Functional Imaging of Tremor Circuits and Mechanisms of Treatment Response
Phase: PHASE4
Conditions: Essential Tremor, Tremor
Sponsor: University of California, San Diego

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Project Title:  Functional Imaging of Tremor Circuits and Mechanisms of Treatment Response 
 
Principal Investigator:  Fatta Nahab M.D., Associate Professor of Neurosciences, University of California San Diego 
 
NCT#: 02495883 
 
Date:  January 8, 2014 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
Bi o m e di c al I R B A p pli c ati o n  I n str u cti o n s 
P a g e 2  
 
U C S D H u m a n R e s e ar c h Pr ot e cti o n s Pr o gr a m  
N e w Bi o m e di c al A p pli c ati o n  
R E S E A R C H P L A N  
I n str u cti o n s f or c o m pl eti n g t h e R e s e ar c h Pl a n ar e a v ail a bl e o n t h e H R P P w e b sit e.  
T h e h e a di n g s o n t hi s s et of i n str u cti o n s c orr e s p o n d t o t h e h e a di n g s of t h e R e s e ar c h Pl a n.  
G e n er al I n str u cti o n s: E nt er a r e s p o n s e f or all t o pi c h e a di n g s.  
E nt er “ N ot A p pli c a bl e” r at h er t h a n l e a vi n g a n it e m bl a n k if t h e it e m d o e s n ot a p pl y t o t hi s pr oj e ct.  
V er si o n d at e: 0 5/ 1 1/ 2 0 1 1  
1.  
P R O J E C T TI T L E  
F u ncti o n al I m a gi n g of Tr e m or Circ uits a n d M e c h a nis ms of Tr e at m e nt R es p o ns e 
2.  
P RI N CI P A L I N V E S TI G A T O R   
F att a B. N a h a b, M. D.  
3.  
F A CI LI TI E S  
U ni v ersit y of C alif or ni a S a n Di e g o  
D e p art m e nt of N e ur osci e nc es  
F u ncti o n al I m a gi n g of N e ur o d e g e n er ati v e Dis or d ers L a b  
C e nt er f or Tr a nsl ati o n al I m a gi n g a n d P ers o n aliz e d M e dici n e  
K ec k C e nt er f or F u ncti o n al M a g n etic R es o n a nc e I m a gi n g ( C F M RI), U C S D  
Cli nic al a n d Tr a nsl ati o n al R es e arc h I nstit ut e, ( C T RI), U C S D  
 
4 . 
E S TI M A T E D D U R A TI O N O F T H E S T U D Y  
T h e esti m at e d d ur ati o n of t his st u d y is 5 y e ars f or s u bj ect r ecr uit m e nt, f M RI t esti n g, d at a a n al ysis a n d 
p u blic ati o n.   T his pr ot oc ol is b ei n g tr a nsiti o n e d t o U C S D d uri n g y e ar 3 of 5  fr o m t h e U ni v ersit y of Mi a mi. 
5.  
L A Y L A N G U A G E S U M M A R Y O R S Y N O P SI S ( n o m or e t h a n o n e p ar a gr a p h)  
Ess e nti al tr e m or ( E T) c a us es u nc o ntr oll a bl e s h a ki n g, us u all y of t h e h a n ds.  S e v er al m e dic ati o ns ar e us e d t o 
tr e at E T; h o w e v er, t h e y ar e oft e n o nl y p artl y eff ecti v e a n d c a n h a v e si d e eff ects t h at ar e n ot w ell t ol er at e d. 
M a n y p e o pl e wit h tr e m or  h a v e s o m e r eli ef fr o m dri n ki n g alc o h ol. It is u ncl e ar h o w e v er w h at br ai n ar e as 
pr o d uc e tr e m ors i n E T a n d h o w t h es e ar e as c h a n g e d uri n g v ari o us acti viti es or wit h m e dic ati o ns t h at c a n 
s u p pr ess tr e m or.  W e pl a n t o  st u d y t h e s o urc e of t h es e tr e m ors usi n g f u ncti o n al m a g n etic r es o n a nc e i m a gi n g 
(f M RI) a n d h o w tr e m or m e dic ati o ns m a y i m p act t h e acti vit y of v ari o us br ai n r e gi o ns.  
6.  
S P E CI FI C AI M S  
Ess e nti al Tr e m or ( E T) is t h e m ost c o m m o n tr e m or dis or d er, c urr e ntly aff ec ti n g a n esti m at e d 2. 9 milli o n 
A m eric a ns a n d l e a di n g t o dis a bility a n d d ecr e as e d q u ality of lif e i n 7 5 % of c as es.  Tr e m or aff ects t h e ar ms 
dis pr o p orti o n at ely m or e t h a n t h e h e a d, l e gs, v oic e a n d f ac e.   E T m ay occ ur at a ny a g e, t h o u g h pr ev al e nc e 
i ncr e as es after t h e a g e of 4 0. T h e p at h o p hysi ol o gy of E T is p o orly u n d erst o o d.  T h e s o urc e of t h e tr e m or r e m ai ns 
c o ntr ov ersi al si nc e all st u di es s h o w i ncr e as e d activity i n t h e c er e b ell u m (i ncl u di n g mi mick e d tr e m or i n c o ntr ols), 
w hil e a ni m al m o d els of E T usi n g h ar m ali n e  a n d a si n gl e h u m a n P E T st u dy i m plic at e t h e i nf eri or oliv ary n ucl e us i n 
t h e br ai nst e m.  Tr e at m e nt of E T f oc us es o n p h ar m ac ol o gic al a g e nts of v ari o us m ec h a nis ms ( e. g. -bl ock ers, 
a ntic o nv uls a nts, b e nz o di az e pi n es) a n d r ar ely d e e p br ai n sti m ul ati o n of t h e Vi m  t h al a m us.  D es pit e t h e 
ass ort m e nt of a g e nts  us e d t o tr e at E T, o nly ~ 5 0 % of p ati e nts b e n efit fr o m a p artic ul ar a g e nt.  F urt h er, t h eir 
m ec h a nis ms of acti o n o n tr e m or ar e n ot k n o w n a n d syst e mic a dv ers e eff ects ar e c o m m o n.  
O ur l o n g -t er m g o al is t o i m pr ov e tr e at m e nt o utc o m es t hr o u g h t h e d ev el o p m e nt of m or e f oc us e d t h er a pi es f or 
E T, w hil e mi ni miz i n g a dv ers e eff ects.  T h e g o al of t his pr o p os al is t o i d e ntify t h e br ai n r e gi o ns a n d n et w orks 
ass oci at e d wit h v aryi n g E T p h e n oty p es a n d d eli n e at e t h e m ec h a nis ms by w hic h tr e at m e nt alt ers a b err a nt 
activity i n t h es e n et w orks.  T h e c e ntr al h y p ot h esis is t h at bl o o d o x y g e n l e v el d e p e n d e nt ( B OL D) f u ncti o n al 
m a g n etic r es o n a nc e i m a gi n g (f M RI) c orr el at es will i d e ntif y t h e E T n e ur al n et w or k al o n g wit h m ec h a nis ms t o 

