Low Intensity Focused Ultrasound Treatment for Epilepsy: A Pilot Trial
Phase: NA
Conditions: Drug Resistant Epilepsy
Sponsor: Brigham and Women's Hospital

 
Detailed Protocol 
 
Title: Low Intensity Focused Ultrasound Treatment for Drug-Resistant Epilepsy: An 
Efficacy Trial 
 
Version: 3 
 
Version Date: December 28, 2018 
 
I. Background and Significance  
 
Epilepsy and Proposed Treatment  
 
Epilepsy is one of the most common neurologic disorders, affecting 3.1 million 
Americans and 65 million people worldwide. Approximately 67% of patients with 
epilepsy achieve seizure control with antiepileptic drugs, leaving 33% of patients 
with persisting seizures despite medication. Ongoing seizures can be very 
debilitating, and are often associated with significant morbidity and even 
mortality. Many of these patients endure ongoing cognitive impairment related to 
persisting seizures and ongoing polypharmacy, which in turn has been associated 
with low quality of life. Because of the severity of the disease, there are high rates 
of seizure-related injuries (burns, falls), accidental deaths and an elevated suicide 
rate seen in this population. There also high rates (1:100) of sudden unexpected 
death in epilepsy (SUDEP) in this population. More people die from seizure-
related injuries per year than from breast cancer. 
 
Though the population affected by this disorder is large and the morbidity is high, 
epilepsy research remains largely underfunded. There are very few new 
treatments, pharmacologic or non-pharmacologic, coming down the pipeline to 
address this at-risk population. Despite this, the importance of reducing patients’ 
seizure burden remains high. Ongoing seizures over the lifetime can result in 
progressive neurologic damage, along with the multitude of side effects 
antiepileptic polypharmacy carries. Reducing seizure burden can lessen the 
cognitive, behavioral, and psychosocial problems experienced by epilepsy 
patients, reducing their overall morbidity and mortality.  It is clear that for many 
patients, antiepileptic medications will never stop their seizures [1].  Aside from 
epilepsy surgery, for which only a percentage of these patients are eligible, there 

 
are few other options to help reduce seizure frequency in this population. 
Neurostimulatory devices such as Responsive Neurostimulation (Neuropace) and 
Vagal Nerve Stimulation (VNS) have been shown to be of some benefit, though 
these are limited to small, specific patient populations and responses vary. 
Noninvasive neurostimulation such as transcranial magnetic stimulation (TMS), 
though highly effective for some psychiatric illnesses, has produced disappointing 
outcomes in reducing seizures [2]. This is in large part due to the inability of TMS 
to reach deeper structures in the brain, such as the hippocampus in patients with 
epilepsy.  
 
Thus, the large population of patients suffering from drug-resistant epilepsy with 
little or no treatment options warrants investigation using alternative forms of 
noninvasive neuromodulation for the treatment of epilepsy.  Pulsed Low-Intensity 
Focused Ultrasound (PLIFUS) has been shown to safely modulate neuronal tissue, 
and is non-invasive and painless. Several human studies have shown the ability of 
PLIFUS to suppress somatosensory evoked potentials and induce functional 
magnetic resonance imaging (MRI) responses. To date, a reported 102 healthy 
subjects have been enrolled in these studies, and no adverse effects were 
reported from PLIFUS stimulation to the brain [3]–[9].  
 
The most recent study using PLIFUS involved attempting to induce or suppress 
tactile sensation by transmitting FUS to somatosensory cortex regions [9].  
Parameters were sonication frequency (f0) = 210 kHz, pulse period (PP) = 1 ms, 
pulse repetition frequency (PRF) = 500 Hz, sonication duration (SD) = 0.5 s, inter-
stimulation interval (ISI) = 7 s, and 20 sonications per pulse train (dose) taking a 
total of 140 s. These pulse trains were transmitted to multiple locations at least 2 
times in each location. Subjects underwent neurological and anatomical 
examination during FUS exposure, directly after treatments, and weeks after 
treatments for subject safety evaluation. No health issues or other irregular signs 
related to the FUS exposures were found in MRI, EEG, or Mini–Mental State 
Examination. Follow-up interviews conducted 2 months after FUS experiments 
revealed no discomforts or changes in the mental or physical status associated 
with the FUS exposure. Similar safety guidelines were used in other studies to 
suppress Somatosensory Evoked Potentials (SSEP) and activate brain regions 
identified by functional MRI with PLIFUS resulting in no health physical or mental 
health issues [3, 8].    
 

 
Human and non-human primate studies have investigated the bioeffects of either 
repeated or long-term PLIFUS exposure. During a device evaluation study for 
delivering repeated PLIFUS through the temporal lobe in order to treat stroke, 
FUS exposure was transmitted for 2 hours at a maximum of ISPTA = 0.72 W/cm2 (f0 
= 2.0 MHz, PRF = 8.3 kHz, and pulse duration [PD] = 5 μs) into 15 healthy 
volunteers. None experienced any adverse effects indicated by the neurological 
examinations during, immediately after the exposure, and at 24 hours, and no 
abnormality of the blood brain barrier was identified on post-MRI [10]. A non-
human primate study examining the effects of long-term FUS for drug delivery 
through the BBB used f0 = 1.0 MHz, 2 sonications every 2 weeks for 4 months. The 
FUS device was implanted into the skull. None of the subjects experienced any 
adverse effects in regard to the FUS exposure and it was concluded from positron 
emission tomography images with fluorine-18–labeled fluorodeoxyglucose (FDG) 
that no changes in the cerebral metabolism of glucose were identified. No 
epileptiform signs or pathological central nerve conduction were observed in EEG 
and SSEP recordings either. Behavior in all animals remained normal and 
histological analysis showed no signed of tissue damage [11]. The device was later 
investigated in a clinical trial with 17 human subjects and resulted in no 
detectable adverse effects during neurological evaluation or MRI [12]. Another 
non-human primate study used a similar protocol but with a non-invasive FUS 
transducer (f0 = 500 kHz) and multiple target locations were exposed to FUS for 
each treatment session. The study included on average 8 targets locations with SD 
= 120 s, approximately 25 sonications per month, and for up to a 12-month 
course of treatment (long-term). Behavioral testing and MRI revealed no adverse 
effects in subjects due to FUS [13]. There are two current clinical trials in humans 
using PLIFUS, one to suppress seizure activity [14], another to stimulate thalamic 
regions in subjects with disorders of consciousness following acute severe brain 
injury [15]. In the latter, the device was reported to wake a subject who was in a 
coma from a brain injury for 19 days. FUS parameters were f0 = 650 kHz, PRF = 
100 Hz, SD = 30 s, ISI = 30 s, and PP = 0.5 ms. A total of 10 sonications were 
administered in 3 different trials, with an approximate derated ISPTA = 0.72 W/cm2. 
 
