Relationship Between Attention and Emotional Regulation Post-TBI: Probing Neural Circuitry With Transcranial Direct Current Stimulation
Phase: NA
Conditions: Traumatic Brain Injury
Sponsor: NYU Langone Health

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Relationship between attention and emotional function after traumatic brain injury (TBI): 
probing neural circuitry with transcranial direct current stimulation (tDCS) 
 
I. 
PURPOSE OF THE STUDY AND BACKGROUND 
 
1. 
Purpose of the study 
The purpose of this pilot study is to investigate the relationship between attention  and 
emotional function post-TBI in an effort to better understand the cognitive mechanisms of 
emotional processing in patients with TBI, and explore novel treatment strategies to improve 
emotional regulation using tDCS to modulate activity in the dysfunctional  prefrontal-limbic 
circuits. This project will provide pilot data for extramural funding to expand on this topic. 
 
The specific aims are: 
1) To examine the relationship between alerting, orienting and executive attention and 
emotional recognition, reactivity and regulation in patients with TBI and controls. 
Hypothesis: Patients with TBI will show clear patterns of attentional and emotional impairment 
compared with controls. Deficits in executive attention will be related to deficits in emotional 
appraisal in patients.  
 
2) To determine whether anodal tDCS applied over the dorsolateral prefrontal cortex in 
conjunction with computer assisted cognitive re-training of attention will lead to greater 
improvement in attention and/or emotional regulation compared with sham-tDCS + 
cognitive re-training. Hypothesis: Patients receiving tDCS + cognitive re-training will show 
greater improvement in post-intervention measures of attention and emotional regulation. 
 
3) To determine whether resting-state activation patterns in the fronto-limbic connections 
of patients receiving tDCS + cognitive re-training show greater improvement compared 
with sham-tDCS + cognitive re-training, using functional connectivity MRI (fMRI). 
Hypothesis: Patients receiving tDCS + cognitive re-training will show higher temporal 
correlation between the frontal and limbic areas compared to baseline than patients receiving 
sham tDCS + cognitive re-training. 
 
2. 
Background and Significance 
2.1  
Cognitive, emotional and behavioral sequelae of Traumatic Brain Injury (TBI) 
According to the CDC/National Center for Injury Prevention and Control, approximately 
1.4 million individuals sustain a TBI annually in the United States, of which 235,000 are 
hospitalized and a large proportion become long-term survivors (Brown, Elovic et al. 2008). Key 
behavioral disturbances that impact life after TBI include inattention, impulsivity, unawareness 
of problems, apathy, interpersonal difficulties, communication problems, somatic difficulties, 
and difficulty with emotional adjustment (Kolitz, Vanderploeg et al. 2003). The mechanisms of 
these behavioral difficulties and the interrelationships between them are not fully understood, but 
are crucial for planning appropriate treatments to improve quality of life and reduce the societal 
burden of TBI. Cognitive disturbances following TBI have been shown to occur in the domains 
of attention, memory, and other aspects of executive functioning, and patients usually undergo 

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detailed neuropsychological testing to define the extent of these deficits (Brown, Elovic et al. 
2008). However, one recent study examined subjective and objective reports of cognitive and 
behavioral problems in fifty-four individuals 10 years after TBI and found no strong 
relationships between subjective reports of cognitive problems and test performances; much 
stronger relationships were found between subjective reports of cognitive change and emotional 
state (Draper and Ponsford 2009). The results suggest that improved understanding of the 
interaction between aspects of cognition and emotion is needed to understand and treat 
behavioral disturbances post-TBI.  
Accurate interpretation of emotion in oneself and others is critical for the successful 
negotiation of social interactions. Several studies have found that a significant proportion of 
individuals with TBI are unable to recognize and understand affective information from the face, 
voice, bodily movement, and posture of others, suggesting that they are impaired in emotional 
appraisal (Bornhofen and McDonald 2008; McDonald, Bornhofen et al. 2009). Lack of response 
to emotional stimuli is more prevalent for negative emotions, which may further accentuate the 
impact of the emotional processing deficit in social situations and contribute significantly to the 
behavioral dysfunction (Saunders, McDonald et al. 2006). In fact, difficulty  identifying 
emotions has been associated with poorer quality of life, even when depression and anxiety are 
controlled for, and has also been uniquely associated with executive function deficits (Henry, 
Phillips et al. 2006).  
 
It has also been suggested that the inability to recognize emotions may be related to 
deficits in error processing during sustained attention to response tasks (O'Keeffe, Dockree et al. 
2004), even when controlled for severity of injury (McAvinue, O'Keeffe et al. 2005). Error 
feedback has been shown to lead to improvement in emotional recognition (McAvinue, O'Keeffe 
et al. 2005), but training in focused attention and mimicry have not (McDonald, Bornhofen et al. 
2009). One recent study in a group of healthy volunteers found that individuals who had 
difficulty understanding, processing, or describing emotions (alexithymics) on the Toronto 
Alexithymia Scale (TAS-20) showed less efficient voluntary control of executive attention (Gu, 
Liu et al. 2008). Elucidating the relationships between specific aspects of attention and emotional 
processing inform the development of more effective, clinically translatable treatment strategies 
for behavioral dysfunction post-TBI.  
Behavioral assessments have been used to quantify neurobehavioral outcomes in TBI, 
among which the Neurobehavioral Rating Scale-Revised (NRS-R) has shown subsets of 
symptoms that tend to present together (Vanier, Mazaux et al. 2000; McCauley, Levin et al. 
2001). These subsets support two broadly defined clinical profiles in TBI (Zappala, Thiebaut de 
Schotten et al. 2012) - disinhibition, difficulty coping, and social inappropriateness arising from 
damage to the orbitofrontal networks of the prefrontal cortex (PFC) (Berlin, Rolls et al. 2004; 
Beer, John et al. 2006); and disinterested, unmotivated pseudo-depression arising from damage 
to the ventromedial networks of the PFC (Shamay-Tsoory, Tomer et al. 2003; Hornak, 
O'Doherty et al. 2004; Jorge, Robinson et al. 2004; Leopold, Krueger et al. 2011).The PFC is a 
crucial region for sophisticated information processing involved in social cognition and 
emotional intelligence (Forbes and Grafman 2010), and is particularly vulnerable to diffuse 
axonal injury (DAI) in TBI. While symptom classification with the NRS-R supports this 
paradigm, there is a gap in our understanding of mechanisms of emotional dysfunction after TBI 
to link recurrent patterns of behavioral symptoms to specific treatments.  

