Use of a Functional Neuroimaging Battery for the Evaluation of a Meditation
Conditions: Healthy
Sponsor: Thomas Jefferson University

MeditationRetreat SPECT/fMRI.12.06.11 
 
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Use of a Functional Neuroimaging Battery for the 
Evaluation of a Meditation Retreat  
 
1. General Information 
 
1.1 Title:  
Use of a Functional Neuroimaging Battery for the Evaluation of a Meditation Retreat 
 
 
1.2 Principle Investigator 
Andrew B. Newberg, M.D. 
 
Director of Research Myrna Brind Center of Integrative Medicine 
 
1015 Chestnut Street, Suite 412 
 
Philadelphia, PA 19107 
 
215-503-3422 
 
Andrew.newberg@jefferson.edu 
 
1.3 Authorized Signature 
Andrew B. Newberg, M.D. 
 
Director of Research Myrna Brind Center of Integrative Medicine 
 
1015 Chestnut Street, Suite 412 
 
Philadelphia, PA 19107 
 
215-503-3422 
 
Andrew.newberg@jefferson.edu 
 
1.4 Medical Expert 
Andrew B. Newberg, M.D. 
 
Director of Research Myrna Brind Center of Integrative Medicine 
 
1015 Chestnut Street, Suite 412 
 
Philadelphia, PA 19107 
 
215-503-3422 
 
Andrew.newberg@jefferson.edu 
 
1.5 Investigators Responsible for Conducting Protocol 
Andrew B. Newberg, M.D. 
 
Director of Research Myrna Brind Center of Integrative Medicine 
 
1015 Chestnut Street, Suite 412 
 
Philadelphia, PA 19107 
 
215-503-3422 
 
Andrew.newberg@jefferson.edu 
 
1.6 Physician Responsible for Trial Site Related Medical Decisions 
Andrew B. Newberg, M.D. 
 
Director of Research Myrna Brind Center of Integrative Medicine 
 
1015 Chestnut Street, Suite 412 
 
Philadelphia, PA 19107 

MeditationRetreat SPECT/fMRI.12.06.11 
 
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215-503-3422 
 
Andrew.newberg@jefferson.edu 
 
 
1.7 Clinical Laboratories and Departments 
 
 
Myrna Brind Center of Integrative Medicine 
 
Thomas Jefferson University 
 
Department of Emergency Medicine 
 
935 Chestnut Street 
Philadelphia, PA 19107 
 
 
Nuclear Medicine Department 
 
Department of Radiology 
 
Thomas Jefferson University Hospital 
 
Philadelphia, PA 19107 
 
 
Department of Pathology and Laboratory Medicine 
 
Thomas Jefferson University Hospital 
 
Philadelphia, PA 19107 
 
2. Background Information 
 
2.1 Test Article 
 
The test article used in this study is DaTSCAN (GE Medical) which is an approved 
product for SPECT imaging and will be utilized in the same manner, dose, and route of 
administration.  
 
2.2 Findings from Non Clinical and Clinical Trials 
 
Serotonin Transporters. 
 
Serotonin, or 5-hydroxytryptophan (5-HT), is a neurotransmitter found in the brain, 
spinal cord, and enteric nervous system.  Serotonin transporters (5-HTT) are macromolecular 
complexes which are designed to remove serotonin from the synaptic cleft and move it intact 
back into the neuronal cytoplasm where it can be repackaged for re-use or metabolized.  
Serotonin transporter sites are located on 5-HT nerve terminals and on somatodendritic sites on 
5-HT cell bodies. They are widely distributed throughout the brain, but particularly dense on 
GABAergic and peptidergic neurons. Human studies have indicated that the distribution can be 
very heterogeneous. Animal studies using [3H]cyanoimipramine, a radioligand developed at the 
University of Pennsylvania (Kovachich 1992; Gurevich 1996) demonstrated a high density of 
serotonin transporter sites a number of regions including the thalamus, hypothalamus and 
portions of the amygdala. There are also patches of high density in the ventral striatum and 
nucleus accumbens. In the cortex, relatively high binding is observed in cingulate gyrus and in 
the occipital lobe. There are apparently no serotonergic receptors in the cerebellum. These 
findings show that serotonin transporters are found in some of the most strategic regions of the 
primitive and neolimbic system.  Their localization on the amygdala, which mediates rage, and 
the nucleus accumbens, which participates in the mediation of euphoria, clearly implicate the 

MeditationRetreat SPECT/fMRI.12.06.11 
 
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serotonergic system in the modulation of normal as well as abnormal emotion.  Their localization 
in the hypothalamus and nucleus accumbens suggests that serotonin plays a role in normal drive 
states and the abnormal drive states that characterize mood disorders.  In fact, the evidence 
implicating a role for serotonin in the pathogenesis of depression is now considerable. The 
evidence includes reduced CSF concentrations of 5-HIAA, the principal metabolite of 5-HT;  
reduced concentrations of 5-HT and 5-HIAA and an increased density of 5-HT2 receptors in 
post-mortem samples from suicide victims; a decreased density of serotonin transporter sites 
(5HTT) in post-mortem brain samples from suicide victims (Arango 1995), a reduced level of 
5HTT in postmortem brain sections of patients with depression (Perry 1983; Mann 1998); 
preliminary SPECT studies in depressed patients (Malison 1998); and a relapse in depression 
when patients who have initially responded to serotonergic antidepressants undergo a tryptophan 
depletion protocol (Moreno 1999), tryptophan being the precursor for 5-HT. 
 
There is a growing body of knowledge in literature that neurotransmitter systems in the 
brain cannot be considered in isolation. Alterations in one neurotransmitter system will 
frequently lead to alterations in other neurotransmitter systems. This has been particularly well 
documented for serotonin and dopamine. Dopamine neurons in both the VTA and the substantia 
nigra receive serotonergic input from the raphe nuclei (Bonhomme and Esposito, 1998). In 
addition, limbic forebrain areas, containing serotonin terminals are linked to the nucleus 
accumbens via glutaminergic afferents (Cador et al., 1991). Electrophysiological experiments 
have shown that serotonin exerts an inhibitory influence on mesolimbic dopamine function and 
that this is mediated via 5-HT2 (probably 5-HT2C) receptors (Prisco et al., 1994). In keeping 
with these findings acute administration of SSRIs reduces the spontaneous activity of 
dopaminergic neurons in the VTA (Di Mascio et al., 1998). On repeated administration, 5-HT2 
receptors become desensitized and SSRIs no longer inhibit the activity of VTA dopamine 
neurons. It has been suggested that repeated administration of SSRIs leads to an increased 
function of the mesolimbic dopaminergic system via an inhibitory effect to its serotonergic input 
and that it is this effect that is responsible for antidepressant activity (Bonhomme and Esposito, 
1998). 
 
