to the FDA in the course of approximately 11 million exams. 
Our site has never experienced any difficulty in this regard. 
Acoustic Noise: The sound generated by an MR system usually consists of a series of repetitive 
pulses. The relevant safety parameters required to characterize such a noise are the peak 
impulse sound pressure level (Lpeak) and the time integral of the A-weighted sound pressure 
level (Leq). In MR applications, the peak impulse sound pressure level is dependent upon the 
peak amplitude of the individual pulses, while the time integral of the A-weighted sound pressure 

level is dependent upon the continuous exposure to a series of such pulses. Acoustic noise is a 
result of the mechanical vibration produced by the gradient coils when the nominally large currents 
are applied to them to create time varying imaging gradient fields. The sound produced can be 
loud enough to produce temporary deafness (up to 95 dB). Foam earplugs will attenuate this 
noise by up to 30 dB. They are in routine use at the 3T systems, and have been proven effective. 
Claustrophobia: While inside the magnet, subjects may experience an acute panic attack due to 
claustrophobia. Subjects are all prescreened for fear of tight places. Once inside the magnet, the 
subject will be given a squeeze ball to signal the MR operator if he or she is under acute distress. 
Potential Risks related to Anesthesia 
Risks associated with intravenous catheter placement include brief, local discomfort and possible 
bruising, which can occur at the site of the IV line. There is also a possible (rare) chance of 
infection, but every precaution will be taken to reduce this risk by keeping the IV site clean and 
dry. Risks associated with propofol administration include: pain at the site of injection, possible 
allergic reaction to the drug, depression of respiration which may necessitate placement of an 
endotracheal tube to assist breathing, and mechanical ventilation, or a decrease in blood pressure 
which may necessitate giving a drug or IV fluids to bring the subject's blood pressure up. These 
effects disappear when propofol is discontinued. 
Justification for the Risks Involved 
The risks of the proposed procedure are minimal, and the importance to mankind of the potential 
knowledge gains is substantial, making the risk/benefit ratio very low. We combine the state-of-
the-art brain imaging facility currently in place in the University of Michigan Health System with 
the experience of the imaging staff and clinic anesthesiologists in the Department of 
Anesthesiology. These experiments will provide a unique opportunity to understand the 
neurophysiological mechanisms of anesthesia modulation of human consciousness. Therefore, 
we will provide a unique opportunity to expand our knowledge of anesthesia-modulated human 
consciousness.  
Procedures for Minimizing Risks 
All research subjects will go through a screening process for inclusion and exclusion criteria 
performed by licensed physician. A licensed physician will be present at all MRI scanning 
sessions to monitor the subjects. When subjects express or exhibit anxiety regarding the scanner 
setting, they will be allowed to discuss these feelings. Attempts will be made to minimize the 
discomfort and anxiety. When in the scanner, subjects will be provided with a squeeze-ball alarm 
that will alert the scanner technician and the researcher that the subject desires to come out of 
the scanner. In such instances, the subject will immediately be removed from the scanner and 
appropriate measures will be taken to ensure his or her psychological health. Earplugs, 
demonstrated to reduce scanner noise to a non-damaging level, will be used to minimize hearing 
risks.  
In addition, any other health problem that would be aggravated by an MRI scan will also be a 
cause for terminating the subject’s participation. In the event of serious cardiac-respiratory 
problems or other medical emergencies, the hospital code team will be activated. Other medical 
problems will be treated by the monitoring physician. Any medical problems that arise after 
release, although unlikely, will be treated by a physician from the research team. All subjects will 
have to arrange transportation after the study, and agree to not drive, work, operate machinery, 
or make legal decisions for 24 hours after the study. Subjects will be informed of their right to 
withdraw from the study at any time. 

