Evaluating the Effects of Transcranial Focused Ultrasound (tFUS) on Fronto-striatal Resting State Functional Connectivity in Healthy Individuals
Phase: NA
Conditions: Healthy
Sponsor: Medical University of South Carolina

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PROTOCOL TITLE: 
Evaluating the effects of transcranial focused ultrasound (tFUS) on fronto-striatal resting state 
functional connectivity in healthy individuals 
 
PRINCIPAL INVESTIGATOR: 
 Bashar Badran, PhD 
 
 

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1.0 
Objectives / Specific Aims 
 
Aim: Evaluate whether sonicating the Nucleus Accumbens (NAc) with transcranial focused 
ultrasound modifies functional connectivity between the NAc and the prefrontal cortex (PFC). 
 
In this single visit, open-label pilot trial, we 
plan to evaluate whether transcranial focused 
ultrasound (tFUS), delivered to the nucleus 
accumbens (NAc) within the magnetic 
resonance imaging (MRI) scanner will 
impact resting state functional connectivity 
between the NAc and functionally connected 
brain regions like the prefrontal cortex (PFC) 
and the anterior cingulate cortex (ACC) in up 
to 10 healthy individuals.  
 
HYPOTHESIS : tFUS will reduce prefrontal 
cortex (PFC)-NAc functional connectivity, 
in healthy individuals. We will investigate 
this hypothesis by administering tFUS 
within to MRI scanner to healthy individuals 
and 
conduct 
resting 
state 
functional 
neuroimaging before- and after the tFUS 
stimulation.  
 
2.0 
Background 
 
Currently, several brain stimulation approaches have attempted to modulate pain, mood, and behavior with limited 
success. The two most studied approaches are transcranial magnetic stimulation (TMS) and transcranial direct current 
stimulation (tDCS).  TMS, which is FDA approved for treating depression and OCD, can only stimulate the surface 
of the brain and can only stimulate deeper by increasing the intensity, and spreading the field. It is thus not deep and 
focal but deep and broad. Unlike TMS, which is a cortical stimulation approach, deep brain stimulation (DBS), which 
is FDA approved for treating Parkinson’s Disease (PD), can stimulate deep in the brain with high spatial specificity. 
DBS has been also investigated experimentally to manage neuropathic pain; however, the surgical risk and 
implantation of the electrodes are semi-permanent 
and arguably not worth the benefit. Lastly there is 
tDCS, a low cost, low-amplitude electric current 
delivered to the scalp and ultimately through brain. 
tDCS is not powerful enough to depolarize neurons, 
although it has been demonstrated to influence the 
level of excitability and modulate the firing rate of 
individual neurons. Of all brain stimulation 
approaches, there is a need for a safe, noninvasive, 
focal, and effective approach that can reliably 
modulate neural tissue. This proposal addresses this 
gap, by advancing transcranial focused ultrasound 
(tFUS), a technological advancement on the 
forefront of neuroscience and neuromodulation 
(Figure 2). 
 
 
Functionally connected areas of the Nucleus Accumbens (NAc). Key emotional, 
pain, and reward systems are connected through the NAc, including the insula, dorsal 
anterior cingulate cortex (dACC), prefrontal cortex (PFC), thalamus (Tha), amygdala 
(Amy), and periaqueductal gray (PAG). Additionally, the NAc receives excitatory 
inputs from the ventromedial PFC, dACC, amygdala, and hippocampal formation (not 
shown) and dopaminergic inputs from the ventral tegmental area (VTA) of the 
midbrain. 
 
Figure 2. On the right, the electric fields produced by tDCS and TMS are 
presented. These two commonly utilized forms of brain induce 
biologically active electrical fields in broad (>4cm) cortical targets. 
Alternatively, tFUS (right) has the capability to focally deliver energy to 
cortical and subcortical tissue with <1cm resolution.(33) 

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This open-label pilot study is investigating the basic underlying mechanism of tFUS, and evaluating whether this 
technology can stimulate deep brain structures associated with reward, pain, and addiction – the nucleus accumbens. 
We aim to use resting state neuroimaging to understand what happens to functional neural circuitry of connected 
brain structures to the site of stimulation. 
 
