A Feasibility Study of Focused Ultrasound to Perform Bilateral Medial Thalamotomy for the Treatment of Chronic Trigeminal Neuropathic Pain
Phase: NA
Conditions: Trigeminal Neuropathic Pain
Sponsor: InSightec

Protocol Version Date 06 December 2019 
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Clinical Protocol:  ClinicalTrials.gov ID NCT03309813   Date: August 16, 2023 
Version Date 
December 6, 2019 
Amendment No. 
Amendment 2 
Protocol Number 
NP002 
IDE Number 
G170077 
Protocol Title 
A Feasibility Study of Focused Ultrasound to Perform Bilateral 
Medial Thalamotomy for the Treatment of Chronic Trigeminal 
Neuropathic Pain 
 
Approvals: 
Site 
Sponsor 
 
 
______________________________________ 
 
 
 
______________________________________
 
 
Nadir Alikacem, PhD                         Date 
VP Global Regulatory Affairs and CRO  
InSightec      
 
 
 
 
 

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Table of Contents 
1.0 
PRECIS ....................................................................................................................................... 4 
2.0 
BACKGROUND ......................................................................................................................... 5 
2.1 
The problem of neuropathic pain .............................................................................................. 5 
2.2 
Neuropathic pain syndromes of the head and neck .................................................................... 5 
2.3 
The origins of stereotactic surgery to treat pain ......................................................................... 7 
2.4 
Rationale for medial thalamotomy ............................................................................................ 8 
2.5 
Results of medial thalamotomy ................................................................................................ 9 
2.6 
Central lateral thalamotomy: refinement… ............................................................................... 9 
2.7 
Stereotactic radiofrequency CL thalamotomy ......................................................................... 10 
2.8 
Stereotactic focused ultrasound CL thalamotomy ................................................................... 10 
2.9 
Rationale for this study:  focused ultrasound medial thalamotomy for…  ................................ 11 
2.10 
Outcome reporting in  neuropathic pain: ................................................................................. 12 
3.0 
OBJECTIVES............................................................................................................................ 13 
3.1 
Safety..................................................................................................................................... 13 
3.2 
Efficacy ................................................................................................................................. 13 
4.0 
HYPOTHESIS ........................................................................................................................... 15 
4.1 
The Hypotheses Tested .......................................................................................................... 15 
4.2 
Case Report Form Data .......................................................................................................... 15 
5.0      DESCRIPTION OF PATIENT POPULATION ........................................................................... 15 
Subject Selection ............................................................................................................................... 15 
5.1 
Subject Enrollment ................................................................................................................. 16 
5.2 
Inclusion Criteria ................................................................................................................... 16 
5.3 
Exclusion Criteria .................................................................................................................. 17 
6.0 
INVESTIGATIONAL PLAN..................................................................................................... 20 
6.1 
Study Design .......................................................................................................................... 20 
6.2 
Sham Study Design ................................................................................................................ 20 
6.3 
Pre-Treatment Procedures ...................................................................................................... 21 
6.4 
Randomization ....................................................................................................................... 23 
6.5 
Treatment Procedures ............................................................................................................. 23 
6.6 
Sham Procedures .................................................................................................................... 27 
6.7 
Follow-up .............................................................................................................................. 27 
6.7.1 
Day 1 ............................................................................................................................. 28 
6.7.2 
Day 7 ............................................................................................................................. 28 
6.7.3 
Month 1.......................................................................................................................... 28 

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6.7.4 
Month 3.......................................................................................................................... 28 
7.0 
STUDY REQUIREMENTS AND VISIT SCHEDULE .............................................................. 30 
8.0 
DATA ANALYSIS PLAN ......................................................................................................... 31 
8.1 
Safety..................................................................................................................................... 31 
8.2 
Efficacy ................................................................................................................................. 31 
8.3 
Subject Health Status ............................................................................................................. 31 
8.4 
Statistical Considerations and Sample Size ............................................................................. 31 
8.5 
Subject Confidentiality ........................................................................................................... 31 
9.0 
RISK MITIGATION ................................................................................................................. 32 
9.1 
General Device Related Risks ................................................................................................ 32 
9.2 
Risk of Contrast Agent ........................................................................................................... 33 
9.3 
Risks incidental to the MRgFUS treatment ............................................................................. 33 
9.4 
Risks Associated with the MRgFUS Treatment ...................................................................... 33 
9.5 
Risks related to bilateral lesioning of central lateral thalamic nucleus ..................................... 36 
9.6 
Risks Related to the Sonication Pathway ................................................................................ 38 
9.7 
Neurological Risks ................................................................................................................. 39 
9.8 
Anticipated Treatment Side Effects from MRgFUS ................................................................ 40 
9.8.1 
Procedure-related events include:.................................................................................... 40 
9.8.2 
Events which are Unrelated to the ExAblate device include: ........................................... 40 
9.8.3 
Drug reactions include: ................................................................................................... 41 
9.8.4 
Events related to malfunction or mis-use of the device include: ....................................... 41 
9.9 
Adverse Reactions and Precautions ........................................................................................ 42 
9.10 
Criteria for Removal from the Study ....................................................................................... 42 
9.11 
Criteria for Stopping the Study ............................................................................................... 42 
10.0 
Adverse Event Reporting ........................................................................................................... 42 
10.1 
Adverse Events Analysis ........................................................................................................ 43 
11.0 
POTENTIAL BENEFITS .......................................................................................................... 44 
12.0 
MONITORING PLAN............................................................................................................... 44 
12.1 
Electronic Data Capture (EDC) .............................................................................................. 45 
13.0 
INVESTIGATOR RESPONSIBILITIES.................................................................................... 45 
14.0 
APPENDICES ........................................................................................................................... 46 
15.0 
REFERENCES .......................................................................................................................... 46 
 
 

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A Feasibility Study of Focused Ultrasound to Perform Bilateral Medial 
Thalamotomy for the Treatment of Chronic Trigeminal Neuropathic Pain  
 
The goal of this prospective, randomized, sham-controlled, crossover study is to generate data to 
evaluate the safety and feasibility of ExAblate 4000 treatment of chronic trigeminal neuropathic 
pain. 
 
Indication of Use: Bilateral ablation of medial thalamic nuclei for treatment of trigeminal 
neuropathic pain. 
 
1.0 
PRECIS   
Focused ultrasound has proven effective for deep brain lesioning through the intact skull, and 
MRI can be utilized for stereotactic targeting and continuous temperature monitoring.  Recently, 
focused ultrasound was used to successfully perform ventrolateral thalamotomy to alleviate 
essential tremor – an event paving the way for the first FDA approval in brain.   
Historically, medial thalamotomy, the termination of the primary pain pathway from the spinal 
cord, has suggested efficacy for the treatment of various pains.  Neurosurgical interventions for 
pain have been plagued, however, by open label studies confounded by heterogeneous pain 
conditions and imperfect outcome measures.     
This pilot study will investigate the feasibility of focused ultrasound to safely perform a bilateral 
medial thalamotomy and the potential to relieve neuropathic pain (NP).   The neuropathic pain 
from trigeminal neuropathies and other craniofacial pain syndromes represent a relatively 
homogenous condition that is disabling and notoriously refractory to medical treatment.    This 
study is rigorously designed as a randomized, sham-controlled trial where the ten patients and 
their assessors are blinded to the treatment assignment.  Validated pain scales and functional 
measures of pain and quality of life will be assessed by a multidisciplinary team.  Objective 
measures of treatment effect will be determined by functional brain imaging.   
 

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2.0 
BACKGROUND 
2.1 The problem of neuropathic pain 
Neuropathic pain, defined by the International Association for the Study of Pain as “pain 
initiated or caused by a primary lesion of dysfunction of the nervous system,” is a disabling and 
chronic pain with limited effective treatments. Surveys of primary care patients estimate the 
incidence of neuropathic pain in communities to approximate 10%. 1,2 This pain is difficult to 
treat despite multimodal therapies with ~50% patients achieving only partial relief.3 
Pain remains a major societal problem and has resulted in an opioid epidemic.  Approximately 
20% of patients presenting to physician offices with pain receive an opioid prescription.4  In 
2012, clinicians wrote 259 million prescriptions for opioids for pain, enough for every adult in 
the United States to have a bottle.5   Opioid pain medication use presents serious risks, including 
overdose and opioid use disorder.6  From 1999 to 2014, over 165,000 persons died in the U.S. 
from overdose related to opioid pain medication.7  Prescriptions for opioids have increased in 
parallel with opioid-related overdose deaths.8  The Drug Abuse Warning Network estimated that 
420,000 emergency department visits in 2011 were related to the misuse or abuse of narcotic 
pain relievers.9    
2.2 
Neuropathic pain syndromes of the head and neck 
With damage to the peripheral nervous system, sensory symptoms develop including numbness, 
tingling, allodynia, paresthesia and neuropathic pain.   Neuropathic pain is the prominent and 
most disabling manifestation of most peripheral neuropathies.  This is similarly observed with 
cranial nerves and nerves of the head and neck region.  Craniofacial neuropathic pain occurs 
from a variety of etiologies and can manifest as a severe, disabling and difficult to treat pain 
syndrome.     
Trigeminal neuralgia is perhaps the most commonly recognized craniofacial pain syndrome, and 
perceived as one of the most severe pain conditions afflicting humans.  As a rule, trigeminal 
sensation is preserved, and the disease solely manifests as pain.  Fortunately, there are several 
medical and surgical therapies which can be effective.  While the disease may not be cured, it 
can be managed effectively. 
 
Trigeminal neuropathy, on the other hand, is a similarly painful condition where the nerve is 
damaged with resulting associated sensory deficits.  The pain of trigeminal neuropathy is 
notoriously refractory to medical and surgical treatments.  Because of the differential response to 
therapy, the diagnostic distinction between trigeminal neuralgia and trigeminal neuropathy is 
imperative.  There are a variety of etiologies for trigeminal neuropathic pain.  The condition 
usually results from axonal damage, but can be associated with demyelination.  Some common 
disorders resulting in trigeminal neuropathy include:  trauma, infection, tumors, and iatrogenic.   
Burchiel proposed a classification for common facial/trigeminal pains10: 
 
 

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Diagnosis 
History 
Spontaneous 
onset 
Trigeminal neuralgia, type 1 
>50% episodic pain 
Trigeminal neuralgia, type 2 
<50% episodic pain 
 
Trigeminal 
injury 
Trigeminal neuropathic pain 
Unintentional injury, trauma, MS, tumor  
Trigeminal deafferentation pain 
Intentional deafferentation 
Postherpetic neuralgia 
Herpes zoster, shingles 
Atypical facial pain 
Somatoform pain disorder 
 
There are other cranial neuralgias besides trigeminal that can affect the head, neck, and face 
region.  These cranial neuralgias can be successfully treated with surgery and medicine, although 
the surgical options are limited, and there are minimal choices for those that are refractory to the 
traditional approaches.  Geniculate and glossopharyngeal neuralgia similarly respond to 
microvascular decompression, but when the surgery is unsuccessful or associated with cranial 
neuropathy morbidity, severe medically refractory pain conditions result. 
 
Craniofacial neuropathic pain shares many similarities in that the pain conditions can be rather 
similar in their severity, disability, and refractoriness to intervention.  Craniofacial pain 
syndromes are one of the most severely debilitating pain conditions of the peripheral or central 
nervous system.  They can result in anxiety and mood disorders and loss of work. 
An overview of craniofacial pain syndromes is included below.  This study is proposed to 
investigate a cohort of patients with treatment-resistant pain from trigeminal and other cranial 
neuropathies.  These subjects will be refractory to at least 3 trials of medication therapy and 
failed interventional or surgical procedures.  We intend to exclude trigeminal neuralgia where 
neural function is preserved and may represent a different pathophysiology than the other 
neuropathies included.  Similarly, craniofacial pains from malignancy will be excluded as many 
of these manifest a nocioceptive component, and the primary investigation here is for 
neuropathic pain.   
 
