Repetitive Transcranial Magnetic Stimulation (rTMS) for the Treatment of Depression & Other Neuropsychiatric Symptoms After Traumatic Brain Injury (TBI)
Phase: PHASE2
Conditions: TBI Depression
Sponsor: Johns Hopkins University

NCT02367521 
Repetitive Transcranial Magnetic Stimulation (rTMS) for the Treatment of 
Depression & Other Neuropsychiatric Symptoms After Traumatic Brain 
Injury (TBI) 
PI: Vani Rao, MD 
October 28, 2013 

 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 1 of 31 
 
Date:  October 28 2013  
Principal Investigator: Vani Rao, MD 
Application Number: ___________ 
 
 
JHM IRB - eForm A – Protocol 
 
 
 
 Use the section headings to write the JHM IRB eForm A, inserting the appropriate material 
in each. If a section is not applicable, leave heading in and insert N/A. 
 When submitting JHM IRB eForm A (new or revised), enter the date submitted to the field at 
the top of JHM IRB eForm A. 
 
*************************************************************************************************** 
Repetitive Transcranial Magnetic Stimulation (rTMS) for the Treatment of Depression & Other 
Neuropsychiatric Symptoms after Traumatic Brain Injury (TBI) 
 
1. 
Abstract  
 
Background: Traumatic brain injury (TBI) is frequently complicated by depression and other 
neuropsychiatric symptoms (NPS), such as post traumatic stress disorder (PTSD), sleep disturbance, 
cognitive deficits and behavioral problems. Untreated depression & comorbid psychiatric symptoms can 
lead to reduced productivity and poor global outcome. There are no Food and Drug Administration (FDA) 
approved drugs for the treatment of TBI-related NPS symptoms/syndromes. There have been only two 
controlled medication trials for the treatment of TBI-associated depression, and neither provided strong 
evidence that antidepressants are superior to placebo. A major limitation of these previous studies was their 
focus on a limited subset of depressive symptoms and use of agents with narrow therapeutic profiles. We 
propose to address   these limitations by use of a novel non-invasive technique, repetitive transcranial 
magnetic stimulation (rTMS) that has the potential to induce widespread neuromodulation, and assessment 
of a broad range of neuropsychiatric symptoms that are frequently comorbid in post-TBI depression.  
 
Objective/Hypothesis: The overarching goal of the proposed proof of concept study is to determine the 
effectiveness of low frequency right (LFR) rTMS for the treatment of post-TBI depression and co-morbid 
neuropsychiatric symptoms.  
Specific Aim 1: To determine the effectiveness of LFR rTMS for the treatment of: (a) post-TBI depression 
and (b) suicidal ideation. We hypothesize that LFR rTMS will be superior to sham treatment in: (a) 
reducing symptoms of depression and (b) reducing suicidal thoughts.  
 
Specific Aim 2: To determine the effectiveness of LFR rTMS for the treatment of neuropsychiatric 
symptoms that are commonly seen as co-morbid phenomena in patients with post-TBI depression: (a) post 
traumatic stress disorder (PTSD) (b) sleep disturbance and (c) cognitive deficits. We hypothesize that LFR 
rTMS will be superior to sham treatment in reducing symptoms of PTSD, sleep disturbance and cognitive 
deficits, more specifically, memory, attention and executive function deficits. In addition, effectiveness of 
rTMS for the treatment of other behavioral symptoms (e.g. apathy, aggression) will be assessed.  
 
Exploratory Analysis: A subset of subjects will be assessed using diffusion tensor imaging (DTI) to 
determine white matter integrity pre- and post-treatment in an effort to better understand neuro-anatomical 
correlates of NPS symptoms,symptom improvement, and the potential for LFR rTMS to influence white 
matter integrity.  
 
Study Design: The study design will include a double-blind placebo-controlled trial of 30 TBI patients of 
mild & moderate severities. Subjects will be randomized to either active LFR rTMS (N=15) or sham 
treatment (N=15). All subjects will receive 20 LFR rTMS or sham treatments over 4 weeks, and will be 
followed thereafter for 3 months. Well-validated psychiatric instruments and cognitive assessments will be 

 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 2 of 31 
 
used to compare the effectiveness of LFR rTMS versus sham treatment cross-sectionally at each of the 
visits and over time. 
 
Relevance: If the proposed rTMS treatment is found to be efficacious, it can be transferred to clinical 
practice for soldiers with TBI-associated depression and other psychiatric symptoms. rTMS has minimal 
long-term side effects and is not known to negatively interact with pharmacotherapies. rTMS has the 
potential to have a broad impact on multiple areas of life functioning and, thus, has the potential to lead to 
improved instrumental life activities, employability, community re-integration and overall quality of life. 
Soldiers & civilians with increased emotional stability and improved cognitive skills can more effectively 
manage stress which, in turn, can dramatically reduce the likelihood of developing disorders associated 
with chronic stress.     
 
2. 
Objectives  
The overarching goal of this proposed proof of concept study is to determine the effectiveness of low 
frequency right (LFR) rTMS for the treatment of post-TBI depression and co-morbid psychiatric 
symptoms.  
SPECIFIC AIMS & HYPOTHESES 
Aim 1: To determine the effectiveness of LFR rTMS for the   treatment of: (a) post-TBI depression and (b) 
suicidal ideation. We hypothesize that LFR rTMS will be superior to sham treatment in: (a) reducing 
symptoms of depression and (b) reducing suicidal thoughts.  
 
Aim 2: To determine the effectiveness of LFR rTMS for the treatment of neuropsychiatric symptoms that 
are commonly seen as co-morbid phenomena in patients with post-TBI depression: (a) post traumatic stress 
disorder (PTSD) (b) sleep disturbance and (c) cognitive deficits. We hypothesize that LFR rTMS will be 
superior to sham treatment in reducing symptoms of PTSD, sleep disturbance and cognitive deficits, more 
specifically, memory, attention and executive function deficits. In addition, effectiveness of rTMS for the 
treatment of other behavioral symptoms (e.g. apathy, aggression) will be assessed. 
 
Exploratory Analysis: A subset of subjects will be assessed using diffusion tensor imaging (DTI) to 
determine white matter integrity pre- and post-treatment in an effort to better understand neuroanatomical 
correlates of NPS symptoms,symptom improvement, and the potential for rTMS to influence white matter 
integrity.  
 
3. 
Background  
TBI is often called “the silent epidemic” because emotional, behavioral and cognitive symptoms 
(collectively referred to here as comorbid neuropsychiatric symptoms), which are the major cause of 
disability, are not immediately apparent1. Neuropsychiatric problems occur at increased rates and last 
longer in persons with TBI compared with those in the general population2,3.  Comorbidity is high with 
about 40% of patient with TBI suffering from two or more psychiatric disorders in the first year after 
injury4, and about 48% having at least one major mental illness 30 years post injury3. Corrigan et al5 
reported that about 40% of persons with TBI will have at least 1 ‘unmet need’ in the first year after TBI, 
the two most common being cognitive deficits (34%) and emotional problems (28%). The entire spectrum 
of TBI severity, from mild to severe, is associated with high rates of psychiatric morbidity6. Data collected 
for the PI’s NIH funded Career Development Award (K23 MH066894) are consistent with published data 
indicating high rates of neuropsychiatric disturbance in patients with TBI. The broad aim of that research 
was to determine clinical risk factors for the development of depression after TBI. First-time head injured 
adult subjects with all severities of TBI who were hospitalized for evaluation were recruited from two 
trauma centers: the Trauma Unit at Johns Hopkins Hospital and the Brain Injury Unit at Kernan Hospital, 
University of Maryland. Subjects were interviewed using the Structured Clinical Interview for DSM IV 
disorders (SCID IV) to determine Axis I psychiatric disorders. As seen in Table 1, 85% of subjects had at 
least 1 major mental illness. Comorbidity was high in this sample with at least 60% of subjects meeting 
criteria for 2 or more psychiatric disorders. Depression was the most common psychiatric illness (52%), 
and of these, 30% had a new onset mood disorder. 

 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 3 of 31 
 
Table 1: Percentages of psychiatric diagnoses in the first year after TBI 
 
Psychiatric Diagnoses 
Percentages (N=103) 
Any Psych Dx 
85.4% 
2 or more Axis 1 Psych Dx 
60.1% 
Any Depression 
52.4% 
Any alcohol or substance abuse/dependence 
36.9% 
Pathological crying/laughter 
33 % 
Any Anxiety d/o 
31.1% 
New onset mood disorder 
30% 
Personality change 
15.5 % 
PTSD 
8.7% 
Apathy 
8.7% 
 
TBI Depression 
As seen in Table 1, of all the psychiatric sequelae seen after TBI, depression is the most common diagnosis. 
A review of the published literature7 reveals that the prevalence of depression following TBI ranges 
between 6%-77% with most studies8.9 reporting a prevalence of 25-50%. This rate is significantly higher 
than the general population, which has a lifetime prevalence of major depressive disorder of approximately 
21%10. Depression following TBI (hereafter referred to as “TBI depression”) is characterized by persistent 
sadness, anhedonia, feelings of worthlessness, hopelessness, loss of interest in work and family activities, 
poor motivation, decreased social contact and suicidal thoughts11. Wood et al12, in a study of 105 patients 
with TBI of all severities, found suicidal ideation in 33%, compared to 1.4% of normal healthy controls. 
Untreated depression is associated with suicide attempts, occasionally completed suicide, reduced work 
productivity, decreased psychosocial functioning, and poor global outcome both in the acute and chronic 
TBI period13,14. Persistent postconcussive symptoms are more common in those with mild TBI and 
comorbid depression compared to mild TBI without depression and depression without history of TBI15.  In 
addition to the negative impact of TBI depression on patients themselves, high levels of anxiety and 
depression are reported in family members involved in the care of TBI patients and comorbid mood 
disturbances16,17. Thus TBI depression has an adverse impact on individuals, their families, and the 
community at large through lost productivity. TBI depression has been found to be associated with a host 
of factors including pre-injury factors, including presence of prior psychiatric history and pre-TBI 
psychosocial dysfunction; injury-related factors such as lesions to strategic brain regions such as the fronto-
temporal basal ganglia, and post-injury factors , particularly poor psychosocial functioning11,18,19. A pilot 
study by Rao et al20 to determine the neuroanatomical correlates of post-TBI depression revealed that it was 
not the severity of injury but dysfunction of the fronto-temporal-basal ganglia regions that was associated 
with the development of major depression.  
 
Post-TBI Depression & Comorbid Neuropsychiatric Symptoms/Syndromes  
 
Post traumatic stress disorder (PTSD): PTSD can occur independently of depression after TBI or co-
morbidly. Risk factors for PTSD following TBI include past psychiatric history21; female gender22 and past 
history of acute stress disorder23. Other correlates of PTSD include poor quality of life, impairment in 
physical health, and reduced interpersonal/social functioning.24,25  Thus TBI depression and co-morbid 
PTSD are associated with significant impairment in physical and emotional health, underscoring the 
importance of accurate diagnosis and treatment. 
 
Sleep Disturbances: Rao et al26 have noted that the  presence of sleep disturbance in the early TBI period 
predicts the development of new onset major depression and new onset anxiety disorder in the chronic TBI 
period. Results from the PI’s NIH funded study on TBI depression (K23 MH066894) reveal that sleep 
problems in the post-TBI period are generally greater than those occuring pre-injury26 (Table 2). Correlates 
of sleep disturbance in the acute TBI period included generalized anxiety disorder secondary to a general 

 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 4 of 31 
 
medical condition (TBI), and major depression secondary to a general medical condition (TBI) in the three 
month post-TBI period (Table 3). Regression analysis, using the overall sleep score (Sleep Problem Index 
2) as the dependent variable and several psychosocial factors as independent variables (Table 4), revealed 
that sleep disturbance in the early TBI period was associated with the development of depression (all sub-
types inclusive) within the 1-year follow-up period, new-onset major depression at 6 and 12 months post 
TBI, impaired psychosocial functioning at 6 months post TBI, poorer performance on a test of executive 
function (letter fluency test) and increased dependency on others for instrumental activities of daily living 
at 6 months post-TBI.  
 
Cognitive Deficits: Several studies have shown an association between depressive symptoms and cognitive 
deficits after TBI27-29. In a study of 74 TBI patients, Rapoport et al30  noted that subjects with major 
depression  following TBI (28%), when compared to those without depression, had significantly lower 
scores on tests of working memory, processing speed, verbal memory and executive functioning.  
Executive functioning impairments were also found to be related to depression in a very recent study of 
mild to moderate TBI in the early phases of recovery31.   These associations suggest that cognitive 
impairments are a common comorbidity of post-TBI depression. Research suggests that self-appraisal of 
post-TBI abilities, which can be negatively affected by cognitive impairments, is strongly associated with 
the presence of depression after TBI and may potentially explain the relationship between cognitive 
impairment and depression32.    
 
