Developing rTMS as a Potential Treatment for Nicotine Addiction
Phase: NA
Conditions: Nicotine Dependence
Sponsor: Medical University of South Carolina

Office Title:  
Repetitive Transcranial Magnetic Stimulation (rTMS) for Nicotine Addiction 
NCT#: 
NCT02401672 
Document Date:  
8/21/2014 
 

Version: 2 – 08/20/2014 
1 
 
Study Title:   Developing rTMS as a potential treatment for nicotine addiction 
 
PI: Xingbao Li   
 
SPECIFIC AIMS 
   
Cigarette smoking is the leading cause of preventable death in the United States1, 2.  Unfortunately smoking 
cessation is difficult, with the majority quit attempts resulting in relapse3-5 and the average smoker attempts to 
quit five times before a successful quit attempt. While a number of pharmacotherapeutic agents and cognitive 
behavioral therapies alone or in combination with medication have demonstrated efficacy 5, 6, even with 
combined treatment, the most common outcome at one-year following a quit attempt is relapse 7. Only 6% of 
the 35 million smokers who report wanting to quit each year are successful in doing so for more than a month 8, 
9. Clearly, there is room for improvement in smoking cessation treatment. 
 
Human brain imaging studies have provided insight into the brain regions associated with cue-induced 
cigarette craving, a frequent cause of relapse10-12. Furthermore, improved ability to resist cue-induced craving 
is associated with a reduction in cue-induced activation of limbic and prefrontal brain regions 12-14. Transcranial 
magnetic stimulation (TMS) provides a non-invasive means of modulating brain neural activity15, 16. 
Neuroimaging studies of repetitive TMS (rTMS) over dorsal lateral prefrontal cortex (DLPFC) demonstrated 
that rTMS normalized brain areas of anomalous activity due to depression17, 18. Given this previous research, 
rTMS may reduce cue craving to smoking and treat nicotine dependence through modulating cortical and 
subcortical areas associated with smoking cue-induced craving. 
 
To date, several studies have reported that rTMS reduced cue craving in nicotine dependence 19-22. However, 
these studies are limited by small sample sizes, variation in stimulation parameters, and in some cases the 
lack of sham-controlled design and objective measures of tobacco smoking. Furthermore, in all of these 
studies, stimulation location was targeted to a fixed brain region based on standard skull landmarks. rTMS 
studies in depression have showed that antidepressant effects are likely depend on coil positioning 23, 24. 
Personalized coil placement based on a pre-treatment MRI has the potential to enhance outcomes. 
Additionally the duration or reduced craving following rTMS has yet to be examined. Taken together, while 
rTMS has demonstrated promise in facilitating smoking cessation, further double-blind investigation is required 
to determine optimal stimulation parameters and the duration of effect of rTMS in smokers. Furthermore, MRI 
guided TMS may help us to identify the optimal stimulation location to enhance the effectiveness of the 
treatment.  
 
This R21 will build on exciting pilot work and advance our knowledge concerning the potential utility of 
rTMS in smoking cessation by conducting a controlled, double-blind method comparing the impact of 
ten daily treatments of active rTMS and sham rTMS, on cue-induced craving and cigarette 
consumption in nicotine-dependent cigarette smokers with extensive monitoring of side effects and 
smoking outcomes. We propose to directly stimulate the left DLPFC with Brainsight in smokers. In the two 
years of project, we plan to recruit 42 cigarette males and females of all ethnic and racial groups between the 
ages of 18 and 60 to participate in the study. Specific Primary Aims include: 
 
Aim 1: To determine under rigorous experimental conditions, whether 10 MRI guided rTMS of left 
DLPFC  treatment sessions over a 2 week period result in superior clinical outcomes compared to 
sham rTMS in smoking cessation.  
Hypothesis 1: We hypothesize that 10  rTMS sessions (15 minutes 10 Hertz active rTMS at 100% resting 
motor threshold-rMT) over DLPFC will significantly reduce cue-elicited craving and cigarettes per day as 
compared to sham rTMS. 
 
Aim 2: To evaluate the longevity of clinical benefit of 10 rTMS sessions on smoking measures 
including cigarettes per day and level of nicotine dependence with following-up 3 months after the last  
rTMS session.  

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Hypothesis 2: We will predict that the effects of rTMS will dissipate over 3 months following-up time in some 
smokers. We also will predict that the effects of rTMS will last more than 3 months in other smokers. The 
following-up data will provide the best fit of the relapse-time data relative to a variety of parametric alternatives.  
 
 
Aim 3: To demonstrate whether the active rTMS and sham groups differ significantly in side effect 
profiles, and whether the frequency and severity of side effects decreases over the course of 
treatment.  
Hypothesis 3: The frequency and severity of side effects will not differ between the active rTMS and sham 
groups, and decreases over the course of the treatment, suggesting adaptation or tolerance.  
 
RESEARCH STRATEGY 
1. Significance 
Nicotine dependence remains a significant public health concern. In 2011, the World Health Organization 
(WHO) reported that tobacco use continues to be the leading global cause of preventable death, killing nearly 
6 million people and causing hundreds of billions of dollars of economic damage worldwide each year 25. In the 
United States, cigarette smoking is the leading preventable cause of mortality accounting for approximately 1 
out of every 5 deaths 1. On average, smokers die 13 to 14 years earlier than nonsmokers 26. Cigarette smoking 
is the most common form of tobacco use and 45.3 million persons (19.3% of the population) are current 
cigarette smokers. Additionally the estimates for average annual smoking-attributable productivity losses are 
$96.8 billion and the total economic burden of smoking is approximately $193 billion per year 27. 
 
The 2010 National Health Interview Survey revealed that approximately 70% of current smokers want to quit 
and 41% have tried to quit, however few of these attempts were successful with only 4.7% of current smokers 
able to stop smoking for at least three months 2. Despite the availability of therapeutic options  for smoking 
cessation, only 6% of the 35 million smokers who report wanting to quit each year are successful in doing so 
for more than a month 8, 9. Clearly, there is room for improvement in smoking cessation.  
 