 
Transcranial Focused Ultrasound 
 
The physics of FUS are similar to how clinical ultrasound-imaging probes work 
except the ultrasound energy is transmitted into a focal location (beam focus) 

 
instead of spreading energy over an imaging region. FUS is a useful method for 
noninvasively delivering therapy to deep tissue targets since the spatial 
distribution of ultrasound energy over a sufficiently large area ensures that no 
therapeutic effect can occur except at the geometric focus of the transducer.  
Transcranial FUS has been studied for over 60 years [16]. Its safety and usefulness 
have since been largely assessed for many medical treatments. Transmission FUS 
frequencies below 800 kHz are typically chosen to avoid skull heating during 
transcranial applications. The absorption of ultrasound energy by the skull 
increases approximately linearly with transmission frequency. FUS is generally 
classified into two separate categories of high and low intensity. High-intensity 
FUS causes heating of tissue at the beam focus. The most recent clinical use of 
high-intensity FUS is noninvasive Thalamotomy for treating Essential Tremor [17]. 
A high intensity FUS beam is directed to the ventral intermediate nucleus of the 
thalamus, which causes the tissue at the beam focus to heat up resulting in 
localized tissue necrosis. Several other brain applications are currently under 
investigation using high-intensity levels. Real-time monitoring techniques have 
been to developed to guided or monitor the safety of FUS procedures. Real-time 
MRI-thermometry values are used to display tissue temperature increase as the 
FUS intensity is increased at the beam focus. Acoustic Emission Detection (AED) is 
another intraoperative technique used to assurance no tissue cavitation occurs 
during FUS transmission. Cavitation is the formation of bubbles within tissue in 
response to overbearing FUS intensities and can damage tissue in the FUS beam 
path. AED sensors are microphones programmed to listen for cavitation, which 
would instantly shutdown the FUS transmission if cavitation is identified.  
       
In low-intensity FUS thermal rise and irreversible mechanical effects are negligible 
so thermometry and cavitation monitoring are not required. Low intensity FUS 
uses substantially lower intensity levels than high intensity FUS, so low as to not 
result in any ablative effect, tissue damage, permanent anatomical changes, and 
does not cause adverse effects as a result of treatment. Some recent examples of 
low-intensity FUS performed on humans are microbubble enhanced Blood Brain 
Barrier (BBB) disruption drug delivery and transcranial neuromodulation. The drug 
delivery method via BBB disruption uses the combination of IV injection of anti-
cancer agent infused with microbubbles and positioning the beam focus over 
brain tumor sites to temporarily open the BBB to deliver drug into tumors. Clinical 
investigations are underway to evaluate this method in humans [18]. PLIFUS 
neuromodulation has been investigated in several human studies to successfully 

 
show the temporary suppression or induction of auditory, visual, sensory, or 
motor functions by positioning the beam focus over specific portions of the cortex 
[19], [3], [4], [20]. FUS is pulsed during most low-intensity applications in order to 
distribute FUS energy exposure over time, avoiding overexposure the tissue 
target but still able to induce a physiological response. This allows the tissue to 
“rest” in between pulses, whereas in high-intensity FUS, the ultrasound is 
transmitted continuously at high intensities for long durations to maximize tissue 
exposure, causing an ablation.     
 
Preclinical studies have demonstrated the ability of PLIFUS to suppress seizures in 
Kainic acid epilepsy models [21].  PLIFUS exposure can also temporarily expand 
extracellular and paravascular spaces in brain [22]. Thus, we hypothesize that 
PLIFUS stimulation will result in mechanical disruption of the target tissue (here, 
the epileptogenic focus), preserving the integrity of the tissue but rendering it 
unable (or less able) to mount seizure activity for a period of time.   
 
In this study, we propose long-term, repeated PLIFUS stimulation of brain regions 
containing epileptic tissue, with the goal of decreasing seizure activity in subjects 
with drug-resistant temporal lobe epilepsy. We target temporal lobe epilepsy 
because it is the most common form of epilepsy; the temporal bone is also 
thinner than other areas of the skull, making the temporal window most 
amenable to sonification.  The course of treatment will be 1 month in duration, 
spread over 2 sessions per week for 4 weeks of 45 minute PLIFUS treatment per 
session. Outcomes will be assessed by the reduction in seizure frequency and 
changes in electroencephalography (EEG). 
 
 
II. Specific Aims: 
The aim of the proposed pilot study is to investigate patient tolerability and 
efficacy of moderate term, repeated exposure of PLIFUS in patients with drug-
resistant temporal lobe epilepsy. We hypothesize that the treatments will be well-
tolerated, subjects’ EEGs will show improvement (fewer and/or attenuated 
epileptiform discharges), and that subjects will experience a reduction in seizure 
frequency as a result of the treatment without adverse events.  
 
III. Subject Selection: 

 
To be eligible for participation in this study, participants must be eighteen years 
or older with a diagnosis of drug-resistant temporal lobe epilepsy and meet the 
inclusion and criteria below. There are no exclusions based on race, ethnicity or 
gender. Study wide, the plan is to consent and enroll approximately ten (10) 
participants. 
 
Inclusion Criteria: 
- Subjects at least eighteen (18) years of age 
- Subjects with drug-resistant temporal lobe epilepsy whose seizures involve 
altered awareness (ie failed at least two trials of antiepileptic drugs for 
seizures), as determined by one of the BWH epilepsy neurologists based on 
clinical seizure semiology and/or EEG findings. 
- Subjects who experience at least 1-2 seizures per month on average, are 
aware of or have reliable caregivers who are aware of when seizures occur 
and can reliably log seizure frequency 
- Subjects who have the cognitive ability to read and understand the consent 
form, describe any potential symptoms experienced during or after 
treatments. 
 
Exclusion Criteria: 
- Subjects with a cognitive or psychiatric disorder that limits the ability to 
give informed consent or are unable to cooperate with testing 
- Subjects with dementia or other progressive degenerative disease, delirium 
or active psychosis 
- Subjects with ferromagnetic materials in the head 
- Subjects with severe cardiac disease, increased intracranial pressure, or a 
Transcutaneous Electrical Nerve Stimulation (TENS) unit 
- Subjects who have primary generalized epilepsy or non-epileptic seizures 
- Subjects who have experienced status epilepticus in the 3 months leading 
up to enrollment in the study 
- Subjects (females) who are pregnant, or are of childbearing potential and 
not willing to use reliable birth control during the treatment period. 
- Subjects who are unable to get a brain MRI for any reason (implanted metal 
in body, inability to lie still) 
- Subjects with current brain tumors or an intracranial vascular lesion 
- Subjects with severe, uncontrolled medical problems, such as diabetes 
mellitus, hypertension, pulmonary or airway disease, heart failure, 

 
coronary artery disease, or any other condition that poses a risk for the 
subject during participation.  
- Subjects with holes in the treatment area of the skull from trauma or prior 
surgery 
- Subjects with pacemakers, medication pumps, and other implanted 
electronic hardware.  If a subject has a working Vagal Nerve Stimulator in 
place, the device will be turned off prior to each treatment session and 
then turned back on after each session. 
 
