Clinical trial NCT03033784
Conditions: Autism Autism Spectrum Disorder
Keywords: Neuroscience
Sponsor: Emory University
Start date: 2017-05-10; Completion date: 2018-10-03
Enrollment: 51 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The main goal of the study is to look at the effects of intranasal oxytocin on the brain in Autism Spectrum Disorder (ASD). Oxytocin is a hormone that exists naturally in the body and the brain, affecting a wide range of social behaviors and emotions. The investigators will study the effects of different treatments (3 doses of oxytocin and one dose of placebo) on brain functional connectivity at rest in patients with ASD, using functional magnetic resonance imaging (fMRI). Investigators also seek to study how the effects of oxytocin treatment can be affected by genetic, immune and environmental factors.

Detailed description:
This study consists of investigating the effects of several doses of acute administration of intranasal oxytocin on brain activity in adults with Autism Spectrum Disorder (ASD). There is increasing evidence for the role of intranasal oxytocin (IN-OT) in enhancing social skills in ASD. Nevertheless, there is still a need of determining target engagement for oxytocin's action on brain and behavior. Here, investigators are studying the effects of different doses of IN-OT on the modulation of behavioral outcomes and neural responses in a double blind crossover study in individuals with ASD.

The aims of the research are to:

1. Study the effects of IN-OT doses on the modulation of brain functional connectivity between key socio-emotional brain regions during resting state in ASD
2. Study the effects of IN-OT doses on the blood-oxygen-level dependent (BOLD) activity of key emotional and perceptual brain networks in response to social cues (such as faces)
3. Study the effects of IN-OT on the BOLD activity of brain regions during an interactive social environment (ball game) in ASD

Investigators will compare the neuroimaging and behavioral results of individuals with ASD to control healthy males who will receive intranasal placebo. Investigators are also investigating the role of genetic factors, behavioral or clinical sub-groups of ASD, immune and environmental factors in modulating the effect of IN-OT on brain and behavior.

Participants with ASD will undergo 4 clinical visits during which they receive various randomly assigned doses of intranasal oxytocin and placebo. Both participants and the experimenter will be blind to the type of the treatment administered.

There will be only one visit for healthy controls who will all receive placebo spray. The visit for healthy controls will be conducted in a single-blind design. The experimenter will be aware that the subject is receiving placebo. However, the participant will be told that he might receive oxytocin or placebo.

Arms: arm 1: Male participants diagnosed with ASD will receive 12 puffs (6 in each nostril) of intranasal oxytocin (syntocinon) and placebo (assigned randomly) during 4 study visits. arm 2: Age matched healthy controls will receive placebo intranasal spray (12 puffs, 6 per nostril) during one study visit.
Interventions: intervention 1: 8 International Units (IU) of Oxytocin intervention 2: 24IU of Oxytocin intervention 3: 48IU of Oxytocin intervention 4: Placebo
Intervention descriptions: intervention 1: Participants will receive one dose of intranasal oxytocin at a dose of 8IU. intervention 2: Participants will receive one dose of intranasal oxytocin at a dose of 24IU. intervention 3: Participants will receive one dose of intranasal oxytocin at a dose of 48IU. intervention 4: Participants will receive an intranasal placebo to match the oxytocin doses.

Protocol documents:
Prot_SAP_001.pdf: 
    
Target engagement for intranasal oxytocin in Autism Spectrum Disorders, an 
fMRI dose response study. 
 
Short title: Autism Oxytocin Brain project (AOB) 
Principal Investigator:  
Elissar ANDARI, PhD 
Department of Behavioral Neuroscience and Psychiatric Disorders. 
Yerkes National Primate Research Center  
Protocol version number: version 6, July 10, 2019 
NCT Number: NCT03033784 
 
 
Precis/Abstract  
Interventions for autism are limited. This study consists of investigating the effects of several 
doses of acute administration of intranasal oxytocin on brain activity in adults with Autism 
Spectrum Disorders (ASD). There is increasing evidence for the role of intranasal oxytocin (IN-
OT) in enhancing social skills in ASD. Nevertheless, there is still a need of determining target 
engagement for oxytocin’s action on brain and behavior. Here, we are investigating the effects of 
different doses of IN-OT on the modulation of behavioral outcomes and neural responses in a 
double blind study in individuals with ASD. The first objective is to study the effects of IN-OT 
doses on the modulation of brain functional connectivity between key socio-emotional brain 
regions during rest in ASD. The second objective is to study the effects of IN-OT doses on the 
BOLD (Blood-Oxygen-Level Dependent) activity of key emotional and perceptual brain networks 
in response to social cues within a static and within an interactive social environment. We are 
also investigating the effects of IN-OT doses on the behavioral outcome measures such as visual 
fixation and emotion recognition. We will compare the neuroimaging and behavioral results of 
individuals with ASD to control healthy males who will receive intranasal placebo. The results of 
this study will provide more information on the mechanisms of action of IN-OT and its precision in 
affecting the brain and behavior.  
 
 
 
 
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Introduction and Background:  
Summary of the primary hypothesis, purpose, rationale and prior literature.  
Autism spectrum conditions (ASD) are a group of neurodevelopmental conditions characterized 
by impairments in social reciprocity, communication difficulties, and repetitive and stereotyped 
behaviors. High-functioning ASD subjects show pronounced selective social deficits despite 
preserved intellectual and linguistic capacities. These individuals display decreased eye-to-eye 
contact, impairments in orienting attention towards social stimuli (Klin et al., 2002; Nakano et al., 
2010), and alterations in responding to social rewards (Izuma et al., 2011). At a neurobiological 
level, ASD patients do not activate reward circuitry in response to socially rewarding stimuli such 
as smiling faces and have abnormal brain responses while looking at faces (Schultz et al., 2000).  
One source of social cognition deficits could be related to lack of motivation to social cues which 
is characterized by a lack of attention and reward sensitivity to these cues. Another potential 
source of the social difficulties is the presence of co-occurring alexithymia in ASD (Silani et al., 
2008), which is characterized by a reduced emotional awareness and empathy capacities.  
 
One potential approach for treating social deficits in ASD is to target the neural systems involved 
in socio-emotional processing as a means to enhance social cognition and function. In particular, 
oxytocin (OT) has emerged as a key modulator of social behavior and is being extensively 
considered as an intervention to enhance social functioning in ASD (Andari et al., 2010). We 
believe that OT affects complex social behaviors by modulating fundamental processes, such as 
the salience of social stimuli and the rewarding value of those social stimuli.  OT interacts with 
the dopamine system in the ventral striatum to facilitate the formation of a social attachment 
(Young and Wang, 2004).  Remarkably, there are dozens of studies suggesting that intranasally 
(IN) delivered OT has a similar prosocial effect on human behavior (Domes et al., 2007; Heinrichs 
et al., 2009; Rimmele et al., 2009; Hurlemann et al., 2010). IN-OT increases trust in others, 
attention to the eye region of faces, and enhances the ability to infer the emotions of others from 
viewing images of the eyes.  fMRI studies have shown that IN-OT is affecting emotional brain 
regions relevant to saliency, such as the amygdala (Kirsch et al., 2005; Gamer, 2010), and to 
reward, such as the caudate nucleus, during face perception or during reciprocated cooperation 
(Rilling et al., 2012).  
Andari et al. 2010 used a Cyberball game to demonstrate that IN-OT enhanced the ability of ASD 
subjects to detect and respond to social reciprocity.  The social exchanges between players 
created two extreme partner profiles (one reciprocating and another not reciprocating).  Healthy 
subjects quickly adjusted their ball tossing to favor the reciprocating player, while ASD subjects 
did not.  Remarkably, IN-OT enabled ASD subjects to detect relevant social information regarding 
the degree of reciprocation of each partner, to evaluate the significance of partners’ actions, and 
to subsequently toss the ball more frequently to the reciprocating player. IN-OT also increased 
the patients’ visual attention to the face region and in particular to the eye region (Andari et al., 
2010). Today, there are more than 19 papers showing positive effects of oxytocin on social 
cognition and brain function in individuals with ASD. In particular, Auyeung et al. 2015 have 
replicated our initial work showing that IN-OT enhances gaze behavior. Authors observed that 
oxytocin administration selectively enhanced gaze to the eyes in autism and control groups. In 
particular, within the autism group, oxytocin has the most effect on fixation duration in individuals 
with impaired levels of eye contact at baseline.  
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Authors showed that IN-OT to young individuals (Guastella et al., 2010) (12-19 years old, 18IU or 
24IU) improved performance on the reading the mind in the eyes especially for easy items and 
for younger participants. Researchers conducted a long term trial in 19 adults with adults 
(Anagnostou et al., 2012) (24IU twice a day for 6 weeks) and showed no serious adverse effects 
and some improvements in emotional cognition and quality of life but not in other clinical 
measures.  
Tachibana et al. 2013 (Tachibana et al., 2013) have shown that chronic administration of IN-OT 
(twice a day for a period of 6 months) to children (11.9 years old on average) with ASD was safe 
and patients did not show any side effects (blood pressure, serum osmolarity, serum sodium 
concentration, urine osmolarity, bone metabolism and short term memory).  
A recent promising study of Yatawara et al. 2015 (Yatawara et al., 2016) published in Molecular 
Psychiatry have shown that chronic administration of oxytocin (twice a day for a total of 24IU per 
day) for 5 weeks to children with autism lead to significant improvements on the primary outcome 
of caregiver-rated social responsiveness.  
At the brain level, several fMRI experiments have been conducted in ASD as well. Our group  has 
shown that IN-OT enhances the BOLD (Blood-Oxygen-Level Dependent) activity of visual areas 
during the processing of facial stimuli and reduces amygdala activity during interaction with other 
players. IN-OT also triggered the activity of OFC during social reciprocity and anterior insula 
during the perception of unfair players in ASD. The group of Hidenori Yamasu (Aoki et al., 2014) 
in Japan has shown that 24IU administration of oxytocin to 20 males with ASD increased the 
correct rate in inferring other’s social emotions and enhanced the originally diminished brain 
activity in the right anterior insula while performing this task. Domes et al. 2013 (Domes et al., 
2013) have shown that IN-OT (24IU) to 14 individuals with Asperger syndrome increased the 
activity of right amygdala (as well as for healthy subjects) that was shown initially decreased as 
compared to a control group during face processing (face and house discrimination task).  Gordon 
et al. 2013 (Gordon et al., 2013) have shown that IN-OT administration to 17 children with autism 
increased the BOLD activity in the striatum, the nucleus accumbens and superior temporal sulcus 
during the judgment of social stimuli (eyes).  
Watanabe et al. 2014 showed that IN-OT (24IU) (Watanabe et al., 2014) enhanced non-verbal 
judgments of social stimuli while increasing the brain activity of medial prefrontal cortex in adults 
with ASD.  
Watanabe et al. 2015 (Watanabe et al., 2015) showed that chronic administration of IN-OT for a 
6 week interval reduced core symptoms of ASD in social reciprocity (using ADOS criteria). These 
behavioral improvements were associated with enhanced functional connectivity at rest between 
the anterior cingulate cortex and dorso-medial prefrontal cortex. Also, the long term administration 
enhanced patients’ capacities during the social judgment task and the activity in the anterior 
cingulate and medial prefrontal cortex as well as the functional connectivity between these two 
regions. This resting state increased functional connectivity between ACC and mPFC was found 
correlated with the oxytocin-induced clinical deficits in ADOS of social reciprocity.  
A recent meta-analysis has shown that the oxytocin receptor gene is associated with ASD (in 
particular the rs7632287, rs237887, rs2268492 and rs2254298 OXR single-nucleotide 
polymorphisms (LoParo et al., 2016). Also, the team of Smith at Emory showed an association 
between epigenetic modifications of OXT via DNA methylation, which is an indirect approximation 
of OXT brain expression (presumably lower OXT DNA methylation is linked to higher OXT 
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expression), and attachment style, social processing (recognition of emotional expressions) and 
brain function during socio-cognitive tasks (Haas et al., 2016).  
Despite the quick progress in this field, more research is needed in order to study oxytocin’s 
therapeutic potential in alleviating social difficulties in neuropsychiatric disorders. 
An important question that has been addressed by Thomas Insel (Insel, 2016) in his latest review 
concerns target engagement for intranasal oxytocin. Here we would like to address this question 
by performing a dose response study for intranasal oxytocin and study its effects on functional 
connectivity of intrinsic activity during resting state and in response to external social cues. This 
will allow us to better understand the mechanisms of action of this molecule.  
 