 
 
Bi o m e di c al I R B A p pli c ati o n  I n str u cti o n s 
P a g e 3  
r e g ul at e it.  O ur h y p ot h esis was f or m ul at e d b as e d o n o ur o w n pr eli mi n ar y d at a usi n g est a blis h e d m et h o ds  as 
w ell as a n o v el a p pr o ac h w e h a v e d e v el o p e d.  R es ults o bt ai n e d fr o m t h e pr o p os e d st u d y will pr o vi d e t h e 
critic al k n o wl e d g e n e e d e d t o p urs u e t ar g et e d dr u g a n d s ur gic al d e v el o p m e nt a n d ulti m at el y i m pr o v e 
tr e at m ent of E T . 
 
Ai m 1. D o es t h e c er e b ell u m h a v e i ncr e as e d bl o o d fl o w a n d f u ncti o n al c o n n ecti vit y at r est ?   W e will c oll ect 
f u ncti o n al M RI (f M RI) d at a w hil e p artici p a nts ar e at r est a n d n ot ex p eri e nci n g tr e m or.   Acc el er o m etry will b e 
us e d t o c o nfir m t h at n o tr e m ors occ urr e d d uri n g d at a ac q uisiti o n.  W e will utiliz e o ur C o nt ext Diff er e nti al 
A ut oc orr el ati o n M a p pi n g ( C D A M) m et h o d t o c o m p ar e gl o b al f u ncti o n al c o n n ectivity i n a gr o u p of s u bj ects wit h 
E T t o a gr o u p of a g e -m atc h e d c o ntr ols.  W e hy p ot h esiz e t h at t h e i nf eri or oliv e, c er e b ell u m, a n d r e d n ucl e us 
( M oll ar et’s tri a n gl e) will h av e si g nific a ntly gr e at er f u ncti o n al c o n n ectivity i n t h e E T gr o u p c o m p ar e d wit h 
c o ntr ols. 
 
Ai m 2 . Ar e p ost ur al a n d ki n etic tr e m ors ass oci at e d wit h diff er e nt a b err a nt n et w or ks ?   W e will c o ll ect f M RI 
d at a w hil e E T s u bj ects p erf or m t w o s e p ar at e t asks.  D uri n g o n e t ask, s u bj ects will b e v er b ally c u e d t o el ev at e 
t h eir ar m i n a t o nic p ositi o n t o m a nif est p ost ur al tr e m or d uri n g f M RI d at a ac q uisiti o n, i n a bl ock-d esi g n 
p ar a di g m.  Acc el er o m etry wil l b e us e d t o q u a ntify t h e fr e q u e ncy a n d s ev erity of t h e p ost ur al tr e m or.  D uri n g a 
s ec o n d t ask, s u bj ects will b e si mil arly c u e d t o dr a w a n Arc hi m e d es s pir al t o elicit ki n etic tr e m or.  T a bl et dr a wi n gs 
will b e di gitiz e d t o q u a ntify t h e fr e q u e ncy a n d s ev erity  of t h e ki n etic tr e m or.  W e will us e est a bli s h e d f M RI 
a n alysis m et h o ds t o g e n er at e st atistic al p ar a m etric m a ps (S P Ms) a n d C D A M t o c o m p ar e t h e r e gi o n al diff er e nc es 
i n activ ati o n a n d c o n n ectivity b et w e en p ost ur al a n d ki n etic tr e m or.  W e hy p ot h esiz e t h at p ost ur al tr e m or will b e 
ass oci at e d wit h gr e at er i nf eri or oliv e activ ati o n a n d c o n n ectivity, w hil e ki n etic tr e m or will h av e gr e at er 
c er e b ell ar activ ati o n a n d c o n n ectivity. 
 
Ai m 3. W h at r e g ul at or y c h a n g es i n t h e tr e m or n et w or ks occ ur t o ex pl ai n t h e tr e m or -s u p pr essi o n eff ects of 
et h a n ol a n d pr o pr a n ol ol?  Us i n g t h e r esti n g, p ost ur al, a n d ki n etic p ar a di g ms i n Ai ms 1 a n d 2, w e will ass ess t h e 
f M RI-b as e d activ ati o n a n d c o n n ectivity c h a n g es f or all E T s u bj ects u n d er t hr e e c o n diti o ns:  b as eli n e ( n o dr u g), 
ac ut e et h a n ol ( 5 0 ml of 4 0 % Et O H) c h all e n g e, a n d st a bl e d os e of pr o pr a n ol ol.  W e will ass ess t h e r e gi o n al 
activ ati o n a n d f u ncti o n al c o n n ectivity r es p o ns es f or e ac h c o n diti o n usi n g S P M a n d C D A M m et h o ds.  W e 
hy p ot h esiz e t h at et h a n ol’s m ec h a nis m of tr e m or s u p pr essi o n is by r e d ucti o n of oliv o -c er e b ell ar c o n n ectivity, 
w h il e pr o pr a n ol ol acts t o r e d uc e i nf eri or oliv e activ ati o n. 
Wit h r es p ect t o ex p ect e d o utc o m es, t h e fi n di n gs of ai ms 1 -3 ar e ex p ect e d t o i d e ntify t h e n e ur o a n at o mic al 
c orr el at es of E T, wit h p artic ul ar att e nti o n t o t h e d efi ni n g c h ar act eristics of p ost ur al a n d ki n etic tr e m ors of E T, 
a n d t h e u n d erlyi n g m ec h a nis ms of acti o n o n t h e str uct ur es i d e ntifi e d of t w o existi n g a g e nts wit h k n o w n 
effic acy.  T h e k n o wl e d g e g ai n e d by t his w ork will h av e dir ect a p plic a bility t o t h e d ev el o p m e nt of: n ov el 
p h ar m ac ol o gic al a g e nts a n d  s ur gic al d evic es wit h t h e ai d of a n e ur oi m a gi n g bi o m ark er.  I n a d diti o n, t h es e 
fi n di n gs st a n d t o i m p act cli nic al m a n a g e m e nt by pr ovi di n g i nf or m ati o n t h at c a n b e us e d t o t ail or tr e at m e nt t o 
i n divi d u al p ati e nt c h ar act eristics, t h er e by av oi di n g t h e tri al-a n d -err or m et h o ds c urr e ntly us e d t o g ui d e a g e nt 
s el ecti o n ( e. g. if -bl ock ers ar e f o u n d t o act m or e eff ectiv ely o n a sit e ass oci at e d wit h p ost ur al tr e m or).  I n 
a d diti o n, w e pl a n t o c oll ect D N A s a m pl es o n t his ric h d at as et f or f ut ur e i m a gi n g -g e n o mics st u di es.  
7.  
B A C K G R O U N D A N D SI G NI FI C A N C E  
Ess e nti al Tr e m or ( E T) is t h e m ost c o m m o n tr e m or dis or d er, c urr e ntl y aff ecti n g a n esti m at e d 2. 9 milli o n 
A m eric a ns a n d l e a di n g t o dis a bilit y a n d d ecr e as e d q u alit y of lif e i n 7 5 % of c as es.   I n di vi d u als wit h E T 
c o m m o nl y ex p erie nc e tr e m ors i n v ol vi n g t h e ar ms t h at m a nif est d uri n g m o v e m e nt ( ki n etic tr e m ors) or d uri n g 
s ust ai n e d a nti-gr a vit y p ost ur es ( p ost ur al tr e m ors).   T his h as a dir ect i m p act o n t h e i n di vi d u al’s a bilit y t o 
f u ncti o n i n th e w or k pl ac e a n d/ or p erf or m t h eir acti viti es  of d ail y li vi n g ( e. g. e ati n g, b at hi n g).  Di a g n osis of E T is 