Table 2. Comparison of Sleep Scores Pre- and Post-TBI 
 
Sleep Variable 
Pre-TBI 
3 months Post-TBI 
F, P variables 
Sleep Disurbance 
17.5 (15.9)1 
27.7 (24.1) 
6, p=0.018 
Snoring 
18.4 (30.2) 
14.5 (26.9) 
0.72, p=0.4 
SOB/HA2 
0.39 (2.8) 
14.1 (27.5) 
0.72, p=0.4 
Sleep Adequacy 
26.7(28.2) 
38.6 (31.1) 
5.5, p=0.023 
Daytime Sleepiness 
17.3 (17.5) 
31.8 (26.9) 
10.8, p=0.002 
SPI 13 
14.4 (14.0) 
28 (22.3) 
16.8, p=<0.001 
SPI 24 
17.2 (12.7) 
29.3 (20.5) 
13.2, p=0.001 
1Mean (SD); 2Shortness of breadth/headache; 3-4 Sleep problem Index & overall Sleep score 
Table 3. Association Between Participant Characteristics and Sleep Domains/Summary Scores 
 
Sleep 
disturbance 
Snoring 
SOB/HA1 
Sleep 
Adequacy 
Daytime 
Sleepness 
SPI 12 
SPI 23 
Age 
0.01 (0.2)4 
0.42 (0.2)* 
-0.04 (0.22) -0.05 (0.3) 
0.47 (0.2)* 
0.12 (0.2) 
0.11 (0.2) 
Female 
4.91 (6.6) 
-3.67 (7.4) 
15.63 
(7.3)* 
4.06 (8.8) 
8.25 (7.4) 
8.56 (6.1) 
7.12 (5.6) 
MDGMC5 
21.12 (9.2)* 
6.96 (10.8) 
10.68 
(11.0) 
11.49 
(12.8) 
18.42 (10.6) 
17.86 
(8.8)* 
18.69 (7.9)* 
GADGMC6 27.42 
(9.4)** 
12.72 
(16.2) 
8.94 (16.8) 
21 (16.9) 
38.86(14.4)** 
25.62 
(9.8)* 
26.35(8.7)** 
GMHR7 
-5.28 (3.4) 
-2.6 (3.9) 
-0.87 (4.0) 
-0.22 (4.7) 
-5.85 (3.9) 
-3.7 (3.3) 
-3.65 (3.0) 
Body 
Injury 
-5.21 (6.5) 
-1.15 (7.4) 
5.63 (7.5) 
-9.3 (8.7) 
-5.41 (7.4) 
-2.79 (6.2) 
-5.35 (5.6) 
GCS8 
-0.69 (1.0) 
-0.17 (1.1) 
-0.08 (1.1) 
0.7 (1.3) 
-0.05 (1.1) 
-0.68 (0.9) 
-0.45 (0.8) 
1Shortness of Breath/ Headache; 2-3 Sleep Problem Index overall sleep score;4 Beta (SE); 5Major Depressive-like Episode due to 
General medical disorder; 6 Generalized Anxiety Disorder due to General Medical Condition; 7 General Medical Health Rating; 
8Glasgow Coma Scale.  *p<0.05; **p<0.01. 

 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 5 of 31 
 
 
Table 4.  Predictors of Sleep Disturbance 
 
 
Beta (SE) 
p-value 
Adj. R2 
Any Depression  1yr post-TBI 
24.8 (5.5) 
<0.01 
0.17 
New-onset Depression  6m post-TBI  
22.2 (9.9) 
0.03 
.0.04 
New-onset Depression 12m post TBI 
50.7 (10) 
<0.01 
0.20 
Letterfluency 1yr post-TBI 
1.3 (0.63) 
0.05 
0.07 
Psychosocial function 1yr post- TBI 
55.3 (19.8) 
<0.01 
0.11 
IADL Dependence  6m  post-TBI 
1.6 (0.75) 
0.04 
0.06 
 
Behavioral Issues:  Post-TBI Depression is often associated with other comorbid symptoms, such as 
anxiety, apathy, anger/aggression, impulsivity and disinhibition. These symptomscan be an integral 
component of a depressive syndrome, a consequence of brain injury, or both33. In a study of 67 individuals 
with first-time TBI seen within three months of injury, Rao et al33 noted rates of aggression (predominantly 
verbal) to be about 28%.  When participants with and without TBI aggression were compared (Table 5), 
participants with aggression  had a higher prevalence of new-onset major depression (p=0.02).   No group 
differences were observed for any other Axis 1 psychiatric diagnoses. Participants with aggression were 
also more likely to have poorer social functioning (p= 0.04) and increased dependence on others for 
personal and instrumental activities of daily living (p=0.03).  Importantly, there were no differences 
between those with and without aggression on pre-TBI or post-TBI history of alcohol or substance abuse, 
pre or post-TBI legal problems, pre- or post-TBI history of adult behavior problems and childhood 
behavior problems. These findings underscore the point that TBI aggression is related specifically to post-
TBI depression.  
 
Other common co-morbid psychiatric symptoms seen following TBI include anxiety, apathy, disinhibition, 
and impulsivity. Rates of anxiety disorders in post-TBI depression is high, ranging from 40-77%11,34. 
Persons with post-TBI depression and co-morbid anxiety have longer duration of symptoms compared to 
those with post-TBI depression alone (7.5 months versus 1.5 months). Apathy, defined as lack of 
motivation, anhedonia and disengagement is a common symptom after TBI. Kant et al35 noted apathy and 
depression in 60% and apathy alone in 11% of TBI subjects.  
 
In summary, post-TBI depression is the most common psychiatric sequela of TBI, but it usually does not 
occur alone. Co-morbidity is high and adds to the distress and disability that is experienced by individuals 
following TBI. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 6 of 31 
 
Table 5: Comparison of TBI subjects with and without Aggression on clinical variables 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pathophysiology of TBI & TBI Depression 
The pathophysiological consequences of trauma to the brain may be best conceptualized as the result of a 
combination of direct impact forces (i.e. at the site of impact) and acceleration-deceleration forces36. The 
two most common sites of focal injury include the anterior and inferior frontal regions and the tips of the 
temporal lobes, as they sit on bony protuberances of the skull and are thus vulnerable to the impact forces37. 
In addition to focal injury secondary to acceleration and deceleration forces, there are also 
backward/forward and rotational movements of the brain within the skull during TBI, resulting in diffuse 
axonal injury38. Following acute TBI-induced physical injury, a cascade of metabolic events occurs, 
resulting in more damage.  It is unclear how long neurotransmitter imbalances persist following TBI, as 
decreased levels of acetylcholine, serotonin and dopamine have all been noted, even in the chronic TBI 
period39. Thus, the pathophysiology of TBI includes a combination of mechanical damage, metabolic 
disturbance, cytotoxic damage and neurotransmitter alterations which can persistfor a prolonged period. In 
many patients, neuronal changes following TBI are subtle and cannot be identified by routine magnetic 
resonance imaging (MRI) or computerized tomography (CT) scans. However, Diffusion Tensor Imaging 
(DTI), which is known to be sensitive to the microscopic anatomical status of axonal structures, may have 
the potential to detect diffuse microstructural injury40. DTI measures the microscopic random translational 
motion of water molecules41. Because freedom of motion is restricted by interactions with other molecules, 
the structure of axons, and integrity of neuronal membranes, DTI measures can be used as markers of tissue 
organization at a microscopic level. Therefore, DTI represents a promising approach to quantify 
microscopic brain damage by measuring both water diffusion (mean diffusivity; MD) and the degree of 
diffusion directionality, or anisotropy (fractional anisotropy; FA)42.  In a pilot study to determine whether 
diffusion tensor imaging (DTI) measures of fractional anisotropy (FA) and mean diffusivity (MD), 
collected within 1 month of mild TBI (mTBI) could predict incident depression, Rao et al43 noted a 
negative association between FA in the left superior and middle temporal gyri and  severity of depression 
(indicating that decreased white matter integrity in these regions is associated with increased depression) 
and a positive correlation between  MD  and  severity of depression in several fronto-temporal regions 
(indicating that increases in microstructural abnormalities in these regions are associated with increases 
depression). One goal of the current  study is to determine whether these preliminary findings can be 
replicated. Because this is a treatment protocol, we also hope to characterize DTI changes associated with 
successful treatment of TBI depression and comorbid neuropsychiatric disturbances. 
 
 
Variables 
Aggression  
No Aggression 
t 
df 
p-value 
Major Depression Pre-TBI 
2 (10.5%) 
4 (8.3) 
FET 
 
1.00 
Major Depression Recurrent Post-TBI 
0 
1 (2.1) 
FET 
 
1.00 
New onset Depression post TBI 
5 (26.3) 
2 (4.2) 
FET 
 
0.02 
Post-TBI Anxiety Disorder 
6 (31.6) 
6 (12.5) 
0.07 
1 
0.07 
Pre-TBI Alcohol abuse/dependence 
9 (47.4) 
26 (54.2) 
0.62 
1 
.79 
Childhood Behavior Problems 
6 (31.6) 
13 (27.1) 
.71 
1 
0.77 
Adult Behavior Pre-TBI 
6 (31.6) 
14 (29.2) 
.85 
1 
1.00 
Social Functioning Post-TBI 
.33 (.15) 
.25 (.14) 
-2.2 
64 
.03 
Personal & Instrumental activities of 
daily living Post-TBI 
9.6 (8.1) 
5.3 (6.6) 
-2.3 
64 
.03 

 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 7 of 31 
 
 
Treatment of TBI Depression 
Despite its high prevalence and socio-economic burden, little research has been conducted on the treatment 
of TBI depression. The bulk of studies evaluating the efficacy of antidepressants for the treatment of post-
TBI depression have involved selective serotonin reuptake inhibitors (SSRI's).  Results from these studies 
are inconsistent, and generally reveal that a significant number of patients fail to respond to medication. 
There are currently no FDA approved drugs for the treatment of post-TBI depression or its co-morbidities, 
and use of antidepressants for the treatment of TBI-related neuropsychiatric illnesses is considered off-
label. Below, we have summarized  results from the pharmacological and non-pharmacological studies in 
the treatment of post-TBI depression 
 
Cassidy44 reported moderate-marked improvement in 5 of 9 severe TBI patients with major depression 
following treatment with fluoxetine. Fann et al45 conducted an 8-week nonrandomized, single-blind, and 
placebo run-in trial of sertraline in 15 mild TBI patients diagnosed with major depression 3-24 months after 
injury. Eighty seven percent of patients responded to treatment, and remission was seen in 67%. There was 
also a statistically significant improvement in psychological distress, anger, aggression, functioning and 
postconcussive symptoms with treatment. Rapoport et al46  reported much lower response and remission 
rates in an open label study of citalopram of 20-60 mg in a study of  mild-moderate TBI depressed subjects. 
Remission rates at 6 and 10 weeks were 24 and 27% respectively. Perino et al.47 conducted an open label 
trial of citalopram (20 mg/day) combined with carbamazepine (600 mg/day) in 20 TBI subjects with mood 
and behavioral disturbances. Compared to pre-treatment, the group was found to have significant 
improvements in both mood and behavior when treated with this combination.  
 
Reports of the efficacy of tricyclic antidepressants for the treatment of TBI depression have also been 
inconsistent. Saran48  reported no improvement from treatment with amitriptyline in any of 10 minor head 
injured patients who suffered from “depression with melancholia” in contrast to 12  control patients with 
primary depression and melancholia who all showed significant improvement. Dinan and Mobayed49 also 
observed no significant improvement associated with amitriptyline treatment in 13 depressed minor head-
injury patients when compared to 13 “functionally” depressed patients. The only randomized controlled 
trial50 of tricyclic antidepressants in a study of 10 severe TBI subjects noted improvement of depressive 
symptoms in 6 of the 7 completers treated with desipramine. However, remission and responses rates were 
not calculated, and some of the participants were being treated with other psychotropics in addition to 
desipramine. There are some case reports of successful treatment of post-TBI depression with 
psychostimulants such as dextroamphetamine, methylphenidate and pemoline51. However patients on these 
medications should be monitored closely to prevent abuse or toxic effects such as headaches, irritability, 
seizures, cardiovascular symptoms and/or psychotic symptoms52.   
 
There are only two controlled trials of post-TBI depression. The first,a study by Lee et al53 , was a double 
blind parallel group 3-arm trial  that compared methylphenidate (20 mg/day) to sertraline (100 mg/day) and  
placebo. Thirty TBI subjects with depression were recruited to this 4 week study. Methylphenidate and 
sertraline were found to be superior to placebo. No difference was found between the 2 active drugs on 
depressive symptoms, but those on methylphenidate (but not sertraline) had improved cognition relative to 
placebo. A major limitation of the study was the lack of analyses of response and remission rates. The 
second study by Ashman et al.54 compared sertraline to placebo in 52 subjects with post-TBI depression 
who were, on average, 17 years post injury. In this 10 week trial, subjects in both groups showed 
improvement. Although the group receiving sertraline had a higher response rate compared to the group 
treated with placebo (59% versus 32%), differences between the two groups were not significant. 
 
Other types of treatment such as physical activity and cognitive behavior therapy (CBT) have also been 
studied for the treatment of post-TBI depression.  Driver et al55 studied 16 subjects and assigned them to 
either 8 weeks/24 sessions of swimming, or a similar number of vocational rehabilitation sessions. Those in 
the swim group were noted to have improvement in depression and other symptoms, such as anger, anxiety 
and fatigue, when compared to the group in vocational rehabilitation. Two other studies evaluating the 

 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 8 of 31 
 
efficacy of aerobic exercise for the treatment of post-TBI depression noticed no statistically significant 
improvement in mood scores in the experimental group versus the control group56.57. A few CBT studies  
found overall improvement in mood and cognition in the intervention group compared to the control 
group58-60.  However, most of these studies noted a low compliance rate. Also, none of these studies 
specifically studied major depression. Small uncontrolled studies have also evaluated the utility of 
alternative treatments for TBI depression. Maric et al61 noted improvement in depression scores in 4 out of 
6 post-TBI depressed persons with growth hormone deficiency after treatment with growth hormone for 6 
months. In the only known retrospective electroconvulsive treatment study of TBI depression, Kant et al62 
noted improvement in depression in 9 out of 11 subjects. Notably, there was no decline in cognition.   
 
