Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT02973165 |
| Other study ID # |
361-2011 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
N/A
|
| First received |
November 22, 2016 |
| Last updated |
November 22, 2016 |
| Start date |
August 2013 |
| Est. completion date |
August 2021 |
Study information
| Verified date |
November 2016 |
| Source |
Malcom Randall VA Medical Center |
| Contact |
John B Williamson, PhD |
| Phone |
352-376-1611 |
| Email |
john.williamson[@]ufl.edu |
| Is FDA regulated |
No |
| Health authority |
United States: Federal Government |
| Study type |
Observational
|
Clinical Trial Summary
Objectives: Mild traumatic brain injury (mild TBI) occurs frequently in combat personnel and
has been linked to complaints of emotional symptoms in up to 85% of those injured, with high
rates of PTSD symptoms, anxiety, depression, and mood swings. TBI may cause cerebral white
matter injury and changes in white matter integrity have been correlated with behavioral
changes even with very mild TBI. Patients with mild TBI also have higher rates of
dishonorable discharge from the military, as well as substance abuse. Many of these
behavioral changes are associated with alterations in frontal-subcortical networks, which
are heavily dependent on white matter connectivity. Our primary goal in this investigation
is to begin to understand the specific neurological mechanisms that may underlie emotional
dysfunction following mild TBI.
Research Plan: We will compare patients with PTSD but no TBI to patients with TBI with and
without emotional symptoms. It may be that the basic emotional responses of these
populations are different and that these differences may help elucidate the mechanism
accounting for these changes in mood and emotional behaviors. Finding a neurological and
injury-specific basis for the constellation of chronic emotional symptoms observed in this
population could have treatment implications such that the treatment of patients with versus
those without injury induced PTSD may have different efficacies (e.g., exposure therapy may
work best for the patients with non-injury related PTSD).
Methods: We will recruit 60 subjects with mild TBI from our OEF/OIF poly-traumatic and 60
controls (30 with PTSD but no TBI). We will test emotional behaviors using an affective
neuroscience methodology with indicators chosen based on the reported symptoms profiles in
this population. Specifically, we will assess the relationship between white matter injury
in the uncinate fasciculus and anterior limb of the internal capsule and alteration of
affective response physiology (e.g., startle response while viewing high intensity
positively and negatively valecned visual scenes) and cognitively (identification of the 6
primary emotions including ratings of intensity and arousal). To determine the integrity of
white matter pathways, we will use high-resolution diffusion weighted imaging (DWI) with
diffusion tensor imaging (DTI) and related analysis techniques.
Description:
Specific Aims:
Aim 1: Emotional cognition: To learn if damage to specific white matter structures and
pathways subsequent to mild TBI alters emotional cognition Hypothesis Rationale Comment
Research on hemispheric laterality of emotion is complicated. Because research at this level
of specificity is relatively new, it is unclear whether injury to white matter structures
will cause release or blunting effects on different emotions (e.g., injury to right uncinate
fasciculus might cause exaggerated anger responses, but blunted positive affect). It depends
on the nature of the contributions of the various components of the limbic pathways under
study. For example, does damage to the uncinate fasciculus result in a lack of regulatory
input to the amygdala from the orbitofrontal cortex? If so, is the function of that circuit
to inhibit or modulate amygdala activity? Because of this complexity, our
hypotheses/predictions are bi-directional.
Hypothesis 1 Left Hemisphere: Decreased white matter integrity in the left uncinate
fasciculus and left anterior limb of the internal capsule will affect positively valenced
emotional cognition (i.e., patient ratings of valence and intensity of positive emotional
images). The effect will be blunting or release effects (such as reductions or increases in
ratings of intensity of positive emotional stimuli).
Hypothesis 2 Right Hemisphere: Decreased white matter integrity in the right uncinate
fasciculus and right anterior limb of the internal capsule will affect negative emotional
cognition (i.e., patient ratings of valence and intensity of negative emotional images). The
effect will be blunting or release effects (such as reductions or increases in ratings of
intensity of negative emotional stimuli).
Aim 2: Emotional physiology: To examine the impact of white matter injury in specific tracts
and structures of interest [e.g., uncinate fasciculus and anterior limb of the internal
capsule] in mild TBI on autonomic nervous system response to emotional images.