 
 
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commonly made based on consensus clinical criteria, and a history of alcohol- responsive tremors is highly 
suggestive of ET.  Clinical management for moderate to severe cases begins with selection of a 
pharmacological agent with at least modest efficacy and favorable side effect profile, based on published 
treatment practice guidelines.  Categories of centrally-active agents shown to have at least modest efficacy on 
ET include beta-blockers (e.g. propranolol), antiepileptics (e.g. primidone, topiramate), and benzodiazepines 
(e.g. clonazepam).  Despite the seeming diversity of agents for ET, 25- 55% of patients gain no benefit and side 
effects are common and may limit long-term use.  Furthermore, there appears to be a dissociation of tremor 
subtypes, with some patients showing greater improvement in one subtype of tremor than the other, though 
this has not been rigorously studied.  The proposed work seeks to address many of these current barriers to 
progress in ET research including: 1) limited knowledge of the brain regions generating ET; 2) unknown and 
possibly independent mechanisms for postural and kinetic tremors; and 3) unknown mechanism of action of 
various agents on the tremor network(s).  Using a non-invasive method like fMRI to study the whole brain, we 
aim to further characterize the ET neural network(s), determine whether postural and kinetic tremors are 
associated with different neural networks, and elucidate the mechanism of action of two pharmacological 
agents on the ET neural network(s).  Knowledge gained from this study will have a direct impact on the 
development of targeted agents with less systemic adverse effects and will provide additional knowledge 
about the phenotypic variability of ET.  Ultimately, this will potentially lead to more patient-specific treatment 
algorithms and will improve quality of life for patients with ET. 
8. 
PROGRESS REPORT  
1. Our recruitment efforts have been maintained during the past year.  In addition to enrollment from Dr. 
Nahab’s clinic, we are receiving numerous inquiries from potential participants who find this project listed on 
the International Essential Tremor Foundation (IETF), Tremor Action Network, and HopeNET websites.  In 
addition, the IETF organized a number of ET information events across the country.  Dr. Nahab and/or the 
study coordinator attended meetings in Boca Raton, Miami, and Tampa, Florida with study-related materials 
and information to minimize the complexity of travel to Miami.  In addition, a number of individuals have 
personally flown to Miami to participate from Nevada, Georgia, and even South America.  To date, we 
enrolled 22 subjects with Essential tremor and 8 matched controls for a total of 30 subjects from the 
University of Miami, 27 of which have completed their participation.  Three subjects did not complete the 
study.  One ET subject withdrew prior to MRI due to a new serious medical condition that took precedence 
over participating in study.  Another ET subject was “lost to follow-up” and the third control subject did not 
complete due to experiencing claustrophobia just prior to starting MRI.  We have no adverse events to report 
and no subject receiving alcohol experienced intoxication based on both clinical assessment and the use of 
the standardized Alcohol Intoxication Scale.  Of those subjects who were enrolled on tremor medications, all 
were able to safely taper off of their medications with an expected worsening of their tremors.  Since we plan 
to collect up to 55 ET subjects and 33 matched controls over the life of the grant, we continue to allow for a 
slight lag in the collection of the controls to ensure we collect subjects well-­‐matched to our ET subject group 
and since the recruitment of controls is likely to be a simpler process. 
2. Recruitment efforts for the upcoming year in San Diego will maintain collaborations with the various 
national and international tremor foundations. In addition, subjects will be enrolled from the UCSD 
Movement Disorders Center and the surrounding community.  We continue to anticipate no problems in 
recruiting the sample size proposed. 
3. Data analysis has been proceeding on the numerous datasets collected in this proposal, including clinical 
rating scales (MDS-UPDRS, TETRAS, MoCA, etc.), spirography data, accelerometry, and the diverse set of 
imaging (3D-T1, arterial spin labeling, fMRI, diffusion tensor imaging, etc.).  An extensive amount of time has 
been spent trying to optimize the pre-­‐processing algorithms of the respective data types in order to improve 
sensitivity and specificity.  Since the sample sizes remain well below our numbers needed to test our 

 
 
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hypotheses, we have not performed any formal analyses.  Nonetheless, we are currently at a point where we 
can evaluate the efficacy of our tasks at producing activation patterns in expected motor related brain regions 
and those group analyses are currently underway. 
4. Preliminary Results:  Here we provide a representative sample of data taken from a subject with ET (P08).  
Analysis of the fMRI data was performed on the baseline spirography task that is designed to elicit kinetic 
tremor (see Figure 1).  
 