As limited and inconsistent as the available data on post-TBI depression are, there are even fewer studies 
on the treatment of other TBI-related neuropsychiatric symptoms.  Standard treatment approaches using 
drugs with narrow therapeutic profiles may be unsuccessful because of the complex TBI pathology, which 
includes focal/diffuse damage, physical/biochemical damage and involvement of multiple cortical-
subcortical pathways.  
 
We propose to address some of the limitations of previous studies of post-TBI depression by use of a novel 
non-invasive technique, repetitive transcranial magnetic stimulation (rTMS), that has the potential to 
induce widespread neuromodulation63,64. Studies in non-TBI depression have postulated that the therapeutic 
effect of rTMS is secondary to its neuromodulator effect and strengthening of synaptic connections in the 
fronto-subcortical-limbic circuitry65.  
 
Repetitive transcranial magnetic stimulation (rTMS) 
TMS is a non-invasive modality for focally stimulating the peripheral and central nervous system. A 
changing electromagnetic field passes unimpeded through skin, muscle and bone depolarizing underlying 
neurons. Repetitive pulses or trains of pulses (rTMS) applied to the head can provoke long-lasting up- or 
down- regulation of activity at synapses, including in brain regions that regulate emotion and movement66.  
These long lasting changes in synaptic transmission are critical to the therapeutic effects of rTMS for the 
treatment of depression. Although the electromagnetic field only reaches 1 – 2 cm into the cortex, 
activation of neurons in that region trigger activation of neurons at more distal sites, as demonstrated by 
functional imaging studies 67 .  
 
TMS was first utilized in the 1980’s by neurologists to painlessly and non-invasively map brain function. In 
the early 1990’s, it was noted that stimulation over the left dorsolateral prefrontal cortex (DLPFC) could 
affect mood68.  Over the next ten years, more than 30 sham-controlled studies of rTMS demonstrated its 
efficacy for treating major depressive disorder (MDD). rTMS is not associated with any systemic side-
effects experienced with pharmacological treatment. Moreover, although it is not as effective as ECT, 
rTMS has the advantages of not requiring anesthesia and not being associated with cognitive side-effects. It 
was approved as a treatment for MDD by the FDA in 2008. There are now more than 300 clinics offering 
rTMS for the treatment of idiopathic depression around the country. 
 
Several studies have demonstrated that low frequency right-sided (LFR) rTMS over the DLPFC at 1 Hz, 
which inhibits cortical activity, is efficacious for treating MDD, and that response rates are comparable to 
high frequency left-sided (HFL) rTMS over the DLPFC which is excitatory69-70.  This finding is consistent 
with previously described opposing effects  of the two brain hemispheres on mood regulation67,71.  LFR 
rTMS is increasingly utilized by clinicians, and is being incorporated into treatment guidelines, especially 
for depressed patients with significant anxiety and PTSD, for which it may be more efficacious than 
HFLrTMS72-74.  There are considerable advantages to using LFR rTMS over HFL rTMS. The most 
important advantage is that because LFR reduces cortical excitability, seizure risk is lower than with HFL 
treatment (which is already exceedingly low when parameter sets comply with rTMS safety guidelines). 
The anticonvusant effect of low frequency rTMS was recently demonstrated in a meta-analysis of studies 
utilizing rTMS for intractable epilepsy75. In addition, Dell'osso et al76 have also noted that remission could 
be maintained at least for a year after acute response to LFR rTMS in a study of 11 depressed subjects. As 
the patient population for the proposed study may be at a higher risk for seizures than a non-TBI cohort, we 

 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 9 of 31 
 
will utilize LFR to minimize this risk. Another major advantage of LFR over HFL rTMSis better 
tolerability of treatment,  less localized discomfort at the stimulation site, less stimulation of the facial 
nerve, and fewer headaches69, 77-79.  
 
The TMS seizure risk is estimated at <0.1% of patients who are administered treatment, which is 
comparable to the seizure risk associated with an antidepressant medication. In studies of patients with 
established neuropathological lesions such as from stroke or multiple sclerosis, seizure risk from TMS also 
appears to be exceedingly low. Out of 1200 stroke patients who received TMS, there has been only one 
reported seizure in an alcoholic patient administered high frequency rTMS ipsilateral to the site of the 
lesion. See eIRB application section 21(section 21.5 -> Magstim Super Rapid -> 6) for a thorough review 
of safety issues, especially seizure risk, related to administration of LFR rTMS.   
 
 
Although rTMS is now an accepted treatment for idiopathic depression, far less is known about the 
potential effect of rTMS on behaviors such as impulsivity and apathy that are mediated by the prefrontal 
cortex, and which are secondary targets in this study, in addition to depression. A recent rTMS study84 of 
healthy subjects using continuous theta-burst stimulation over the right DLPFC, which is inhibitory, 
showed decreased impulsivity in a discounting delay reward task, when compared with sham. Little is 
known about the effect of rTMS on apathy.  This has been explored in a few trials, especially in 
schizophrenia patients, using HFL rTMS, with mixed results85. 
 
We will also assess the potential for LFR rTMS to treat the cognitive sequelae of TBI. As mentioned 
above, rTMS is not associated with adverse cognitive effects, and improvement in cognitive measures has 
been noted in parallel with improvements in mood in depressed patients69,86.  In non-depressed patients, 
transient improvement in cognition in a variety of cognitive domains has been reported with both HFL and 
LFR stimulation87. 
 
It is with this background that we propose a pilot proof of concept study to determine the effectiveness of 
LFR rTMS for the treatment of TBI depression and its common comorbidities.  
 
.   
 
4. 
Study Procedures 
Study Overview: The proposed proof of concept study will recruit 30 subjects with traumatic brain injury of 
mild-moderate severity who also meet DSM IV criteria for major depression. We will screen as many 
potential subjects as possible to get a total of 30 subjects.  
 
Written informed consent will be obtained from all subjects prior to enrollment.   
 
All enrolled subjects will be evaluated using structured and semi-structured psychiatric interviews to 
determine a series of baseline outcome measures. Subjects will be randomly divided into two groups and 
treated in a double-blind fashion with LFR rTMS vs sham treatment; Subjects will receive a total of 20 
treatments – 5/week for 4 weeks. Subjects will then be followed monthly for the next 3 months i.e. will be 
evaluated at 8, 12 and 16 weeks). 
We have contacted the FDA regarding the proposed study and the use of rTMS in persons with TBI and  
have been told to proceed with applying for Hopkins  IRB review rather than embarking on an IDE 
 
 
 
 
 
 
 
 
 

 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 10 of 31 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Overview: Figure 1 
Recruitment:  Subjects will be recruited from several sources: (1) The Brain Injury Clinic at Johns 
Hopkins Bayview Medical Center (the PI is the Medical Director of the clinic), (2) The Outpatient 
NeuroRehabilitation Program at Johns Hopkins Hospital, (Co-investigator Dr. Kathleen Kortte is the 
Program Director), (3) referrals from other Johns Hopkins Medicine inpatient and outpatient clinics,  (4) 
brain injury support groups organized by the Brain Injury Association of Maryland, and (5) IRB-approved 
advertisements placed in local newspapers and on the internet, and (6) other local hospitals such as the 
Walter Reed National Military Medical Center (WRNMMC), the Medstar National Rehabilitation 
Network, and Sheppard Pratt Hospital. An IRB approved ‘telephone script’ will be used to discuss the 
study with those who call in response to advertisements or flyers. Patients who are willing to participate 
will be brought to the research clinic to obtain written informed consents and undergo face-to-face 
evaluations.   
 
Study Site: The study sites will bethe Geriatric & Neuropsychiatry Clinics at Johns Hopkins Hospital, and 
Johns Hopkins Bayview Medical Center. Polysomnography studies will be undertaken at the Johns 
Hopkins Bayview Clinical Research Unit which is a component of an Institutional Clinical Translations 
Research program. DTI brain scans will be completed at the Kirby Center, Kennedy Krieger Institute.   
 
Study population. Persons with history of mild –moderate traumatic brain injury and depression will be 
included in the study. Potential participants will only be considered for this study once they have been 
Identification of subjects  
Informed Consent 
Screening; Enrollment N=30 
 
Pre-Treatment: Baseline Assessment 
rTMS Fitness: Screening questionnaire; Blood test; urine test in females; Depression SCID & 
HAMD; PHQ9; Severity of Illness; CGI-S ; Suicide: BSS;  Sleep: Pittsburgh Sleep Quality Index, 
and the Epworth Sleep Scale & Polysomnography; PTSD:  Davidson Trauma Scale; Cognition: 
Neuropsychological test battery, Behavior: Neurobehavioral Rating Scale; White matter integrity: 
DTI  
 
Experimental Group N=15 
20 sessions RFL rTMS treatment
Control Group N=15 
20 sessions sham treatment 
Follow-up: 4, 8, 12 , 16 weeks   Post-treatment 
Response to treatment: CGI-I; Depression severity:  HAMD, PHQ9; Suicide: BSS; Sleep: 
Pittsburgh Sleep Quality Index, and the Epworth Sleep Scale; PTSD:  Davidson Trauma 
scale; Behavior: Neurobehavioral Rating Scale. At 16 weeks additional  
polysomnograpgy, cognitive tests & DTI 

 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 11 of 31 
 
safely weaned off all psychotropic medications by their treating physicians (see inclusion and exclusion 
criteria below). 
 
 
Study Visits: Study visits include: (1) An initial screening visit to confirm eligibility and obtain informed 
consent;  (2) Twenty treatment visits  (5 visits per week for 4 weeks); (3) Three monthly follow-up visits 
(week 8, 12 and 16).  
The total number of visits include: 1 + 20 + 3 = 24 visits. If subjects are unable to come to Hopkins for 
follow-up visits, we will conduct telephone evaluations at the same timepoints. 
 
Study Design: We propose a double-blind placebo controlled proof of concept pilot study of active versus 
sham LFR rTMS for the treatment of TBI depression. As noted above, all subjects will be screened prior to 
randomization. During the screening visit, all subjects will undergo a complete psychiatric evaluation as 
well as formal cognitive testing. In addition, if there is any possibility of pregnancy or unstable medical 
status, the PI or physician co-investigator will ask the potential subject’s treating psychiatrist or primary 
care physician (PCP) to conduct a urine pregnancy test and/or bloodwork to rule out infections and liver, 
kidney or thyroid abnormalities. If the potential participant does not have a PCP or psychiatrist, a lab 
requisition will be provided to the participant. He/she will be considered for the study only after the lab 
results are reviewed by the study physician and found to be normal. .  
 
Subjects will be randomized using a custom   in-house software method, and will be stratified on time since 
injury: <5 years post injury versus≥5 years. 
All members of the research team will be blind to individual subjects’ treatment condition, with the 
exception of the rTMS staff member, Mr. Michael Tibbs. The success of subject blinding will be evaluated 
by asking subjects, during the first and last week of treatment, whether they believe that they received 
active or sham rTMS treatment. The rTMS technician will ask this question and note down the answer in 
the weekly assessment form. 
 
Study Treatment: Subjects will receive either LFR rTMS or sham treatment.  
 
rTMS Treatment & Sham Treatment: rTMS will be delivered at the Brain Stimulation Program at The 
Johns Hopkins Hospital, using a Magstim Super Rapid 2 stimulator with a focal double 70-mm air cooled 
coil. Control patients will receive treatment using an identically appearing coil that produces the same 
sound and is the same weight as the active coil, but has negligible magnetic field strength. Scalp sensation 
in control subjects will be simulated using the sham system described in Borckardt et al88. Prior to each 
treatment, subjects will be instructed to insert earplugs. The head of the seated subjectwill be secured in a 
head and coil holder chair and stand assembly (Rogue Research Inc.). Motor threshold (MT) will be 
ascertained by delivering single pulses to the area of the motor cortex (right side) controlling the 
contralateral abductor pollicis brevis (APB). Electrical activity in APB will be recorded using surface 
electrodes. MT will be defined as the lowest intensity of stimulation that produces motor evoked potentials 
of at least 50 µV in 5 out of 10 trials. MT will be determined prior to the first treatment and weekly 
thereafter. The stimulation site for LFR over the DLPFC will be F4 of the International 10-20 System for 
Electrode Placement.  . Treatment will be delivered by a TMS technician, or by co-investigator Dr. Reti, or 
by another physician credentialed to deliver TMS at The Johns Hopkins Hospital and approved by the IRB. 
 
To determine optimal TMS treatment parameters we have reviewed the published literature reporting LFR 
rTMS for the treatment of major depression, and also rely on our own clinical experience using LFR rTMS 
to treat  patients with idiopathic depression. We also take into account that although we are excluding 
subjects at increased risk for seizure with rTMS, such as those with a history of epilepsy, abnormal EEGs 
or focal abnormality on brain imaging, our TBI study population may nonetheless be at a higher risk.  
 