Source of subjects and recruitment methods: 
 
Recruitment will primarily take place through BWH and MGH epilepsy clinics.  Dr. 
Bubrick (PI) and her colleagues in the Division of Epilepsy at BWH will refer eligible 
patients to the study.  The PI will discuss the trial in detail with the epilepsy 
division at MGH, and her research assistant will also screen epilepsy clinics at 
BWH and MGH for eligible subjects and alert the primary epileptologist (either Dr. 
Bubrick or one of her colleagues) when a patient is identified as eligible for the 
trial.  If the patient meets eligibility criteria, the primary epileptologist will ask 
permission for the research team to approach him/her regarding the study.  If 
interested in participating, Dr. Bubrick will meet with each subject to discuss all 
aspects of the trial and will obtain informed consent.  Advertisements will also be 
posted at BWH, MGH, and online.  
 
In the event that the potential subject is one of the PI’s patients, the study team 
will ensure that patients do not feel obligated to participate in study by writing to 
the patient first and given the opportunity to make the first contact if he/she is 
interested, or a physician colleague (Co-I, Dr. Daniel Weisholtz) may initially 
explain the study or re-contact the potential subject after the Investigator has 
presented the study.  We also plan to send the Consent Form home with any 
potential subjects to review it thoroughly and call back if they wish to participate 
or have any questions or concerns.   
 
IV. Subject Enrollment: 
 
Written informed consent will be obtained prior to study enrollment or 
administration of any measures or procedures. The consent process will be 
administered in person by the PI (Principle Investigator) or Dr. Weisholtz (who will 

 
serve as CO-I (Co-Investigator) and back-up epilepsy attending if the PI is ever 
unavailable), both of whom have received research ethics training. The PI or Co-I 
will assess whether the potential participant understands the study procedures, 
and will ensure that all questions related to the study are answered. Potential 
subjects will be informed that participation is completely voluntary, that they may 
discontinue their participation at any time without penalty, and that declining to 
participate or discontinuing participation from the study will not in any way alter 
the clinical care they receive by their epilepsy physician. The PI will make the 
ultimate determination of whether a participant meets all the enrollment criteria 
and is appropriate to enter the study. Participants that do not meet the study 
criteria will be informed that based on the information collected, it has been 
determined they are not eligible for the current study. 
 
 
V. Study Procedures: 
Study Visits and Timeline 
 
The study procedures include the following visits: 
1) screening (1 hour) 
2) updated MRI if previous MRI was completed 3 months prior to screening 
(2 hours) 
3) treatment visits (8 sessions over 4 weeks with each lasting approximately 
2 hours) 
4) post treatment visit (1 hour) 
5) phone follow-up (15 minutes) 
 
Detailed Subject Procedures:   
 
Screening Visit  
The subject will meet with the PI of the study, Dr. Ellen Bubrick, to determine if 
the subject qualifies for the study. If the subject is an appropriate candidate, the 
PI will review this consent form with the subject and review the details of the 
study and what exactly is involved including any potential risks and/or benefits.  
Any questions the subjects have regarding the trial will be answered to the best of 
her ability.  If the subject decides to enroll in the study, the subject will need to 
sign this consent form before starting in the trial. Seizure frequency will also be 
confirmed upon review of the medical record including the month prior to 

 
enrollment, and the subjects will log their seizure frequency using a daily seizure 
log diary form for one month prior to beginning the treatment.  
We will collect de-identified clinical information regarding all subjects who 
participate in the study including basic demographics (age, sex) as well as 
information regarding each subjects’ epilepsy (age of onset, duration of illness, 
medication history, laterality, mesial vs neocortical), tolerability of the trial, and 
any potential changes in seizure frequency or adverse effects. 
 
Pre-treatment MRI  
Once the subject is enrolled in the study, the subject will be scheduled for a 
standard brain MRI scan at BWH if they have not had one in the last 3 months. An 
updated brain MRI will be obtained on each subject to exclude the possibility of 
any potential de novo lesions that may have developed since the subject’s last 
clinical scan, and it will also be used to correlate with the neuronavigation 
software and to measure skull thickness in the treatment area.  This will be 
reviewed by a BWH neuroradiologist, and an official clinical read will be placed 
into Epic, but the scan will be paid for by the study.  If any new lesions or 
concerns are identified on that MRI scan, the PI will notify the patient’s primary 
epileptologist to discuss with the patient. 
 
The MRI scan (including MPRAGE T1 and also high resolution T2 sequences) will 
be performed on each subject with registration fiducials (PinPoint 128, Beekley 
Medical, Bristol, Connecticut) attached at multiple sites on the head (e.g., across 
the forehead, face, and behind the ears). After obtaining the scan, the navigation 
system (Polaris Vicra, NDI, Waterloo, Ontario) will be used to register the fiducials 
with the MRI dataset (3D Slicer, Boston, Massachusetts). Four anatomical sites—
inion, nasion, and pre-auricular points—will also be registered to the same MRI 
dataset using tracked probes. The registration data will be saved for the 
treatment sessions. 
 
Daily Seizure Log Diary and Questionnaires  
The subject will be asked to keep track of their seizure events in the Daily Seizure 
Log Diary from the screening visit until 2 months after the last treatment session. 
The subject can complete the daily seizure activity on the subject’s schedule 
outside of the hospital. 
 

 
Each subject will be asked to complete a Beck Depression Inventory and a Quality 
of Life in Epilepsy (QOLIE-10) inventory at the beginning of the treatment period, 
and again one month after study completion. 
 
PLIFUS Treatment Sessions 
The treatment period will include 8 treatment sessions total.  These will occur 2 
days per week for 4 weeks, each lasting approximately 1-2 hours, starting 1 
month after seizure logging begins.  The PI or the Co-I will be present at all 
treatment sessions.  
 
EEG leads will be placed on the subject’s scalp at the time of the first treatment 
session and at the last treatment session.  Up to 22 EEG scalp electrodes will be 
positioned over the subject’s scalp as well as a head-tracker band. Special 
conductive paste or sticky gel dots will be used to fasten the electrodes to the 
subject’s scalp. The conductive paste and sticky gel dots are non-toxic, 
hypoallergenic, non-staining, and non-irritating for most patients. Connecting the 
electrodes may take up to 30 minutes. The subject will be seated in a comfortable 
therapy chair or adjustable bed where the subject will remain for approximately 1 
hour for the duration of the therapy session. We are performing the first visit 
under EEG guidance to ensure no increased cortical irritability (i.e. epileptiform 
spiking) is seen after approximately 30 minutes of baseline EEG is obtained, and 
to identify any changes in interictal epileptiform spiking during the treatment.  A 
repeat EEG will be obtained after completion of all treatments for comparison.  
 