Dopamine Transporters 
 
Imaging the dopamine transporter in vivo has become the primary means of assessing the 
dopaminergic system in controls and several patient populations including movement disorders 
and depression. Transporter concentrations can now be visualized non-invasively with several 
radiopharmaceuticals.  Investigators from many different institutions have shown that transporter 
ligands can differentiate patient populations from controls with very high degrees of sensitivity.  
Quantitative measurements of transporter concentrations appear strongly correlated with several 
clinical features of the disease.  We have developed [Tc-99m] TRODAT-1, a transporter imaging 
agent with several highly advantageous features. Our research using [Tc-99m] TRODAT-1,  
demonstrated that drug free uptake values are significantly related to age and several 
neuropsychological task performance scores in both patients and controls.  Unlike other 
transporter imaging agents, the radiopharmaceutical [Tc-99m] TRODAT-1, is labeled with 
Technetium-99m, which gives it the potential to be used in conventional clinical settings.   
 
Dopamine participates in the mediation of cognition, emotion, and movement (McHugh 
1989; Alexander 1990).  Dopaminergic circuits help regulate and coordinate the execution of 
many complex neuropsychological functions (Leibowitz 1979a, 1979b; Silverstone 1980; Geary 
1985; Smith 1988).  The dopamine transporter is one of the primary regulators of dopaminergic 

MeditationRetreat SPECT/fMRI.12.06.11 
 
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tone.  The reuptake of intact dopamine molecules from the synaptic cleft is performed by a 
macromolecular complex which is embedded in the axonal membrane (Giros 1993). It includes a 
dopamine receptor portion that is exposed to the intrasynaptic milieu.  When free dopamine in 
the intrasynaptic space binds the receptor portion, a conformational change occurs in the 
structure of the transporter complex which allows dopamine to be physically moved, or 
“transported”, across the axonal membrane against a concentration gradient.  The rate at which 
dopamine is removed from the synaptic cleft may be the primary mechanism for maintaining 
constant dopaminergic tone.  Once removed from the synapse and transported inside the axonal 
bouton, structurally intact dopamine molecules can then be conserved by being repackaged 
within the storage vesicles.  Alternatively, the level of dopamine, and hence the tone of the 
dopaminergic system, can be reduced by oxidative enzymes in the cytoplasm that make it 
unavailable for another transmission. 
 
The presynaptic dopamine transporters are located at the distal-most terminals of 
dopaminergic axons that originate from neuronal cell bodies located in relatively distant regions 
of the brain.  Transporter concentrations are thought to reflect the vitality of these distant 
neurons.  However, many symptoms produced by the dopaminergic degenerative diseases are 
attributable to dysfunction in the otherwise healthy neurons they enervate.  Reciprocal 
dopaminergic fibers enervate the basal ganglia, the midbrain, hippocampus, amygdala, 
mammillary bodies, cingulate gyrus, and the thalamus.  This may explain why most Parkinsonian 
syndromes are characterized by disorders of cognition and mood as well as motor dysfunction 
(Mayeux 1986; Standaert 1989; Stern 1993; Vingerhoets 1994a, 1994b; Caparros-Lefebvre 
1995).   Similarly, this may explain why transient dysregulation of the system by dopaminergic 
drugs like amphetamine and cocaine affects cognition and emotion as well as psychomotoric 
behavior (Imperato 1992; Wiess 1994).  Chronic blockade of the extra-striatal transporters may 
also contribute to the dysphoric affects and cognitive impairment that are associated with cocaine 
withdrawal (Goeders 1983; Feldman 1984; Hurd 1989; Kuhar 1991; Robertson 1991). 
Neuroimaging studies have consistently shown that the concentration of dopamine transporters is 
decreased in most elderly volunteers when compared to the levels in young adults (Martin 1989; 
Sawle 1990; Shimuzu 1991; Kaufman 1993; Volkow 1994; Cordes 1994).     
 
DaTSCAN 
 
DaTSCAN is a currently approved radiopharmaceutical that enables measurement of both 
the serotonin and dopamine transporter in a single scan. DaTscan binds to both the serotonin 
transporter (SERT) and dopamine transporter (DAT) so that we can measure both 
neurotransmitter systems with a single scan. DaTscan requires preadministration of Lugol’s 
solution which helps to block the thyroid gland from exposure to the I-123 isotope that is part of 
DaTscan. This is standard protocol for diagnostic studies of this type. DaTscan is injected 
intravenously and then SPECT imaging is performed approximately 3 hours post injection. The 
images can then be quantitatively analyzed to determine SERT and DAT binding by analyzing 
the midbrain and basal ganglia respectively. SERT and DAT activity has been widely evaluated 
in a number of disease states such as Parkinson’s disease and depression. DaTscan has been one 
of the major radioactive tracers that has been involved in these studies. DaTscan is therefore an 
excellent tracer for its cost, availability, and ability to quantify changes in SERT and DAT 
binding in association with a meditation retreat. 
 
Functional Brain Imaging Studies of Meditation 

MeditationRetreat SPECT/fMRI.12.06.11 
 
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We are aware of a growing number of reports utilizing functional brain imaging 
techniques for studying subjects practicing meditation.  In two studies, positron emission 
tomography (FDG-PET) was used to measure changes in glucose metabolism in subjects 
undergoing Yoga meditative relaxation (Herzog 1990-1991; Lou 1999). A third, functional 
magnetic resonance imaging was used to measure similar changes in subjects practicing a yoga 
relaxation technique (Lazar 2000). We have conducted a study of cerebral blood flow utilizing 
SPECT imaging (see below).  One study utilized FDG PET to evaluate the Dopaminergic system 
during meditation. This latest study demonstrated significant increases in dopaminergic tone in 
the basal ganglia associated with meditation. 
 
