Neuromodulation of Conscious Perception: Investigating Thalamic Roles Through Ultrasonic Stimulation
Phase: NA
Conditions: Thalamus
Sponsor: University of Michigan

Neuromodulation of Conscious Perception: Investigating 
Thalamic Roles through Ultrasonic Stimulation 
 
 
 
Date of IRB Approval: September 28, 2023 
 
NCT06083493 
 
 

Neuromodulation of Conscious Perception: Investigating 
Thalamic Roles through Ultrasonic Stimulation 
 
Dr. Zirui Huang and Dr. Anthony G. Hudetz 
 
General Goal 
The overarching aim of this study is to investigate the impact of transcranial low-intensity 
focused ultrasound pulsation (LIFUP) on conscious perception. Our central hypothesis is 
that specific subcortical brain areas play pivotal roles in conscious perception, and by 
altering neural activity in these regions, we can uncover their distinct contributions. To 
test this hypothesis, we will employ both psychological assessment and noninvasive brain 
stimulation techniques. In particular, we will evaluate perceptual outcomes using a near-
threshold perceptual task, employing Signal Detection Theory (SDT) metrics. 
Concurrently, we will utilize LIFUP to stimulate select subcortical brain regions and 
assess their causal influence during conscious perception. 
This research serves two critical purposes. First, it contributes to our understanding of the 
neural underpinnings of consciousness—a fundamental and unresolved issue in 
neuroscience. Second, from a clinical perspective, the findings hold promise for potential 
applications of LIFUP in medical settings, such as facilitating the recovery of 
consciousness during the emergence from anesthesia. 
Introduction 
The neural mechanisms underlying conscious perception have long intrigued the field of 
neuroscience 1–16. While extensive research has focused on the cortical aspects of 
conscious perception 6,7,15, the role played by subcortical structures has received 
relatively little attention. Among various important subcortical sites, such as brainstem 
and basal forebrain nuclei 17, the thalamus stands out as a critical structure due to its 
extensive bidirectional connections and interactions with the cerebral cortex 18,19.  
Within the thalamus, two major cell classes exist, known as "core" and "matrix" cells 20,21. 
These cells project differently to the cortex. The human thalamus can be coarsely divided 
based on the prevalence of these two cell types (Figure 1). Core cells are preferentially 
distributed in the posterior thalamic areas, while matrix cells are more abundant in the 
anterior regions 22. Core cells primarily innervate the granular layers of the cerebral 
cortex, sending axonal projections to Layers III and IV of sensory cortices in a retinotopic, 
tonotopic, and somatotopic manner. In contrast, matrix cells innervate the supragranular 
cortex in a relatively diffuse manner, indicating a preference for interactions with higher-
order cortical areas 22. Understanding the distinct roles of these thalamic cell classes 
could significantly contribute to unraveling the mysteries surrounding conscious 
perception. 

 
Figure 1. The distribution of two distinct sub-populations of thalamic projection cells (core and 
matrix). The cell types were identified based on mRNA expression levels of two calcium-binding 
proteins, Calbindin (CALB1) and Parvalbumin (PVALB), as provided by the Allen Human Brain 
Atlas 23. The relative weighting of the CALB1 and PVALB level differences was measured using 
the CPT metric 22, where blueish values indicate regions with higher CALB1 levels (matrix-rich), 
and greenish values indicate areas with higher PVALB levels (core-rich). The thalamus is coarsely 
divided into four sections: ventral anterior (VA), dorsal anterior (DA), ventral posterior (VP), and 
dorsal posterior (DP). 
To investigate the functional role of thalamic areas in conscious perception, it becomes 
imperative to causally alter their activity. Traditional brain stimulation methods either 
involve invasive procedures or have low target resolution. For instance, deep-brain 
stimulation involves surgically implanted electrodes whereas transcranial magnetic 
stimulation suffers from low spatial resolution. Optogenetic approaches offer unparalleled 
precision but require genetic manipulation, making them unsuitable for use in humans. 
The novel method of transcranial low-intensity focused ultrasound pulsation (LIFUP) as 
an attractive alternative that overcomes these limitations. LIFUP has the unique ability to 
non-invasively target deep brain nuclei, including specific thalamic areas, with remarkable 
precision of sonication focus 24. Despite the growing body of literature on LIFUP-induced 
behavioral modifications 25, its effect on conscious perception remains largely unexplored. 
Employing LIFUP to noninvasively modulate the activity of select brain regions has the 
potential to shed light on the intricate neural mechanisms of conscious perception in 
humans.  
Research Objectives 
The primary objective of this study is to investigate the causal role of thalamic areas in 
conscious perception using LIFUP. We hypothesize that stimulating different thalamic 
regions by LIFUP will result in distinct perceptual outcomes, potentially affecting 
subjective perception as quantified by criterion and detection sensitivity as described in 
detail under Data Analysis and Statistics. 
To test these hypotheses, we have devised a three-fold approach: 
1. We will conduct a near-threshold perceptual task to assess the perceptual 
outcomes under different conditions. 