One particularly salient feature of nicotine-dependent cigarette smoking is the ability of associated 
environmental cues to elicit craving and cigarette-seeking behaviors. The systematic study of craving has 
occurred primarily via cue reactivity paradigms 28, 29 in which nicotine-dependent individuals are exposed to 
cues previously associated with smoking (e.g., cigarette, lighter, ashtray) and subjective craving and 
physiological reactions are measured 30, 31. Numerous laboratory-based studies, including studies conducted in 
our laboratories at Medical University of South Carolina (MUSC), have demonstrated that exposure to 
smoking-related cues elicits robust craving and measurable physiological reactivity among smokers 32.  These 
findings represent some of the most compelling evidence in support of a causal relationship between craving 
and cigarette smoking. Thus, the concept of craving has become an important focus of studies on smoking 
behavior, relapse and smoking cessation treatment. In conclusion, these findings imply that escalation of 
withdrawal symptoms, craving, and smoking urges during a quit attempt may contribute to smoking relapse. 
The reduction of cue craving and smoking urges may facilitate the treatment of nicotine dependence 
and prevent relapse during a smoking quit attempt. 
 
Transcranial magnetic stimulation (TMS) is a noninvasive (and relatively painless) brain stimulation technology 
that can focally stimulate the brain of an awake individual 33, 34. A localized pulsed magnetic field transmitted 
through a TMS coil is able to focally stimulate the cortex by depolarizing superficial neurons 35, 36  inducing 
electrical currents in the brain 16. If TMS pulses are delivered repetitively and rhythmically, the process is called 
repetitive TMS (rTMS). rTMS for the treatment of depression was approved for one manufacturer by the U.S. 
Food and Drug Administration (FDA) in October, 2008 37, 38 and for a different device in January 2013. 
Researchers are investigating rTMS potential treatment effects in other neuropsychiatric disorders 
(schizophrenia, pain, alcohol, cocaine, stroke) 39. Taken together, TMS techniques could be used to 
improve the efficacy of smoking cessation.  
 

Version: 2 – 08/20/2014 
3 
 
To date, several human studies have begun to evaluate the effects of rTMS applied to the lateral or medial 
prefrontal cortex on cue-induced craving and cigarette consumption 19-22. In one study, investigators20 
administered high frequency rTMS to the left DLPFC of treatment-seeking smokers.   Subjects received 20 
trains of either real or sham rTMS (20Hz, 90% motor threshold, 2.5 secs-on, 42.5 sec intertrain intervals for a 
total of 1000 pulses) over the left prefrontal cortex.  While real rTMS was associated with significant reduction 
in terms of the number of cigarettes smoked in comparison with sham stimulation (p < .01), levels of craving 
did not differ significantly between the groups. In contrast, Amiaz and colleagues reported that rTMS (100% 
rMT, 10Hz, 20 train/day, total 1000 pulses) of the DLPFC reduced both cigarette craving and consumption 19.  
In a preliminary parallel-groups sham-controlled trial of rTMS in combination with the nicotine patch in heavily 
nicotine-dependent smokers with schizophrenia 40, rTMS did not increase abstinence rates, but did significantly 
reduce tobacco cravings induced by short-term (30-60 minutes) abstinence, which was assessed before 
application of the nicotine patch. More recently, Rose and colleague used 10 versus 1-Hz TMS over the 
superior frontal gyrus (SFG) in 15 volunteer smokers and found that craving after smoking cue presentation 
was elevated in the 10-Hz SFG condition, whereas craving after neutral cue presentations was reduced 22. 
These preliminary studies suggest that the location of the stimulation is critical and high frequency rTMS of the 
DLPFC, but not the medial area, might attenuate nicotine consumption and craving. Taken together, the 
significance of these effects are limited and further investigation is required to identify the appropriate 
stimulation parameters and targets needed to enhance the effectiveness of the treatment. As such, future 
replication studies using a valid sham TMS and exploring the number of treatments and duration of 
effects are greatly needed to further investigate the therapeutic potential of rTMS in nicotine 
dependence. In particular, future studies using MRI to guide location will help to optimize the 
parameters for the use of rTMS in the treatment of nicotine addiction. 
 
In conclusion, nicotine dependence is the leading preventable cause of mortality in the world today. In spite of 
treatment advances, there is much room for improvement in the therapeutic approaches. Recent advances 
make it possible to utilize rTMS to modify behavior, cognitions and regional brain activity. Preliminary trials 
suggest potential therapeutic applications of rTMS in the area of nicotine dependence. The purpose of this 
proposal is to preliminarily explore the efficacy of 10 daily MRI-guided DLPFC rTMS in decreasing cue-
induced craving and cigarette consumption in nicotine-dependent cigarette smokers.  Information 
gathered through this study will inform future studies in terms of optimal parameters for the use of 
rTMS  in the treatment of nicotine-dependent smokers.  
 
2. Innovation 
As mentioned above, several previous studies have demonstrated that rTMS applied to the lateral or medial 
prefrontal cortex can impact cue craving and/or consumption of cigarettes 19-22 . However, in all studies to date 
the form of sham TMS did not cause similar scalp or facial sensation compared to real TMS leading to 
questions about the validity of the comparisons.  In the proposed study, we will use an active E-sham condition 
41, 42 which produces scalp/facial sensations that are comparable to rTMS.  In addition, studies to date have 
used a 5 cm rule for prefrontal location determination which is imprecise and as many as 30% of participants 
may have been  treated over the supplementary motor area rather than the prefrontal cortex 43.  Finally, a 
meta-analysis 44 and a prospective clinical trial 45 suggest that use of a greater number of rTMS stimulations 
may be more effective in depression treatment. Previous rTMS studies in smoking used 1000 pulses, much 
less than the dosage of TMS pulses demonstrated to be efficacious in depression, and higher doses have not 
been explored. This R21 proposal is innovative in three respects: this is the first time that a double blind rTMS 
study will be compared to an active E-sham stimulation in smokers; in addition, we will use MRI to determine 
stimulation site over prefrontal cortex; finally, we will employ more stimulation pulses (3000 pulses) than 
previous studies, allowing us to quantitatively and qualitatively investigate both short and longer term effects of 
rTMS in smoking cessation.  
 