Herzog et al (1990-1991) utilized FDG-PET to measure regional glucose metabolism in 
subjects undergoing Yoga Meditative Relaxation.  In this study of eight meditators there was a 
significant increase in the frontal: occipital ratio of cerebral metabolism. Specifically, there was 
only a mild increase in the frontal lobe, but marked decreases in metabolism in the occipital and 
superior parietal lobes.  However, the subjects did not experience deep meditative states and the 
measurement of cerebral metabolism did not evaluate specified regions were not evaluated.  
Another study utilized [15O]H2O PET to evaluate subjects practicing Yoga Meditative 
Relaxation by following a meditation tape (Lou 1999).  These subjects demonstrated relative 
decreases in the posterior brain structures, but no significant increase in the frontal structures.  It 
may be that this “passive” type of meditation was associated with a lack of change in the frontal 
regions since subjects were following verbal instructions rather than actively concentrating on 
the meditation.  A study of word generation demonstrated that internally generated words 
resulted in activation of the prefrontal cortex while repeating words did not (Crosson 2001).  We 
suspect that a similar following of instructions for meditation may not have the same effect as 
actually performing the practice volitionally.  However, other changes in cerebral activity may 
be similar if the ultimate subjective experience is similar. This appears to be the case since 
several studies demonstrated increased activity in the limbic structures (in those studies that 
evaluated these regions).  A study utilizing functional magnetic resonance imaging (fMRI) of 
subjects performing a similar yoga relaxation technique designed to bring about the “relaxation 
response” demonstrated relative increases in cerebral blood flow in the frontal lobes as well as 
the limbic system (Lazar 2000).   
Our preliminary study of cerebral blood flow utilizing SPECT imaging during Tibetan 
Buddhist meditation demonstrated a number of complex changes including relatively increased 
cerebral blood flow (CBF) in the prefrontal cortex, the orbitofrontal cortex, and cingulate gyrus, 
and relatively decreased CBF in the superior parietal region.  The results from this study 
supported the basic hypotheses in this proposal in that there was increased activity in the 
structures underlying attention and memory processes (Frith 1991).  Furthermore, a study by 
Lazar et al (2005) demonstrated that experienced practitioners of Insight meditation 
demonstrated increased cortical thickness in the prefrontal cortex when compared to controls. 
One potential implication is that meditation practice induces long term changes in the brain, but 
this has not been widely studied on a functional level. Furthermore, functional changes in 
metabolism and neurotransmitters should theoretically precede structural changes. 
The above described functional imaging studies of meditation suggest that there is a 
network associated with such practices that includes changes in the attentional system of the 
brain including the prefrontal cortex, cingulate gyrus, and superior parietal lobes.  There also 
appears to be changes of activity in the limbic areas such as the amygdala, hippocampus, and 
thalamus.  An analysis of functional changes will have implications for understanding complex 

MeditationRetreat SPECT/fMRI.12.06.11 
 
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neurocognitive and affective tasks.  Such findings can also assist toward focusing future clinical 
studies of meditation techniques on specific disorders known to be associated with the same 
nervous system structures.  
 
We have chosen fMRI imaging of cerebral blood flow for several reasons.  We have 
increasingly utilized fMRI in our studies and fMRI can provide multiple scans on subjects in the 
same session. This allows for the ability to compare meditation to baseline as well as to other 
control conditions.  
 
 
2.3 Risks and Benefits 
 
Potential Risks of Radiation Exposure:  The I-123 label on I-123 DaTSCAN is radioactive, 
which results in some exposure to ionizing radiation.  The amount is acceptable for human 
research in subjects who will not benefit from the test. 
 
Pharmacological Risks:  No pharmacological effects have been encountered in animal models 
or in human subjects for DaTSCAN.     
 
Special Risk Factors:  There are no significant additional risks.  
 
Risks of venous cannulation.  Venous cannulation is a routine clinical procedure that carries 
minimal risks when performed by trained personnel.  It is possible that bruising could occur 
in some subjects.  There is a theoretical risk of phlebitis or infection which is very remote.   
 
Blood loss.  The maximum amount of blood that will be drawn from each subject will be less 
than 4 Tablespoons (< 1 fluid ounces).  This is less than half the amount of blood that 
volunteers donate to the Red Cross (450 mls).  Additional screening will only be performed if 
not already performed for clinical purposes. 
 
Teratogenic Effects: Pregnancy Category C 
 
Animal reproduction studies have not been conducted with I-123 DaTSCAN.  It is not known 
whether DaTSCAN injection can cause fetal harm when administered to a pregnant woman or 
can affect reproduction capacity.  Therefore, DaTSCAN injections should not be administered to 
a pregnant woman unless the potential benefit justifies the potential risk to the fetus. 
 
Nursing Mothers 
 
The effects of DaTSCAN injection on human breast milk are unknown.   
 
We will not enroll a woman who is nursing or pregnant into the study.   
 
MRI Risk:  The fMRI scan does not involve any radiation exposure. Due to the strength of the 
magnetic field of the MRI, there is a risk of being injured if an unsecured metal object flies into 
the MRI scanner.  In order to minimize this risk, you will be asked to remove all metal objects 
from your person.  Also, all metal objects will be cleared from the area prior to the scan.  This is 

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the standard practice when subjects undergo MRI exams.  It is important when discussing the 
study that you inform the staff if they have any of the following:   
− Surgically implanted electrical devices 
− Pacemaker  
− Surgically placed metallic clips (aneurysm clips) 
− Ear implants 
− Any history of metal fragments in the eye 
− Subjects will be asked to complete a standardized Metals Screening From prior to receiving 
an MRI. If an MRI is contraindicated the subject will not receive an MRI or fMRI. 
 
Subjects may participate in other studies for research or medical diagnosis involving exposure to 
radiation.  However, they must inform the investigators of their participation in other studies. 
 
Incidental Findings: Any abnormal incidental findings from the scans or other procedures may 
cause stress and anxiety in the subjects. However, the incidental findings will be discussed with 
the subject by the study PI or a designated physician. The subject will be counseled on the 
findings and provided information on how to follow up with his or her neurologist or primary 
care physician. Any information will be made available to the subject’s primary care physician 
so that it can be properly addressed.  
 