At the beginning of the treatment sessions, navigational trackers will be attached 
to the subject’s head using an elastic headband. The tracked probe will be used to 
re-register the subject’s head—via the inion, nasion, and pre-auricular points—to 
the subject’s MRI dataset. The same MRI dataset will be registered to the 
ultrasound transducer using the navigation system, thus establishing registration 
between the subject’s head, the MRI, and the ultrasound transducer. The 
navigational trackers will remain strapped to the subject’s head during the 
treatment to maintain registration. Compounded errors (MRI-to-subject, subject-
to-transducer), including inaccuracies in anatomical landmarking, leads to a 
spatial accuracy error estimation of 2 mm. Subject motion will be tracked at high 
temporal resolution during the treatment, so is not anticipated to contribute 
significantly to the error estimation. 
 

 
The PLIFUS device will then be placed against the subject’s scalp, just above the 
ear on the side the subject’s doctor has determined the subject’s seizures come 
from. The device uses a water filled membrane (“water bag”) placed against the 
side of the subject’s head to transmit PLIFUS stimulation to the subject’s brain 
through the subject’s skull. The contact area against the subject’s temple is 
approximately the entire side of the subject’s head (above the subject’s lower eye 
line but not covering the subject ear). The membrane is slightly larger than a large 
earmuff pad. The device and its water bag membrane are held in place by an 
adjustable positioning bench. Ultrasound gel will be applied between the 
subject’s skin and the membrane to ensure sufficient acoustic coupling (i.e. the 
gel prevents air bubbles from being trapped between the subject’s scalp and the 
device, which blocks ultrasound waves). Ultrasound gel may be reapplied multiple 
times throughout the therapy session. The ultrasound gel is non-toxic, 
hypoallergenic, non-staining, and non-irritating to most patients.  
 
On the opposite side of the subject’s head (in the same region), a stabilizer pad 
made of soft material will be placed. The pad is about half the size of the water 
bag and will adjust to hold the subject’s head steady against the water bag. The 
subject head will be positioned forward looking in a comfortable manner. 
Although the subject will be asked to keep the subject’s head as still as possible 
during the PLIFUS stimulation, accidentally moving the subject’s head will not 
disrupt the stimulation. The navigation system allows us to correct for any 
unintentional head movements.  An EKG (or cardiac) lead may also be placed on 
the chest so we can monitor the subject’s heart rate during the treatments. 
 
Once the subject is comfortably connected to the PLIFUS device, we will begin the 
PLIFUS treatment session which will take approximately 50 minutes. The PLIFUS 
stimulation is activated when the operator presses a “Start Button” and he/she 
will tell the subject several seconds before he/she will push the button. One 
button push turns the PLIFUS stimulation “ON” for 2 minutes and 20 seconds. This 
time frame is called a “dose.” The subject may receive up to 16 Doses during the 
50 minute treatment. After each dose is delivered there will be a pause of at least 
30 seconds until the operator pushes the On button again. The 30 second time 
period is used for the operator to steer the PLIFUS stimulation position to 
different parts of the subject’s brain. It also gives the subject time to rest in 
between doses. After the last dose for that session is delivered, we will disconnect 

 
the PLIFUS system from the subject’s head and remove any EEG or EKG electrodes 
that were placed. 
 
At the end of each treatment session, the patient will be assessed for any 
potential symptoms including pain or discomfort by a member of the study team.  
An adverse effects form will be completed by the patient after each treatment 
session.  Subjects will be encouraged to report any symptoms or discomfort 
experienced during treatment sessions or in between sessions, at which point the 
subject will be assessed by the PI or Co-I and a determination will be made as to 
whether it safe for treatment to be continued. Target areas for the Focused 
Ultrasound (FUS) will include the hippocampus and/or the anterior temporal lobe.  
 
 
Post Treatment Follow-ups 
 
The subject will also have a post-treatment follow up visit with the study PI or the 
subject’s primary epilepsy neurologist approximately 1 month after the last 
treatment session.  Subject will also be called by a study team member 3 months 
after treatment to check how the patient is doing generally and assess seizure 
frequency.  
 
Study Schedule 
Visit 
Screening Treatment 
1 
Treatment 
2-7 
Treatment 
8 
Post 
Treatment 
Follow-
up call 
Timeline 
Day 0 
Month 1 
Month 1-3 Month 3 
Month 5 
Month 
6 
Consent 
X 
 
 
 
 
 
Review of 
Inclusion/Exclusion 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Review of Epilepsy 
History 
X 
 
 
 
 
 
Neurological Exam 
 
 
 
 
 
 
BDI-II 
 
X 
X 
X 
X 
 
QOLIE-10 
 
X 
X 
X 
X 
 
Adverse Event 
 
X 
X 
X 
X 
 
Seizure Log 
X 
X 
X 
X 
X 
 
EEG 
 
X 
 
X 
 
 
EKG 
 
X 
 
 
 
 

 
MRI 
X 
 
 
 
 
 
 
 
Subject Compensation 
 
Each subject will be compensated $50 after 4 treatment sessions are completed, 
and then an additional $150 at completion of the study for a total of $200 if 
completed all study visits and assessments.  Parking at BWH will also be 
compensated.  
 
 
Device Platform 
 
The ultrasound transducer was designed, constructed, and characterized at the 
Focused Ultrasound Laboratory (FUS Lab) of the Brigham and Women’s Hospital 
(Director, Nathan McDannold, PhD). It is composed of a spherically focused 
piezocermic element (Piezo Kinetics, Bellfonte, Pennsylvania) mounted by room-
temperature-vulcanizing silicone in an acrylic housing that maintains air backing 
under submersion in water at STP. Eletrical coupling and passive matching 
circuitry were likewise designed and constructed within the electronic and 
machine shops of the FUS Lab’s main research facility at 221 Longwood Avenue, 
EBRC 521, Boston, MA. The device is currently stored at the FUS Lab within a 
secured laboratory. When the study begins, the device will be stored in the EEG 
Lab, a clinical facility located within the BWH Hale Building for Transformative 
Medicine, 60 Fenwood Road, Boston, MA.  
 
Detailed drawings, system calibration and maintenance procedures, and other 
comprehensive device specifications can be found in the Device Manual. The 
Device Manual is written to provide details of the custom device platform for the 
institutional review board Biomedical Engineering and Radiation Safety review 
process. We applied for and received an Investigational Device Exemption from 
the FDA Documentation supporting non-significant risk assessment is included in 
the IRB proposal packet.  
 

 
 
The noninvasive device includes 5 subsystems including the FUS transducer, 
positioning system, water bag membrane, and water tank system, control system 
and safety monitoring interface, Neuronavigation system, and calibration 
equipment. All electronic hardware near or touching the patient are powered by 
isolation transformers. Device operation, calibration, and maintenance 
instructions are listed under the Device Manua.  
 
Stopping Rules for PLIFUS Treatment Sessions 
The device operator will be in possession of a “STOP” button, which will be 
pressed immediately if he / she sense the subject are having any discomfort due 
to the stimulation. We do not expect this to occur, as no adverse events have 
been reported in prior studies as discussed above, but will proceed this way in an 
abundance of caution. The subject will be encouraged to let the study staff know 
if the subject feel any discomfort at any time, or want to stop the treatment for 
any reason.  If this occurs, the operator will also push the “STOP” button 
immediately.  The PI or Co-I who are BWH epilepsy neurologists will be present 
during the treatment session.  If any symptoms are reported during the treatment 
session, the physician will evaluate the subject and assess if the subject need 
urgent medical care and whether it is safe to continue in the study. 