RESEARCH PLAN 
 
Rationale. Several lines of evidence suggest that repetitive TMS (rTMS) over the left DLPFC can affect 
processes involved in nicotine addiction. First, stimulation of the DLPFC can induce release of dopamine in the 

Version: 2 – 08/20/2014 
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caudate nucleus 46. Therefore, repeated stimulation may induce neuroadaptations in the dopaminergic system. 
Moreover, while administration of drugs induces an acute increase in dopamine levels, during withdrawal 
dopaminergic activity is reduced. Decreased dopaminergic activity has been associated with increased levels 
of craving and relapse 47. Therefore, it is possible that even transient increases in dopamine released by TMS 
may help reduce levels of craving 48. Second, the effects of brain stimulation can extend beyond the directly 
targeted area, including cross-hemispheric cortical and subcortical activity in remote neural networks 
connected to the stimulated regions 49, 50. Therefore, given the ability of TMS to modulate cortical excitability, it 
is possible that TMS can alter neuroadaptations and synaptic plasticity in the brain reward system. Third, it is 
well known that the PFC is strongly implicated in drug-seeking behaviors. The DLPFC plays an executive role 
in controlled response inhibition through its connectivity. Therefore, it is possible that repeated DLPFC 
stimulation could lead to improved inhibitory control and thereby reduced levels of drug-seeking. These 
theoretical underpinnings have led researchers, including our group at MUSC, to conduct pilot studies to 
explore the impact of rTMS of the left DLPFC in reducing craving for cigarettes 19, 20, 22.  
Several studies have shown that stimulation of the motor cortex can produce inhibitory or excitatory 
intermediate effects (lasting several minutes) following stimulation 51, 52. Investigations of the intermediate 
effects of TMS have been used to develop a better understanding of brain functioning with respect to 
movement, vision, memory, attention, speech, neuroendocrine hormones and mood 53-60. Longer-term effects 
of TMS (days to weeks) are not well understood at a neurobiological level, but there is some evidence to 
support longer-term effects on mood, seizure activity and pain 61-64. As discussed above, rTMS for the 
treatment of depression was approved by the FDA in 2008. Thus, we hypothesize that 10 sessions daily active 
rTMS will induce a longer lasting decrease in cue-induced craving and a reduction in cigarette consumption.  
 
In a recent pilot project conducted by our research team, rTMS at 100% resting motor threshold (rMT), 10 Hz, 
5 seconds on, 10 seconds off, total 3000 pulses over DLPFC was 
tested in 14 non-treatment seeking nicotine-dependent smokers 42. 
Compared to sham TMS, one session of high frequency DLPFC 
rTMS significantly reduced smoking cue-induced craving (Figure 
1). In addition, the correlational analyses showed that the effect of 
rTMS on cue craving was positively correlated with Fagerstrom 
Test for Nicotine Dependence (FTND) score (Figure 2). This study 
was the first to show a clinically significant reduction in craving 
after prefrontal rTMS. However, we were not able to measure the 
duration 
of 
effect 
or 
whether 
repeated 
sessions 
might 
have 
added  
therapeutic 
effect. 
The 
current proposal extends this study, advancing it in a 
step-wise manner to a potential treatment. Further, we 
will use MRI to determine stimulation site instead of the 
imprecise 5 cm rule. Additionally, we will employ 10 
session rTMS over two weeks period. We hypothesize 
that rTMS with the MRI TMS navigation will reduce cue-
induced craving and cigarettes per day more than will 
sham TMS.  
                                                            
 
TMS research has been ongoing in the Brain Stimulation Laboratory (BSL) at MUSC for the past 15 years. The 
members of the BSL have been actively researching TMS in depression41, 50, 65-67, schizophrenia 68, post-
Figure 1. Effects of rTMS of DLPFC on 
subjective 
nicotine 
craving 
provoked 
by 
smoking cue (t = 2.692, n = 14, p = 0.018) 
0.0
10.0
20.0
30.0
40.0
50.0
60.0
70.0
80.0
Sham
TMS
Subjective cue craving rating 
*
Figure  2.  Correlation between Effects of rTMS and 
FTND score (N=14, r = 0.575, p = 0.031); 
 
-40
-20
0
20
40
60
80
100
120
0
5
10
Effect of rTMS on cue craving 
(% change)
FTND score

Version: 2 – 08/20/2014 
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traumatic stress disorder (ongoing), Tourette’s syndrome 69, alcohol dependence (unpublished data), 
methamphetamine (paper in preparation), food craving 70 and cigarette smokers 42 . Dr. Mark S. George is one 
of the world leaders in refining the use of TMS to treat depression and other neuropsychiatric and substance 
use disorders.  Additionally, we have also studied other minimally invasive brain stimulation technologies such 
as transcranial direct-current stimulation (tDCS) 71, electroconvulsive therapy (ECT) (ongoing), deep brain 
stimulation (DBS) 72 and vagus nerve stimulation (VNS) 73 for over a decade. In conclusion, the research group 
assembled for this project has vast experience in the use of TMS in clinical trials on neuropsychiatric diseases, 
including substance use disorders.   
 
The treatment of nicotine dependence has been an interest of our research group for many years 74-76. As one 
of world leaders in addiction research, Dr. Kathleen T. Brady has been conducting clinical trials and human 
laboratory research focused on nicotine dependence for decades 12, 76-79. In an ongoing study, our group is 
exploring the use of real time fMRI biofeedback to reduce cue-induced craving in smokers 12. In the pilot TMS 
study in nicotine dependence, Drs. Li and Hartwell collaborated to recruit 14 nicotine-dependent cigarettte 
smokers in 6 months.  Thus, our research team has experience in recruiting and retaining nicotine dependent 
participants for clinical trial participation and can easily recruit 42 smoking participants during two years.  
 
Our previous work demonstrates the experience of the investigative team in a number of areas of direct 
relevance to the proposed project. The investigators have expertise and experience in developing and 
conducting rTMS protocols. With regard to the study of TMS and nicotine dependence, the team includes 
world-renowned experts in both TMS and nicotine dependence research. The investigative team has 
developed a single session rTMS protocol that reduces craving and might lead to a treatment for nicotine 
dependence with further development as proposed in this R21 proposal. This R21 proposal is designed to 
ascertain whether repetitive TMS can affect smoking cue-induced craving and consumption of cigarettes over 
a 3 months period. Additionally, it will provide information on the treatment parameters and dose of rTMS, 
effects on the longer-term outcomes. The findings of the study can be used to inform the design of a larger, 
more definitive clinical trial to investigate the use of rTMS in smoking cessation. 
 