• 
At first, we will study the effects of IN-OT doses on the resting state functional 
connectivity between key socio-emotional brain regions (using fMRI) that are shown to be 
deficient in ASD. Resting state functional connectivity is a task-independent metric of brain activity 
that is based on correlations between low-frequency fluctuations of the blood oxygen level-
dependent signal between several brain regions. It reflects the strength of a functional connection 
that is in good agreement with the underlying neuroanatomy but goes beyond simple 
monosynaptic connections as it provides a system-level understanding of brain function. The 
power of this technique lies in its relative ease of acquisition and stability within and across scans 
sessions  making it ideal for longitudinal experimental designs, including assessments of different 
treatments. Task-free acquisition precludes equating levels of performance – or motivation – 
between individual participants and across comparison groups. Large-scale brain networks are 
of particular relevance to this study. These networks include the - default mode network (DMN), 
which is centered on nodes in the mPFC, the midline posterior cingulate cortex (PCC), and the 
parahippocampal gyrus that has been implicated in mindwandering, planning the future and 
reflections on the past. The salience network (SN) centered on nodes in the dorsal anterior 
cingulate cortex and he frontoinsular cortex and sometimes including the ventral striatum that is 
implicated in the facilitation of attentional orientation to internal or external stimuli. The insular 
cortex is also involved in interoception and mapping internal bodily and subjective feelings states 
that are found deficient in Autism and related to a lack of alexithymia. The executive control 
network (ECN) is centered on nodes in the dorsolateral PFC and the lateral posterior parietal 
cortex that are associated with attending to and processing exogenous, attentionally-driven 
executive function. SN and ECN: are task-positive networks, which mean that these regions are 
identified at rest but are also activated during performance of most cognitive tasks. DMN usually 
deactivates during task performance. An overactivation or a reduced deactivation of the DMN and 
reduced ECN activation leads to decrements in task performance for healthy subjects and various 
neuropsychiatric diseases (Sonuga-Barke and Castellanos, 2007). We are particularly interested 
in networks that are relevant to oxytocin intake as based on the increased expression of oxytocin 
receptors in the brain, function of IN-OT on the brain and deficits in ASD.  
rsFC measure can provide clinically useful diagnostic, predictive biomarker of oxytocin’s effects 
on the brain and behavior as based on different patterns of dysfunctions, as compared to healthy 
subjects and based on different patterns of activation. We expect to find a reduction in functional 
connectivity not only within the different brain networks that were cited above but also in between 
networks. Based on previous studies, there is a reduced rsFC between mPFC and ACC as well 
as with PCC. We also expect a reduction in functional connectivity between anterior insula and 
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ACC and vmPFC and somatosensory areas and a reduction in connectivity between amygdala 
and insula and vmPFC/ACC as well as ventral striatum.  
There are several evidence on the effects of intranasal oxytocin functional connectivity of 
amygdala. 40 IU normalizes amygdala functional connectivity in PTSD by increasing functional 
connectivity between amygdala (right CeM subregion) and vmPFC in males (Koch et al., 2016). 
In autism, authors have found that six-week administration of oxytocin enhanced the connectivity 
between ACC and dmPFC at rest. At rest, intranasal oxytocin increased functional connectivity 
between amygdala and ACC (Kovacs and Keri, 2015). IN-OT enhanced rsFC of amygdala and 
ACC/mPFC in individuals with generalized social anxiety disorder (Dodhia et al., 2014). Acute 
administration of oxytocin was found to enhance the BOLD activity of several brain regions such 
as striatum, mPFC, OFC (Gordon et al., 2013).  
We will study the effects of several doses of IN-OT (8IU, 24IU and 48IU) on the rsFC between 
the salience network anterior insula and ACC, vmPFC as well as the amygdala functional 
connectivity with insula, vmPFC/ACC and ventral striatum (nucleus accumbens, VTA) and to the 
connectivity between vmPFC and ACC. We will also study the effects of IN-OT on the BOLD 
activity and functional connectivity of key brain regions that are involved in perception of social 
cues and reward sensitivity to these cues during social tasks. We will also compare the brain 
activity at rest after placebo intake in ASD to a group of healthy controls, matched for age, sex, 
ethnicity and full scale IQ.  
Following resting state, participants will perform an emotional face task that consists of looking at 
morphed faces. We will record eye-movements (via an eye tracker) while participants are looking 
into faces. Participants will also perform a social ball game (adapted version from our previous 
project IRB00064623) during which they interact with several other players. Participants will also 
play a prisoner dilemma game that was previously used by James Rilling’s work (investigator at 
Emory) to look into neural correlates of reciprocal cooperation and defect.  
Following the scanner, participants will perform some behavioral task and complete some 
questionnaire in order to study OXT’ effects on behavior (such as emotion recognition and 
alexithymia).  
Social reward and social saliency are key phenomena for studying the core deficit of social 
dysfunction in ASD and for targeting oxytocin manipulation.  
We are looking into the effects of IN-OT on brain activity and behavior in a precision medicine 
fashion. As exploratory analysis, we will look into the different clinical, behavioral and genetic 
moderators that can moderate the effects of IN-OT on behavior.  
The major hypothesis of this project is that intranasal oxytocin affects the activity of brain regions 
and brain connectivity between areas that are involved in sensory and emotional processing as 
well as interoceptive networks.  
Objectives:  
Aim 1: The effects of intranasal oxytocin on brain function at rest in adults with autism (35-
43 minutes after spray).  
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We hypothesize that IN-OT will enhance the functional connectivity at rest in ASD within and 
between several brain networks that are involved in salience and emotional processes such as 
insula, amygdala, ACC, mPFC and ventral striatum.  
Primary outcome measure: 
The primary outcome measure consists of studying the difference in resting state functional 
connectivity (rsFC) between treatment conditions in socio- emotional brain and perceptual 
networks in patients with ASD (Fig.1, anterior insula-amygdala-mPFC-OFC-ACC, temporal areas 
and insular-somatosensory cortices). This stems from the hypothesis that oxytocin affects brain 
network that is implicated in emotion evaluation, social and affective processing. Seeds will be 
considered within the insula region (we expect to find an increased activity between anterior 
insula, ACC, amygdala, vmPFC and somatosensory cortex); the different sub-regions of 
amygdala and study its connectivity with vmPFC/OFC, insula/ACC, ventral striatum (VTA, NAcc) 
and temporal areas. We expect the ventrolateral part of the amygdala to be functionally connected 
with perception areas such as fusiform, superior temporal sulcus, OFC; medial amygdala with 
vmPFC and dorsal amygdala with ACC and insula. We will also consider the NAcc as a seed 
region and study its connectivity to other reward regions (caudate, putamen, ACC) and frontal 
areas, PCC and precuneus (or default network). We will also look into the vmPFC as a region of 
interest and study its functional connectivity to ACC, PCC and subcortical regions. We expect to 
find differences between doses of IN-OT in terms or rsFC in these key brain regions as well as 
differences between IN-OT and placebo intake.  
Secondary outcome measure:  
The secondary outcome measure consists of correlating the effects of treatments (whereas the 
differences between high and low doses or between high and placebo) on rsFC with clinical and 
behavioral improvements following IN-OT (as compared to small dose or as compared to placebo) 
in these individuals with ASD. Clinical improvements will be rated by a clinician as a global clinical 
improvement as based on a videotaped interview (BB-CGI) post scanner. Behavioral 
improvements will consist of improvements in natural socio-emotional responses (emotional 
responses and eye contact) during this clinical interview.  
Aim 2: The effects of intranasal oxytocin on the BOLD activity of the social brain network 
(SBN) in response to social cues (50-60 minutes after IN-OT) 
We hypothesize that IN-OT will enhance the brain activity of regions involved in perception and 
emotional process in response to morphed emotional faces as compared to neutral faces in 
subjects with ASD.  
Primary outcome measure: The primary outcome measure consists of measuring the difference 
between treatments in terms of BOLD activity in response to emotional social cues (Face 
perception task (FPT)). We expect to find that a higher dose of IN-OT will enhance BOLD activity 
in emotional and perceptual regions known to be active during the perception of emotional face, 
(inferior occipital cortex, fusiform cortex, superior temporal cortex, intra-parietal sulcus, superior 
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parietal lobule, nucleus accumbens, amygdala and OFC), as compared to a lower dose of IN-OT 
or to placebo.  
Secondary outcome measures: We will study the effects of the difference between treatment 
conditions in modulating the visual fixation or gaze duration on the face and eye region of faces 
during this emotional face test in ASD (measured by the eye tracker inside the scanner). Based 
on the growing evidence in the literature, we expect to find that higher doses will increase the 
duration of eye gaze on the face region as compared to placebo and other smaller doses of IN-
OT.  
Aim 3: Effects of intranasal oxytocin on the BOLD activity of SBN in response to an 
interactive social reward task (60-70 minutes after IN-OT) 
We hypothesize that high levels of IN-OT will enhance brain activity and functional connectivity of 
social brain networks areas involved in perception and emotional processes in response to 
dynamic social cues as compared to non-social cues. We are also interested in looking into the 
effects of IN-OT on reducing the activity of amygdala and anterior hippocampus in a context 
dependent fashion (as based on level of stress). We also believe that the clinical/behavioral and 
endophenotypes will play a fundamental role in determining OXT’s effects on brain activity.  
Primary outcome measure: Here, we are looking to differences between treatments conditions on 
BOLD activity of perceptual and emotional brain regions while participants play a multi-player ball 
game. We predict that a higher dose of IN-OT will enhance the BOLD activity of reward brain 
regions (such as OFC, ventral striatum, Nucleus accumbens, ventral tegmental area) and 
perceptual brain regions (such as inferior occipital, fusiform gyrus, superior temporal sulcus, 
amygdala, superior parietal lobe) and insight awareness (insula and ACC) for facial expressions 
as compare to neutral non-social trials, regions that are expected to be less activated in placebo 
as compared to healthy subjects. We also expect increased activity in rewarding brain regions in 
response to positive social feedback as compared to neutral social feedback. We also expect to 
find a main effect of IN-OT on reducing the activity of amygdala and hippocampus during the ball-
game, in a context dependent manner (which could be related to a reduction of stress and 
anxiety). Indeed, we expect to find the neutral feedback trials to be more stressful and activating 
more the amygdala when compared to the positive trials. 
Indeed, in contrast to positive feedback, we expect the neutral to be eliciting negative social 
feedback in this kind of social context.  
Secondary outcome measure:  
We are looking into differences between treatment conditions on behavioral outcome of social 
learning paradigm (post scanner) following the ball-game. We are looking into implicit effects of 
learned emotional associations on reaction time. We expect to find more emotional implicit social 
biases with IN-OT.  
Aim 4: Plasma oxytocin concentration and exposome/metabolome 
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Here we hypothesize that IN-OT will enhance plasma oxytocin concentration in a dose 
dependent fashion.  
Primary outcome measure: We will investigate the differences between treatment conditions in 
oxytocin plasma concentration. We expect to find that higher doses of IN-OT will enhance 
significantly the plasma OXT concentration as compared to lower dose of IN-OT and to placebo. 
Secondary outcome measure: We will study the differences between healthy subjects and 
patients with ASD in terms of baseline oxytocin concentration. We expect significant difference 
and reduced levels of OXT at baseline in ASD. 
different nature of social dysfunctions. 
Procedures 
Pilot study:  
Before we conduct the clinical trial, we will test few volunteers (number maximum 10, friends and 
colleagues or study staff, men between 18 and 45 years old) on the different tasks of the MRI 
functional sequences. This will allow us to validate that everything is working (eye tracker 
installation, presentation of stimuli, synchronization of all data, etc.). We will use the same fMRI 
screening form as for healthy subjects. It is possible that 2 or 1 pilot will be enough to validate all 
the MRI parameters. 
 
Inclusion criteria for the pilot study participants:  
- 
Males between 18 and 45 
Exclusion criteria for the pilot study participants: 
- 
History of seizures 
- 
Neurological disorder or head trauma 
- 
Presence of a severe medical problem 
- 
Cardiovascular Disease 
- 
Current frequent and untreated asthma 
- 
Current frequent and untreated migraines 
- 
Pacemakers, cochlear implants, surgical clips of metal fragments.  
The pilot volunteers will perform all the same tasks inside the MRI scanner as described above. 
They will not need a debriefing given that they will know that the social tasks are not based on 
real interactions. Given that the pilot volunteers will be staff members or colleagues, it is possible 
that they will be informed about the study through direct conversation or through a phone 
conversation. We will document methods of recruitment and screening. They will complete the 
MRI screening form and sign appropriate pilot consent form. We will provide all the instructions 
about the different tasks that they will perform inside the scanner. They will also perform the 
trainings and quizzes for the tasks that they will conduct inside the MRI scan. We will set up the 
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camera on the coil of the MRI machine and calibrate their pupil and their eye movements in order 
ensure quality of recording of eye movements during face processing task. They will also wear 
the sensor inside the MRI scanner. They will perform the resting state sequence, face perception 
task and the ball game. All the details of these tasks are explained below.  
Clinical Trial 
1-  Screening and recruitment 
All information collected during phone and email correspondences will be documented in an excel 
sheet on a HIPPA protected location (such as Emory box).  
Subjects or and families (healthy subjects and subjects with ASD) will be contacted by email 
and/or by phone. We are recruiting participants who have previously participated in another study 
(IRB protocol #64623, where Dr. Andari is an investigator) and who agreed to be contacted for 
future studies or agreed to participate in this study and who have the basic criteria to be eligible 
for the study (such as IQ>70 and autism diagnosis as based on ADOS and ADI criteria). Contact 
information will be collected from protocol 64623.  We will contact them to ask if they are still 
interested and available to participate in this AOB project. Based on the records that we collected 
from project 64623, we will be able to know which patient with autism have his parents as legal 
guardian or legal representative. 
Recruitment:  
We will contact patients and healthy subjects by phone or/and email by following recruitment 
phone and email scripts. We will introduce ourselves and introduce the study and ask participants 
if they are still interested in participating in the study. We are likely to call the parents of patients 
with autism to ask them if their son is interested in participating given that some patients don’t like 
to be in touch by phone and don’t respond to emails. In some cases, we need to call parents who 
have legal guardianship in order to see if they would be available to accompany or willing to mail 
us a signed consent form so that their son can participate in the study.   
In some cases, we will try to do the recruitment, screening and scheduling in the same phone call.  
Screening: 
The medical screening form (that includes inclusion and exclusion criteria) will be first 
reviewed over the phone for both healthy subjects and ASD (following an oral consent for 
screening). In case there is any doubt in the results, the research staff will contact the PI 
or study physician to make sure that the person can be included in the study. For this 
initial screening, we do not require study physician signature to enroll a patient in the 
study. During the research visit, the participant will be asked to review it and sign his name 
on the form. The legal guardian, if applicable, will be also asked to sign it. The nurse 
practitioner or the MD need to sign the form also.  
The MRI screening form will be also reviewed over the phone with the participant (or with 
the parent of the patient in case it’s difficult for the patient to have the discussion over the 
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phone) following an oral consent. In case there is a doubt in any of the points, we will ask 
the MRI specialist to see if we can still include the subject in the study. During the research 
visit, the participant will review it and sign it and we will give a copy to the MRI technician. 
The legal guardian, if applicable, will also be asked to sign it. 
ASD 
Over the phone, the staff member will go through the oral consent for screening for eligibility. Over 
the phone, we will conduct the medical screening in order to assess eligibility (as based on the 
inclusion and exclusion criteria of the study). We will introduce the study and answer any 
questions about the content of the study. We will also go through the MRI screening in order to 
assess safety and eligibility. We can send them the MRI screening form by email to review. We 
will ask participants if they have a legal guardianship. We will document in a screening log who 
conducted the discussion over the phone, whether the person is eligible, whether there are 
questions for the PI or MD investigators, and the dates of the phone interview. We will follow a 
screening phone script to contact patients. It is very likely that we need to contact patients several 
times in order to finish the screening or to come back to patients about eligibility (in case there 
were questions to the PI).  
In some cases, we need to contact the parents of patients to schedule patients’ visits given that 
the parents are managing their son’s schedule, or that it’s difficult to reach patients (by email or 
phone) or that it’s difficult for patients to understand instructions over the phone or by email. In 
these cases, we will need to conduct the interview with the parent. We will go through the same 
phone script for recruitment and screening that includes an oral consent and eligibility criteria and 
screening assessment (same phone script as above). We will ask parents to inform the patient 
about all the details of this interview and ask them if they are interested in participating in the 
study. We will document that the interview was done with the parent and not with the patient in 
the screening log documentation. When patients show up for their first visit, we will make sure to 
go over the eligibility and screening forms again. We will follow-up with the parent and patient by 
email or phone to schedule all the visits and to confirm appointments.  
It is also possible that we do the same phone screener with both parents and patients in case 
there are some doubts about some answers.  
In addition to the phone interview, it is likely that we send the parents and/or patients the MRI 
screening form via email to go over it in order to double check all the criteria. We will use an email 
recruitment template. 
We will respond to emails and phone calls of parents and patients who have questions or need 
more information about the study.  
For adults who have legal guardianship or legal authority representative, parents need to sign the 
consent form also (in addition to the adult subject’s signature). The parent needs to be present 
during the first visit and is not required to stay for the rest of the visits. However, we are not asking 
the permission from the legal guardian to conduct the phone screening process. The LAR will be 
asked to sign the screening form. We will conduct a parent phone call by following a LAR phone 
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parent script. We will contact the parent by phone and ask them first to verbally confirm if they 
have the authority to make research decisions (power of attorney, legal guardianship). Once 
confirmed, we will introduce the study briefly and ask them if they can accompany their sons for 
the first research visit. We will explain to them that we need their signature on the consent form 
in order for their son to participate in the study. In this case, the parent and the patient will sign 
and date the consent form, as well as the screening forms, during the first research visit. During 
the research visit, the staff member will discuss the consent form with both patient and parent, 
and will ask them to read it, to ask questions and to sign it when they are ready. The staff member 
will provide a copy of the consent to the patient and to the parent. There is no need for parents to 
accompany their sons for all the visits. 
If the parent cannot accompany their son to the research visit (onsite at Emory), we will ask the 
parent (during the phone interview) if we can mail them the consent form and we will ask them for 
the mailing address. We will discuss the consent form over the phone. We will let them know that 
they cannot scan and email us back the consent form. They have to mail the signed consent form 
back to us to the address 1462 Clifton Rd, Rm 269. We will mail a copy of the consent form to the 
parent (one for them to keep as a copy and one for them to sign and send it back to us by mail) 
and the screening form with a returned envelop (and a stamp) and ask parents to read and sign. 
We will make sure to have colorful post-it on the pages where the parent needs to sign, date and 
time. We will ask them to email us or call us in case they have a question. We will make sure that 
we receive the signed consent form and screening forms from the parent before patient’s first 
research scheduled visit. If the form was not dated or timed correctly or if the parent forgot to add 
date and/or time, we will write a note to file regarding this event describing the omission of the 
date and time. We will go ahead and mail again the form to the parent (with the return envelope 
and a stamp) and ask them to add the date or/and time. The same applies for signature omission 
or if the signature is misplaced. We will call them or email them to let them know that we are 
mailing them the consent because of the omission. Once the consent is signed by the 
experimenter and the patient, we will send a signed copy to the parent by mail or we send 2 
signed copies of the consent with the patient (one for the parent).  
We will follow a legal guardian phone script while making this phone interview with the legal 
guardian. We will document who discussed with the parent and what was the content of the 
discussion in the screening log document.  
All the informed consent process with LAR will be documented in the informed consent process 
note and will be added to subject’s individual folder.  
We will respond to email requests and phone calls for information with form recruitment email, 
including available times, documentation and screening form attached if necessary.  
If the patient is eligible for the study, we will request an appointment with the CRN and put an 
appointment in the calendar. We will also reserve the MRI scanner. 
Once the CRN approves, we will notify the patient with a reminder email, we will notify Dr. Haroon 
or Dr. Cubells and notify IDS.  
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Healthy subjects screening: 
Given that the healthy group of males should match patients with ASD on age, sex and intellectual 
quotient (IQ), we will first contact patients (from the data base of the previous protocol 64623) and 
see who is interested and eligible before selecting the matching healthy men controls. We will 
select healthy participants who already participated in our previous research study (64623). We 
will use the information collected in project #64623 to match their IQ and age. We will contact 
participants who agreed to be contacted in the future studies in the consent form of protocol 
64623. We will contact healthy subjects by phone and/or email (again from the data base of 
64623) to see if they would be interested to participate and whether they are eligible (based on 
eligibility criteria for healthy subjects and based on safety screening). We will follow a phone script 
and email for recruitment for healthy subjects. We will respond to email requests for info and 
include screening form attached.  
Given that mid-way study, we have trouble bringing back healthy participants who have 
participated previously in protocol 64623, we need to recruit new people from general population 
in Atlanta. We will use flyers to recruit more people. We will post these flyers in different locations 
around Atlanta area (like in restaurants, college, Marta stations etc). We will need to conduct the 
IQ test and color blindness prior their main visit to the hospital. Healthy controls should match 
ASD patients with IQ and race. We are adding race so that samples from both groups stay 
matched as much as possible.  
We have already conducted the total number of patients for this study. The average IQ of ASD 
patients is 98.39 and the standard deviation is 16.28. The race ratio for ASD is 82% white, 12.5% 
African American and 6% more than one race, 
Accordingly, we are adding a new informed consent and another inclusion criterion for this 
separate group of healthy subjects (labeled II). The inclusion criteria will include Caucasian race 
and IQ range between 70 and 115.  
The reason that we are adding Caucasian to the inclusion criteria for this new set of healthy 
subjects is that we have already 2 or 3 contacts from the previous study who are African American 
and who are interested to participate. This will make approximately 10% of the healthy subject’s 
sample if we were able to recruit 30 total.  
If the IQ was higher or lower than this range, we will exclude the participant from participating in 
the study. For this new set of healthy subjects, they need to come for 2 separate visits. The first 
visit will consist of performing the IQ (at the hospital or at Clifton 1462) test and consent signature 
as well as review of eligibility criteria and color blindness test. The second visit will consist of the 
main clinical visit at the Hospital  
If the subject is eligible for the study, we will request an appointment with the CRN and put an 
appointment in the calendar.  
Once the CRN approves, we will notify the subject with a reminder email, we will notify Dr. Haroon 
or Dr. Cubells and notify IDS.  
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For both healthy subjects and ASD subjects, in case there is any doubt in the screening form or 
eligibility of participants, prior scheduling the research visit, the PI will be notified and will review 
the screening form and if needed consult with study physician or study nurse practitioner. If it is 
determined that the subject meets inclusion/exclusion criteria, the research staff will schedule the 
different visits of the subject. On the day of the scheduled visit, the study staff will review the 
consent form with the subject and give them the opportunity to ask any questions before asking 
them to sign in person.  
Subjects will meet the study staff at the entrance of the Emory Hospital.  
Patients will participate in 5 visits total and these visits can be separated by a one-week interval 
approximately (± 2 to 3 days). We have to be little flexible in the schedule given that we are dealing 
with complicated scheduling system (scheduling CRN units at the hospital, MRI scanner at BITC, 
nurse practitioner or physician, patients’ availability).   
2- Visit1-pre clinical (around 3 hours) 
All the visits for healthy subjects and ASD subjects will occur at the Emory Hospital. With the 
help of ACTSI facility, we will use one of their external outside CRN unit rooms to test 
participants on computer tasks, make interviews, collect saliva samples, filling questionnaires 
and getting snacks. For all the medical and health assessments (physical exam, vital signs, 
blood withdraw, spray intake) will occur inside the CRN outpatient services. For the MRI scan, 
we will conduct it at BITC scanner. All post-scanner questionnaires will be conducted in this 
external room provided by ACTSI inside the hospital.  
ASD subjects 
Upon arrival, staff will review the screening form previously filled as well as eligibility criteria and 
the MRI screening form out for correctness and affirm that no changes in their health or medical 
history have occurred. If any changes have occurred, the study staff will consult with the PI or the 
study physician, if necessary. We will review the consent form with the subject. We will also 
assess his understanding of the consent by asking specific questions that are part of an 
assessment of capacity form. The experimenter will ask the questions to the patient and will take 
notes of his responses. If the patient did not answer correctly to all questions, we will review the 
consent again and ask the questions again to ensure a full understanding of the consent. Once 
the patient understands the consent, we will proceed to the signature. This assessment of 
capacity form will be only administered to patients with ASD and not to healthy subjects. 
The nurse practitioner or the study physician will conduct a brief history and physical. The nurse 
practitioner will go through the inclusion and exclusion criteria again to ensure that the patient is 
ready to participate in the subsequent clinical visit. This health assessment will be reviewed again 
one more time during one of the subsequent clinical visits. 
Participants will fill a family history form related to themselves and to their family history . 
We will collect saliva samples (3 DNA Genotek kits) for genotyping analysis and methylation 
analysis.  
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The patient will complete several questionnaires.  
Given that there is lot of questionnaires to complete, we can ask participants if they prefer to 
complete them at home. Participants can complete the questionnaires and bring them back during 
the following visits.  
Participants will also perform a social learning test during which the participants match faces or 
words as fast as possible. This test is an adaptation of the implicit association task during which 
we study implicit associations. 
Participants will be trained on the different behavioral tasks that they will be performing during the 
MRI scanner: the face perception task and the social games. There will be specific instructions 
and a practice session on the computer screen for each of these tasks. Participants will complete 
a quiz for the face perception task and for the ball-game to double check the comprehension of 
the task. If there are errors in responses, the experimenter will repeat the instructions or, if 
necessary, present some training sessions on the screen and repeat the questions that 
participants did not answer correctly, until he has all the answers correct.  
At the end of this visit, participants will go through a brief clinical standardized interview (Bio-
behavioral clinical global interview BB-CGI) with the experimenter during which the experimenter 
will ask questions to the subject and record their interactions.  
This clinical test will be repeated at the end of each of the following 4 MRI visits in order to evaluate 
the progress or come up with a score of socio-emotional, verbal, physiological and clinical index 
of improvement.  
We will take a photo from this video to keep the photo identification in the folder of the patient.  
At the end of the interview, the study staff will take the patient to the BITC MRI scanner at the 
Emory Hospital for a practice/habituation session. The participant will lay down in the scanner 
(same way as described below during the clinical visits), get familiarized with the coil and the 
tunnel, with the response box (that he will use to answer during games), with the noise, and to 
with some examples of the tasks that he will perform during the actual clinical visits. We will run 
an fMRI sequence for few minutes (that might include a resting state, face test, ball-game). At the 
end of the MRI training/habituation, we will ask participants few questions about his experience. 
The participant will be also asked about any adverse events. In case of mild anxiety, the 
experimenter will make sure to give the participant time to rest and ask him if he would like to 
continue habituation.  
Participants will also have a look at the CRN unit.  
Given the complexity of scheduling MRI scanner, the CRN unit and the nurse practitioner, the 
tasks above do not need to be performed in a particular order. Even the health assessment can 
be performed at any time given that the goal of the health assessment is to make sure that the 
subject is healthy before its inclusion in the subsequent 4 clinical visits. 
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Of note, the results of the health assessment do not determine whether the subject can or cannot 
participate in this first non-clinical visit.  
Given that the MRI scanner is always functioning, we will make sure to collect MRI screening 
forms from subjects before approaching the magnet.  
 