Benefit: The subjects will obtain no medical benefit from this study unless some neurological 
disease is detected during the study.  Subjects will be informed of objective evidence of changes 
in their brain function using SPECT or fMRI scans. It is anticipated that this study poses minimal 
risk to the involved subjects as the methods have been extensively used on medical patients and 
healthy controls. 
 
2.4 Justification for Route, Dose, and Period of Administration 
The amount of radioactivity administered will be according to the recommended dosage in the 
package insert and will be111 to 185 MBq (3 to 5 mCi) for each DaTscan. 
Each subject will receive a single DaTscan injection at baseline, and then after a meditation 
program.   
 
2.5 Compliance 
 
This study will be conducted in compliance with Good Clinical Practices and applicable 
regulations 21 CFR 50 and 56 and 312, and will be approved by the Internal Review Board.  
 
2.6 Population 
 
Subjects will be healthy controls. 
 
2.7 References 
 
Please see end of protocol for references. 
 
3. Trial Objectives and Purpose 
1. To determine if various neuropsychological states related to a meditation retreat program 
are associated with changes in the serotonin and dopaminergic systems.  

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2. To determine if there will also be changes in cerebral blood flow using fMRI of that are 
associated with the dopamine and serotonin transporter activity. 
3. To analyze and compare pre and post imaging and neuropsychological changes in healthy 
controls who participate in a meditation retreat program. 
 
4. Trial Design 
 
4.1 Endpoints 
 
DaTSCAN binding changes, and CBF changes, associated with the pre and post 
meditation program states. 
 
4.2 Trial Design 
 
Overall:  
This study will initially utilize DaTSCAN and fMRI in healthy subjects within one month 
of entering a meditation retreat program. In addition, they will complete a variety of 
questionnaires and scales to assess their psychological status. They will then undergo the retreat 
and will return within one week of completing the retreat to repeat the scans and questionnaires.  
Thus, they will receive 2 DaTSCAN scans and 2 fMRI scans over the course of the study.  
 
Approximate Timeline for DaTSCAN SPECT  
 
Time 
Procedure 
09:00 a.m. 
Subject arrival.  Review informed consent procedures.  
09:30 a.m. 
beta-HCG (if necessary) 
09:45 a.m. 
SSKI (Lugol’s solution) 
10:00 a.m. 
Insert i.v. catheter 
10:15 a.m. 
Inject DaTSCAN 
11:00 a.m. 
Subject may take a break for 4 hours during which several 
qualitative scales will be performed 
01:15 p.m. 
Begin SPECT imaging 
02:15 p.m. 
SPECT scan completed 
02:30 p.m. 
Study completed 
 
 
Medical assessment procedures.  A trained physician will take a detailed medical history on 
each subject and perform a standardized review.  Structured physical, neurological, and 
psychological examinations will be performed.  A set of clinical laboratory studies may be used 
to screen potential subjects with benign histories and normal physical examinations.  A urine test 
for pregnancy will be performed in all women of childbearing potential.  Female subjects with 
negative pregnancy tests will be enrolled. 
 
Quantifying subjective phenomena.  This protocol will add the administration of a number of 
neuropsychological tasks, psychological inventories, and spiritual scales at the time of imaging.  
These tests and questionnaires should take approximately two hours to complete, and many have 
already been widely used in both control and patient populations.  These well established tests 

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were originally validated in large populations of people, and have since been used extensively in 
both clinical and research settings.  Our lab has its own normative data base, which has been 
generated for people of all age ranges.  The battery may include the following tests: 
 
The Speilberger State Trait Anxiety Inventory (STAI) contains a total of 40 questions, half of 
which relate to the way subjects are feeling at the moment and half of which ask them to describe 
how they usually feel.   The Profile of Moods Scale (POMS) will be administered.  The Beck 
Depression Inventory (Beck 1972) is a standard 21 item questionnaire probing cognitive and 
somatic symptoms of depression. Additional scales may include: Short Form-12; Hood 
Mysticism Scale (Lifetime); Brief Multidimensional Measure of Religiousness/Spirituality; 
Gratitude Questionnaire; Daily Spiritual Experience Scale; ASPIRES (self-rated and observer-
rated transcendence); Index of Core Spiritual Experiences (INSPIRIT); FACIT-Sp-12; Cloninger 
Self-Transcendence Scale, and Five Facet Mindfulness Questionnaire.
   
 
 
Women and minorities.  While this is a limited study in terms of subject numbers, all efforts 
will be made to select volunteers that reflect the diverse demographics of the local urban 
community will be recruited for this project.  It should be possible to enroll essentially equal 
numbers of men and women.  All of our previous studies have suggested that it will be feasible 
to recruit a racially mixed population of subjects that includes African Americans and people 
whose families originated from the Pacific Rim. 
 
Imaging Procedures. 
 
a) OVERVIEW – All subjects will receive a DaTSCAN SPECT scan and an fMRI scan 
within 7 days of each other and within one month of beginning the meditation retreat program. 
fMRI scans will be performed within the same period of time, ideally on the DaTSCAN imaging 
day. Subjects repeat the neuroimaging battery and neuropsychological tests to evaluate for 
change after the retreat program. Subjects may engage in various activities or practices in 
between the scans in order.                                                                                                                                         
 
 
b) DaTSCAN SPECT ACQUISITION, PROCESSING, AND ANALYSIS – Subjects will be asked 
to arrive at the Nuclear Medicine SPECT Center in the morning. A signed consent form will be 
documented after all questions have been answered. Women of child-bearing potential must have 
a negative pregnancy test within 48 hours before proceeding with the SPECT study.  Subjects 
will be given 16 drops of concentrated Lugol’s solution in order to block the thyroid.  An 
intravenous catheter will be inserted and capped. Subjects will spend 20 minutes lying supine on 
an examination table before the radiopharmaceutical is administered to allow them to recover 
‘physiologically’ from the stress of the catheter insertion. 111 to 185 MBq (3 to 5 mCi) 123I 
DaTSCAN will then be administered intravenously. After injection of the 123I DaTSCAN, the 
subject will have the intravenous catheter removed. They will be able to take a break for lunch. 
Subjects will then return to the nuclear medicine imaging room 3 hours after 123I DaTSCAN 
administration for a 60 minute brain scan. The reason for this delay is that kinetic modeling data 
performed on 123I DaTSCAN has demonstrated that estimation of the binding potential can be 
made without arterial sampling at this time period (Acton 1998). The subject can be moved from 
the imaging table after the SPECT study is completed.   
 
