Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders

Study Overview
=================
Brief Summary
-----------------
The current trial aims to explore the neural and behavioral effects of oxytocin in autism spectrum disorders (ASD). Oxytocin is a nonapeptide produced by the paraventricular and supraoptic nuclei of the hypothalamus and is known to play a pivotal role in a variety of complex social behaviors. Initial studies showed that intranasal administration of oxytocin can have a positive effect on social functioning in ASD. However, future studies are necessary to explore whether and how oxytocin effects neural processes in the brain underlying these behavioral improvements. This trial will not only measure behavioral enhancements, but will specifically focus on elucidating the associated neurophysiological changes by guiding the administration of oxytocin with regular neurophysiological assessments.

Detailed Description
-----------------
The present study is a monocentric, between-subjects, randomized, placebo-controlled trial. The investigators will recruit approximately 40 young-adult, male individuals with a clinical diagnosis of Autism Spectrum Disorder (ASD). Participants will be randomly allocated to an experimental group (Oxytocin (OT)) and a control group (Placebo (PL)). All participants will receive the same frequency and duration of intervention. Behavioral and neural outcome measures will be assessed at multiple time points in a period of a year. Participants will be tested at 5 occasions: before and after a single dose of nasal spray, after multiple doses of nasal spray (1 daily dose of nasal spray during 4 weeks), after a 4-week retention period and after a 1-year retention period. At each time point participants will be tested at both the behavioral and neural level. Test performance of both participant groups (OT vs PL) will be compared by measuring reaction times and accuracy rates in a computerized task assessing a person's ability to recognize bodily emotional states from point light displays. In addition, attachment, social functioning, restricted behaviour, general quality of life and mood will be assessed via self-reported questionnaires. Functional MRI measurements will be performed in a 3T MR Philips Intera scanner. Before scanning, subjects will undergo a training session to familiarize them with the task instructions. In addition to the fMRI measurements, resting state fMRI and Diffusion Tensor Imaging (DTI) will also be performed to reveal alterations of the functional and structural connectivity between critical regions. Statistical analysis of the behavioral data will have a between-subject factor of group (OT vs PL) and within-subject factors of time (change-from-baseline). Image analysis will be performed with Statistical Parametric Mapping (SPM) software. The investigators will contrast for either decreased or increased activation, as different regions may show divergent changes due to the received nasal spray (either OT or PL).

Official Title
-----------------
Oxytocin-based Pharmacotherapy for Autism Spectrum Disorders: Investigating the Neural and Behavioral Effects of a Promising Intervention Approach

Conditions
-----------------
Autism Spectrum Disorders

Intervention / Treatment
-----------------
* Drug: Syntocinon (Oxytocin)
* Other: Placebo (Physiological water (solution of sodium chloride (NaCl) in water))