3.0 
Intervention to be studied (if applicable) 
 
Transcranial Focused Ultrasound (tFUS) 
Transcranial focused ultrasound (tFUS) is a 
promising new technology that is both noninvasive 
and may be focally applied to deep brain targets(1-4) 
(Figure 3). tFUS utilizes transducers which contain 
piezoelectric elements to produce pulses of ultrasonic 
waves that summate deep in the brain(5-7). tFUS 
noninvasively stimulates deep brain targets with a 
high level of spatial resolution. No other current 
technologies exist for noninvasive deep brain 
stimulation which makes tFUS a highly promising 
technology that may have substantial research and 
clinical potential(1, 4, 8-12). Transcranial focused 
ultrasound (tFUS) uses a single large concave transducer fixed in a head-worn apparatus on the scalp to produce 
ultrasonic waves (650kHZ) pulsed in 30 second intervals. Unlike traditional diagnostic ultrasound, which constantly 
transmits ultrasound and ‘listens’ to the echo to form an image, tFUS delivers the ultrasound in trains or short bursts 
of pulses. It is still unclear whether tFUS, at the FDA-prescribed power limits, depolarizes neurons, however is 
hypothesized that tFUS acts on neurons via a mechanical force mechanism of action, leading to increased conductance 
of neurons and opening of ion channels(13).  
Due to the inherent fundamentals of the waveform of ultrasonic forces, tFUS 
maximal energy can be focused both deep in the bran (2-12cm under the cap; 
for comparison, traditional TMS can stimulate 1-3.4cm2 deep(14, 15)) and 
focally (as small as 0.5mm in diameter, and up to 1000mm; the facility of a 
standard, commercially-available 70mm figure-of-8 TMS coil is roughly 
50mm2 (14, 15)). Furthermore, tFUS has been demonstrated to safely 
stimulate neural tissue(12, 16-18), proposing cellular mechanisms for its 
efficacy(12, 18-23), and now is being used in human patients(24). 
Recently, tFUS administered to the thalamus of coma patients was 
demonstrated to assist in recovery of consciousness(24). Thus, tFUS is 
an extremely promising, new form of noninvasive deep brain stimulation 
that can be focused on deep brain structures to elicit meaningful 
behavioral responses. This proposal plans to use tFUS, administered to 
deep brain structures involved in reward and pain, to produce changes in 
brain functional connectivity. 
 
We will be using the Brainsonix Low intensity focused ultrasound pulsation device. (BX Pulsar 1001). 
Please see the manufacturers description (Technical Summary) along with appendixes about the actual 
safety of the device itself.  
 
FDA Status of the BX Pulsar 1001 device.  
 
 
The BX Pulsar device was initially tested at UCLA in epilepsy patients. This research required an FDA 
IDE, which I have attached to the IRB application. After this study was done and safety was established, 
 
Figure 3. Screenshots from our custom-made software (47) used to show 
the tFUS transducer (left) placed on the scalp, and (right) the theoretical 
peak sonication area deep within the brain based on the fixed focal length 
of the specific transducer used. 
 
Figure 
4. 
transcranial 
focused 
ultrasound (tFUS) holder system 
containing the tFUS transducer. 

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the UCLA IRB now does not require an IDE and treats this form of ultrasound just like it does regular 
diagnostic ultrasound, which is non-significant risk. The diagnostic ultrasound devices and this one are 
the same in terms of what they can produce.  
 
Attached is the letter of approval from the UCLA for using this device in testing memory, Alzheimer’s 
disease, coma, the amygdala and emotions, and the thalamus with healthy controls.  
 
Additionally, the MUSC IRB1 has approved this system to investigate a new potential treatment for pain, 
which was shown to be safe at the proposed parameters and published recently(25). Additionally there is 
an ongoing trial using the same system (PI George) approved the IRB 1 in generalized anxiety disorder.  
 
Importantly, this device can only deliver the power of a diagnostic ultrasound device. It is not able to 
deliver the power needed for High Intensity Ultrasound Ablation such as is used in neurosurgery. This 
would require multiple machines, precisely focused, delivering over 1000 times more energy than we are 
using.  
In this study, up to 10 participants will receive two, 10minute sessions of either active or sham tFUS 
delivered to the nucleus accumbens (NAc) within the MRI environment.  
 