Hypothesis 3 Decreased white matter integrity in the left uncinate fasciculus will be
associated with lower resting vagal tone (due to preferential access of the left hemisphere
to parasympathetic nervous system regulation) Hypothesis 4 Decreased white matter integrity
in the right uncinate fasciculus will be associated with higher resting vagal tone (due to
preferential access of the right hemisphere to sympathetic nervous system control)
Hypothesis 5 Decreased white matter integrity in the left or right uncinate fasciculus and
left or right anterior limb of the internal capsule will be associated with either increased
startle response or decreased startle response (same laterality prediction issue as in Aim
1) Hypothesis 6 Decreased white matter integrity in the left or right uncinate fasciculus
and left or right anterior limb of the internal capsule will be associated with either
increased or decreased vagal response to emotional images (depending on positive or negative
valence).
Pilot Phase:
Aim 1: Emotional Cognition: To determine if vagal nerve stimulation alters emotional
cognition in patients with mild TBI and PTSD. A sub-aim to this is to evaluate the impact on
affective communication (facial emotions, body language, etc.) versus affective induction
(e.g., pictures of bodily waste or pollution) using an established protocol and battery of
stimuli. This aim may (optional) include fMRI fear condition learning tasks (on and off
stimulation).
Hypothesis 1: Intensity ratings of positive and negative stimuli will be modulated towards
neutral, or alternatively, only negative stimuli ratings will be modulated towards neutral.
Hypothesis 2: Identification of emotional stimuli will be faster, particularly for positive
imagery. This will be most pronounced in emotional face pictures/videos versus non-social
imagery.
Hypothesis 3: Fear condition learning will be normalized by tVNS in patients with mTBI/PTSD,
PTSD, more resembling healthy controls.
Aim 2: Emotional Physiology: To determine if vagal nerve stimulation alters autonomic
reactivity in the context of baseline and emotional stress response.
Hypothesis 1: Baseline cardiac vagal tone will be higher and more robust through positional
manipulation during active VNS.
Hypothesis 2: Autonomic and startle responses to negative imagery will be less pronounced
(e.g.,respiratory sinus arrhythmia, heart rate) during active VNS.
Aim 3: Sleep Quality: Patients with PTSD have symptoms of sleep disruption including changes
in sleep architecture and frequent occurrence of nightmares. Vagal nerve stimulation
decreases amygdala activity, as previously shown with fMRI response to VNS (Kraus et al.,
2007), and the amygdala/prefrontal EEG signal is altered in patients with PTSD. We will
evaluate sleep architecture changes in patients with TBI/PTSD and also qualitative ratings
of sleep quality during vagal nerve stimulation. Hypothesis 1: Sleep architecture will
appear more normal with VNS than without.
Hypothesis 2: Qualitative ratings of sleep will improve with VNS compared to without.
6. Research Plan: Recruitment goals Because no published data exist that directly tests the
relationships between the variables we are collecting and the specific outcome measures,
power analyses were deemed to be unhelpful. Rather, we estimated our sample need based on
research from Dr. Porges' lab examining cognitive, affective and physical stressor impacts
on respiratory sinus arrhythmia (RSA) in normals, my research using similar methods in adult
hostile men, and stroke patients, the incidence of emotional symptoms after mild TBI, and
the documented impact of white matter changes on fronto-subcortical systems in mild TBI. We
intend to recruit 60 subjects with mild TBI and PTSD, 60 subjects with PTSD but no TBI, and
60 subjects with history of combat exposure but no TBI or PTSD). We will recruit as many
subjects as we can to participate in pilot testing. This will be dependent on funding and
time, but, for the purposes of IRB enrollment, we will likely not need more than 100
subjects for the pilot (distributed across the subject categories).
General procedures for study visit Participants will be examined in a comfortable and
private testing office at the VAMC for the neuropsychological and ANS methods and in the
"state of the art" McKnight Brain Institute imaging center at UF for the MRI procedures. The
order of the administration of the tests of emotion and cognition will be counterbalanced
across subjects to prevent test order effects and control for potential systematic impacts
of fatigue. This protocol may require two visits (due to coordination of the neuroimaging
evaluation) and it is expected to take 3-4 hours (in total). For participants who are
invited and choose to participate in the pilot testing, an additional 3-4 hours is
necessary.