All SPECT images may be coregistered with the corresponding anatomic MRI and a 
previously described template (Resnick 1993), focusing on selected ROIs, will be fit on each 

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MRI and copied onto the DaTSCAN SPECT images. These ROIs will include the basal ganglia, 
amygdala and hippocampus, thalamus, brain stem, and cerebellum. To reduce the effects of 
volume averaging in the axial direction, ROIs will not be placed on the slices that contain the 
upper most and lower most portions of the structures they represent. This will tend to limit the 
small ROIs to the central aspect of structures they represent. The primary outcome measure will 
be the SERT and DAT binding ratios in which the ROI is compared to a reference region 
(cerebellum) at 4 to 5 hours post administration, when the distribution of 123I DaTSCAN has 
approached a transient, near equilibrium-like state that reflects the k3/k4 ratio and is related to 
the binding potential. This allows for a quantitative assessment of SERT binding as described in 
the Preliminary Studies section.  
 
The reference region has typically been the cerebellum because this region has such low 
activity on 123I DaTSCAN scans and no appreciable DAT or SERT receptors.  However, values 
will be obtained for both whole brain regions above the basal ganglia and cerebellar regions in 
order to confirm the findings. The procedures will be implemented with a commercial statistical 
package (StatS, Think Point Software, Inc). The reliability of SPM will be evaluated similarly by 
having two different technicians run the analyses independently. We have found the reliability of 
the image analysis techniques to be high with intra-class correlations consistently above 0.95.  
 
c)  MR image acquisition: Subjects will be studied to evaluate the effects of the 
meditation retreat program on cerebral activity using fMRI. This approach will enable us to track 
changes and activation in cerebral activity that result from the program. This data will be 
correlated to standardized neuropsychological and behavioral measures of cognition, mood, and 
spirituality.  
 
The fMRI images will be co-registered and comparable slices of the cerebral cortex will 
be examined pre and post program. We will evaluate changes in baseline brain function while the 
subject is at rest as well as during the meditation practice itself. Two different analysis 
approaches will be used since they can provide different types of information. A region of 
interest analysis will be performed to assess changes of activity in specific brain regions. A 
comparison between meditation and baseline cerebral activity will indicate which regions of the 
brain are activated at various stages of meditation. 
 
Images will also be analyzed utilizing a semiautomated method such as statistical 
parametric mapping (SPM). This provides a voxel by voxel analysis in order to assess 
differences between scan states. Voxel by Voxel analysis is also referred to as voxel based 
morphometry (VBM). Brain morphometry starts with noninvasive brain imaging typically 
obtained from magnetic resonance imaging (MRI ) to measure brain structures and changes in 
the brain. VPM helps to identify structural abnormalities that are found in persons with 
Alzheimer's disease and other disorders. VBM procedure involves normalizing structural 
(anatomic) brain images to a standard template, segmenting those into gray and white matter. In 
healthy subjects VPM assists in understanding the changes in the brain associated with learning 
and the effect of specific practices activation of brain regions.  This method can provided a more 
detailed assessment, but is sometime over conservative in its results. For these reasons, we 
typically perform and report both types of analysis.  
 
 
4.3 Minimization of Bias 
Scans will not be identified by name so that the reviewer can be blinded to the subject’s clinical 
condition.  When such blinding cannot be maintained as determined by the principal investigator, 

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11 
an impartial reviewer who has had no connection with the subject or the subject data will 
confirm the analysis.  
 
4.4 Dosage and labeling 
 
SSKI. Subjects will be administered 130 mEq of a potassium iodide solution before 
administration of the tracer.  The KI will be supplied by the Hospital pharmacy as per USP, 
either 16 drops of a 5% wt/vol Lugol’s preparation or 5 drops of a super saturated potassium 
iodide solution. 
 
[I-123] Radioactivity.  The dose of  111 to 185 MBq (3 to 5 mCi) for each DaTscan [I-123] will 
be administered for each scan and will be given as per the package insert with regard to dose and 
route of administration.  The amount of radioactivity in each syringe containing [I-123] 
DaTSCAN will be measured in a Capintec CRC Radioisotope Calibrator before and after 
injection.   
 
 
4.5 Duration of Participation 
 
Subjects will undergo the SPECT and fMRI scan in one day and will be followed for the 
course of that day. Subjects will also be scanned following the meditation retreat program. Thus, 
subjects will undergo a second SPECT and fMRI scan and will be followed for the course of that 
day.   
 
 
4.6 Discontinuation Criteria 
 
Individual Subjects: Since I-123 DaTSCAN is a commercially approved diagnostic 
radiopharmaceutical, it is not anticipated that there should be any pharmacological response that 
would necessitate stopping an individual from participating in the scanning procedure.  In the 
event that the subject cannot tolerate lying still in the scanner due either to pain or 
claustrophobia, then efforts will be made to allow for mild pain relief medications or sedation of 
the subject, as determined by their referring physician, and provided that they have a person who 
can transport them home after the scan, or the subject may withdraw from the study without 
prejudice.  If the subject develops a systemic allergic reaction such as generalized hives, 
shortness of breath or hemodynamic compromise, the current scanning session will be 
terminated and the subject will no longer participate in the study.  However, the subject will 
continue to be followed from a safety and clinical perspective at six months after the adverse 
event or every six months until the event resolves. 
 
4.7 Accountability Procedures 
 
The drug will be obtained from GE Healthcare and handled by the Nuclear Medicine 
department using the standard procedures for clinically approved radiopharmaceuticals.  
 
4.8  Randomization Codes 
 
Since this is a diagnostic study, subjects are not randomized. 
 