Experiment Approach 
 
1. General Design of the Study. Forty two treatment-
seeking nicotine dependent participants between the 
ages of 18 and 60 will be randomly divided into two 
groups on a 1:1 basis. One group will receive sham 
rTMS and the second group will receive active rTMS 
over DLPFC on a daily basis for 10 sessions (See 
Figure 3). Treatment is standardized at 100% magnetic 
field intensity relative to the patient’s resting motor 
threshold (rMT), at 10 pulses per second for 5 
seconds, with an intertrain interval of 10 seconds. 
Treatment sessions last for 15 minutes (60 trains) with 3000 pulses. The masked randomization status will be 
maintained for the entire enrollment period, until the last subjects have completed the study in the second year. 
Cue craving rating and cigarette consumption will be assessed before and after active rTMS or sham rTMS for 
10 days. All participants will have two follow-up visits at 1 week and 1 month after the last rTMS session and a 
follow-up phone after 3 months of the last rTMS session. Safety will be assessed by collecting information on 
all relevant adverse events experienced. 
 
2. Study Subjects and Entry Criteria 
Inclusion Criteria:  
Subjects will:  
(1). Be between the ages of 18 and 60 years old.  
(2) Smoke 10 or more cigarettes per day and have a carbon monoxide (CO) level > 10 ppm indicative of recent 
smoking.  
 
 
Figure 3. Study Design 

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(3) Not received substance abuse treatment within the previous 30 days.  
(4) Meet criteria for nicotine dependence as determined by the FTND.   
(5) Be in stable mental and physical health.  
(6) If female, test non-pregnant and use adequate birth control.  
(7) No evidence of focal or diffuse brain lesion on MRI.  
(8) Be willing to provide informed consent.  
(9) Be able to comply with protocol requirements and likely to complete all study procedures. 
                                       
Exclusion Criteria:  
Subjects with:  
(1) Current dependence, defined by DSM-V criteria, on any psychoactive substances other than nicotine or 
caffeine.  
(2) Contraindication to MRI (e.g., presence of metal in the skull, orbits or intracranial cavity, claustrophobia).  
(3) Contraindication to rTMS (history of neurological disorder or seizure, increased intracranial pressure, brain 
surgery, or head trauma with loss of consciousness for > 15 minutes, implanted electronic device, metal in the 
head, or pregnancy).  
(4) History of autoimmune, endocrine, viral, or vascular disorder affecting the brain.  
(5) History or MRI evidence of neurological disorder that would lead to local or diffuse brain lesions or 
significant physical impairment.  
(6) Unstable cardiac disease, uncontrolled hypertension, severe renal or liver insufficiency, or sleep apnea.  
(7) Life time history of major Axis I disorders such as: Bipolar Affective disorder (BPAD), Schizophrenia, Post-
traumatic Stress disorder (PTSD) or Dementia or Major Depression.  
(8) Self report of >21 standard alcohol drinks per week in any week in the 30 days prior to screening. 
(9) Other forms of nicotine delivery, such as nicotine patch, electronic cigarettes 
 
3. Screening Procedures:  
 (1) Phone pre-screen: Healthy subjects will be recruited from the greater Charleston area via flyers, Catalyst 
advertisements, internet and emails. We have used these methods to successfully recruit nicotine-dependent 
smokers for participation in clinical trials in the past 41.  Prospective subjects will be screened over the phone 
by trained research staff at MUSC. Subjects that qualify based on the preliminary phone-screen will be invited 
for an initial assessment to MUSC. Drs. Li and Hartwell and trained study personnel will be assigned to seek 
and obtain informed consent for all subjects. 
(2) Initial assessment: An informed consent procedure will be completed prior to conducting any research 
procedures.  Study personnel will review the consent with the participants and assess participant’s 
understanding of the study.  Participants not able to understand the consent after help from the study 
personnel, and those either excluded or unwilling to participate after the informed consent procedure, will be 
provided with an appropriate referral for smoking cessation if they are interested.  
(3) After the informed consent is obtained, participants will be assessed for study inclusion/exclusion criteria.  
Participants will complete a battery of assessments listed below.   
 
Psychiatric interview using the Mini International Neuropsychiatric Interview (MINI) will be conducted for 
the inclusion and exclusionary Axis I psychiatric diagnoses. Baseline CO level will be assessed using a 
Bedfont microsmokerlyzer (Bedfront Scientific Ltd., Kent, United Kingdom).   
 
Alcohol breathalyzer test and a urine drug/cotinine/pregnancy tests will be performed.  The results from 
the alcohol breathalyzer and urine drug tests will be used, in conjunction with the MINI, to screen for 
current substance use disorder.  
(4)  Each potential subject will be asked about their current height and weight, past medical history focusing on 
chronic (and current) medical problems, seizure history, medications, psychiatric disorders, and substance 
use. The research procedures, risks and benefits will be explained. Subjects meeting inclusion/exclusion 
criteria will be invited to participate in the laboratory investigation.   
 
4. Baseline Evaluation (see schedule of data collection for details) 
    The baseline evaluation will occur on the same day if the subjects meet the inclusion/exclusion criteria and 
sign the consent form. 