Screening 
And health 
asessment 
Consent  DNA Questionnaires Computer 
tasks 
Clinical 
interview 
Training 
on 
behavioral 
tasks 
and 
MRI 
+ 
questionnaire 
Prior 
visits 
X 
 
 
 
 
 
 
Pre-
MRI 
visit 
X 
X 
xxx 
X 
X 
X 
X 
Table 1: Pre-clinical Visit 1 for subjects with ASD  
3- Second visit: clinical visit for ASD (total duration= around 3 to 4 hours) 
Subjects will meet the study staff at the Emory University Hospital. The different behavioral 
questionnaires, trainings and physical exams will be performed inside the hospital (in a separate 
room of the CRN unit). All the vitals as well as the nasal spray delivery and blood samples and 
DNA saliva samples will be performed inside the CRN unit in the presence of a nurse.  
Given that the staff researcher needs to synchronize between MRI scan appointment, CRN unit, 
IDS and hormone timeline, we will be flexible with the order of administering questionnaires, 
training and practice sessions to participants (dependent on breaks and fatigue of participants).  
Inside the scanner, participants will perform these 2 tasks: 
Task number 1: Face perception task (FPT): participants will be given a tutorial and a short trial 
practice session to familiarize them with the procedure of the task. The Subjects will also complete 
a simple quiz to insure the comprehension of the task. If the subject incorrectly answers one or 
more question, the researcher or coordinator will explain why the answer was wrong and will not 
proceed with the experiment until convinced that the subject understands the game. During this 
test, we will use an eye tracker (from the SMI company) to track participants’ eye movements 
inside the scanner.  
Task number 2: Multi-player emotion-based ball game (MP-EBG): participants will be given 
instructions and a short trial practice session to familiarize them with the procedure of the game. 
The Subjects will also complete a simple quiz to insure the comprehension of the task. If the 
subject incorrectly answers one or more question, the researcher or coordinator will explain why 
the answer was wrong and will not proceed with the experiment until convinced that the subject 
understands the game. 
Subjects will be asked to refrain from use of caffeinated drinks or tobacco for at least 12 hours 
prior the blood pressure and heart rate measurement.  
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• 
Consent and training: We will first review the screening and the consent form. 
Participants will also perform the training/practice and quizzes on the face perception task 
and the ball-game that will be performed inside the scanner. Participants will also be asked 
to complete simple questionnaire (such as the face rating questionnaire). Questions about 
the mood will be again asked after spray intake.  
• 
Vital signs: Prior to hormone administration, temperature, heart rate and blood pressure 
will be measured and recorded by the CRN nurses. Weight and height will be also 
measured. If heart rate is above 100bmp, or blood pressure is above 140/90, vitals will be 
re-measured. If levels remain elevated after 3 successive recordings in both limbs (total 
of 6 recordings) measured at least 5 minutes apart, the study physician will be notified and 
asked to advise on how to treat the subject and whether it is safe to continue with the 
protocol. Subjects may still be included at the discretion of the study physician. This is 
done in order to proceed with baseline vital signs that are within post-hormone 
administration guidelines. Researcher will ask if the subject is experiencing any adverse 
events at this time, to provide a baseline before hormone administration.  
• 
Blood draw: A registered nurse from the CRN will collect 10 ml of blood by venipuncture 
for subsequent baseline measurement of plasma oxytocin. Blood will be collected in a 
lavendar-top EDTA-treated tube. Samples will be immediately centrifuged at 4C by the 
CRN core laboratory and the plasma and blood cells will be stored at -80 until assay at 
the CRN unit.  
• 
Spray intake: Patients with ASD will receive intranasal administration of either syntocinon 
oxytocin spray 8IU or 24IU or 48IU or placebo. Given that it is a double blind study, we 
will make sure that all participants receive the same amount of puffs (12 total puffs) across 
all visits across all doses and placebo. Nurse will instruct the patient to clear the nose from 
obvious obstruction before administration. The nurse will prime the bottle by spraying in 
the air before administration. The nurse instructs the subject to sit with the head upright 
with little tilting to the back. The patient can close one nostril with one finger while the 
nurse is administering the spray to the other nostril. The nurse will ask the patient to sniff 
and breathe in gently directly after each delivery and block the opposing nostril. The 
insertion depth of the spray should be greater than 1.5 cm into the nostril. Ideal is around 
1 cm. The nurse will hold the bottle on angle > 45 degrees from tip of spray bottle to 
horizontal plane. The nurse will make sure that the correct amount was entered and that 
there is no drainage from the nose. We are adding an appendix on chemistry and design 
at the end of this protocol to provide more details on the drug design. The placebo solution 
will contain all the inactive ingredients of the OXT solution except for the active oxytocin 
neuropeptide. The placebo and the Syntocinon spray will be purchased from a pharmacy 
in Switzerland. Both the experimenter and the subject will be blind to the solution they are 
receiving. Nurses will be trained on the instructions for the application of the nasal spray. 
They need to make sure that they depress the lever until the subject feels the mist of spray 
in the nostril and then let them breathe in deeply through the nose and afterwards to place 
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the applicator in the other nostril and repeat the process with some few seconds interval. 
Subjects will be asked to answer some questions on whether he could discriminate the 
different doses of oxytocin or oxytocin from placebo. Participants will be asked on whether 
they think they took placebo or oxytocin following spray intake. A stopwatch will be started 
at the middle of the administration of the spray so that the resting state fMRI starts exactly 
at 40 minutes later.  
 
Healthy subjects will only receive 12 puffs of placebo spray. They will not receive 
Syntocinon spray. However, they believe that they might be taking placebo or Syntocinon.  
• 
Blood draw: 5 minutes after spray intake, a registered nurse from the CRN will collect 10 
ml of blood by venipuncture for subsequent baseline measurement of plasma oxytocin. 
Blood will be collected in a lavendar-top EDTA-treated tube. Samples will be immediately 
centrifuged at 4C by the CRN core laboratory and the plasma and blood cells will be stored 
at -80 until assay.  
• 
Vital signs: 15 minutes after spray intake, temperature, heart rate and blood pressure will 
be re-evaluated by the CRN nurse to check for any side effects of IN-OT. There are several 
evidence of safety and absence of side effects from chronic and acute intake of IN-OT. 
Thus, we do not expect any side effects from the hormone oxytocin intake. However, we 
will ask subjects if they feel any side effects. If no side effects are reported, but 
temperature has increased or decreased more than 2 degrees, heart rate is above 100 
bpm, or blood pressure is above 140/90, the vitals will be re-measured. If levels remain 
elevated after 3 successive recordings in both limbs (total of 6 recordings) measured at 
least 5 minutes apart, the study physician will be notified and asked to advise on how to 
treat the subject and whether it is safe to continue with the protocol. Subjects may still be 
included at the discretion of the study physician. If subjects were to experience a serious 
adverse event, such as a heart attack or an anaphylactic reaction, a code will be called 
and, if necessary, the subject will be taken to the Emory ER. Dr. Haroon or/and Dr. Cubells 
and the CRN nurses will be notified by the experimenter. Dr. Haroon or Dr. Cubells will 
call to admit the subject to the ER. As we already mentioned, it is not likely that oxytocin 
has any side effects based on the growing evidence in the literature. In addition to vital 
signs, we will ask participants if they feel any side effects.  
• 
MRI scanner (one-hour duration): Subjects will next be escorted to the Biomedical 
Imaging Technology Center in Emory University Hospital from the CRN, accompanied by 
study staff. Subjects will next be positioned in the MRI scanner (Siemens, 3T). Subjects 
will lay motionless inside. Padded head restraint will minimize head movement during 
scanning. Each scanning session will begin with a scan to localize the position of the brain 
within the magnet.  A vitamin E capsule will be taped to the subjects left temple as a 
localizer for the images collected. Participants will be given a button box which they will 
use to perform all the tasks. We can also give them a blanket if they are cold. We will 
explain to participants how to use the box for each of the tasks. Before starting the tasks 
below, we will run localizer sequence. 
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• 
At first, (40 minutes after spray intake) participants will be asked to rest and not think 
of something specific for 8 minutes. We will be recording brain activity during resting state 
(no task involved).  
• 
Second, (FPT or face perception task) participants will be told that faces will be 
presented at the screen and that these faces will be separated by a fixation cross that can 
be blue or red. They are asked to press a key whenever they observe a blue cross. During 
this task, participants’ eye movements will be recorded by an eye tracker that will be 
implemented inside the MRI scanner. Participants will not be told about the eye tracker 
given that we don’t want to bias their attention. Participants will be wearing the watch 
sensor. Participants will be debriefed about the presence of the eye tracker at the end of 
the study. 
• 
Third, (MP-EBG or multi-player’s emotion-based ball game) participants will play 
several runs of the ball game with several players. We might have a discussion that will 
be shown at the screen with another coordinator to convince participants that they are 
playing with other players that are staying in another room. Participants were already 
instructed about the details of the game.  
• 
Anatomical Image Acquisition: Field map and T1 will be acquired (this can be acquired 
in the middle in between games or at the end of the session).  
• 
Post MRI scan: Subjects will be escorted to the office next to the scanner and will be 
asked to rest and then complete some tasks and questionnaires. It is possible that we 
offer participants some snacks or lunch. Participants will complete: 
      
• 
Face Rating questionnaire (post MRI): participants are asked to rate (on a scale 
1 to 7) faces. 
• 
A social learning test (SLT): participants are asked to match faces and words as 
fast as they can.  
• 
Emotion Matching test (EMT): participants are asked to identify the emotion that 
is displayed on a face by matching the emotional face that appears on the left to 
one of the faces that appears to the right (different faces but same emotion).  
• 
Toronto Alexithymia scale: participants are asked to complete a simple 
questionnaire.  
• 
Mood questionnaire (PANAS scale). 
• 
BB-CGI (clinical interview): the same interview that is performed during the pre-
MRI visit will be performed during this visit in order to collect a clinical score of 
improvement as well as physiological, verbal and socio-emotional improvements.  
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4- Second, Third and Fourth visit of scan (ASD subjects) (total duration= around 3 to 4 hours 
each): The exact same procedures will be performed during these other 3 visits. These 3 
additional visits will be conducted only in ASD subjects. Also, participants will receive 
different content of spray (either different dose of oxytocin or placebo).  
Of note, the health assessment will be reviewed one more time (in addition to the assessment 
during the first pre-clinical visit) by the nurse practitioner or the study physician during one of the 
4 clinical visits, if the original health assessment expires (more than 30 days). 
 
Screening and 
consent 
review/training 
Vital 
signs 
1  
Blood 
samples 
Pre 
Hormone 
Spray 
(PL, 8, 24, 
48 IN-OT) 
Blood 
samples 
post 
Vital 
signs 
2 
MRI 
scan 
Post 
MRI 
scan 
Visit 
1 
X 
X 
X 
X 
X 
X 
Rest+ 
3 
tasks 
Quest+ 
2 tasks + 
clinical 
interview 
Visit 
2 
X 
X 
X 
X 
X 
X 
Rest+ 
3 
tasks 
Quest+ 
2 tasks + 
clinical 
interview 
Visit 
3 
X 
X 
X 
X 
X 
X 
Rest+ 
3 
tasks 
Quest+ 
2 tasks + 
clinical 
interview 
Visit 
4 
X 
X 
X 
X 
X 
X 
Rest+ 
3 
tasks 
Quest+ 
2 tasks + 
clinical 
interview 
Table 2: Clinical trial visits for subjects with ASD 
Visits will be separated by a one-week interval approximately (± 2 to 3 days). We have to be 
flexible with the scheduling given that we are facing challenges while scheduling all the units and 
personals. Every patient will receive the 3 doses of IN-OT (8IU, 24IU, 48IU) and placebo in a 
double blind, placebo controlled trial. 
It is also possible that some patients will feel tired and will not be able to go through all the tests 
inside the MRI scanner. In this case, we will stop as based on participants’ level of fatigue. We 
will try to have similar number of tests across 4 clinical visits. 
I would like to mention here that given the complexity of this study, we expect that some of the 
tasks/procedures will be omitted or not completed during each of the 5 visits. We do not expect 
that all patients perform all the tasks described above (inside or outside the MRI scanner). We 
will try our best to test participants on all these tasks above but we could face some challenges 
and decide not to complete them. For instance, we will be based on the fatigue level of patients 
and patients’ feedback to make these decisions. The level of fatigue varies from one participant 
to another.  
Healthy subjects  
Healthy subjects will participate only in one visit (around 4 hours) during which they will:  
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- 
Revision of the screening forms which includes eligibility criteria and MRI screening form 
by the PI or study coordinator. The PI will update the physician at regular meetings about 
the inclusion of these subjects. If there is any doubt about inclusion criteria, the PI will ask 
physician for advice. However, there is no need for the signature of the physician or the 
nurse practitioner on the eligibility criteria given that we are including healthy subjects and 
we are administering only placebo spray. The nurse practitioner or the study physician will 
not conduct a health assessment.  
- 
Read and sign the informed consent (no assessment of capacity is necessary).  
- 
Complete some questionnaires: Symptom Checklist SCL-90, the interpersonal Reactivity 
Index, emotion rating of faces 
- 
Complete a computer test of social learning test 
- 
Complete a training on the face perception task and social games (as described above) 
and will perform quizzes 
- 
Subjects will refrain from use of caffeinated drinks or tobacco for at least 12 hours the 
testing.  
- 
Blood draw as described above 5 minutes after the spray 
- 
Vital signs collection directly after the blood draw (no need to wait for an exact 15 minutes) 
- 
Spray intake as described above. Subjects will think that they might be taking oxytocin or 
placebo. The experimenter is aware that the subject is receiving placebo. The nurses who 
are administering the drug are not necessary aware of the content of the drug.  
- 
Second blood draw 5 minutes after spray intake 
- 
Vital signs collected 
- 
MRI scan: Subjects will also complete the resting state, the FPT task and the ball-game 
inside the MRI scanner. Ideally, subjects will also start around 40 minutes after the spray 
intake. The timing will be more flexible given that subjects are not receiving drug. 
- 
Participants will complete face rating questionnaire, the SLT and the EMT as well as the 
Toronto Alexithymia and mood questionnaire.  
We will not collect physiological data on healthy subjects as we are not conducting an interview. 
We might be able to collect some data while they are inside the MRI scanner. 
 