4.0 
Study Endpoints (if applicable) 
 
Primary Outcome: Neuroimaging/Fronto-Striatal Resting State Functional Connectivity 
 
The main outcomes of this study are brain imaging related. Using a neuroimaging technique called resting 
state functional connectivity, which is a statistical dependence between time series of electro-physiological 
activity and (de)oxygenated blood levels in distinct regions of the brain. Functional connectivity “strength 
calculation” determines whether the activity between a pair of brain regions covaries or correlates over 
time. We will investigate the strength of the functional connectivity between the stimulation target (Nucleus 
Accumbens) and connected areas, including the prefrontal cortex, hippocampus, amygdala, and sensory 
areas of the brain at baseline, and then will determine whether tFUS increases or decreases the resting-state 
connectivity between these regions after the NAC has been stimulated. 
 
 
5.0 
Inclusion and Exclusion Criteria/ Study Population 
 
Healthy volunteers of all ethnic and racial categories will be accepted into this study protocol. No preference 
will be given based on race, gender, or ethnicity. Pregnant persons and children under the age of 18 will be 
excluded for safety reasons. No vulnerable populations or special classes of subjects will be considered for 
participation.  
 
Inclusion Criteria  
 
Age 18-65  
 
Have the capacity and ability to provide one’s own consent and sign the 
informed consent document  
 
 

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Exclusion Criteria 
 
Contraindicated for MRI. 
 
Any current or recent untreated medical, neurological, or psychiatric 
conditions 
 
Metal implant devices in the head, heart, or neck. 
 
History of brain surgery. 
 
History of myocardial infarction or arrhythmia, bradycardia. 
 
Personal or family history of seizure or epilepsy or personal use of 
medications that substantially reduce seizure threshold (e.g., olanzapine, 
chlorpromazine, lithium). 
 
Personal history of head injury, concussion, or self-report of moderate to 
severe traumatic brain injury.  
 
Individuals suffering from frequent/severe headaches. 
 
Individuals with a reported history of psychosis or mania, or individuals 
who are actively manic or psychotic.   
 
Regular or recent pain medication use 
 
Moderate to severe alcohol use (>3 drinks/day) or illicit substance use 
(urine confirmed).  
 
Persons who are pregnant or lactating 
 
6.0 
Number of Subjects 
 
We will enroll up to 10 healthy adults for this study. 
 
7.0 
Setting 
 
All participants will complete the study tasks on at the MUSC 30 Bee Street Center for Biomedical 
Imaging. Subjects will be consented and educated about the study in a private screening area within the 30 
Bee Street center. tFUS will be administered within the MRI scanner.   
 
8.0 
Recruitment Methods 
 
Healthy participants will be recruited from the MUSC community (students and staff) as well as general 
population from the greater Charleston region. We will recruit via word of mouth and flyers.  
 
9.0 
Consent Process 

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Consent procedures will be conducted in a private, quiet room at the MUSC 30 Bee Street Center for 
Biomedical Imaging. Approved study personnel will walk through the consent procedures with the 
participant. Furthermore, after the consenting procedures, the consent form will be printed and provided to 
all participants to independently review to ensure understanding, including describing the laboratory 
measures, study duration, and equipment and materials. The study team will describe 
confidentiality/privacy measures, participant right to withdraw, risks/benefits, and that up to $100 
compensation will be provided. In addition, participants will be prompted to ask questions throughout 
consenting to further ensure understanding. After signing the consent form, they will also be offered a hard 
copy. 
 