2. Utilizing transcranial LIFUP, we will selectively stimulate (both excite and inhibit) 
the anterior and posterior thalamic areas. These areas are chosen because they 
are known to be differentially enriched by matrix and core thalamic cells, 
respectively. 
3. We will evaluate the quality of conscious contents using two orthogonal quantities 
derived from Signal Detection Theory: criterion (c) and sensitivity (d'). Criterion (c) 
represents a subject's tendency to report subjective recognition of a target 
stimulus, irrespective of its presence or absence. On the other hand, sensitivity (d') 
measures a subject's ability to differentiate between trials with a target present and 
trials with a target absent (Figure 2). 
 
Figure 2. An overview of Signal Detection Theory 
We expect that exciting the matrix cell-rich areas of the thalamus, such as the ventral 
anterior section, will lead to a decrease in criterion (c), indicating a shift of the decision 
criterion towards a more liberal response bias. Conversely, exciting the core cell-rich 
areas of the thalamus, like the dorsal posterior section, will increase sensitivity (d'), 
resulting in improved differentiation ability in stimulus perception. Conversely, we also 
anticipate that inhibiting the ventral anterior thalamus will have the opposite effect on 
criterion (c), leading to a more conservative decision bias. Inhibiting the dorsal posterior 
thalamus will reduce sensitivity (d'), resulting in a decreased ability to differentiate 
between stimuli. By observing these effects, we aim to unravel the distinct causal roles of 
the anterior and posterior thalamus in conscious perception. This disentanglement will 
provide valuable insights into the mechanisms of specific thalamic regions in shaping 
perceptual processes. 
Number of Subjects, Recruitment and Informed Consent 
Our study will involve the enrollment of 60 participants, who will be randomly assigned to 
two groups, with each group consisting of 30 participants. The participants will be divided 
based on the type of transcranial LIFUP they will receive, either excitation or inhibition, 
targeting four specific thalamic areas. 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. If interested, the participant will 

complete the questionnaires, which will be reviewed by the study team. Once eligibility is 
confirmed by the study team, the one-time research study session will be scheduled.  
Participants may be screened for COVID-19 prior to entry into the hospital per hospital 
guidelines.  
 
Figure 3. Randomized study group assignment. A total of 60 participants will be enrolled in the 
study and randomly assigned to two groups, each comprising 30 participants. The group 
assignment will be based on the type of transcranial LIFUP they will receive, either in the form of 
excitation or inhibition. 
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.  
Compensation 
Participants will be compensated $100 for completing the one-time visit. Participants who 
have shaved or no hair, or those willing to shave the right side of their temple will be 
compensated an additional $75. Participants who are willing to shave an area around 
their right side of their temple should do this prior to arriving to their scheduled study visit. 
Inclusion and Exclusion Criteria 
Volunteers are screened using a medical history and demographics questionnaire.  
Inclusion Criteria:  
x Healthy adults ages 18 – 40.  
x Must be right-handed. 
x Must have normal or corrected-to-normal vision (while wearing contact lenses).  
x Must not be on any medications for any neurological, psychological, or 
psychiatric conditions. 
x Must be English speaking.  
x Must be capable of giving written informed consent.  
 