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2.2  
Diffuse Axonal Injury (DAI) leads to shearing of limbic-prefrontal circuits 
TBI is caused by rapid acceleration-deceleration of the brain inside the skull, which 
causes DAI, or disruption of axonal connections between widespread regions of the brain. 
However, the extent of DAI is difficult to quantify (Inglese, Makani et al. 2005) as it requires 
sophisticated imaging techniques that are not widely available (Cohen, Inglese et al. 2007). 
Realistic in vivo and in vitro models of TBI have been able to demonstrate that DAI, marked by 
bead-like pattern of beta-amyloid precursor protein (beta-APP) in damaged axons, leads to early 
degeneration particularly in axons of the cingulum bundle and external capsule leading to 
disconnection between the cortical and thalamic neurons with delayed apoptotic death in the 
nuclei of the limbic cortex, the seat of emotions (Dikranian, Cohen et al. 2008; Kilbourne, Kuehn 
et al. 2009). Similarly, a functional magnetic resonance imaging (fMRI) study that compared 
patterns of cortical activation in patients with cognitive impairment after TBI and controls during 
a Stroop task, showed that TBI patients showed decreased activity in the anterior cingulate 
cortex which may reflect cortical disinhibition attributable to disconnection or compensation for 
an inefficient cognitive process (Soeda, Nakashima et al. 2005). Many of the behavioral 
symptoms of TBI such as prominent impulsivity, affective instability, disinhibition, difficulties 
with substance use, sexual expression, and aggression (McAllister 1992) stem from perseverative 
behavior that can be explained by damage to the prefrontal cortex and/or disconnection between 
limbic and prefrontal circuits (Morgan, Romanski et al. 1993; Neave, Nagle et al. 1997; Sotres-
Bayon, Cain et al. 2006; Hartley and Phelps 2010). Detailed electrophysiologic and functional 
neuroimaging studies on the emotion of fear have revealed that interactions between the 
amygdala and hippocampus in the limbic system and the ventromedial prefrontal cortex 
(VMPFC) and dorsolateral prefrontal cortex (DLPFC) support the acquisition, storage, retrieval, 
and regulation of emotional memory (Sotres-Bayon, Cain et al. 2006; Hartley and Phelps 2010).    
 
2.3  
Stimulation of dorsolateral prefrontal cortex (DLPFC) and prefrontal-limbic circuit 
plasticity  
A primary goal of cognitive therapy is to enable the patient to more accurately assess a 
situation, using cognitive strategies such as emotional reappraisal, selective attention and 
reframing (Gross 1998; Gross and John 1998), in order to regulate the associated emotional 
responses (Allen, McHugh et al. 2008). In turn, successful treatment of emotional dysregulation 
(altering the emotional response) after TBI involves the employment of cognitive strategies that 
require the patient’s active engagement and cognitive reappraisal of the event (Olsson and 
Ochsner 2008; Macnamara, Ochsner et al. 2010). Functional neuroimaging studies on reappraisal 
of negative affect have consistently reported increased activation of the DLPFC and/or VLPFC 
and decreased amygdala activation (Wager, Davidson et al. 2008; Ochsner, Hughes et al. 2009; 
McRae, Hughes et al. 2010). The cognitive regulation of emotion model (Ochsner, Bunge et al. 
2002; Delgado, Nearing et al. 2008; Schiller and Delgado 2010) proposes that the DLPFC is 
involved in the effortful manipulation or interpretation of the emotional stimulus and the VLPFC 
may have a function in the selection of emotional interpretation (Wager, Davidson et al. 2008). 
The changes observed in the amygdala are thought to result from top-down modulation of the 
emotional meaning of the stimulus.  

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However, patients with TBI show reduced responsiveness to these cognitive strategies 
(McDonald, Bornhofen et al. 2009). It is possible that stimulation of the residual prefrontal-
limbic circuits may increase the efficacy of cognitive interventions for emotional regulation post-
TBI. Transcranial magnetic stimulation (TMS) and transcranial direct current stimulation 
(tDCS), particularly anodal tDCS, have been shown to increase excitability and induce long-
lasting changes in motor (Bolognini, Pascual-Leone et al. 2009; Edwards, Krebs et al. 2009; 
Reis, Schambra et al. 2009) and cognitive systems (Miniussi, Cappa et al. 2008). In one study 
that used cranial electrotherapy for emotional control post-TBI, improvement was seen on all 
negative mood factors on the Profile Of Mood States on pre-post analysis with alternating 
current cranial electrotherapy compared with sham-treated and placebo controls, with good 
tolerance and no significant adverse effects (Smith, Tiberi et al. 1994). TDCS is promising as a 
relatively simple, non-invasive and safe modality to probe the mechanisms behind cognitive 
regulation of emotion and investigate whether increasing excitability in prefrontal-limbic 
pathways, that show reduced excitability post-TBI, will enhance the responsiveness of patients to 
cognitive strategies that mediate emotional regulation.  
The rationale for neuromodulatory effects of tDCS is that at the cellular level, the effect 
of applied electricity can be considered on three levels (Gross 2007). The applied electric 
currents may (1) change the electrical state of neurons by triggering or blocking action 
potentials); (2) change neurotransmitter (e.g. glutamate, dopamine, serotonin) activity or 
neuromodulator (e.g. endogenous opioids) levels; (3) alter electrical activity within neuronal 
circuits and networks (e.g., in the complex “mood/affects/emotion regulating” network). All 
devices delivering non-invasive electrical brain stimulation consist of two components: a unit 
generating the current and at least two electrodes that enable the current to enter and to leave the 
brain. The clinical effects of brain stimulation depend on the dose of electricity delivered to the 
brain and on brain structures that are targeted (Kleiman 2004).      
 
2.4  
We will use resting state functional connectivity MRI (fMRI) to directly test the 
hypothesis that tDCS strengthens fronto-limbic connections involved in emotional 
processing. Resting state functional connectivity MRI (fMRI) is a recently evolving method 
from which functional connectivity between distant brain regions is extracted based on low-
frequency fluctuations. It allows for the identification of discrete functional networks in the 
brain. Distributed networks of brains regions have been shown to display temporally correlated 
patterns of spontaneous activation. This temporal coherence tends to occur in the brain regions 
that are anatomically connected (Zhang and Raichle 2010). Furthermore, functionally connected 
networks derived using resting state approaches mirror activation patterns found in task-based 
functional imaging studies. For clinical purposes, the strength and nature of network connections 
can be compared in clinical and healthy populations, or resting state can be used in a repeated 
measures fashion to assess changes within clinical groups. Resting state fMRI had been 
employed in a small number of studies of TBI patients to examine how network connectivity 
changes with recovery (Nakamura, Hillary et al. 2009; Hillary, Slocomb et al. 2011). 
 
3. 
Study Design. 
Forty (40) individuals status post TBI with complaints of emotional dysfunction 6 months 
post-brain injury and twenty-five (25) healthy controls will participate in the study.  We expect a 

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total of 65 subjects to enroll.   After obtaining informed consent, they will be screened to ensure 
that they meet inclusion-exclusion criteria at Visit 1. At visit 1 subjects also will be tested on 
chemosensory performance evaluation using Sniffin’ sticks test and occulomotor movement 
evaluation using King-Devick test Subjects meeting criteria will then be tested at baseline on 
neuropsychological assessments, tests of attention ( at Visit 2), and the emotional function 
battery (at Visit 3). The TBI subjects will also undergo resting-state MRI (at Visit 4). 
There will be a total of 4 testing visits (visits 1, 2 3 and 4 as described above) prior to 
starting the study, after which, subjects will receive treatment for visits 5-16).  After completion 
of treatment, the subjects will then be re-tested on the baseline assessments and resting state MRI 
(Post-intervention Visits 17, 18, 19 and 20the total amount of visits for TBI subjects will be 20.). 
Healthy Control Subjects will have a total of three testing visits   (1-3) only. 
 