Neuropsychological testing Subsequent to a structured interview to gather demographic data,
health history, and TBI history (including # of TBIs), a 30 minute cognitive screening will
be administered to characterize the sample and to examine relationships of the affective
battery to cognitive measures associated with disruption of white matter pathways. The
following tests will be administered:
Wechsler Test of Adult Reading (WTAR): Because cognitive ability is a common protective
factor for many conditions (e.g., stalling the onset of clinical syndromes in
neurodegenerative diseases, decreasing the likelihood of mental illness), we will assess
several aspects of intellectual function. The WTAR (Wechsler, 2001) is a commonly used tool
for the estimation of premorbid cognitive ability. It was developed and co-normed concurrent
with the Wechsler Adult Intelligence Scale - 3rd Edition (WAIS-III) and the Wechsler Memory
Scale- 3rd Edition (WMS-III). It is highly correlated with the verbal intelligence quotient
(IQ) derived from the WAIS-III (Wechsler, 1997). The WTAR requires participants to read
aloud a series of increasingly infrequent words with irregular grapheme-to-phoneme
translation.
Epworth Sleepiness Scale - This is an eight question scale designed to assess sleepiness.
Pittsburgh Sleep Scale - Scale designed to assess sleep quality. Neurobehavioral Symptom
Inventory (NSI) - Scale that assesses frequent symptoms after TBI.
Phonemic Fluency: Phonemic fluency (Controlled Oral Word Association Test) (Benton et al,
1994) requires production of words quickly to phonemic confrontation (e.g., F, A, S). It is
a timed test (60 seconds per trial). Phonemic fluency was chosen because of research
suggesting differential performance in clinical populations with the potential of
identifying separate executive processes based on involvement of different areas of
prefrontal cortex (Stuss et al., 1998).
Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) - The RBANS is a
screening instrument that has been used to assess mild TBI populations in the past (e.g.,
Cooper et al., 2010). It is comprised of measures of list, logical, and visual memory,
semantic fluency, digit span, coding, and visuospatial construction. It takes about 20
minutes to administer.
Test of Memory and Malingering (TOMM) Effort testing is essential in any behavioral study of
mild TBI due to secondary gain potential and literature demonstrating litigation status as a
moderating factor for the presence of chronic cognitive deficits. The TOMM (Tombaugh, 1997)
is designed to assist in the assessment of effort. It is a 50 item visual recognition
paradigm. Participants are shown 50 easily identifiable line drawings. Immediately after,
they are shown a series of line drawing that include both novel and previously viewed items.
Participants must indicate if they have or have not seen each item. The test is repeated
immediately and then after a 10 min delay.
Beck Depression Inventory - II (BDI-2) To characterize current mood and compare mood ratings
to our measures of emotional processing, we will administer several commonly used
questionnaires (for comparison to other studies) The BDI-2 is a self-report scale designed
to measure current depressed mood disturbance. It is comprised of 21 multiple choice
categories (e.g., sadness, suicidally, regret) (Beck, 1996). The questionnaire takes
approximately five minutes to complete and is validated for use with people aged 13 to 80.
PTSD Checklist-Military (PCL-M) The PCL-M (Weathers et al., 1994) is a Likert based
checklist designed to assess symptoms associated with PTSD. It is tailored to the military
experience. This is an often used and current tool for establishing the effects of trauma on
the presentation of PTSD symptoms (e.g., McGhee et al., 2009; Souza et al., 2008; Richardson
et al., 2006).
The Migraine Disability Assessment Test (MIDAS) and the Headache Impact Test (HIT-6) These
two time-efficient scales assess the impact of headache (MIDAS = 7-items) (HIT-6 = 6 items)
(Stewart et al., 2001; Kosinski et al., 2003) Symptom Checklist 90 Revised (SCL-90-R) The
SCL-90-R (Derogatis, 1994) is a widely used 90-item self-report psychological inventory that
measures nine primary symptom dimensions and generates three global indices of psychological
and symptomatic distress. This tool has been shown to be sensitive to issues patients
experience with mild TBI (Westcott & Alfano, 2005).