 
Screening and 
consent, 
questionnaires, 
practice 
on 
behavioral 
tasks, 
computer tasks 
Vital signs 
1 
Blood 
samples 
Pre 
Spray 
(Pl) 
Blood 
samples 
post 
Vital 
signs 
2 
MRI 
scan 
Post 
MRI 
scan 
Visit 
1 
X 
X 
X 
X 
X 
X 
Rest+ 
3 
tasks 
Quest+ 
2 tasks 
 
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The new group of healthy subjects that we are recruiting from general 
population to match patients with autism will have to do two visits. 
The first visit will consist of revision of informed consent and screening 
tests (that includes an IQ test and a color blindness test). 
The second visit will be the same as above.  
Risks/discomforts and potential benefits  
DNA: A breach in confidentiality, resulting from inadvertent disclosure of genetic information to 
parties outside the research group, has the potential to negatively affect participant’s insurability, 
employability or reproduction plans, and could have a negative impact on family relationships 
and/or could result in paternity suits or stigmatization. 
DNA methylation: DNA methylation data is not informative for individual identification.  
Intranasal OT administration (Syntocinon): In rare cases, nausea, vomiting, headache, 
irregularities of the pulse, skin rashes and allergic reactions in combination with shortage of 
breath, blood pressure decreases or circulatory collapse are reported as adverse effects of 
regular and repeated administration of Syntocinon. However, it is important to note that no serious 
adverse side effects have been reported following the administration of one single dose in any of 
the previously published studies using intranasal oxytocin.  
Today, there are several studies with single doses and chronic oxytocin administration to 
individuals with ASD. Aoki et al. 2014 administered 24IU to 40 ASD with an average age of 29.6 
and reported no adverse side effects. Auyeung et al. 2015 administered 24IU to individuals with 
ASD (34 years old on average) and found no serious side effects. They reported runny nose (in 
3 cases with oxytocin vs 5 cases with placebo), tiredness (2 cases of oxytocin vs 3 cases with 
placebo), sore throat (1 case with oxytocin vs 0 case with placebo), shakiness (0 with oxytocin vs 
1 case with placebo). Healthy subjects who received placebo spray reported runny nose, 
tiredness and mild nausea. Guastella et al. 2010 showed no difference in the number of reported 
side effects between oxytocin and placebo conditions in ASD (18IU or 24IU). Under oxytocin, they 
felt tired, relaxed and sweating. Under placebo, they felt tired, relaxed, headaches and coughing.  
In a chronic administration (2months administration of 8IU, 6IU and 24IU) to ASD subjects 
between the ages of 10 and 14, Tachibana et al. 2013 conducted a safety study. They monitored 
blood pressure, urine osmolality, urine sodium concentration and serum osmolarity, serum 
sodium concentration and plasma OXT concentration, serum bone specific alkaline phosphatase 
and short memory and found no side effects. Hence, studies in the literature show that oxytocin 
administration is safe, especially in our study context. We do not expect serious adverse events 
related to oxytocin and do not expect significant differences in adverse effects between oxytocin 
doses and placebo.  
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Blood draws: The needle stick for the blood draw may cause momentary pain or discomfort.  In 
rare cases, bruising at the site of the draw may occur.  In rare cases, the subject may feel light-
headed or faint as a result of the blood draw. 
MRI: Potential risk to subjects without contraindications includes mild anxiety, claustrophobic 
reaction, and movement of ferromagnetic objects.  Certain MRI scanning procedures can produce 
loud (>100 dB) noises, so ear protection will be provided by the use of sound-reduction earplugs.  
Beyond these risks, there are no known side effects of MRI to subjects without contraindications.   
Participants might feel fatigued from the several hours of testing. 
Procedures for minimizing risks: 
Genetic testing: We recognize the sensitive nature of genetic information and the need to 
maintain strict confidentiality procedures for data that may ultimately be available to the wider 
scientific community. To minimize the risk of inadvertent disclosure of research information to 
outside parties, all information obtained from participants will be kept strictly confidential. No 
individual genetic results will be given to participants or their relatives. DNA used in this study will 
be assigned a code and the link to further identifying information concerning the individual will be 
available only to the PI. Release of data from NIMH to the wider scientific community will be in 
accordance with confidentiality procedures that have been established by the NIMH Genetics 
Initiative. We will adhere to the guiding principle that study identifiers cannot be connected with 
personal identifiers at any state of the data collection. Personal identifiers (i.e. name, address, 
email contact details) will be maintained on a secure server that follows HIPAA regulations.  We 
will be transferring blood cells, plasma samples to other laboratory within Emory and outside 
Emory (after getting a permission of a medical transfer agreement). We will make sure to send 
de-identified coded samples. The same applies for saliva samples.  
We would like to add more specific details about the processing of plasma samples. We are 
transferring some of the plasma samples of healthy subjects and patients with ASD from the CRN 
unit to Shota Nishitani who is at Emory University. He will be analyzing the levels of oxytocin in 
plasma. The plasma samples are coded and do not contain names. However, there are some 
identifiers that are present on the samples: such as date of submission and other. We added 
Shota to the staff personnel.   
We are likely to give him saliva samples too to measure DNA methylation of the oxytocin receptor 
gene.  
 
Intranasal OT administration: With a single dose of Syntocinon, no adverse side effects of the 
substance are to be expected.  To further minimize risk, subjects will receive OXT at Emory 
Hospital (CRN unit at ACTSI).  To monitor potential side effects of OXT administration, 
temperature, heart rate and blood pressure will be measured before hormone administration and 
15 minutes after hormone administration. Experimenter will again ask if the subject is 
experiencing any of the following symptoms: chest pain, difficulty breathing, itching. If the subject 
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reports any of these symptoms, the study physician or study nurse practitioner will be contacted 
and asked to advise on how to treat the subject and whether it is safe to continue with the protocol. 
If necessary, a code will be called. If no side effects are reported, but temperature has increased 
or decreased more than 2 degrees, heart rate is above 100 bpm, or blood pressure is above 
140/90, the subject will be asked to sit quietly for 10 minutes after which vital signs will be re-
measured. If vital signs are within the normal range, and no side effects are reported, they will 
proceed through the experiment. If not, the study physician or study nurse practitioner will be 
contacted and asked to advise on how to treat the subject and whether it is safe to continue with 
the protocol. If subjects were to experience a serious adverse event, such as a heart attack or an 
anaphylactic reaction, a code med will be called and, if necessary, the subject will be taken to the 
Emory ER. Dr. Haroon or Dr. Cubells and the CRN nurses will be notified by the project 
coordinator. Dr. Haroon or Dr. Cubells will call to admit the subject to the ER. 
Blood Draw: Subjects will be monitored for signs that they may faint such as clammy skin, 
dizziness, confusion, irregular breathing, and decreased blood pressure.  If these signs are 
observed, subjects will be asked to lie down with their legs elevated and blood pressure will be 
monitored until symptoms subside.  If a subject loses consciousness and requires medical 
attention while in the Anthropology Building, Emory First Responders will be contacted (911).  If 
a subject loses consciousness and requires medical attention while at the Biomedical Imaging 
Technology Center in Emory University Hospital, study staff will instruct the MRI technician to call 
a hospital code for medical care. 
 
MRI: Risks will be minimized in the following manner: 1) Subjects will be screened for 
contraindications as described above.  In particular, subjects who have a history of moderate or 
severe claustrophobia may be excluded at the discretion of the PI. Subjects with a history or 
possible history of intra-ocular, intracranial, intrathorax, or intra-abdominal metal or cardiac 
pacemakers will be excluded.  2) Anxiety will be minimized by thoroughly explaining the 
procedures and the nature of the magnetic resonance scanner to subjects prior to study.  During 
the scanning procedures, the subjects are continually monitored visually and auditorily for any 
potential problems, and subjects are assured that they can and will be removed from the scanner 
at any time if problems should arise or they indicate that they are experiencing discomfort.  As 
noted above, subjects will be screened twice prior to study, once at the time of initial contact, and 
a second time when they arrive at the MRI facility prior to study. All of the data collected for these 
studies will be kept strictly confidential.  Under no circumstances will individually identifiable data 
be released to anyone without the written consent of the subject. MRI copies of the brain anatomy 
will be provided to subjects. 
 
 
Risk-Benefit Ratio: 
Subjects participating the study will receive a monetary compensation to compensate for their 
time and effort. The results of this study can provide more knowledge about the role of intranasal 
oxytocin in autism and about the neural correlates of its action. It will also provide knowledge 
about the heterogeneity in oxytocin effects that could be related to different intrinsic factors (such 
as DNA methylation, clinical classification, genetic polymorphisms, environmental factors, 
metabolites and immune factors). It will also provide more information on the biological basis of 
social functioning in ASD. It is hoped that such knowledge will ultimately lead to a better 
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understanding of psychiatric disorders involving social behavioral deficits. These potential 
benefits outweigh the minimal risk this research poses to subjects.   
Type of information collected 
 
1- We are collecting behavioral data from questionnaires and computerized social games 
and tasks. Responses to questionnaires, accuracy during games or tasks, reaction time 
will be collected and responses.  
2- Video-taping participants and getting a photo during the clinical interview BB-CGI (see 
above).  
3- Clinical diagnosis of severity of symptoms based on the BB-CGI that will rated by a 
psychiatrist.  
4- Based on the video-taping, staff members will code behavioral and emotional expressions 
and verbal aptitudes of participants and synchrony with the experimenter.  
5- Physiological measures from the sensor watch that will consist of temperature, 
electrodermal activity (or skin conductance), heart rate variability.  
6- MRI scans of anatomy that will be kept for future  
7- FMRI data (functional BOLD signal) in response to cues and in response to rest 
8- Vital signs (BP, Temp, RR, HR), weight, height 
9- General information form: the questions regarding participants are: medication, difficulties, 
current occupation, activities, social network, participation in behavioral therapy or group 
activities to stimulating social aptitudes, specific interest and knowledge, specific talents). 
The questions regarding subject’s family will consist of: number of siblings, gender of 
siblings, education/occupation/social aptitudes of siblings, parents and grandparents, 
health-related questions, presence of any psychiatric, autism-related disorders. 
10- Eye tracking data: eye movements of subjects while they are laying down in the scanner 
performing a task. We will quantify subjects’ visual duration and fixation on regions of 
interest of the stimuli that are presented on the screen. 
11- Physical that is performed by the NP.  
Specimens  
3 Saliva samples will be collected for DNA analysis. We will use the Oragen DNA kits. Some 
samples might be used to quantify DNA methylation of OXTR and OXT gene or OXTR 
polymorphisms, MET gene. The remaining samples will be kept safe for potential future use. We 
will not collect saliva samples from healthy subjects. 
8 blood samples (EDTA purple tubes of 10 ml each) will be collected per subject for all 4 MRI 
visits (4 blood samples will be collected before intranasal administration and 4 blood samples will 
be collected after oxytocin administration for all visits). Samples were kept chilled in ice and 
centrifuged within 1 h from collection at 1600 g for 15 min at 4 °C. Plasma was removed and 
initially frozen at −20 °C, then stored at −80 °C. Plasma samples and blood cells will be extracted 
and stored at −80 °C until the assays were performed. The centrifuging will be performed at 
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ACTSI and the samples will be stored at CRN until we are ready to transport some of the samples 
for the different laboratory to analyze it.  
We intend to send some aliquots of plasma from each of these 8 samples to public health to 
quantify oxytocin concentration in the plasma and to quantify the exposome and metabolome 
(chemicals/pesticides). 
Plasma will be analyzed for cytokines levels.  
Blood cells from 4 blood samples (prior to OXT administration) will be sent to analyze the DNA 
methylation and/or to analyze OXTR polymorphism analysis.  
The rest of blood cells and plasma will be kept safe at CRN unit for future analysis.  
All these specimens are collected from healthy subjects and from patients with autism.  
Randomization and blinding 
Clinical trial for ASD subjects: The trial will be a double-blind, placebo-controlled, several doses 
of oxytocin, within subject design study. Patients will undergo 4 clinical visits (in addition to a first 
pre-clinical visit) during which they receive 12 puffs (6 in each nostril) of 8IU total, 24IU and 48IU 
oxytocin (syntocinon) and placebo (assigned randomly). The placebo will contain the same 
ingredients as syntocinon, except the active molecule oxytocin. This is essential for making sure 
that the patient does not recognize the type of treatment he is receiving. Hence, both patients and 
the experimenter will be blind to the type of the treatment administered.  
The pharmacy IDS of Emory will be in charge of the randomization sequence and one of the staff 
members of the team (who is not involved in testing procedures) will be de-blinded.  
We will break the blind after testing 25 patients with ASD to check the results half-way for a mid-
point analysis. The mid-point analysis will focus on measures where effect sizes are anticipated 
to be large enough that the risk of false positives is minimal. We are expecting larger effect size 
on some measures and therefore we break the blind for those measures to be analyzed and 
published. Additional data on these measures will continue to be collected and we will attempt to 
publish the combined analysis at the end to avoid publication bias.   
However, the data collection will continue until a sample size equal to 50. Given that we are facing 
challenges with ASD recruitment and that the study requires the participation in 5 long visits, it is 
possible that the study will stop at N=30 or 40, in case the PI was not able to recruit more ASD. 
We also expect dropouts after recruitment. We believe that we will be able to test 30 patients with 
ASD.  
It is possible that this project will be funded by other grant funds which will allow adding more 
participants (more 50 ASD). In this case, the PI will submit an amendment accordingly.  
Healthy subjects: There will be only one clinical visit for healthy subjects and they will all receive 
placebo spray (12 puffs, 6 per nostril). The study will be conducted in a single-blind design. The 
PI is aware that the subject is receiving placebo. However, the participant will be told that he might 
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receive oxytocin or placebo. This is important in order to control for the placebo effect on behavior 
and brain activity.  
 
Storage:  
Saliva DNA samples will be stored in a locked place   
Blood samples will be centrifuged into plasma and blood cells at the CRN unit and stored at -80˚C 
at CRN unit until the PI is ready to transfer the tubes to laboratories for analysis. The PI will make 
sure that he has all the transfer material documents in place and all the procedures detailed in 
the IRB protocol before sending the samples for laboratories. All the samples that will be 
transferred to other locations for specific analysis will be de-identified and coded and will not have 
any personal identifiers related to participants’ identity. Only the PI will have access to the 
identifiers and link between codes and participants’ identity. Physical material such as files and 
folders (that includes identifiable information) will be stored in a secure and locked place. All the 
electronic excel data that are linked to identifiers will be saved on the psychiatry server (which is 
HIPAA compliant). Collaborators who will conduct the analysis cited above will collect the results 
in an excel sheet but will include only coded de-identified information. They will send the PI the 
excel files with the results via Emory email and only the PI will have access to the links between 
identifiers and the coded results.  
Our collaborators at public health have communicated with us the details of the storage of the 
plasma 
samples 
for 
oxytocin 
measurement 
and 
metabolites/exposome/pesticides 
measurements:  
Data files obtained from metabolic profiling will be stored on a secure, offsite RAID that was 
specifically designated for use by the Clinical Biomarkers Laboratory.  Feature tables will be 
stored on the network hard drive available to Biomarkers personnel associated with the project 
only.  All analyses of the result files will be logged, and include type of analysis, statistical 
parameters, date of analysis, investigator and summary of results.  All method operational 
parameters will be printed and stored with raw analysis logs, and any alterations to instrumental 
configuration will be noted in a log book kept for that specific instrument.  Laboratory notebooks 
will be maintained by all project personnel, with all entries made in ink.  Due to the nature of the 
research completed by the Clinical Biomarkers Lab, all technical infrastructures required for data 
management are in place and can be adapted for use for this project. 
Future use:  
All the samples remaining will be stored at the CRN unit/Emory hospital until further notice. The 
PI will decide when to destroy the samples. All the data and materials of this project (including 
samples, specimens, behavioral results, brain function, physiology and other) will be used only 
by the PI (Elissar Andari) or with her permission for future analysis, future studies etc. If the PI 
(Elissar Andari) leaves Emory, she would like to have access to all the samples and data for future 
studies. Any future study/collaboration at Emory or other locations using any data or materials 
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that were collected under this protocol (genetics, clinical, behavior, brain, etc) is possible only 
after permission of Elissar Andari.  
 