 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 12 of 31 
 
Although LFR rTMS is often delivered to patients at 120% MT (consistent with FDA approval of HFL 
rTMS at 120% MT), most studies of LFR rTMS use 110% MT, which would carry a lower seizure risk 
than 120% MT. Accordingly, we will use 110% MT in our study.  Two leading TMS groups studying LFR 
rTMS as an antidepressant have used 900 pulses daily over 4 weeks78 and 1600 pulses daily over 2 weeks70 
in controlled studies. Both produce similar decreases in HAMD at their respective endpoints. Other sham-
controlled studies have demonstrated an antidepressant effect with as few as 300 – 600 pulses daily 
delivered for 2 – 3 weeks69, 74, 89. Pulses are sometimes delivered in one continuous train70,78 and at other 
times they have been delivered in several trains separated by an intertrain interval (ITI) of 30 – 
60seconds69,89,90, which could reduce seizure risk still further. We propose to deliver 1200 pulses daily at 
110% MT for 4 weeks using four trains of 300 pulses daily separated by an ITI of 60 seconds. This 
parameter set also lies well within TMS safety guidelines most recently updated in Rossi et al91.  
 
The rTMS treatment sheet will be used after each treatment to record treatment parameters, treatment 
interruption, if any, and adverse events during treatment. The form has been uploaded in the IRB 
application under Section 19 – ‘Supplemental Study Documents.. 
 
All participants will also receive supportive care. This will include education about TBI and depression and 
a discussion of the importance of maintaining structure/routine, regular physical exercise, engaging in 
hobbies and maintaining balanced/regular nutrition. Subjects who become suicidal or develop problems 
that require aggressive treatment during the course of the study will be withdrawn, and followed at the PI’s 
Brain Injury Clinic, if appropriate care can be provided on an outpatient basis. If outpatient care is not 
appropriate, the PI will be responsible for admitting subjects to the psychiatric inpatient units at either 
Johns Hopkins Bayview Medical Center or Johns Hopkins Hospital.   
 
Justification for use of Placebo: 
The post-TBI depression field is currently at equipoise regarding the efficacy of antidepressant medications 
vs. placebo. There are no studies that have done a risk-benefit assessment on the use of anti-depressants vs 
placebo in the treatment of post-TBI depression. As the proposed treatment trial duration is only 16 weeks 
and all participants will have regular follow-up visits, those receiving sham treatment will not be at a great 
disadvantage compared to those receiving active LFR  rTMS, as they will also receive regular supportive 
care. There is no evidence in psychiatric research that short-term treatment with placebo produces lasting 
harm (Addington and Quitkin 1999). However, if during follow-up visits, it is ascertained that a 
participant’s depression is worsening with development of active suicidal thoughts, the participant will be 
withdrawn from the study for more active treatment (inpatient admission vs day hospital admission vs. 
aggressive outpatient treatment with medications). Careful screening of all participants will be done and no 
one who has responded well to a particular medication in the past will be enrolled in the study. Finally, the 
study will be carefully discussed with all participants emphasizing the risks and benefits of joining the 
study. All participants will also be encouraged to talk to their physicians about the pros and cons of joining 
a placebo-controlled trial.  
In summary, the proposed study has the potential to reveal the effectiveness of LFR rTMS over placebo or 
vice-versa, underscoring the clinical utility and scientific merit of the study.  
 
Justification for use of a two arm study versus a cross-over design study:  
A cross-over design has the potential to confound study results, as the effect of rTMS  treatments may last 
considerably longer than the duration of administration, and this prolonged effect is of unpredictable and 
unmeasurable duration. For this reason, crossover designs are no longer used to assess the efficacy of 
antidepressants/rTMS in treatment of major depression in general.  As such, we do not feel it would be 
appropriate for assessing the efficacy of LFR rTMS for the treatment of post-TBI depression.   
 
Informed Consent: The PI or her research coordinator (trained by the PI) will obtain written informed 
consent of all patients recruited into the study. The details of the study, including its potential risks and 
benefits, will be discussed with all participants. As much time as necessary will be spent to obtain a written 
informed consent from each participant, including time to discuss and answer any questions regarding the 

 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 13 of 31 
 
study. Procedures for obtaining informed consent and evaluating the ability to give truly informed consent 
will follow those that have been approved by the Johns Hopkins and the DoD Institutional Review Boards 
(IRBs). Any data to be used in statistical analyses will be collected only after obtaining informed consent.     
To ensure that subjects understand the study’s purpose and procedures,  participants will be asked to 
answer the following five questions:  
 
1) Do you understand that this is a research study? 
2) Do you realize that participation in the study is entirely voluntary? 
3) Do you understand that you will be assigned to either the experimental group or the control group? 
4) Do you understand that you will have 20 treatment sessions, 5/week over 4 weeks?  
5) Do you understand that you will be followed at monthly intervals for 3 months after treatment? 
 The same procedure including the 5 questions will be used at each of the follow-up visits (4, 8 and 12 
weeks) to ensure that continual cognitive capacity to consent is maintained. 
 
The following will be made clear to all subjects interested/enrolled in the study: A Department of Defense 
(DoD) organization is funding the study;  representatives of the U. S. Army Medical Research and Materiel 
Command (USAMRMC or the DOD) are authorized to review research records; if requested, private health 
information willbe disclosed to representatives of the USAMRMC. 
 
For those subjects referred to the PI by other physicians from Hopkins, a HIPAA waiver will be obtained to 
contact them directly. Very often, the Hopkins physicians may call the PI or her research coordinator and 
provide the name and telephone number of a person that he/she believes meetsstudy inclusion criteria and 
who has given verbal consent. The PI/research coordinator will then call this patient directly to explain the 
study and invite them to participate if he/she meets the study inclusion criteria. 
 
Inclusion/Exclusion Criteria 
Adult TBI patients will be considered for the study in accordance with the following inclusion and 
exclusion criteria.  
 
Inclusion criteria: 
a) 
Adults aged 18 and over 
b) 
H/o closed head injury   
c) 
Must meet DoD criteria for mild or moderate TBI 
d) 
Time duration since injury greater than 3 months 
e) 
Must meet criteria for major depression as assessed by the Structured Clinical Interview for DSM-
 
IV  (SCID) and a score greater than 10 on the HAM-D17  
 
Exclusion criteria: 
a) 
Subjects with skull fracture 
b) 
Less than 3 months since injury 
c) 
Subjects who meet DoD criteria for severe TBI 
d) 
Subjects who are on psychotropics or mood stabilizing medications (e.g. antidepressants,
 
antipsychotics, anxiolytics, sedative/hypnotics. 
e) 
Subjects who are medically unstable  
f) 
History of active substance abuse x 1 month  
g) 
Current psychotic illness 
h) 
Evidence of frontal lesions on brain scan (including patients who have undergone surgery 
for hemorrhage or clot evacuation in the frontal lobe, and patients who have had frontal lobe 
contusions and or subdural hematoma in the frontal regions)  
i) 
Individuals with a significant neurological disorder that could increase risk for seizures  
 
such as brain tumor, cerebral aneurysm, any h/o seizures and/or family h/o seizures 

 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 14 of 31 
 
j) 
Dementia 
k) 
Mini Mental State Exam score of less than or equal to 24  
l) 
A positive and unmitigated response to any question on the Transcranial Magnetic 
 
Stimulation Safety Screen questionnaire 
m) 
ECT treatment within 6 months prior to the screening visit  
n) 
History of treatment with rTMS therapy for any disorder  
o) 
History of treatment with Vagus Nerve Stimulation (VNS) 
p) 
History of treatment with Deep Brain Stimulation (DBS) 
q) 
Cardiac pacemakers, implanted medication pumps, intracardiac lines,  
r) 
Intracranial implant (e.g., aneurysm clips, shunts, stimulators, cochlear implants, or 
 
electrodes) or any other metal object within or near the head, excluding the mouth,that 
 
cannot be safely removed.  
s) 
Implanted neurostimulators 
t) 
Known or suspected pregnancy 
u) 
Investigators, personnel affiliated with this study, and their immediate families. 
 
 
5. 
Drugs/ Substances/ Devices  
The device used in this study is a Magstim Super Rapid 2 stimulator with a focal double 70-mm air cooled 
coil, for the administration of LFR rTMS.  rTMS has been used successfully in the treatment of idiopathic 
depressive disorders, but its safety and tolerability has not been tested in patients with post-TBI depression. 
Because this is a two-arm rTMS versus sham treatment study, subjects will be randomly assigned to either 
active rTMS or sham treatment. All subjects will receive 20 treatments (active or sham) for 5 days a week 
for a total of 4 weeks.  All subjects will be brought back for follow-up visits at weeks 8, 12 and 16. 
 
Concomitant medications  
Subjects who are currently on psychotropics or mood stabilizing medications (e.g. antidepressants, 
antipsychotics, anxiolytics, sedative/hypnotics, will be excluded from the study. If subjects who otherwise 
meet inclusion criteria are on psychotropics that have not been effective and are willing to be off 
medications to participate, they will be included in study. Potential participants will only be considered for 
this study once they have been safely taken off all psychotropic medications by their treating physicians.  
Study participants will continue to receive concomitant medications necessary to treat co-morbid medical 
conditions, such as hypertension diabetes and so forth.  
The two exceptions to use of concomitant psychotropics during the course of the study is that patients may 
use trazodone up to 150 mg at bedtime as a sleep aid, and also may use up to three 0.5 or 1 mg doses of 
lorazepam for acute agitation per week during the course of the study.  
 
All participants will also receive supportive care. This will include education about TBI and depression, 
and discussion of the importance of maintaining structure/routine, regular physical exercise, engaging in 
hobbies and maintaining balanced/regular nutrition 
 
 
The rationale for choosing the device to be used. 
There is no Food and Drug Administration (FDA) approved drug for the treatment of TBI-related NPS 
symptoms/syndromes.  There are only two controlled medication trials in TBI-associated depression, and 
neither provided strong evidence that antidepressants are superior to placebo.  A major limitation of 
previous studies has been their focus on limited symptoms and use of agents with narrow therapeutic 
profiles. We propose to address some of these limitations by use of a novel non-invasive technique, LFR 
rTMS, that has the potential to induce widespread neuromodulation. 
 

 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 15 of 31 
 
Justification and safety information if FDA approved drugs will be administered for non-FDA approved 
indications or if doses or routes of administration or participant populations are changed. NA 
 
Justification and safety information if non-FDA approved drugs without an IND will be administered. NA. 
We anticipate that the Johns Hopkins IRB will classify our trial as significant risk, in which case we will 
require an IDE from the FDA. 
 
6. 
Study Statistics 
General Description     
a. Definition and selection of dataset: Intention-to-treat (ITT) will include all subjects who are randomized to 
participate in the protocol. The per-protocol (PP) population will include all subjects in the ITT population 
who meet the additional criteria of no major protocol violations and compliance with study treatment.  
Baseline demographic and clinical features, including medical comorbidity, pain, fatigue, and post-
concussive symptoms will be included in the ITT dataset.  Effect assessment will be included inboth the 
ITT and PP dataset.  
 
b. Basic exploratory analyses will first be conducted, including checking of distributional assumptions, 
assessment of relationships among covariates, and missing-value multiple imputations.  
 
c. Continuous variables will be described using means, standard deviations, medians, minimums and 
maximums, and 95% confidence intervals for parameter estimation. Graphical display (spaghetti plots) of 
the outcome scores will also be generated for 5 visits (baseline,  end of 20 LFR rTMS sessions, week 8,12, 
and 16) by group. Category and count variables will be described using frequency or proportions.  
 
d. Analyses will be conducted using STATA 11.2 (StataCorp, Texas, 2009) or R 2.13.2 (2011).  All statistical 
tests will be judged for significance based upon a two-sided p-value of less than 0.05.  
 
Primary objective: To determine the effectiveness of LFR rTMS for the symptomatic treatment of: (a) 
post-TBI depression as assessed by the Hamilton Depression Rating Scale (HAMD), Patient Health 
Questionnaire 9 (PHQ9) and the Clinical Global Impression-Improvement (CGI-I) scale; and (b) suicidal 
ideation as assessed by Beck Scale for Suicide Ideation (BSS). 
 
Hypothesis:  
a. Participants in the rTMS group (Experimental group), when compared to the sham treatment group 
(Control group) will have statistically significantly lower HAMD   PHQ 9 scores (improvement in 
depression) and higher CGI-I scores (global improvement) at the end of the active treatment period (i.e., 
after 20 sessions) and during the follow-up period (i.e., week 8, 12, and 16 follow-up).  
 
b. Participants in the rTMS group (Experimental group) compared to the sham treatment group (Control 
group) will have significantly lower scores on the BSS (i.eless suicidality  ) at the end of the active 
treatment period (i.e., after 20 sessions) and during the follow-up period (i.e., week 8, 12, and 16 follow-
up).  
 
Data Collection: The PI will be responsible for conducting comprehensive clinical evaluations on all 
subjects and for maintaining the psychiatric, medical and TBI data. rTMS and sham treatments will be 
administered by Dr. Reti, another TMS credentialed psychiatrist or the TMS technician. Data pertaining to 
treatments will be maintained by the TMS Program Coordinator. Three TMS forms ( adverse effects, 
Weekly assessment & Operator form) have been uploaded for review.  Co-investigator, Dr.McCann will be 
responsible for the sleep data and Dr. Kortte will be responsible for the cognitive data. At the end of the 
study, the PI and her research coordinator will be responsible for obtaining databases from each of the co-
investigators, and merging data into a master database.  
 
Variables and Measures: 
Demographic & Clinical Variables: Demographic information including age, gender, education level, 
vocational status, living situation, annual income and marital status will be collected as part of the baseline 
evaluation. Other pertinent clinical variables, such as cause of trauma (assault vs. motor vehicle accident), 

 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 16 of 31 
 
and litigation status will also be recorded. The VA/DoD definition of severity of TBI will be used to assess 
severity of TBI. 
 