Craniofacial Pain Syndromes to be included in this trial 
Trigeminal neuropathic pain 
• Trauma  (facial fractures, sinus surgery) 
• Tumors  (cavernous sinus meningioma) 
• Infection (Tolosa Hunt) 
• Multiple sclerosis 
Trigeminal deafferentation, anesthesia dolorosa  
Postherpetic neuralgia 
 
 
 

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Other Craniofacial pain syndromes not to be included in this study  
Trigeminal neuralgia, idiopathic (type 1) 
Trigeminal neuralgia, atypical (type 2) 
Craniofacial pain of malignancy 
Atypical facial pain 
Migraine 
Headache syndromes 
Temporomandibular joint syndrome 
2.3 The origins of stereotactic surgery to treat pain   
The evolution of neurosurgical procedures to treat pain conditions is based on the anatomy of 
pain transmission to the thalamus and a history of targeting these discrete pathways. First 
described and illustrated in 1906, the spinothalamic 
tract is recognized as the primary pathway conveying 
nocioceptive information from the spinal cord to the 
brain.11  Nocioceptive information is conveyed 
primarily through the anterior quadrant of the spinal 
cord as the spinothalamic or spinoreticular tracts with 
much smaller components to parabrachial, 
mesencephalic, and hypothalamic areas.  There are 
certainly other projections of the spinothalamic tract as 
only 10% of the axons reach thalamic terminals.12  The 
spinothalamic tract terminates laterally to the ventral 
posterolateral, somatosensory thalamus and likely 
conveys the discriminative components of pain with a 
strong somatotopic organization.   The most posterior 
and inferior region of the lateral thalamic group 
(VMpo) contains neurons that are nocioceptive-
specific and produce sensations of pain or cold during microstimulation in humans with a distinct 
architecture and histology.13  The predominant nocioceptive projection to the medial thalamus 
derives from the spinoreticular tract terminating at the pontomedullary reticular formation.  
Medial spinothalamic projections are primarily to the central lateral nucleus (CL) 14-16  but also 
to centromedian (CM) and parafasicular (Pf) nuclei.15  
Neurons of the medial pain system have larger receptive fields that are poorly localizing and 
more likely involved in the affective aspects of pain like arousal, attention, and emotion.17,18    
Nocioceptive-responsive neurons responding to pin prick or heat have been identified in human 
CM-Pf.19-21  Intralaminar neurons that are nocioception-responsive are more likely to process the 
intensity rather than location of the stimulus.22  While both lateral and medial thalamic regions 
project to somatosensory cortex, the latter also projects to the anterior cingulate and insula and 
thus has been implicated in the emotional aspects of pain. In fact, nocioceptive stimulation has 
been shown by functional imaging to activate both somatosensory and limbic regions of the 
cortex.23-29    

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Surgical sectioning of the spinothalamic tract in the anterolateral quadrant of the spinal cord 
proved effective for pain conditions, especially those originating from malignancy.30,31  Pain 
relief could be achieved without loss of sensation.  The tract was later targeted at the level of the 
mesencephalon to treat pain conditions of the upper extremities and head which are less 
effectively treated by spinal cordotomy.32,33  But early, ‘open’ mesencephalotomy procedures 
required sectioning of the overlying medial lemniscus, resulting in numbness and often 
dysesthesia.  ‘Stereotactic’mesencephalotomy allowed for more discrete lesioning without 
lemniscal damage.34,35   Nashold refined the procedure with functional stimulation mapping, 
confirming that dysesthesia likely resulted from medial lemniscus damage and that the emotional 
aspects of pain could also be treated by including the medial reticular formation.36-38  Stereotactic 
(extralemniscal) mesencephalotomy was 76-85% effective for pain relief, but failed acceptance 
because of morbidity including dysesthesia and extraocular deficits as well as a risk of 
mortality.39-43   
 
The termination of the spinothalamic tract at the ventral posterolateral and posteromedial nucleus 
was targeted as a lateral thalamotomy.  The sensory representation of these nuclei had been well 
established with primate studies.44      But lesions of the lateral sensory thalamus resulted in a 
high incidence of numbness and deafferentation pain.  Spiegel & Wycis had demonstrated in the 
laboratory and in patients that the spinoreticular tract was involved in pain transmission.45,46  
Thus the medial thalamus, recipient of both ascending spinothalamic and spinoreticular 
projections, was proposed as a more favorable thalamotomy for pain alleviation.47     
 
2.4 
Rationale for medial thalamotomy  
There were several events leading to the development of bilateral medial thalamotomy for pain 
alleviation.  First, anatomic evidence shows a significant proportion of nocioceptive fibers in the 
anterolateral quadrant of the spinal cord project to the medial thalamus and its intralaminar 
nuclei.  It is been estimated that 80% of these fibers represent spinoreticular tract48, and 
spinothalamic fibers also project medially: most densely to the CL but also to the CM and Pf 
nuclei.49  The lateral pain system (‘neo-spinothalamic’), which consists primarily of 
spinothalamic projections to ventrolateral thalamus, is involved in the discrimination of pain.  
The medial pain system (‘paleo-spinothalamic’) is conveyed by spinoreticular to the intralaminar 
nuclei and is implicated in the affective aspects of pain.   
Secondly, mesencephalotomy is effective in lesioning ascending 
pain pathways with significant rates of pain relief.32,34,36-41,50  
Bilateral medial thalamotomy may relieve pain to a lesser 
degree than mesencephalotomy, but procedural morbidity is 
dramatically reduced.50   Third, thalamotomy of the ventral 
posterolateral thalamus, the primary terminus of the 
spinothalamic tract, is associated with significant risk of 
worsening deafferentation pain and numbness.  In a prospective 
DBS study for pain, medial thalamic stimulation of the CM-Pf 
complex proved more effective than VPL/VPM.51,52 

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2.5 Results of medial thalamotomy  
The medial thalamic nuclei have been stereotactically targeted with electrophysiologic 
mapping53 and also with MRI guidance.54-56   Physiologic localization of nocioceptive regions is 
imperfect because many of the intralaminar nuclei elicit a recruiting response57 as originally 
described during identification of the dorsomedian nucleus in epilepsy58 that may be nonspecific.  
Importantly, while nocioceptive-responsive neurons have been identified in the medial thalamus 
with microelectrode recordings, the vast majority of cells are unresponsive.53 
The most common bilateral medial thalamotomy performed for pain has targeted the CM-Pf 
complex and is performed bilaterally, even in the setting of unilateral pain. Bilateral medial 
thalamotomy procedures have not been associated with higher rates of morbidity than unilateral 
procedures.  Numerous series of medial thalamotomy exist documenting initially favorable rates 
of pain relief.42,59-62  CM lesions result in pain relief without sensory loss.61   Two large reviews 
of the literature have assimilated the results of numerous studies over several decades.  Lenz and 
Dougherty reported 73% of 913 patients with initial, partial relief of pain, and the outcomes 
diminished with time as expected for lesional procedures and clinical trials of pain.63   The 
recurrence rate was ~25% and occurred more commonly for neuropathic than 
noicioceptive/cancer pains.  In his review, Tasker also noted a difference between patients with 
nocioceptive (N=175) and neuropathic (N=47) pain with relief from medial thalamotomy at 46% 
and 29%, respectively.62   
All series consistently report relatively low morbidity from these procedures that is most 
commonly reported as transient cognitive disturbance and sensory deficits if the lesions extends 
laterally to the ventrolateral nuclear groups.60  Symptomatic hemorrhagic complications likely 
occur at the same rate (<1%) as other stereotactic electrode procedures.64 
More contemporary series have utilized stereotactic radiosurgery to perform bilateral medial 
thalamic lesioning.55,56  Leksell’s original intention for developing stereotactic radiosurgery and 
the Gamma Knife was for the noninvasive treatment of intractable pain.65,66   Central pain from a 
thalamic infarction has been successfully treated with stereotactic radiosurgery targeting the CM 
nucleus.55  Young et al treated 20 intractable pain patients with 140-180 Gy to the lateral MD and 
CM-Pf region.56  Sixty-five percent who were followed for longer than 3 months reported over 
50% relief, but one patient developed an atypical large lesion with hemiparesis and another 
developed fatal radiation necrosis by 14 months.  There are certainly theoretical benefits of 
thermal lesioning over ionizing radiation including lesion consistency.67,68 
2.6 Central lateral thalamotomy: refinement of the medial thalamotomy 
 
Stereotactic medial thalamotomy for pain syndromes has been refined over a couple decades by 
Jeanmonod and colleagues to target the central lateral nucleus (CL) based on anatomic, 
physiologic, and clinical studies.69  The medial ascending fibers of the spinothalamic tract 
project to intrathalamic regions with the CL nucleus receiving the most dense spinothalamic 

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innervation.14,15,70     Hirai and Jones described clusters of cells in the posterior region of CL 
(CLp) that stain richly for acetylcholinesterase, encephalin, and substance P.71  During the 
development of her stereotactic atlas of the human basal ganglia and thalamus72, Morel noted 
that these neurons of the CLp also express calbindin and calretinin.73   
 
During extensive single cell microelectrode mapping during medial thalamotomy surgeries, 
Jeanmonod et al identified bursting cells correlating to this region of CLp.60,74   These low 
threshold calcium spike bursts had previously been described by Lenz in neuropathic and 
deafferented human VPL thalamus.75  There is controversy whether these bursting neuronal 
patterns are pathologic or a physiologic response to neurogenic pain.59  Jeanmonod and Llinas 
have proposed a unifying concept of thalamocortical dysrhythmia syndrome based on the 
observation of the bursting cells in a variety of neurologic conditions.74,76 
 
2.7 Stereotactic radiofrequency CL thalamotomy 
Stereotactic radiofrequency CL thalamotomy localized with micro-
electrode recordings was reported in 96 patients with a variety of 
chronic therapy-resistant peripheral and central neuropathic pain 
syndromes.77   Fifty three percent of the patients were deemed 
responders (at least 50% pain relief) and complete pain relief was 
achieved in nearly 19% of the study.  Reduced drug requirement 
was noted for 32%.  The mean follow-up was 3 years and 9 
months.  There was no correlation between pain relief and duration 
or prior procedure, and a slight trend was noted for improvement 
with peripheral compared to central conditions.  Morbidity 
primarily resulted from hemorrhagic events identified in six of eleven patients and one of these 
resulted in a significant neurologic injury.  These events occurred early in the series and may 
have been attributed to electrode design and extensive electrode mappings of the CL target.69  
The other five complications involved reversible somatosensory deficits, which were attributed 
to explorations of the lateral portion of the nucleus early in the study.77    In a recent report 
utilizing comprehensive measures of cognition and mood from neuropsychologists, there were 
no effects on these measures following CL thalamotomy in eight patients treated for chronic 
neuropathic pain conditions.78 
 
2.8 Stereotactic focused ultrasound CL thalamotomy   
More recently, Jeanmonod et al. achieved bilateral central lateral thalamotomy ablations with 
submillimeter precision79 for therapy resistant neuropathic pain syndromes using focused 
ultrasound.54  Mean pain relief using a visual analog scale was reported as 49% at 3 months, and 
57% at one year.  There was a single thalamic hemorrhage resulting in neurologic morbidity, and 
this complication led to the universal adoption of cavitation detectors in the technology.80  
 

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2.9 Rationale for this study:  focused ultrasound medial thalamotomy for the trigeminal 
and other craniofacial neuropathic pain syndromes  
Contemporary MR guided focused ultrasound is capable of delivering 
high intensity energy through the intact human skull with precision to 
deep brain targets.  Thalamic lesions have been created within 1-2 
millimeters of accuracy 79,81 and temperature monitoring of the focus 
and surrounding brain is possible with a resolution of ~1⁰ Celsius.82-87  
A recent international, randomized, controlled trial in 76 patients 
resulted in FDA approval of the ExAblate Neuro in July 2016.88   Please 
see Appendix B for a list of prior investigations using ExAblate Neuro. 
 
Medial thalamotomy for pain should represent an iterative advance in the use of MR-guided FUS 
where the medial thalamic (CL) target is less associated with eloquent structures than the 
ventrolateral thalamus.  This cohort of treatment-resistent craniofacial neuropathic pain is 
intended to represent a severe pain condition with few treatment options.  The etiologies may be 
diverse but the pathophysiology for the development of neuropathic pain is more homogenous 
and results from peripheral injury/ neuropathy to cranial nerves or those of the head and neck.    
We intend to exclude trigeminal neuralgia where neural function is preserved and may represent 
a different pathophysiology than the other neuropathies included.  Similarly, craniofacial pains 
from malignancy will be excluded as many of these manifest a nocioceptive component, and the 
primary investigation here is for neuropathic pain.     
This proposed pilot study has several innovative aspects: 
1. Painful, trigeminal neuropathy and other craniofacial pain syndromes are ideal conditions 
for investigation of pain relief because: 
• A relatively homogenous disorder resulting from injury or pathophysiology of a 
cranial nerve.      
• Associated neuropathic pain is notoriously refractory to medical therapies 
• Surgical options are quite limited and not amenable to common neuromodulation 
therapies like spinal cord stimulation or intrathecal narcotics 
• Severely affects functional status and quality of life  
2. Focused ultrasound has been demonstrated to be a precise stereotactic lesioning modality, 
and the technique can be performed without incisions or craniotomy. 
3. Medial thalamotomy for the alleviation of nocioceptive and neuropathic pains is safe and 
historical studies have suggested efficacy.   
4. Rigorous evidence of neurosurgical interventions for pain relief is lacking, and traditional 
clinical studies have been confounded by heterogeneous patient populations and 
uncontrolled studies. 

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5. The technology is ideal for using sham procedures as a control, and the symptom of pain 
is extremely susceptible to placebo effects during treatment.    Thus a randomized, 
controlled study is appropriate even at this early stage of investigation.   
2.10 Outcome reporting in neuropathic pain:    
The Numeric Pain Rating Scale (NPRS) has been shown to be clinically significant when at least 
a two point change occurs.96 Farrar et al suggested this 30% change was clinically meaningful 
based on its relationship to global assessments of change in multiple studies of chronic pain. The 
association of the NPRS and the PGIC is highly consistent over multiple trials regardless of the 
disease, treatment, trial outcome, or patient demographic factors.96 
The PROMIS inventory (Patient-Reported Outcomes Measurement Information Systems) was 
developed by the NIH over a decade as a precise set of tools to measure various aspects of health 
status across patients with varying conditions and especially chronic diseases.  From the over 70 
domains assessed, pain represents a key component with items addressing:  Intensity, 
Neuropathic and Nocioceptive Quality, Behavior and Interference.   
 