Participant selection:  
50 ASD between the ages of 18 and 45 will participate in this study. 30 healthy controls who are 
matched by IQ, race, ethnicity and age will also participate in this study. All participants are males.  
Healthy subjects will only receive placebo spray. Healthy subjects will be told that they might 
receive placebo or oxytocin spray (one of the 3 doses). Healthy subjects will participate in one 
visit during which they complete questionnaires, behavioral tasks, clinical interview and training 
on the different tasks that they will be doing inside the MRI scanner. They will get a physical, vital 
signs, blood draws, placebo spray, MRI scan (including all the tasks that are described above) 
and behavioral tasks after the MRI scan.  
ASD subjects will participate in a pre-clinical visit and will perform all the tasks and procedures 
that are described above. They will also participate in 4 clinical visits that will include treatment 
intake (syntocinon spray 8IU, 24IU, 48IU and placebo), blood draws, vital signs, MRI scan, 
behavioral tasks and questionnaires (see below the procedure for more details). It is a placebo-
controlled randomized clinical trial, double-blind and within subject design.  
Subjects will have normal or corrected-to-normal (with contact lenses) visual acuity of 20/40. MRI-
compatible glasses are available for those who wear glasses rather than contact lenses. A 
medical history will be obtained and reviewed by the study physician or study nurse practitioner, 
including information about prescription and non-prescription medications.  
Inclusion/exclusion criteria for ASD subjects: 
Given that the inclusion criteria list and the screening will be first conducted during the first pre-
clinical visit (by E. Andari or staff and not by nurse practitioner), the experimenter will contact 
physician Dr. Cubells or Dr. Haroon or the nurse practitioner in case there were some doubts.   
The nurse practitioner will conduct this screening again during the first clinical visit to make sure 
that the entire subject meets the criteria of inclusion and exclusion.  
Inclusion: 
- 
Sex males (we are excluding women for this present study given the difficulty to find the 
same number of women with ASD. Autism is found in men 4 times more than in women 
as based on CDC epidemiological studies). Also, only male will be included to minimize 
possible side effects of oxytocin administration that can be related to uterine contractions 
and lactation in females and to minimize confounding factors that can arise from hormonal 
interactions with estrogen in women. We are including male sex which means that a 
gender male person who was born as a woman is not considered part of the inclusion 
criteria.  
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- 
Age: between 18 and 45 years old.  
- 
Have an ASD diagnosis based on the ADOS and ADI criteria, gold standards of research-
based autism diagnosis.  
- 
Not color blind (some of the behavioral tasks inside the scanner require detection of color) 
- 
IQ>70 
- 
Normal or corrected-to-normal vision  
Exclusion: 
- 
Recent occurrence of seizures (past 5 years) (lot of patients with autism have seizures 
when they were young and these seizures never re-reappear and do not provide a risk for 
subjects in this study).  
- 
Brain damage or head trauma (can be included at discretion of PI and sponsor) 
- 
Cardiovascular disease 
- 
Presence of a severe medical problem 
- 
Severe mental retardation  
- 
Alcoholism or substance abuse  
- 
Asthma (can be included at the discretion of study physician/nurse practitioner if episodes 
are infrequent and no active problems at time of the study) 
- 
Migraine headaches (at the discretion of the nurse practitioner or the study physician) 
- 
Claustrophobia (at discretion of study physician/designee/PI) 
- 
Pacemakers, cochlear implants, surgical clips or metal fragments 
In the general form, we will take note of any comorbid psychiatric disorder, current medications, 
current medical problems such as diabetes, migraines and take these factors as covariates in our 
analysis. We will also take a note of the date of last event and the frequency. We want to try to 
include as many patients with ASD as possible to represent at best the general population with 
high functioning autism.  
Those who are on medication, we do not exclude them from the study but ask them to continue 
their treatment as normal.  
Inclusion/exclusion criteria for healthy subjects:  
Inclusion: 
- 
Sex males between 18 and 45 years old (given that they should be controls for ASD 
subjects) 
- 
Matched to ASD group  
- 
Not color blind 
- 
IQ > 70 
 
Exclusion: 
- 
History of seizures (past 5 years) 
- 
Neurological disorder 
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- 
Current psychiatric disorder  
- 
Previous psychiatric disorder (can be included at discretion of PI). If the data of the last 
episode is more than one year ago then the PI will include him. If the date of the last 
episode dates to less than a year, at discretion of PI).  
- 
Head trauma (can be included at discretion of PI) 
- 
Alcoholism or substance abuse 
- 
Cardiovascular disease 
- 
Asthma (can be included at the discretion of study physician/nurse practitioner if episodes 
are infrequent and no active problems at time of the study) 
- 
Migraine (at the discretion of the nurse practitioner or the study physician) 
- 
Claustrophobia (at discretion of study physician/designee/PI) 
- 
Presence of a severe medical problem 
- 
Severe mental retardation 
- 
Pacemakers, cochlear implants, surgical clips or metal fragments 
Given that midway of the study, we had trouble recruiting healthy subjects that are matched with ASD, 
we asked to add another group of heatlhy subjects with more selective criteria of inclusion.  
We are adding Caucasian as a criterion of inclusion and IQ within the range of 70 and 115.  
Of note, given that healthy subjects will not be evaluated by a NP or study physician, the PI and 
the coordinator will rely on the self-report of these healthy subjects. They will sign the inclusion 
criteria document.  
Subjects will be studied only if they pass the Society of Magnetic Resonance Imaging 
standardized MRI screening protocol (exclusions for ferrous metal in any part of body, such as 
pacemakers, cochlear implants, surgical clips or metal fragments, serious medical conditions). 
Subjects with claustrophobia will be excluded at the discretion of the PI based on consultation 
with the subject. Subjects with claustrophobia will be carefully monitored and reminded that they 
are free to withdraw from the study at any time. Subjects who report a history of asthma or 
migraine headaches will be included at the discretion of the study physician or study nurse 
practitioner only if episodes are infrequent; there are no active problems at the time of the study. 
Subjects with a history of head trauma or psychiatric illness will be included at the discretion of 
the PI. Any cognitive consequence of head injury could be taken into account during the decision. 
Subjects will be asked to refrain from use of caffeinated drinks or tobacco for at least 12 hours 
prior the blood pressure and heart rate measurement.  
Given that this project is the continuity of the previous IRB protocol 64623, we will contact healthy 
subjects and patients with autism that were already recruited in this previous protocol. We are 
planning to contact those who gave us approval to be contacted (in the consent form). We will go 
through the screening process (see above for more details) over the phone with the patient and 
family member if necessary and make sure he is interested and he is eligible for the study. The 
study coordinator will then schedule them for the first pre-clinical visit.  
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If a subject withdraws from the study, we will prepare a note to file (and put it in the regulatory 
binder) and report to the IRB during the continuing review.  
We expect to recruit at least 30 patients with autism and 20 healthy controls. We expect a drop 
off of patients with ASD given that they need to come for 5 visits.   
 
Informed consent process 
• 
Consent forms will be obtained in person from adult participants. All participants, 
including patients with autism and healthy subjects are adults and capable of 
understanding the consent form. However, some of our patients with autism have 
legal guardianship or legal authority representative by one of the parents because 
of money expenses and other. For these cases, we will ask for a signature from 
the parent as well as from the adult subject. 
• 
We will ensure that compensation is in line with effort and time required for the 
study. We will ensure comprehension of the informed consent information by 
allowing time for questions, verbally summarizing the material with the subject 
instead of just having them read it and asking subjects to answer a few questions 
to gauge understanding.  
Communication of results: given that we are including MRI scans, we will be asking a medical 
doctor to look at them to double check any un-anticipated or incidental findings (such as tumors 
or apparent lesions). We will communicate incidental findings with the participant in person (after 
contacting him by email), only if the medical doctor decides that the MRI scan should be reviewed 
by an expert neurologist with a medical MRI to double check some doubts. We will be reporting 
only apparent incidents that could be life-threatening to the subject. We are not equipped to share 
with the participant’s minor or more subtle problems given that we are conducting a research MRI 
scan and not a medical MRI. Participants will be provided a copy of the MRI anatomy scan. 
General results of the study can be communicated with participants after publication.  
Compensation: Patients with autism will receive a total of $200 for their participation in 5 
research visits ($40 per visit). Healthy subjects will receive a total of $80 for their research visit.  
Statistical analysis:  
Power analysis (using G power 3.1 software) shows that a sample size of 50 subjects with ASD 
receiving 4 different treatments is needed to reliably detect (95% power) effect sizes small or 
larger (Cohen’s d=0.2) on one measure. In this study, we expect to find small to medium size 
effects of oxytocin inhalation on behavioral measures (based on previous meta-analysis of 
Bakermans-Kranenburg and Van I Jzendoorn. 2013). Authors found a combined effect size of 
d=0.32 (95% confidence interval: 0.18-0.47). As mentioned above, we are planning to break the 
blind with N=25 ASD subjects for a mid-way analysis, which is sufficient to detect effect sizes 
between medium and small (Cohen’s d=0.3). We expect larger effect sizes on measures of brain 
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activity (BOLD activity and functional connectivity). Therefore, these measures will be mainly 
analyzed during the mid-way analysis for potential publications. Of note, we are also planning to 
publish the combined analysis with the total number of subjects on the measures that were 
published mid-way to avoid any publication bias.  
For healthy subjects, we need at least 30 subjects receiving on treatment to reliably detect (95% 
power) the differences between social and non-social conditions or emotional faces versus neutral 
faces in the aims above with an effect size between small and medium (Cohen’s d=0.35).  
When comparing healthy subjects to patients with autism (placebo administration only), the above 
numbers are sufficient to reliably detect small effect sizes between groups (Cohen’s d=0.2) for 
one measure.  
The PI will submit an annual report to the IRB and address whether the study is safe and whether 
it is appropriate to continue. This report will include compliance, review of eligibility, treatment 
review, summary of responses, survival, adverse events and safety monitoring rules.  
Given that we do not expect serious adverse events and we are investigating the effects of this 
hormone on brain activity and behavior, we do not expect an early stopping.  
There will be analysis at various stages of the trial. We might need to analyze the behavioral and 
physiological data for data monitoring committee, in any or to write reports to NIH about the 
progress. There will be analysis of primary outcome measures of the different aims (cited above) 
during mid-way analysis (when we break the blind half way at N=25 of ASD). The analysis will 
also be conducted at the final stage of the trial.  
Brain imaging procedures using MRI, fMRI will be conducted at the Biomedical Imaging 
Technology Center (BITC) at Emory. Anatomical Image Acquisition: participants will be positioned 
supine in the MRI scanner (Siemens, Magnetom Prisma, Trio 3T) with instructions to lie 
motionless. Padded head restraint will minimize head movement during scanning sessions, each 
of which will begin with a 15 second scout scan to localize the position of the brain within the 
magnet. This will be followed by T1-weighted MPRAGE scan (TR= 2300 ms, TE = 4 ms, matrix = 
256x256, FOV=256, slice thickness = 1.00 mm, gap = 0 mm). 
For aim 1, the primary outcome measure consists of investigating the effects of different 
treatments (3 doses of oxytocin and one dose of placebo) on brain functional connectivity at rest 
in patients with ASD, using fMRI. During resting state functional image acquisition (8 minutes), 
participants will be asked to remain awake and not moving. Image acquisition will be obtained 
using a multi-band slice accelerated gradient echo-planar imaging (EPI) pulse sequence 179, 180 
with the following parameters: TR = 1000 ms, TE = 24 ms, matrix = 74 x 74, FOV = 220 mm, slice 
thickness = 2.0 mm, 64 axial slices, to reduce magnetic susceptibility artifact in the OFC region.  
The aim of this analysis is to determine whether there is target engagement for intranasal oxytocin 
by demonstrating differences between doses of IN-OT on BOLD rsFC or whether there is a simple 
oxytocin effect. We define target engagement OXT effect (TEE-OXT) as any differential effect 
between a dose of OXT from another dose of OXT on brain or behavior. We define oxytocin effect 
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(OXT-Effect) as any differential effect between oxytocin (any dose) and placebo administration in 
ASD.  
Initial preprocessing steps for single-subject resting-state fMRI data will be conducted with FSL 
software or SPM with the help and training of Dr. Gopinath. FMRI data will undergo standard 
preprocessing steps: realignment, slice-timing correction, volume registration, spatial 
normalization to MNI152 template, spatial smoothing with 5 mm FWHM Gaussian filter and 
temporal band-pass filtering (0.01-0.1 HZ). Corrections for head motion, whole-brain signals, 
ventricular signals, white matter signals. We will define specific regions of interest that includes 
the social brain network that we discussed in the sections above (MPFC, OFC, PCC, precuneus, 
insula, ACC, ventral striatum, amygdala, temporal areas, SMA etc). We will compare the 
functional connectivity between and within the different social brain networks (including the 
default, the salience network and temporal network) between the different treatment conditions. 
This analysis will be performed based on the GLM using corresponding regressors. We will also 
compute the rsFC between the different regions of interest by calculating a Pearson’s correlation 
coefficient between the time series of the preprocessed functional MRI signals. In order to study 
target engagement effect on within network correlations, the resulting of the cross-correlation 
maps will be Fisher transformed to z-scores and fed into a 2-factor (4 treatment condition X 3 
networks (default, salience, temporal); covariate: visit order) ANOVA. In order to study target 
engagement effect on between network correlations, the resulting of the cross-correlation maps 
will be Fisher transformed to z-scores and fed into a repeated Anova (4 treatment condition X 3 
networks (Salience+Default; Salience+Temporal; Default+Temporal); covariate: visit order) 
ANOVA. In order to determine simple oxytocin effect, T-contrast maps will determine the 
differences in rsFC between placebo and each of the different doses of oxytocin. Multiple 
comparison correction will be conducted. The specificity of the results will also be conformed in a 
whole brain analysis. Given that baseline rs-FC is not acquired, and in order to account for non-
specific fluctuations, we will use a two-stage GLM procedure during which we account for within-
subject variability (across the different visits). Time regressor will be added to the model as a 
covariate to control for external factors that could influence rs-FC other than the treatment. 
The secondary outcome measure consists of correlating the effects of treatments on rsFC with 
the clinical improvements following treatments and post scan in ASD. The variables consist of 
BB-CGI clinical score (that will be rated blindly by a physician) and a socio-emotional behavioral 
score (rated by PI or staff blindly) during the BB-CGI. These two variables will be analyzed 
separately as they are dependent (based on the same test) but answer two different questions. 
We will conduct correlation analysis (Spearman or Pearson) between TEE-OXT or OXT-effect on 
rsFC and behavioral and clinical improvements. Behavioral variables will include: emotional 
responses, gestures, eye contact with experimenter and synchrony).  
For aim 2: The primary outcome measure of the second aim consists of investigating the 
differences between the effects of the different treatments on BOLD activity of socio-emotional 
brain regions in response to social cues (Face perception task) in ASD.  ROI analysis will include 
regions such as inferior occipital cortex, fusiform gyrus, superior temporal cortex, intra-parietal 
sulcus, superior parietal lobule, nucleus accumbens, amygdala and OFC). In this analysis, we 
have two variables that we will contrast (BOLD signal in response to emotional faces versus 
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neutral faces) and 4 treatment conditions within subject design (8IU, 24IU, 48IU and placebo) with 
covariates (order of visits to control for familiarity effects given that the treatment conditions are 
completely randomized). The presence of TEE-OXT will consist of finding differences between 
different treatment conditions of OXT and not only between OXT and placebo. We will also 
compare each of these OXT treatments with placebo condition separately to study OXT-effect. 
The secondary outcome measure will consist of studying the effects of different treatments on a 
behavioral measure that is recorded during the MRI scan of the FPT: visual fixation duration on 
facial stimuli. Here, we have one variable (duration of visual fixation or eye gaze on emotional 
and neutral faces) and 4 treatment conditions. We will analyze the data with ANOVA repeated 
measures for determining TEE-OXT and t-tests for simple OXT-effects.  
For aim 3: The primary outcome measure of the third outcome measure consist of studying the 
different effects of treatments on BOLD activity of key brain regions (OFC, ventral striatum, inferior 
occipital cortex, fusiform gyrus, amygdala, superior parietal lobe, insula and ACC) while playing 
a social interactive ball-game in ASD. During this ball-game, we will analyze the BOLD brain 
activity during social output videos that will display either neutral or positive face expressions. We 
expect more rewarding brain regions to be more activated during the process of positive social 
feedback with oxytocin treatment. In order to determine TEE-OXT, we will conduct repeated 
ANOVA analysis with variables (BOLD activity in response to positive and neutral) and treatments 
(8, 24, 48, placebo). We will also investigate the general effect of TEE-OXT on the BOLD activity 
of socio-emotional brain regions in response to both positive and neutral faces with the variable 
(BOLD activity in response to all faces) and treatments. We will also investigate the differences 
between oxytocin treatment and placebo. We expect at least the doses of 24IU and 48IU to be 
different from placebo. Covariates such as visit order will be entered in the GLM model as a 
regressor to control for habituation effects.  
The secondary outcome measure consists of studying the effects of treatments on behavioral 
outcome measure (post scanner on social learning). In this behavioral task, we will analyze the 
accuracy and reaction time in recognizing faces as familiar. We will conduct ANOVA and t-tests 
to compare the performance in these 2 variables (accuracy and reaction time) between the 4 
treatment conditions. 
For aim 4: The primary outcome measure of the fourth outcome measure consists of investigating 
the differences between treatments on the modulation of brain activity of reward brain regions in 
response to punishment and helpful behavior. In the GLM model, we will conduct an ANOVA or 
t-tests with 4 treatment conditions and the BOLD signal in NAcc, OFC, VTA and ACC.  
For aim 5:  
The primary outcome measure consists of investigating the differences between treatment 
conditions in oxytocin plasma concentration in ASD. Samples of post-administration of IN-OT will 
be analyzed. We will conduct ANOVA repeated measures on the different OXT concentration in 
4 treatment conditions.  
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The secondary outcome measure consists of studying the differences between baseline oxytocin 
concentration between healthy subjects and ASD. T-tests will be conducted to determine the 
difference between two groups.  
In this protocol, we have thought of several exploratory or secondary aims that include to compare 
brain function and functional connectivity between healthy controls and patients with ASD in 
response to resting state, in response to social cues and in response to interactive social games. 
We will also investigate the differences in behavioral and physiological responses between ASD 
and healthy subjects. We will also investigate differences between these two groups (during 
placebo administration) in baseline plasma OXT concentration, metabolome and exposome and 
cytokines levels.  
In our exploratory analysis, we suggested to study the different factors that could explain 
heterogeneity in ASD such as clinical dissociation (different kinds of social deficits), behavioral 
and genetic and epigenetic contribution. We will conduct separate correlation analysis for each of 
these aims with the severity of ASD and brain function differences with controls. It is also possible 
to conduct factor analysis to study which behavioral variable for instance best predict ASD 
severity in clinical and brain function. The same applies for the best predictors of target 
engagement. We believe that not all patients with ASD will benefit from IN-OT. Hence, we will 
study the genetic factors, epigenetic factors, clinical classifications and behavioral patterns in 
determining TEE-OXT or OXT-effects.  
It is possible that we publish separately target engagement results (comparison between doses 
of OXT) and oxytocin effects (24 and 48 as compared to placebo) on the same tasks that are 
conducted inside the MRI scanner.  
Withdrawals, missing data and ineligible patients will be stated. Data will be controlled and double 
checked by the PI before publishing papers. Outliers will be investigated with statistical tools. 
Post-analysis will be checked for quality and checked for confounder factors, covariates. 
Additional precision on the type of analysis (behavioral, physiological and brain) will be submitted 
as amendments once the PI and staff members start working on the analysis of the data of the 
project.  
Data and Safety Monitoring Plan 
Pre-clinical visit (visit 1) Participants will perform behavioral tests, fill questionnaires, provide 
saliva DNA samples and conduct training (see above for more details). The training might occur 
at the Emory hospital or at the Laboratory of Darwinian Neuroscience (as part of the collaboration 
with Dr. James Rilling, PhD) that is located at the anthropology building at Emory University. 
Participants with ASD might be able to lay down inside the scanner for training purposes to 
habituate to the context. 
We do not expect any serious adverse event and if any adverse event happened during the first 
visit. We expect several adverse events:  
1- Tiredness 
34 
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2- Moderate anxiety or fear reaction in response to lying down in the MRI scanner for ASD. 
Participants will be asked how they feel. However, the PI or the experimenter will make sure to 
take note of these potential adverse events or any unexpected adverse events. All unexpected 
adverse events related to the first visit will be reported promptly to the IRB and DSMB. All serious 
adverse events related or not to the first visit will be reported promptly to the IRB, DSMB and to 
the sponsor. Serious adverse event (based on FDA documentation) includes: life-threatening 
adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or 
significant incapacity or substantial disruption of the ability to conduct a normal life functions, or a 
congenital anomaly/birth defect). Unexpected adverse event is an adverse event that is not listed 
in the investigator brochure or is not listed at the specificity or severity that has been observed or 
is not consistent with the risk information described in the protocol.  
Severity grading scale for adverse events will be based on this following chart (FDA-based):  
- 
Grade 1: mild: asymptomatic or mild symptom; clinical observations only; no intervention 
indicated 
- 
Grade 2: Moderate: minimal, local or noninvasive intervention indicated, have some effect 
on daily activity 
- 
Grade 3: Severe or medically significant that affects daily activity but not immediately life-
threatening; hospitalization or prolongation of hospitalization indicated; disabling. 
We do not consider any event as related to the study unless if the participant was on-site at Emory 
with the experimenter. All events that occurred before participants’ arrival and after participants’ 
departure will be considered unrelated.  
Clinical visits (4 visits): Each participant will participate in 4 clinical visits at the CRN unit at the 
Emory Hospital and at BTCI MRI scanner. All the rules below apply for healthy subjects and for 
patients with ASD.  
Based on prior literature, we have a list of expected adverse events that could be linked to 
oxytocin inhalation or placebo inhalation. This list includes any random symptom that was 
mentioned in trials previously conducted on single administration of oxytocin and placebo. They 
are considered random because some of them occurred during placebo spray intake, some of 
them were not found to be significantly different between placebo and oxytocin, and some of them 
are mentioned in the medical brochure. The list of expected adverse events includes:  
1- Nausea or mild nausea 
2- Vomiting or tendencies to vomit  
3- Headaches  
4- Irregularities of the pulse (tachycardia, bradycardia, arrhythmia, very rare hypertension) 
5- Skin rashes and allergic reactions  
6- Shortage of breath  
7- Blood pressure decrease  
8- Circulatory collapse  
9- Runny nose 
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10- Tiredness 
11- Sore throat 
12- Shakiness 
13- Sweating  
14- Coughing 
Participants will not be given this list and asked explicitly about it. Instead, the experimenter will 
ask participants how they are feeling following spray administration.  
Participants will be also asked upon arrival on the 2nd, 3rd, 4th and 5th visit if there were any changes 
in their health.  
In this clinical trial, we do not expect serious adverse events, and given that the subject is 
receiving 3 doses and placebo across 4 different visits (within the same study), we would like to 
define the terminology of reportable events and a plan to notify the IRB of reportable events:  
Relatedness: the PI will consider that any event (serious, unanticipated, death, adverse 
event, not serious) is related to the treatment only if the event occurred internally during 
the clinical visit after spray intake (4 clinical visits at CRN unit at Emory Hospital and BITCI 
MRI scanner at the Emory Hospital). Thus, an event is considered as a related adverse 
event or a related unanticipated event if it occurred during the few hours of testing (up to 
4 hours) and will not be considered related to the treatment once the subject leaves the 
hospital. The PI will take note of all related expected adverse events (list above) in a log 
document and report them periodically to the sponsor and the IRB during the continuing 
review. The PI will report promptly any unanticipated problem (not expected, related, and 
provides a risk to the participant) to the IRB and to the sponsor. The PI will also report 
promptly any serious adverse event that is related to the spray intake (that occurred on 
site visits of CRN unit) to the IRB and the sponsor. The PI will also report to the IRB 
periodically if any serious adverse event not related to the spray but during the period of 
the study that occurred off site Emory or before spray intake or after the participant left the 
hospital and between study visits (please see the definition below of unrelated events). 
The PI prefers to report promptly any unrelated or related serious adverse events to the 
IRB and to the sponsor with a precision of relatedness to avoid any problems or 
misunderstanding. The PI will also report serious adverse events to the sponsor (Larry 
Young). The serious adverse events include: death, life threatening experience, 
hospitalization, disability or permanent damage, medical or surgical intervention, 
emergency seizures.  
 