Exclusion Criteria:  

x Vision that is not 20/20, or vision that is not corrected to 20/20 while wearing 
contact lenses.  
x History of significant head injury with loss of consciousness.  
x Learning disability or other developmental disorder. 
x Any impairment (sensory or motor loss), activity, or situation that in the judgment 
of the study coordinator or Principal Investigators would prevent satisfactory 
completion of the study protocol. 
Methods and Procedures 
LIFUP Method. The mechanism of action of LIFUP have been associated with 
mechanically induced changes in membrane capacitance, cavitation events, and 
mechanical sensitivity of voltage-gated ion channels 26–28. A neuronal intramembrane 
cavitation excitation model 29,30, which accounts for differential effects as a function of 
cell-type, emerged as an explanation for the stimulus parameter-dependent range of 
excitatory vs. inhibitory effects. In this model, the LIFUP parameter duty cycle (DC) likely 
determines excitation (higher DC, allowing for longer sonication-on periods) and inhibition 
(lower DC, allowing for short ultrasonic bursts with longer periods between bursts) 
independent of the other sonication parameters. Excitation occurs optimally at a high duty 
cycle of 70%, allowing for a trade-off in regular-spiking and fast-spiking neurons between 
charge accumulation during the ultrasound and discharge during the off periods of 
ultrasound 25. In contrast, a low duty cycle (e.g., DC < 10%) produces a suppressive effect 
31–39. Thus, LIFUP can bidirectionally modulate the circuitry of interest depending on the 
choice of duty cycle. 
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 previous work, we plan to administer a pulse repetition frequency of 10 
Hz, pulse width of 0.5 ms, and a duty cycle of 70% to induce an excitatory effect and a 
duty cycle of 5% to induce a suppressive effect. For each thalamic area, a total of 10 
sonications (in 10 minutes) 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 (Figure 4). We will utilize the Brainsight Navigation system, developed by 
Brainbox Ltd, 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. Electromyography (EMG) recordings will complement the behavioral data, 
providing valuable information about muscle activity and response patterns during the 

study. 
 
Figure 4. Conceptual illustration of LIFUP setting and parameter configuration (adapted from 33 
and https://brainsonix.com/technology/). 
Experimental Design. The experimental will consist of a 10-minute baseline period 
(LIFUP-OFF) followed by four 10-minute sessions of stimulating (LIFUP-ON) four 
thalamic areas. The order of thalamic area stimulation will be counterbalanced across 
participants and will include the ventral anterior (VA), dorsal anterior (DA), ventral 
posterior (VP), and dorsal posterior (DP) sections of the thalamus. The center coordinates 
of these thalamic regions will be derived from a previous study on thalamic parcellation 
40. Given that previous studies have not indicated any functional lateralization of the 
thalamic areas, we will target only the left hemisphere for the sake of convenience in this 
study. 
Perceptual Task. The quality of conscious perception will be assessed by a well-
established psychometric approach, the near-threshold perceptual task 41,42. This task 
allows one to compare the neural activity evoked by identical weak stimuli that are 
sometimes perceived and sometimes remain subliminal (Figure 5). It thus rules out 
potential confounds of variability derived from the differences in physical property of the 
stimuli. All stimuli will be programmed using E-Prime (Psychology Software Tools, 
Pittsburgh, PA) and delivered via a laptop computer. 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”). 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, they should respond “no”. 

 
Figure 5. Visual task design. During each 10-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, the latter will be created by 
phase-shuffling of a randomly chosen real image from each category to preserve category 
specific low-level image features 41,42. Because scrambled images serve as “catch trials” 
to determine the subjects’ baseline tendency to give positive responses to a question 
about their recognition experience. The pre-stimulus interval will vary randomly from trial 
to trial between 2 and 4 seconds to prevent stimulus timing predictability. The stimuli will 
be presented in a randomized order to prevent category predictability. 
Primary Outcome Measure 
Perceptual criterion (c) and sensitivity (d’) derived from the Signal Detection Theory (SDT) 
analysis. These measures will be assessed over a timeframe spanning from the baseline 
to 60 minutes after the LIFUP stimulation.  
Data Analysis and Statistics 
For each 10-min session, we will calculate sensitivity (d’) and criterion (c) using subjective 
reports of recognition as “yes” or ”no”. (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. (c) reflects 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”.  
We will conduct a repeated-measures ANOVA, considering measurements taken during 
both the baseline and the four thalamic areas' stimulation sessions. This analysis will be 