4.9 Case Report Forms 
 
All safety and scan procedural information, including radiopharmaceutical information 
and dose, adverse events, and subject reports will be included in the case report forms and 

MeditationRetreat SPECT/fMRI.12.06.11 
 
12 
adverse event forms as indicated.  Subject source data including exam findings, medications, and 
prior radiographic and scintigraphic studies when deemed necessary by the principle 
investigator, to assess proper use of inclusion and exclusion criteria will also be included and to 
ensure all criteria are met (see below).   
 
The DaTSCAN and fMRI scans and the qualitative and quantitative data will be kept as 
computer files and will not be a part of the case report forms.   
 
5. Selection and Withdrawal of Subjects 
 
5.1 Subject Inclusion Criteria 
 
a.  Subject selection 
 
Subjects will be given informed consent at the Myrna Brind Center of Integrative 
Medicine or in the Department of Nuclear Medicine on the day of the study. After signing 
informed consent, all subjects will receive a physical, neurological, and psychiatric evaluation to 
ensure that none of the study subjects has a disorder that might affect cerebral metabolism, blood 
flow, or other brain functions (i.e. stroke, tumor, epilepsy, Axis I psychiatric disorders).  
Screening laboratory studies assessing electrolytes, complete blood cell count, liver function, 
thyroid function tests, pregnancy test if necessary, and urine toxicology screen may be obtained 
in order to confirm the subject meets inclusion criteria as determined by the PI.  
Subjects will be excluded if: (1) they are taking medications that may alter cerebral blood 
flow as per the P.I., although supplements and medications to aid with mild dementia will be 
allowed if on a stable regimen, (2) they cannot lie still in the scanner due to physical or 
psychiatric reasons as per the P.I., or (3) they have physical, neurological or psychological 
disorders that might affect cerebral metabolism or blood flow as per the Principal Investigator.  
Female subjects of childbearing potential who are not pregnant or breastfeeding will be included 
in the study if they have received a negative pregnancy test (blood or urine) within 48 hours from 
the day of the study.  
 
 
The subjects will meet the following criteria: 
 
Inclusion criteria. 
1. 
Able to give informed consent and willing to complete the study. 
2. 
Willing to undergo the full imaging procedures. 
3. 
Women of childbearing potential with a negative serum pregnancy test. 
 
Exclusion criteria. 
1. 
Any neurological or psychiatric disorders, including drug or alcohol abuse, that may 
interfere with cerebral blood flow as determined by the principle investigator. 
2. 
Any medical conditions that may interfere with cerebral blood flow as determined by the 
principle investigator. 
3. 
Currently taking medication that might affect cerebral blood flow (i.e. antidepressants, 
antipsychotics, anxiolytics, benzodiazepines, sedatives, antiseizure medications) 
4. 
Subject is unable or unwilling to lie still in the scanner (i.e. due to claustrophobia or weight 
> 350 pounds) 

MeditationRetreat SPECT/fMRI.12.06.11 
 
13 
5. 
Subject has metal in their body or other reason that they cannot undergo magnetic 
resonance imaging. 
6. 
Previous brain surgery or intracranial abnormalities they may complicate interpretation of 
the brain scans (e.g., stroke, tumor, vascular abnormality). 
7. 
Pregnancy. 
8. 
Allergy to iodine or shellfish. 
9. 
Concurrent participation in another research protocol that might affect the outcome of this 
study as determined by the principle investigator. 
 
b.  Sample Size 
 
We anticipate recruiting up to 30 subjects for the study.   
 
5.3 Subject Withdrawal Criteria 
 
5.3.a. When and How to Withdraw Subjects 
a. The subject cannot tolerate lying still in the scanner due either to pain or 
claustrophobia that cannot be corrected by pain medications or sedation of 
the subject.  
b. The subject develops a systemic allergic reaction.   
c. The subject experiences significant hemodynamic compromise that 
requires medication and hospitalization.  
d. The subject is free to withdraw at any time they choose without affecting 
their continuing care for their illness.   
e. If any of the above criteria are met, the subject will no longer undergo 
DaTSCAN scans.  A discontinuation form will be completed and placed in 
the subject’s binder. 
f. If a subject is withdrawn, they will be requested to continue follow up 
only if they experienced an adverse event as per the protocol. 
 
5.3.b. Type and Timing of Data Collection 
1.  All data will be collected at the time of the scanning procedure and at the time that it 
is determined that the subject is to be withdrawn from the study. 
2.  Any data from the scan will be removed from the data analysis due to possible 
confounding of the actual scan data related to the subject’s inability to complete the scan. 
3.  Clinical data that can be used as part of the study can continue to be evaluated and the 
subject may continue with a clinical arm of the trial.  However, the subject’s data will not be 
included in any analysis of DaTSCAN or fMRI scan findings and their relationship to clinical 
variables. 
 
5.3.c. Subject Replacement 
Subjects that cannot or do not complete the study will be replaced in order to obtain 
enough data. If a subject experiences a serious adverse event directly related to the DaTSCAN or 
fMRI scan, then no further subjects will be recruited until the cause of the event is determined 
and it is ensured that no future such events will occur. 
 
5.3.d. Follow up of Withdrawn Subjects 
1.  They will continue to have medical follow up as necessary. 

MeditationRetreat SPECT/fMRI.12.06.11 
 
14 
 
6.  Treatment of Subjects 
 
6.1 Treatment to be Administered 
 
DaTSCAN is not a therapeutic radiopharmaceutical. However, as a diagnostic agent, it 
will be administered intravenously in a single bolus. 
 
 
6.2  Other Medications Permitted and Not Permitted 
 
This is a study of healthy controls. Medications will be reviewed by the Principal 
Investigator prior to imaging. Subjects may not have taken Prozac for 6 weeks, SSRIs for two 
weeks. Vitamins, over the counter drugs and herbal supplements will also be evaluated. 
 
6.3  Subject Compliance 
 
Since the DaTSCAN SPECT and fMRI scans are given only in the hospital setting, all 
subjects will necessarily be compliant. 
 
7.  Assessment of Efficacy 
 
7.1 Specification of Efficacy Parameters 
 
This study will determine if there is a change in DaTSCAN related to meditation 
programs. 
 