Figure 1:  Statistical parametric map of brain regions showing task-­‐correlated BOLD responses during a 
spirography task in 1 subject with Essential Tremor.  A) Axial fMRI shows areas of task-­‐correlated response 
(p<10-­‐13), with left primary motor cortex and right cerebellum (circled).  B) Sagittal fMRI demonstrating 
midline activations and a pontine activation (circled) showing a highly task-­‐correlated hemodynamic 
responsive seen in C) with the subject responsive shown in black and the stimulus paradigm overlaid in red.  
NOTE:  The broad activation patterns are expected since this task also requires visual input.  We do not 
anticipate visual areas will, however, be modulated by tremor severity across our population once that 
covariate is introduced into the analysis. 
Publications: 
There have been no direct peer-reviewed publications related to the specific aims.  Several relevant 
manuscripts were published by the PI during this award period and are included in eSNAP.  These peer-
reviewed manuscripts provide the rationale and validation for the methods employed in this research 
proposal.   
9. 
RESEARCH DESIGN AND METHODS 
The study population will include patients diagnosed with essential tremor (ET) and healthy volunteers 
without a major neurological disorder based on inclusion/exclusion criteria described in section 10.  All 
subjects will be recruited nationally with the aid of ET foundations and support groups, locally, and from the 
movement disorder clinic at UCSD.  Every potential subject expressing interest in participating will undergo a 
telephone pre-screening to ensure they fulfill inclusion-exclusion criteria before being invited for the formal 
evaluation (screening visit).  In order to balance the ethical conflicts of clinician and researcher, all potential 
participants will be provided with the informed consent form beforehand to review with their loved ones, 
thus eliminating the pressure to decide immediately whether to participate in study. Informed consent will be 
discussed with the subject by the study team.  The informed consent phase will engage not only the subject 
but also the family members and/or friends and everyone involved is given the opportunity to ask questions 
and address concerns.  Subjects providing informed consent will then be enrolled into the study.  
Healthy Volunteer Study Procedures 
SCREENING  
After being screened for eligibility and providing informed consent, volunteers will have a thorough 

 
 
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examination that will lasts approximately 2-hours.  PI will obtain medical history, and a videotaped 
neurological exam that includes the following assessments: United Parkinson’s Disease Rating Scale (UPDRS), 
Essential Tremor Rating Assessment (TETRAS), Montreal Cognitive Assessment (MOCA), Scale for the 
Assessment and Rating of Ataxia (SARA), baseline Spirography and Accelerometry.  If PI finds any non-ET 
abnormalities during the evaluation, the subject will be excluded and advised to consult their personal  
physician.   
VIDEO RECORDING  
As part of the evaluation, a video recording will be collected to document exam findings.  Participants decide 
whether these videos may be used solely by the research team for this research project, or additionally may 
be used for other purposes such as educational or scientific meetings.  
BLOOD SPECIMEN COLLECTION 
As a part of the screening visit, participants will be asked permission to collect a blood sample that will be 
used as a control for future genetic research on ET and related disorders.  The total amount of blood removed 
will not exceed 20 ml (4 teaspoons). 
FUNCTIONAL MRI (FMRI)  
After completion of the screening visit, subjects will be scheduled for the fMRI visit that will last no more than 
2-hours.  Subjects will be asked to lie still for up to 15 minutes at a time.  An accelerometer device will be 
placed on the hand to measure movement.  We will use fMRI to observe the brain’s activity during three (3) 
different activities:  arms resting by the side, right arm elevated and maintained in the air, and while drawing 
a spiral with the right hand. These tasks will be performed multiple times during 5-minute runs. 
 
At the completion of study participation, subjects will receive payment for their participation.  Payments for 
incomplete participation will be prorated based on consent form guidelines. 
 
ET Volunteer Study Procedures 
SCREENING 
Subjects will be screened for eligibility and after providing informed consent, PI will conduct an examination 
to confirm the diagnosis of Essential Tremor (ET) and to exclude any other neurologic disorder.  PI will obtain 
medical history, and a videotaped neurological exam that will include the following assessments: United 
Parkinson’s Disease Rating Scale (UPDRS), Essential Tremor Rating Assessment (TETRAS), Montreal Cognitive 
Assessment (MOCA), Scale for the Assessment and Rating of Ataxia (SARA), baseline Spirography and 
Accelerometry.  A urine pregnancy test will be performed on female participants of childbearing potential.  
VIDEO RECORDING  
As part of the evaluation, a video recording will be collected to document exam findings.  Participants decide 
whether these videos may be used solely by the research team for this research project, or additionally may 
be used for other purposes such as educational or scientific meetings.  
BLOOD  SPECIMEN COLLECTION 
As a part of the screening visit, participants will be requested to provide a blood sample that will be used for 
future genetic research on ET and related disorders.  The total amount of blood removed will not exceed 20 
ml (4 teaspoons). 
MEDICATION TAPER 
A tremor medication consultation will be conducted with the PI reviewing the medication history.  
Participants taking no medications for ET will proceed to be randomized to one of the two fMRI visits (A or B).   
If a subject is on tremor medications and gives consent to participate in this study, tremor medications will 
need to be discontinued.  This plan may be carried out by either the subject’s primary physician or study PI in 
consultation with the Safety Advisory Committee (see section 14), depending on preference of subject and 

 
 
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treating physician.  If subject has a treating physician, the PI will contact the physician to discuss whether 
there are any potential safety concerns with tapering tremor medications and review the plan to taper/titrate 
medications; taper will only occur with physician approval.  The duration of the medication taper prior to MRI 
visit A depends on the type of tremor medication the subject is on with the period being at least five half-
lives. In terms of the period between MRIs, this may be as short as two weeks and up to several months, 
though no explicit time limitations are set.  The duration depends upon the time needed for a subject to taper 
off all tremor medications for MRI visit A, and the time necessary to reach a steady state of propranolol SR for 
MRI visit B. If a subject cannot tolerate the medication taper (e.g. worsening tremors create undo disability or 
the presence of an unexpected adverse effect), the PI will consult with the Safety Advisory Committee and 
discuss restarting medications with subject and treating physician (if present) and subject will be withdrawn 
from the study. 
 