Version: 2 – 08/20/2014 
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1) Demographic Data: Basic demographic information including age, gender, race, and social history will be 
collected. 
2) Mini International Neuropsychiatric Interview (MINI) 80: This is a well-standardized structured instrument 
used to provide quick and accurate DSM-IV psychiatric diagnoses.  The MINI will be used to confirm the 
inclusionary/exclusionary diagnoses in the participants.  
3) Tobacco Use History:  Detailed history of current and past tobacco use will be obtained, including cigarette 
smoking.  The questions addressed will include the amount, frequency, duration of smoking, preferred 
brand, reasons for smoking, smokeless tobacco, family history, etc.  
4) Fagerstrom Test for Nicotine Dependence (FTND)81:  This is a self-rating questionnaire for nicotine 
dependence.     
5) Questionnaire of Smoking Urges- Brief (QSU-B ) 82:  This is a 10-item self-rating questionnaire for 
assessment of craving.  The questionnaire will be used to track the level of craving during the study.  In 
addition to a total score, the QSU provides scores on two factors: 1) hedonic craving, in anticipation of 
positive effects, and 2) craving in anticipation of withdrawal relief. 
6) Beck Depression Inventory II (BDI) 83: BDI is a 21-item self-rating scale to assess symptoms of major 
depression.  We will monitor depressive symptoms during the study due to strong association between 
smoking and depressive disorders.     
7) Minnesota Withdrawal Scale - Revised (MNWS-R) 4: MNWS-R is a DSM-IV based instrument to assess 
symptoms of nicotine withdrawal. 
8) Biomarkers: Urine cotinine levels will be used as biomarkers for cigarette smoking.  We will use a dipstick 
urine cotinine (NicAlert, Nymox Pharmaceuticals).  NicAlert is a semi-quantitative enzyme linked 
immunoassay (Elisa test) dipstick measure of salivary or urine cotinine with ranges of 0 – 10, 10 – 30, 30 –
100 ng/ml, etc.  The NicAlert dipstick will be done at each study visit.  We will also use carbon monoxide 
(CO) level in the expired air by a standard CO breathalyzer at each visit.    
9) Tobacco diary: This is a daily diary of all tobacco products consumed in the period between visits, including 
cigarettes.  Participants will maintain a daily tobacco diary, which will be collected at each visit.  We have 
piloted a similar diary in our previous studies.  Time-Line Follow-Back is not designed for daily prospective 
monitoring and hence a tobacco diary will be used.   
10) Other drug diary: If participant uses marijuana and other drugs, diaries to document other substance use 
will be provided. 
11) Modified Cigarette Evaluation Questionnaire- mCEQ: This questionnaire assesses the reinforcing effects of 
smoking. 
12) Self Assessment Manikin (SAM) 84.  SAM is a graphical picture-oriented instrument that can directly assess 
the pleasure, arousal, and dominance experienced in response to a cue exposure.  SAM ranges from a 
smiling, happy figure to a frowning, unhappy figure when representing the pleasure dimension, and from an 
excited, wide-eyed figure to a relaxed, sleepy figure for the arousal dimension.  The dominance dimension 
represents changes in control with changes in the size of SAM: a large figure indicates maximum control in 
the situation.  The participants will rate their subjective “happy”, “excited”, and “control” states.   
 
Table 1. Schedule for data collection 
Assessments 
Baseline 
The 1st Week 
TMS 
The 2nd Week 
TMS 
The 1st Follow-
up Visit One 
Week After 
TMS   
The 2nd Follow-
up Visit One 
Month After 
TMS 
Follow-up 
Phone 
Three Months 
After TMS 
 
Demographic 
x 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
Physical exam 
x 
 
 
 
 
 
Neuro exam 
x 
 
 
 
 
 
MINI 
x 
 
 
 
 
 
Psychiatric 
evaluation 
x 
 
 
 
 
 
Tobacco history 
x 
 
 
 
 
 
FTND 
x 
x 
x 
x 
x 
x 

Version: 2 – 08/20/2014 
8 
 
QSU-B 
x 
x 
x 
x 
x 
 
BDI 
x 
 
 
 
 
 
MNWS-R 
x 
 
 
 
 
 
CO 
x 
x daily pre  
x daily pre  
x 
x 
 
Craving rating 
panel 
x 
x daily pre 
post 
x daily pre post 
 
 
 
Tobacco diary 
x 
x 
x 
x 
x 
x 
Adverse Events 
x 
x daily pre 
post 
x daily pre post 
x 
x 
x 
Drug diary 
x 
 
 
 
 
 
mCEQ 
x 
x 
x 
x 
x 
 
Hematology 
x 
 
 
 
 
 
Routine urinalysis 
x 
 
 
 
 
 
Urine cotinine 
x 
x 
x 
x 
x 
 
Pregnancy test 
x 
 
 
 
 
 
Urine drug 
x 
 
 
 
 
 
MRI scan 
x 
 
TMS Day 10 
 
 
 
Best guess 
x 
 
x 
 
 
 
 
5. Randomization. Subjects will be randomized to either sham rTMS over DLPFC or real rTMS over DLPFC 
with Data Coordination Unit (DCU) at MUSC. Briefly, the subject will be assigned a study number and will then 
be assigned either a sham or active TMS smart card. An Active Smart Card will only allow TMS treatment with 
the active TMS head coil. A Sham Smart Card will only work with the sham TMS coil.  
6. MRI Scanning Procedures. At baseline and at the TMS 10 visit, subjects will have a 3.0 T MRI scan of the 
head with vitamin E tablets placed over the Abductor Pollicis Brevis (APB) motor cortex. Vitamin E tablets are 
easily visible on the MRI without artifact. We will acquireT1, T2, and FLAIR images to rule out coincidental 
pathology. These will be followed by high-resolution 3D SPGR images through the whole head (124 
contiguous sagittal 0.9 mm slices) for accurate localization.  
7. TMS Procedures 
1). All TMS procedures will be performed by a highly trained faculty or staff member of the Brain Stimulation 
Laboratory at MUSC under the supervision of a licensed M.D. with specialized training in TMS delivery. All 
participants will be fitted with a white lycra swim cap at the initial setting.  This cap will be worn during the 1st 
TMS sessions and in the MRI scanner in order to insure proper placement of the TMS coil across visits. The 
motor cortex will be located and the TMS motor threshold will be assessed. With Brainsight™ neuronavigation 
software (Rogue Research, Montreal, Canada), the TMS coil will then be moved over the left prefrontal cortex. 
Using a black permanent marker, landmarks will be placed on the cap to allow for proper refitting for following 
TMS sessions.  
2). Treatment parameters and grouping – The time in the chair and the number of pulses on the head will be 
the same for all subjects. Active or sham TMS will be the only difference.  The sham group only receives sham 
at all treatments. Stimulation frequency for all active subjects: 10 Hertz – Pulse train duration (on time) 5 
seconds, Inter-train interval (off time) 10 seconds (15 second cycle time), Power (intensity) level 100% rMT, 
Total 60 trains, 15 minutes, Total pulses 3000 per day, 3000 x 10 = 30000 pulses for 10 sessions. 
     Group 1 = Sham treatment over DLPFC  
     Group 2 = Active treatment over DLPFC 
3). Treatment Scheduling - All participants will be treated Monday – Friday for 10 treatments.  Ideally, all 
participants will be treated in the morning, at the same time of day throughout the study, with a note of any time 
deviation in the case report form (CRF). Each treatment will last about 35 minutes, including 15 minutes of 
rTMS or sham treatment delivery and 20 minutes pre and post craving rating (10 minutes each). At the end of  
5th and 10th rTMS sessions, subjects will be assessed  for craving and cigarette consumption.  
4). Subject Preparation for TMS delivery - The subject will be asked to remove and store any glasses or 
earrings, and to remove wallets from their pockets if they contain magnetic media (e.g., credit cards).   They 
will be asked to empty their bladder to avoid treatment interruption. Ear protection will be provided. 
5). Resting Motor Threshold (rMT): At entry, we will determine each subject’s rMT and all rTMS dosing will be 
given relative to this value. Surface electromyogram (EMG) will be recorded with silver-silver chloride 

