Welcome to today’s AIR-P/ATN Advances in Autism Research & Care Webinar Series! This research activity was supported by a cooperative agreement UA3 MC11054 through the U.S. Department of Health and Human Services, Health Resources and Services Administration, Maternal and Child Health Research Program to the Massachusetts General Hospital. This work was conducted through the Autism Speaks Autism Treatment Network serving as the Autism Intervention Research Network on Physical Health.
RELATIONSHIP BETWEEN GASTROINTESTINAL DISORDERS AND STRESS REACTIVITY, IMMUNITY, AND BLOOD SEROTONIN IN AUTISM SPECTRUM DISORDERS David Beversdorf, M.D. Principal Investigator AIR-P/ATN Webinar Monday, November 24, 2014
Relationship Between Gastrointestinal Disorders and Stress Reactivity, Immunity, and Blood Serotonin in Autism Spectrum Disorder Investigators / Collaborating Sites: David Beversdorf, M.D. Missouri Jeremy Veenstra-VanderWeele, M.D. VUMC
Relationship Between Gastrointestinal Disorders and Stress Reactivity, Immunity, and Blood Serotonin in Autism Spectrum Disorder BACKGROUND • High rate of GI disorders in ASD, but biology and etiology is unknown • In general population, strong relationship between stress and GI • There is an augmented stress response in ASD • Therefore, it is possible for GI symptoms in ASD to vary as a function of stress reactivity
Relationship Between Gastrointestinal Disorders and Stress Reactivity, Immunity, and Blood Serotonin in Autism Spectrum Disorder Pilot Study • Conducted at the University of Missouri Thompson Center for Autism and Neurodevelopmental Disorders • 16 children(mean age 12.3±3.6 years(±sdev), range 5-19) • 8 children with ASD with GI problems, 8 with ASD without GI • GI symptomatology verified by parent report on the Questionnaire on Pediatric Gastrointestinal Symptoms – Rome III Version (QPGS Rome-III) • Skin Conductance data collected during rest and in response to vibrotactile and cold pressor stimulation (stressors)
Relationship Between Gastrointestinal Disorders and Stress Reactivity, Immunity, and Blood Serotonin in Autism Spectrum Disorder Pilot Data * Figure 1 . Mean skin conductance (microsiemens) for ASD GI and ASD NO GI groups during baseline. * p < .05.
Relationship Between Gastrointestinal Disorders and Stress Reactivity, Immunity, and Blood Serotonin in Autism Spectrum Disorder Pilot Data Figure 2. Mean skin conductance (microsiemens) for ASD GI and ASD NO GI groups during vibrotactile stimulation ( p = 0.083)
Relationship Between Gastrointestinal Disorders and Stress Reactivity, Immunity, and Blood Serotonin in Autism Spectrum Disorder • Next Steps • Explore in a more definitive manner in a larger sample • Examine other systems that may be affected by GI disorders in ASD • A three- aim study was proposed…
Aim 1 – Explore Relationship Between GI Problems and Stress 80 Children 40 Children from ATN from ATN Registry from Registry from Missouri Vanderbilt ECG and GSR Data Recordings During Stress Stimuli Is Stress HRV and Mean Implicated in GI Skin Problems in Conductance ASD?
Aim 1 – Explore Relationship Between GI Problems and Stress • Hypothesis • Heart Rate Variability as GI symptoms increase • Skin Conductance as GI symptoms increase
Aim 1 – Explore Relationship Between GI Problems and Stress • Skin Conductance Level (SCL) • Average conductance over time • Heart Rate Variability (HRV) • pNN50 – percentage of normal R-R interval pairs that differ by 50ms or more.
Aim 2 – Examine Immune and Endocrine Markers in GI Disorders in ASD 80 Children 40 Children from ATN from ATN Registry from Registry from Missouri Vanderbilt Collect Blood and Saliva Samples Are there immune Examine IL-6 and endocrine and TNF-alpha differences in and salivary those with GI and cortisol ASD?
Aim 2 – Examine Immune and Endocrine Markers in GI Disorders in ASD Hypothesis • Immunological Functioning • Altered IL-6 and TNF-alpha cytokine levels in those with greater stress reactivity • Cortisol • Salivary cortisol as GI symptoms
Aim 2 – Examine Immune and Endocrine Markers in GI Disorders in ASD Atypical Immune Response in ASD • Immune markers affected in ASD: IL-12, IFN- γ, IL -2, IL- 6, IL-10, and TNF-alpha (Ashwood et al., 2006) • TNF- α, IL -12, IL-10, and IL-6 are associated with GI symptomatology (Ashwood et al, 2006; Jyonouchi et al., 2011) • Significant overlap between what is observed in ASD and immune markers associated with the stress response (IL-6 and TNF- α) Cortisol Levels Increased in ASD and in GI Alone • Increased stress response in ASD (Corbett et al., 2008) • In general population, increased stress response in those with GI disorders (Lyte, et al., 2011)
Aim 3 – Examine Whole Blood Serotonin and GI in ASD 80 Children from 40 Children from ATN Registry ATN Registry from Missouri from Vanderbilt Collect Whole Blood Samples Are there Examine Whole differences in Blood Serotonin serotonin levels Levels in ASD and GI?