 
7.2 Methods and Timing for Evaluating Efficacy 
  
We will evaluate changes in DaTSCAN and regional CBF related to the meditation 
programs before and after the program. The scans are performed in a single day. 
 
8.1 Specification of Safety Parameters 
 
Safety Assessment:  DaTSCAN is a commercially approved tracer so this study is not designed 
to specifically evaluate safety. However, subjects will be asked if they experienced any unusual 
effects during the study and the debriefing period.  Any adverse events will be recorded in the 
subject’s data, either in the case report form or on the serious adverse events form.   
 
Safety Evaluation: Adverse events will be recorded in the subject’s data.  Additional side 
effects and symptoms will be recorded in each subject’s case report forms.  This data will be 
pooled at the conclusion of the study in order to assess any additional safety concerns with the 
radiopharmaceutical or the imaging procedure.  It should be noted that any study participant who 
experiences a serious adverse event directly related to the  DaTSCAN will be excluded from 
further study using this radiopharmaceutical.  For the purposes of this study, any adverse events 
or serious adverse events occurring within the duration of the study procedures that include the 
administration of  DaTSCAN and the SPECT scan will be recorded and reported as indicated by 
regulation and IRB policy.  However, events occurring after the SPECT scan dates and prior to 
the follow up scan dates will not be considered adverse events for the purposes of this study. 
 
8.2 Methods and Timing for Evaluating Safety 

MeditationRetreat SPECT/fMRI.12.06.11 
 
15 
 
Since all safety monitoring of  DaTSCAN will be performed on the day of the scan, 
safety information will be available on an immediate basis.  Should a significant subject reaction 
occur during the administration of the DaTSCAN, no additional studies will be performed until 
the specific batch of DaTSCAN can be fully analyzed and tested for purity, pyrogenicity, and 
sterility by GE Medical.  If it is determined that there was not a problem with the  DaTSCAN 
product, the subject will be withdrawn from the study and additional subjects may be injected 
and scanned with DaTSCAN.  If however, there is a problem with the batch of DaTSCAN, no 
studies will be performed until the problem with the batch can be evaluated and corrected in 
future batches. 
 
8.3 Procedures for Eliciting Reports and Reporting Adverse Events 
 
Subjects will be evaluated during the injection period, immediately post injection, and 
prior to leaving on the day of imaging with a brief examination of the injection site and with a 
clinical evaluation to determine if the subject had any unusual experiences during the injection or 
scanning procedure.  Subjects will be contacted by phone approximately one week after the 
scanning in order to assess for any further adverse events. For the purposes of this study, any 
adverse events or serious adverse events occurring on the day of administration of DaTSCAN 
and scan will be recorded and reported as indicated by regulation and IRB policy.  After the 
imaging day , the subject will be considered to have completed the study and will not longer be 
followed.  
 
8.4 Type and Duration of Follow-up of Subjects After Adverse Events 
 
Subjects will be followed six months after the injection if they experienced an adverse 
event directly related DaTSCAN.  If there is no further problem, this will terminate the follow 
up.  However, if the subject continues to have problems directly related to the DaTSCAN, then 
they will continue to be followed at six months intervals until the adverse event resolves or until 
the subject’s death. 
 
9.  Statistics 
 
9.1 Description of Statistical Methods 
Region of Interest Analysis. 
 
The images of each of the scans will be reconstructed and resliced, using an oblique 
reformatting program, according to the anterior-posterior commissure line.  The SPECT images 
will be co-registered with the anatomical MRI and comparable slices of the cerebral cortex will 
be examined.   A previously validated template methodology consisting of regions of interest 
(ROI) corresponding to the major cortical and subcortical structures will be placed over the scans 
(Resnick 1993).  For the purposes of this study, we will examine the regional CBF, serotonin 
transporter and dopamine transporter activity in only a selected number of ROIs which will be 
hypothesis driven.  The ROIs to be examined based on the hypotheses described above and the 
preliminary findings will be the inferior frontal, superior frontal, dorsolateral prefrontal, 
orbitofrontal, dorsal medial cortex, inferior temporal, amygdala, hippocampus, superior parietal, 
inferior parietal, occipital, and sensorimotor areas, as well as the caudate, putamen, thalami, 
midbrain, hypothalamus, cerebellum, and cingulate gyrus regions.  Each ROI will have its 
placement adjusted manually in order to achieve the best fit according to the atlas.  The ROIs 
will then be copied directly onto each of the scans.  This will be possible because the images will 

MeditationRetreat SPECT/fMRI.12.06.11 
 
16 
already resliced into the same planes as described above.  Counts will be obtained for each ROI 
and normalized to the mean whole brain counts.  This will result in ratios of activity in each ROI 
will be compared across scans for each neuropsychological state.  Other covariables such as age, 
and psychological measures, can also be included in the statistical analysis.  The cerebral 
structures will be identified by their Talairach coordinates (Talairach 1988). 
 
Statistical parametric mapping (SPM):   
 
The traditional method for analyzing brain fMRI and SPECT images involves the ROI 
method described above. However, it has long been known that ROI definition, particularly on 
functional images, is time-consuming, subjective and prone to operator bias. Small regular ROI's 
are capable of resolving localized focal changes between images, although they are subject to a 
loss of specificity due to the problems associated with multiple comparisons. Alternatively, large 
ROI's encompassing an entire brain structure may dilute small activation foci, with a subsequent 
loss of sensitivity. Unless a study is very strongly hypothesis driven, and comparisons between 
images are only being made in highly specific regions, ROI analysis lacks the power to 
accurately distinguish regional variations between a set of images. The solution to this problem 
has been the development of pixel-based statistical analyses, where the regions are effectively 
reduced to single pixels (Acton 1998). This method can also be utilized to observe changes in 
structures not included as part of the ROI analysis. 
 