 
An adverse event for this trial is defined as any neurologic or systemic symptom 
or sign that may occur during a treatment session, and persists even after 
sonication ends (when the “STOP” button is pressed or device is turned off).    
In the unlikely event that a major clinical event occurs that in any way seemed to 
be associated with the treatment, enrollment will be stopped and no further 
treatments will be performed until a comprehensive safety evaluation of the 
device and procedures is completed.  The study would only begin re-enrolling 
patients and continuing treatments once the safety issue had been identified and 
completely rectified.  Any adverse events that may occur during the trial will be 
reported to our IRB and the FDA. 
VI. Biostatistical Analysis:  
Specific data variables being collected for the study are patient demographics 
(including de-identified subject #, age, sex, duration of epilepsy and seizure 
history, number of antiepileptic medication trials, baseline EEG findings, seizure 
onset area), pre-determined target areas, FUS dosage parameters, skull thickness, 
EEG changes during or after treatment, patient tolerability, adverse events or 
reported symptoms during treatment, effect on seizure frequency via seizure 
logs. Study endpoints are patient tolerability, seizure frequency. We aim to 
evaluate only for any trends in seizure frequency, as our small number of only 10 
subjects and the pilot nature of the trial does not provide the statistical power for 
more significant analyses.  
VII. Risks and Discomforts: 
 
Risks to subjects 
 
All participants will be carefully screened prior to treatment for contraindications 
to PLIFUS (see exclusion criteria). Subjects may decline treatment at anytime, or 
take breaks as needed, or ask for the PLIFUS stimulation to be stopped at any 
time. PLIFUS will be administered by the PLIFUS operator with a physician present 
in the treatment room or in the building and immediately accessible by page. The 
PLIFUS operator will be a trained and qualified individual supervised by the PI to 
deliver, or assist in delivery of, PLIFUS. Training includes the knowledge of safety 
considerations and precautions associated with experimentally delivering PLIFUS 
stimulation to subjects.  
 

 
The FUS platform that will deliver PLIFUS is adjustable in intensity, duration of 
stimulation, and steerable by neuronavigation software, which our group has 
extensive experience using in TMS and other transcranial stimulation modalities. 
The isotropic spatial accuracy of the optical tracking system (NDI Polaris Vicra) is 
0.35 mm RMS (0.5-mm 95% confidence interval), as reported by the vendor’s 
performance specifications assessment 
(https://www.ndigital.com/medical/products/polaris-family/). With our probe in 
place, the isotropic spatial accuracy was measured to be 0.93 mm (SD 0.74 mm) 
by comparative analysis of eight measured points in 3-dimensional space. A 
computer controlled mechanical positioning system (Velmex, Bloomfield, New 
York) was used as the gold standard (0.076-mm accuracy).  When targeting the 
hippocampus (specifically, the anterior 2/3rds of the structure), we will be 
sonicating it perpendicularly across its anatomical axis. Even with the conservative 
assumption that the half-intensity focus must remain wholly within the 
hippocampus in cross-section, the tabulated average of 20 mm for the average 
adult human hippocampus diameter would required a targeting accuracy of 
approximately 7.6 mm. Our measured accuracy of 0.93 mm falls well within this 
requirement.  The measured half-intensity beam widths of our transducer’s 
ellipsoid focus are 4.8 mm (short axis) and 56.7 mm (long axis). Given the typical 
adult hippocampus cross-sectional diameter of 20 mm and our systems spatial 
accuracy of 0.93 mm, the 4.8 mm beam width ensures that no region outside the 
hippocampus lateral to the ultrasound propagation path will be affected. Due to 
the 56.7-mm beam length, the anatomical regions situated approximately 19.3 
mm lateral and/or medial to the hippocampus could be affected. Anatomically, 
this would include the temporal lobe laterally, and medially the structures in the 
ambient cistern (alveus, fimbrae, cerebrospinal fluid, posterior cerebral artery, 
vein of Rosenthal and optic tract) and upper midbrain (tectum).   
 
The proposed intensity levels are calibrated to only potentially yield functional 
neuromodulatory effects at the focus (i.e., no measureable temperature rise or 
mechanical tissue destruction is anticipated). Beyond the focus, any induced 
effect would be vanishingly small and transient.  Any leakage lateral to the 
hippocampus (ie temporal lobe) is unlikely to produce any adverse effects, that 
area is often resected along with the hippocampus in a temporal lobectomy 
surgery for epilepsy.  Medially, the structures running through the ambient 
cistern, specifically the artery and vein noted above, are unlikely to be affected at 
proposed intensities.  Involvement of the optic tract could potentially result in a 

 
brief disruption in the corresponding visual field. A mild, transient visual or 
hearing disturbance could potentially also be experienced by sonicating the 
tectum.  None of these are anticipated, however with the proposed intensities. 
 
In addition, an extra layer of safety will be integrated into the device control 
system as a failsafe circuit so the maximum acoustic intensity output cannot 
exceed a set maximum safety threshold. Each subject will have an individual 
water bag membrane assigned to him/her throughout the course of treatment. 
Water bag membranes will be cleaned with alcohol before and after each 
treatment session. Subjects will be asked if they are sensitive to latex, and if they 
are, a non-latex water bag will be used. 
 
To date, there are no standards specifically designed for the use of transcranial 
repeated, long-term PLIFUS exposure to humans. In our study, we will use the 
exact same PLIFUS parameters reported where PLIFUS was delivered to human 
subjects in single-session investigations in which no adverse effects resulted [3]. 
In this trial we will expand the safe single-session protocol into a multi-session 
course of treatment. We derive our “repeated, long-term” parameters by 
adapting what has been reported from existing PLIFUS studies in which repeated 
or long-term PLIFUS investigations on human or non-human primates were shown 
to be safe. These parameters include a 30 second rest time in-between PLIFUS 
dosages, similar to what has previously been used in repeated, long-term 
exposure of transcranial magnetic stimulation treatment trials for epilepsy [2] and 
other neurological disorders [23].   
 
The maximum AI reported in past human studies was a derated Ispta = 3.5–4.4 
W/cm [9], which accounts for a transmission rate through the skull that varied 
from 20 - 25 % depending on  skull thickness (4.7 to 7.8 mm at the entry position 
of the FUS beam). Transmissions occurred through the calvarium to target the 
cortex, whereas the FUS transmissions for temporal lobe target regions will occur 
through the less thick temporal bone. We make the AIloss calculation as described 
earlier in the Device Power Settings and Limits section for scaling down the AI of 
the FUS transmission to account for the thinner temporal bone through which we 
will be transmitting FUS.  
 