FUNCTIONAL MRI (FMRI) OVERVIEW  
After completion of the screening visit, subjects will be scheduled for the fMRI visit that will also last 
approximately 2-hours.  Women of childbearing potential will undergo a second urine pregnancy test prior to 
MRI visit A.  ET participants already on stable doses of Propranolol SR will first undergo fMRI on Propranolol 
SR.  Participants taking no medications for ET will be randomized to one of the two fMRI visits (A or B). After 
completion of one, participants will undergo the other visit type. 
FMRI VISIT A 
During this visit, subjects will remain off tremor medications for a set period of time.  The PI will provide 
specific instructions about how to do this since it varies based on the individual subject’s medication history.  
Women of childbearing potential will undergo a second urine pregnancy test prior to MRI.  During this visit, 
subject will be asked to perform three different activities: arms resting by the side, right arm elevated and 
maintained in the air, and while drawing a spiral with the right hand.  Subject will perform these tasks multiple 
times during 5-minute runs.  PI will then provide subject with a single 50-ml serving (1 shot) of 40% ethanol to 
drink and a high resolution structural MRI is performed, during which time the tremor suppression effects will 
begin.  The same tasks performed during the first half of the study will be repeated.  PI will complete an 
Alcohol intoxication Scale at the onset of the visit and again after MRI to ensure subjects are not intoxicated 
upon discharge.  Subjects who demonstrate signs of intoxication will be monitored until they are back to their 
baselines. 
FMRI VISIT B 
During this visit, we will study how the brain and tremors respond to propranolol SR (Inderal LA).  Before 
participating in this visit, subjects will need to be on a stable dose of this medication.  In order to accomplish 
this, the subject will receive detailed instructions from PI on how to start and increase the medicine in 
consultation with the treating physician and/or Safety Advisory Committee.  Subject responses to medication 
(benefits and adverse effects) will be monitored through weekly telephone calls.  Once a stable dose of 
medication has been achieved, the subject will be scheduled for the fMRI scan.  During this visit, the subject 
will be asked to perform three different activities: arms resting by the side, right arm elevated and maintained 
in the air, and while drawing a spiral with the right hand.  At the completion of the visit, the study investigator 
will instruct the subject on how to taper off this medicine based on consultation with the treating physician 
and/or Safety Advisory Committee.   
STUDY COMPLETION 
Three (3) scenarios exist for study completion/termination: 
1) Premature termination prior to completion of all visits 
In this scenario, the subject will return to their baseline medications under the direction of their treating 

 
 
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physician and/or PI in consultation with the Safety Advisory Committee. Payments for incomplete 
participation will be prorated based on consent form guidelines. 
2)  Subject who was not initially on tremor medications completes the study.  PI will discuss with the subject 
whether they wish to return to being on no medications or whether they wish to remain on propranolol SR.  If 
no medications are requested, PI will guide/assist with tapering schedule in consultation with the treating 
physician and/or Safety Advisory Committee.  If subject wishes to stay on propranolol SR, PI will assist or 
coordinate with primary treating physician to keep subject on the medication after the completion of the 
study at the subject’s expense.  Subject will receive payment for study completion. 
3)  Subjects who were on tremor medication(s) at start of the study.  The PI will confirm with subject their 
desire to restart their tremor medications.   PI will guide/assist with titration schedule in consultation with the 
treating physician and/or Safety Advisory Committee. Subject will receive payment for study completion. 
 
10. 
HUMAN SUBJECTS 
Population: 
88 volunteers (Age 21 or over) will participate in this study. This includes a total of 55 ET subjects and 33 
matched controls. Of these, 27 subjects have already completed participation and were enrolled at the 
University of Miami.  Thus, 61 additional subjects will be enrolled at UCSD.  Participants will be selected 
without regard to ethnicity or race.  
Inclusion Criteria ET Patients: 
• Age 21 or over 
• Subjects willing to abstain from caffeine or alcohol for 48 hours prior to the fMRI scanning 
• Diagnosis of Essential Tremor by a Movement Disorder specialist based on Tremor Research Group 
criteria 
Age-matched Controls: 
• Age 21 or over 
• Absence of a primary neurological diagnosis 
Exclusion criteria All Subjects: 
• Abnormal findings on neurological exam consistent with an organic disorder 
• Presence of a resting tremor on exam 
• Pregnant, nursing, or suspected pregnancy 
• Finding on the MRI safety questionnaire contraindicating MRI  
• History of dementia, brain tumor, stroke, head trauma or a vascular malformation as obtained by 
history or from imaging studies  
• History of a severe medical condition, such as cardiovascular disease, preventing subject from lying flat 
for up to 120 minutes 
• Lacking the capacity to provide informed consent 
• Claustrophobia or other restrictions that prevent subject from undergoing a scan in a confined space 
for up to 120 minutes 
• Acute or chronic medications that influence hepatic metabolism or CNS function and cannot be 
temporarily discontinued for the length of the study 
• Use of beta blocker medications for the management of hypertension 
ET Patients: 
• Movement frequency and severity preventing safe and effective MRI data collection 
• Active or prior history of alcohol abuse or dependence 
• Subject unwillingness to take a potentially intoxicating drug (ethanol) 

 
 
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• You do not have an accompanying adult who can provide transportation for you after consuming 
alcohol during one of the MRI visits 
• You have an allergy to alcohol (ethanol)  
• History of deep brain stimulation surgery or thalamotomy 
Age-matched Controls: 
• Use of a medication known to have tremor effects that cannot be temporarily tapered and 
discontinued (see below). 
 
List of Medications with Known Tremor Activity: 
Benzodiazepines (any) 
Beta-blockers (any) 
Carbemazepine 
Gapapentin 
Levetiracetam 
Oxybate 
Phenytoin 
Primidone 
Topiramate 
Valproic acid 
Zonisamide 
 
PI will rely on self-reporting for inclusion/exclusion criteria.  If PI has validity questions after informed consent 
is provided during the screening visit, medical records will be requested for further review. 
11. 
RECRUITMENT 
Multiple methods will be employed to recruit subjects into this study, including direct enrollment by the PI. 
We anticipate referrals from other faculty members in the division of movement disorders at UCSD.  In 
addition, we will recruit through, local community outreach (performed by PI and study coordinator), and 
national outreach through the various tremor foundations and support groups.  We intend to use 
ResearchMatch to contact prospective participants.  The proposed recruitment message is included in a 
separate page labeled, “ResearchMatch Message to Potential Participants.” Additional recruitment methods 
that may be employed include: flyers/posters, web postings, contact letters to physicians and clinics, and 
newspaper ads which will be submitted to the IRB for approval prior to use. 
12. 
INFORMED CONSENT 
Subjects that have shown interest to participate in this study will be contacted by phone and will be asked to 
give verbal consent for the researcher to write down contact details and the answers to a few screening 
questions related to health and MRI safety.  This screening presents no more than minimal risk of harm to 
subjects and involves no procedures for which written consent is normally required outside the research 
context, which justifies obtaining a verbal consent.  Subjects who are eligible based on this pre-screen will be 
scheduled for a formal screening visit where documented informed consent will be obtained. 
13. 
ALTERNATIVES TO STUDY PARTICIPATION 
The alternative is not to participate in this study.  Subjects can decide to stop participating at any time without 
affecting medical care. 
14. 
POTENTIAL RISKS 
RISK OF MRI 
The major risks and discomforts of this study are those associated with MRI scanning.  People are at risk for 