The subjects with TBI will then be randomly assigned to one of two groups, each 
consisting of 10 subjects. Subjects will be randomized by a simple randomization method. They 
will have a 50/50 chance of being in either group by flipping of a coin. Randomization will be 
carried out by the PI. Subjects and study personnel performing assessments and data analysis 
will be blind to group assignment. Only the PI will be unblinded.  
The experimental group will receive active tDCS for 20 minutes and computerized 
cognitive training twice a week for 30-45 minutes for 6 weeks as described below. The control 
group will receive sham-tDCS 20 minutes and computerized cognitive training for 30-45 minutes  
twice a week  for 6 weeks (12 training sessions). The sham group will not receive real tDCS after 
completion of the study. 
In addition, we will conduct a qualitative interview with each of the subjects. Giorgi’s 
phenomenology (Giorgi 1985; Kleiman 2004) is the method that will be used to describe the 
experiences of persons undergoing tDCS for treatment of TBI.  In-person audio-taped interviews 
will be conducted at the completion visit by an experienced qualitative interviewer and 
immediately transcribed verbatim. Interviews are expected to range from 30 minutes to 1 hour.  
Each of the subjects will be asked the open-ended question, “Please tell me about your 
experience undergoing tDCS for the treatment of traumatic brain injury.”  Probes included the 
following questions:  “What was the experience like for you?  What should we continue to do 
and what should we change to make the experience better for patients?” Themes will be derived 
using the constant comparative method (Sandelowski 1995; Thorne 2000). 
 
 
II. 
CHARACTERSTICS OF THE RESEARCH POPULATION  
 
1. Number of Subjects. Forty  (40) patients with complaints of emotional dysfunction 6 
months post-brain injury between 18 and 85 years of age, and twenty-five (25) healthy 
control subjects will participate. The patients will be referred after discharge from the 
inpatient brain injury units of Bellevue Hospital and Hospital for Joint Diseases and from 
their outpatient TBI clinics, and will meet the inclusion-exclusion criteria listed below. 
 

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2. Gender of Subjects. Both male and female subjects will be included. We will attempt to 
recruit 50% of male and 50% female subjects. There will be no gender based enrollment 
restrictions.  
 
3. Age of Subjects. The age range of subjects is between 18 and 85 years. The goal of this 
study is to understand emotional dysfunction in adult patients. Individuals below the age of 
18 will be excluded from this study since pediatric TBI is relatively rare and the mechanisms 
of recovery may differ. Adults over 85 will be excluded to rule out possible confound of co-
morbid medical conditions. 
 
4. Racial and Ethnic Origin. There are no exclusions based on gender or ethnic group. 
 
5. Inclusion Criteria.  
(1) Brain Injury at least 6 months prior. 
(2) Family or self-identification of cognitive or emotional difficulties. 
(3) Unchanged and stabilized medical treatment in the three weeks prior to the screening.  
 
6. Exclusion Criteria.  
(1) Any social or medical problem that precludes completion of the protocol.  
(2) Presence of focal motor deficits in the upper extremities. 
(3) Comorbid psychiatric disease such as schizophrenia, or active substance abusers (except 
nicotine). 
(4) History of craniectomy, active infection, or seizure activity beyond 1 week post-TBI. 
(5) Complicating medical problems such as uncontrolled hypertension, diabetes with signs of 
neuropathy, and previous neurological illness such as head trauma, prior stroke, epilepsy 
or demyelinating disease, implanted neuromodulatory or electronic device, metal in head 
(6) Pregnancy 
 
7. Vulnerable Subjects. Although TBI patients have some cognitive impairment, we will only 
consent patients who have been determined to have the capacity to give consent. This 
determination will be made by Dr. Preeti Raghavan, Dr. Brian Im or Dr. Joseph Rath who are 
specialists in Brain Injury and will screen patients to determine if they are in a stable 
cognitive state, whose capacity to give consent is not expected to fluctuate.  Only such 
patients will be enrolled in the study. We will provide information to the subjects in terms 
that they can fully understand, and capacity to consent will be determined by the subject’s 
verbal understanding of the protocol as determined by the PI. We will not exert any overt or 
covert coercion, and no financial incentive will be offered. The consent document that each 
potential subject will be asked to sign will be written in the language that he or she 
understands, and will be approved by the IRB. 
 
III. 
 METHODS AND PROCEDURES 
 
1. 
Methods and Procedures. 

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Patients will sign informed consent and be required to undergo self-assessment (using the 
TIRR symptom checklist), caregiver assessment (using the Neurobehavioral Functioning 
Inventory/NFI), and clinician assessment (using NRS-R) to determine neurobehavioral status on 
study entry. Screening procedures will also include medical history and interview, review of 
medications and imaging records to ensure that participants meet inclusion/exclusion criteria. 
Screening procedures will take place at the Motor Recovery Laboratory. The following outcome 
measures will be administered at baseline and at the end of the 6-week tDCS intervention.  
 
 
1.1  
NeuroCognitive Testing 
 
Neurocognitive Domains  Neurocognitive Measures 
Premorbid Functioning  
Wechsler Test of Adult Reading (Wechsler 2001) n = 60, a = .95 Time = 10 
min 
Attention/Working 
Memory 
Trails A (Reitan and Wolfson 1985) n = 25, a = .73 Time = 3 min 
WAIS Subtest: Digit Span (Wechsler 2008) n ~ 16, a = .94 Time = 4 min 
Auditory Consonant Trigrams (Peterson and Peterson 1959) n = 20, a = .85 
Time = 10 min 
Executive Function 
Trails B (Reitan and Wolfson 1985) n = 25, a = .87 Time = 5 min 
Stroop Color-Word (Golden 1978) n ~ 300, a = .83-.91 Time = 5 min 
Information Processing 
Speed 
Symbol Digit Modalities Test (Smith 1993) n ~ 110, a = .80 Time = 5 min 
n = # items; a = alpha; Time = time to administer 
 
Premorbid Neurocognitive Functioning:  
Wechsler Test of Adult Reading (Wechsler 2001). The WTAR estimates pre-morbid 
intellectual functioning for adults (16-89 years old).  Thus, it allows for the identification of 
relative impairments by detecting discrepancies between levels of premorbid functioning and 
current functioning. This is particularly important for detecting impairment in higher functioning 
individuals, who may currently have average performance where they performed in the superior 
range premorbidly.  
 
Attention/Working Memory:  
Trails A (Reitan and Wolfson 1985) is a test of attention and complex visual scanning with a 
psychomotor speed component. Trails A requires individuals to connect randomly arranged 
numbers sequentially from lowest to highest number. Like many attention and motor speed 
measures, Trails A is sensitive to cognitive decline. 
Digit Span (Tulsky, Zhu et al. 1997) requires the respondent to recall digits forward and 
backward and is used to measure working memory. Although forward span usually remains 
stable and resistant to brain disorders  (Lezak, Howieson et al. 2004), individuals with diffuse 

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damage (e.g., mild TBI) can have mental tracking difficulties and those with more severe TBI 
can perseverate from previous items (Ruff, Evans et al. 1986). However, backward span is more 
sensitive to brain disorders, particularly diffuse damage which is characteristic of TBI (Fork, 
Bartels et al. 2005).   
Auditory Consonant Trigrams (Peterson and Peterson 1959) is a test of information processing 
and divided attention. Three consonants are presented to the individual, who must remember 
them after intervals of 0, 9, 18 and 36 seconds. During intervals, the person is required to count 
backwards aloud by threes from different starting points. The task captures everyday experience 
of momentary distraction and subsequent loss of recently learned information and can identify 
dysfunction following mild neurological changes (Boone 1999).   
 