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Clinical diagnosis of Autism Spectrum Disorder, Asperger Syndrome or Autism Male Age between 18 and 40 years old Exclusion Criteria: Associated neuro(psycho)logical disorder (i.e. epilepsy, concussion, stroke) Eye sight worse than + or - 7 Genetic syndrome Color blindness Any contraindication to neuroimaging research as assessed with the MRI screening list: MRI contraindications: pacemaker, implanted defibrillator, ear implant / a cochlear implant, insulin or implanted pump, a neurostimulator or VP shunt, any metallic object in the eyes (metallic fragments)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Syntocinon (Oxytocin, product code RVG 03716)<br>Administration via nasal spray | Drug: Syntocinon (Oxytocin)<br>* Syntocinon nasal spray. A single dose (24IU) of nasal spray (3 puffs of 4IU per nostril), followed by 4 weeks of a daily single dose (24IU; 3 puffs of 4IU per nostril) of nasal spray<br>|
| Placebo Comparator: Placebo (Physiological water(sodium chloride (NaCl) solution))<br>Administration via nasal spray | Other: Placebo (Physiological water (solution of sodium chloride (NaCl) in water))<br>* Placebo nasal spray. A single dose (24IU) of nasal spray (3 puffs of 4IU per nostril), followed by 4 weeks of a daily single dose (24IU; 3 puffs of 4IU per nostril) of nasal spray<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Brain Activity During Task (Task-based fMRI) After a Single Dose of Nasal Spray | Change From Baseline in Task-related Brain Activity During Biological Motion Recognition Task (Task-based fMRI) After a Single Dose of Nasal Spray BOLD response (Blood-oxygen-level-dependent response) | Value at 30 minutes minus value at baseline | 
| Change From Baseline in Brain Activity During Task (Task-based fMRI) After 4 Weeks of Nasal Spray | Change From Baseline in Task-related Brain Activity During Biological Motion Recognition Task (Task-based fMRI) after 4 weeks of nasal spray BOLD response (Blood-oxygen-level-dependent response) | Value at 4 weeks minus value at baseline | 
| Change From Baseline in Brain Activity During Task (Task-based fMRI) After 8 Weeks, Including 4 Weeks Without Nasal Spray | Change From Baseline in Task-related Brain Activity During Biological Motion Recognition Task (Task-based fMRI) after 8 weeks, including 4 weeks without nasal spray BOLD response (Blood-oxygen-level-dependent response) | Value at 8 weeks minus value at baseline | 
| Change From Baseline in Brain Activity During Task (Task-based fMRI) After 52 Weeks, Including 48 Weeks Without Nasal Spray | Change From Baseline in Task-related Brain Activity During Biological Motion Recognition Task (Task-based fMRI) after 52 weeks, including 48 weeks without nasal spray BOLD response (Blood-oxygen-level-dependent response) | Value at 52 weeks minus value at baseline | 
| Change From Baseline in Brain Connectivity During Rest (Resting-state fMRI) After a Single Dose of Nasal Spray | Change From Baseline in Brain Connectivity During Rest (Resting-state fMRI) After a Single Dose of Nasal Spray Amygdala connectivity (Change-from-baseline z-transformed r-value) Higher z-transformed r-value indicates higher connectivity (higher correlated brain activity) | Value at 30 minutes minus value at baseline | 
| Change From Baseline in Brain Connectivity During Rest (Resting-state fMRI) After 4 Weeks of Nasal Spray | Change from baseline in brain connectivity during rest (resting-state fMRI) after 4 weeks of nasal spray Amygdala connectivity (Change-from-baseline z-transformed r-value) Higher z-transformed r-value indicates higher connectivity (higher correlated brain activity) | Value at 4 weeks minus value at baseline | 
| Change From Baseline in Brain Connectivity During Rest (Resting-state fMRI) After 8 Weeks, Including 4 Weeks Without Nasal Spray | Change from baseline in brain connectivity during rest (resting-state fMRI) after 8 weeks, including 4 weeks without nasal spray Amygdala connectivity (Change-from-baseline z-transformed r-value) Higher z-transformed r-value indicates higher connectivity (higher correlated brain activity) | Value at 8 weeks minus value at baseline | 
| Change From Baseline in Brain Connectivity During Rest (Resting-state fMRI) After 52 Weeks, Including 48 Weeks Without Nasal Spray | Change from baseline in brain connectivity during rest (resting-state fMRI) after 52 weeks, including 48 weeks without nasal spray Amygdala connectivity (Change-from-baseline z-transformed r-value) Higher z-transformed r-value indicates higher connectivity (higher correlated brain activity) | Value at 52 weeks minus value at baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Performance on the Emotion Recognition Task (Accuracy/Reaction Time) After a Single Dose of Nasal Spray | Change from baseline in performance on the emotion recognition task (accuracy/reaction time) after a single dose of nasal spray Emotion recognition from point-light displays conveying biological motion. Accuracy (acc) is measured in % of correct responses. Reaction time (rt) is measured in milliseconds. Higher (accuracy/ reaction time) ratio indicates better performance. | Value at 30 minutes minus value at baseline | 
| Change From Baseline in Performance on the Emotion Recognition Task (Accuracy/ Reaction Time) After 4 Weeks of Nasal Spray | Change from baseline in performance on the emotion recognition task (accuracy/ reaction time) after 4 weeks of nasal spray. Emotion recognition from point-light displays conveying biological motion. Accuracy (acc) is measured in % of correct responses. Reaction time (rt) is measured in milliseconds. Higher (accuracy/ reaction time) ratio indicates better performance. | Value at 4 weeks minus value at baseline | 