Although our treatment falls into the low-intensity FUS category, we will employ 
extensive safety monitoring of electrophysiology and FUS AI levels transmitted 

 
during the FUS exposure. These include real-time EEG monitoring (during first 
treatment for each subject), and real-time cavitation detection via AED. We are 
adding these extra safety precautions since this is the first human study to 
combine long-term (8 sessions over 1 month) and repeated (45 minute sessions) 
FUS exposure to temporal lobe regions. None of the human studies reported use 
of real-time AED safety monitoring. This was because the FUS parameters used 
were not expected to produce cavitation or adverse effects. Every study reported 
adequate safety of the technique, but most of these studies were performed in 
healthy tissue and FUS exposure was not repeated over multiple sessions. Since 
our study will involve sonicating epileptogenic tissue and repeated long-term FUS 
exposure over multiple beam focus targets, we are including these extra layers of 
safety monitoring out of an abundance of caution. 
 
FUS parameters in the proposed study will be F0 = 548kHz, PP = 1 ms, PRF = 500 
Hz, SD = 0.5 s, ISI = 7 s, and 20 sonications per dose taking a total of 140 s. We 
also define safety guidelines on the amount and timing of FUS doses delivered in 
a treatment session and for the course of treatment.  Safety guidelines are as 
follows:  
1) maximum dose count per session= 16  
2) maximum doses per target location per session= 3  
3) minimum rest period between each dose= 30 sec  
4) maximum sessions per week= 2 .  
 
AI during the 1st week of treatment will be set to 25 % of AImax and be increased to 
50, 75, and 100 % the 2nd, 3rd, and 4th weeks of treatment, respectively. Even 
though no human studies have reported tissue cavitation occurring at these low-
intensities levels during pulsed FUS transmission, we will perform a pre-treatment 
Acoustic Calibration Session (ACS) as an extra layer of safety. The session will 1) 
verify no cavitation occurs while delivering the 4 proposed AI levels at all FUS 
beam focus target chosen in each subject using a generic cavitation alarm 
algorithm and 2) obtain patient-specific baseline AED signals to calibrate real-time 
cavitation detection alarm algorithms for use during the remaining course of 
treatment. There will be 3 types of AED signals acquired and assessed from 
multiple locations around the head. 1) Global AED (gAED), which is the summed 
receiving signal of all the 8 AEDs sensors integrated into the 10-20 EEG grid. 2) 
Reflected AED (rAED) (2 cm diameter, 3 mm thick) oriented in a ring around the 
transmitting therapy transducer housing. 3) Far-field AED (fAED) is the receiving 

 
signal of one piezoelectric disk (30 mm diameter, 3 mm thick) adjacent to the 
scalp opposite side of the water bag. The ASC includes steering the FUS 
transducer to all the FUS beam targets and ramping up the AI to each of the 4 
intensity levels to obtain the AED baseline signals. 
 
For example, an ACS will be performed in the following way where PLIFUS 
exposure is being applied to the entire left hippocampus. A FUS target T1 may be 
assigned to MRI coordinates (R2.0, A1.3, S5.3) corresponding to the most anterior 
region of the left hippocampus and T2 (Q1 = 650) is assigned 4 mm posterior at 
(R2, P0.7, S5.3) on the next portion of the left hippocampus. Once the FUS 
transducer is positioned for sonication delivery to T1, the transducer AI will be set 
to 25 % of AImax and transmit a train of 5 sonications. A gAED, rAED, and fAED 
signal will be recorded for each sonication and then averaged for obtaining the 
patient-specific baseline AED signals. This will be repeated for 50, 75, and 100 % 
of AImax. Next, the transducer will be manually steered for FUS exposure at T2 
where the train of sonications is performed again. This procedure will be 
performed for all targets. 
 
The transducer holder is largely constructed with aluminum and acrylic, so EM 
compatibility issues are not expected.  The BWH Biomedical Engineering 
Department will perform a thorough and extensive assessment of electrical 
leakage and EM compatibility tests before we will be allowed to apply it to human 
subjects per Partners IRB stipulation.  Interference is highly unlikely; (1) the 
equipment is shielded and the XDCR is submerged in deionized water, and (2) the 
respective operating frequencies are very far apart.  In the unlikely event that 
electrical leakage or EM compatibility is noted to be an issue (e.g., impacting 
patient safety or interfering with the navigation system), we will suspend the 
study to investigate and correct the conditions that led to the issue. 
 
Methods for ensuring safety of subjects and escape criteria during study 
 
The PI or Co-I will be present during all treatment sessions.  Subjects will be 
encouraged to report if they feel any discomfort during a treatment, feel a seizure 
coming on or begin having a seizure while in the treatment room.  If any 
symptoms are reported, the operator will immediately shut down the PLIFUS 
system. The PI or Co-I, both quite experienced in evaluation and treatment of 

 
acute seizures, will perform a neurologic exam and evaluate the subject 
immediately.  The PI or Co-I will assess if the subject requires any medical care, 
and whether it is safe to continue in the study.  If a subject has one of his/her 
typical seizures during a treatment session, the treatment session will be aborted 
and the PI or Co-I will evaluate the subject. Further treatment sessions may 
continue as scheduled, as long as the subject has fully recovered from the seizure 
by the time the next treatment session is due. If a subject has a seizure that the 
seizure is worse (more intense or longer in duration) during a treatment session, 
the treatment session will be aborted and the PI or Co-I will evaluate the subject 
and determine if he/she requires urgent medical care or observation, in which 
case he/she will be taken to the BWH Emergency Department. It will later be 
determined by the PI whether it is safe for that subject to continue with future 
treatments or not.  If a subject has a typical seizure while enrolled in the study, 
but not on a treatment day, he/she will be asked to log it in the seizure diary.  If 
the seizure is worse than usual in any way, or if a subject’s seizures are occurring 
more frequently while participating in the study, the PI will determine whether it 
is safe for that subject to continue with future treatments or not.  Patients will be 
observed for up to an hour after the first treatment session to evaluate for any 
potential symptoms or issues.   
 
In the unlikely event that a major clinical event occurs that in any way seemed to 
be associated with the treatment, enrollment will be stopped and no further 
treatments will be performed until a comprehensive safety evaluation of the 
device and procedures is completed.  The study would only begin re-enrolling 
patients and continuing treatments once the safety issue had been identified and 
completely rectified.  As always, any adverse events that may occur during the 
trial will be reported to our IRB and the FDA. 
 