Psychiatric Disturbances: The presence or absence of major depression and other psychiatric illness will 
be determined by administration of the Structured Clinical Interview for DSM IV (SCID-IV94). The SCID-
IV is designed to identify major Axis I DSM IV diagnoses. It is administered by a clinician and includes an 
introductory overview followed by nine modules, seven of which represent major Axis-I diagnostic classes. 
Using a decision tree approach, the SCID guides the clinician in testing diagnostic hypotheses as the 
interview is conducted. The output of the SCID is a record of the presence or absence of each of the 
disorders being evaluated, for current episode and for lifetime occurrence. It has been found to be 
diagnostically accurate and significantly better than the unstructured traditional diagnostic assessments95. 
The major mental Illness variable will be the presence or absence of any major mental illness (e.g.,  
presence/absence of major depression, presence/absence of PTSD).   
 
 
Depression: The severity of major depression will be assessed by the Hamilton Depression rating scale 
(HAM-D). This is a 17-item scale that evaluates depressed mood, vegetative and cognitive symptoms of 
depression. Its validity has been demonstrated in a number of studies and its inter-rater reliability has been 
consistently high across a number of studies96. The depression variable will be the total score on the HAM-
D with higher scores indicating the presence of more depressive symptomatology. Severity of depression 
will also be assessed using a second scale the Patient Health Questionnaire 9 (PHQ9). The PHQ9 is brief, 
and can be completed by the patient and used over the telephone. 
 
Suicide: Beck Scale for Suicide Ideation (BSS):  BSS  is a clinician rating scale administered as a semi-
structured interview that measures severity, pervasiveness, and characteristics of suicidal thoughts  and 
plans  in adults. The total score ranges from 0 to 38, with higher scores indicating more intense levels of 
suicidal ideation The internal consistency, concurrent validity, test-retest reliability and predictive validity 
has been established97.  
 
Treatment response: The Clinical Global Impression (CGI)98,99  scales are used to rate the severity of 
illness and assess response to treatment. CGI-Severity scale (CGI-S) is used to assess the severity of illness 
and CGI – Improvement scale (CGI-I) is used to assess treatment response in psychiatric patients. Both are 
7-items scale. The CGI-S ranges from 1= normal to 7 = extremely ill.. The CGI-I rates participants 
improvement from baseline: 1=very much improved; 7=very much worse. 
 
Primary Efficacy Measures: Changes in HAMD, PHQ9 and BSS;  
 
Statistical Analysis  
 
a. 
All subjects will be tracked over the study period in order to capture (1) the number subjects 
randomized to each group; (2) the number of subjects who drop-out or are lost to follow-up, and (3) the 
compliance of each subject across the study period.   
 
b. 
Baseline balance analyses: At baseline, the two groups (Experimental and Control) will be 
compared on demographic and clinical features, including medical comorbidity, pain, fatigue and post 
concussive symptoms.  
 
c. 
Effectiveness analyses: Random effects models will be used to evaluate the efficacy of the 
intervention as assessed by HAMD and PHQ9 with comparison of the slopes of the rTMS (Experimental) 
and sham treatment groups (Control). Random effects models will also be used to compare the two groups 
over time, controlling for baseline variables found to be statistically significant between the two groups, 
and the coefficient of interest, such as the interaction between time and treatment assignment. Similar 
analysis will be done for the CGI-I and BSS scores.  
 
In addition, remission rates (as defined by HAMD score ≤7 or PHQ9 = 0) and Improvement rates (as 
defined by CGI-I scores ≤2) between the two groups will be calculated using Fischer’s Exact test. 
 

 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 17 of 31 
 
Secondary Objective: To determine the effectiveness of LFR rTMS for the treatment of common co-
morbid neuropsychiatric symptoms: (a) Post traumatic stress disorder (PTSD) (b) Sleep disturbance and (c) 
Cognitive deficits.  
 
Hypothesis:  Participants in the rTMS group (Experimental group) compared to the sham treatment group 
(Control group) will have statistically significantly improvement on the: (a) Davidson Trauma Scale (DTS)  
(b) the Pittsburgh Sleep Quality Index(PSQI), theEpworth Sleepiness scale (EPS), and sleep 
polysomnogram (PSG) measures and (c) Cognitive domains including global cognitive functioning, 
memory, attention and executive function at the end of the active treatment period (i.e., after 20 sessions) 
and during the follow-up period (i.e., weeks 8, 12, and 16).  
 
Variables: 
Posttraumatic Stress Disorder: The Davidson Trauma Scale (DTS)100 will be administered to measure 
severity of post-traumatic stress disorder. This is a 17-item self-report scale. The frequency and severity of 
symptoms are reported on a 4 point scale (0=not at all; 4= everyday); distress is also rated on a 4 point scale 
with higher scores indicating more severe distress. The scale is valid, with high internal consistency 101. 
The PTSD variable will be the total score on the DTS.   
 
Subjective Measurement of Sleep Disturbance: Two different subjective sleep scales will be 
administered at the initial and all follow-up visits. At the initial visit, subjects will also be interviewed for 
their pre-TBI sleep status.  The Epworth Sleepiness Scale102 is a well validated scale to assess daytime 
sleepiness. The Pittsburgh Sleep Quality Index (PSQI)103 is a self-report questionnaire that examines sleep 
quality and disturbances in adults. It has been shown to be a valid and useful sleep disturbance screening 
measure for patients with TBI104.  
 
Objective Measures of Sleep Disturbances: Polysomnogram (PSG): Subjects’ willingness to have sleep 
studies will be evaluated at the time of the initial evaluation, and only those willing will be enrolled in the 
study.  For PSGs, participants  will be admitted to the Johns Hopkins Bayview Clinical Research Unit, 
which is a component of an Institutional Clinical Translations Research program, for 2 overnight sleep 
studies (initial study at baselineand second study at week 16).. At both of these timepoints, subjects will 
undergo standard PSGs on 2 consecutive nights.  The first PSG will be conducted for adaptation purposes. 
Only data from the second night will be used in data analyses. In summary, there will be a total of 4 PSGs, 
two pre and 2 post treatment. At both these times, the first night is adaptation night and data will not be 
used in statistical analyses. Data from the second night will be used in statistical analyses 
EEG montages used in PSGs will include 6 EEG channels. These will include frontal, central, and temporal 
electrodes with a non-mastoid linked reference to minimize non-homogeneous current flow and possible 
misinterpretation of asymmetry data.  In addition, right and left electro-oculograms will be linked to a 
single mastoid reference (EOGs), and 3 EMGs will be collected, including a bipolar submentalis EMG, and 
2 bipolar tibial EMGs and an EKG.  Respiratory function will be measured via a nasal pressure transducer 
& oral-nasal airflow thermocouple, pulse oximetry and piezoelectric abdominal and thoracic strain gauges.  
Periodic leg movement (PLM) measures will also be collected. Registered PSG technicians responsible for 
recording and scoring polysomnograms will be blinded to study hypotheses. Primary sleep PSG measures 
of interest include: sleep latency, total sleep time, time spent in each sleep stage, wake after sleep onset 
time, sleep efficiency, periodic limb movements/hr, and Apnea-Hypopnea Index. 
 
Neuropsychological Tests: All subjects will complete neuropsychological testing at two time points: 
during the baseline visit and at the 3-month follow-up visit. The test battery will be constructed to allow 
evaluation of multiple domains of cognitive functioning, including global cognitive functioning, executive 
functioning, attention, and memory (Table 6). Briefly, the raw scores on all cognitive measures will be 
converted to scaled scores using the cumulative frequency distribution of each measure. Scaled scores will 
then be regressed on age, gender, race, years of education, and estimated premorbid IQ based on the revised 
National Adult Reading Test (NART)105,106 . No additional control for education is necessary. 
 
Table 6: Neuropsychological Tests  

 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 18 of 31 
 
 
 
 
 
 
 
 
 
 
 
 
 
Behavior Problems: The Neurobehavioral Rating Scale—Revised (NBRS-R) will be used to measure 
behavioral disturbances following TBI.  The NBRS-R is a clinician-based multidimensional instrument and 
has been validated as a secondary outcome measure to assess behavior problems after brain injury107.   
 
Secondary Efficacy Measures: DTS; PSQI, EPS, PSG and cognitive measures. 
 
Statistical Analysis: Analyses will be similar to Aim1.  Random effects model will be used to compare of 
the slopes of the LFR rTMS (Experimental group) versus the sham treatment group (Control group) on the 
Davidson Trauma Scale scores.  Random effects models will also be used to compare the two groups over 
time, controlling for baseline variables found to be statistically significant between the two groups, and the 
coefficients of interest, such as the interaction between time and treatment assignment.  
 
This same statistical analysis approach will be used to compare the two groups on the sleep scales (PSQI & 
EPS) and on the primary PSG sleep variables, global cognitive functioning and memory, attention and 
executive functioning. 
 
 
Exploratory Analyses: 
The two groups will also be compared using similar statistical analyses of the NBRS-R scores.  
Additionally, a subset of subjects will also undergo MRI/DTI at baseline and at 3-month follow-up 
timepoint.  DTI measures that will be used include fractional anisotropy (FA) and mean diffusivity (MD). 
The two groups will be compared on FA and MD values obtained at baseline and at 3-month follow-up 
using t-tests and linear regression analysis. Regions of interest will include frontal and temporal regions, 
fornix, cingulate, anterior limb of the internal capsule and genu and splenium corpus callosum. 
 
 
 
 
 
Neuroimaging Analyses: As noted above, s subset of subjects will undergo MRI DTI scans pre- and post- 
LFR rTMS treatment. At the time of the initial screening,  all subjects will be assessed for MRI safety using 
the questionnaire below. A positive answer to any one of the question will exclude them from having MRI. 
Also, only subjects who definitively agree to have brain MRI will have the scan. 
 
MRI Questionnaire 
 
Please reply yes or no to the following questions.  
Do you have the following?: 
Brain aneurysm clips  
Any type of artificial heart valve  
A heart defibrillator or pacemaker  
Inner ear (cochlear) implants  
Recently placed artificial joints  
Montreal Cognitive Assessment 
Test of global cognitive functioning 
Wechsler Test of Adult Reading (WTAR) 
Pre-morbid Intelligence 
Trails B 
Test of Executive functioning 
Controlled Oral Word Association Test (COWAT) 
Test of Executive functioning 
Wisconsin Card Sorting test (WCST) 
Test of Executive Functioning 
Stroop Test  
Test of Executive Functioning 
Brief test of Attention (BTA) 
Test of  auditory attention 
Trails A 
Test of visual attention 
Hopkins Verbal learning test (HVLT) 
Verbal Memory Test 
Brief Visual Memory Test (BVMT) 
Visual Memory Test 

 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 19 of 31 
 
Any type of vascular stent  
Any metal pieces in your body or eyes  
 
 
DTI data will be acquired with a single-shot, echo-planar imaging (EPI) sequence with sensitivity encoding 
(SENSE), using a parallel-imaging factor of 2.5. The imaging matrix is 96 X 96 with a field-of-view of 212 
X 212 mm (nominal resolution, 2.2 mm), zero-filled to 256 X 256 pixels. Transverse sections of 2.2 mm 
thickness will be acquired parallel to the anterior commissure-posterior commissure line. A total of 60-65 
sections will cover the entire hemisphere and brainstem without gaps. Diffusion-weighted images at b = 
700 s/mm2 along 32 directions will be acquired in addition to five additional images with minimal diffusion 
weighting (b ≈ 33 mm2/sec). The scanning time per dataset will be approximately 4 minutes. To enhance 
the signal-to-noise ratio, this procedure will be repeated 3 times. From this, fractional anisotropy (FA) and 
mean diffusivity (MD), and eigenvalues will be calculated. In this proposal, we will perform hypothesis-
based regional analysis of the DTI-derived parameters using manual regions of interest (ROI). ROI will 
include frontal and temporal regions, the fornix, cingulate, anterior limb of the internal capsule, genu and 
splenium corpus callosum. We will also perform whole-brain analyses using a brain normalization 
technique developed in Dr. Mori's lab108. Combination of the two approaches (manual regional and 
automated whole brain analyses) will ensure the robustness and regional specificity of the ROI-based 
findings.  
 
Other Scales: Other scales described below will be used to assess medical comorbidity, pain, fatigue and 
postconcussive symptoms all of which can confound the results and will be controlled in the different 
regression analyses. 
 
Medical Co-morbidity: The General Medical Health Rating (GMHR)109 will be used to assess overall 
medical co-morbidity. The scale is simple to use and provides a rating of overall general medical health 
taking into consideration all medical problems and medications. The scores on this scale ranges from 1 
(poor; unstable medical health) to 4 (stable; excellent health). The PI has used this scale previously in her 
TBI studies. 
 
Pain: The SF-36 bodily pain scale110 will be used to assess pain. It has been found to be a valid measure of 
pain assessment.  
 
Fatigue:  The Fatigue Severity Scale111 will be used to assess the severity of fatigue. It has been used both 
clinically and for research applications, and has been used in the assessment of fatigue in neurological and 
non-neurological conditions.   
 
Post-Concussive Symptoms: As a myriad of post-concussive symptoms are present after TBI, the 
Rivermead Postconcussive Questionnaire112 will be used to determine post-concussive symptoms and 
calculate the total score.  
 