A protocol has been established to handle unexpected medical emergencies arising in the 
scanner suite. This protocol deals with medical issues and the duties of each team member. This 
includes stopping the scanner, removing the patient and calling for outside medical assistance. 
All members of the research team participate in periodic emergency protocol drills in the scanner 
suite and a copy of the written protocol and protocol termination guidelines are present at all 
times. Subjects requiring intervention for any neurological or cardiovascular adverse event will be 
transferred to the Emergency Department for further evaluation and treatment as seen fit by the 
attending physician. More serious cardiac events such as ventricular tachycardia, ventricular 
fibrillation or any unstable rhythm will be immediately treated according to current Advanced 
Cardiovascular Life Support (ACLS) protocols. Research team physicians have immediate 
access to valium, diphenhydramine, epinephrine, lidocaine, and NTG for emergency use, in 
addition to a fully supplied and operational “crash cart” with EKG, defibrillator, suction, oxygen, 
and airway management equipment. 
We plan to keep the LIFUP’s intensity strictly under the FDA limit for diagnostic ultrasound 
(https://www.fda.gov/regulatory-information/search-fda-guidance-documents/marketing-
clearance-diagnostic-ultrasound-systems-and-transducers). We will also perform a few pilot 
experiments to evaluate possible mild and moderate symptoms without the administration of 
propofol anesthetic. 
Adverse Events 
Adverse events will be monitored throughout the procedures and for 24 hours after the procedure 
via a phone call to the subjects.  We will follow their medical record for 30 days following the 
procedure.  Complications or adverse events that are observed by the investigator or reported by 
the subject will be recorded.  For all adverse events and complications, a description of the event, 
date first observed, any action taken and ultimate outcome will be recorded. 
For all adverse events, sufficient information will be pursued and/or obtained as to permit 1) an 
adequate determination of the outcome of the event (i.e. whether the event should be classified 
as a serious adverse event) and; 2) an assessment of the causal relationship between the adverse 
event and the investigational device, or if applicable, the other study treatments of diagnostic 
product(s).  Adverse events felt to be associated with the investigational device, or if applicable, 
other study treatment or diagnostic product(s) will be followed until the event (or it sequelae) or 
the abnormal test finding resolves or stabilizes at a level acceptable to the sponsor-investigator. 
Adverse events will be reported to the IRB according to their reporting guidelines. 
Serious and Unanticipated Adverse Device Events 
An unanticipated adverse device event is defined as “any serious adverse effect on health or 
safety or any life-threatening problem or death caused by, or associated with, a device if that 
effect, problem, or death was not previously identified in nature, severity, or degree of incidence 
in the investigational plan, or any other unanticipated serious problem associated with a device 
that relates to the rights, safety or welfare of subjects. 
The sponsor-investigator will promptly review documented adverse events and abnormal test 
findings to determine 1) if the abnormal test finding should be classified as an adverse event; 2) 
if there is a reasonable possibility that the adverse event was caused by the investigational device 
or, if applicable, other study treatment of diagnostic products(s) and 3) if the adverse event meets 
the criteria for a serious adverse event. The sponsor shall promptly report the results of an 
evaluation of any serious and unanticipated adverse event to the FDA, the University of Michigan 
IRBMED and participating investigators (if any) as soon as possible, but not later than 10 working 
days after the sponsor first receives notice of the effect.  
Confidentiality 

Strict subject confidentiality will be maintained. Subjects will be assigned a code number following 
their first contact in the protocol. This number will be used throughout the experiment and will be 
the only identifier on behavioral and physiological archival data, and magnetic resonance (MR) 
scans. The identity of subjects will not be revealed at scientific meetings, in publications or other 
vehicles of public communication. Data will be pooled across subjects where appropriate. Only 
the PIs, Co-investigators, and the study coordinator will have access to the ID code, which will be 
stored in a locked file separate from the data. 
Any behavioral data collected on the subjects will be coded by study ID numbers and entered 
directly into notebook computers used in the field. These computers are password protected and 
stored behind a locked door when not in use. Clinical and biographic data are entered into the 
database using the ID number only. Only select staff members have access to the actual paper 
copies. Medical information will be released by name only to health care providers, and then only 
with written permission from the subject. 
 
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