Ohio State University TBI Identification Method Short From - A standardized, short,
structured interview designed to elicit a rich lifetime TBI history.
State-Trait Anxiety Inventory (STAI) The STAI is a psychological inventory based on a
4-point Likert scale and consists of 40 questions on a self-report basis. The STAI measures
two types of anxiety - state anxiety, or anxiety about an event, and trait anxiety, or
anxiety level as a personal characteristic. Higher scores are positively correlated with
higher levels of anxiety. Its most current revision is Form Y.
Tests of Emotion In order to test emotional processing, we will measure physiological
response to two sets of emotional stimuli (visual scenes, and affective faces). Further, we
will compare patients with mild TBI to both controls and normative samples for their
evaluation of emotional content (e.g., intensity, valence, reaction times, and categorical
ratings). Moreover, we will examine how emotional context (e.g., looking at a high arousal,
negatively valanced visual scene) influences startle response in the presence of specific
white matter changes.
For all of the following conditions, physiological monitoring (as described under
psychophysiology methods) will be recorded continuously and event markers will be used to
identify the condition segments. Each condition will be preceded by 3 minute physiological
baselines and followed by 3 minute physiological recovery periods. Pictures (International
Affective Picture System - IAPS) and videos (Dynamic Affect Recognition System - DARE) will
be presented on a 22 inch LCD monitor and participants will be seated in a comfortable chair
throughout the administrations.
Startle-Blink Procedure and International Affective Picture System Startle-blink responses
have been shown to differentiate normal, clinical, and subclinical populations with respect
to individual differences in emotional processing (physiology and cognition) including
depression, schizophrenia, specific phobias, anxiety, and personality disorders (Sanchez et
al., 2009; Schact et al., 2009; Li Li et al., 2009). Further, startle response has been
shown to be sensitive to differences in white matter structure in other populations (e.g.,
autism; McAlonan et al., 2002). The startle blink procedure will be divided into two
administration conditions, neutral (unprimed) and emotion (primed). In the unprimed
condition, startle-blink response will be elicited with single 50 ms bursts of white noise
(95 db, instantaneous rise time) delivered binaurally through stereo headphones. There will
be 12 probes delivered in random time intervals in the absence of any other stimulus
(unprimed startle). The emotion condition will use pictures drawn from the International
Affective Picture System (IAPS) (Lang et al., 2001) normative study (Lang et al., 2001b) and
from a large study in which participants rated IAPS pictures for discrete emotions
(intensity and valence) (Bradley et al., 2001). Forty-eight pictures (12 disgust, 12 fear,
12 neutral, and 12 pleasant) will be used in which a startle probe will be presented and
sixteen non-probe trials administered. For a more complete example of the methodology please
see Miller et al., (2009).
Dynamic Affect Recognition Evaluation The processing of emotion in humans is especially
geared towards response to faces. Facial affect processing is critical to proper social
engagement and is influenced by physiological state. For example, trait hostility
(personality) has been associated with inaccurate identifications of anger in neutral
affective faces and altered patterns of cardiovascular response when under stress (Herridge
et al., 2004). The amygdala, an important limbic structure with strong white matter
connections to frontal cortex and autonomic nuclei in the brain stem, has been shown
repeatedly to preferentially respond to emotional faces (e.g., Blasi et al., 2009; Derntl et
al., 2009). Further, Adolphs et al. (2000) suggested that damage to white matter tracts
should give rise to emotional perception deficits. In a study similar in design to the
proposed investigation, though using static faces and more severe TBI, damage to white
matter subsequent to TBI was associated with impaired performance on emotional face
perception (Green et al, 2004). However, their study used CT scans for localization of
damage and visual identification. They suggest using MRI to further quantify/qualify these
relationships.