 
 

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3.0 
OBJECTIVES 
This proposed pilot study will investigate the safety and initial effectiveness of focused 
ultrasound lesioning of the bilateral medial thalamus for severe, treatment-refractory chronic 
trigeminal neuropathic pain.   
Safety: To evaluate the incidence and severity of adverse events associated with ExAblate 
lesioning of the bilateral medial thalamus for painful neuropathies of the face and head that are 
severe and treatment-refractory.    
Efficacy: To determine the level of efficacy of the treatment of medication-refractory painful PN 
using validated numeric pain scales and patient-reported measures of pain.   
 
3.1 
Safety 
The safety of Exablate lesioning of the bilateral medial thalamus using the ExAblate device will 
be determined by an evaluation of the incidence and severity of device- and procedure-related 
complications from the first / treatment day visit through the post–treatment visits. Safety 
analysis will also include monitoring for any worsening of pain related to painful PN. Events that 
are neither device- nor procedure-related will be captured and recorded but will not be 
considered reportable device events unless caused by the device. Relative Safety will be 
evaluated using a common description of Significant Clinical Complications for patients treated 
in this study. 
3.2 Efficacy   
Outcome assessments will primarily be made at baseline, one, and three months post procedure 
for patients receiving either the active treatment or sham procedure.   Clinical assessments of 
pain will be made at the all clinic visits.  
 
Primary outcome:  safety as assessed from adverse event reporting and MRI evaluation 
 
Primary efficacy outcome measure will compare the change of WORST pain experienced in 24 
hours before and at 3 months following bilateral FUS medial thalamotomy versus sham 
procedures as determined from the 11-point numeric pain rating scale.    
 
Secondary outcome measures will include other patient-reported outcomes including the Global 
Impression of Change and the Pain Domain from the PROMIS Inventory including items for 
intensity, quality, behavior and interference.      
 
Imaging assessments will be obtained before and after treatment.   The location and precision of 
the treatment, as well as the volume of the lesion, will be determined from pre- and posttreatment 
MRI at baseline, 1 day, 1 week, 1 month and 3 months.  Functional imaging assessments with 
Dynamic 2-[18F] fluoro-2-deoxy-D-glucose Positron Emission Tomography (FDG PET) will be 
obtained at baseline and three months for each patient.  Functional imaging will serve as an 
objective measure to correlate with clinical pain assessment. 
 
 

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A summary of outcome measures is listed: 
 
Primary (efficacy) outcome:  11-point numeric pain rating scale NPRS (“worst” NPRS score 
over 24 hours).  The change in pain rating from baseline to 3 months posttreatment will be 
determined and compared between treatment and control cohorts.  
 
Secondary outcomes:  
Patient-reported outcome measures: 
• PROMIS scale v1.0 – Pain Intensity 3a 
• PROMIS scale v2.0 – Neuropathic Pain Quality 5a 
• PROMIS scale v2.0 – Nocioceptive Pain Quality 5a 
• PROMIS scale v1.0 – Pain Behavior 7a 
• PROMIS scale v1.0 – Pain Interference 8a 
• Patient Global Impression of Change, 7 point  
Functional imaging assessments:  
• Dynamic FDG PET  
  
 
  
 
 

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4.0 
HYPOTHESIS 
Study hypothesis: For patients with treatment-refractory chronic trigeminal neuropathic pain, 
ExAblate Neuro can safely create lesions in the bilateral thalamic nuclei to reduce pain and 
provide functional benefits in daily activities.   
4.1 
The Hypotheses Tested 
➢ For patients with treatment-refractory chronic trigeminal neuropathic pain, MR guided 
focused ultrasound can safely create lesions, bilaterally, in thalamic nuclei to reduce pain 
and provide functional benefits in daily activities. 
➢ FUS under MRI-guidance and MRI-based thermometry can be safely delivered through 
an intact human skull with a low risk of transient adverse effects as evaluated during 
blinded follow-up of up to 3 months and an additional 3 months follow-up in open-label 
setting for those subjects who were initially randomized to Sham treatment. 
➢ Pre-defined medial thalamic target volumes inside the brain can be precisely ablated, as 
demonstrated on post-treatment MRI. 
 
4.2 Case Report Form Data 
The study data will be collected electronically. This electronic data capture (EDC) system 
complies with the current guidance of 21 CFR Part 11, Electronic Records and Signatures.  
5.0 
DESCRIPTION OF PATIENT POPULATION    
Subject Selection   
The cohort of subjects with chronic trigeminal neuropathic pain should represent a relatively 
homogenous pain condition that can be quantitatively diagnosed and treated with a minimal 
number of confounding factors (e.g. mood disorders, secondary gain, and additional 
interventions).  Subjects diagnosed with a painful cranial neuropathy that is deemed treatment-
resistant will be eligible for this study.   The principal investigator has a clinical practice of 
surgery for medication-refractory cranial neuralgias and neuropathies, and he has experience in 
the classification and diagnosis of these chronic trigeminal neuropathic pain syndromes.98 
 
Subjects will first be consented in the study, and then will receive the standard clinical, 
psychological, and imaging work-up as part of their study baseline requirements.  A total of ten 
(10) subjects will be recruited from University of Virginia Health System in this feasibility 
study.   

Protocol Version Date 06 December 2019 
Page 16 
 
5.1 
Subject Enrollment 
a)  
Subjects will be referred primarily from the Neurosurgery or Pain Management clinics at 
the University of Virginia.  Information concerning preliminary eligibility for the study will 
initially be taken from the subject’s case history. Subjects who appear to be eligible will be asked 
if they would like to participate in this study.  
b) 
Written informed consent will be obtained from each participating subject prior to 
collecting a subject history or other testing. The subject will be counseled concerning the 
research nature of this study, and the risks and possible benefits to participation. Participation is 
fully voluntary.  
5.2 
Inclusion Criteria 
1. Men and women, between 18 and 75 years, inclusive 
2. Subjects who are able and willing to give consent and able to attend all study visits 
3. Severe chronic, trigeminal neuropathic pain of ≥6 months duration.  
4.  Severity is defined as: Worst NPRS score of ≥ 5 out of 10 at current visit and the subject 
reports having a similar level of pain for at least the past two months. 
5. Pain is medication-refractory to adequate trials of at least 3 prescription medications 
commonly used for symptomatic relief of neuropathic pain with current adjunctive use of 
at least one medication. An adequate medication trial is defined as a therapeutic dose of 
each medication without sufficient effect. 
6. Pain is treatment-resistant to at least one interventional therapies including injections, 
procedures, neuromodulation, and surgery.  The interventions trialed depend on the 
disease and are more specifically defined below:  
• Trigeminal neuropathic pain:  failed peripheral injection, percutaneous RF ablation, 
transcutaneous stimulation, peripheral nerve stimulation, caudalis DREZ lesioning, 
trigeminal tractotomy, motor cortex stimulation, intraventricular or intrathecal 
medication infusions, or deep brain stimulation   
• Trigeminal deafferentation pain:  pain has resulted from failed trigeminal procedures 
including percutaneous RF rhizotomy, percutaneous chemical rhizotomy, 
percutaneous balloon compression rhizotomy, stereotactic radiosurgery, 
microvascular decompression , or intracranial partial sensory rhizotomy 
• Postherpetic neuralgia of the trigeminal nerve:  failed peripheral injection, 
percutaneous RF ablation, transcutaneous stimulation, peripheral nerve stimulation, 
caudalis DREZ lesioning, trigeminal tractotomy, motor cortex stimulation, 
intraventricular or intrathecal medication infusions, or deep brain stimulation   
7. Central lateral nucleus of thalamus can be targeted by the ExAblate device.  The CL 
region of the thalamus must be apparent on MRI such that indirect targeting can be 
performed by measurement from a line connecting the anterior and posterior 
commissures of the brain.  
8. Able to communicate sensations during the focused ultrasound treatment 

Protocol Version Date 06 December 2019 
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9. Stable prescribed doses of all symptomatic pain medications for 30 days prior to study 
entry and for the duration of the 3-month blinded phase of the study.  
10.  
5.3 
Exclusion Criteria 
1. Craniofacial pain syndromes related to malignancy of the head and neck 
2. Idiopathic trigeminal neuralgia   
3. Headache syndromes like migraine, cluster headache 
4. Temporomandibular joint syndrome 
5. Atypical facial pain or pain related to a somatoform disorder 
6. Subjects deemed poor candidates by a licensed psychologist with expertise in screening 
for pain procedures as evidences by: 
a. Significant clinician concern about reliability of subject-reported information, 
such as subject in active process of seeking disability for neuropathic pain 
b. Subjects exhibiting any behavior(s) consistent with ethanol or substance abuse as 
defined by the criteria outlined in the DSM-V as manifested by one (or more) of 
the following occurring within a 12 month period:  Recurrent substance use 
resulting in a failure to fulfill major role obligations at work, school, or home 
(such as repeated absences or poor work performance related to substance use; 
substance-related absences, suspensions, or expulsions from school; or neglect of 
children or household). Recurrent substance use in situations in which it is 
physically hazardous (such as driving an automobile or operating a machine when 
impaired by substance use)  
c. Recurrent substance-related legal problems (such as arrests for substance related 
disorderly conduct) 
d. Continued substance use despite having persistent or recurrent social or 
interpersonal problems caused or exacerbated by the effects of the substance (for 
example, arguments with spouse about consequences of intoxication and physical 
fights).  
7. Subjects with active psychiatric illness will be excluded.  For the purpose of this study, 
active psychiatric illness includes: 
a. Exhibiting current suicide ideation and/or a history of suicide attempt within past 
2 years 
b. been hospitalized for the treatment of a psychiatric illness within the past 2 years 
c. received transcranial magnetic stimulation for depression treatment  
d. received electroconvulsive therapy for depression  
8. Any presence or history of psychosis will be excluded. 
9. Subjects with unstable cardiac status including: 
a. Unstable angina pectoris on medication 

Protocol Version Date 06 December 2019 
Page 18 
 
b. Subjects with documented myocardial infarction within six months of protocol 
entry 
c. Significant congestive heart failure defined with ejection fraction < 40  
d. Subjects with unstable ventricular arrhythmias  
e. Subjects with atrial arrhythmias that are not rate-controlled 
10. Severe hypertension (diastolic BP > 100 on medication)  
11. Subjects with standard contraindications for MR imaging such as non-MRI compatible 
implanted metallic devices including cardiac pacemakers, size limitations, etc.  
12. On medications that increase the bleeding risk, we are following the published guidelines 
which are currently recognized by the American Society of Regional Anesthesia and Pain 
Medicine, American Academy of Pain Medicine and the North American 
Neuromodulation Society (Reg Anesth Pain Med 2015;40: 182–212); specifically: 
a. Aspirin or another antiplatelet medication (clopidogrel, prasugrel, ticlopidine, 
abiciximab) for the last 7 days prior to treatment. 
b. Oral, subcutaneous or intravenous anticoagulant medications, such as oral vitamin 
K inhibitors for the last 7 days, non-vitamin K inhibitor oral anticoagulant 
(dabigatran, apixaban, rivaroxaban) for the last 72 hours.  
c. Intravenous or subcutaneous heparin-derived compounds for the last 48 hours. 
13. Individuals who are not able or willing to tolerate the required prolonged stationary 
supine position during treatment (can be up to 4 hours of total table time.)  
14. Subjects participating or have participated in another clinical trial in the last 30 days 
15. Presence of systemic neurological disease or dysfunction 
16. Known life-threatening systemic disease 
17. Subjects with risk factors for intraoperative or postoperative bleeding from a documented 
coagulopathy or if their serum coagulation studies (platelet count, PT, PTT, and INR) 
exceed the institutional laboratory limits. 
18. Subjects with brain tumors or any significant intracranial mass.  Trigeminal or cavernous 
sinus tumors causing neuropathic pain are not excluded.   
19. Any illness that in the investigator's opinion preclude participation in this study  
20. Pregnancy or lactation  
21. Legal incapacity or limited legal capacity  
22. Subjects with a deep brain stimulation implant or with a prior stereotactic thalamic 
ablation  
23. Skull density ratio, calculated from the baseline noncontrasted head CT, is less than 0.4 
24. History of hemorrhagic stroke or cerebrovascular event within the past year of treatment 
exhibiting incomplete resolution 
25. History of seizures within past year of treatment 
26. Severe kidney disease or on dialysis 

Protocol Version Date 06 December 2019 
Page 19 
 
27. Subjects who are unable to tolerate medications due to intolerable side effects. 
28. Subjects whose primary pain is other than craniofacial neuropathic pain. 
 
 

Protocol Version Date 06 December 2019 
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6.0 
INVESTIGATIONAL PLAN 
6.1 
Study Design 
This study is designed as a prospective, double-blinded, randomized trial in 10 subjects with 
sham procedures serving as the control. A rigorous clinical trial design is required for the 
subjective measurement of pain and clinical outcome where a placebo effect is anticipated.  
Primary safety and efficacy assessments will be made before and after treatment through the 3 
month blinded phase.  After 3 months, subjects in the sham arm will be offered a focused 
ultrasound bilateral thalamotomy as an open label extension of the study.  All subjects receiving 
treatment, either during the primary blinded analysis or open-label extension phase, will be 
followed for at least 3 months post-thalamotomy.   
 