10.0 Study Design / Methods 
 
 Study Overview: After determining eligibility and interest, written informed consent will be 
obtained from participants at the MUSC Center for Biomedical Imaging. Enrolled participants will 
be placed into the 3T MRI outfitted with a concurrent tFUS plus fMRI acquisition system 
(Brainsonix). First, participants will have baseline resting state functional neuroimaging conducted 
to quantify the functionally connected areas to the nucleus accumbens. Afterwards, while still in 
the MRI scanner, we will administer tFUS to the nucleus accumbens. Lastly, we conducted post-
tFUS neuroimaging (same as pre-tFUS). This entire MRI procedure will take approximately 1 hour. 
Participants will be compensated $100 for their time.  
 Recruitment, Screening, and Consent Procedures: Healthy participants will be recruited from the 
MUSC community (students and staff) as well as general population from the greater Charleston 
region. We will recruit via flyers around campus, e-mail announcements and word of mouth. If 
interested in learning more about the study, potential subjects will be phone screened and educated 
regarding the study’s details. If interested in participating in the study, they will be consented and 
enrolled into the study’s protocol. We then will conduct a multi-panel urine drug screen to confirm 
they are not using illicit drugs and ask for their alcohol consumption (>3 drinks per day is 
exclusionary). 
 Pregnancy Test Procedures: If participants are individuals biologically capable of becoming 
pregnant, they will be provided with a pregnancy test strip After completing the pregnancy test, 
participants with negative results will be asked to continue to the remaining study procedures, 
whereas those with a positive result will be debriefed and released.  
 tFUS Procedures: All tFUS will be administered in similar mythology to that in our prior published 
work (25). Within the MRI scanner, participants receive two, 10-min sessions of either active or 
sham tFUS spread 10 min apart targeting the nucleus accumbens [fundamental frequency: 650 kHz, 
Pulse repetition frequency: 10 Hz, Pulse Width: 5 ms, Duty Cycle: 5%, Sonication Duration: 30s, 
Inter-Sonication Interval: 30 s, Number of Sonications: 10, ISPTA.0 995 mW/cm2, ISPTA.3 719 
mW/cm2, Peak rarefactional pressure 0.72 MPa].  
 Sham tFUS Procedues: Participants will be randomized to receive either two, 10 minute active tFUS 
sessions, or two 10 minute sham tFUS sessions within the scanner. The sham sessions will include 
a transducer that is connected in a similar fashion to that of active tFUS, however the cable will not 
be plugged into the system, thus no ultrasound will be delivered to the participant. Participants will 
not know or be told whether they are receiving active- or sham- tFUS. 
 Neuroimaging Procedures: All MRI imaging will be performed using a Siemens 3.0 T Prisma 
scanner equipped with a 32-channel head coil. MRI data will be acquired from all participants before 
and after tFUS administration.  All MRI scan visits will be held at the MUSC Center for Biomedical 
Imaging (CBI; see the Facilities and Resources section). Each MRI scan session will include a high-
resolution T1-weighted structural scan (whole brain sagittal acquisition, 224 slices, TR=2530ms, 

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TE=3.65ms, TI=1100ms, 1mm thick slices, FOV=256, 256x176, flip angle = 7 degrees.), followed 
by 24 minutes of resting-state scanning, then a concurrent tFUS/fMRI paradigm, and lastly, 24 more 
minutes of post-tFUS resting-state scanning. All functional scans will use the high-resolution fMRI 
protocol described in the Preliminary Study: whole brain acquisition, 136 axial slices, 
1.5x1.5x1.5mm voxel size, TR=2000ms, TE=30ms, FOV=204mm, multi-band factor=3.  
 
 
12.0 Data Management  
 
All data will be stored in the Redcap database as well as in paper documentation. Information about the 
participant (including their identifiable private information) may have all their identifiers removed and used 
for future research studies or distributed to other researchers for future research without additional informed 
consent. After participation, RedCAP data will be downloaded in excel format to the secure MUSC server. 
Paper documentation will be stored in locked cabinet within a locked office of the study team. In terms of 
publication, data will be published in aggregate form, so individual participants will not be identifiable in 
the final manuscript. No identifying information will be published. 
 
Neuroimaging data will be collected from the 3T MRI scanner at 30 Bee Street. All imaging data will be 
automatically transferred to and stored on a password-protected, encrypted secure server that limits data 
access to personnel directly involved with the study. The data will be analyzed using standard imaging 
analysis software packages such as FSL and SPM.  
Confidentiality and Quality Control: All study personnel will complete Social-Behavioral-Educational 
research CITI training, and also complete in-lab training regarding data security practices. Study personnel 
will be trained in the IRB protocol. The investigator, and co-investigators will be available to monitor data 
collection to ensure quality, confidentiality, and adherence to the IRB protocol. 
 
The study’s procedures will take place at the MUSC 30 Bee Street Neuroimaging. Regarding 
documentation, participant names will appear only on the IRB-approved Consent and HIPAA. Patients will 
be receiving tFUS within the MRI scanner and they will be aware of this information prior to choosing to 
participate.  
 
13.0 Provisions to Monitor the Data to Ensure the Safety of Subjects 
 
There are three areas in which safeguards to protect subjects from undue risk require discussion. These 
Include: (1) procedures used to obtain informed consent, (2) procedures used to ensure confidentiality of 
the subject data, and (3) procedures used to minimize possible risks associated with the laboratory 
procedures. Regarding informed consent, participants are fully advised on the research procedures to be 
used, the amount of time required of them, the possible risks and benefits of the procedures, their right to 
refuse participation in the study without prejudice, their right to terminate participation at any moment 
without prejudice, and the name and telephone number of the principal investigator. All subjects will be 
required to have capacity to consent. Regarding confidentiality, subjects are informed that the information 
they provide will be kept strictly confidential, with access limited to the research staff. Participation in the 
study will be treated as confidential, as will all records. The identity of subjects will be protected with 
alphanumeric codes. All data will be kept in locked file cabinets file cabinets or on secure servers designed 
for use and access by study team only.  
 