 
 
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injury from the MRI magnet if they have pacemakers or other implanted electrical devices, brain stimulators, 
dental implants, aneurysm clips (metal clips on the wall of a large artery), metallic prostheses (including metal 
pins and rods, heart valves, and cochlear implants), permanent eyeliner, implanted delivery pump, or 
shrapnel fragments.  Welders and metal workers are also at risk for injury because of possible small metal 
fragments in the eye of which they may be unaware.  We will utilize standard clinical screening methods 
employed by the department of Radiology to identify such conditions prior to the study.  In addition, all 
magnetic objects (for example, watches, coins, jewelry, and credit cards) will be removed before entering the 
MRI scan room based on UCSD standard operating procedures.  Women who are pregnant will not participate 
in this study.  Individuals with fear of confined spaces who may become anxious during an MRI will be 
excluded.  Otherwise, there are no known long-term risks or consequences of MRI scans.  Incidental findings 
of pathology noted on MRIs will be reported to the study participant and they will be advised to obtain clinical 
follow up with their primary physician for further testing/management. 
 
RISK OF DISCONTINUATION OF MEDICATIONS 
This study requires subjects with ET to discontinue tremor medications prior to certain imaging visits. This 
may result in temporary worsening of tremor.  All adjustments and recommendations with regard to 
medications will be carried out at the discretion of and in concert with the subject’s treating physician with 
safety being the highest concern.  No safety concerns are associated with the slow taper off tremor 
suppressing medications, but subjects will be informed by the PI and through the Informed Consent that their 
tremors may transiently worsen.  If a subject cannot tolerate medication discontinuation (e.g. worsening 
tremors create undo disability or another unexpected adverse effect), the PI will discuss restarting 
medications with subject and treating physician (if present) and subject will be withdrawn from the study.  It 
should be noted that this scenario is unlikely, since the efficacy of all tremor medications currently FDA-
approved are modest at best.  In addition, an independent Safety Advisory Committee comprised of 
movement disorders specialists (e.g. Drs. Stephanie Lessig, Irene Litvan and David Song) will meet with the PI 
on a monthly basis to review medication changes and safety concerns associated with the study. No explicit 
stopping rules are set, since the driving force of stopping a medication will be the subjects themselves. In the 
case that the PI is also the subject’s primary treating physician, he will document conferring with the Safety 
Advisory Committee. Subjects will be informed of these risks in the consent and told that the tremors will 
improve once medication is restarted at the completion of the study.  It is always the subject’s right to 
withdraw from the study at any time prior to completion.  The PI also reserves the right to exclude or 
withdraw subjects from the study if participation poses a safety risk.  
 
RISK OF ALCOHOL 
As a part of the fMRI study, there is a risk of intoxication associated with the use of alcohol.  To minimize this 
potential risk, subjects will receive a single serving of alcohol (40% Ethanol by volume).  The study team will 
monitor subjects for intoxication during the entire scan session.  To further minimize risk, subjects will 
undergo an intoxication evaluation before and after the study visit by a study investigator to confirm the 
subject can leave safely.  If subjects show signs of intoxication, the study team will monitor them until all signs 
of intoxication have resolved.  Additionally, subjects are required to have an accompanying adult who will 
provide transportation.  
 
RISK OF GENETIC TESTING 
As a part of this proposal, we intend to collect DNA samples for the purpose of future imaging genomics 
research.  No analysis will take place during this proposal and samples will simply be collected, processed and 
stored for future study.  Assuming future analysis and use of this data, there is a theoretical risk for 

 
 
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discrimination towards individuals who are at risk for a medical disorder or have a medical disorder/condition 
in their family.  Potential discrimination may include barriers to insurability, employability, or other 
unidentified adverse effects.  Extensive efforts are made to protect all research subjects from prejudice, 
discrimination, or uses of this information that will adversely affect them.  
 
In the event of further research studies of this genetic information, no results will be provided to participants. 
However, any significant new findings developed during the course of this research that may bear upon the 
participants’ condition or their willingness to continue participation in the research will be provided.  It is 
possible that future studies will identify information about the participant that was previously unknown 
(disease status or risk, non-paternity).  Such incidental findings, if any, will not be shared with the participant 
or the participant’s relatives unless the incidental finding will significantly impact health outcomes or 
reproductive choices for the participant and/or his/her immediate family.  This determination will be made on 
a case by case basis by the PI with guidance from the UCSD Institutional Review Board.  Such incidental 
findings will not be shared with anyone related to the participant unless the incidental finding is life 
threatening.  Cells, tissue, blood, tumor tissue, or other biological specimens removed from the participant 
during the course of this study may be valuable for scientific, research, or teaching purposes, or for the 
development of a new medical product.  These samples are unavailable for clinical (diagnostic) purposes and 
any future diagnostic testing as a result of this or other research must be performed on a new sample.  Risks 
associated with participation in this study also include the minor risks associated with venipuncture to obtain 
blood for DNA, such as bruising or fainting.  
 