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electrodes with a tendon-belly arrangement from the APB muscle. The signals will be filtered (band-pass 10 Hz 
to 1 KHz), amplified, displayed, and stored in a laboratory computer for offline analysis using Signal Software 
(Cambridge Electronic Design Limited, Cambridge, UK). Resting motor threshold (rMT) will be determined 
using a Neuronetics® Model 3600 with a solid focal coil TMS machine (Neuronetics, Malvern, PA, USA) by 
starting with 80% of the machine output and 1 Hz stimulus frequency. The coil will be positioned over the area 
of the skull roughly corresponding to the motor cortex and then systematically moved and adjusted until each 
pulse results in isolated movement of the right thumb. Once we completed “threshold hunting”, we will use a 
modified PEST algorithm attached EMG to determine rMT.  
6). Localizing the TMS Coil over DLPFC: At a visit after providing informed consent, but before the MRI 
scanning session, participants will be fitted with a white lycra swim cap. This cap will be worn during the MRI 
scan and during all TMS sessions in order to insure proper placement of the TMS coil across visits. While 
sitting upright in a comfortable position, the cap will be placed securely over the head, and pulled down to 
insure an adequate snug fit. Using a black permanent marker, landmarks will be placed on the cap to allow for 
proper refitting. Localization of the stimulation site in the prefrontal cortex will be performed using Brainsight ™ 
software along with a brain surface reconstruction. This software allows simultaneous display of high resolution 
MRIs in the coronal, sagittal and axial planes along with a brain surface reconstruction. Furthermore, after 
identification of the anterior and posterior commissures, correction for images tilt and limiting the outer brain 
extension in all planes, the images are normalized to the Talairach coordinate system. First we identify the 
superior frontal sulcus on the axial images, normally starting with the more superior slices where this sulcus is 
better displayed. From there, the sulcus is telescoped onto the coronal plane and we select the coronal plane 
that intercepts the brain 1 cm rostral to the anterior tip of the genu of the corpus callosum. A landmark is picked 
up on the cortex corresponding to the midpoint of the middle frontal gyrus, and its position is checked on the 3 
image planes as well as on the surface reconstruction to confirm that it falls on the middle frontal gyrus. Finally, 
the Talairach coordinates of the landmark in both the anterior-posterior and dorsal-ventral directions are 
checked. This landmark, and thus the stimulation site, should lie within the conservative range of Talairach 
coordinates of Brodmann area 46. Once TMS coil is localized, the location of TMS will be marked on the swim 
cap and be recorded with the coordinates of Neuronetics chair which will be used for subsequent treatments. 
7). Treatment administration: The Neuronetics TMS therapy is an FDA-cleared non-invasive medical treatment 
for patients with major depression who have not benefited from initial antidepressant medication. The 
Neuronetics TMS device to be used in this study has several important features for this study. First, the TMS 
coil is iron-filled, and thus does not overheat during repeated stimulation of multiple subjects, as in this clinical 
trial. Second, Neuronetics has developed a sham coil that looks and sounds much like the real coil, but has a 
layer of metal between the coil and the brain which blocks magnetic fields from entering the brain. The device 
also has a rigid arm-holder for positioning the TMS coil on the person’s head. Finally, the generator has smart 
cards, which can be individualized for each subject. Following randomization, each subject will receive a 
specific card for the treatment. The TMS machine will not work if the wrong coil (real or sham) is attached to 
the machine for that person. The treatment parameters for an entire 15-minute session can be flexibly 
programmed. Thus, the intensity of stimulation can gradually be increased over the first minute, which should 
help with patient tolerability, especially for higher intensity stimulation. Both active and sham treatments will be 
delivered as programmed into the Smart Card assigned to each subject at the time of the first treatment. The 
same card will be used each day that the patient returns for treatment.   
8). Active Sham rTMS: Successful patient and operator masking is key to the success of this trial. In one of our 
previous studies, we have successfully developed an active sham system 41. The subject and the treatment 
operator will be masked to the treatment group assignment, as will all research personnel. Randomization 
information will be controlled and coordinated through operator ‘Smart’ cards, distributed by the MUSC CDU. 
Active sham TMS involves the use of a specially designed sham TMS. The sham TMS system will be 
connected to an electrical generator on a 9 V battery and electrodes will be placed over the prefrontal cortex. 
The regulator is triggered by the TMS machine to allow brief, microsecond, pulses of the electrical current 
through to the skin on the subjects' forehead. Electrical stimulation will be triggered by the TMS machine to 
correspond to the sham TMS pulses. To further assess the adequacy of the mask, TMS administrators, clinical 
raters, and patients will complete “best guess” questionnaires, assessing their best guess as to treatment 
condition, and their level of confidence in this guess. 
9) Potential problems: (1) Missed treatment: Every attempt shall be made to complete each treatment session 
as per the protocol.  Interruptions during the treatment are allowed as needed for patient comfort or 

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convenience by using the “pause” selection on the device.  However, in the event that an incomplete treatment 
is given, this information will be recorded.  In the event that a treatment is missed, the following procedure will 
be followed:  1 day missed, or 2 days missed in a row—continue into the subsequent week to complete the 
missed days.  Evaluation will still occur after every 5 treatments.   3 or more days in a row—treatment must be 
aborted and the subject discontinued from their current phase and likely dropped from the study. (2)Monitoring 
for seizure activity: During the treatment procedure, the treatment administrator must observe the subject 
closely for any sign of imminent seizure activity or muscle twitching.  The administrator must be an individual 
trained to be perceive to warning signs, and will be familiar with the emergency management of seizure 
activity.  Emergency equipment (oxygen, suction, CPR equipment) will be readily available in the treatment 
suite.  (3)Recording of adverse events: During the treatment procedure, the administrator will assess for and 
record any adverse events.  Prior to leaving the facility following each treatment, the subject will be assessed 
for the occurrence of adverse events by a qualified individual who is masked to the subject’s assigned 
treatment group.  Immediately prior to, and following each TMS treatment session, all patients will complete a  
Visual Analog Scale to assess within session changes in side effects.   
 