6.2 Sham Study Design 
The randomized, control arm subjects will undergo a sham procedure that is identical to the 
treatment except the energy output will be disabled.  These control subjects will then be 
followed up for 3-months post-sham procedure to assess study endpoints; study follow-up:  
1 day, 1 week, 1 and 3 month visits.   
At the 3-Month time point, all subjects will be unblinded and offered crossover to the actual 
treatment.  All these crossover subjects will be followed again according to the same schedule as 
the treatment through the Month 3 post treatment study visit. 
  
Baseline/ 
screening 
=> 
Qualified
Test Arm
Randomiza
tion
Sham Arm
ExAblate 
TXT
Sham TXT
1 Week
Crossover 
1 Week
Arm
Month 1
Month 1
Month 3
Month 3
Neuropathic Pain Study Flow

Protocol Version Date 06 December 2019 
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6.3 Pre-Treatment Procedures  
1. PRE-SCREENING: Subjects with medication-refractory, trigeminal or other craniofacial 
neuropathic pains may be eligible for the study. The diagnosis will be confirmed by the 
neurosurgeon from the patient’s medical history and physical examination.     
2. CONSENT: Those who meet the preliminary criteria for the study based on pre-screening 
of available information will be offered an Informed Consent to sign prior to further 
evaluation (see Appendix-B for an Informed Consent template).  Those who accept will 
be assigned a subject study number.  No study specific tests or procedures will be done 
until the subject has signed consent. 
3. SCREENING and ENROLLMENT: 
a. All current medications will be documented in the medical record and 
any changes over the past two months will be noted.  Record prescribed 
and PRN medication usage. 
b. The investigator will review and document any medical history that 
pertains to study eligibility. 
c. Subjects will complete screening questionnaires 
• Worst 24 Hr NPRS assessment, including report of pain levels 
over past two months (for eligibility) 
• PROMIS  (patient reported outcomes of pain) 
a. Intensity 
b. Neuropathic pain quality 
c. Nocioceptive pain quality 
d. Behavior  
e. Interference 
 
d. Focused neuro-exam by neurosurgeon including: 
• Cranial nerve examination 
• Sensory examination  
• Gait  
e. Screening blood tests: Blood will be drawn by venipuncture for PT, 
PTT, Metabolic panel, and CBC including platelets 
f. Women of childbearing age will undergo a urinary or serum Beta-hCG 
test for pregnancy.  If the test is positive, the subject will be excluded 
from the study. If the test is negative, she must agree to maintain a 
suitable form of birth control throughout study.  This includes the 
screening period until study completion.  

Protocol Version Date 06 December 2019 
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g. A comprehensive assessment of pain symptoms, functional limitations, 
and comorbid mood issues will be made by licensed pain psychologist.  
The evaluation consists of a clinical interview, as well as 
questionnaires/assessment tools that address mood and identify potential 
biopsychosocial factors that may contribute to the patient’s pain 
experience.  The Patient Health Questionnaire (PHQ-9) identifies 
potential depressive symptoms and the Generalized Anxiety Disorder 7-
Item Scale (GAD-7) addresses anxiety.  Additionally, the Pain 
Catastrophizing Scale (PCS) is helpful in recognizing a patient’s 
tendency toward catastrophic thinking that is likely to negatively impact 
surgical or other invasive interventions’ outcomes.  Lastly, the Brief 
Battery for Health Improvement 2 (BBHI-2) is a psychometrically sound 
instrument that is normed on patients with pain and provides objective 
information related to underlying pain-related issues that are 
biopsychosocially related. Standard screening for pain procedures 
includes assessments of anxiety and mood: 
• GAD-7 
• PHQ-9 
• PCS 
• BBHI-2 
h. Evaluation by a pain management physician. 
i. CT Imaging: For the purpose of this study, the CT Exam should be an 
Axial scan with bone filter, an image resolution of 512x512, and image 
thickness of 1mm with zero (0) spacing 
j. MR Imaging: For the purpose of this study, unenhanced MR Exams will 
be performed and include: volumetric MPRAGE, axial and coronal T2-
weighted sequences, and axial and coronal diffusion-tensor imaging 
(DTI) 
k. Once all items required for eligibility are completed, the principal 
investigator will review and sign eligibility or document the screen-
failure.  If at this point it is determined that the subject does not meet all 
Inclusion and Exclusion criteria and cannot be treated, the subject will 
be removed from the study. These subjects will be considered screening 
failures, and will not be included in any of the safety or efficacy 
endpoint analyses.   
l. If the subject is deemed eligible for the study based on the screening 
criteria, then the following will be scheduled: 
• Presurgical evaluation by the anesthesiology team 
• Baseline assessments including Dynamic FDG PET imaging using 
the following process 
a. Placement of IV catheter 

Protocol Version Date 06 December 2019 
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b. Slow injection with ~10 mCi of the FDG tracer via the 
catheter 
c. Imaged using the PET/CT scanner for 60 minutes starting 
at injection 
d. The final 10-15 minutes of the 60 minute scan will consist 
of a static FDG PET scan.  
• Procedure (sham or treatment).  
4. BASELINE ASSESSMENTS:   
During the week prior to the procedure, the subject will be provided with time to complete all 
questionnaires per the schedule of events.  These will establish the baseline measures for 
these particular data points.  Baseline assessments include: 
▪ NPRS  
▪ PROMIS measures of pain 
▪ History and physical exam 
▪ Concomitant medications 
▪ Dynamic FDG PET 
 
6.4 Randomization 
Randomization occurs at the start of the focused ultrasound procedure, immediately prior to the 
first sonication.  Subjects will be randomized in a 1:1 fashion to receive either a sham procedure, 
where the acoustic power is disengaged, or a bilateral medial thalamotomy.  The treatment team 
(neurosurgeon and clinical research coordinator) will be aware of the treatment assignment.  The 
assessment team (pain management specialist, pain psychologist, and nuclear medicine 
radiologist who interprets PET) and the subjects will be blinded throughout the three month 
study period.  Subjects are unblinded at the end of the three month visit and sham subjects will 
be offered cross-over to treatment arm at that time. 
6.5 Treatment Procedures  
On the day of the treatment, the following clinical team members should be present: 
Neurosurgeon: leads the planning and guidance of the treatment. They will also monitor 
the neurological performance and clinical status of the subject. They will be responsible 
for the overall management of the subject. The neurosurgeon will evaluate the subject’s 
comfort level and direct sufficient sedation to maintain this comfort. Feedback of 
symptom relief is not expected to be necessary for this procedure.  
The anesthesiologist or nurse anesthetist: they will monitor vital signs and provide 
necessary medications to keep the subject comfortable. 
 
The overall treatment procedure steps will be performed as follows: 
 

Protocol Version Date 06 December 2019 
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1. Subjects will be reminded to not take any anticoagulant (e.g. warfarin) or antiplatelet 
(e.g. aspirin) therapy in the week prior to and in the week after the focused ultrasound 
procedure.  
2. The subject will be instructed not to eat or drink after midnight prior to the MRgFUS 
procedure, in order to permit the use of immediate general anesthesia in case of a 
treatment complication that may require emergency intervention. 
▪  
3. Medications will be reviewed to confirm regimen is unchanged since study enrollment.  
Record prescribed and PRN medication usage. 
4. An IV line will be positioned for the delivery of fluids and any medications required 
during the procedure. Some of the subjects may require a urinary catheter to keep the 
bladder empty during treatment. Noninvasive monitoring of heart rate, blood pressure, 
systemic oxygen saturation, electrocardiogram, and end-tidal CO2 will be maintained 
throughout the procedure using standard MR-compatible monitoring devices. 
o The anesthesiologist or nurse anesthetist will administer appropriate medications 
for subject management if necessary. Since the medial thalamotomy procedure is 
image-guided and does not rely on intraprocedural feedback for targeting, 
intravenous sedation may be used as necessary for comfort.  Subjects will not be 
intubated.   
 
5. The subject’s head will be carefully shaved and examined for pre-existing scalp scars or 
any other scalp lesions. 
 
6. Graduated compression stockings will be worn to prevent deep venous thrombosis in the 
lower limbs.  
 
7. The subject’s head will be placed in the immobilization unit (similar to those used in 
stereotactic radiotherapy head fixation). 
 
8. Subject will be positioned supine and headfirst on the MRgFUS therapy table.   
 
9. The half-spherical helmet containing the elements of MRgFUS transducer will be 
positioned around the subject's head in the treatment position.  This should be done 
according to measurements taken from the pre-operative/imaging session(s).  
 
10. A rubber diaphragm will be attached to the subject's head and to the transducer to create 
the acoustic coupling system between the ultrasound transducer and the scalp.  
 
11. The immobilization system will be secured over the subject head to maintain a constant 
relationship between the target and the transducer. 
 

Protocol Version Date 06 December 2019 
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12. A localizer scan (quick T1) and a non-contrast T2-FSE MR scan will be obtained to 
allow further refinement of the position the MRgFUS transducer focal point with respect 
to the targeted zone.  
 
13. The interface within the rubber diaphragm will then be filled with degassed water.  This 
volume will be completely filled with care to avoid air bubbles between the face of the 
transducer and the scalp. Through active circulation and cooling system, the water will be 
maintained chilled throughout the procedure to avoid undesired heating of the scalp and 
skull. 
 
14. A series of MR images will be acquired to identify the target area, and plan the actual 
treatment   
o T2 Weighted imaging exam along at least 2 axes: Axial and Coronal 
o Other MR imaging series may also be acquired 
15.  The pre-therapy MRI and CT image datasets will be registered to the T2 weighted MR 
images that were just acquired. This image fusion of pre-operative MR assists in the 
accurate delineation of the target area and determination of a safe sonication pathway 
o The fusion of the CT data is required for the computation of phase correction 
values to correct for skull aberration, and identification of intracranial 
calcifications 
o Scars of the scalp will be designated to ensure the ultrasound beam avoids these 
specific areas  
 
16. The treatment volume and plan will be defined by the neurosurgeon. The MRgFUS 
system will automatically compute the number of sonications, and the (per sonication 
spot) phase and amplitude corrections necessary for the system to produce a focal spot at 
each of the desired locations.  
 
17. An intravenous line will be maintained throughout the procedure. Noninvasive blood 
pressure, systemic arterial oxygen saturation, electrocardiogram, and end-tidal carbon 
dioxide will be monitored throughout the MRgFUS treatment using standard MRI-
compatible monitoring devices. 
 
NOTE:  All procedures for both arms are the same to this point.  Below is the description of 
treatment for ExAblate Arm.  The Sham will be identical except that the energy will be 
turned to 0.  
 
18. A central point in the targeted area will be targeted with a low dose, sub-lethal energy 
level sonication to confirm the targeting accuracy on the MR images. Focal point position 
and/or transducer location will be adjusted as necessary. The bilateral lesioning will be 
planned and executed as follows: 

Protocol Version Date 06 December 2019 
Page 26 
 
a. Stereotactic planning of both (left and right) medial thalamic targets will be 
performed on the ExAblate Neuro workstation in the pre-planning phase.    
The central lateral thalamic nucleus CLT nucleus will be targeted by 
stereotactic coordinates in reference to the midcommissural point of the 
ACPC line.   
b. If the pain symptoms are asymmetric or unilateral, the CLT nucleus 
contralateral to the most symptomatic side will be treated first.  The acoustic 
energy will be escalated in a series of incremental sonications until a 
therapeutic ablation of temperature of 60-65⁰C is reached by peak voxel, MR 
thermometry.  The second, ipsilateral CLT target will then be treated with the 
same protocol. 
c. If the pain symptoms are symmetric, the nondominant CLT will be treated 
first.  The dominant side CLT will be treated as the second target. 
19. To enhance the procedure safety and mitigate some of the inherent risks of thermal 
lesioning of brain tissue: 
a. The thalamotomy treatment will be performed as a series of sonications with 
small increments in power within the designated target volume. 
b. The subject will be examined periodically by the clinical team for neurologic 
signs and symptoms. 
c. Sonication will start with low energy prior to permanent thermal ablation.  This 
is to ensure the planned sonication to be centered on the CL nucleus of the 
Thalamus. Low energy sonication will non-destructively warm the target. The 
warming will be captured by the MR thermometry and the MR thermal images 
will be displayed in real time to the treating physician. The physician will then 
verify that the warming is centered on the anatomic target. This will allow the 
centering of the eventual permanent thermal lesion in the correct location, in 
the center of the CL nucleus of the Thalamus.   
d. The titration of escalating focal sonications will continue up to 60ºC within a 5 
mm diameter centered on CL, or until potential side effects are reported by the 
subject or observed by the clinical team.  
e. The MRgFUS system is equipped with Stop Sonication Buttons: one for the 
subject to utilize, one for the nurse/anesthesiologist, and one for the treating 
physician to use.  Hence, in the event of discomfort or pain, the subject will 
have the ability to abort the sonication at any time by activating the Stop 
Sonication Button.  Once this button is activated, the system will instantly stop 
the energy delivery.  The same thing will happen in the event the treating 
physician or the nurse activates their button.  After addressing the subject 
concerns or discomfort, the procedure may continue without further delay.  All 
adverse events that may be caused by these potential activation(s) of the Stop 
Sonication Button will be captured on the CRFs.  
  