Written IND safety reports will be submitted to the FDA by the IND sponsor, for serious, 
unexpected suspected adverse reactions within 15 calendar days of learning of its 
occurrence. If the event is fatal or is deemed to be life threatening, the report will be made 
within 7 calendar days.  The IND sponsor will also make an assessment of whether the 
event constitutes an unanticipated problem posing risks to subjects or others (UP). This 
assessment will be provided to the Emory University IRB, which, in turn will make a final 
36 
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determination.  If the Emory IRB determines an event is a UP it will notify the appropriate 
regulatory agencies and institutional officials. 
 
Unrelated events: If an event happened while the subject is coming to the first visit 
(before spray intake) or after the subject left the hospital (after spray but not at visit sites) 
or in between the 4 visits (not at visit sites) and that the subject told the experimenter 
about it, the event will be considered as an unexpected adverse event but unrelated to the 
treatment. Some patients might have comorbid anxiety traits or hyperactivity traits or being 
on drugs (other than oxytocin) and so sometimes these symptoms could underlie the 
medical baseline condition and are considered not related.  
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 5. 
Reportable events for the IRB (regarding the clinical visits). 
 
The sponsor does not require reporting above and beyond IRB requirements.  
Expected  
Adverse 
events 
(please see 
the 
list 
above) 
Unanticipated  
Problems 
(related, 
unexpected and 
risk to subjects) 
Protocol 
deviations 
and non-compliance 
Serious 
adverse 
events  
(deaths) 
related and 
unrelated 
Reportable to 
IRB 
during 
continuing 
review board 
Promptly 
reportable 
to 
IRB and DSMB 
Promptly reportable to 
IRB  
 
Promptly 
reportable 
to IRB and 
DSMB with 
specificity of 
relatedness 
Reported to 
the sponsor 
at 
regular 
intervals 
Promptly 
reportable to the 
sponsor 
Reported 
to 
the 
sponsor 
at 
regular 
intervals 
Promptly 
reportable 
to 
the 
sponsor  
Not 
reportable to 
the FDA 
Not reportable to 
the FDA, if not 
serious 
Not reportable to the 
FDA 
Promptly 
reportable 
to the FDA 
by 
the 
sponsor  
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The PI will review the overall data safety periodically. The PI is actually actively involved in testing 
participants and will make sure that all adverse events are written down and logged into adverse 
events templates after testing. Every week, the PI will review the regulatory binder to make sure 
that all the adverse events and procedures are done accordingly to the protocol. If there is any 
deviation or any unexpected adverse event or serious adverse event, the PI will report promptly 
all that to the IRB. The PI will make sure to review the literature on intranasal oxytocin (single 
doses) periodically and search for any adverse events. If there is any addition in the literature that 
the PI heard about or read about, she will inform the IRB promptly.  
Regarding the plan for site monitoring for data quality and protocol compliance, the PI will review 
the data after each subject visit and the research coordinator will monitor for protocol compliance 
and data quality. In addition, we will perform self-monitoring (twice a year) using the EU-Self-
monitoring Tool. The PI will meet at regular intervals (once per month) with the sponsor (L. Young) 
to update him about the study and the adverse events. The sponsor will be responsible for 
ongoing safety evaluation and will inform the PI of new safety information. The PI will inform the 
sub-investigators and the IRB if she is provided with new safety information. The sponsor will 
inform the FDA.  
Based on the literature and the growing evidence of safety of intranasal oxytocin administration 
and that prior data suggest that the intervention does not have potential to induce significant risks 
or toxicity to subjects, we do not think that a DSM or DSMB is necessary. However, the PI has a 
plan for reporting adverse events and any deviations promptly or periodically based on IRB 
policies and regulations. We have discussed these reportable evens in the section above and 
table 5.  
 
When the data collection stops, the DSMB and self-monitoring will stop too given that there are 
no more data that are being collected.  
For data analysis, we will be working closely with Dr. Jennifer Stevens and her technician Tom 
Ely here at Emory to process the neuroimaging data. 
Human subjects’ data to be collected includes 1) DNA from saliva samples for genetic analysis, 
2) hormone levels assayed from blood plasma, DNA genotyping from blood cells, immune 
analysis from plasma, exposome and metabolome analysis from plasma. 3) behavioral responses 
during computerized tests, during MRI scans, during clinical interviews, questionnaires and forms 
3) functional and anatomical brain images, 4) physiological responses such as EDA and HRV, 5) 
Vital signs. Subject data will be identified by ID number, with only the PI of this study (E.A.) having 
access to the list linking subject names and ID #s. This list will be saved on the Emory server of 
the department of Psychiatry that is highly secured and protected by my emory login and 
password. All data will be collected specifically for the purpose of this research project.   
Before the end of each year prior to the IND annual report oxytocin, a literature review on single-
dose intranasally administered oxytocin studies will be done to assess any new safety information 
pertaining to the administration of this hormone.    The results of this review will be kept in the 
38 
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regulatory binder, and any discovery of additional adverse effects of oxytocin or any changes 
relevant to the safety of the subjects will be reported to the IRB and the FDA.  Additionally, protocol 
changes would be made to account for these safety issues based on study physician 
recommendations.  The dates of this review will be kept in the outlook calendar of the project 
coordinator. 
In addition to the above plan, we would like to add that the clinical aspects of the study will be 
conducted under the auspices of the Department of Psychiatry, which has a well-established 
procedure to deal with adverse events resulting from our planned studies. All study participants 
will be evaluated by Dr. Haroon or Dr. Cubells or the nurse practitioner before taking the treatment 
spray. The clinical aspects of the study procedures and assessments will be performed in the 
Atlanta Clinical and Translational Science Institute (ACTSI) – which is a dedicated research unit 
housed inside the Emory University Medical Center in the same building which houses Emory 
Intensive Care Unit, Pulmonary and Critical Care Service and Emory Emergency Room. The 
ACTSI is staffed by fully trained nurses who are experienced in providing support to NIH-funded 
studies in all medical specialties. The ACTSI management is highly qualified, consisting of Dr. 
Thomas Ziegler, who is a Professor of Internal Medicine and Endocrinology.  
The adverse events will be also reviewed by the PI and clinical investigators and also will be 
reviewed by the Emory Data Safety Monitoring Board (DSMB). All adverse events will be reported 
annually to the Emory DSMB.  
The co-chair of the DSMB is Boady Dunlop, MD and other clinical researchers who serve as the 
external DSMB for investigator-initiated clinical trials conducted by Emory researchers in the 
Department of Psychiatry and Behavioral Sciences.  
At least four weeks prior to DSMB meeting, the research coordinator/study staff will prepare a 
report to be reviewed during that meeting. The report will include the number of participants who 
signed consent for the study and were randomized, the number of post-randomization dropouts, 
reasons for these dropouts, and safety concerns, adverse events, etc. An up-to-date consent form 
will be provided, as well as a summary of measures taken to protect confidentiality (data storage, 
use of coded ID numbers, etc). The PI will also prepare a report summarizing any new 
data/evidence that might alter the risk/benefit ratio for participating in the study (such as newly 
published studies, etc). The PI will report any serious and unexpected adverse events in timely 
fashion to the Emory DSMB and Emory IRB. Actions taken by the IRB in response to adverse 
event reports will be immediately reported to the Emory DSMB. 
Confidentiality:  
All information obtained from participants will be kept strictly confidential. No individual genetic 
results will be given to participants or their relatives. DNA as well as other measures (brain scans, 
saliva samples, blood samples) will be assigned a code and the link to further identifying 
information concerning the individual will be available only to E. Andari.  The PI will provide codes 
to the majority of the measures collected on the computer and other devices. The materials that 
have the linkage information and personal information about the subject (folders) will be kept 
39 
Version 6_AOB_07_10_2019 
 


safely in locked offices. All electronic files that have the linkage (such as charts) will be saved on 
a HIPAA compliant server of Emory University.  
The identifiable information will be destroyed once the E. Andari decides that the data is no longer 
needed.  
We are likely to submit the data to NIH/ NDAR and Rdoc to help contribute to autism research. 
NDAR usually send us guides and we need to fill names and identifiers but NIH does not receive 
any identifiable information.  
After each scan, intranasal spray bottles containing drug or placebo residual will be kept in a 
locked filing cabinet until leftover amounts in intranasal spray bottles are recorded.  Then, the 
intranasal spray bottles will be de-identified, and then the bottles and leftover drug amounts will 
be incinerated per recommendation of the Investigational Drug Service (IDS).  A log will be kept 
in the regulatory binder to keep a current record of this process. 
Amendment 5: 
We are submitting an amendment 5 (July 2019) to ask permission from patients with autism and 
from healthy subjects to provide authorization to submit their deidentified data to NDA or National 
database for Autism Research. These data can include anything that has been collected from 
subjects during this protocol: behavioral, clinical, imaging and genetics.  
In the same amendment, we are asking patients with autism to give E.A. permission to use video-
taped interviews and or/photos publically (during conferences, talks) for educational and research 
purposes. The goal of presenting these videos is to present the different characteristics of autism 
deficits and also what patients area capable of. The goal is also to present potential effects of 
drug (oxytocin), if any, on social interaction and improvements in eye gaze, emotional expressions 
and other types of behavior. 
This will help researchers, general public and students to get a better idea of what is autism, its 
phenotypical heterogeneity and deficits as well as aptitudes. These video-taped interviews 
consisted of interviews that were conducted during the AOB project between the patient and E.A. 
They include face/body and voice of the patient. These interviews consisted of discussions about 
different topics related to social cognition, empathy and emotions. These video-taped interviews 
were collected during each of patients’ 5 visits.  
Showing these clips will allow researchers to have a much better idea of the different phenotypical 
in patients and the nature of heterogeneity.  
In order to get permission, we will adopt these above steps” 
1- Contact patients or/and parents by phone and provide them with the general idea of the 
content of the consent and that I will be sending it to them by secure email or by mail.  
2- Sending patients and/or parents the informed consent by secure email or/and mail for 
signature. For the mail option, we will mail a copy of the consent to the patient/parent (one 
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Version 6_AOB_07_10_2019 
 


for them to keep as a copy and one for them to sign and send it back to us by mail) with a 
returned envelop (and a stamp) and ask parents/patients to read and sign. 
3- Expect to receive the consent scanned by email from subjects or to receive the original by 
mail. They will mail us the consent to the address of Yerkes 954 Gatewood road, Atlanta 
GA 30329. They can also fax it to 404 727 8070 (administration of Dr. Young).  
For those who have legal-guardian, both parents and patients will co-sign on the consent.  
 