 
 
Power Analysis:  
The power calculation for this study is based on the study by Fann et al45 and our clinical experience. In the 
open labeled study of sertraline (Zoloft) for the treatment of TBI depression, Fann et al found a response 
rate (decrease in Hamilton depression scale score of > or = 50%) of 87% and remission rate (Hamilton 
depression scale score of < or = 7 at the end of treatment) of 67%.  Based on these results, we hypothesize 
improvement in symptoms on the HAMD of 60-70% in the experimental group; and based  on our clinical 
experience, we hypothesize a remission rate of 10% in the Control group.  The table (Table 7) below 
depicts sample sizes for these remission rates with various degrees of power. As this is a pilot study, we 
have chosen a sample size (N=30) that is feasible and that will allow us to complete the study in the 
allocated time. Results from this study will help us to develop future studies with larger sample sizes and 
more conservative numbers. Sample size was calculated with (StataCorp, Texas, 2009) alpha was set at 
0.05.  
 

 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 20 of 31 
 
 
 
 
Table 7: Calculation of Sample Size. 
Power Remission rate in Experimental 
group 
( control group is 0.1) 
N1 
(Experimental 
group) 
N2 
(control 
group) 
N 
(total) 
0.9 
0.7 
15 
15 
30 
0.8 
0.7 
13 
13 
26 
0.75 
0.7 
12 
12 
24 
0.7 
0.7 
11 
11 
22 
0.6 
0.7 
10 
10 
20 
0.9 
0.6 
21 
21 
42 
0.8 
0.6 
17 
17 
34 
0.75 
0.6 
16 
16 
32 
0.7 
0.6 
15 
15 
30 
0.6 
0.6 
13 
13 
26 
 
Safety and tolerability: The following safety measures will be used:  
 
1) Collection of vital signs  
 
2) Collection of adverse events/side effects. All adverse events including minor rTMS side-
effects like post-treatment headache as well as serious and unexpected adverse events like 
seizure will be recorded. All participants will be encouraged to call or page the PI if they 
notice any adverse effect or if they are concerned about any medical issues. Side effects will 
be monitored at each treatment and office visit.  
  
An Adverse Events questionnaire will be used to record study side-effects. This questionnaire will capture 
the date, visit number, adverse event description, event start date, event end date, relationship to the device, 
severity, whether it is a SAE (Serious Adverse Event), action taken and outcome, The PI and/or, Medical 
Monitor and clinical co-investigators will make decisions regarding the severity of the side-effects, the 
relationship to the device and whether or not  it a SAE.  
 
Early stopping rules:  
Subjects will be removed from the study early if it becomes clear that the risks of continuing treatment 
outweigh the benefits of continuing the study. In this research study, there is no alternative treatment other 
than treatment with LFR rTMS vs sham. If subjects are unable to complete the study, they will be either be 
absorbed in the PI’s Brain Injury clinic or referred to appropriate treatment centers, if they so desire. 
 
The following will be used to define unacceptable tolerability:  
This decision will be made by a review committee chaired by the Medical Monitor. 
 
(a) 
Clinically judged treatment-related death in one research participant. Clinically judged medication 
related death in one research participant. If a death occurs the case will be reviewed to decide if the death 
was medication related. The review committee will include Dr. Rao (PI), and members of the Data & 
Safety monitoring board:  Dr. Constantine Lyketsos, Dr. Christopher Marano and Dr. Paul Rosenberg. All 
members of the DSM board are psychiatrists and faculty Johns Hopkins University. The 3 DSM members 
are not connected with the study.  
 
Dr. Christopher Marano will also serve as the medical monitor.  He is currently involved in several clinical 
trials and therefore, is well-suited for this role.  As the medical monitor, his job will be to: (a) review and 
provide appropriate recommendations to address unanticipated problems that may arise during the study, 
and  
 

 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 21 of 31 
 
(b) if anything adverse happens during the study period, he will provide an unbiased written report to the 
Johns Hopkins IRB and Department of Defense Human Research Protection Office (DoD HRPO) within 
10 days of the event.  He will not work under the supervision of the PI or any other research staff but will 
be available to the PI and research team to address any issues that arise during the study period.  He will 
have the authority to stop the study, remove subjects from the study  and take whatever steps are necessary 
to protect the safety and well-being of research volunteers until the IRB can assess the medical monitors 
report. 
 
 
(a) Clinically judged treatment related hospitalization and/or emergency room visit in 20 % or more 
participants.  
 
(b) Drop out of the study secondary to intolerable side-effects in 30% or more of participants  
If any of the above happens, the study will be immediately terminated. 
 
If either of the above happens, the study will be immediately terminated. 
 
Otherwise, the Adverse-Events Protocol will be used to track the nature, visit time, and severity of side-
effects 
 
The PI and her research team will meet regularly to discuss the progress of the study. 
In summary, all unanticipated problems involving risk to subjects or others related to participation in the 
study will be promptly reported both to Hopkins IRB and to the USAMRMC, Office of Research 
Protections, 
Human 
Research 
Protection 
Office 
(tel:301-619-2165; 
email 
- 
hsrrb@det.amedd.army.mil<mailto:hsrrb@det.amedd.army.mil or by facsimile 301-619-7803).   
A complete written report will follow the initial notification.  In addition to the methods above, the 
complete report will also be sent to the U.S. Army Medical Research and Materiel Command, ATTN: 
MCMR-ZB-PH, 504 Scott Street, Fort Detrick, Maryland 21702-5012.”    
 
7. 
Risks    & Benefit            
As with any medical treatment, rTMS carries a risk of side effects. However, rTMS is generally well-
tolerated and only a small percentage of patients discontinue treatment because of side effects which are 
even less frequent with LFR than with HFL rTMS.  
 
During the treatment, the patient may experience tapping, facial twitching, or painful sensations at the 
treatment site during stimulation. These types of sensations are reported by about one third of patients 
receiving rTMS. In addition, about half of patients treated with rTMS experience headaches. Both 
discomfort and headaches tend to get better over time and headaches generally respond very well to over-
the counter pain medications. Because the TMS device produces a loud click with each pulse, patients must 
wear earplugs during treatment to minimize the risk of hearing loss. There have been no reported cases of 
permanent hearing loss with properly functioning hearing protection.  
 
The most serious known risk of rTMS is the triggering of a seizure. Although there have been a few case 
reports of seizures with the use of TMS devices, the risk is extremely small and even lower with LFR than 
with HFL. Moreover, patients with a personal or family history of a seizure disorder or with focal brain 
pathology will be excluded from the study. Also, the TMS stimulation parameters utilized in this trial fall 
well within established safety guidelines for the use of TMS that are designed to minimize the risk of 
seizures with this technique. 
 
As with all antidepressant treatments, there is a small risk for the emergence of mania with rTMS therapy. 
Also, rTMS therapy is not effective for all patients with depression, and there is a risk that the patient’s 
depression will get worse. Moreover, 50% of subjects in this trial will receive sham stimulation. 
There are no known adverse cognitive effects associated with rTMS therapy.  
 

 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 22 of 31 
 
TMS should not be used by anyone who has non-removable magnetic-sensitive metal in their head or 
within twelve inches of the electromagnetic coil. Objects that may have this kind of metal include: 
aneurysm clips or coils; stents in your neck or brain; implanted stimulators; cardiac pacemakers or 
implantable cardioverter defibrillator (ICD); cardiac stents; electrodes for monitoring brain activity; 
metallic implants in the ears or eyes; shrapnel or bullet fragments; facial tattoos with metallic or magnetic 
sensitive ink; other metal devices or objects implanted in or near the head. Patients with any such objects 
will be excluded from the trial.   
 
The risks of exposure to TMS in pregnancy are unknown. Therefore, women of childbearing capacity who 
are eligible for the study will be asked to take a pregnancy test and will be required to use protection during 
the study. Pregnant women will be excluded. 
 
There are no known long-term adverse effects reported with the use of rTMS. However, as this is a 
relatively new treatment, there may be unforeseen risks in the long-term that are currently unknown. 
In summary, Most common side effects of rTMS  include seizures, headache, scalp discomfort at the site of 
stimulation, tingling, spasms or twitching of facial muscles, lightheadedness, discomfort from noise during 
treatment. Less common side-effects include seizures, mania, particularly in people with bipolar disorder 
and hearing loss due to inadequate ear protection during treatment 
 
If subject experiences seizures or any of the side effects develop and become intolerable, the subject will be 
removed from the study treatment.  
 
Participants are at risk for injury from MRI if they have pacemakers, aneurysm clips (metal clips on the 
wall of a large artery) or shrapnel fragments. Welders and metal workers are also at risk for injury because 
of possible foreign bodies in the eye. The magnetic field in the scanner may make pacemakers or watches 
malfunction and may make metal objects move or be dislodged. Therefore participants will be asked to 
remove all metallic objects on their clothing or jewelry before entering the scanner room. If subjects 
become uncomfortable in the scanner, they will have an alarm system at their disposal to stop the scan 
immediately. They may also become frustrated or bored or claustrophobic during these scans. They can be 
removed from the magnet at any point in the test. 
 
Psychological risks include: worsening of depression. The research team will monitor the subject 
regularly, provide twenty-four hour access, and carefully educate the subject and caregiver about these 
risks and about when to call the research team. Subjects will be removed from the study early if it becomes 
clear that the risks of continuing treatment outweigh the benefits of continuing the study. 
 
There are risks of confidentiality regarding the results of the evaluation, which might be used to 
discriminate against the person. All patients’ files will be kept in locked cabinets. Additional confidentiality 
safeguards include: use of uniquely-coded study numbers, and maintenance of separate files of statistical 
vs. potentially identifying information. At all times, information about participants will be kept anonymous 
to study personnel other than the study staff. All members of the research team will have participated in 
human subjects training. Procedures for the protection of human research subjects will continue to be 
supervised and approved by the Institutional Review Board. Information will be disclosed whenever 
necessary only to the FDA, IRB, or the Department of Defense (DoD).. 
 
There are no known social, legal, or other risks at this time. If such risks become known, the research team 
will immediately inform all subjects. 
 
In this research study, there is no alternative treatment other than rTMS treatment. If subjects are unable to 
complete the study, they will be referred to appropriate treatment centers.  
 
Steps taken to minimize the risks: As above 
 
Plan for reporting unanticipated problems or study deviations: Any unanticipated problems or study 
deviations will be reported to Hopkins IRB and the DoD. 
 
Financial risks to the participants: There are no financial risks to the patients. 

 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 23 of 31 
 
All subjects will be instructed to call if they experience any new or worsening in symptoms. 
 
 
Benefits 
Study benefits include free comprehensive psychiatric evaluations, sleep studies and brain scans. These 
results if requested by the study participants will be made available to them. 
 
There are currently no established protocols for the treatment of post-TBI depression & comorbidities. 
Hence the results of this study will make a significant contribution to the TBI literature. Results from this 
pilot study will be used to design study with larger sample size. 
 
If the proposed rTMS treatment is found to be efficacious, it can be transferred to clinical practice for 
soldiers with TBI-associated depression and other psychiatric symptoms. rTMS has minimal long-term side 
effects and is not known to negatively interact with pharmacotherapies. rTMS has the potential to have a 
broader impact on multiple areas of life functioning and, thus, has the potential to lead to improved 
instrumental life activities, employability, community re-integration and overall quality of life. Soldiers 
with increased emotional stability and improved cognitive skills can more effectively manage stress which, 
in turn, can dramatically reduce the probability of developing disorders associated with chronic stress.  
 
The major strength of this study is that it will be the first study to determine the effectiveness of low 
frequency right-sided rTMS for the treatment of common psychiatric disturbances that often co-occur  with 
TBI. If successful, this will be a major advancement in the treatment of TBI because rTMS, has minimal 
long-term side effects and is not known to negatively interact with other drugs – important factors to be 
considered in this medically fragile population. Other unique aspects of the proposal include: (a) the use of 
a treatment strategy that is not purely symptom-based but has the potential to enhance cortical 
reorganization, increase synaptic connectivity and enable functional rehabilitation (b) the potential to study 
the pathophysiologic impact of rTMS on white matter connectivity as determined by DTI and (c) the 
possible beneficial effect of rTMS on other TBI related problems such as pain, spasticity, gait, 
coordination. Finally, if the results of the clinical trial are not positive, the study will still yield novel and 
abundant information on the nature of TBI sleep disturbance as well as anatomical correlates of TBI related 
neuropsychiatric disturbances, which have potential as diagnostic and prognostic markers 
 
8. 
Payment and Remuneration 
Subjects will be paid $54.00 for travel & snacks per visit. 
 
1000.00 will be paid to each subject for their visits and treatment ($175.00/week for each of the 4 weeks 
they get rTMS/sham treatment; $75.00 for each of the 3 follow-up visits; bonus of $75.00 at the end of 
study).   
 
In addition, they will be paid $400.00 for the overnight sleep studies ($200.00 for pre-treatment and 
$200.00 for post treatment). Subjects will have to spend 2 nights at the sleep lab, both at pre and post-
treatment (total 4 nights).  
 
The total cost per subject for 30 subjects will be $1,400 for participation and completion of study. 
Twenty five subjects will receive an additional $50.00 for the brain scan done pre-treatment and $50.00 for 
scan done post treatment.  These twenty five subjects will receive $1400.00 + $100.00 = $1500.00.  All 
payments will be by cash, as we have done in our previous  TBI studies. 
 
As per the Department of Defense (DoD) rules, active duty research volunteers cannot receive any payment 
for participation unless they are off duty or on leave during the time they are participating in the study. 
 
9. 
 Costs 
The cost of treatment (rTMs or Sham) is $70.00 per treatment. 
The cost for MRI 3T scanner for an hour of scanning =  $645.00. 
The cost for 2-overnight Polysomnography = $450.00 

 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 24 of 31 
 
 
 
 
 
REFERENCES: 
 
1. Vaishnavi S, Rao V, Fann JR (2009). Neuropsychiatric problems after traumatic brain injury: unraveling 
the silent epidemic. Psychosomatics. 50(3): 198-205.  
 