Executive Function:  
Stroop Color-Word Test (Golden 1978) is a measure of selective attention, verbal processing 
speed, cognitive flexibility and response inhibition. Poor performance on the Stroop has been 
found to be associated with frontal systems dysfunction secondary to closed head injury 
(Trenerry, Crosson et al. 1989). The test is a good discriminator between individuals with TBI 
and controls (Asikainen, Nybo et al. 1999; Bate, Mathias et al. 2001; Wallesch, Curio et al. 
2001). 
 
Trails B (Reitan and Wolfson 1985) is a speeded test of attention, sequencing, mental flexibility, 
visual search and psychomotor speed. The participant draws lines connecting alternating circles 
with numbers and letters in sequence. Speed of performance on Trails B is considered to be 
vulnerable to the subtle cognitive effects of TBI (Lezak 1995; Rasmusson, Carson et al. 1996) . 
Test-retest reliability over two weeks was reported as .44 in a non-disabled sample and .67 in 
people with disabilities. Trails B errors are considered valid measures of dorsolateral prefrontal 
dysfunction (Stuss and Levine 2002).  
 
Information Processing Speed:  
 
Symbol Digit Modalities Test (Smith 1993) is used to measure visual scanning, tracking and 
motor speed, and it is sensitive to subtle cognitive impairment. A score below 1.5 standard 
deviations below the mean is indicative of cerebral dysfunction. Performance declines are 
observed with increasing age, demonstrating that cognitive changes could be detected with this 
measure. This test is sensitive to brain injury (Lezak 1995; Spreen and Strauss 1998).  
 
Attention Network Test-Revised (ANT-R): The ANT-R is a computerized half-hour test that 
provides a measure of the efficiency of the attentional networks involved in alerting, orienting 
and executive attention, three aspects of attention that have been shown activate anatomically 
distinct networks in the brain and are differentially innervated by neuromodulatory systems (Fan, 
McCandliss et al. 2005). The components of attention described by the ANT encompass the 
clinical modules  such as focused, sustained, selective, alternating, and divided attention 
(Sohlberg and Mateer 1989), but are better suited to understand the underlying mechanisms. 
Alerting describes the function of tonically maintaining the alert state and physically responding 
to a warning signal (similar to sustained attention or vigilance), and activates thalamo-cortical 
networks involving anterior and posterior cortical sites. Efficiency of the alerting network is 

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examined by changes in reaction time (RT) resulting from a warning signal. Automatic and 
voluntary orienting are involved in the selection of information among multiple sensory inputs 
(similar to focused attention), and activate the parietal cortex and frontal eye fields. Efficiency of 
orienting is examined by changes in RT that accompany cues indicating where the target will 
occur. Executive attention describes a set of more complex operations that include detecting 
and resolving conflicts in order to control thoughts or behaviors (encompasses selective, 
alternating and divided attention), and activates the anterior cingulate along with several other 
brain areas. The efficiency of the executive network is examined by requiring the subject to 
respond by pressing two keys indicating the direction (left or right) of a central arrow surrounded 
by congruent, incongruent or neutral flankers. However, the three networks are also integrated 
and interact during functional tasks (Fan, Gu et al. 2009).   
 
Moss Attention Rating Scale (MARS): The Moss Attention Rating Scale (MARS) is a recently 
developed clinical measure of attention deficits for patients with TBI in the acute inpatient 
rehabilitation setting (Whyte, Hart et al. 2008). It involves ratings of observed patient behavior 
by rehabilitation professionals such as nursing staff, occupational therapists, speech therapists 
etc. The items on the MARS measure deficits in three distinct subcomponents of attention: 
restlessness/distractibility, sustained/consistent attention, and initiation. Restlessness/ 
distractibility is defined as the ability to inhibit preservative, restless, or irrelevant responses 
(similar to executive attention on the ANT-R), sustained/consistent attention is defined as the 
ability to sustain attention and persist on tasks (similar to alerting on the ANT-R), and initiation 
is defined as the ability to initiate a task without cueing (similar to orienting on the ANT-R). This 
scale will be completed by the PI or her delegates during the visit.  
 
Sniffin’ Stick test: Sniffin’ sticks is a nasal chemosensory performance evaluation test using pen 
like odor dispensing devices which was introduced by Kobal et al. It comprised three subsets 
namely an odor identification test, an odor discrimination test, and a test for olfactory threshold. 
The screening 12 test used in our experiment is a smell identification test with 12 different 
everyday smells. The patients will name the smells using a multiple choice form which offers 
four definitions for each pen, among which only one choice would be correct. Chemosensory 
impairments are common after traumatic brain injury occurring in about 20 percent of patients 
depending on the mechanism of injury. This test can be used to estimate whether a TBI subject 
has normal or reduced olfactory capacity and also can be used to understand the relationship 
between olfactory dysfunction and emotional dysregulation. 
 
King-Devick Test: King-Devick test is an objective way of measuring visual tracking and 
saccadic eye movements. It is based on the identification of impaired eye movements and 
saccades which indicates a suboptimal brain function. The subjects are asked to read out the 
numbers aloud on three different cards from left to right as quickly as possible without making 
any errors. The final score is the sum of the three test card scores. The charts become 
progressively difficult form the first to the third.  It can be used as a good visual screening test in 
addition to other test in patients with traumatic brain injury. Deficiency of saccadic eye 
movements can be an indicator of mild traumatic brain injury or concussion injury.  
 

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1.2  
Emotional Function Testing 
Toronto Alexythimia Scale (TAS): Alexithymia refers to the condition of having trouble 
identifying and describing emotions, and minimizing emotional experience while focusing 
attention externally. The TAS is a well-validated and commonly used 20-item instrument to 
measure alexithymia. It is a self-reported scale with 3 subscales: describing emotions, identifying 
emotions, and externally-oriented thinking; each item is rated using a 5-point Likert scale 
whereby 1 = strongly disagree and 5 = strongly agree. The total alexithymia score is the sum of 
responses to all 20 items, while the score for each subscale factor is the sum of the responses to 
that subscale: equal to or less than 51 indicates non-alexithymia, equal to or greater than 61 
indicates alexithymia. Scores of 52 to 60 indicate possible alexithymia. The scale demonstrates 
good internal consistency (Cronbach’s alpha = .81) and test-retest reliability (.77, p<.01). 
Research using the TAS-20 demonstrates adequate levels of convergent and concurrent validity. 
The 3 factor structure was found to be theoretically congruent with the alexithymia construct. In 
addition, it has been found to be stable and replicable across clinical and nonclinical populations 
(Bagby, Parker et al. 1994; Bagby, Taylor et al. 1994). 
Emotional Function Battery 
For a comprehensive objective measurement of emotional function, we will employ paradigms 
from basic affective science to comprehensively assess multiple aspects of emotional function, 
including emotional recognition, reactivity, and regulation in an ecologically valid manner using 
film clips (Werner, Roberts et al. 2007; Goodkind, Gyurak et al. 2010). 
 