 
Appendix A 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Oral consent + Phone screening 
for eligibility N=50 
Pre-clinical visit 
Consent signature 
(N=40-50) 
Phone screening for eligibility 
N=30 
ASD subjects 
Healthy subjects 
Clinical visit 1 
(Treatment 
intervention + fMRI) 
N=40-50 
Clinical visit 1 
(Placebo intervention 
+ fMRI) 
Single blind, N=25-30 
Random allocation of 
treatment (OXT 8IU, OXT 24IU, 
OXT 48IU, placebo) 
Double blind 
  
Clinical visit 2 
(Treatment 
intervention + fMRI) 
N=40-50 
Clinical visit 3 
(Treatment 
intervention + fMRI) 
N=40-50 
Clinical visit 4 
(Treatment 
intervention + fMRI) 
N=40-50 
41 
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Appendix B 
 
 
Procedures 
Screening 
by 
phone/ 
Eligibility 
 (Visit 1) 
 (Visit 2) 
 (Visit 3) 
 (Visit 4) 
 (Visit 5) 
Inclusion/Exclusion 
criteria/Screening 
form 
X    X 
X    X 
 
 
 
 
Informed Consent 
X    X 
X    X 
 
 
 
 
Family history 
form 
 
      X 
 
 
 
 
DNA saliva 
collection (3) 
 
      X 
 
 
 
 
Questionnaires* 
 
X    X 
 
 
 
 
Behavioral tasks** 
 
X    X 
 
 
 
 
Practice session 
1*** 
 
X    X 
 
 
 
 
Bio-behavioral 
clinical global 
interview (BB-CGI) 
 
     X 
 
 
 
 
Practice session 
2**** 
 
X 
 
 
 
 
Revision of tasks 
and consent 
 
 
    X 
 X 
X 
X 
Simple 
questionnaires 
(rating faces) 
 
X 
    X 
X 
X 
X 
Physical and 
history assessment 
(by NP) 
 
    X  
 
 
 
 
Vital signs 
 
X 
    X 
X 
X 
X 
Blood draw  
10ml 
 
X 
    X 
X 
X 
X 
Spray intake 
(treatment: OXT 
8IU or OXT 24IU or 
OXT 48IU or PL) 
 
X (placebo 
only) 
    X 
X 
X 
X 
Blood draw 
10ml (5 minutes 
after spray) 
 
X 
    X 
X 
X 
X 
42 
Version 6_AOB_07_10_2019 
 


 
Vital signs  
 
X 
    X 
X 
X 
X 
MRI scan: resting 
state (40 min after 
spray) 
 
X 
    X 
X 
X 
X 
MRI scan: Face 
perception task 
 
X 
    X 
X 
X 
X 
MRI scan: Ball 
game 1 
 
X 
    X 
X 
X 
X 
MRI scan: 
Anatomy 
 
X 
    X 
X 
X 
X 
Post scan: Face 
questionnaire 
 
 
 
 
 
 
Post scan: Social 
learning 
 
X 
    X 
X 
X 
X 
Post scan: Emotion 
Matching test 
 
X 
    X 
X 
X 
X 
Post scan: Toronto 
Alexithymia scale 
 
X 
    X 
X 
X 
X 
Post scan: Mood 
questionnaire 
 
 
 
 
 
 
BB-CGI 
(clinical interview) 
 
 
    X 
X 
X 
X 
Debriefing  
 
 
X 
 
 
 
X 
X: Healthy subjects 
X: ASD subjects 
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Klin, A., Jones, W., Schultz, R., Volkmar, F., and Cohen, D. (2002). Visual fixation patterns during viewing 
of naturalistic social situations as predictors of social competence in individuals with autism. 
Arch Gen Psychiatry 59, 809-816. 
Koch, S.B., Van Zuiden, M., Nawijn, L., Frijling, J.L., Veltman, D.J., and Olff, M. (2016). Intranasal 
Oxytocin Normalizes Amygdala Functional Connectivity in Posttraumatic Stress Disorder. 
Neuropsychopharmacology 41, 2041-2051. doi: 10.1038/npp.2016.1. 
Kovacs, B., and Keri, S. (2015). Off-label intranasal oxytocin use in adults is associated with increased 
amygdala-cingulate 
resting-state 
connectivity. 
Eur 
Psychiatry 
30, 
542-547. 
doi: 
10.1016/j.eurpsy.2015.02.010. 
Loparo, D., Johansson, A., Walum, H., Westberg, L., Santtila, P., and Waldman, I. (2016). Rigorous tests 
of gene-environment interactions in a lab study of the oxytocin receptor gene (OXTR), alcohol 
exposure, and aggression. Am J Med Genet B Neuropsychiatr Genet 171, 589-602. doi: 
10.1002/ajmg.b.32359. 
Nakano, T., Tanaka, K., Endo, Y., Yamane, Y., Yamamoto, T., Nakano, Y., Ohta, H., Kato, N., and Kitazawa, 
S. (2010). Atypical gaze patterns in children and adults with autism spectrum disorders 
dissociated from developmental changes in gaze behaviour. Proc Biol Sci 277, 2935-2943. doi: 
10.1098/rspb.2010.0587. 
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Rilling, J.K., Demarco, A.C., Hackett, P.D., Thompson, R., Ditzen, B., Patel, R., and Pagnoni, G. (2012). 
Effects of intranasal oxytocin and vasopressin on cooperative behavior and associated brain 
activity in men. Psychoneuroendocrinology 37, 447-461. doi: 10.1016/j.psyneuen.2011.07.013. 
Rimmele, U., Hediger, K., Heinrichs, M., and Klaver, P. (2009). Oxytocin makes a face in memory familiar. 
J Neurosci 29, 38-42. doi: 10.1523/JNEUROSCI.4260-08.2009. 
Schultz, R.T., Gauthier, I., Klin, A., Fulbright, R.K., Anderson, A.W., Volkmar, F., Skudlarski, P., Lacadie, 
C., Cohen, D.J., and Gore, J.C. (2000). Abnormal ventral temporal cortical activity during face 
discrimination among individuals with autism and Asperger syndrome. Arch Gen Psychiatry 57, 
331-340. 
Silani, G., Bird, G., Brindley, R., Singer, T., Frith, C., and Frith, U. (2008). Levels of emotional awareness 
and autism: an fMRI study. Soc Neurosci 3, 97-112. doi: 10.1080/17470910701577020. 
Singer, E. (2012). Diagnosis: Redefining autism. Nature 491, S12-13. 
Sonuga-Barke, E.J., and Castellanos, F.X. (2007). Spontaneous attentional fluctuations in impaired states 
and pathological conditions: a neurobiological hypothesis. Neurosci Biobehav Rev 31, 977-986. 
doi: 10.1016/j.neubiorev.2007.02.005. 
Tachibana, M., Kagitani-Shimono, K., Mohri, I., Yamamoto, T., Sanefuji, W., Nakamura, A., Oishi, M., 
Kimura, T., Onaka, T., Ozono, K., and Taniike, M. (2013). Long-term administration of intranasal 
oxytocin is a safe and promising therapy for early adolescent boys with autism spectrum 
disorders. J Child Adolesc Psychopharmacol 23, 123-127. doi: 10.1089/cap.2012.0048. 
Watanabe, T., Abe, O., Kuwabara, H., Yahata, N., Takano, Y., Iwashiro, N., Natsubori, T., Aoki, Y., Takao, 
H., Kawakubo, Y., Kamio, Y., Kato, N., Miyashita, Y., Kasai, K., and Yamasue, H. (2014). 
Mitigation of sociocommunicational deficits of autism through oxytocin-induced recovery of 
medial prefrontal activity: a randomized trial. JAMA Psychiatry 71, 166-175. doi: 
10.1001/jamapsychiatry.2013.3181. 
Watanabe, T., Kuroda, M., Kuwabara, H., Aoki, Y., Iwashiro, N., Tatsunobu, N., Takao, H., Nippashi, Y., 
Kawakubo, Y., Kunimatsu, A., Kasai, K., and Yamasue, H. (2015). Clinical and neural effects of 
six-week administration of oxytocin on core symptoms of autism. Brain 138, 3400-3412. doi: 
10.1093/brain/awv249. 
Yatawara, C.J., Einfeld, S.L., Hickie, I.B., Davenport, T.A., and Guastella, A.J. (2016). The effect of 
oxytocin nasal spray on social interaction deficits observed in young children with autism: a 
randomized clinical crossover trial. Mol Psychiatry 21, 1225-1231. doi: 10.1038/mp.2015.162. 
Young, L.J., and Wang, Z. (2004). The neurobiology of pair bonding. Nat Neurosci 7, 1048-1054. doi: 
10.1038/nn1327. 
 
 
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ICF_002.pdf: 
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Target engagement for intranasal oxytocin in Autism Spectrum Disorders, an fMRI dose 
response study. 
 
Informed Consent Form Date: October 16, 2017 
NCT Number: NCT03033784 
 


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Version4_Date: 10.16.2017_ASD 
IRB Form 04152016 
  
 
 
Emory University 
Consent to be a Research Subject / HIPAA Authorization  
ASD 
 
Title: Target engagement for intranasal oxytocin in Autism Spectrum Disorders, an fMRI dose response study. 
 
Principal Investigator: Elissar Andari, PhD 
 
Sponsor: Larry J. Young, PhD 
 
Introduction 
You are being asked to be in a medical research study. This form tells you everything you need to think about 
before deciding if you want to be a part of the research study.  It is entirely your choice.  If you decide to 
take part, you can change your mind later on and withdraw from the study. The decision to join or not join 
the study will not cause you to lose any medical benefits.  If you decide not to take part in this study, your 
doctor will continue to treat you. 
 
Before making your decision: 
• 
Please carefully read this form or have it read to you 
• 
Please listen to the study doctor or study staff as they explain the study to you  
• 
Please ask questions about anything that is not clear 
 
You can take a copy of this consent form to keep. Take your time to think about whether you would like to 
participate. You may wish to discuss your decision with family or friends. Do not sign this consent form unless 
you have had a chance to ask questions and get answers that make sense to you.  By signing this form, you 
will not give up any legal rights. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. law. This 
web site will not include information that can identify you. At most, the web site will include a summary of the 
results. You can search this web site at any time. 
 
What is the purpose of this study? 
The purpose of this study is to look at behavioral and brain responses to social interactions. We are also 
studying emotional and social characteristics, genetic and immune factors, and the levels of chemicals and 
hormones. This will help us to understand individual differences in Autism Spectrum Disorder (ASD).  
The main goal of the study is to look at the effects of intranasal oxytocin on the brain in ASD. Oxytocin is a 
hormone that exists naturally in our body and our brain. It affects a wide range of social behaviors and 
emotions. We will also study how the effects of oxytocin treatment can be changed by the above factors. 
 
You will participate in five visits: the first visit is pre-clinical and then 4 clinical visits. During the first visit, you 
will complete a health assessment, personality tests, questionnaires, computerized tests and practice 
sessions. At the 4 clinical visits we will collect images of your brain and you will receive one of these four 
solutions intranasally on each clinical visit (using a nose spray):  
- 
Dose 1 of oxytocin (8IU) 
- 
Dose 2 of oxytocin (24IU) 
- 
Dose 3 of oxytocin (48IU) 
- 
Placebo (a solution without oxytocin).  


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Each participant will receive all these 4 solutions over the course of the study in a random order. Neither you 
nor the study team will know which solution you will receive during the clinical visits.  
You will also have a pre-clinical visit (first visit).  
 
We ask you to volunteer because you are on the Autism Spectrum and you are a male between the ages of 18 
and 45. The time needed for you to complete this study is about 3.5 to 4 hours per visit. Almost 50 adults with 
ASD will participate in this portion of the study at Emory University.  
 
What will I be asked to do? 
All the study visits will take place on main Emory Campus at the Emory Hospital. 
The first pre-clinical visit includes: 
- 
Review of inclusion and exclusion criteria and MRI screening. 
- 
A nurse or study physician will perform a basic health, history and physical assessment and review 
medical eligibility. Given that this health assessment is done at the CRN unit of the Emory hospital, the 
CRN nurses will also do basic nursing assessments for their records. 
- 
Complete a general form that is related to family history. 
- 
Provide saliva by spitting in 3 test tubes. DNA will be taken for genetic analysis. Your genetic 
information will be kept strictly confidential. We will store the saliva sample for this study and for future 
studies conducted by Dr. Andari. Your DNA will not be placed in a repository. The results of the genetic 
tests will not be made available to you or to your referring health care providers.  
- 
Complete several questionnaires and forms. You can take some questionnaires or forms to complete at 
home if you would like. You can bring them back during the following visits. 
- 
Complete behavioral tasks on the computer screen. 
- 
Complete several practice sessions and quizzes on the tasks that will be conducted during the four 
clinical visits.  
- 
Conduct a short clinical interview with the experimenter. You will be asked to wear a sensor. This 
sensor detects your heart rate, skin temperature, skin conductance and movement. The experimenter 
will also wear this sensor. The clinical interview will be video-taped and will be analyzed by the study 
staff.  
- 
Walk to BITC and explore the MRI scanner. This includes: 
o lying down inside the scanner 
o resting for few minutes and looking at a fixation cross 
o looking at pictures on the screen and pressing a key when participant sees a blue fixation cross 
o detecting a color in a ball game 
o answering questions, 
o using the response box 
o listening to the noise of the MRI scan.  
The MRI scanner uses a strong magnet and radiowaves (not x-rays) take a picture of your brain. We will ask 
you to enter a large room where a powerful magnet is located. We will tell you to remove all jewelry and metal 
objects. You will enter into a small tunnel about 6 feet long and 25 inches across. We will ask you to lie still 
during the scan.  
Snacks will be provided. 
 
The different tasks do not need to be performed in a particular order. Even the health assessment can be 
performed after the tasks described above given that this assessment should just be performed before your 
inclusion in the subsequent clinical visit. This health assessment is not a requirement for your inclusion in this 
first pre-clinical visit. 
 
Four clinical visits:  
You will meet at the Emory University Hospital.  


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The health assessment that was performed during the first visit (brief history and physical assessment) might 
be reviewed by the nurse or study physician one more time at some point during one of these 4 clinical visits 
(in case if the original health assessment expires (more than 30 days)).  
 
During your first clinical visit: 
- 
We will review the screening forms.  
- 
You will complete computer practice sessions and training.  
- 
You will be asked to complete quizzes to assess whether you understand the game. If you answer a 
question incorrectly, a research assistant will explain why the answer was wrong and make sure that 
you understand before continuing. You will then complete practice rounds of three tasks.  
- 
You will complete some simple questionnaires. 
- 
The nurses will measure your body temperature, heart rate, and blood pressure. They will also 
measure your weight and height. If your blood pressure was higher than 140/90 or your heart rate 
higher than 100, the nurses will ask you to rest for 5 minutes and then take the measurement again. If 
the measurements stay high, we will continue collecting vital signs for a total of 6 times in both limbs 
before contacting a physician to ask for advice. 
- 
You will have a small sample of blood (~10 ml) drawn from your arm. We will use it to measure 
hormones, chemicals, genetic and epigenetic markers, and immune factors. Your blood will be stored 
for future studies that are related to Dr. Andari. Your DNA and blood will not be placed in a repository. 
The results of the genetic tests will not be made available to you or to your referring health care 
providers.  
- 
You will receive one of the 4 solutions intranasally (as a nose spray): oxytocin dose 1 (8IU), dose 2 
(24IU), dose 3 (48IU) or placebo. The nurse will instruct you to clear the nose before spray 
administration. The nurse will instruct you to sit with the head upright and little tilting to the back. During 
administration, you can close one nostril within one finger while the nurse is administering the spray in 
the other nostril. The nasal applicator will be placed in one nostril. You will be asked to breathe in 
deeply through the nose while blocking the opposing nostril, and the lever will be pressed until you feel 
a spray in the nostril. The nurse will repeat these steps for the other nostril. You will receive a total of 12 
sprays. This process is not painful, and tissues will be provided if needed. Neither you nor the study 
team knows which of the four solutions you will receive.  
- 
You will have another small sample of blood (~10 ml) drawn from your arm 5 minutes after spray 
intake. We will use it to measure hormones, chemicals, genetic and epigenetic markers, and immune 
factors. Your blood will be stored for future studies that are related to Dr. Andari.  
- 
We will measure body temperature, heart rate, and blood pressure. If your temperature changes by 
more than 2 degrees, or if your heart rate or blood pressure changes above or below normal, we will 
take more measurements after a pause. If these measures stay abnormal after 6 consecutive times, we 
will notify the physician and ask for advice. We do not expect these changes with oxytocin or placebo 
inhalation, and side effects are expected to be minimal. In case of emergency, the Emory University 
Hospital Emergency Room is immediately available. In previous studies that used these solutions, no 
subjects withdrew because of side effects.  
- 
We will ask you if you experience any adverse effects because of the nasal spray. If so, we will consult 
with the physician on call. We will ask you whether you think you took placebo or oxytocin.  
- 
We will escort you the MRI Center in Emory University Hospital from the CRN unit.  
- 
The MRI scanner uses a strong magnet and radiowaves to take a picture of your brain. We will ask you 
to enter a large room where a powerful magnet is located. We will tell you to remove all jewelry and 
metal objects. You will enter into a small tunnel about 6 feet long and 25 inches across. We will ask you 
to lie still during the scan. You will wear a sensor inside the scanner to measure your physical state.  
- 
After a few minutes of localizer scans, we will conduct functional Magnetic Resonance Imaging (fMRI) 
brain scans. 
o First, you will be asked to rest for 8 minutes and to look at a cross symbol in front of you without 
thinking of anything specific and without sleeping. 


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o Second, you will perform 2 sessions of a face task. You will be asked to press a key when you 
see a blue cross. You will see faces separated by red or blue crosses. 
o Third, you will play several sessions of a social ball-tossing game. You will play with other 
players who are connected with you by internet. You will play several games with several 
groups of people. You will play with 2 players at a time for several rounds. These players gain 
money based on how well you perform. You will receive a feedback from the computer about 
your performance after each trial. You will also briefly see the partner’s face via a camera. They 
might communicate their approval or disapproval. You will also play several games with the 
computer for training purposes. 
We will ask you questions about your feelings towards the other players. We will ask you about 
the emotional states of the other players. 
- 
We will take a structural magnetic resonance image scan to make detailed images of your brain. 
- 
We will remove you from the scanner. 
- 
We will take you to another room next the MRI scanner to rest. We will offer you some snacks. We will 
ask you to complete:  
o Questionnaires  
o Behavioral tasks on the computer screen 
o A clinical interview. We will ask you to wear a sensor.  
The total time inside the scanner will be one hour.  
All four clinical visits are similar.  
At the end of the 5th visit, we will debrief you about this study and the previous study (IRB00064623). 
 
Who owns my study information and samples? 
If you join this study, you will donate your samples and study information.  You will not receive any extra 
compensation if your samples or information are used to make a new product. If you withdraw from the study, 
the data and samples we collected may still be used for this study.  
 
What are the possible risks and discomforts? 
There may be side effects from the hormone or procedures that are not known at this time.   
You should not proceed with this study if you have the following medical conditions: 
- 
Recent seizures (with the past 5 years) 
- 
Brain damage or head trauma (can be included at discretion of PI and sponsor) 
- 
Alcoholism or substance abuse  
- 
Severe medical problems 
- 
Severe mental retardation 
- 
Cardiovascular disease  
- 
Current and frequent untreated asthma  
- 
Current and frequent untreated migraines 
- 
Pacemakers, cochlear implants, surgical clips or metal fragments 
 
You will be asked to refrain from use of caffeinated drinks or tobacco for at least 12 hours prior the blood 
pressure and heart rate measurement during clinical visits.  
 
DNA: We recognize the sensitive nature of genetic information and the need for strict confidentiality for data 
that may eventually be available to the scientific community. Your DNA will be collected from saliva and blood 
samples you provide. A breach in confidentiality, resulting in accidental disclosure of genetic information to 
outside parties, can negatively impact your insurability, employability, or your reproductive plans. It could have 
a negative impact on family relationships and/or could result in paternity suits or stigmatization. To reduce the 
risk of accidental disclosure of information to outside parties, all information obtained from you will be kept 
strictly confidential. No individual genetic results will be given to you or your relatives. DNA used in this study 
will be assigned an ID number with no identifying information. The link to your identifying information will be 
available only to E. Andari and limited research staff.  