2. Deb S, Lyons I, Koutzoukis C, Ali I, McCarthy G (1999).  Rate of psychiatric illness 1 year after 
traumatic brain injury. Am J Psychiatry 156:374-378 
 
3. Koponen S, Taiminen T, Portin R, Himanen L, Isoniemi H, Heinonen H, Hinkka S, Tenovuo O (2002).  
Axis I and II psychiatric disorders after traumatic brain injury: a 30-year follow-up study.  Am J Psychiatry 
159(8): 1315-1321 
 
4. Hibbard MR, Uysal S, Kepler K, Bogdany J, Silver J (1998). Axis I psychopathology in individuals with 
traumatic brain injury. J Head Trauma Rehabil 13(4): 24-39 
 
5. Corrigan JD, Whiteneck G, Mellick D (2004). Perceived needs following traumatic brain injury. J Head 
Trauma Rehabil. 19(3): 205-16. 
 
6. Fann JR, Burington B, Leonetti A, Jaffe K, Katon WJ, Thompson RS (2004).  Psychiatric illness 
following traumatic brain injury in an adult health maintenance organization population:  Arch Gen 
Psychiatry  61(1): 53-61  
 
7. Jorge RE, Starkstein SE, Arndt S, Moser D, Crespo-Facorro B, Robinson RG (2005).  
Alcohol misuse and mood disorders following traumatic brain injury. Arch Gen Psychiatry 62(7): 742-9. 
 
8. Kreutzer JS, Seel RT, Gourley E (2001). The prevalence and symptom rates of depression after traumatic 
brain injury: a comprehensive examination. Brain Inj. 15(7): 563-76. 
 
9. Gualtieri T, Cox DR (1991). The delayed neurobehavioural sequelae of traumatic brain injury. Brain Inj. 
5(3): 219-32. 
 
10. Kessler RC, Chiu WT, Demler O, Walters EE (2005). Prevalence, severity, and comorbidity of twelve-
month DSM-IV disorders in the National Comorbidity Survey Replication (NCS-R). Archives of General 
Psychiatry  62(6): 617-27 
 
11. Jorge R, Robinson RG, Moser D, Tateno A (2004). Major depression following traumatic brain injury. 
Arch Gen Psychiatry 61, 42-50 
 
12. Wood RL, Williams C, Lewis R (2010). Role of Alexithymia and suicidal ideation after traumatic brain 
injury. J Int Neuropsychol Soc 16 (6): 1108-14 
 
13. Wilson JT, Pettigrew LE, Teasdale GM (2000).Emotional and cognitive consequences of head injury in 
relation to the glasgow outcome scale. J Neurol Neurosurg Psychiatry. 69(2): 204-9. 
 
14. Whitnall L, McMillan TM, Murray GD, Teasdale GM (2006). Disability in young people and adults 
after head injury: 5-7 year follow up of a prospective cohort study. J Neurol Neurosurg Psychiatry. 
77(5):640-5. 
 

 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 25 of 31 
 
15. Suhr JA, Gunstad J (2002). Postconcussive symptom report: the relative influence of head injury and 
depression.  J Clin Exp Neuropsychol. 24(8): 981-93. 
 
16. Marsh NV, Kersel DA, Havill JH, Sleigh JW (1998).  Caregiver burden at 1 year following severe 
traumatic brain injury.  Brain Inj  12(12): 1045-1059  
 
17. Norp A, Siert L, Lykke Mortensen  E (2010). Emotional distress and quality of life in relatives of 
patients with severe brain injury: the first month after injury. Brain Inj  24 (2); 81-8  
 
18. Jorge RE, Robinson RG, Starkstein SE, Arndt SV (1993). Depression and anxiety following traumatic 
brain injury. J Neuropsychiatry Clin Neurosci. 5(4): 369-74. 
 
19. Bay E, Donders J (2008). Risk factors for depressive symptoms after mild-to-moderate traumatic brain 
injury. Brain Inj.  22(3): 233-41. 
 
20. Rao V, Munro CA, Rosenberg P, Ward J, Bertrand M, Degoankar M, Horská A, Pham D, Yousem DM, 
Barker PB (2010). Neuroanatomical correlates of depression in post traumatic brain injury: preliminary 
results of a pilot study. J Neuropsychiatry Clin Neurosci. 22(2): 231-5. 
 
21. Ozer EJ, Best SR, Lipsey TL, Weiss DS (2003). Predictors of posttraumatic stress disorder and 
symptoms in adults: a meta-analysis. Psychol Bull. 129(1): 52-73  
 
22. Ursano RJ, Goldenberg M, Zhang L, Carlton J, Fullerton CS, Li H, Johnson L, Benedek D (2010). 
Posttraumatic stress disorder and traumatic stress: from bench to bedside, from war to disaster. Ann N Y 
Acad Sci. 1208: 72-81.  
 
23. Ehring T, Ehlers A, Cleare AJ, Glucksman E (2008). Do acute psychological and psychobiological 
responses to trauma predict subsequent symptom severities of PTSD and depression? Psychiatry Res. 
161(1): 67-75 
 
24. Mendlowicz MV, Stein MB (2000). Quality of life in individuals with anxiety disorders. 
Am J Psychiatry 157(5): 669-82. 
 
25. Olatunji BO, Cisler JM, Tolin DF (2007). Quality of life in the anxiety disorders: a meta-analytic 
review. Clin Psychol Rev.  27(5): 572-81  
 
26. Rao V, Spiro J, Vaishnavi S, Rastogi P, Mielke M, Noll K, Cornwell E, Schretlen D, Makley M (2008). 
Prevalence and types of sleep disturbances acutely after traumatic brain injury. 
Brain Inj. 2008 22(5): 381-6 
 
27. Satz P, Zaucha K, Forney DL, McCleary C, Asarnow RF, Light R, Levin H, Kelly D, Bergsneider M, 
Hovda D, Martin N, Caron MJ, Namerow N, Becker D (1998). Neuropsychological, psychosocial and 
vocational correlates of the Glasgow Outcome Scale at 6 months post-injury: a study of moderate to severe 
traumatic brain injury patients. Brain Inj. 12(7):555-67. 
 
28. Silver JM, McAllister TW, Arciniegas DB (2009). Depression and cognitive complaints following mild 
traumatic brain injury. Am J Psychiatry 166(6): 653-61 
29. Chamelian L, Feinstein A (2006). The effect of major depression on subjective and objective cognitive 
deficits in mild to moderate traumatic brain injury. J Neuropsychiatry Clin Neurosci. 18(1): 33-8. 
 

 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 26 of 31 
 
30. Rapoport MJ, McCullagh S, Shammi P, Feinstein A (2005). Cognitive impairment associated with 
major depression following mild and moderate traumatic brain injury. J Neuropsychiatry Clin Neurosci. 
17(1): 61-5. 
 
31. Schiehser DM, Delis DC, Filoteo JV, Delano-Wood L, Han SD, Jak AJ, Drake AI, Bondi MW (2011). 
Are self-reported symptoms of executive dysfunction associated with objective executive function 
performance following mild to moderate traumatic brain injury? J Clin Exp Neuropsychol. 33(6): 704-14. 
 
32. Malec JF, Brown AW, Moessner AM, Stump TE, Monahan P (2010). A preliminary model for 
posttraumatic brain injury depression. Arch Phys Med Rehabil.  91(7): 1087-97. 
 
33. Rao V, Rosenberg P, Bertrand M, Salehinia S, Spiro J, Vaishnavi S, Rastogi P, Noll K, Schretlen DJ, 
Brandt J, Cornwell E, Makley M, Miles QS (2009). Aggression after traumatic brain injury: prevalence and 
correlates. J Neuropsychiatry Clin Neurosci. 21(4): 420-9.  
 
34. Picccinelli M, Patterson M, Braithwaite I et al. (1999).  Anxiety and depression disorders 5 years after 
severe injuries: a prospective study. J Psychsom Res. 46 (5) 454-464  
 
35. Kant R, Duffy JD, Pivovarnik A (1998).. Prevalence of apathy following head injury. Brain Injury 12 
(1) 87-92 
 
36. Büki A, Povlishock JT (2006). All roads lead to disconnection?--Traumatic axonal injury revisited. 
Acta Neurochir 148(2): 181-93 
 
37. Wilde EA, Hunter JV, Newsome MR, Scheibel RS, Bigler ED, Johnson JL, Fearing MA, Cleavinger 
HB, Li X, Swank PR, Pedroza C, Roberson GS, Bachevalier J, Levin HS (2005).  
Frontal and temporal morphometric findings on MRI in children after moderate to severe traumatic brain 
injury. J Neurotrauma. 22(3): 333-44. 
 
38. Meythaler JM, Peduzzi JD, Eleftheriou E, Novack TA (2001). Current concepts: diffuse axonal injury-
associated traumatic brain injury. Arch Phys Med Rehabil 82(10): 1461-71  
 
39. McAllister TW. Neurobiological consequences of traumatic brain injury. Dialogues Clin Neurosci. 
2011;13(3):287-300. 
 
40. Niogi SN, Mukherjee PJ (2010) Diffusion tensor imaging of mild traumatic brain injury. Head Trauma 
Rehabil 25(4): 241-55  
 
41. Beaulieu C. and PS. Allen (1994). Determinants of anisotropic water diffusion in nerves. Magn. Reson. 
Med 31: 394-400. 
 
42. Pierpaoli C, Basser PJ (1996). Toward a quantitative assessment of diffusion anisotropy. Magn Reson 
Med. 36(6): 893-906. 
 
43. Rao V, Mielke M, Xu X, Smith G, McCann U, Bergey A, Doshi V, Pham DL,  Yousem D and Mori S 
(2011). Diffusion Tensor Imaging Atlas-Based Analyses in Major Depression after Mild Traumatic Brain 
Injury. Manuscript in preparation.  
 
44. Cassidy JW (1989). Fluoxetine: a new serotonergically active antidepressant. J Head Trauma Rehabil 4: 
67-69. 
 

 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 27 of 31 
 
45. Fann JR, Uomoto JM, Katon WJ (2000). Sertraline in the treatment of major depression following mild 
traumatic brain injury. J Neuropsychiatry Clin Neurosci. 12(2): 226-32. 
 
46. Rapoport MJ, Chan F, Lanctot K, Herrmann N, McCullagh S, Feinstein A (2008). An open-label study 
of citalopram for major depression following traumatic brain injury. J Psychopharmacol. 22(8): 860-4. 
 
47. Perino C, Rago R, Cicolini A et al  (2001). Mood and behavioral disorders following traumatic brain 
injury: Clinical evaluation and pharmacological management.  Brain Injury 15 (2): 139-148.  
 
48. Saran AS (1985). Depression after minor closed head injury: role of dexamethasone suppression tes and 
antidepressants. J Clin Psychiatry 46 (8): 335-338.  
 
49. Dinan TG. Mobayed M (1992). Treatment resistance of depression after head injury: a preliminary 
study of amitriptyline response. Acta Psychiatr Scand 85 (4): 292-294. 
 
50. Wroblewski BA, Joseph AB, Cornblatt RR (1996). Antidepressant pharmacotherapy and the treatment 
of depression in patients with severe traumatic brain injury: a controlled, prospective study. J Clin 
Psychiatry 57(12): 582-7. 
 
51. Gualtieri CT (1988). Pharmacotherapy and the neurobehavioral sequelae of traumatic brain injury. 
Brain Injury 2: 101-129, 1988 
 
52. Zasler ND (1992). Advances in neuropharmacological rehabilitation for brain dysfunction. Brain Injury 
6: 1-14, 1992.  
 
53. Lee H, Kim SW, Kim JM, Shin IS, Yang SJ, Yoon JS (2005). Comparing effects of methylphenidate, 
sertraline and placebo on neuropsychiatric sequelae in patients with traumatic brain injury. Hum 
Psychopharmacol.  20(2): 97-104.  
 
54. Ashman TA, Cantor JB, Gordon WA, Spielman L, Flanagan S, Ginsberg A, Engmann C, Egan M, 
Ambrose F, Greenwald B (2009). A randomized controlled trial of sertraline for the treatment of depression 
in persons with traumatic brain injury. Arch Phys Med Rehabil. 90(5): 733-40. 
 
55. Driver S, Ede A (2009). Impact of physical activity on mood after TBI. Brain Inj 23(3): 203-12.  
 
56. Bateman A, Culpan FJ, Pickering AD, Powell JH, Scott OM, Greenwood RJ (2001). The effect of 
aerobic training on rehabilitation outcomes after recent severe brain injury: a randomized controlled 
evaluation. Arch Phys Med Rehabil.  82(2): 174-82. 
 
57. Hoffman JM, Bell KR, Powell JM, Behr J, Dunn EC, Dikmen S, Bombardier CH (2010). A randomized 
controlled trial of exercise to improve mood after traumatic brain injury. PM R.  2(10): 911-9. 
 
58. Tiersky LA, Anselmi V, Johnston MV, Kurtyka J, Roosen E, Schwartz T, Deluca J (2005). A trial of 
neuropsychologic rehabilitation in mild-spectrum traumatic brain injury. 
Arch Phys Med Rehabil 86(8): 1565-74. 
 
59. Bradbury CL, Christensen BK, Lau MA, Ruttan LA, Arundine AL, Green RE (2008). The efficacy of 
cognitive behavior therapy in the treatment of emotional distress after acquired brain injury. Arch Phys 
Med Rehabil. 89(12 Suppl): S61-8. 
 