The Dynamic Affect Recognition Evaluation (DARE) (Porges, Cohn, Bal, & Lamb, 2007) will be
used for the standardized presentation of emotional expressions (facial). The DARE stimuli
were developed from the Cohn-Kanade Action Unit-Coded Facial Expression Database. The
database includes approximately 2000 image sequences from more than 200 human subjects. In
the current research, a modified version of the stimuli developed by Cohn et al. (Cohn,
Zlochower, Lien, & Kanade, 1999) will be used. The stimuli include uncompressed video files
(i.e., series of still images) consisting of six basic emotions. These images were morphed
and the final videos include a face starting with a neutral expression and slowly
transitioning into one of the six target emotions. Recently, for example, Pelphrey et al.
(2007) used a similar procedure (i.e., fearful and angry emotion morphs) and reported
hypoactivation of the right amygdala and fusiform gyrus in adults with autism when viewing
dynamic expressions, suggesting appropriate network involvement for the proposed mild TBI
investigation. In the current study, video length varies (ranged from 15 to 33 seconds)
depending on the number of the frames in the original image sequences (independent of
emotion category). The DARE software also provides an output file showing the order of the
videos presented and the latency to recognize the emotions.
Neuroimaging and Analysis Approach Diffusion Tensor Imaging (DTI) will be the primary tool
used to evaluate the integrity of white matter in the proposed investigation. DTI measures
the aggregate movement of water molecules in an image voxel. Movement of water is affected
by cell membranes, proteins and lipids, including the myelin sheath generated by
oligodendroglia in the telencephalon. Deterioration of myelin is detectable via measurement
of this diffusion. One measure of white matter integrity derived from DTI is Fractional
Anisotropy (FA). FA is an index of the randomness of water movement in the brain. An FA
value of zero indicates that the movement of water is random, whereas an FA value of one
indicates that the movement of water is in one direction (non-random). White matter fibers
that are oriented in one direction (a tract), will have a higher FA than a collection of
axons that have dispersed orientations. As white matter tracts degrade (E.g., from injury),
FA values decrease due to increased randomness of diffusion. Thus, FA values can be used as
a measure of the integrity of white matter connections. The quality of DTI maps (ability to
see specific white matter tracts and structures) is dependent, primarily, on two variables,
number of scanning directions (vectors) and resolution; although pulse sequences and other
factors also play a role. At the McKnight Brain Institute at the University of Florida, in
collaboration with Dr. Thomas Mareci, members of the Crosson lab have been using a technique
called HARDI (High Angular Resolution Diffusion Imaging).
Use of HARDI allows for oversampling of the diffusion in a voxel, resulting in enhanced
signal to noise ratio for measurements of FA compared to standard DTI measures. HARDI also
has advantages in estimation of the probability of water diffusion direction in a voxel
compared with standard DTI approaches.
The total MRI acquisition protocol will be approximately 1 hour. The sequences used will be
different for those who do the pilot versus those who do not. The pilot sequences will
include task dependent fMRI, whereas the non-pilot sequences will not.
Image Analyses and Regions of Interest Definition (Post-Processing): Processing will be
completed using our array of MRI analysis tools.
Psychophysiology methods and analysis approach Heart rate data will be collected using a
three-lead ECG configuration. The ECG signal will be acquired at a sampling rate of 1 kHz
using Biopac amplifiers and acquisition software. Offline software will be used to detect
the R-wave in sequential heart beats from the ECG to generate a series of sequential heart
periods defined by R-R intervals. The heart period data will be visually inspected and
edited to identify missed and faulty R-wave detections and remove the effect of ventricular
arrhythmias (i.e., RSA is an atrial rhythm). Editing consists of integer arithmetic (e.g.,
dividing intervals when detections are missed or adding intervals when spuriously invalid
detections occur). These data will be used to calculate heart rate variability statistics
including measures of respiratory sinus arrhythmia (RSA) (an index of vagal tone or
parasympathetic nervous system activity).
Tilt Table:
To assess baroreceptor activity, we will use a tilt procedure. Subjects will lie down on a
table designed for tilt procedures at the BRRC. Continuous blood pressure (using a finger
cuff and arm cuff) will be measured along with ECG while the subjects are slowly moved from
90 degrees (upright) to 60 degrees (slightly reclined) to 30 degrees (reclined a little
more) and then back up to 60 degrees and to 90 degrees. Each angle will be held for three
minutes.