Gastrointestinal Disorder Assessment • Questionnaire on Pediatric Gastrointestinal Symptoms, Rome III Version (QPGS-RIII) • Measures frequency, severity, and duration of functional GI disorders • Can be used to assess whether a person meets criteria for a GI disorder • We created a scoring algorithm to assess a range of GI symptoms • Higher scores = greater GI impairment
Selection of Participants at Each Site Screened ATN Inclusion Criteria Exclusion Criteria Registry Patients • • Mitochondrial/genetic ASD Diagnosis Contacted disorder • Age 6-18 • Sensitivity to adhesives QPGS Rome-III • Inability to remain still Questionnaire Administered • Bleeding disorder • Medical Condition • Lack of reliable informant Invited to Participate in • Inability/unwilling to Study provide consent
Study Demographics Mean Age SD Min Max N 11.89 3.75 6 18 120 Sex Number Percentage of Sample Male 108 90 Female 12 10
Aim 1 - Results Scatterplot With Regression Line Root-Arcsine Transformed pNN50 Baseline, Cold Pressor-Baseline, Vibro-Baseline on GI Sum Scores 0.4 0.8 0.4 Vibro-Base Cold-Base Baseline 0.2 0.6 0.0 0.0 0.4 -0.2 0.2 -0.4 -0.4 0.0 0 10 20 30 40 50 0 10 20 30 40 50 0 10 20 30 40 50 Upper GI Sum R3 Upper GI Sum R3 Upper GI Sum R3 0.4 0.8 0.4 Vibro-Base Cold-Base 0.2 Baseline 0.6 0.0 0.0 0.4 -0.2 0.2 -0.4 -0.4 0.0 0 10 20 30 40 50 0 10 20 30 40 50 0 10 20 30 40 50 Lower GI Sum R3 Lower GI Sum R3 Lower GI Sum R3 ATN/AIR-P -- GI/Stress Data assembled on 20141110 MGH Biostatistics Center Draft analysis -- not audited
Aim 1 - Results Scatterplot With Regression Line Scatterplot With Regression Line Root-Arcsine Transformed pNN50 Baseline, Cold Pressor-Baseline, Vibro-Baseline on GI GSR Baseline and Cold Pressor on GI Sum Scores Sum Scores 6 12.5 15 Cold Presor Cold-Base 0.4 Baseline 0.8 0.4 10.0 Vibro-Base 2 Cold-Base Baseline 10 0.2 0.6 7.5 0.0 0.0 -2 0.4 5 5.0 -0.2 0.2 2.5 0 -6 -0.4 -0.4 0.0 0 10 20 30 40 50 0 10 20 30 40 50 0 10 20 30 40 50 0 10 20 30 40 50 0 10 20 30 40 50 0 10 20 30 40 50 Upper GI Sum R3 Upper GI Sum R3 Upper GI Sum R3 Upper GI Sum R3 Upper GI Sum R3 Upper GI Sum R3 6 12.5 0.4 15 Cold Presor 0.8 0.4 Cold-Base Vibro-Base Cold-Base Baseline 0.2 Baseline 10.0 2 0.6 10 0.0 7.5 0.0 0.4 -2 5 -0.2 5.0 0.2 -0.4 -0.4 2.5 0.0 0 -6 0 0 10 10 20 20 30 30 40 40 50 50 0 0 10 20 30 40 50 10 20 30 40 50 0 0 10 10 20 30 40 50 20 30 40 50 Lower GI Sum R3 Lower GI Sum R3 Lower GI Sum R3 Lower GI Sum R3 Lower GI Sum R3 Lower GI Sum R3 ATN/AIR-P -- GI/Stress ATN/AIR-P -- GI/Stress Data assembled on 20141110 Data assembled on 20141110 MGH Biostatistics Center MGH Biostatistics Center Draft analysis -- not audited Draft analysis -- not audited
Aim 1 - Results Summary of findings Spearman Correlation P-value (95% CI) 0.18 (-.02, 0.36) †0.076 pNN50 baseline Upper GI 0.21 (.01, 0.39) *0.034 pNN50 baseline Lower GI -0.18 (-.37, 0.02) †0.072 pNN50 vibration-base Lower GI -0.24 (-.42, -.04) *0.018 pNN50 cold pressor-base Lower GI -0.21 (-.42, 0.02) †0.070 GSR: cold pressor- base Upper GI
Aim 1 - Results SUMMARY OF REGRESSION ANALYSIS -UPPER GI predominantly related to pNN50 baseline (small contribution from heart rate) -LOWER GI predominantly driven by pNN50 cold pressor minus baseline (but very closely interrelated with baseline
Aim 2 - Results • Aim 2 results are forthcoming… • IL-6 and TNF-alpha ELISAs are being analyzed at the moment
Discussion • Psychophysical factors – Parasympathetic markers (pNN50) appear to be related to Lower GI and to some extent Upper GI – GSR limited findings- technically challenging – Baseline and stimulated HRV closely related – Post-hoc frequency analysis underway to more closely examine sympathetic and parasympathetic components from HRV
Discussion – Psychophysical factors • GI symptoms also related to some behavioral aspects (Vineland, ABC) • Cytokines completed, being analyzed
Discussion • Would be of interest in future to look at other factors, how stress genetics relate, microbiome • Future implications may also include impact on treatment • May serve as a biomarker that impacts treatment plan
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