 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 28 of 31 
 
60. Topolovec-Vranic J, Cullen N, Michalak A, Ouchterlony D, Bhalerao S, Masanic C, Cusimano MD 
(2010). Evaluation of an online cognitive behavioural therapy program by patients with traumatic brain 
injury and depression. Brain Inj.  24(5): 762-72. 
 
61. Maric NP, Doknic M, Pavlovic D, Pekic S, Stojanovic M, Jasovic-Gasic M, Popovic V (2010). 
Psychiatric and neuropsychological changes in growth hormone-deficient patients after traumatic brain 
injury in response to growth hormone therapy. J Endocrinol Invest. 33(11): 770-5.  
 
62. Kant R, Coffey CE, Bogyi AM (1999). Safety and efficacy of ECT in patients with head injury: a case 
series. J Neuropsychiatry Clin Neurosci.  11(1): 32-7. 
 
63. Bashir S, Mizrahi I, Weaver K, Fregni F, Pascual-Leone A (2010). Assessment & modulation neural 
plasticity in rehabilitation with transcranial magnetic stimulation. PM R. 2010 Dec; 2(12 Suppl 2): S253-
68. 
 
64. Demirtas-Tatlidede A, Vahabzadeh-Hagh AM, Bernabeu M, Tormos JM, Pascual-Leone A (2011). 
Noninvasive Brain Stimulation in Traumatic Brain Injury. J Head Trauma Rehabil. Jun 17. 
 
65. Baeken C, De Raedt R (2011). Neurobiological mechanisms of repetitive transcranial magnetic 
stimulation on the underlying neurocircuitry in unipolar depression. Dialogues Clin Neurosci. 13(1): 139-
45. 
 
66. Huang Y, Edwards MJ, Rounis E, Bhatia KP, Rothwell JC (2005). Theta burst stimulation of the human 
cortex. Neuron  45:201-206 
 
67. Fitzgerald P, Laird A, Maller J, Daskalakis Z (2008). A meta-analytic study of changes in brain 
activation in depression. Human brain mapping 29: 683-695  
 
68. Pascual-Leone A, Rubio B, Pallardó F, Catalá MD (1996). Rapid-rate transcranial magnetic stimulation 
of left dorsolateral prefrontal cortex in drug-resistant depression. Lancet 27; 348(9022): 233-7  
 
69. Fitzgerald P, Brown T, Marston N, Daskalakis Z, De Castella A, Kulkarni J (2003). Transcranial 
magnetic stimulation in the treatment of depression: A double-blind placebo-controlled trial. Arch Gen 
Psychiatry 60: 1002-1008 
 
70. Stern W, Tormos J, Press D, Pearlman C, Pascual-Leone A (2007). Antidepressant effects of high and 
low frequency repetitive transcranial magnetic stimulation to the dorsolateral prefrontal cortex: A double-
blind, randomized, placebo-controlled trial. J Neuropsychiatry Clin Neuroscience 19: 179-186 
 
71. Garcia-Toro M, Salva J, Daumal J, Andres J, Romera M, Lafau O, Echevarria M, Mestre M, Bosch C, 
Collado C, Ibarra O, Aguirre I (2006). High (20 Hz) and low (1 Hz) frequency transcranial magnetic 
stimulation as adjuvant treatment in medication-resistant depression. Psychiatry Research: Neuroimaging 
146: 53-57  
 
72. Rosenberg P, Mehndiratta R, Mehndiratta R, Wamer A, Rosse R, Balish M (2002).  Repetitive 
magnetic stimulation treatment of comorbid posttraumatic stress disorder and major depression. J 
Neuropsychiatry Clin Neurosci 14: 270-276 
 
73. Mantovani A, Lisanby S, Pieraccini F, Ulivelli M, Castrogiovanni P, Rossi S (2007). Repetitive 
transcranial magnetic stimulation (rTMS) in the treatment of panic disorder with comorbid major 
depression. Journal of Affective Disorders 102: 277-280 

 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 29 of 31 
 
 
74. Rossini D, Lucca A, Malaguti A, Smeraldi E, Colombo C, Zanardi R (2010). A symptom-specific 
analysis of the effect of high-frequency left or low-frequency right transcranial magnetic stimulation over 
the dorsolateral prefrontal cortex in major depression. Neuropsychobiology 62: 91-97 
 
75. Hsu WY, Cheng CH, Lin MW, Shih YH, Liao KK, Lin YY (2011). Antiepileptic effects of low 
frequency repetitive transcranial magnetic stimulation: A meta-analysis. Epilepsy Research 2011; 96: 231-
240 
 
76. Dell'osso B, D'Urso N, Castellano F, Ciabatti M, Altamura AC (2011). Long-term efficacy after acute 
augmentative repetitive transcranial magnetic stimulation in bipolar depression: a 1-year follow-up study. J 
ECT. 27(2): 141-4. 
 
77. Fitzgerald P, Hoy K, Gunewardene R, Slack C, Ibrahim S, Bailey M, Daskalakis Z (2011a) . A 
randomized trial of unilateral and bilateral prefrontal cortex transcranial magnetic stimulation in treatment-
resistant major depression. Psychological Medicine 41: 1187-1196 
 
78. Fitzgerald P, Hoy K, Maller J, Herring S, Segrave R, McQueen S, Peachey a, Hollander Y, Anderson J, 
Daskalakis Z (2011b). Transcranial magnetic stimulation for depression after a traumatic brain injury: A 
case study. Journal of ECT  27:38-40  
 
79. McDonald W, Durkalski V, Ball E, Holtzheimer P, Pavlicova M, Lisanby S, Avery D, Anderson B, 
Nahas Z, Zarkowski P, Sackeim H, George M (2011).  Improving the antidepressant efficacy of 
transcranial magnetic stimulation: Maximizing the number of stimulations and treatment location in 
treatment-resistant depression. Depression and Anxiety  0:1-8 
 
 
84. Soo Cho S, Ko J, Pellecchia G, Van Eimeren T, Cilia R, Strafella A (2010).  Continuous theta burst 
stimulation of right dorsolateral prefrontal cortex induces changes in impulsivity level. Brain Stimulation 
3:170-176 
 
85. Stanford A, Sharif Z, Corcoran C, Urban N, Malaspina D, Lisanby S (2008).  rTMS strategies for the 
study and treatment of schizophrenia: A review. Int J Neuropsychopharmacology 11: 563-576 
 
86. Fitzgerald P, Benitez J, De Castella A, Daskalakis Z, Brown T, Kulkarni J (2006). A randomized, 
controlled trial of sequential bilateral repetitive transcranial magnetic stimulation for treatment-resistant 
depression. Am J Psychiatry 163: 88-94 
 
87. Vanderhasselt M, De Raedt R, Baeken C, Leyman L, D’haenen H (2006): The influence of rTMS over 
the left dorsolateral prefrontal cortex on Stroop task performance. Exp Brain Res 2006; 169: 279-282 
 
88. Borckardt J, Walker J, Branham K, Rydin-Gray S, Hunter C, Beeson H, Reeves S, Madan A, Sackeim 
H, George M (2008). Development and evaluation of a portable sham TMS system. Brain Stimulation 
1:52-59 
 
89. Pallanti S, Bernardi S, Di Rollo A, Antonini S, Quercioli L (2010). Unilateral low frequency versus 
sequential bilateral repetitive transcranial magnetic stimulation: Is simpler better for treatment of resistant 
depression?. Neuroscience  167: 323-328.  
 

 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 30 of 31 
 
90. Fitzgerald P, Hoy K, Daskalakis Z, Kulkarni J (2009). A randomized trial of the anti-depressant effects 
of low- and high-frequency transcranial magnetic stimulation in treatment-resistant depression. Depression 
and Anxiety 26: 229-234 
 
91. Rossi S, Hallett M, Rossini P, Pascual-Leone A, The Safety of TMS Consensus Group (2009): Safety, 
ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical 
practice and research. Clinical Neurophysiology 120:2008-2039 
 
92. Addington, D., Williams, R., Lapierre, Y., & el-Guebaly, N. (1997). Placebos in clinical trials of 
psychotropic medication. Canadian Journal of Psychiatry 1997, 42(3), 6. 
 
93. Quitkin, F. M. (1999). Placebos, Drug Effects, and Study Design: A Clinician's Guide. American 
Journal of Psychiatry, 156(6), 829-836  
 
94. First MB, Spitzer RL, Gibbon M. & Williams JB (1996). Structured Clinical Interview for DSM-IV 
Axis I Disorders, Clinician Version (SCID-CV). Washington, D.C.: American Psychiatric Press, Inc. 
 
95. Miller PR, Dasher R, Collins R et al: Inpatient diagnostic assessments (2001). 1. Accuracy of structured 
vs unstructured interviews. Psychiatry Res 2001,   105 (3): 255-64. 
 
96. Morriss R, Leese M, Chatwin J, Baldwin D (2008) THREAD Study Group. Inter-rater reliability of the 
Hamilton Depression Rating Scale as a diagnostic and outcome measure of depression in primary care. J 
Affect Disord  111(2-3): 204-13. 
 
97. Beck AT, Brown GK, Steer RA (1997). Psychometric characteristics of the Scale for Suicide Ideation 
with psychiatric outpatients. Behav Res Ther. 35(11): 1039-46. 
 
98. Guy W (1976). ECDEU Assessment Manual for Psychopharmacology —Revised (DHEW Publ No 
ADM 76-338). Rockville, MD, U.S. Department of Health, Education, and Welfare, Public Health Service, 
Alcohol, Drug Abuse, and Mental Health Administration, NIMH Psychopharmacology Research Branch, 
Division of Extramural Research Programs, pp 218–222 
99. Guy W (2000). Clinical Global Impressions (CGI) Scale. Modified From: Rush J, et al.: Psychiatric 
Measures, APA, Washington DC. 
100. Davidson JR, Book SW, Colket JT, Tupler LA, Roth S, David SD, Hertzberg M, Mellman T, 
Beckham JC, Smith RD, Davison RM, Katz R and  Feldman ME !997). , Assessment of a new self-rating 
scale for post-traumatic stress disorder. Psychol. Med. 27, 153–160. |  
101. McDonald SD, Beckham JC, Morey RA, Calhoun PS (2009). The validity and diagnostic efficiency of 
the Davidson Trauma Scale in military veterans who have served since September 11th, 2001. J Anxiety 
Disord 23(2):247-55. 
102. Johns MW (1991). A new method for measuring daytime sleepiness: the Epworth sleepiness scale. 
Sleep  14 (6): 540–5. 
 
103. Buysse DJ, Reynolds CF 3rd, Monk TH, Berman SR, Kupfer DJ (1989). The Pittsburgh Sleep Quality 
Index: a new instrument for psychiatric practice and research. Psychiatry Res. 28(2): 193-213. 
 
104. Fitchtenberg NL, Zafonte RD, Putnam S, Mann NR, Millard AE (2002). Insomnia in a post-acute 
brain injury sample. Brain Inj. 16(3): 197-206. 
 

 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 31 of 31 
 
105. Heaton RK, Miller SW, Taylor MJ, Grant I (2004). Revised comprehensive norms for an expanded 
Halstead-Reitan Battery: Demographically adjusted neuropsychological norms for African American and 
Caucasian adults. Lutz, FL: Psychological Assessment Resources, Inc. 
 
106. Ivnik RJ, Malec JF, Smith GE, Tangalos EG (1992). Mayo's Older Americans Normative Studies: 
WAIS--R norms for ages 56 to 97. The Clinical Neuropsychologist 6: 1-30. 
 
107. Soury S, Mazaux JM, Lambert J, De Seze M, Joseph PA, Lozes-Boudillon S, McCauley S, Vanier M, 
Levin HS (2005). The neurobehavioral rating scale-revised: assessment of concurrent validity. Ann 
Readapt Med Phys. 48(2): 61-70 
 
108. Oishi K, Zilles K, Amunts K, Faria A, Jiang H, Li X, Akhter K, Hua K, Woods R, Toga AW, Pike 
GB, Rosa-Neto P, Evans A, Zhang J, Huang H, Miller MI, van Zijl PC, Mazziotta J, Mori S (2008). Human 
brain white matter atlas: identification and assignment of common anatomical structures in superficial 
white matter. Neuroimage 43(3): 447-57  
 
109. Lyketsos CG, Galik E, Steele C, Steinberg M, Rosenblatt A, Warren A, Sheppard JM, Baker A, 
Brandt J (1999). The General Medical Health Rating: a bedside global rating of medical comorbidity in 
patients with dementia. J Am Geriatr Soc. 47(4): 487-91. 
 
110. Linde L, Sørensen J, Ostergaard M, Hørslev-Petersen K, Hetland ML (2008). Health-related quality of 
life: validity, reliability, and responsiveness of SF-36, 15D, EQ-5D [corrected] RAQoL, and HAQ in 
patients with rheumatoid arthritis. J Rheumatol. 35(8): 1528-37 
 
111. Kleinman L, Zodet MW, Hakim Z, Aledort J, Barker C, Chan K, Krupp L, Revicki D (2000). 
Psychometric evaluation of the fatigue severity scale for use in chronic hepatitis C. 
Qual Life Res. 9(5): 499-508. 
 
112. King NS, Crawford S, Wenden FJ (1995). The Rivermead Post-Concussion Symptoms Questionnaire: 
a measure of symptoms commonly experienced after head injury and its reliability. J Neurol 242:587-592