8. Assessments and Instruments (Specific Aim 1 & 3) 
1). Craving Assessment:  Upon arrival at the laboratory, participants will be observed smoking their last 
cigarette before beginning to complete questionnaires.  Immediately prior to, and following each TMS 
treatment session, all patients will complete a Likert Visual Analog Cue Craving Scale to assess within session 
changes in subjective craving. 
2). QSU – Brief: Cue presentation and Craving Assessment: Scenic images, neutral control images and 
cigarette smoking cue images are presented in four blocks. Immediately after viewing each block of cue 
images, subjects will completed an adapted QSU-B utilizing a computerized visual analog scale (CVAS) 
designed to assess craving. Each question is followed by a CVAS (the range of 0 and 100).  
3). Carbon Monoxide: Subjects will be measured CO before TMS daily and at 1 week and 1 month follow-up 
visits. 
4). Weekly Assessments: At the end of the 5th and the 10th treatment and 1 week and 1 month follow-up visits,  
subjects will complete FTND, MNWS-R, Tobacco diary, mCEQ and adverse events. 
5). At the end of the experiment, subjects will be asked what treatment (active or sham) he/she believes was  
completed. 
 
9. Follow-up (Specific Aim 2). The treatment period of the study will conclude on the end of two weeks. 
Participants will then enter the follow-up phase of the study. The two follow-up visits will be scheduled one 1 
week and 1 month after the 10th rTMS session. Data will include craving ratings, tobacco diary, CO, QSU-B 
and FTND. We will conduct a follow-up phone survey of participants 3 months after the 10th treatment. 
Cigarette consumption will be evaluated by asking: ‘How many cigarettes do you now smoke on an average 
day?’. Craving will be assessed by asking: ‘How much do you want to smoke a cigarette right now on a scale 
from 1 to 10?’ and “When was your last cigarette?’. Nicotine dependence will be assessed by the FTND. 
 
10. Data Analyses. All data will be analyzed in consultation with Data Coordination Unit (DCU) at MUSC. 
Quantitative measures of nicotine dependence: Craving rating panel, Tobacco diary, CO, QSU-B and FTND. 
Side effects: Following standard procedures, frequency and severity measures of side effects will be 
constructed from the clinical measures. Significance testing: All tests will be two-sided, performed at 
significance =0.05, except where noted. The statistical approach will use an ANOVA for each outcome 
variable. Some data may be longitudinal as well as cross-sectional and we will include random effects to 
account for within-subject correlation.  
 
Power Analysis. The primary efficacy of rTMS for this study will be the abstinence rate and the number of 
cigarettes smoked per day at the end of treatment. One previous study of rTMS reported that 10 sessions of 
rTMS significantly reduced the number of cigarettes per day by the 10th treatment (18.11 ± 2.61 vs. 10.71 ± 
2.19) 19. A power analysis was conducted based upon this two group design, a power of 0.8, and an alpha 
level of 0.05; a significant difference is anticipated with 18 subjects in each group. The attrition rate in the 
above mentioned study was 8%. The attrition rate for our previous study was 12% 31. According to the attrition 

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rate from our study (which is more conservative), we will randomize 21 subjects per group (total N=42) to have 
ample power to detect a clinically meaningful difference. We will use 1 week, 1 month and 3 months follow-up 
data to calculate power for future R01 studies.  
 
HUMAN SUBJECTS RESEARCH 
Protection of Human Subjects 
1. Human Subjects Involvement and Characteristics. Subjects will be women and men aged 18 to 60 years. 
Subjects meeting inclusion/exclusion criteria (see detail in Study Plan) will be offered participation, regardless 
of racial/ethnic group. The sample composition will reflect the Charleston-area population distribution of healthy 
adult smokers.  
 
2. Sources of Materials. Research material obtained from the individual subjects will include psychiatric 
examination results, drug (including nicotine) use assessment results, urine for cotinine levels, expired air 
breathalyzer alcohol and CO tests, blood samples, heart rate, skin conductance, and subjective ratings (e.g., 
craving).  Urine samples for the urine drug screen and pregnancy will also be obtained. Research data will be 
obtained specifically for research purposes. We will not use existing specimens, records or data.  
 
3. Potential Risks. Investigational Device Exemption: Transcranial Magnetic Stimulation is an investigational 
device. The IRB at MUSC (in cooperation with the FDA) has determined repetitive TMS to be a non-significant 
risk intervention.  
1). Potential Risks of TMS: The major risk using repetitive TMS subjects is the possibility of inducing a 
seizure. We have now studied and given rTMS to more than several hundred subjects over past 15 years. 
None of these patients has developed a seizure. We will exclude patients with a prior history of seizures. 
We have reported that single session doses of 12,960 stimulations were safely given to volunteers with 
inducing seizures 85. We will carefully adjust each person's stimulus intensity to his or her motor threshold, 
before beginning treatment.  
2). Potential hearing loss: The discharge of the rTMS coil generates a high-energy click that may cause 
cochlear damage. Foam earplugs can protect against these changes and will be worn by the subjects and 
the researchers present during TMS sessions.  
3) Potential risks of active Sham TMS: When subjects receive sham TMS they may experience mild 
discomfort on their scalp.  
4) Potential loss of confidentiality: Despite efforts to maintain subjects’ anonymity and confidentiality, there is 
always some minimal risk of people other than the study investigators gaining access to subjects’ information. 
Every effort will be made to ensure that subject information will be collected and stored in a manner that 
ensures the highest level of protection of confidentiality. 
 
4. Adequacy Of Protection Against Risks.  
1). Recruitment and Informed Consent: Healthy subjects will be recruited from the greater Charleston area 
via flyers, Catalyst advertisements, internet and emails. Drs. Li and Hartwell and trained study personnel will 
be assigned to seek and obtain informed consent for all subjects. All prospective subjects will be judged 
clinically competent to give written informed consent. The informed consent form will detail the procedures, 
the time commitment, potential risks, confidentiality (HIPAA), and compensation for participation. The 
subjects will always have the right to discontinue participation in the study at any time without penalty and 
will be informed of this. If a subject is judged to be having any ill-effects from the experimental procedures, 
they will be withdrawn from the study by the PI and appropriate medical care will be arranged by available 
nurses, physicians and/or psychologists at MUSC hospital at no charge to the subject. 
2). Confidentiality of Subjects’ Responses: In the informed consent form, subjects will be told that the 
information they provide and all findings will be kept strictly confidential, with access limited to the research 
staff and the possible exception of state or federal regulatory personnel. No one but the project staff has 
access to the master list linking subjects’ names to code numbers, and all information obtained is coded.  
The respective master lists are kept under strict lock and key.   
3). Research Procedures: We have described above the potential risks of the research procedures. If the 
subject can’t continue the treatment, further participation will be terminated. We will minimize the risk of 

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seizure by prescreening subjects for a seizure history, getting a detailed medication history and by tailoring 
each person's TMS intensity to their own motor (and indirectly seizure) threshold. We will exclude subjects if 
they are taking medications that are associated with lowering of seizure threshold including stimulants 
(except for caffeine). We will minimize hearing damage by having all subjects wear earplugs to protect their 
hearing during the TMS sessions. Subjects will be stimulated with TMS in private clinical settings. A 
resuscitation cart including an Ambu bag and oxygen will be available. A licensed MD will be readily 
available during all TMS procedures to quickly respond to medical emergencies if they should arise.  
 