| Change From Baseline in Performance on the Emotion Recognition Task (Accuracy/ Reaction Time) After 8 Weeks (Including 4 Weeks Without Nasal Spray) | Change from baseline in performance on the emotion recognition task (accuracy/ reaction time) after 8 weeks (including 4 weeks without nasal spray). Emotion recognition from point-light displays conveying biological motion. Accuracy (acc) is measured in % of correct responses. Reaction time (rt) is measured in milliseconds. Higher (accuracy/ reaction time) ratio indicates better performance. | Value at 8 weeks minus value at baseline | 
| Change From Baseline in Performance on the Emotion Recognition Task (Accuracy/ Reaction Time) After 52 Weeks (Including 48 Weeks Without Nasal Spray) | Change from baseline in performance on the emotion recognition task (accuracy/ reaction time) after 52 weeks (including 48 weeks without nasal spray) Accuracy (acc) is measured in % of correct responses. Reaction time (rt) is measured in milliseconds. Higher (accuracy/ reaction time) ratio indicates better performance. | Value at 52 weeks minus value at baseline | 
| Change From Baseline in Informant-based/ Self-report Scores on Questionnaires Assessing Attachment, Social Functioning, Quality of Life and Mood After 4 Weeks of Nasal Spray | The Social Responsiveness Scale (for adults) (SRS-A) uses a four-point Likert-scale. Higher scores indicate lower social responsiveness. The Repetitive Behavior Scale - Revised (RBS-R) uses a four-point Likert-scale. Higher scores indicate a higher frequency and/or higher severity of restricted and repetitive behaviors. The State Adult Attachment Measure (SAAM) uses a seven-point Likert-scale.Higher scores indicate lower perceived secure attachment on the attachment avoidance and attachment anxiety subscales, and higher perceived secure attachment on the attachment security subscale. Inventory of Parent and Peer Attachment (IPPA) uses a four-point Likert-scale. Higher scores indicate indicate increased feelings of secure attachment towards peers or parents. World Health Organization Quality of Life - Bref (WHO-QL) uses a five-point Likert scale. Higher scores indicate better quality of life. Profile of Mood States (POMS). five-point Likert scale. | Value at 4 weeks minus value at baseline | 
| Change From Baseline in Informant-based/ Self-report Scores on Questionnaires Assessing Attachment, Social Functioning, Quality of Life and Mood After 8 Weeks, Including 4 Weeks Without Nasal Spray | The Social Responsiveness Scale (for adults) (SRS-A) uses a four-point Likert-scale. Higher scores indicate lower social responsiveness. The Repetitive Behavior Scale - Revised (RBS-R) uses a four-point Likert-scale. Higher scores indicate a higher frequency and/or higher severity of restricted and repetitive behaviors. The State Adult Attachment Measure (SAAM) uses a seven-point Likert-scale.Higher scores indicate lower perceived secure attachment on the attachment avoidance and attachment anxiety subscales, and higher perceived secure attachment on the attachment security subscale. Inventory of Parent and Peer Attachment (IPPA) uses a four-point Likert-scale. Higher scores indicate indicate increased feelings of secure attachment towards peers or parents. World Health Organization Quality of Life - Bref (WHO-QL) uses a five-point Likert scale. Higher scores indicate better quality of life. Profile of Mood States (POMS). five-point Likert scale. | Value at 8 weeks minus value at baseline | 
| Change From Baseline in Informant-based/ Self-report Scores on Questionnaires Assessing Attachment, Social Functioning, Quality of Life and Mood After 52 Weeks, Including 48 Weeks Without Nasal Spray | The Social Responsiveness Scale (for adults) (SRS-A) uses a four-point Likert-scale. Higher scores indicate lower social responsiveness. The Repetitive Behavior Scale - Revised (RBS-R) uses a four-point Likert-scale. Higher scores indicate a higher frequency and/or higher severity of restricted and repetitive behaviors. The State Adult Attachment Measure (SAAM) uses a seven-point Likert-scale.Higher scores indicate lower perceived secure attachment on the attachment avoidance and attachment anxiety subscales, and higher perceived secure attachment on the attachment security subscale. Inventory of Parent and Peer Attachment (IPPA) uses a four-point Likert-scale. Higher scores indicate indicate increased feelings of secure attachment towards peers or parents. World Health Organization Quality of Life - Bref (WHO-QOL) uses a five-point Likert scale. Higher scores indicate better quality of life. Profile of Mood States (POMS). five-point Likert scale. | Value at 52 weeks minus value at baseline | 
| Change From Baseline in Scores on Questionnaire Assessing Mood After a Single Dose of Nasal Spray | Change from baseline in scores on one questionnaire assessing mood (Profile of Mood States - POMS) after a single dose of nasal spray. This instrument comprises emotional adjectives subdivided in five domains: tension (6 items). depression (8 items). vigor (5 items). fatigue (6 items) and anger (7 items) which have to be rated on a five-point Likert scale ranging from 0 (not at all), 1 (a little), 2 (moderately), 3 (quite a lot), to 4 (extremely). Only for the vigor scale, higher scores indicate improvement. | Value at 30 minutes minus value at baseline | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Oxytocin, Autism Spectrum Disorders