a. Emotional Reactivity: Patients will view a series of short (~3 min.) film clips that have been 
selected for their ability to produce particular positive and negative emotions (Gross and 
Levenson 1993; Gross 2007). During each film, physiological responses will be measured and 
facial behavior will be coded. Following each film clip patients will be asked to provide 
subjective ratings of the nature and intensity of their emotional responses to the film clips. Film 
clips intended to induce happiness, sadness, fear, and neutral emotion will be used.  
 
b. Emotion Recognition: Following each of the reactivity film clips described above, 
participants will also be asked to identify how the characters in the clips were feeling. Answers 
will be scored based on predetermined correct responses. We will also use picture stimuli to 
sample a broader range of positive and negative emotions for patients to identify. 
 
c. Emotional Regulation. Both instructed and uninstructed (or spontaneous) emotion regulation 
will be assessed. Physiological, behavioral and subject responses will be measured under several 
conditions. Patients will watch films that are known to produce the emotion of disgust under 
three different instructional conditions: suppress, amplify, no regulation (Gyurak, Goodkind et 
al. 2012). The emotion of disgust will be used because it is highly arousing and one of the easiest 
emotions to elicit in the laboratory context. The instructions for each condition are based on 
previous research, are as follows: “We will now be showing you a short film clip. It is important 
to us that you watch the film clip carefully. (Suppress: “Watch the film clip carefully. If you 
have any feelings as you watch the film clip, please try your best not to let those feelings show." 

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Amplify: “Watch the film clip carefully. If you have any feelings as you watch the film clip, try 
your best to let those feelings show." No regulation: “Watch the clip carefully”). 
 
Startle responses 
Startle probes have been used previously as reliable indicators of emotional reactivity and 
regulation. At the end of the experimental session, we will administer the following startle 
probes: 
 
a. Unwarned Startle. Emotional reactivity will also be assessed in response to an unwarned, 
high intensity (115 dB, 100ms) acoustic startle that sounds like a gunshot going off behind the 
head. The response to this probe consists of two reactions, starting with the primary defensive 
response, which includes a sequence of motor responses to protect the body(eye closure, 
shoulder raise) as well as increased electrodermal activity (Ekman, Levenson et al. 1983). The 
secondary response involves an emotional reaction to the primary startle. The high intensity 
acoustic startle taps into very basic, low-level aspects of defensive reactivity that are largely 
brain-stem mediated, as well as more complex aspects of emotion response as individuals reflect 
on their primary reaction (a typical secondary response includes behavioral displays and self-
reports of embarrassment/amusement) (Sturm, Rosen et al. 2006). The simple startle probe also 
offers the advantage of being a reliable elicitor of response across individuals and being a highly 
controlled and easily standardized stimulus. Physiological, behavioral, and subjective responses 
to the unwarned startle will be assessed. 
 
b. Uninstructed Emotion Regulation (anticipated startle). The startle task described above 
will be repeated, but this time participants will be warned that they will be startled again. A 20-
second countdown will signify exactly when the startle will occur. Previous research has shown 
that people typically “brace” themselves during the countdown and spontaneously recruit 
regulatory strategies to control their reactions.  
 
1.3 
Quality of Life Measurements 
Quality of Life will be measured with the Quality of Life Enjoyment and Satisfaction 
Questionnaire – Short Form (Q-LES-Q – SF), a 16-item scale that measures general well-being 
and, is among the most frequently used outcome measures in psychiatry research (Endicott, Nee 
et al. 1993 ). The internal consistency and test–retest coefficients were 0.9 and 0.93, respectfully. 
Almost all items significantly correlate to the total score and other measures used in the study, 
with the correlations ranging 0.41–0.81. The responsiveness parameters indicate Q-LES-Q – SF 
is 80% sensitive and 100% specific. The psychometric properties of the questionnaire indicate 
that it can produce reliable and valid clinical assessments of quality of life (Stevanovic 2011). 
 
1.4 
Resting functional connectivity MRI 
 
T1- and T2-weighted anatomic images will first be obtained to identify focal lesions. 3D 
magnetization prepared rapid acquisition gradient echo (MPRAGE) will be used to produce 
reference images of overlying resting state fMRI activation maps. To capture resting state 
images, subjects will be instructed to keep their eyes closed and to remain motionless in the 
scanner. Whole-brain images will be collected using a T2-weighted gradientech echoplanar 

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imaging sequence (repetition time_3000 ms, echo time_35 ms, number of slices_35, slice 
thickness_4 mm, matrix size_128_128, and field of view_220_220 mm) on a 3T scanner. 
 
1.5 
Intervention with active and sham tDCS and computerized cognitive re-training  
 
After providing informed consent approved by the IRB of New York University School 
of Medicine (NYUSoM), all patients will undergo testing with the above listed outcome 
measures. They will then be randomized into the two intervention groups, the groups being (1) 
tDCS + cognitive re-training, and (2) sham tDCS + cognitive re-training.  The intervention will 
be carried out for 20 minutes twice a week for 6 weeks during which the subjects in each group 
will be engaged in re-training using visual cognitive re-training software programs for 30-45 
minutes during each session (www.positscience.com). These re-training programs have been 
used in patients with TBI and have been shown to be effective (Fisk, Novack et al. 2002; 
Calvanio, Williams et al. 2004; Novack, Banos et al. 2006). Cognitive re-training will thus be 
individualized to each patient’s cognitive level, but still be systematic, and will not need direct 
one-on-one supervision by a neuropsychologist.  
 
Transcranial direct current stimulation will be delivered by 
trained study personnel using the saline-soaked pair of surface sponge 
electrodes (35 cm2) delivered by a specially developed, battery-driven, 
constant direct current stimulator (Fisher Wallace Cranial Stimulator, 
Fisher Wallace Laboratories, New York) with a maximum output of 4 
mA (Fig. 1). FDA approval: The Cranial Stimulator is an FDA cleared 
device indicated for application of electrical stimulation to a patient’s 
head to treat insomnia, depression, or anxiety.  TBI subjects experience 
insomnia, depression and anxiety and all subjects enrolled in this study 
will have some combination of these problems. The purpose of this 
study is to understand the mechanisms behind the depression, anxiety and insomnia that patients 
with TBI experience. The hypothesis is that emotional dysregulation contributes to the 
symptoms. This device will therefore be used in alignment with FDA clearance indications. To 
stimulate the DLPFC, the anode electrode will be placed over F3 according to the 10–20 
international system for EEG electrode placement (Fregni, Boggio et al. 2005) (Fig.2). The 
cathode will be placed over the contralateral supraorbital area.  
We will focus our investigations on the left DLPFC, as 
modulation of this area by tDCS has been shown to enhance 
working memory (Fregni, Boggio et al. 2005) which also 
demands similar attentional resources as emotional control 
(Anderson and Knight 2010). A constant current of 2 mA 
intensity will be applied for 20 min. Patients will feel the current 
as an itching sensation at both electrodes at the beginning of the 
stimulation. For sham stimulation, the electrodes will be placed 
in the same position; however, the stimulator will be turned off 
after 5 seconds (Siebner, Lang et al. 2004) so that patients will 
feel the initial itching sensation in the beginning, but receive no 
current for the rest of the stimulation period; this procedure has 
Fig.1. FDA approved 
Fisher Wallace 
Cranial Stimulator. 
Fig.2. Placement of electrodes 
(Rosa and Lisanby 2012).  

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been used to blind patients to the stimulation condition (Nitsche, Liebetanz et al. 2003; Nitsche, 
Schauenburg et al. 2003). 
 