5. Potential Benefits Of The Proposed Research To The Subjects And Others  
For the proposed studies, the risks are minimal with very little chance of long-term or serious harm. 
Participants may experience a reduction in the number of cigarettes smoked per day and cigarette craving as 
benefit from study participation. Subjects will be compensated $70 for the screening visit which includes $20 
for drug screen, $25 for physical examination and assessments, and $25 for the baseline MRI. Subjects will be 
compensated $40 per visit for each visit attended during the treatment. Subjects will be compensated $25 for 
MRI scanning. During the follow-up phase of the study, subjects will be compensated $50 at the 1 week and 1 
month visits. Thus, the total compensation could potentially equal $595 over 3 months, depending on the 
number of visits.  Subjects will be paid in cash. 
 
Payments subjects receive from MUSC for participating in a research study are considered taxable 
income per IRS regulations. Payment types may include, but are not limited to: checks, cash, gift, 
certificates/cards, personal property, and other items of value. If the total amount of payment you receive from 
MUSC reaches or exceeds $600.00 in a calendar year, you will be issued a form 1099. 
 
6. Subject Safety And Minimizing Risks (Data And Safety Monitoring Plan) 
1). Trial Management: The study will be managed from the Brain Stimulation Lab within the Department of 
Psychiatry and Behavioral Sciences at the Medical University of South Carolina.   
2). Data Management and Analysis: Data will be entered by research assistants directly into a computer 
using standard database software.  The data analysis plan is outlined in the Data Analysis Plan section.  
3). Quality Assurance: The PI will have weekly meetings with the research assistants to discuss qualitative 
comments received during data collection and any problems in data collection.  The statistician will 
periodically examine the database to look for irregularities.  Initial data analyses will examine distributions of 
variable scores, and comparability of baseline characteristics across conditions in case analyses need to be 
adjusted for these.  Confidentiality protections are outlined above. 
4). Regulatory Issues: All unexpected Adverse Events (AEs) will be reported to the MUSC IRB and 
Committee on Human Research within 48-business hours.  Serious AEs will be reported within 24-business 
hours.  Follow-up of all unexpected and serious AEs will also be reported to these agencies.  
5). Definition of AE and SAE: An AE is defined as any untoward medical occurrence in a study subject 
administered a pharmaceutical product that does not necessarily have a causal relationship with this 
treatment (ICH GCP).  Any unwanted change, physically, psychologically or behaviorally, that occurs in a 
study participant during the course of the trial is an adverse event.  A Serious Adverse Event (SAE) is 
defined as an adverse event that has one of the following outcomes: death, life-threatening, inpatient 
hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity, a 
congenital anomaly/birth defect.  
6). Documentation and Reporting: AEs/SAEs are documented and reported as per IRB requirements. 
Research staff will identify adverse events and obtain all available information to assess severity, 
seriousness, study relatedness, expectedness, outcome and the need for change or discontinuation in the 
study intervention.  Adverse events are generally documented on AE Logs and AE Case Report Forms 
(CRFs).  Additional relevant AE information if available will be documented in a progress note in the 
research record as appropriate to allow monitoring and evaluating of the AE.  If the AE meets the definition 
for serious, appropriate SAE protocol specific reporting forms are completed and disseminated to the 
appropriate persons and within the designated timeframes as indicated above.  For each AE/SAE recorded, 
the research staff will follow the AE/SAE until resolution, stabilization or until the participant is no longer in 

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the study as stated in the protocol. We will report adverse events to the Medical MUSC IRB online per the 
IRB’s guidelines.   
7). Inclusion of Women and Minorities: Both men and women who meet study criteria will be eligible to 
participate.  Since this study is designed to examine adult smokers, children will not be included. Our 
minority enrollment is limited by the demographics of our county and state. At MUSC, the population of our 
county (Charleston , South Carolina) includes 0.3% Native American, 1.1% Asian American, 34.5% African-
American, 0.1% Native Hawaiian or other Pacific Islander, and 2.4% Hispanic. We anticipate a recruitment 
and participation of minorities lower than what the Census 2000 reports for Charleston County since a large 
portion of Charleston County is rural and suffers from similar ‘barriers for mental health treatment’ identified 
by the Surgeon General’s 2001 report and African Americans smoke at lower rates than Caucasians. In 
addition, MUSC is centrally located and in proximity of both major African-American and Hispanic 
communities in Charleston. We will take advantage of several intensive out-reach programs already in place 
at MUSC to enhance minority recruitment. For the reasons listed above we expect our enrollment to include 
2% of Hispanics, 15% African-Americans or Blacks and 1.4% of Asians. Other minorities are almost non-
existent in our catchments area. 
 
Targeted/Planned Enrollment Table-Total Planned Enrollment: 42 
Targeted/Planned Enrollment: Number of Subjects 
 
Sex/Gender 
Ethnic Category 
Females 
Male 
Total 
Hispanic or Latino 
1 
1 
2 
Not Hispanic or Latino 
20 
20 
40 
Ethnic Category Total of All Subjects* 
21 
21 
42 
Racial Categories 
 
American Indian/Alaska Native 
0 
0 
0 
Asian 
0 
0 
0 
Native Hawaiian or Other Pacific Islander 
0 
0 
0 
Black or African American 
3 
3 
6 
White 
18 
18 
36 
Racial Categories: Total of All Subjects* 
21 
21 
42 
*The “Ethnic Category Total of All Subjects” must be equal to the “Racial Categories Total of All Subjects.” 
 
 
 
 
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