Protocol Version Date 06 December 2019 
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20. The physician may decide to terminate the sonication procedure at any time.  For 
example for any of the following reasons: 
a. the subject’s wish to terminate due to pain, severe discomfort, or any other 
reason, 
b. development of focal neurological deficits, 
c. occurrence of seizures, 
d. MRI signs of intracranial bleeding or significant brain swelling 
e. targeting difficulties, due to subject motion, 
f. inability to observe the focal point during sonication, 
g. inability to communicate with the subject  
h. any other medically indicated reason 
21. After the procedure, an initial series of T1 or T2 weighted MR images will be acquired 
along two planes to assess the early treatment effects. Comprehensive MR imaging is 
obtained the following day with a head coil to optimally characterize the lesion.  This will 
include: T1, T2, SWI, DWI, and DTI. 
In the event of new neurological deficits or seizures are observed, other imaging 
modalities (including CT) should be performed immediately in addition to neurological 
and physical examinations. 
22. The subject will be removed from the ExAblate table and taken to the hospital for 
recovery and neurological observation until the next morning. The neurosurgeon will 
evaluate the subject’s neurological status and make a decision whether or not to discharge 
the subject. Subjects who are found to be neurologically unstable will remain in the 
hospital until the neurosurgeon determines it is medically indicated to discharge. 
23. Subject will be asked the “Patient Blinding Question” to determine whether or not they 
believe they had a sham or real procedure. 
6.6 Sham Procedures  
For all subjects randomized to a sham procedure, all activities will occur including I.V. lines, 
planning MRI’s, etc, and an identical procedure will be performed with the energy output 
disabled.   The treating physician will determine a sonication (treatment) time for sham subjects 
to be similar to that which is occurring in the treatment arm to maintain consistency between 
arms.  It should be noted that all treatment times of study arms will be captured in the study 
CRF. 
6.7 Follow-up  
Subject follow-up will be completed at Day 1, Day 7, Month 1, and Month 3 for all subjects who 
underwent CL lesioning/ablation using ExAblate system. Subject follow-up will be similar for 
those who underwent sham treatment. At 3 months, subjects who had sham treatment will be 
unblinded and offered MRgFUS.   

Protocol Version Date 06 December 2019 
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Subjects will be evaluated at all follow-up visits for general health, neurological changes and 
efficacy measurements as well as for device/procedure related adverse events that may have 
occurred during the follow-up period.   Medication regimen and PRN usage will be recorded at 
each follow-up along with the following assessments: 
6.7.1 
Day 1 
• Evaluation of general health and neurological changes 
• NPRS (Worst pain in 24 hrs) 
• PROMIS  
• Assess patient blind 
• Assess safety and update adverse events as needed 
• Review medications and record any changes 
• MRI 
6.7.2 
Day 7 
• Evaluation of general health and neurological changes 
• NPRS (Worst pain in 24 hrs) 
• PROMIS 
• PGIC  
• Assess patient blind 
• Assess safety and update adverse events as needed 
• Review medications and record any changes 
• MRI 
6.7.3 
Month 1 
• Evaluation of general health and neurological changes 
• NPRS (Worst pain in 24 hrs) 
• PROMIS 
• PGIC  
• Assess patient blind 
• Assess safety and update adverse events as needed 
• Review medications and record any changes 
• MRI 
6.7.4 
Month 3 
• Evaluation of general health and neurological changes 
• NPRS (Worst pain in 24 hrs) 
• PROMIS 
• PGIC  
• Assess patient blind 
• Neuropsychological Pain Assessment 
• GAD-7 
• PHQ-9 
• PCS 
• BBHI-2 
• MRI 

Protocol Version Date 06 December 2019 
Page 29 
 
• Dynamic FDG PET 
• Assess safety and update adverse events as needed 
• Review medications and record any changes 
• Evaluation by a pain management physician 
 
All pre-treatment and post treatment MR images will be de-personified (i.e.: subject identifiers 
made anonymous), archived and sent to InSightec.  These analyses will also include full 
radiological assessments from baseline through all follow up visits. 
In this study, subjects who use alternative treatments (not including medication change) during 
the 3-month follow-up period will be exited from the study, after completing required study 
examinations. The reason(s) for study exit will be noted on the Case Report Forms.   
 
 

Protocol Version Date 06 December 2019 
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7.0 
STUDY REQUIREMENTS AND VISIT SCHEDULE  
The table below summarizes the study visit schedule and procedures.   
Table 1 Schedule of Events 
 
Procedures 
Screening  
Baseline 
(within 1 
week of 
day 0) 
Day 0 
(Proced
ure) 
Day 1 
Day 7 
(±3 
days) 
Months 1 
(±7 days) 
Month 3 
(±14 
days)1 
Written Consent 
X 
 
 
 
 
 
 
Check Eligibility 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
History and Physical Exam 
 
X 
 
 
 
 
 
Screening Labs 
X 
 
 
 
 
 
 
CT Scan 
X 
 
 
 
 
 
 
MRI 
X 
 
 
X 
X 
X 
X 
Dynamic PET 
 
X 
 
 
 
 
X 
NPRS and PROMIS Pain 
Questionnaires2 
X 
X 
 
X 
X 
X 
X 
PGIC 
 
 
 
 
X 
X 
X 
Neurological Exam 
X 
 
 
X 
X 
X 
X 
Pain Psychological Exam3 
X 
 
 
 
 
 
X 
Pain Management Exam 
X 
 
 
 
 
 
X 
MRgFUS Treatment or Sham 
Procedure 
 
 
X 
 
 
 
 
Assessment of patient blind 
 
 
X 
X 
X 
X 
X 
Concomitant Medications 
(prescribed and PRN) 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
 
 
X 
X 
X 
X 
X 
1 Subjects will be un-blinded to randomization arm at the completion of month 3 visit.  Subjects who 
initially were randomized to the sham arm may go back to day 0 in schedule of events and receive an 
unblinded MRgFUS thalamotomy.  
2 Five PROMIS fixed length short forms to be completed on paper at each indicated timepoint.  PROMIS 
scale v1.0: Pain Intensity 3a, Pain Behavior 7a, Pain Interference 8a.  PROMIS scale v2.0: Neuropathic 
Pain Quality 5a, Nociceptive Pain Quality 5a. 
3 To include: GAD-7, PHQ-9, PCS, BBHI-2 

Protocol Version Date 06 December 2019 
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8.0 
DATA ANALYSIS PLAN 
A statistical analysis is not proposed. For this study, the Safety and Effectiveness assessment will 
be descriptive with no statistical endpoints.  The results will be examined and analyzed and used 
as a basis for determining the nature of future studies. 
8.1 
Safety 
All adverse events will be recorded and categorized according to severity, relationship to 
procedure and relationship to device.  Any subject who receives at least one sonication will be 
considered Intent to Treat (ITT) for safety assessments. All AEs will be assessed for their 
relationship to the study device or procedure. Standard Code of Federal Regulation definitions 
for Serious Adverse Events (SAEs) and Unanticipated Adverse Device Effects (UADEs) will be 
used in assessment of AEs. 
8.2 Efficacy 
The primary efficacy outcome is the change in worst NPRS score from baseline to 3 months 
compared between medial thalamotomy and sham procedures with no change or increase in 
baseline pain medications.  A mean change of 2 points has been shown to be clinically 
significant.99  Responder analysis (e.g. number of subjects who have 3-point or better 
improvement in worst NPRS pain score at 1 and 3 months) will also be performed. Data analyses 
will also be performed on all PROMIS measures and other subject-reported measures, including 
PET.  
If there is a significant symptomatic pain medication change following MRgFUS treatment, the 
subject’s data will not be used in the Efficacy analysis but the aspects of their procedure will still 
be included in the Safety analysis. 
8.3 Subject Health Status 
The results from the physical and neurological exams will be recorded in the CRFs and will be 
analyzed.  
8.4 Statistical Considerations and Sample Size 
This is a feasibility study of ten (10) subjects who will be randomized in 1:1 fashion to receive 
either bilateral FUS medial thalamotomy or a sham procedure.  A statistical analysis is not 
proposed. Nevertheless, reported adverse events will be examined and analyzed and used as a 
basis for determining the nature and extent of future studies. 
8.5 Subject Confidentiality  
Subject confidentiality will be maintained throughout this study, including all publications.  Data 
collected and entered into the CRFs are the property of Insightec as the study sponsor.  
Representatives from the study sponsor or authorized sponsor representatives, the Institutional 

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Review Board Ethics Committee or other regulatory bodies may receive copies of the study 
records and may review medical records related to the study. 
 
9.0 
RISK MITIGATION 
 
Worldwide, over 12,500 treatments have been performed to date with the MR guided FUS 
ExAblate body system.  Risk analysis for InSightec ExAblate systems/clinical investigations has 
been conducted as part of previously approved FDA IDE submissions (G930140, G990151, 
G990184, G990201, G000203, G010225, G020001, G020182, G050177, and G060023, 
G070022, G080009, G080206).  This data has been re-examined by InSightec and it has been 
concluded that this risk analysis has limited applicability to the proposed clinical investigation.  
The key consideration here is the fact that this proposed study is conducted with an ExAblate 
Neuro that is completely different from the body system. This system is referred to internally as 
the Exablate Neuro system.  However, in principle, the body and brain systems have the same 
purpose namely to coagulate soft tissue within the body by means of MR guided high intensity 
focused ultrasound.  The potential risks described below will be explained to the subject in the 
informed consent process. 
9.1 General Device Related Risks 
Risk of Magnetic Resonance Scanners: 
MRI has no known deleterious biological effects in subjects with no contraindications. The 
incidence of claustrophobia during MRI examinations is approximately 10-15%, although it is 
expected to be less frequent in the study population due to the use of sedation. 
Risk of Intravenous (IV) Catheter: 
There is a potential risk from the IV catheter used during the ablation. Participants can expect a 
small amount of pain and/or bleeding/bruising at the IV site.  There is a small risk of infection.  
This procedure will follow the ‘standard of care’ at the study sites. 
Risks related to Dynamic FDG PET imaging: 
PET Scan:  This imaging study involves radiation exposure from a Positron Emission 
Tomography (PET) scan combined with a Computed Tomography (CT) scan using the 
radiopharmaceutical F-18 FDG. Using the standard way of describing radiation dose, from 
participating in this study, the wall of your bladder, heart, and pancreas will receive the most 
radiation from this study. All other organs will receive smaller amounts of radiation. Although 
each organ will receive a different dose, the total effective radiation dose you will receive from 
one procedure is approximately 10 mSv. You will have 2 of these scans. For comparison, this 
dose is roughly 40% the annual radiation dose safely allowed for a radiation worker such as the 
person performing your scan.  
 
This radiation exposure is not necessary for your medical care but is necessary to obtain the 
research information desired. This radiation dose is what you will receive from this study only 
and does not include any exposure you may have received or will receive from other tests. If you 

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are pregnant or breastfeeding, you may not participate in this research study. It is best to avoid 
radiation exposure to unborn or nursing children since they are more sensitive to radiation than 
adults. 
9.2 Risk of Contrast Agent  
This study does not intend to use MRI or CT contrast agents. 
9.3 Risks incidental to the MRgFUS treatment 
• There is a potential risk of conscious sedation, which includes reaction to the drugs or 
over-sedation.  
• There is a potential risk from the intravenous catheter used during the treatment. Subjects 
can expect a small amount of pain and/or bleeding/bruising at the IV site.  There is a 
small risk of infection.  This procedure will follow the ‘standard of care’ at the Study 
Sites. 
• There is a potential risk to the subject of deep venous thrombosis from lying stationary 
for 3 to 4 hours. The risk to the subject from lying still for this treatment should be no 
greater than that of lying still for any other reason.  Subjects will be provided 
compression stockings, as described above (Section 4.3), to use during treatment.  All 
subjects will be screened for DVT prior and post-ablation procedure.  This will further 
reduce the risk to subjects by screening out all those with DVT risk prior to ablation. 
• There is a risk that the subject may experience a sore neck or discomfort from lying in the 
same position for a long time during the treatment.   
• There is a potential risk from a urinary catheter if used during the procedure.  Participant 
may expect varying levels of Urinary Tract Infection due to the use of the urinary 
catheter.  In a different study for the MRgFUS treatment of uterine fibroid (Pivotal study 
under IDE G020001 that lead to PMA approval under PMA # P040003), the incidence of 
this risk was found not to exceed 3.7%.  This procedure will follow the “standard of care” 
at the study sites. 
9.4 Risks Associated with the MRgFUS Treatment 
• There is a potential risk of hemorrhage during MRgFUS treatment. In MRgFUS thermal 
ablation, the high temperature at the focal point results in immediate protein denaturation 
and coagulative necrosis. This should be expected to rapidly stop any bleeding that might 
occur in the capillary bed and within small vessels.  At the end of the MRgFUS 
procedure an unenhanced MR scan is performed to assess the treated area and adjacent 
tissues.   
• There is a risk of discomfort to the subject caused by heating of tissue.  Focused 
ultrasound therapy involves precisely controlled pulses of thermal energy resulting in 
tissue coagulation (typically 55-65°C for several seconds) in small tissue volumes. This 
induces thermal coagulation of the targeted soft tissue.  The energy intensity at the level 