2. 
Data Analysis and Data Monitoring. 
Power Analysis: This is a pilot feasibility study hence sample size is small and arbitrary. Power 
analysis from these pilot data will be used to determine sample size in future studies. Subjects 
with TBI will be randomized to the 2 treatment groups n=10 in each group.  
Data Analysis: 
1) To examine the relationship between alerting, orienting and executive attention and 
emotional recognition, reactivity and regulation in patients with TBI and controls. 
Hypothesis: Patients with TBI will show clear patterns of attentional and emotional impairment 
compared with controls. Deficits in executive attention will be related to deficits in emotional 
appraisal in patients.  
 
Scoring of emotional recognition, reactivity and regulation: 
1) Emotional reactivity film clips: Physiological responses (cardiac inter-beat, finger pulse 
amplitude, finger pulse transmission time, ear pulse transmission time, and respiration 
period) will be recorded, and input from baseline will be subtracted from input across the 
most intense segment of the clip. Data will be combined into a single aggregate score for 
each diagnostic group to increase reliability and reduce noise; aggregate scores of patients 
and controls will then be compared. Facial behavior will be recorded and coded for displays 
of the target emotion across the most intense segment of the clip; data from patients and 
controls will then be compared. 
2) Emotional recognition: Responses to emotion recognition questions, using both the 
reactivity film clips described above and picture stimuli will be recorded and coded; coded 
data from patients and controls will be compared. 
3) Emotional regulation with disgust videos: For the three conditions, physiological 
responses (as described above) will be recorded, and input from baseline will be subtracted 
from input across the most intense segment of the clip. Facial behavior will be recorded and 
coded. Data from patients and controls will be compared. 
For coding facial behavior, coders will be blind to the diagnostic status of the participant and 
code videos with sound muted; coding will be assessed for inter-rater reliability 
 
Pearson's correlation analysis will be performed to examine the relationship between reaction 
time (RT) scores indicating alerting, orienting and executive attention on the ANT-R and 
emotional recognition, reactivity and regulation scores. Differences in patients and controls will 
be computed. We will also correlate the clinical scores on the MARS with the ANT-R and the 
TAS-20 scores with the emotional battery scores. We expect that deficits in selective or 
executive attention will be related to deficits in emotional appraisal in the patients. 
 

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2) To determine whether anodal tDCS applied over the dorsolateral prefrontal cortex in 
conjunction with computer assisted cognitive re-training of attention will lead to greater 
improvement in attention and/or emotional regulation compared with sham-tDCS + 
cognitive re-training. Hypothesis: Patients receiving tDCS + cognitive re-training will show 
greater improvement in post-intervention measures of attention and emotional regulation. 
 
A 2 (condition) x 2 (pre and post session) repeated measures ANOVA with a priori orthogonal 
contrasts will be performed on the variables related to executive attention and emotional 
appraisal to determine whether there is a difference both within and between groups. This 
analysis will also provide data for power analysis to determine the sample size for subsequent 
interventional studies. We expect that patients receiving tDCS + cognitive re-training will show 
greater improvement in post-intervention measures of attention and emotional regulation.   
 
3) To determine whether the tDCS intervention produces stronger functional connectivity 
between fronto-limbic networks compared with sham-tDCS. Hypothesis: Patients receiving 
tDCS + cognitive re-training will show higher temporal correlation between the frontal and 
limbic areas compared to baseline than patients receiving sham tDCS + cognitive re-training. 
 
Analyses of the resting state fMRI images will be performed using AFNI and FSL software 
packages (www.fmrib.ox.ac.uk/fsl/) using standard procedures. The images will be slice-time 
corrected, despiked, and motion corrected using AFNI, and time series detrending will be 
performed. The Brain Extraction Tool (Smith 2002; Smith, Jenkinson et al. 2004; Woolrich, 
Jbabdi et al. 2009) (BET) will be used to skull strip the images, which will be spatially smoothed 
using a Gaussian kernel. In the first stage analysis, data from each subject will be individually 
modeled. The stimulus time course will be convolved with a gamma function and the general 
linear model (GLM) will be employed with motion parameters as covariates. Additionally we 
will use temporal bandpass filtering (0.01 Hz < f < 0.1Hz), regression of the six motion 
parameters and of white matter and cerebrospinal fluid signals. Average resting state time series 
will be obtained for all the seeds of interest, particularly in the cingulate motor cortex, and 
dorsolateral premotor cortex based on prior studies.(Marshall, Zarahn et al. 2009) FSL FEAT 
will be employed to find the brain voxels that correlate with the seed time series in each subject. 
Individual functional connectivity maps will be registered to the MNI space and entered into 
group-level analyses. Higher level analyses will be carried out using FEAT. Connectivity 
patterns pre- and post-treatment will be compared for all the seeds of interest. Gaussian random 
field theory will be used for cluster-level multiple comparisons correction (minimum Z > 2.3; p < 
.05, corrected) for the resting state analyses. 
 
Data Monitoring: The PI will be overall responsible for data monitoring.  
 (1) Types of Data or Events: All accumulated outcome data, enrollment numbers, reportable 
event data (including adverse reactions and unanticipated problems) and overall compliance with 
the protocol will be monitored. 
(2) Responsibilities and roles for gathering, evaluating, and monitoring the data: The PI will be 
responsible for monitoring the data collected, including data related to adverse events and 

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unanticipated problems. Accuracy of data collection from assessments at the Motor Recovery 
Laboratory will be verified on an ongoing basis and at weekly lab meetings. Compliance with the 
protocol will be verified by the PI and co-investigators. Independence of judgment will be 
assured by using independent assessors for outcomes. 
(3) Reporting adverse events and unanticipated problems to the monitoring entity: Any adverse 
reaction to the assessment procedures or intervention procedures, although expected to be 
minimal, will be reported to and compiled by the PI and Co-PI jointly on an ongoing basis. 
Reportable events will be reported by the PI to the IRB at NYU Medical Center within 5 
business days. 
(4) Assessments: Assessments will be performed on a quarterly basis to review and assess all the 
data or events captured under the Data Monitoring Plan to examine any "unanticipated problems 
involving risks to participants or others" (i.e., as to whether they are unexpected, related to the 
research, or harmful). 
(5) Criteria for action: If significant research-related and harmful adverse events are found at the 
quarterly assessments, the study will be terminated. 
(6) Procedures for communicating; dissemination of safety information: Outcomes of monitoring 
entity reviews will be communicated to the IRB at NYU Medical Center annually unless there 
are reportable adverse events or criteria for action. 
3. 
Data Storage and Confidentiality. Data from assessments at the Motor Recovery 
Laboratory will be stored securely in the PI's office,, at the Rusk Institute of Rehabilitation 
Medicine, NYU Medical Center. All data will be labeled by subject codes only, and stored on 
password-protected computers and/or in locked filing cabinets in the secure offices of the PI. 
Videotapes of the assessments will be stored on password-protected computers and servers, and 
backed up on DVDs stored in locked cabinets, in the secure offices of the PI. Videotapes will be 
stored for at least 3 years following the conclusion of the study, and may be stored indefinitely 
thereafter. Data collection computers will be in locked, fixed locations (no mobile laptops), 
password protected, and on local networks. Only the PI and her HIPAA certified delegates will 
have access to the data.  
 