EMG and startle-blink response Surface Ag-AgCl electrodes will be positioned under the
participants' left and right eyes to record electromyographic (EMG) activity from the
orbicularis oculi muscle. Data from each participant will be visually examined with clear
artifacts (e.g., eyeblinks before probe onset) rejected upon identification. Additionally,
trials in which the participant turns away or closes their eyes will be discarded. Data
reduction will be completed using a data condensing software program. Latency and amplitude
of the peak response within 20-120 ms subsequent to probe onset will be determined. Trials
with a peak latency outside of this range will be discarded (likely unrelated to probe). A
left and right eye standardized score will be generated, using each participant's
performance as their "baseline." For a full description of this approach please see Miller
et al. (2009). Dawn Bowers, a consultant on the proposed investigation and senior author for
Miller et al. (2009), helped plan the methodology for startle-blink response assessment in
this project.
Pilot Experiment 1:
We will attempt to recruit 100 subjects including combat exposed healthy controls, people
with mTBI and PTSD, people with PTSD only, and people with mTBI only.
External, Transcutaneous Vagal Nerve Stimulation Participants will undergo either
transcutaneous vagal or sham (non-vagal) nerve stimulation with an established protocol
(Kraus et al., 2007, 2013) using the FDA approved nerve stimulator Digitimer DS7A. Small
Ag-AgCl electrodes will be placed around and on the ear, in particular just behind the
tragus on the anterior wall of the outer auditory canal and on the posterior side of the
outer auditory canal. Subjects and researchers will be blinded to which set of electrodes
(i.e. treatment vs. sham) are actually used with a stimulus blinding box. Stimulus intensity
will be increased from nothing (0mA & 0V) until the threshold of discomfort and then reduced
below this threshold to achieve an effective but comfortable stimulus intensity, producing a
"comfortable electro-massaging sensation" according to previous research. The frequency of
stimulation will be 8Hz. The absolute maximal voltage and current is limited by the device
to a maximum of 400V and 100mA, respectively, although we expect to use stimulation
intensities of <50V and <50mA per previous research and clinical reports.
Stimulation/sham stimulation tests: Subjects will receive stimulation/sham stimulation
during the following tests:
Startle-Blink Procedure and International Affective Picture System (see above) Dynamic
Affect Recognition Evaluation (see above) Tilt Table (see above)
Sleep Study:
Electroencephologram (EEG) Testing:
A researcher will attach EEG (electroencephalogram) surface electrodes/sensors to the
subject's face and scalp prior to treatment with eVNS. We will place up to 14 EEG
(electroencephalogram) surface electrodes/sensors on the subject's face and scalp. These
small electrodes will be attached using a conductive electrode paste and then secured with
small pieces of gauze and pieces of surgical tape. After the electrodes are placed, subjects
will be asked to sit quietly with their eyes open for ten minutes, and then to sit quietly
with their eyes closed for ten minutes. This procedure will be done before the testing
described below, and may be repeated after the testing.
Electroencephologram (EEG) recording: There is a potential risk of minor skin irritation
and/or discomfort from when the electrodes and sensors are placed on the skin. Minimal,
temporary hair loss is unlikely but may occur locally at the electrode sites. The EEG device
is battery operated and there is no risk of electrical shock from the device.
The description below outlines the steps for electrode attachment
1. The placement locations will be gently abraded using a cotton swab and pumice paste.
2. The area will then be cleaned using rubbing alcohol.
3. In locations which are not in the subject's hairy zone, electrodes referred to as "snap
electrodes" will be used, which adhere to the subject's skin.
4. In the hairy zone on the scalp, gold electrodes filled with a hypoallergenic electrode
gel will be attached using conductive electrode paste and secured with small pieces of
gauze and pieces of surgical tape.
5. All electrode leads will then insert into a hand-held clinical EEG data acquisition
device (SOMNOmedics Corp.)