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of the skin is quite low, and there should be no local heating, hence no sensation of pain 
at the scalp.  The rise in temperature in the skull should be kept to below pain level by 
active cooling of the water within the rubber diaphragm. Because the focal point of the 
beam will be > 2.5 cm from the dura and there are no pain receptors in the brain, there 
should be no pain associated with ablation. The subject will be in verbal contact with the 
physician and appropriate action can be taken in the event that a subject does experience 
discomfort. Remedies could involve lowering energy levels, increasing the time interval 
between consecutive treatment pulses, or increasing the level of sedation and/or 
analgesia. The subject also has the ability to abort the sonication at any time by activating 
a handheld cut off circuit (i.e., stop switch). 
• There is a risk of imprecise targeting of the focal point, and ablation of an area of tissue 
outside the planned treatment volume. If this occurred it is possible that serious 
neurological deficit or even death could result. To limit the risk of this occurring, the 
treatment process includes a mandatory verification step that requires the operator to first 
check the alignment of the subject anatomy, the focal point of the transducer and the MR 
imaging system.  This procedure, done while the subject is in position for treatment, uses 
a very low energy sonication to confirm of the alignment of the focal point and the 
targeted treatment point in all three axes. For each sonication delivered during treatment, 
the operator gets continuous feedback on the position of the intended treatment point 
superimposed on the thermal dosimetry image and can make corrections where required. 
At any point in the treatment process this low-power verification of the localization may 
be repeated prior to full power sonication. 
• There is the risk that the tissue along the path to the target (scalp, skull, dura, brain, etc) 
could become heated to the point where tissue-damage or a burn might occur. This 
heating could be caused by direct improper treatment targeting, irregularities on the skin 
surface (e.g.: scars), treatment of a volume of tissue too close to the skin or bone, energy 
absorption by the bone, or the conduction of sufficient heat to cause a burn at the surface. 
In the case of a first or second degree burn of the scalp, the skin should heal without a 
scar. In the case of a 3o burn, a scar, or loss of sensation in the area of the burn could 
result.   
• Although skin burn is a risk associated with both the ExAblate Neuro and body systems, 
there have been no cases of skin burn in all ExAblate Neuro treatments;  over 400 
subjects have been treated with the ExAblate Neuro system to date.  However, over the 
last decade, there have been four reports of skin burns in breast treatments and two 
reports of skin burns in uterine fibroid treatments.  These subjects were treated with the 
ExAblate body system.  The circumstances of these events are not applicable to the 
ExAblate Neuro system.  However, the heating in the energy pass zone is always 
monitored and an additional cooling time can be administered when elevated 
temperatures are detected. Because the issue of energy absorption and overheating of the 
skull and scalp is so critical in the brain application, this system includes an active 
cooling sub-system that circulates the water in the space between the face of the 
transducer and the scalp. This will help keep the scalp within a safe temperature range 
and reduce the risk of overheating. If non-superficial tissue along the path to the target 

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were to become heated to the point that damage occurs, there is the possibility that it 
would result in significant neurological damage or even death. To reduce the possibility 
that this could occur, several measures will be taken: 
➢ 
First, the procedure is performed in the MR scanner. During the treatment MR 
images will be acquired. Using specific scanning sequences and a rapid post-
processing program, changes in temperature can be detected, and a thermal map of 
the brain generated. This thermal map will reveal any potentially dangerous 
elevations in temperature. 
➢ 
Third, MR-compatible pulse oximeter, blood pressure cuff, and EKG monitor will 
be monitored throughout the procedure. This information will permit detection of 
tissue damage, edema, or bleeding, if brain or blood vessels along the beam paths 
are injured by heat. 
➢ 
Finally, the subject and the neurosurgeon will each have a stop switch that can 
instantaneously interrupt the energy delivery at any time. The subject is given a stop 
switch in case aberrant tissue heating causes any compromise to speech, word 
finding, or other communication difficulties. The subject will be instructed prior to 
the proceeding that they should use the stop switch any time they feel excessive 
pain, discomfort, disorientation or any other unusual sensation. The neurosurgeon 
has a stop switch so that if there is any sign of neurological change, the energy 
delivery can be immediately stopped and the subject carefully evaluated. 
Temporary interruption of energy delivery will in no way compromise the potential 
for therapeutic benefit to the subject. Following subject evaluation treatment can 
resume without delay. 
• There is a risk associated with subject motion during a sonication or between sonications. 
This could cause a movement of the tissue relative to the planned treatment volume on 
the system, and in extreme cases could result in the treatment of a point outside the 
planned treatment volume.  Also, because the skull functions as a defocusing lens, the 
phase correction map computed for the target spot will become ineffective if the subject 
moves.  To prevent or minimize this risk, there are several precautions taken to prevent 
motion, and to detect it, if it occurs:   
• The system is equipped with a movement detection algorithm.  Prior to each sonication, a 
brief MRI assessment is made of fiducials in the transducer.  If any of the fiducials are 
misaligned within the voxel coordinate system of the MRI, the system will not proceed.  
The movement detection algorithm is set to trigger with alterations of  >2mm. 
• During subject positioning every effort will be made to make the subject comfortable and 
the subject will be educated as to the importance of maintaining their position during the 
treatment.  
• The subject will be managed with conscious sedation.  This will enable them remain still 
during the procedure.  

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• The subject will be placed in a head immobilization unit based on a stereotactic frame. 
This technology has been effective in preventing movement in stereotactic neurosurgery, 
and has been adapted and modified to the specification of MR-guided FUS. 
• One or more members of the medical team will be in the room throughout the sonication 
to monitor the subjects' medical status and comfort.  Hence, subject motion will also be 
monitored. 
• There is a risk of cavitation in the tissue at the focal point. Cavitation is the collapse of 
rapidly developed gas bubbles at the focal point due an extreme intensity of ultrasound 
excitation. This rapid collapse could cause high pressure, shock waves, and high 
temperatures. All systems are now equipped with cavitation detectors.   
• There is a risk of blood brain barrier (BBB) disruption, edema, swelling, hemorrhage 
outside and remote to the targeted area.  These events may theoretically occur due to 
heating effects (ie secondary hot spots) and or to the pressure wave of the ultrasound 
beam.  The secondary hot spots risks are discussed below.  To address the risks due to 
pressure waves of the ultrasound beam path, the system has been designed to be well 
below the “pressure wave threshold” that may trigger events of this nature.  In all cases, 
thermal and regular imaging will be continuously assessed during the procedure.  Finally, 
the subject(s) is continuously monitored by the anaesthesiologist (or nurse anaesthetist) 
during the ablation procedure for any change in the subject condition. 
9.5 Risks related to bilateral lesioning of central lateral thalamic nucleus 
We perceive the following primary risks of bilateral FUS medial thalamotomy based on our 
review of the historical literature of medial thalamotomy, the extensive experience of CL 
thalamotomy by our colleague Jeanmonod, and our experience with FUS Vim thalamotomy for 
ET: 
1. Somatosensory deficit & increase pain – from lateral extension of the lesion to VPL 
2. Transient cognitive disturbance or confusion 
3. Hemorrhagic morbidity – from thermal ablation 
4. Cavitation – from focused ultrasound 
 
Somatosensory deficit & increased pain.   
Medial thalamic lesions target the intralaminar nuclei and do not result in discriminative 
somatosensory deficits.  Historical lesion of the lateral thalamus (VPM/VPL) often resulted in 
somatosensory deficits and increased pain due to deafferentation.  In order to mitigate this risk, 
medial thalamic lesions will be confined to the CL nucleus and will not extend laterally to the 
VPM. The laterality of the coordinates for medial thalamic lesions will be maintained less than 
10 mm.   
The thermal lesioning process with focused ultrasound could cause neurological effects for 
several reasons.  Any effects outside of the treatment area could result in neurologic signs or 
symptoms.  These could occur from the thermal lesioning process that is ‘off-target’ or 

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associated infarction, hemorrhage or edema.  Subjects will be observed and monitored during the 
treatment for signs of neurologic side effects.  They will also be observed overnight on the 
neurosurgical ward.  Most neurologic side effects would manifest within minutes to hours.  
Those related to cerebral edema will be transient and expected to resolve within 2-3 weeks. 
Perioperative confusion has infrequently been observed with medial thalamotomy procedures.     
Jeanmonod reported one case of somnolence from 96 Radio Frequency (RF) CL 
thalamotomies100 and no occurrences when the lesions performed with FUS.54 The risk of this 
almost certainly increases with older age.  In order to mitigate the risks of perioperative 
confusion or cognitive decline, subjects will undergo preoperative psychological assessment to 
gauge their cognitive reserve exclude those with significant cognitive impairment.   The precise 
delivery of acoustic energy with MR-guidance will ensure that lesions are not delivered outside 
of the targeted CL nuclei – a technology that much less susceptible to confounding features like 
brain shift or stereotactic inaccuracies. MRgFUS has been shown consistently with submillimeter 
precision.79,81 
Symptomatic intracerebral hemorrhage with stereotactic procedures has been consistently 
estimated to range from 1 to 2%, and may be slightly higher with pallidotomy procedures which 
have been reported in large series to almost 4%.  Intracerebral hemorrhage from stereotactic RF 
lesions likely occurs in a slightly higher fashion than stereotactic FUS lesioning because 
electrode penetration of the brain is required.  In order to mitigate the risk for intracerebral 
bleeding from FUS, subjects with severe hypertension and coagulopathy will be excluded from 
trial participation, and normotension will be maintained throughout all procedures. 
In the RF ablation experience of the PI, out of a series of 94 radiofrequency lesioning procedures 
for movement disorders, a single 10-mm thalamic hemorrhage was noted in a subject undergoing 
thalamotomy at a probe tip temperature of 70ºC. (unpublished data)   It is difficult to translate the 
probe tip temperature in an RF lesion to the target volume temperature of an MRgFUS lesion, 
but it may be postulated that thermal lesioning at higher temperatures could increase the risks of 
hemorrhage.  In order to minimize such risk, we propose to perform permanent ultrasound 
lesioning bilaterally with a measured temperature of 65ºC at the target.  This temperature is 
sufficient for thermal coagulation of the target but well below the peak temperature observed in 
the case cited above.  The experience of the ExAblate TcMRgFUS thalamotomy in the treatment 
of subjects with neuropathic pain and Essential tremor entailed treatment to 65ºC at target 
without any observed neurologic or hemorrhagic consequences. 
Cavitation.  More recently, Jeanmonod et al. achieved central lateral thalamotomy ablations with 
submillimeter precision79 for therapy resistant neuropathic pain syndromes using focused 
ultrasound.  There was a single thalamic hemorrhage resulting in neurologic morbidity which 
possibly occurred from cavitary effects.  This complication led to the universal adoption of 
cavitation detectors in the ExAblate technology. 54 
Delayed ischemic infarction has been rarely observed with stereotactic RF lesioning of the 
basal ganglia.  The occurrence of this complication has been only reported in 3 of 50 cases of RF 
pallidotomy, and these cases occurred in subjects with a significant history of vasculopathy 

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identified either clinically or radiographically. 101  These ischemic events occurred in a delayed 
fashion at 10, 51, and 117 days following the procedure.  One of 89 subjects undergoing 
subthalamotomy presented with a delayed onset of involuntary movements at one week and 
imaging suggested a thalamic/subthalamic infarction102  It is postulated that these delayed 
infarctions results from damage to the perforating of vessels of the basal ganglia.  
Lenticulostriate perforating vessels are much less prevalent in the medial thalamus. Subjects at 
risk for bleeding (low clotting factors or anticoagulants) are excluded. In addition, heating should 
seal vessels.  
Infection has been rarely observed with stereotactic lesioning and certainly with less frequency 
than occurs with implanted devices from DBS procedures.  We anticipate a negligible risk for 
meningitis or brain abscess with ExAblate thalamotomy as this is not an open brain procedure 
requiring incisions or burr holes through the skull. 
Mortality.  There have been no mortalities in over 400 ExAblate Neuro ablations performed 
worldwide.  The mortality rate with surgical radiofrequency thalamotomy, a much more common 
procedure that has been employed for decades, has not been reported and likely occurs in much 
less than 1% of cases.  At the University of Virginia, over 100 radiofrequency thalamotomies 
have been performed without mortality.  
9.6 Risks Related to the Sonication Pathway 
Skin: The treatment set-up process includes filling the gap between the ultrasound transducer 
and the skull with a water-filled membrane to provide acoustic coupling. There is a possibility of 
small air bubbles remaining attached to the skin.  These could cause a small focal hot spot and 
cause local pain or a burn to the scalp. The active cooling mechanism unique to this system is 
designed to reduce the risk of skin burns and improve subject comfort.  In previous studies, 
MRgFUS treatments have caused burns of the skin (see analysis above). To minimize this risk, 
the scalp will be carefully shaved, and scars or other irregularities (e.g. eczema) will be kept 
outside the treatment pathway. Subjects with remarkable atrophy and poor healing capacity of 
the scalp (> 30% of the skull area traversed by the sonication pathway) will be excluded from 
this study. 
Skull and air-filled spaces: In the treatment planning, air-filled spaces (frontal, ethmoid, 
sphenoid sinus, mastoid) inside the skull are identified in bone window CT images and kept 
outside the pathway. Other irregularities of the skull, which might scatter the acoustic energy, are 
compensated for in the system. Skull may become heated by absorbing more acoustic energy 
than normal soft tissue. The skull cannot sense pain but the overlying soft tissues may sense pain 
if the bone becomes heated. MRI thermometry at 1.5 T is able to detect changes of  ±3 Celsius in 
soft tissues 103. Possible heat transfer from the skull bone to the brain by successive sonications is 
monitored by MRI thermometry of the cortex and white matter. The sonication duration and 
energy levels, and the cooling times between the sonications are adjusted so that the focus in the 
target tissue is heated while allowing other tissue to cool down between sonications. Local bone 
damage is very unlikely because the active cooling mechanism system is designed to keep the 
bone temperature below a temperature that can damage it.  Based on the data acquired to date 
and reviewed by FDA under G020182/S04, the average temperature rise at the skull level ranges 