4. 
Data Stored for Future use: Data will be labeled with unique codes.  Only the PI and 
the study coordinator will have access to the code.  This information will be stored in a password 
protected shared network drive. There are currently no plans for future research. However new 
questions may come up from this study that may be addressed by reanalyzing the collected data.  
If patients specifically request to withdraw their data from the data stored for future use, they 
must do so in writing, which will be kept on file. Their data will be segregated from the rest of 
the data and not used for future analysis. However it will be stored for analysis of the present 
study and as per rules of publication, for at least 7 years post-publication.   
 
IV.  RISK/BENEFIT ASSESSMENT  

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1. Risk. TBI subjects may fatigue easily. We will ensure that subjects are given adequate rest 
breaks to prevent them from becoming fatigued during the experimental protocol. Each 
testing session will not last longer than 3 hours on a single day. The assessments and 
videotapes may pose risks to confidentiality which will be minimized by following the 
protections below. The emotional function videos will assess physiological responses to 
neutral, happiness, sadness, fear and disgust-inducing video clips which mimic everyday 
experiences which may produce these emotions. The unwarned startle probe may be 
emotionally distressing. If a previously undetected, potentially significant medical problem is 
observed, the subject will be informed of it by the-PI by phone so that the matter may be 
investigated further with the subject's regular physician. 
Transcranial Direct Current Stimulation (tDCS), a non-invasive neuromodulatory 
technique that alters neuronal excitability using a low direct current delivered to the frontal 
cortex with saline-soaked sponge scalp electrodes. TDCS modulates the firing rates of 
individual neurons, and influences dopaminergic, adrenergic, and serotoninergic neural 
circuits (Boggio, Rigonatti et al. 2008; Nitsche, Boggio et al. 2009). tDCS utilizes low 
intensity direct current, which is known to have anti-seizure effects. Reversing the 
pathological alterations back to normal with tDCS presents a potential therapeutic option for 
persons with cognitive and emotional dysfunction post-TBI. Past research has demonstrated 
that tDCS safely improves depression in a general psychiatric population (Boggio, Rigonatti 
et al. 2008) and holds promise as a highly innovative therapy that may result in a substantial 
quality of life improvement in patients with TBI. Six weeks after the completion of tDCS 
treatment, its effects were still sustained and significant. Transcranial direct current 
stimulation will be provided by a saline-soaked pair of surface sponge electrodes (35 cm2) 
delivered by a FDA-approved battery-driven, constant current stimulator (Fisher Wallace 
Cranial Stimulator, Fisher Wallace Laboratories, New York). Major safety parameters of 
electrical stimulation utilizing direct current (as opposed to devices producing alternating 
current) are Current Density {A/cm2} = stimulation strength {A}/electrode size {cm2} X 
total stimulation durations(s) (Nitsche, Liebetanz et al. 2003).  Therefore these major 
parameters of safety are determined by the size of the electrodes, the intensity of the current 
and the duration of the stimulation.  A comprehensive review by Sundaram and colleagues 
(2009) evaluated ass existing tDCS protocols involving human subjects from the perspective 
of aforementioned safety limits. Potentially damaging value of Current Density is 25 
mA/cm2, while existing tDCS protocols deliver Current Density ranging between 0.02-0.08 
mA/cm2, well within safety limits.  Potentially damaging value of Total Carge is 216C/cm2, 
while existing protocols deliver 0.002-0.068C/cm2, which is a well-within safety limit. The 
parameters of stimulation in our study will be: size of electrodes 36 cm2, intensity 2mA, 
stimulation time 20 min per sessions, which translates into Current Density 0.08 mA/cm2 
and Current Density 0.08 mA/cm2 and Total Charge 0.068 C/cm2, which is in concordance 
with parameters of other tDCS studies and well within the safety limits.  
 To stimulate the DLPFC, the anode electrode will be placed over F3 according to the 
10–20 international system for EEG electrode placement (Fregni, Boggio et al. 2005). The 
cathode will be placed over the contralateral supraorbital area. We will focus our 
investigations on the left DLPFC, as modulation of this area by tDCS has been shown to 

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enhance working memory (Fregni, Boggio et al. 2005) which also demands similar 
attentional resources as emotional control (Anderson and Knight 2010). A constant current of 
2 mA intensity will be applied for 20 min. These stimulation parameters have been used in 
other tDCS studies (Fregni, Boggio et al. 2006; Fregni, Boggio et al. 2006; Stevanovic 2011), 
and have been shown to produce effects outlasting the stimulation, well within safety limits 
[see detailed review in (Stevanovic 2011)]. To date, the above described stimulation 
parameters have not elicited any treatment-related serious adverse events. Non-serious 
adverse events infrequently occurring in tDCS studies (Poreisz, Boros et al. 2007) include 
short-term headache, transient fatigue or disturbed sensation under electrodes during the 
stimulation, such as mild tingling, itching or mild burning that is a natural sensation related 
to low-intensity current passing through the scalp. The sensation typically disappears 
immediately after the tDCS stimulation. Further, tDCS has not presented with any potentially 
harmful pharmacological interactions (Nitsche and Paulus 2001; Poreisz, Boros et al. 2007). 
Thus study participants receiving tDCS maintain their usual pharmacological regimen.  
Patients having brain scans as part of the research study may feel claustrophobic from 
lying in the magnetic tube. There is risk of injury if there are metal objects in the body. 
Subjects will be required to fill out a questionnaire indicating if this is true. The subjects will 
be told that they may hear loud noises while in the MRI machine. The distress will be 
minimized by providing the subjects with ear plugs and limiting the duration of time in the 
MRI machine to less than 30 minutes. The research MRI scans will be read by the 
investigators within one week of the exam. If a previously undetected, clinically significant 
finding is observed the subject will be notified by the PI by phone so that the matter may be 
investigated further with the subject’s regular physician.  
 
Protection against Risks. Potential risks and discomfort will be minimized to the greatest 
extent possible through such procedures as appropriate training of personnel and monitoring 
of subjects. Subjects may take rest breaks as needed during therapy and assessment sessions 
so that the risk of fatigue is minimized.  
In order to minimize any emotional distress, we will explain to the subjects that they may 
become upset so that they are forewarned. We will explain that the emotional stimuli are 
similar to everyday experiences that evoke emotional responses. The examination of 
emotional reactivity and the treatment included in the study will examine how well they cope 
with real-life situations that may be upsetting to them. In case of any adverse event or 
difficulty, including events unrelated to the study that make it difficult to continue with the 
protocol, the subject will be withdrawn from the study and referred for treatment, counseling, 
or other necessary follow-up. Physicians (Dr. Preeti Raghavan and Dr. Brian Im) and a 
neuropsychologist (Dr. Joseph Rath) who specializes in treating patients with TBI are 
included on the team, and will be available to counsel, treat and provide other necessary 
follow-up in such an event. This study does not provide financial assistance for medical or 
other injury-related costs. 
Risks to confidentiality will be minimized by maintaining a secure, immobile computer 
database. Subjects will be identified by code rather than by name.  
 