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We do not anticipate any adverse events to occur in this study, however the experienced research team has 
a long-standing record of recording and reporting unanticipated adverse events to the IRB. We will report 
any adverse event within 48 hours to the IRB. 
 
 
14.0 Withdrawal of Subjects 
Participants will be informed during consenting that they are free to withdraw from the study at any time. 
They will be informed that they are not obligated to participate once the study is initiated and in particular 
will be reminded prior to tFUS stimulation and neuroimaging that they may discontinue stimulation and/or 
the experiment at any point.   
 
15.0 Risks to Subjects 
 
tFUS Stimulation: 
When used at/below intensities deemed safe by the FDA, no significant and persisting side-effects have 
been reported, as confirmed in healthy volunteers(11), brain injury patients(7)as well as non-human 
primates(26). 
 
In addition, although in the context of a different study, the FDA has granted to the device we will use a 
status of Category B (that is, safe and effective) Investigation Device Exemption (G130290), on 2/12/2014. 
Indeed, this is consistent with the known physics and biophysics of our stimulation protocol in which the 
device is operated at (acoustic) energy levels that are (1) well below those of a typical Pulsed Doppler 
ultrasound conventionally used in the clinical context in adults and children (by around 40%), and (2) within 
the energy limits deemed safe by the FDA. 
 
Safety in case of pregnancy 
We do not know if the study drug will affect mother’s milk or an unborn fetus. Therefore, breast-
feeding and pregnant women are not allowed to take part in the study. If you are pregnant or 
become pregnant, there may be risks to the embryo or fetus that are unknown at this time. 
Women who can become pregnant must take a pregnancy test before the start of the study. 
You should not father a child while on this study as the treatment may indirectly affect an unborn 
child. If you are sexually active and are at risk of causing a pregnancy, you and your female 
partner(s) must use a method to avoid pregnancy that works well or you must not have sex. 
Unless you cannot have children because of surgery or other medical reasons, you must be 
using an effective form of birth control before you start the study. You must also agree to 
continue to use an effective form of birth control for 2 month/s after taking the study drug. 
 
 
Magnetic Resonance Imaging (MRI): 
MRI tests are non-invasive. There are no known risks or side effects associated with conventional MRI 
procedures except to those people who have electrically, magnetically or mechanically activated implants 
(such as cardiac pacemakers) or to those who have clips on blood vessels in their brain. There are no known 
additional risks for combined tFUS+fMRI procedures. However, an MRI may cause you to feel 
claustrophobic (uncomfortable in a small space) or anxious from the noises made by the machine. 
 

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Unknown Risks: 
There is always the possibility of other risks for a relatively new technology. The Study team will let the 
participant know if they learn anything that might make the participant change their mind about 
participating in the study.  
 
Loss of Confidentiality: 
There is a risk of a loss of confidentiality of personal information. Subjects are informed that the information 
they provide, as well as participation in the study, will be kept strictly confidential, with access limited to 
the research staff. The identity of subjects in databases will be protected with alphanumeric codes. All data 
will be kept in locked file cabinets or on secure servers designed for use and access by Study Team members 
only. 
 
16.0 Potential Benefits to Subjects or Others 
 
There will be no direct benefit to the participant in the study. Data from this study, however, will benefit 
society by improving the understanding of if and how tFUS affects brain function and potentially work 
towards developing a novel therapeutic device.  
 
17.0 Sharing of Results with Subjects 
 
There is no plan to inform subjects of the results of the study, but they can always contact the research staff 
and ask. If there are significant new findings during the study, they will be notified. 
 
 
18.0 Drugs or Devices  
 
Brainsonix BX Pulsar 1001 device.  
 
The BX Pulsar device was initially tested at UCLA in epilepsy patients. This research required an FDA 
IDE, which I have attached to the IRB application. After this study was done and safety was established, 
the UCLA IRB now does not require an IDE and treats this form of ultrasound just like it does regular 
diagnostic ultrasound, which is non-significant risk. The diagnostic ultrasound devices and this one is the 
same in terms of what they can produce.  
 
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