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between 1 to 5 Celsius.  Hence, this active cooling strategy should continue to provide the safety 
needed.  
Dura, meningeal arteries and venous sinuses: The dura adjacent the skull may absorb heat if 
the bone becomes heated. Dura itself may sense pain and the main branches of the arteries are 
sensitive to heat. The meningeal arteries can generally be avoided in the treatment planning as 
their grooves in the skull are visible in 3D-CT. Local necrosis of the dura is unlikely, and were it 
to happen, it would not cause cerebrospinal fluid leakage. The venous sinuses between the two 
leaves of the dura, the sagittal sinus, the straight sinus and the transverse sinus may be in the 
sonication pathway. Their heating will be avoided by the active cooling sub system. The sigmoid 
sinus and the cavernous sinus will be kept outside the pathway due to their proximity to the skull 
base and cranial nerves, respectively.  
Subarachnoid space: Cerebrospinal fluid in the thin subarachnoid space between the dura and 
the cortex could possibly transfer heat from bone to the cortex.  There is no specific risk to the 
CSF itself becoming heated.   Because it can flow within the subarachnoid space, this can serve 
as another mechanism to prevent local hot spots next to the skull.  
Cortex:  In prior studies of ExAblate lesioning of thalamus for tremor, nearly one hundred 
subjects have been treated without any neurological or imaging evidence of cortical effects.   All 
subjects have been assessed posttreatment with MRI, and there have not been detectable changes 
outside of the treatment area.  
Brain, cranial nerves and cerebral arteries: In this study the treatment path will avoid cranial 
nerves and major cerebral arteries (ICA, MCA, ACA, BA). 
Micro-calcification:  The subject population of this study may have some level of micro-
calcification present in the brain tissue.  Given calcium’s higher absorption of ultrasound energy, 
its presence may create additional heating effect along the beam path.  This risk is mitigated by 
utilizing the CT data (to localized the calcified areas) and the various tools of the ExAblate 
system to delineate these areas so that the beam is blocked from passing through these calcified 
areas.   
Secondary Hot Spots:  theoretically speaking, there is a potential risk due to secondary hot spots 
that may occur along the beam path outside the focus.  This has been reported in the literature for 
different  types of transducer configurations using similar frequencies.  The ExAblate system, 
with its unique, highly focused transducer configuration, was tested extensively using advanced 
simulations.  The results of this work showed no evidence of significant hot spots away from the 
focal area.  In any case, the real time thermal imaging feedback samples the entire field of view 
around the targeted tumor.  These thermal images are displayed during the course of the energy 
delivery and therefore if there is evidence of any secondary hot spot is observed, the treating 
physician will be able to utilize the other specific feature of the ExAblate system that is “real-
time” stop sonication button that instantaneously halts energy delivery.  Hence, if this risk exists, 
the system is well equipped to handle it in real time and prior to incurring any tissue damage. 
9.7 Neurological Risks  
The thermal lesioning process with focused ultrasound could cause neurological effects for 
several reasons.  Any effects outside of the treatment area could result in neurologic signs or 
symptoms.  These could occur from the thermal lesioning process that is ‘off-target’ or 

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associated infarction, hemorrhage or edema.  Subjects will be observed and monitored during the 
treatment for signs of neurologic side effects.  They will also be observed overnight on the 
neurosurgical ward.  Most neurologic side effects would manifest within minutes to hours.  
Those related to cerebral edema will be transient and expected to resolve within 2-3 weeks.   
9.8 Anticipated Treatment Side Effects from MRgFUS 
All adverse events will be reported in the Case Report Forms (CRFs) and analyzed for their 
relation to the ExAblate device as well as other causes (Expected procedure findings, 
Drug/Contrast media reactions, Medical conditions, and Unrelated to device or procedure). 
Adverse events related to the device or procedure occur during or shortly after the procedure 
(within 30 days) since the effect is a one-time, focal treatment.  Based on existing treatment 
experience in the brain using the ExAblate Neuro Type 1.0 (650 KHz), the following anticipated 
side effects have been identified as possibly occurring during/following the ExAblate procedure.  
9.8.1 Procedure-related events include: 
• Claustrophobia.  Medications may be useful in controlling symptoms, but may also result 
in nausea/vomiting. 
• Pain/discomfort:   
o Sonication-related headache or head/face flushing or warmth.  Usually these are 
transient, but are coincident with a sonication.  Headache may occasionally last 
for several days. 
o Headache may related to the headframe or fasting status.  The brain has no pain 
sensors, but the scalp, dura and bone tissues do. 
o Position-related pain related to being uncomfortable in the scanner (e.g., sore 
neck, back pain, muscle or joint pain. 
• Hypertension/hypotension, and bradycardia/tachycardia may be related to pre-procedure 
nervousness or comorbid conditions / missed medication dose pre-procedure as an NPO 
requirement.  Medications can be administered peri-procedure to control them.  
• Neurological deficits may result from damage to nearby structures in the brain and thus is 
specifically related to the target location.  To date, the following has been reported:  
o vestibular with or without vegetative manifestations   
o paresthesias  
o dysesthesias/pain. 
9.8.2 Events which are Unrelated to the ExAblate device include: 
• Events associated with the headframe, such as pin site pain, pin site or scalp/facial 
edema, pin site burning or bleeding. 
• Events associated with the urinary catheter, such as urinary tract infection. 

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• Events associated with the intravenous line used to administer medications, such as 
infection and/or bruising. 
• Events that are associated with comorbid conditions or unforeseen circumstances. 
9.8.3 Drug reactions include: 
• Nausea or vomiting 
• Dizziness 
• Overdose or mis-dosing in error 
9.8.4 Events related to malfunction or mis-use of the device include: 
• Mis-alignment, mis-targeting or reflection of the ExAblate beam. 
• Heating of structures in the FUS backbeam or forebeam 
• Additionally, the following side effects are thought to be improbable but their relative 
risks remain to be defined: 
Scalp in the sonication pathway: 
● Skin burns (>2o) with ulceration of the skin 
● Scar formation 
● Loss of sensation 
● Atrophy 
Bone in the sonication pathway: 
● Bone necrosis 
Dura, venous sinuses, and cortical veins 
● Subdural bleeding 
● Vein thrombosis 
● Cortex heating 
● Seizures 
● Symptoms from disturbances of 
eloquent cortical areas (motor, sensory, 
auditory, visual, speech) 
Other brain tissue 
● Necrosis of normal tissue due to incorrect 
targeting 
● Thermal damage to adjacent functional 
brain tissue (e.g.: optical tract) 
● Bleeding in the treated area 
● Cerebral infarction 
● Moderate or severe increase in cerebral 
edema as shown by MRI scans 
● Symptomatic increase of intracranial 
pressure 
● Death 
Cerebral arteries 
● Bleeding 
● Coagulation thrombosis 
● Vasospasm 
● Death 
 
Adverse events will be assessed for their relationship to the study device or procedure.  Standard 
Code of Federal Regulation (CFR) definitions for SAEs and UADEs will be used in assessment 
of adverse events.  
Focused Ultrasound thalamotomy has previously been described for essential tremor.  These 
thalamotomies for tremor were performed unilateral to the ventral intermediate nucleus, which is 
located adjacent to the internal capsule and ventral posterolateral somatosensory nucleus of the 
thalamus.  The medial thalamic target for this study will serve as a central lateral thalamus, and 
immediately positioned intralaminar nucleus that should not incur risks for sensory, motor, or 

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cerebellar disturbance.  This nocioceptive region of the thalamus will be targeted bilaterally.  
Acoustic energy will be titrated until peak voxel temperatures at the target reach 55 to 65 degrees 
Celsius.  Intraoperative feedback is less important for this target than for tremor monitoring, so 
subjects can undergo intravenous sedation for comfort without losing localizing clinical 
feedback.  The postoperative care of medial, CL thalamotomy will be the same as those for Vim 
thalamotomy with a one day hospital stay. 
9.9 Adverse Reactions and Precautions 
The subjects will be educated as to what to expect during the procedure and the importance of 
immediately communicating any problems, unusual symptoms, or discomfort, to the investigator 
during the treatment and throughout the follow-up period. Subjects will also be educated as to 
what sensations or perceptions could indicate that neurological damage may be starting to occur. 
They will be told to use their handheld stop sonication button if they felt anything unusual may 
be happening so that they can be neurologically assessed. All adverse reactions occurring in this 
study will be recorded in the Case Report Forms.  Each will be assessed for its probable cause 
(unrelated to the treatment, device related, procedure related, etc) as described below. 
9.10 Criteria for Removal from the Study 
Subjects can be exited from the study at any time if in the opinion of the principal investigator it 
is not in the best interest of the subject to carry on as planned.  In addition, subjects may also 
choose to exit the study at any time, but will be strongly encouraged to participate in the follow-
up visits for safety reasons (continued monitoring of subject safety). 
9.11 Criteria for Stopping the Study 
The study will be stopped for evaluation should: 
1. any death occur, or 
2. if two or more subjects experience 
a.  a cerebrovascular hemorrhage  
b. or serious related neurological adverse event  
c. or a 50% increase in pain from Baseline following two consecutive visits starting 
from 7-days post treatment visit. 
10.0  Adverse Event Reporting 
It is the responsibility of the investigator to document all treatment related and device related 
Adverse Events (AE’s), which occur during the course of the study.  At each visit, the 
investigator will evaluate AE’s. AE’s not previously documented in the study will be recorded 
on the Adverse Event Log within the subject’s CRF. The nature of each event, date and time 
(when appropriate) of onset, outcome, frequency, maximum intensity, action taken, and 
attribution will be recorded. AEs already documented in the CRF (i.e., at a previous assessment) 
and designated as ‘ongoing’, should be reviewed at subsequent visits as necessary. If these have 
resolved, the documentation in the CRF should be completed including an end date for the event. 

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If an AE increases in frequency or severity during a study period, a new record of the event will 
be started. 
Standard Code of Federal Regulation (CFR) definitions for Serious Adverse Events (SAEs) will 
be used for evaluation of adverse events.   
SAE [§803.3(aa)(1)] is an injury or illness that:  
• causes death 
• is life threatening, even if temporary in nature;  
• results in permanent impairment of a body function or permanent damage to a 
body structure; or  
• necessitates medical or surgical intervention to preclude permanent impairment of a 
body function or permanent damage to a body structure. 
All AEs (related or unrelated) meeting the criteria for an SAE require notification of the sponsor 
and the reviewing IRB as soon as possible, with subsequent completion of additional paperwork 
provided by the sponsor fully documenting the course of the event, all treatments, and final 
outcome.  Initial reporting of an SAE should be made to the sponsor no later than two (2) 
working days after the PI learns of the incident.  
Standard Code of Federal Regulation (CFR) definitions for Unanticipated Adverse Device 
Effects (UADEs) will be used for evaluation of this type of adverse event. 
UADE [§812.3(s)] means any serious adverse event 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 application (including a supplementary plan or application), or any other 
unanticipated serious problem associated with a device that relates to the rights, safety, or 
welfare of subjects. 
Any UADEs will be reported to InSightec through the eCRF and to the reviewing IRB as soon as 
possible. However, in no event must this report be made later than two (2) working days after the 
PI learns of the incident.  
Other common non-study or non-device related, minor health complaints will not be collected as 
AEs (for example: colds, sprains, headaches).  Subjects who have a progression of their primary 
disease or symptoms that lead to an alternative treatment will not be reported as an AE. 
10.1 
Adverse Events Analysis 
A Data Safety Monitoring Board will be used to review all AE’s on the study. Their role is to 
evaluate all AE's that occur throughout the study and determine if they are in fact related to the 
ExAblate, or some other cause. We would closely monitor all treatments for any AE's, and 
consider the following questions for AEs in the Test Arm: 
- Was the adverse event serious? 
- life-threatening, caused a disability: required or prolonged hospitalization: caused 
death. 