RISKS OF PROPRANOLOL SR (INDERAL SR) 
Use of this medication during the study is anticipated to improve tremors.  Not all individuals will experience a 
reduction in their tremors.  Although this study excludes any individuals with known contraindications to this 
medication from participating, they may experience additional side effects.  The most common side effects 
include: fatigue, dizziness, constipation, slow heart rate, low blood pressure, depression, insomnia, weakness, 
disorientation, nausea, diarrhea, allergic reaction, bruising, hair loss, and impotence.  Serious side effects 
include: heart failure, severe slowing of heart rate or heart block, bronchospasm, lupus, severe rash, or 
anaphylaxis.  This medication is approved for the treatment of Essential Tremor. 
15. RISK MANAGEMENT PROCEDURES AND ADEQUACY OF RESOURCES 
RISK OF MRI SCANNING  
In this project, a 3 Tesla (3T) MRI scanner will be used.  Such magnetic fields are within the guidelines 
provided by the IEC (International Electro technical Commission, Europe) and the FDA (Food and Drug 
Administration, USA) for clinical imaging and fall within the category of no significant risk.  Screening of the 
subjects for MRI safety will take place at three different time points: before inclusion into the study, at the 
start of a test day, and right before they go into the scanner. 
• Metal objects: Participants and all other people who want to enter the scanner room will be carefully 
screened for metal objects.  Someone with non-removable metal objects is not allowed in the scanner 
room, participants with non-removable metal objects will not be included in this study.  If there is any 
doubt about the nature of implanted material, participants will not be scanned.  In addition, it will be 
ensured that no ferromagnetic objects are in the vicinity of the MRI scanner. 
• Medical devices: Participants with non-removable medical devices that might become dysfunctional 
because of MRI scanning will not be included in this study.  
• Burn wounds: Participants will be carefully screened for anything that could increase the risk of burns. 
Participants with tattoos, permanent make-up or a chance of having metal parts in their eyes will not 
be included in this study.  When participants are placed on the scanning table, special care will be 

 
 
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given to the placing of cables. 
• Scanner noise: All participants will wear earplugs and sound-attenuating headphones.       
• Incidental findings: When abnormalities are spotted on the MRI images, the images will be shown to a 
neuroradiologist working at the UCSD.  If the radiologist agrees that there is a significant abnormality 
on the MRI image, the researcher will inform the participant.  With the permission of the participant a 
follow-up meeting will be arranged with the participant’s primary physician and/or UCSD Radiology 
(depending on the recommendation of the reviewing radiologist). 
RISK OF DISCONTINUATION OF MEDICATIONS 
This study requires subjects with ET to discontinue tremor medications prior to certain imaging visits.  This 
may result in temporary worsening of tremor. If a subject cannot tolerate the medication discontinuation (e.g. 
worsening tremors create undo disability), the PI will discuss restarting medications with the subject, treating 
physician (if present), and or Safety Advisory Committee and the subject will be withdrawn from the study.  It 
should be noted that this scenario is unlikely, since the efficacy of all tremor medications currently FDA-
approved are modest at best.  No explicit stopping rules are set, since the driving force of stopping a 
medication will be the subjects themselves.  No safety concerns are associated with the slow taper off tremor 
suppressing medications, but subjects will be informed by the PI and through the Informed Consent that their 
tremors may transiently worsen.  In the case that the PI is also the subject’s primary treating physician, he will 
document conferring with the Safety Advisory Committee (see section 14, Risks of Medication 
Discontinuation).  Subjects are informed of these risks in the informed consent.  It is always the subject’s right 
to withdraw from the study at any time prior to completion.  The PI also reserves the right to exclude or 
withdraw subjects from the study if participation is not in their best interest  
RISK OF ALCOHOL 
As a part of the fMRI study, there is a risk of intoxication associated with the use of alcohol.  To minimize this 
potential risk, subjects will receive only a single serving of alcohol (40% Ethanol by volume).  The study team 
will monitor subjects for intoxication during the entire scan session.  To further minimize risk, subjects will 
undergo an intoxication evaluation before and after the study visit by a study investigator to confirm the 
subject can leave safely.  If subjects show signs of intoxication, the study team will monitor them until all signs 
of intoxication have resolved.  Additionally, subjects are required to have an accompanying adult who will 
provide transportation. 
RISK OF GENETIC TESTING 
As a part of this proposal, we intend to collect DNA samples for the purpose of future imaging genomics 
research.  No analysis will take place during this proposal and samples will simply be collected, processed and 
stored for future study.  Assuming future analysis and use of this data, there is a theoretical risk for 
discrimination towards individuals who are at risk for a medical disorder or have a medical disorder/condition 
in their family.  Potential discrimination may include barriers to insurability, employability, or other 
unidentified adverse effects.  Extensive efforts are made to protect all research subjects from prejudice, 
discrimination, or uses of this information that will adversely affect them.  In the event of further research 
studies of this genetic information, no results will be provided to participants.  However, any significant new 
findings developed during the course of this research that may bear upon the participants’ condition or their 
willingness to continue participation in the research will be provided.  It is possible that future studies will 
identify information about the participant that was previously unknown (disease status or risk, non-paternity). 
Such incidental findings, if any, will not be shared with the participant or the participant’s relatives unless the 
incidental finding will significantly impact health outcomes or reproductive choices for the participant and/or 
his/her immediate family.  This determination will be made on a case by case basis by the PI with guidance 
from the University of California San Diego Institutional Review Board.  Such incidental findings will not be 
shared with anyone related to the participant unless the incidental finding is life threatening.  Cells, tissue, 

 
 
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blood, tumor tissue, or other biological specimens removed from the participant during the course of this 
study may be valuable for scientific, research, or teaching purposes, or for the development of a new medical 
product.  These samples are unavailable for clinical (diagnostic) purposes and any future diagnostic testing as 
a result of this or other research must be performed on a new sample.  Risks associated with participation in 
this study also include the minor risks associated with venipuncture to obtain blood for DNA, such as bruising 
or fainting. 
RISKS OF PROPRANOLOL SR (INDERAL SR) 
Use of this medication during the study is anticipated to improve tremors.  Not all individuals will experience a 
reduction in their tremors.  Although this study excludes any individuals with known contraindications to this 
medication from participating, they may experience additional side effects.  The most common side effects 
include: fatigue, dizziness, constipation, slow heart rate, low blood pressure, depression, insomnia, weakness, 
disorientation, nausea, diarrhea, allergic reaction, bruising, hair loss, and impotence.  Serious side effects 
include: heart failure, severe slowing of heart rate or heart block, bronchospasm, lupus, severe rash, or 
anaphylaxis.  This medication is approved for the treatment of Essential Tremor.  Participants will be 
encouraged to report any concerns to the physician, who will be available 24 hours a days, 7 days a week, by 
cell phone/voice mail.  All adverse events reported spontaneously by the subject or observed by the 
investigator or his staff will be registered.  All adverse events will be followed up until they have abated, or 
until a stable situation has been reached. 
16. PRIVACY AND CONFIDENTIALITY CONSIDERATIONS INCLUDING DATA ACCESS AND MANAGEMENT 
We have instituted numerous precautions to protect the confidentiality of the data we obtain.  Data on each 
subject will be recorded in a computer database with an individual study ID number.  All identifiers such as 
name, address, and telephone number will be kept in a separate data file from the subject data.  The files can 
only be accessed through a specific UCSD computer account protected by a password.  Computer access is 
based on regulations maintained by the UCSD Administrative Computing and Telecommunications 
department (ACT).  All study information will be stored in locked file cabinets inside a locked office, and only 
study personnel will have access to the identifying data.  Subject identity will not be disclosed to any person, 
except in the event of a medical emergency or if required by law.  Distributed data sets for statistical analyses 
will not include any of the key personal identifiers and will be linked only by the unique study IDs. 
17. POTENTIAL BENEFITS 
Although there is no direct benefit of this research to the participants, the information generated as part of 
this proposal may help us to better understand the physiology of essential tremor. 
18. RISK/BENEFIT RATIO 
The potential findings of this work may provide a better understanding of the brain structures and 
mechanisms that lead to ET, but also help to understand the mechanisms underlying treatment response that 
are currently poorly understood.  This has the potential to lead to a better understanding of the disease and 
also to future treatments that are more targeted toward the structures involved.  While there is a minimal risk 
to the use of Inderal LA or alcohol during this study, these are both well studied agents and Inderal LA is 
approved for clinical management of ET.  Neither agent is therefore likely to represent greater than minimal 
risk.  There is no anticipation that genetic testing obtained in this study will detect any known genetic disease. 
19. EXPENSE TO PARTICIPANT 
The only expense to the participant is medication related. At least 30% of ET subjects enrolled into this study are 
already taking Inderal LA or the equivalent Propranolol SR.  We have evaluated the viability of supplying all 
participants with study-sponsored drug but that solution was not financially viable.  Some of the individuals 
coming into the study may be on the brandname Inderal LA while others may be on the generic Propranolol SR.  
The cost of the brandname is prohibitive and these added costs were not budgeted nor approved by NIH.  