performed at the group level to assess the effects of LIFUP on the perceptual measures. 
To determine statistical significance, we will apply a false discovery rate (FDR) correction 
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differences between the baseline and the different thalamic area stimulations in terms of 
sensitivity (d') and criterion (c). 
Anticipated Results and Interpretation 
We expect to observe differential changes in the perceptual outcomes based on the 
LIFUP stimulation of different thalamic areas. We anticipate that stimulation of the ventral 
anterior thalamus will decrease criterion (c), indicating a shift of the decision criterion in 
the liberal direction. During exciting the dorsal posterior thalamus, we expect an increase 
in sensitivity (d'), reflecting a higher sensitivity in differentiating between stimuli. 
Conversely, when inhibiting the ventral anterior thalamus and the dorsal posterior 
thalamus, we expect the opposite effects on criterion (c) and sensitivity (d') compared to 
the outcomes seen during their respective excitations. The effects of stimulating the 
dorsal anterior thalamus and the ventral posterior thalamus are expected to lie between 
the effects of ventral anterior and dorsal posterior thalamic stimulation. These findings 
should provide valuable insights into the specific contributions of these thalamic regions 
in shaping conscious experiences. 
 
Power Analysis 
We considered a recent review article that summarized 25 LIFUP studies in humans. 
These studies had sample sizes ranging from 1 to 50, with a median value of 16. Since 
the neuromodulation effect is dependent on various factors, such as parameter settings 
and specific brain regions targeted, determining a prior effect size is challenging. However, 
we have planned a subject number of 30 per group, which exceeds the median sample 
size reported in the literature. With a larger sample size, we aim to enhance the statistical 
power, reliability and sensitivity of our findings, enabling us to draw robust conclusions 
about the neuromodulatory effects of LIFUP on conscious perception. 
Biological Variables 
Our participant recruitment will be inclusive, encompassing individuals of all sexes and 
diverse ethnic/racial backgrounds, with the goal of achieving equal representation and 
promoting diversity. However, to minimize age-dependent variation in LIFUP effects, the 
age range of participants will be restricted to 18-40 years. This limitation will help ensure 
a more homogeneous sample for our study, enabling us to focus to reliably determine 
specific effects of LIFUP on conscious perception within the limitation of sample size. 
Human Studies and Safety Profile related to LIFUP 
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 
24,43,44. The majority of studies with ultrasound have reported no adverse events or 
evidence of anatomical damage 35,45–50. Mild and moderate symptoms have been 
occasionally reported, such as neck pain, sleepiness, muscle twitches, itchiness, and 
headaches 51. However, a comprehensive safety survey focusing on ultrasound for 
human neuromodulation found no evidence of serious adverse effects in a large cohort 

of participants52. Out of 120 participants, 64 responded to a follow-up questionnaire, and 
none experienced serious adverse effects. Only 7 out of the 64 participants reported mild 
to moderate symptoms (e.g., neck pain, attention problems, muscle twitches, and anxiety) 
that were perceived as 'possibly' or 'probably' related to their participation in LIFUP 
experiments. Notably, common unrelated symptoms included sleepiness and neck pain. 
Initial transient reports of mild neck pain, scalp tingling, and headaches were extinguished 
upon follow-up, with no new symptoms reported up to one month after the study 52. 
Furthermore, studies have not shown any LIFUP-induced tissue damage in the absence 
of heating, except in cases where contrast agents were used to enhance cavitation effects 
26. Additionally, LIFUP has been shown to be safe even at intensities several times higher 
than the FDA limit for diagnostic ultrasound (720 mW/cm2) 53. Overall, the available 
evidence indicates that LIFUP is a safe and well-tolerated method for human 
neuromodulation, provided the proper guidelines and parameters are followed. 
Justification for the Risks Involved 
The proposed procedure entails minimal risks, while the potential knowledge gains hold 
significant importance for humanity. As a result, the risk-to-benefit ratio is very low. These 
experiments offer a unique opportunity to understand the neuromodulation's impact on 
human conscious perception. The potential insights gained from this study justify the 
minimal risks involved, making it a valuable and worthwhile endeavor. 
Procedures for Minimizing Risks 
All research subjects will undergo a thorough screening process to ensure they meet the 
inclusion and exclusion criteria. Additionally, if any subjects express or exhibit anxiety 
related to the LIFUP procedure, they will have the opportunity to discuss their feelings or 
withdraw from the experiment if they wish. 
We are committed to strictly adhering to the FDA limit for diagnostic ultrasound intensity 
(as outlined in the FDA guidance document on diagnostic ultrasound systems and 
transducers) during the LIFUP procedure to maintain safety and prevent any adverse 
effects. The FDA previously determined that the use of LIFUP in our studies carries 
nonsignificant risk (NSR). 
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 its 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 data identifier. 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. 
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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