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Intranasal oxytocin and placebo administration:  
Although oxytocin is not FDA approved for this indication, it is FDA approved and medically used for labor 
induction and labor support in case of difficult parturition. We also have permission from the FDA to use this 
Investigational New Drug (IND) in the study. Intranasal doses result in very low levels of the neuropeptide, as 
compared to intravenous administration. Therefore, the type of drug administration used in this study is 
expected to have minimal side effects.  
The most common risks and discomforts expected in this study are: 
None 
The less common risks and discomforts expected in this study are: 
- 
Headaches 
- 
Tachycardia, bradycardia  
- 
Nausea, vomiting 
Rare but possible risks include: 
- 
Irregularities of the pulse (arrhythmia, very rare hypertension) 
- 
Skin rashes  
- 
Runny nose 
- 
Tiredness 
- 
Sore throat 
- 
Shakiness 
- 
Sweating 
- 
Coughing 
- 
Allergic reactions to oxytocin leading to shortage of breath, blood pressure decreases or circulatory 
collapses 
 
The effect of the study drug on sperm is not known.  To protect against possible side effects, you should not 
get a sexual partner pregnant for the duration of the study.  You and the study doctor should agree on a 
method of birth control to use throughout the study. 
 
This particular treatment may involve risks to you which are currently unforeseeable.  
 
Blood Draw:  
The needle for the blood draw may cause brief pain or discomfort. In rare cases, bruising may occur. In rare 
cases, you may feel light-headed or faint.  
 
MRI:  
Magnetic Resonance Imaging uses magnetism and radio waves to take pictures. It has been in use for more 
than 20 years and millions of people have had the procedure without injury. Therefore, MRI is considered safe. 
However, no one can guarantee that there are no long-term adverse health effects. The only known risks are 
to individuals with cardiac pacemakers and certain types of metallic implants. If you have either of these, you 
cannot participate in this study because of the effect the magnetic field could have on the pacemaker or 
metallic implant. Be sure to tell us if you know or think you have a pacemaker or metallic implant, such as an 
aneurysm clip. All the equipment and MRI methods used in this study are standard methods approved by the 
U.S. Food and Drug Administration.  
You may become tired from lying down in the scanner. You may become uncomfortable from lying in one 
position for a long period of time. If you become too cold, you may ask for a blanket. Some individuals have 
mild anxiety or claustrophobia while lying in the scanner. If this happens, you may ask to leave the scanner at 
any time. The MRI machine makes loud metallic popping sounds while it is taking pictures that may irritate you. 
We do provide ear plugs to help lessen this loud noise, but it does not completely alleviate it. You can ask to 
stop the MRI scan at any time.  
Although we are trained to identify adverse effects of the study, we are not trained to find medical problems 
with your brain on the MRI scans we collect. The MRI and other images taken in this study are not the right 


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type to show medical problems. Your MRI scan will not be reviewed by a physician to look for abnormalities. 
You understand that if you are not told that there is an abnormality or referred to a specialist, this does not 
mean that an abnormality does not exist. If you have any concerns about your health, you should discuss this 
with your physician. The investigators and Emory University are not responsible if they do not find an existing 
medical problem or unusual condition in your scan.  
However, the investigator may see something on a scan that seems unusual. If this happens, a medical doctor 
will be asked if more tests should be done. If so, the principal investigator will call and tell you. You will need to 
tell your own doctor about the call. If you have no doctor or health care provider, we will help you find one. You 
and your doctor will decide if you should have another examination or treatment. The investigators, the 
consulting medical doctor, and Emory University are not responsible for, nor will they pay for, any examination 
or treatment that you decide to have based on something we might see in your scan. The scans done in this 
study are not for a medical exam. If something unusual is found, it might keep you from getting health or life 
insurance. If you need to talk to someone about your concerns about an unusual finding, you be referred to a 
counselor but at your own expense.  
You will be provided with a copy of the MRI anatomy scan.  
We will arrange for emergency care if you are injured by this research. However, Emory University has not set 
aside funds to pay for this care if a mishap occurs. If you believe you have been injured by this research, you 
should contact Dr. Andari at 404-712 9661.  
 
It is possible that the researchers will learn something new during the study about the risks of being in it.  If this 
happens, they will tell you about it. Then you can decide if you want to continue to be in this study.  You may 
be asked to sign a new consent form that includes the new information if you decide to stay in the study. 
Given the absence of common risks associated with intranasal oxytocin, an adverse event will only be 
considered related to the study if it occurs during one of the 5 visits at Emory. Any adverse event occurring 
before your arrival to Emory, after you leave Emory, or in between visits, will not be considered related to this 
study. 
 
Will I benefit directly from the study?  
This study is not designed to benefit you directly.  This study will help us learn more about the role of the 
hormone oxytocin in social functioning and brain function in Autism. The study results may help others in the 
future. The results of the study may help us to understand more precisely how oxytocin works.  
Will I be compensated for my time and effort? 
You will receive a compensation of $200 for 5 research visits ($40 for each). This compensation includes the 
parking fees that you might need to use while visiting us at Emory.  
If you are injured by or get sick from intranasal oxytocin or the study procedures, we will arrange for medical 
care. We will arrange for emergency care if you are injured by this research. However, Emory University has 
not set aside funds to compensate you if a mishap occurs. If you believe you have been injured by this 
research, you should contact Dr. Elissar Andari at 404-712 9661.  
What are my other options? 
You might not be able to participate in other research studies while you are actively enrolled in this clinical trial.  
In order to better study oxytocin’s effects on the brain and behavior, we prefer that you do not participate in 
other clinical trials that involve drugs, hormones or neuroimaging while you are actively involved in this study. 
 
How will you protect my private information that you collect in this study? 
Whenever possible, a study number, rather than your name, will be used on study records.  Your name and 
other identifying information will not appear when we present or publish the study results. Your private 


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information will be stored on a secure server of Emory University that is protected and/or in a locked cabinet 
with a key. 
Study records can be opened by court order.  They also may be provided in response to a subpoena or a 
request for the production of documents.  
 
Storing and Sharing your Information 
Your samples, genetic data and health information (without personal identifiable information) will be stored and 
shared with other researchers. The samples will be stored in the CRN (Clinical Research Network) unit at 
Emory Hospital, within the ACTSI (Atlanta Clinical and Translational Science Institute) facility. The samples 
and information will be available for any research question to understand what causes certain diseases. It can 
be available to develop new scientific methods, or the study of where different groups of people may have 
come from.  
 
Medical Record 
If you have been an Emory Healthcare patient before, then you already have an Emory Healthcare medical 
record.  If you have never been an Emory Healthcare patient, you do not have one.  An Emory Healthcare 
medical record will be made for you if an Emory provider or facility gives you any services or procedures for 
this study.   
 
Copies of the consent form/HIPAA authorization that you sign will be put in any Emory Healthcare medical 
record you have now or any time during the study.   
 
The results of some study tests and procedures will be used only for research purposes and will not be placed 
in your medical record.  For this study, those items include:  
- 
Behavioral and clinical diagnosis data 
- 
Anatomy and neuroimaging data 
- 
Physiological data 
- 
Effects of oxytocin or placebo on brain function and behavior  
- 
Family information 
- 
Medication that you are currently taking 
- 
Data on hormones, chemicals, genetic and epigenetic markers, and immune factors 
Tests and procedures done at non-Emory places may not become part of your Emory medical record. Also, if 
you decide to be in this study, it is up to you to let your other health providers know.  
 
In Case of Injury 
If you get ill or injured from being in this study, Emory will help you get medical treatment.   Emory and the 
sponsor have not set aside any money to pay you or to pay for this medical treatment. The only exception is if 
it is proven that your injury or illness is directly caused by the negligence of an Emory or sponsor employee.  
“Negligence” is the failure to follow a standard duty of care.  
If you become ill or injured from being in this study, your insurer will be billed for your treatment costs.  If you 
do not have insurance, or if your insurer does not pay, then you will have to pay these costs.   
If you believe you have become ill or injured from this research, you should contact Dr. Elissar Andari at 
redacted. You should also let any health care provider who treats you know that you are in a research study.  
Costs 
There will be no costs to you for participating in this study, other than basic expenses like transportation. You 
will not be charged for any of the research activities. If the study procedures result in any medical 
complications that would not fall under “injury” as discussed above, the cost of treatment for those 
complications may be charged to you or your insurance.   


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Withdrawal from the Study 
You have the right to leave the study at any time.   
The researchers also have the right to stop your participation in this study without your consent for any reason, 
especially if they believe it is in your best interest or if you object to any changes in the study plan. 
 
Confidentiality 
 
There is a Certificate of Confidentiality from the National Institutes of Health for this Study.  The Certificate of 
Confidentiality helps us to keep others from learning that you participated in this study.  Emory will rely on the 
Certificate of Confidentiality to refuse to give out study information that identifies you.  For example, if Emory 
received a subpoena for study records, it would not give out information that identifies you. 
 
The Certificate of Confidentiality does not stop you or someone else, like a member of your family, from giving out 
information about your participation in this study.  For example, if you let your insurance company know that you 
are in this study, and you agree to give the insurance company research information, then the investigator cannot 
use the Certificate to withhold this information. This means you and your family also need to protect your own 
privacy. 
 
The Certificate does not stop Emory from making the following disclosures about you: 
 
Giving state public health officials information about certain infectious diseases. 
Giving law officials information about abuse of a child, elderly person or disabled person. 
Giving out information to prevent harm to you or others. 
Giving the study sponsor or funders information about the study, including information for an audit or evaluation.  
 
Authorization to Use and Disclose Protected Health Information 
 
The privacy of your health information is important to us.  We call your health information that identifies you, 
your “protected health information” or “PHI.”  To protect your PHI, we will follow federal and state privacy laws, 
including the Health Insurance Portability and Accountability Act and regulations (HIPAA).  We refer to all of 
these laws as the “Privacy Rules.”  Here we let you know how we will use and disclose your PHI for the main 
study and for any optional studies in which you may choose to participate. 
 
Main Study 
 
PHI that will be Used/Disclosed:   
The PHI that we will use or share for the main research study includes: 
• 
Medical information about you including your medical history and present/past medications 
• 
Medical and history information about your family 
• 
All information that is collected about you and your family members during the research visits 
• 
Video-taped interview 
• 
Results of exams, procedures and tests  
• 
Laboratory test results, including DNA analysis and other.  
 
Purposes for Which Your PHI will be Used/Disclosed: 
We will use and share your PHI for the conduct and oversight of the research study.  We will use and 
share your PHI to provide you with study related treatment and for payment for such treatment.  We will 
also use and share your PHI to conduct normal business operations.  We may share your PHI with 
other people and places that help us conduct or carry out the study, such as laboratories, data 
management centers, data monitors, contract research organizations, Institutional Review Boards 


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(IRBs) and other study sites. If you leave the study, we may use your PHI to determine your health, vital 
status or contact information. We will share your PHI with other collaborators (without names) and 
researchers to help research on autism. We will share the above information with National Data Base 
for Autism Research. We may share it also with the Research Domain Criteria data base to help make 
progress in autism research.  
 
Use and Disclosure of Your Information That is Required by Law:   
We will use and disclose your PHI when we are required to do so by law. This includes laws that 
require us to report child abuse or abuse of elderly or disabled adults. We will also comply with legal 
requests or orders that require us to disclose your PHI. These include subpoenas or court orders.   
 
Authorization to Use PHI is required to Participate: 
By signing this form, you give us permission to use and share your PHI as described in this document. 
You do not have to sign this form to authorize the use and disclosure of your PHI.  If you do not sign 
this form, then you may not participate in the research study. 
 
People who will Use/Disclose Your PHI: 
The following people and groups will use and disclose your PHI in connection with the research study: 
 
• 
The Principal Investigator and the research staff will use and share your PHI to conduct the 
study and give you study related treatment. 
• 
The Principal Investigator and research staff will share your PHI with other people and groups to 
help conduct the study or to provide oversight for the study. 
• 
Larry J. Young is the Sponsor of the study.  The Sponsor may use and share your PHI to make 
sure the research is done correctly and to collect and analyze the results of the research.  The 
Sponsor may disclose your PHI to study monitors to help conduct the study or to provide 
oversight for the study.   
• 
The following people and groups will use your PHI to make sure the research is done correctly 
and safely: 
o Emory offices that are part of the Human Research Participant Protection Program  
o Offices involved in study administration and billing 
o Emory IRB 
o Food and Drug Administration 
o Emory Research and Healthcare Compliance Offices 
o Emory Office for Clinical Research  
o Government agencies that regulate the research including:   
• 
Public health agencies 
• 
Research monitors and reviewer 
• 
Accreditation agencies 
 
• 
Sometimes a Principal Investigator moves to a different institution. If this happens, your PHI 
may be shared with that new institution and their oversight offices. PHI will be shared securely 
and under a legal agreement to ensure it continues to be used under the terms of this consent 
and HIPAA authorization. 
 
Optional Study/Storage of Data/Specimens for Future Research conducted by the principal 
investigator: 
 
PHI that will be Used/Disclosed for Optional Study:   
The PHI that we will use and/or share for the storage and future use includes:  
- 
General information about you and your family  


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- 
Specimens, including saliva and blood 
- 
Data on hormones, chemicals, genetic and epigenetic markers, and immune factors 
- 
Physiological data 
- 
Behavioral and clinical data 
- 
Anatomical and functional brain data  
- 
All the results of exams, procedures and tests conducted during the study 
- 
All laboratory results 
- 
Video-taped interview 
- 
Your contact information for future research studies 
 
Purposes for which you’re PHI will be Used/Disclosed for Optional Study: 
We will use and disclose your PHI for the conduct of the future studies that will help better research on 
autism.  
 
Authorization for This Use of PHI is required to Participate in Optional Study, but Not in Main 
Study: 
You do not have to authorize the use and disclosure of your PHI.  If you do not authorize the use and 
disclosure of your PHI for the optional study, then you may not participate in the optional storage and 
future use of data.  You can still be in the main research study even if you don’t participate in the 
optional study.    
 
People Who Will Use/Disclose Your PHI for Optional Study: 
The same people and groups who will use and disclose your PHI for the Main Study will also do so in 
connection with the optional research study/storage of PHI for future research. The PI might also share 
your information with trusted collaborators (without sharing names) in the future for conducting novel 
collaborative research projects.  
Of note, this optional use of PHI for future studies is only possible if the PI is aware of it.  
 
Expiration of Your Authorization 
Your PHI will be used until all potential analysis and that future research studies that includes this data directed 
by E. Andari finish. 
 
Revoking Your Authorization 
If you sign this form, at any time later you may take back your permission to use your information.  If you want 
to do this, you must contact Dr. Andari at the following mailing address: redacted 
 
At that point, the researchers would not collect any more of your PHI.  But they may use or disclose the 
information you already gave them so they can follow the law, protect your safety, or make sure that the study 
was done properly and the data is correct.  If you revoke your authorization you will not be able to stay in the 
main study.  
 
Other Items You Should Know about Your Privacy 
Not all people and entities are covered by the Privacy Rules.  HIPAA only applies to health care providers, 
health care payers, and health care clearinghouses.  If we disclose your information to people who are not 
covered by the Privacy Rules, including HIPAA, then your information won’t be protected by the Privacy Rules.  
People who do not have to follow the Privacy rules can use or disclose your information with others without 
your permission if they are allowed to do so by the laws that cover them.  
To maintain the integrity of this research study, you generally will not have access to your PHI related to this 
research until the study is complete.  When the study ends, and at your request, you can receive the general 
results that are published. We may remove identifying information from your PHI.  Once we do this, the 
remaining information will not be subject to the Privacy Rules.  Information without identifiers may be used or 
disclosed with other people or organizations for purposes besides this study.   


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Contact Information 
Contact Dr. Elissar Andari at redacted: 
• 
if you have any questions about this study or your part in it,   
• 
if you have questions, concerns or complaints about the research 
 
Contact the Emory Institutional Review Board at 404-712-0720 or 877-503-9797 or irb@emory.edu: 
• 
If you have questions about your rights as a research participant 
• 
If you have questions, concerns or complaints about the research 
• 
You may also let the IRB know about your experience as a research participant through our Research 
Participant Survey at http://www.surveymonkey.com/s/6ZDMW75 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Consent and Authorization 
 


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Consent and HIPAA Authorization for Optional Study/Studies:   
Please initial below if you opt to participate in and authorize use and disclosure of your PHI in the optional 
study/studies previously described: 
 
Agree to provide saliva samples for genetic and other analysis related to this study 
___ Yes  
 
___ No 
Agree to provide blood samples for genetic and other analysis related to this study 
___ Yes  
 
___ No 
Use of all data collected in this study for future studies that will be led by Dr. E. Andari 
 
___ Yes  
 
___ No 
Contact in the future for participating in future studies that are related to Dr. E. Andari 
___ Yes  
 
___ No 
Approval to be contacted by phone if there is something unusual in the MRI scan 
___ Yes  
 
___ No 
 
Even if I have a legal guardian or a legal representative, I confirm that I am an adult and understood all 
the details of this consent form ___ Initials (N/A, in case if you do not have any legal representative).  
 
 
TO BE FILLED OUT BY SUBJECT ONLY 
Please print your name, sign, and date below if you agree to be in the main study. By signing this consent and 
authorization form, you will not give up any of your legal rights. We will give you a copy of the form to keep. 
 
 
 
Name of Subject  
 
 
 
 
  
Signature of Subject (18 or older and able to consent) 
Date              Time 
 
 
 
 
 
Name of legally authorized representative 
 
 
Signature of legally authorized representative 
 
 
 
Date 
 
Time 
 
 
 
TO BE FILLED OUT BY STUDY TEAM ONLY 
 
__________________________________________________________ 
Name of Person Conducting Informed Consent Discussion 
 
 
 
 
 
Signature of Person Conducting Informed Consent Discussion 
Date              Time