 
 
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Additionally, it would be unethical to switch formulations on a patient who is comfortably taking the brand 
name because it would be cost effective to us.  Therefore, the most viable option would be to have subjects 
purchase the medication, brand or generic, retain their receipts and provide them to the study coordinator.  We 
will reasonably reimburse subjects for the cost of their medication.  
20. COMPENSATION FOR PARTICIPATION 
ET subjects will receive up to $150 for completing this study. If study is not completed, payment will be pro-
rated based on the following schedule: 
$50   Signing Informed Consent and Completion of Screening Visit 
$50   Functional MRI Visit A Completion 
     $50    Functional MRI Visit B Completion 
Healthy Volunteers will receive up to $100 for completing this study.  If study is not completed, payment will 
be pro-rated based on the following schedule: 
$50   Signing Informed Consent and Completion of Screening Visit 
$50   Functional MRI Visit Completion 
21. PRIVILEGES/CERTIFICATIONS/LICENSES AND RESEARCH TEAM RESPONSIBILITIES 
Dr. Nahab is an M.D. and is Associate Professor of Neurosciences at UCSD.  He serves as Principal Investigator 
of this study.  His responsibilities will include supervision of all aspects of this study, subject screenings, 
assisting with data collection, data analysis, and reporting of the study results.  Dr. Nahab has medical 
privileges at UC Medical Centers the CTRI.   
 
Dr. Shen is a Ph.D. and is Assistant Research Project Scientist in the department of Neurosciences at UCSD.  
She serves as a co-investigator on this study.  Her responsibilities include assisting with experimental design 
and implementation, data collection, data analysis and assisting with reporting of the study results. 
 
Ms. Moreno serves as a Research Coordinator in Dr. Nahab’s Functional Imaging of Neurodegenerative 
Disorders Lab in the department of Neurosciences at UCSD.  Her primary responsibilities will include subject 
enrollment, and data management.   
 
All of the above personnel are being funded in part by this NIH grant and have completed the appropriate CITI 
training with completion reports available for review upon request. 
 
22. BIBLIOGRAPHY 
1. Louis ED. Essential tremor. N Engl J Med. 2001 Sep 20;345(12):887-91. 
2. Bain P, Brin M, Deuschl G, Elble R, Jankovic J, Findley L, Koller WC, Pahwa R. Criteria for the diagnosis of 
essential tremor. Neurology. 2000;54(11 Suppl 4):S7. 
3. Nahab FB, Peckham E, Hallett M. Essential tremor, deceptively simple.... Pract Neurol. 2007 Aug;7(4):222-33. 
4. Zesiewicz TA, Elble R, Louis ED, Hauser RA, Sullivan KL, Dewey RB Jr, Ondo WG, Gronseth GS, Weiner WJ; 
Quality Standards Subcommittee of the American Academy of Neurology. Practice parameter: therapies for 
essential tremor: report of the Quality Standards Subcommittee of the American Academy of Neurology.  
Neurology. 2005 Jun 28;64(12):2008-20. 
5. Halliday DM, Conway BA, Farmer SF, Shahani U, Russell AJ, Rosenberg JR.  Coherence between low- 
frequency activation of the motor cortex and tremor in patients with essential tremor.  Lancet. 2000 Apr 
1;355(9210):1149-53. 
6. Hellwig B, Häussler S, Schelter B, Lauk M, Guschlbauer B, Timmer J, Lücking CH.  Tremor-correlated 
 cortical activity in essential tremor.  Lancet. 2001 Feb 17;357(9255):519-23. 
23. FUNDING SUPPORT FOR THIS STUDY 
This study is federally funded by an award from the National Institute of Neurological Disorders and 

 
 
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Stroke/National Institutes of Health (NINDS/NIH)  
 
Grant number: 1R01NS073683-01A1  
24. BIOLOGICAL MATERIALS TRANSFER AGREEMENT 
Not applicable 
 
25. INVESTIGATIONAL DRUG FACT SHEET AND IND/IDE HOLDER 
Not applicable 
 
26. IMPACT ON STAFF 
Nurses from the UCSD Clinical and Translational Research Institute (CTRI) will assist in this study. They will, 
measure blood pressure, heart rate and take a DNA blood sample to be stored for genetics (30 min in total). 
The impact on the nursing staff is in total 30 hrs. 
27. CONFLICT OF INTEREST 
There are no conflicts of interest to declare. 
 
28. SUPPLEMENTAL INSTRUCTIONS FOR CANCER-RELATED STUDIES 
Not applicable 
 
29. OTHER APPROVALS/REGULATED MATERIALS 
Not applicable 
 
30. PROCEDURES FOR SURROGATE CONSENT AND/OR DECISIONAL CAPACITY ASSESSMENT 
No decisionally impaired individuals will be studied in this protocol. 
 
 
 
Version date: May 11, 2011