Foreseeable Risks and Discomforts 
 
Given the safety profile of FUS in both animal and human studies detailed above, 
we believe there are minimal risks to subjects from participating in this study.  
Most of those studies noted above were performed on normal brain tissue, 
though one was on patients with epilepsy.  Other forms of 
neurostimulation/neuromodulation have also proven safe in patients with 
epilepsy including Transcranial Magnetic Stimulation (TMS), Responsive 

 
Neurostimulation (RNS- Neuropace), Deep Brain Stimulation (DBS), and even 
Electroconvulsive Shock Therapy (ECT), which actually induces seizures to treat 
depression.  All of these are significantly more invasive than FUS, except for TMS.  
They all have been used successfully to try to reduce seizures in humans, even 
ECT in the setting of refractory status epilepticus, with varying degrees of success.  
Both DBS and high-intensity focused ultrasound [17] have been shown to be safe 
and highly successful for treatment of tremor and other movement disorders.  In 
fact the advent of neurostimulation/neuromodulation as treatment for epilepsy 
was modeled on the success seen in that of movement and other brain disorders-
the idea of stimulating the tissue that is discharging abnormally as opposed to 
lesioning it.  In all of these types of modalities, epileptic brains have tolerated this 
type of treatment quite well, it is the outcomes that have been disappointing.  We 
believe PLIFUS has more potential for better outcomes in patients with epilepsy 
given its ability to stop seizures [21] in epilepsy models and modulate auditory, 
visual, sensory, or motor responses [20] with beam focus. 
 
Specific risks related to the PLIFUS treatment are described below. Participants 
may be uncomfortable sitting or lying for an extended periods of time in the 
treatment chair during PLIFUS sessions. Study staff will monitor subjects during 
treatment sessions for any skin irritation and advise subjects to report any skin 
issues that may emerge in between sessions or in the month following the course 
of treatment. Conductive water-based or silicone based tacky dots will be used to 
place EEG scalp electrodes to the subject’s head as is done in routine EEGs. The 
dots have similar material properties as EEG conductive electrode coupling gel 
and are expected to contain the same minimal risks as having the gel in contact 
with the scalp over long periods of time as is used clinically in continuous EEG 
monitoring in hospitalized patients. The water-based dots have passed 
biocompatibility and skin irritation testing under testing standard ISO 10993-1. 
 
As PLIFUS has been used in previous human studies to elicit or suppress tactile 
sensory functions by simulating cortical targets, it is possible subjects could 
experience these temporary sensations as minor side effects during PLIFUS [5], 
[9]. The studies conducted reported some subjects having tingling sensations, 
feeling of weak electrical current flow, and numbness in their fingertips when the 
stimulation was turned on. Other types of sensations of heaviness, pressure, 
coolness, and brushing, were also reported, although the occurrences were not 
frequent and only felt when the stimulation was active and shortly after the 

 
stimulation was turned off. But since the temporal lobe is the region being 
targeted with the FUS beam focus in our investigation, the reported sensations 
due to cortical stimulation is unlikely to occur. However, human studies where 
the FUS beam focus passed close to the labyrinth region reported slight auditory 
information being perceived by the subjects [24]. The FUS beam path used to 
target the areas such as the anterior temporal lobe in our investigations may pass 
close to the labyrinth region but the ultrasound energy of the “beam path” in the 
near field is significantly less than what is at the FUS beam focus target. Near field 
is the beam path area leading up to the beam focus from the transducer and the 
far field is the beam path area beyond the FUS beam focus. Another area shown 
to experience slight and temporary functional changes due to FUS stimulation is 
the visual system. A FUS beam focus was positioned to stimulate the optic tract in 
cats. Evoked potentials of the brain centers of the visual system were used as the 
indicator of functional changes. The FUS stimulation temporarily suppressed the 
evoked potentials for several seconds or up to a minute after the stimulation  
[25].  
 
As noted above under PLIFUS Safety Summary, due to the 56.7-mm beam length, 
the anatomical regions situated approximately 19.3 mm lateral and/or medial to 
the hippocampus could be affected. Anatomically, this would include the 
temporal lobe laterally, and medially the structures in the ambient cistern (alveus, 
fimbrae, cerebrospinal fluid, posterior cerebral artery, vein of Rosenthal and optic 
tract) and upper midbrain (tectum).  None of these are anticipated, however, with 
the proposed intensities.  Given the effects on seizures without tissue damage in 
the preclinical studies cited in our proposal as well as those in normal humans 
who were sonicated in eloquent cortex without adverse effects, we hypothesize 
that PLIFUS stimulation will result in mechanical disruption of the target tissue 
(here, the epileptogenic focus), preserving the integrity of the tissue but 
rendering it unable (or less able) to mount seizure activity for a period of time. 
The highest AI level safely delivered to a human by PLIFUS was a derated ISPTA = 
4.4 W/cm2 (average skull thickness of 1.9 mm) in order to stimulate the 
somatosensory cortex and no adverse effects were reported [9]. This is 
approximately a 50% higher AI level (Ispta = 3 W/cm2) than will be used in the 
proposed study. 
Participants will be asked to complete the above-mentioned questionnaires, 
which we estimate will require <1 hour total over the course of the study. 
Minimal risks associated with completing questionnaires are participant fatigue 

 
and the possibility of minor psychological distress associated with answering 
sensitive questions regarding psychological functioning. If any concern for 
depression or suicidality emerges from the questionnaires, the PI will discuss this 
with the patient’s primary epileptologist urgently so this can be addressed. 
 
In the event that subject suffers any complications/adverse events as a direct 
cause of the treatments in this study, the study will pay for their medical care.  If 
the events are unrelated to the treatments, subject’s insurance will be billed. 
 
VIII. Potential Benefits 
 
There is no guaranteed benefit for study subjects. It is possible that participants 
will notice a decrease in seizure frequency or improved mood [36].  Participating 
in this study may serve to improve future epilepsy treatment. 
 
IX. Monitoring and Quality Assurance  
 
Research staff will all receive standard annual training in human subjects 
research, data security, HIPAA regulations, patient and data privacy, and good 
research practice. All personnel involved in this research will receive a copy of the 
approved protocol and the PI will ensure all study stuff understand their role in 
the study and the functions that they must perform. The PI will also be 
responsible for monitoring the accuracy and completeness of the informed 
consent process and documentation and the data collection and entry. Participant 
confidentiality will be maintained by de-identifying personal information and 
following the applicable Good Clinical Practice guidelines for clinical research. 
 
Data safety monitoring plan  
 
Specific aspects of the data safety monitoring plan are: (1) Data sheets will be 
stored in a PI’s locked files in a locked office; (2) Data will be entered in coded 
form; (3) Data will be stored in computer files protected from unauthorized 
access by passwords; (4) Information that might potentially allow an individual 
participant to be identified will not be allowed in any publications, or reports sent 
to individuals outside the study; and (5) All employees who are to handle data will 
be certified in Good Clinical Practice and Human Subjects Protection Training in 
confidentiality policies and procedures. Only information 

 
relevant to the protocol will be recorded.  
 
Management of risks to confidentiality 
 
Strict standards of confidentiality will be maintained. Precautions will be taken to 
prevent disclosure of information to unauthorized parties. All paper records, 
forms and data will be stored in secure files to which only members of the 
investigative team will have access. Computer records will be protected by 
standard measures that limit access of the data to designated trained research 
project personnel. Computers with identifiable subject data will be password 
protected and encrypted to ensure confidentiality and kept behind the Partners 
firewall. 
 