6. After the completion of the study, electrodes will be removed using warm water. EEG
data will be acquired from 6 scalp locations (right and left hemisphere occipital,
central, and frontal sites), EOG electrodes will be placed next to the right and left
eyes, while chin EMG will be acquired for the purpose of detecting REM sleep. In
addition to the measurement of EEG/EOG/EMG from the face and scalp, the device will be
used to monitor respiratory effort (abdominal and thoracic belts),
inspiratory/expiratory air-flow (combined nose/mouth sensor), pulse oximetry
(finger-worn sensor), and actigraphy measurement, such as movement and body position
Study Protocol: After attaching the sensors and electrodes, subjects will be instructed
to lie down on a comfortable bed in a dark quiet room and attempt to fall asleep. The
total maximum nap will be about 1-1.5 hours. However, the study will be terminated in
the event that the subjects are unable to fall asleep within 45 minutes after
initiation of the nap attempt.
The EEG and other physiological signals will be continuously acquired and monitored in
real-time by the researcher. After the termination of the study, the researcher will remove
the electrode/sensors from the subject and the EEG monitoring device.
Data Collection and Analysis. The sleep data acquired from the sleep studies will be
downloaded from the SOMNOmedics device. These data will be subjected to analysis that would
characterize the nap using the EEG signal. These characterizations include time latency to
the first onset of sleep, duration and fluctuations of the sleep stages achieved during the
nap, and more quantitative analysis of EEG in the frequency domain where the spectral
analysis of EEG will be performed over six EEG frequency bands: Delta (δ): 1-3.5 Hz; Theta
(θ): 4-7.5 Hz; Alpha (α): 8-12 Hz; Sigma (σ): 13-16 Hz; Beta (β): 16.5-25 Hz; and Gamma (γ):
40 Hz.
Pilot Experiment 2: tVNS and fMRI, fear condition learning For pilot Phase 2, in the same or
a different (newly recruited) set of participants, we will compare tVNS sham versus tVNS
stim during fMRI with the following protocol. The stimulator is different than for Pilot
Experiment 1. We will use a stimulator unit approved for MRI use, manufactured by Biopaq
that is already integrated into the AMRIS environment and used in research. The electrode
application will be the same as in Pilot Experiment 1.
Stimuli and Design. A differential delayed conditioning design will be used, in which the
orientation of a visual Gabor patch signals the presence (CS+) or absence (CS-) of an
unconditioned stimulus (US) in the form of a 92-dB sound pressure level (SPL) white noise.
During the acquisition phase, the US will be presented during the final interval of CS+
presentation and set to co-terminate with CS+ during the conditioning trials using a 100%
reinforcement ratio. The assignment of Gabor patch orientations to conditions (i.e., CS+
signaling threat and CS- signaling safe) will be counterbalanced across participants.
Stimuli were designed to preferentially engage either the luminance-based or the
chromatic-based channels of the human visual system. The low spatial frequency, luminance
stimulus consisted of a pair of anti-phasic Gabor patches with 7 cycles, covering 8 degrees
of visual angle.They were designed to have 6.8% Michelson contrast and a low spatial
frequency of .875 cpd. The lightest point of the Gabor patch will be ~ 47 cd/m2 and the
darkest point will be ~ 41 cd/m2. The high spatial frequency, chromatic stimuli will be two
isoluminant gray-and-green and red-and-green Gabor patches with 29 cycles, covering 8
degrees of visual angle (3.625 cpd). Both stimuli will be shown on a gray background with a
luminance of 44 cd/m2. Steady-state VEPs will be elicited by pattern reversal for both the
low spatial frequency, luminance and the high spatial frequency, chromatic stimuli.
Presentation will alternate between a stimulus and its counterpart at a rate of 15 Hz or 14
Hz to produce a pattern-reversal ssVEP. Stimuli will be shown on a monitor.
Procedure and design. The experiment will consist of 72 trials in total: 24 habituation
trials, 24 acquisition trials, and 24 extinction trials. Stimulus presentation will be
randomized and fully balanced in each phase, and during acquisition, one of the stimulus
orientations will signal the imminent US noise. All trials except for the CS+ acquisition
trials will be 6.666 s (100 cycles at 15 Hz) or 7.142 s (100 cycles at 14 Hz) in length.
During the acquisition period, 20 cycles will be appended at the end of the CS+ trials to
accommodate concurrent presentation of CS+ with the US. Following each trial will be a
variable inter-trial interval of 9-12 s.