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- Was the adverse event device related? 
- Was the adverse event unexpected? 
- Is there an unreasonable risk in continuing the trial? 
If in fact it is determined that an ExAblate-treated subject experienced an AE that met all of the 
above criteria, we would stop the trial pending further investigation.   If in the opinion of the 
DSMB, a modification of the study protocol were necessary to provide adequate protection to 
future study participants, the modification would be implemented prior to reinitiating the 
investigation.  Any such amendment would be reported to the IRB and FDA as required by the 
applicable regulations. 
11.0 POTENTIAL BENEFITS 
There may or may not be any benefit to participating in this study.  This technique is still being 
investigated.  It may provide some therapeutic value for subjects with few or no other options. 
The symptoms may decrease and/or the quality of life of the subject may improve due to relief of 
symptoms.  However, there is no guarantee that this procedure will reduce, eliminate symptoms, 
or otherwise treat the underlying disorder.  Other subjects may benefit from this procedure in the 
future, if further trials prove it to be a safe and effective therapy.   
12.0 MONITORING PLAN 
Clinical Monitoring for this study will be managed by InSightec. The Clinical Monitor is 
qualified by training and experience to oversee the conduct of this study. The Clinical Monitor’s 
responsibilities include maintaining regular contact with the investigational site through 
telephone contact and on-site visits, to ensure that:  
➢ The trial is conducted according to FDA and ICH-GCP requirements;  
➢ The trial is conducted according to InSightec internal SOP’s 
➢ The Investigational Plan is followed;  
➢ Complete, timely, and accurate data are submitted;  
➢ Problems with inconsistent or incomplete data are addressed;  
➢ Complications and unanticipated adverse effects are reported to the Sponsor and the IRB;  
➢ The site facilities will be monitored to stay adequate to meet the requirements of the 
study.  
The Clinical Monitor will initiate the Study during an on-site visit and will continue to perform 
on-site monitoring visits as frequently as deemed necessary. The first monitoring visit will 
usually be made as soon as possible after enrollment has been initiated. At this visit and all 
monitoring visits, the Clinical Monitor will compare the data entered onto the CRFs with the 
hospital or clinical records (source documents). Source documentation must be available to 
substantiate proper informed consent procedures, adherence to protocol procedures, adequate 
reporting and follow-up of AEs, and device procedure information. Findings from the review of 
CRFs and source documents during a monitoring visit will be discussed with the PI. Completed 
paper or electronic CRFs will be reviewed prior to data closure at each visit. The dates of the 

Protocol Version Date 06 December 2019 
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monitoring visits will be recorded in a Log to be kept at the clinical site. During monitoring 
visits, the Sponsor expects that the study coordinator and the PI will be available, the source 
documentation will be available, and a suitable environment will be provided for review of Study 
related documents.   
Sites should make every effort to contact all subjects for study follow-up to encourage visit 
compliance.  Sites should keep a log of dates of attempted contact and results. After 3 
unsuccessful attempts at contact (e.g., by telephone or email) and sending 1 certified letter to 
solicit their visit compliance a subject may be considered lost to follow-up.    
Monitoring procedures will follow the Sponsor SOPs. 
12.1 
Electronic Data Capture (EDC) 
Electronic CRFs (eCRFs) will be used to capture protocol-specific information during the 
conduct of this study.  This electronic data capture of the eCRFs is based on the Oracle Software 
system, and is designed, run and hosted by InSightec. 
13.0 INVESTIGATOR RESPONSIBILITIES 
The Principal and co-investigators will be required to sign the Investigator Agreement.  All 
investigators will undergo extensive training on the protocol and operation of the MRgFUS 
system, and provide documentation of their specialized training. 
 
 

Protocol Version Date 06 December 2019 
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14.0 APPENDICES 
Appendix – A: Copy of Publication of ExAblate Neuro Treatment of Neuropathic Pain 
Appendix – B: Prior Investigations using ExAblate Neuro (ExAblate Model 4000 Type 1) 
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Appendix A 

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Appendix B 
 
The ExAblate Neuro system Type 1.0 that is approved for Essential Tremor (P#150246) is also 
being investigated for the treatment of Parkinson’s Disease, Brain Tumor and Epilepsy subjects 
(under IDE # G020182, G120017, G140018, G140082, G160021).  The transducer helmet for 
the Type 1.0 system is 650 KHz and is used for ablation of deep brain targets and includes ALL 
clinical features and tools of the current FDA ET IDE approved version, subject interface and 
coupling, etc.  There is no change to the thermal modeling, energy delivery, beam forming, nor 
treatment parameters and guidelines, and mitigating steps.  Furthermore, the manufacturing 
process, device risk analysis, SW and HW verification and validation have also remained 
unchanged. 
Pivotal Study for Essential Tremor IDE - G120246 - ExAblate 4000 Type-1  
This global, multi-center, randomized, sham-controlled pivotal study evaluated the safety and 
efficacy of ExAblate Neuro unilateral thalamotomy for treating medication-refractory Essential 
Tremor.  A total of 76 subjects were recruited for this study and followed for 12 months which is 
the basis for the PMA submission to the FDA under PMA # P150039 and was approved July 
2016.  Regulatory submissions were also submitted to the following regulatory agencies in other 
countries to gain commercial approval for this indication: 
• Korea MFDS  - Approved November 2015 –for the following indication of use: 
ExAblate Model 4000 MR guided focused ultrasound system intended for thermal 
ablation of normal brain structure targets in the Basal Ganglia and Limbic System of 
the brain for the treatment of movement, pain and behavioral disorders by heat 
induced focusing using ultrasound energy under full MR planning and thermal 
imaging control. 
• Health Canada -  Approved by Health Canada License #96969 on May 17, 
2016 for the following indication of use 
The ExAblate Neuro is intended for use in the unilateral Thalamotomy 
treatment of idiopathic Essential Tremor subjects with medication-
refractory tremor.  Subjects must be at least age 22. The designated area 
in the brain responsible for the movement disorder symptoms (ventralis 
intermedius) must be identified and accessible for targeted thermal 
ablation by the ExAblate device. 
• U.S. FDA – Approved July 2016 for the following indication of use: 
The Exablate Neuro is intended for use in the unilateral Thalamotomy 
treatment of idiopathic Essential Tremor subjects with medication-
refractory tremor. Subjects must be at least age 22. The designated 
area in the brain responsible for the movement disorder symptoms 

Protocol Version Date 06 December 2019 
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(ventralis intermedius) must be identified and accessible for targeted 
thermal ablation by the Exablate device. 
• Japan MHLW PMDA – Approved December 2016 for the following indication of use:  
ExAblate Neuro for the non-invasive treatment of essential tremor 
in subjects who have not responded to medication 
 
CE Approval of the ExAblate Neuro MRgFUS System  
In December-2012, InSightec received CE Mark of Conformity approval for the ExAblate 
Model 4000 Type 1 for the following Indication of Use: 
Intended use 
ExAblate 4000 transcranial MR guided focused ultrasound 
(TcMRgFUS) system (type 1) intended for thermal ablation 
of targets in the thalamus, sub thalamus and Pallidum 
regions of the brain. 
Indication for use 
ExAblate 4000 transcranial MR guided focused ultrasound 
(TcMRgFUS) can be used for the treatments of neurological 
disorders (Essential Tremors, Tremor Dominant Idiopathic 
Parkinson’s Disease – Unilateral) and Neuropathic pain in 
the brain by heat induced focusing using ultrasound energy 
under full MR planning and thermal imaging control.  
 
 
 

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Open FDA IDEs 
Open HealthCanada ITAs 
Movement Disorders 
9.11.1.1.1 
Feasibility Study for Brain 
Tumor IDE # G020182 – ExAblate Model 
4000 Type-1 
In 2002, the FDA approved an IDE for a 
feasibility clinical study for the ExAblate 
Neuro system in the treatment of brain 
tumors.104,105  The purpose of this study 
was to evaluate the safety of MRI-guided 
focused ultrasound thermal ablation of 
brain tumors performed through intact 
human skull using the ExAblate system.  
The study is on-going.   
 
Feasibility Study for Brain Tumor . ITA# 
165868  – ExAblate Model 4000 Type-1 
The purpose of this study was to evaluate 
the safety of MRI-guided focused 
ultrasound thermal ablation of brain tumors 
performed through intact human skull 
using the ExAblate system.  The study is 
on-going. 
Feasibility Study for Tremor Dominant 
Parkinson’s Disease IDE - G120017 - 
ExAblate 4000 Type-1 Neuro  System 
This is a multi-center, randomized, sham-
controlled feasibility study to evaluate the 
safety and efficacy of ExAblate Neuro 
unilateral thalamotomy for treating 
medication-refractory Tremor Dominant 
Parkinson’s Disease.  A total of 30 subjects 
were to be recruited for this study.  To date, 
27 subjects have been treated.  The study 
was closed to enrollment as the 20th 
subject randomized to ExAblate was 
treated.  All follow-up is now complete and 
the final clinical study report in progress. 
Feasibility Study for Unilateral 
Pallidotomy for the Treatment Dyskinesia 
(LID) of Parkinson’s Disease – Health 
Canada ITA # 222434 - ExAblate 4000 
Type-1 Neuro System 
This is a, single-center feasibility study to 
evaluate the safety and efficacy of 
ExAblate Neuro unilateral pallidotomy for 
treating medication-refractory LID 
Parkinson’s Disease to be performed at 
Sunnybrook.  A total of 6 subjects will be 
recruited for this study.  This study has 
been approved by Health Canada, and the 
first subject has been treated. 
Feasibility Study for Unilateral 
Subthalamotomy (“STN”) Treatment of 
Dyskinesia of Parkinson’s Disease with 
ExAblate 4000 Type-1 Neuro System – 
FDA IDE # G140018.  
In April 2014, InSightec received the FDA 
approval to conduct a feasibility study for 
A Feasibility Clinical Trial of the 
Magnetic Resonance Guided Focused 
Ultrasound (MRgFUS) for the 
Management of Treatment-Refractory 
Movement Disorders - Health Canada 
Application # 228826  

Protocol Version Date 06 December 2019 
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ExAblate Neuro in the STN treatment of 
dyskinesia in subjects with Parkinson’s 
disease.  Three subjects have now been 
treated. 
 This multicenter (2) study is designed to 
treat (thalamotomy or pallidotomy) any one 
of several movement disorders in a total of 
40 subjects.  Currently, 29 subjects have 
been treated.  Enrollment is on-going. 
Feasibility study for Unilateral 
Pallidotomy for the Treatment Dyskinesia 
Parkinson’s Disease with ExAblate 4000 
Type-1 Neuro System – FDA IDE # 
G140082. 
In June-2014, InSightec received the FDA 
approval to conduct a feasibility study for 
ExAblate Neuro in the GPi treatment of 
dyskinesia in subjects with Parkinson’s 
disease.  The study is on-going. 
Feasibility Study for Unilateral 
Pallidotomy for the Treatment Dyskinesia 
(LID) of Parkinson’s Disease – Health 
Canada ITA # 222434. 
This is a, single-center feasibility study to 
evaluate the safety and efficacy of 
ExAblate Neuro unilateral pallidotomy for 
treating medication-refractory LID 
Parkinson’s Disease to be performed at 
Sunnybrook.  A total of 6 subjects will be 
recruited for this study.  This study has 
been approved by Health Canada, and one 
subject has been treated. 
 
Epilepsy 
Brain Tumor 
Feasibility study for Treatment of 
Subcortical Lesional Epilepsy with 
ExAblate 4000 Type-1 Neuro System – 
FDA IDE #G160021 
In February 2016, InSightec received FDA 
approval to conduct a feasibility study for 
the treatment of subcortical lesions that 
induce epilepsy in 15 adult subjects.  This 
is a multi-center, prospective, open-label 
study that is just starting up. 
Feasibility Safety Study Using the 
ExAblate 4000 System in the Management 
of  Benign Centrally-Located Intracranial 
Tumors Which Require Clinical 
Intervention in Pediatric and Young Adult 
Subjects. In 2016, InSightec received FDA 
approval to conduct a feasibility study on 
benign brain tumors. This is a single center, 
prospective, open-label, descending age 
cohort designed study 
 

Protocol Version Date 06 December 2019 
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Closed Studies using ExAblate 4000, Type I 
Feasibility Study for Neuropathic Pain 
Outside the US - ExAblate 4000 Type-1 
Neuro System 
An investigator initiated and sponsored study 
in the treatment of neuropathic pain was 
conducted at the University Hospital Zurich 
(Zurich Switzerland) using the InSightec 
ExAblate Neuro (650 KHz) system.  The 
study was approved by and performed 
according to the guidelines of the ethics 
committee of the University and the State of 
Zurich. 
Nineteen (19) subjects with chronic, 
medication-resistant neuropathic pain 
underwent selective central lateral 
thalamotomy (CLT) using the ExAblate 
Neuro treatment. Therapy-resistance was 
defined as occurring when the subject’s pain 
was not effectively treated with medication.  
Feasibility Study for Essential Tremor IDE 
- G100169 - ExAblate 4000 Type-1  
InSightec received FDA approval for a 
feasibility trial of ExAblate Neuro System for 
unilateral thalamotomy in the treatment of 
Essential Tremor under IDE # G100169.  
Total of 15 subjects were enrolled and treated 
at one site.  This study has been completed 
and the full results of this study were 
published in the New England Journal of 
Medicine. 106 Based on the investigator and 
the subject’s feedback, subjects have shown a 
great level of acceptance of the procedure.  
Furthermore, subjects have shown a 
significant improvement in their Essential 
Tremor disease following their unilateral 
treatment with the ExAblate Neuro device.  
Subjects who completed the study 
requirements have shown stability of the 
tremor suppression all the way to the end of 
the study.   

Protocol Version Date 06 December 2019 
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For all subjects, the treatment was well 
tolerated and did not result in any side effects 
or neurological deficits.  The only significant 
event reported to date from this study is an 
event of neurological deficit, i.e. “dysmetria 
(dyscoordination) of the right hand, 
dysarthria, motor neglect and gait disorder”.  
This event was reported immediately 
following the last sonication.   
All subjects experienced some level of pain 
relief during the procedure, and at 48 hours 
after the treatment, subjects reported pain 
relief ranging from 30 to 100% (mean = 
68%).80  Partial results of this study were 
published in the Annals of Neurology 
Journal.54 
Feasibility Study for Essential Tremor 
ITA# 166556- ExAblate 4000 Type-1 
A similar feasibility study in 6 subjects was 
also conducted at Sunnybrook, Toronto under 
Health Canada Application # 166556 and 
published in Neurotherapeutics.107