X. References: 
[1] Kwan P, Brodie MJ: Early identification of refractory epilepsy. N Engl J 
Med. 2000;342(5):314‐9 
[2] Chang BS: TMS: A Tailored Method of Stimulation for Refractory Focal 
Epilepsy? Epilepsy Curr. 2013;13(4):162‐3 
[3] Lee W, Kim HC, Jung Y, et al: Transcranial focused ultrasound stimulation 
of human primary visual cortex. Sci Rep. 2016;6:34026 
[4] Lee W, Kim S, Kim B, et al: Non‐invasive transmission of sensorimotor 
information in humans using an EEG/focused ultrasound brain‐to‐brain 
interface. PLoS One. 2017;12(6):e0178476 
[5] Legon W, Sato TF, Opitz A, et al: Transcranial focused ultrasound 
modulates the activity of primary somatosensory cortex in humans. Nat 
Neurosci. 2014;17(2):322‐9 
[6] Mueller J, Legon W, Opitz A, Sato TF, Tyler WJ: Transcranial focused 
ultrasound modulates intrinsic and evoked EEG dynamics. Brain Stimul. 
2014;7(6):900‐8 
[7] Leo A, Mueller JK, Grant A, Eryaman Y, Wynn L: Transcranial focused 
ultrasound for BOLD fMRI signal modulation in humans. Conf Proc IEEE 
Eng Med Biol Soc. 2016;2016:1758‐1761 
[8] Lee W, Kim H, Jung Y, et al: Image‐guided transcranial focused ultrasound 
stimulates human primary somatosensory cortex. Sci Rep. 2015;5:8743 
[9] Lee W, Chung YA, Jung Y, Song IU, Yoo SS: Simultaneous acoustic 
stimulation of human primary and secondary somatosensory cortices 
using transcranial focused ultrasound. BMC Neurosci. 2016;17(1):68 

 
[10] Barlinn K, Barreto AD, Sisson A, et al: CLOTBUST‐hands free: initial safety 
testing of a novel operator independent ultrasound device in stroke‐free 
volunteers. Stroke. 2013;44(6):1641‐6 
[11] Horodyckid C, Canney M, Vignot A, et al: Safe long‐term repeated 
disruption of the blood‐brain barrier using an implantable ultrasound 
device: a multiparametric study in a primate model. J Neurosurg. 
2017;126(4):1351‐1361 
[12] Carpentier A, Canney M, Vignot A, et al: Clinical trial of blood‐brain barrier 
disruption by pulsed ultrasound. Sci Transl Med. 2016;8(343):343re2 
[13] Downs ME, Buch A, Sierra C, et al: Long‐Term Safety of Repeated Blood‐
Brain Barrier Opening via Focused Ultrasound with Microbubbles in Non‐
Human Primates Performing a Cognitive Task. PLoS One. 
2015;10(5):e0125911 
[14] BrainSonix Inc.: Low‐intensity Focused Ultrasound Pulsation (LIFUP) for 
Treatment of Temporal Lobe Epilepsy. 2016. 
https://clinicaltrials.gov/ct2/show/NCT02151175 
[15] Monti MM, Schnakers C, Korb AS, Bystritsky A, Vespa PM: Non‐Invasive 
Ultrasonic Thalamic Stimulation in Disorders of Consciousness after 
Severe Brain Injury: A First‐in‐Man Report. Brain Stimul. 2016;9(6):940‐
941 
[16] Leinenga G, Langton C, Nisbet R, Gotz J: Ultrasound treatment of 
neurological diseases‐‐current and emerging applications. Nat Rev Neurol. 
2016;12(3):161‐74 
[17] Elias WJ, Lipsman N, Ondo WG, et al: A Randomized Trial of Focused 
Ultrasound Thalamotomy for Essential Tremor. N Engl J Med. 
2016;375(8):730‐9 
[18] Roberts M: Scientists breach brain barrier to treat sick patient. BBC News 
online, 2015. 
http://www.bbc.com/news/health‐34775604# 
[19] Legon W, Bansal P, Tyshynsky R, Ai L, Mueller JK: Transcranial focused 
ultrasound neuromodulation of the human primary motor cortex. bioRxiv. 
2018 
[20] Gavrilov LR: Use of focused ultrasound for stimulation of nerve structures. 
Ultrasonics. 
1984;22(3):132‐8 

 
[21] Min BK, Bystritsky A, Jung KI, et al: Focused ultrasound‐mediated 
suppression of chemically‐induced acute epileptic EEG activity. BMC 
Neurosci. 2011;12:23 
[22] Hersh DS, Nguyen BA, Dancy JG, et al: Pulsed ultrasound expands the 
extracellular and perivascular spaces of the brain. Brain Res. 
2016;1646:543‐550 
[23] Lefaucheur JP, Andre‐Obadia N, Antal A, et al: Evidence‐based guidelines 
on the therapeutic use of repetitive transcranial magnetic stimulation 
(rTMS). Clin Neurophysiol. 2014;125(11):2150‐206 
[24] Tsirulnikov EM, Vartanyan IA, Gersuni GV, et al: Use of amplitude‐
modulated focused ultrasound for diagnosis of hearing disorders. 
Ultrasound Med Biol. 1988;14(4):277‐85 
[25] Adrianov OS, Vykhodtseva NI, Fokin VF, Uranova NA, Avirom VM: 
[Reversible functional shutdown of the optic tract on exposure to focused 
ultrasound]. Biull Eksp Biol Med. 1984;97(6):760‐2 
[26] Ammi AY, Mast TD, Huang IH, et al: Characterization of ultrasound 
propagation through ex‐vivo human temporal bone. Ultrasound Med Biol. 
2008;34(10):1578‐89 
[27] Hameroff S, Trakas M, Duffield C, et al: Transcranial ultrasound (TUS) 
effects on mental states: a pilot study. Brain Stimul. 2013;6(3):409‐15 
[28] Miller GW, Eames M, Snell J, Aubry JF: Ultrashort echo‐time MRI versus CT 
for skull aberration correction in MR‐guided transcranial focused 
ultrasound: In vitro comparison on human calvaria. Med Phys. 
2015;42(5):2223‐33 
[29] Willems PW, Van Der Sprenkel JW, Tulleken CA, Viergever MA, Taphoorn 
MJ: Neuronavigation and surgery of intracerebral tumours. J Neurol. 
2006;253(9):1123‐36 
[30] Ahmed J, Metrick M, Gilbert A, et al: Electroconvulsive therapy for super 
refractory status epilepticus.  J ECT.  2018;34(1):e5-e9 
[31] Zeiler F, Matuszczak M, Teitelbaum J, et al: Electroconvulsive therapy for 
refractory status epilepticus: A systematic review. Seizure. 2016;35:23-32. 
[32] Wei KC, Tsai HC, Lu YJ, et al: Neuronavigation‐guided focused ultrasound‐
induced blood‐brain barrier opening: a preliminary study in swine. AJNR 
Am J Neuroradiol. 2013;34(1):115‐20