 

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Potential Benefits to the Subjects. As this is a treatment study, tDCS and cognitive training 
intervention will be provided to participants. This intervention is intended to benefit 
participants by improving their attentional and emotional function. TDCS modulates the 
firing rates of individual neurons, and influences dopaminergic, adrenergic, and 
serotoninergic neural circuits (Boggio, Rigonatti et al. 2008; Nitsche, Boggio et al. 2009). 
Reversing the pathological alterations back to normal with tDCS presents a potential 
therapeutic option for persons with cognitive and emotional dysfunction post-TBI. Past 
research has demonstrated that tDCS safely improves depression in a general psychiatric 
population (Boggio, Rigonatti et al. 2008) and holds promise as a highly innovative therapy 
that may result in a substantial quality of life improvement in patients with TBI. TDCS 
treatment offers several potential advantages, including: i) faster onset of action than 
antidepressants, ii) non-systemic treatment that can be used in patients who cannot tolerate 
antidepressants or psycho stimulants due to side-effects, medication interactions, and co-
morbidities; iii) no observed adverse interactions between pharmacological agents and tDCS; 
iv) usefulness for patients with low performance status, because it does not require patients' 
focused attention or physical effort; and v) it is well-tolerated, brief, safe, and easy to 
administer . In addition, because no adverse interactions have been observed between 
pharmacological agents and tDCS, it can be used as adjuvant therapy in patients who report 
partial relief from pharmacological treatment.   
 
V. 
INVESTIGATORS' QUALIFICATIONS AND EXPERIENCE (CVs attached)  
Preeti Raghavan, MD is the original Principal Investigator and Director of the Motor Recovery 
Research Laboratory at the Rusk Institute of Rehabilitation Medicine. She and her delegates will 
be responsible for administering the assessments, the tDCS intervention, and data analysis. 
Prin Amorapanth, MD will be continuing the role of PI once Dr. Raghavan leaves. 
Brian Im, MD is an Attending Physician in the inpatient brain injury unit. He will refer patients 
with TBI eligible for the study to the PI. 
Joseph Rath, PhD is the Director of Psychology Research at the Rusk Institute of Rehabilitation 
Medicine. She will be responsible for supervising neuropsychological testing and training. 
Anita Madan, PhD is a researcher in the Department of Psychiatry at the NYUSOM. She is an 
expert in the testing of emotional function using film clips and physiological recordings. She will 
assist with the set up for testing of emotional function. 
Mariana Lazar, MD is a neuroradiologist at the NYUSOM. She is an expert in Resting state 
fMRI and will assist in the collection and analysis of resting-state connectivity.  
Mary Rosedale, PhD, PMHNP is researcher in the NYU College of Nursing, and Department 
of Psychiatry, NYSOM., board-certified psychiatric nurse practitioner and expert in the use of 
tDCS She will serve as a co-investigator on this project for issues related to the tDCS 
intervention.   
Viswanath Aluru, MD will be the research assistant on the project and will be responsible for 
the recruitment, data collection, training and data analysis under the supervision of the PI.  
Iain Jeffrey will be a medical student on the project and will assist Viswanath in data collection, 
training and data analysis under the supervision of the PI.  
Zena Moore will be the data associate on the project and will be responsible for subject 
recruitment, and data management and reporting under the supervision of the PI. 

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VI.  SUBJECT IDENTIFICATION, RECRUITMENT, AND CONSENT/ASSENT 
 
1. Method of Subject Identification and Recruitment. Dr. Brain Im will refer patients with 
TBI with symptoms of emotional dysfunction to the Motor Recovery Laboratory, at NYU 
Medical Center's Rusk Institute of Rehabilitation Medicine. Attending physicians, physical 
therapists, and occupational therapists from the outpatient facility at the Rusk Institute will 
also refer patients to the study by providing them with contact information for the PI if they 
meet study criteria. Also, subjects will be recruited by advertisement in the New York 
metropolitan area. Subjects who contact the PI and are found eligible for the study will be 
required to provide informed consent prior to participation in the study. The study protocol 
and informed consent forms will be approved by the IRB at NYU Medical Center. Subjects 
will be informed that they can discontinue the study or its procedures at any time, and that 
further evaluation or treatment will not be withheld. The identification and recruitment of 
subjects will protect the privacy of subjects and be free of undue influence. 
 
We will also place an Ad on Craigslist in the volunteer section to aid in recruitment.  The Ad will be 
listed at: http://newyork.craigslist.org/search/vol 
 
2. Process of Consent. Consent will be obtained from subjects by the PI or her HIPAA-certified 
delegates in the PI's office, which is a private area, at the Rusk Rehabilitation Institute, NYU 
Medical Center, prior to participation in the study. The consent document will be discussed at 
a convenient time, free of time constraints, and each potential subject will be allowed time to 
think about his or her decision. The study and the consent form will be thoroughly discussed 
with each subject, section by section. Subjects will be asked to provide a statement of their 
understanding of the procedures, risks, and general concept of the study. All subjects will be 
given a copy of the written consent form and encouraged to contact the PI if they have further 
questions about the protocol. 
 
All subjects will also provide separate consent for videotaping of functional task assessments 
at the Motor Recovery Laboratory. Videotapes of emotional function battery will be scored to 
understand deficits in emotional recognition, reactivity and regulation. Videotapes of therapy 
sessions and functional task assessments may be used for instruction and training purposes.  
 
3. Subject Capacity. While TBI leads to cognitive impairments, the subjects recruited for this 
study will be community-dwelling individuals with capacity to provide consent. Only subjects 
who have the capacity to consent will be enrolled. 
 
4. Subject/Representative Comprehension. Capacity will be determined by a general 
conversation between the subject or authorized representative and the PI to assess the subject's 
verbal understanding of the protocol, including the nature and purpose of the study, the 
procedures involved, and the risks and benefits of participating vs. not participating; 
appreciation of the significance of disclosed information, and the potential risks and benefits 
of disclosure for the subject's own situation and condition; the ability to engage in a reasoning 

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process about the risks and benefits of participating vs. not participating; and the ability to 
express a choice about whether or not to participate. 
  
5. Debriefing Procedures. No information will be purposely withheld from subjects. 
 
6. Consent Forms. The IRB Standard Consent Form will be used (please see attached). 
 
7. Documentation of Consent. The study and the consent form will be thoroughly discussed 
with each subject, section by section. Subjects will be asked to provide a statement of their 
understanding of the procedures, risks, and general concept of the study. The consent 
document, and documentation of the process, will be stored in the PI's office at the Rusk 
Institute of Rehabilitation Medicine, NYU Medical Center, on a password protected computer 
and/or in a locked filing cabinet. The computer will be in a locked, fixed location (no mobile 
laptop), password protected, and on a local network. 
 
8. Costs to the Subject. Subjects will not incur any costs for the therapy.  
 
9. Payment for Participation. TBI Participants will be compensated a total of $100.00 for 
participating in the study. The first compensation will occur after the subjects complete 
baseline assessments.  At this point they will be compensated $50.00.  The TBI subjects will 
be compensated the remaining $50.00 after they complete the post testing assessments. 
Healthy Control Subjects will be not be compensated for participating in the study. 
 
 
  
References: 
Allen, L. B., R. K. McHugh, et al. (2008). Emotional disorders: a unified protocol. Clinical Handbook of 
Psychological Disorders. D. H. Barlow. New York, Guilford Press. 
Anderson, T. M. and R. G. Knight (2010). "The long-term effects of traumatic brain injury on the coordinative 
function of the central executive." Journal of Clinical and Experimental Neuropsychology: 1-9. 
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