Therefore, SPM2 software (Wellcome Department of Cognitive Neurology, London, UK) 
will also be performed in which the image volumes of transverse slices will be made compatible 
with SPM by creation of usable headers for the images. To begin, a file will be created for each 
image that contains data on image size, number of slices, pixel depth, maximal pixel value, and 
voxel size.  SPM analysis then requires 1) spatial normalization of all images into the same 
stereotactic space, 2) smoothing, and 3) statistical parametric comparisons.  Spatial 
Normalization will begin by having the scans from each individual subject will be coregistered to 
each other, using a rigid-body transformation. To correct for global brain shape differences, the 
individual MRI volume acquisitions will be transformed into a standard 3D space (MNI, 
provided by SPM). The images will be coregistered to a MNI atlas template, using affine 
transformations and nonlinear warping (7 × 8 × 7 basis functions). The resulting spatially 
normalized images had isotropic voxels of size 2 mm. The normalized images will be smoothed 
by convolving with an isotropic FWHM 12 mm Gaussian kernel that allows the subsequent 
voxel-by-voxel analysis. This reduces the effects of image noise and conditions the data for 
subsequent statistical tests performed in SPM. 
Groups of images will be compared voxel-by-voxel using SPM (Friston 1995). 
Statistically significant differences between sets of data will be assessed at each voxel with a 
threshold of P < 0.001. To correct for correlated multiple comparisons, clusters of voxels which 
survive this threshold will be assessed further using the theory of random Gaussian fields 
(Friston 1994, 1995b; Worsley 1994), which calculates the significance of clusters based on their 
peak height and spatial extent.  With this technique, differences in blood flow between and 
within groups will be assessed, and statistic images generated showing significant regional 
differences between groups.  The meditation or activation state can be modeled by a simple one-
way analysis of covariance (ANCOVA) with a group effect (the activation) combined with a 
nuisance or confounding effect (global or reference region activity) to produce the observed data.  
Other covariables such as age, and psychological measures, can also be included in the statistical 

MeditationRetreat SPECT/fMRI.12.06.11 
 
17 
analysis.  The cerebral structures will be identified by their Talairach coordinates (Talairach 
1988). 
 
9.2  Number of Subjects 
 
This is an exploratory study and thus a full power analysis will be based upon the 
determination of the effect size obtained from this data. However, preliminary analyses of our 
studies in other neuropsychological states of subjects as well as in differences in our serotonin 
and dopamine transporter binding differences between various populations and treatment groups, 
we conservatively estimate that the mean differences/changes in these values are approximately 
10% with a 15% standard deviation. A sample size of 25 subjects would have 80% power to 
detect such an effect size using a two group t-test with a 0.05 two-sided significance level. For 
sample size based on correlation analysis, we typically have considered an R=0.5 to be of 
clinical importance and have frequently obtained such as measure in comparing various 
neuropsychological test results to imaging measures. A power calculation to detect a correlation 
between imaging and neuropsychological measures for an R=0.5 would require a sample size of 
30 subjects. Thus, given our usual difference and standard deviation between pre and post studies 
as well as correlational analysis, a sample size of 25 subjects seems appropriate. 
 
9.3  Level of Significance 
 
A significance value of p<0.05 will be required for all statistical measures. 
 
9.4 Criteria for Termination of the Trial 
 
The study will be terminated only if there are serious adverse events that occur in the 
subjects.  Otherwise, we anticipate terminating the trial after 25 subjects are recruited and 
studied. 
 
9.5 Procedure for Accounting for Missing, Unused, or Spurious Data 
 
Missing or unused data will be excluded from analysis and reported in the subject’s study 
binder.  However, other data from that subject will be included in the analysis where appropriate 
and also for all safety evaluations.  Spurious data will be evaluated by a statistician to determine 
how such data should be handled from a research reporting perspective.  However, any data that 
is spurious will be provided to the subject’s physicians in the event that it provides useful clinical 
information. 
 
9.6 Procedures for Reporting Deviations from the Original Statistical Plan 
 
All statistical analyses and deviations from the original statistical plan will be reported in 
any presentation (i.e. publications, oral, or poster presentations) of the results from this study. 
 
9.7 Selection of Subjects to be Included in the Analysis 
 
All subjects entered into this study will have their data included in the imaging analysis 
unless there is relevant missing data or the subject drops out of the study so that critical data 
points are not available.  
 
All subjects will be included for the safety analysis even if there are some missing data 
points (i.e. imaging or clinical). 
 
10.  Direct Access to Source Data 

MeditationRetreat SPECT/fMRI.12.06.11 
 
18 
 
Study related monitoring, audits, Institutional Review Board, Institutional Ethics 
Committee, and regulatory inspections will all have direct access to the source data. 
 
11.  Quality Control and Quality Assurance 
 
The principle investigator will review all data in the case report forms and this data will 
also be evaluated as part of the periodic monitoring plan (see attached). 
 
12.  Ethics 
 
This study will be performed under the auspices of the Institutional Review Board (IRB) 
and the Office of Human Research.  All protocols and consent forms will be approved by the 
IRB prior to performing any studies.  Any ethical issues that arise during the study will be 
brought to the immediate attention of the principle investigator who will hold all studies until an 
appropriate course of action can be undertaken to ensure that the study is performed only after 
such ethical issues are resolved.  All investigators and personnel will also have taken the Thomas 
Jefferson University training programs for performing Human Research. 
 
This study will be carried out in compliance with the protocol and in accordance with the 
standard operating procedures.  These are designed to ensure adherence to Good Clinical 
Practice as described in: 
 
1.  US 21 Code of Federal Regulations dealing with clinical studies (including parts 50 and 56 
concerning informed consent and IRB regulations. 
2.  Declaration of Helsinki, concerning medical research in humans (recommendations Guiding 
Physicians in Biomedical Research Involving Human Subjects, Helsinki 1964, amended Tokyo 
1975, Venice 1983, Hong Kong 1989, Somerset West 1996). 
 
The investigator agrees, when signing the protocol, to adhere to the instructions and procedures 
described in it and thereby to adhere to the principles of Good Clinical Practice that it conforms 
to. 
 
13.  Data Handling and Recordkeeping 
 
Data and record keeping will be overseen by the sponsor/investigator.  The 
sponsor/investigator will also maintain the individual subject’s study binder which includes 
source data and safety data in a secure location. The sponsor/investigator will also keep all 
imaging studies. 
 
14.  Financing and Insurance 
 
Financing of this study will be partially funded by a grant from the Fetzer Foundation. 
 
15.  Publication Policy 
 
The results will be published in peer reviewed scientific journals and will not identify any 
subjects by name. 
 
 
  
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