Fetal alcohol spectrum disorder (FASD), which is caused by prenatal alcohol exposure (PAE), affects an estimated 4% of North Americans, and is the most common preventable cause of intellectual disability. Mental health problems, including anxiety and depression, are experienced by nearly all individuals with FASD. However, there is very limited knowledge about effective mental health treatments for individuals with FASD; effective treatments are hindered in part due to a lack of understanding of the basic neurobiology underlying internalising disorders in youth with FASD.
The Prenatal Exposure And Child brain and mental Health (PEACH) study includes children aged 7–18 years. We will use longitudinal neuroimaging (anatomical T1-weighted, diffusion and passive viewing function MRI) and mental health assessments (Behaviour Assessment Scale for Children, Multi-dimensional Anxiety Scale for Children, Children’s Depression Inventory (CDI-2), Kiddie Scale of Affective Disorders) to: (1) characterise brain development trajectories in youth with FASD, (2) determine whether brain alterations mediate increased anxiety and depression in youth with FASD and (3) identify baseline brain features that predict changes of anxiety and depression symptoms over the next 2 years. All of this will be done while considering sex and adverse postnatal experiences, which can significantly impact mental health and brain outcomes. This project will forge new understanding of FASD and mental health from a neurobiological perspective, highlighting key time periods (ie, sensitive windows) and brain regions (ie, that may be susceptible to neurostimulation), while identifying factors that predict individual trajectories of anxiety and depression symptoms.
This study was approved by the University of Calgary Conjoint Health Research Ethics Board and the University of Alberta Health Research Ethics Board. Study results will be disseminated in peer-reviewed journals, at relevant conferences and in conjunction with our knowledge mobilisation partners.
We use longitudinal neuroimaging to assess brain structure and brain growth.
Alcohol-exposed participants will have confirmed prenatal alcohol exposure, though specific measures of timing, frequency and dose of prenatal alcohol exposure may be difficult to obtain.
We use multiple mental health assessments to measure symptoms of depression and anxiety, and include a comprehensive neurocognitive battery.
This study uses a longitudinal, prospective design and will follow children over 2 years.
We incorporate comprehensive assessment and analysis of both prenatal and postnatal adverse exposures.
Fetal alcohol spectrum disorder (FASD) is a neurodevelopmental disorder caused by prenatal alcohol exposure (PAE). It is characterised by life-long cognitive, behavioural and neurological deficits.
MRI can be used to investigate neurological abnormalities in FASD. The most common MRI finding in individuals with FASD is widespread reductions in brain volume, which have been observed with anatomical MRI from neonates to adults.
Previous studies have related cognitive abilities and clinical features (eg, dysmorphology) to brain structure in FASD
Little is known about the trajectories of mental health symptoms in youth with FASD, though difficulties tend to persist or worsen with age.
Individuals with PAE/FASD frequently have adverse postnatal experiences (~43% have abuse or neglect).
Understanding brain development in individuals with FASD, its relation to internalising symptoms and predictors of positive outcomes is critical for targeting treatments at the right time (eg, age-appropriate therapy),
Characterise developmental trajectories of brain connectivity in youth with FASD.
Determine whether brain structure and function mediate the relationship between FASD and internalising symptoms.
Identify baseline factors that predict changes of internalising symptoms over time in youth with FASD.
We will recruit 125 children and youth with heavy PAE or FASD and 125 unexposed controls aged 7–18 years. This age range was chosen because: (1) FASD diagnosis typically occurs at or after age ~6–7 years in Alberta,
Participants will be recruited through diagnostic clinics throughout Alberta (including the Pediatric FASD Clinic at the Glenrose Hospital in Edmonton and the Cumulative Risk Diagnostic Clinic at the Alberta Children’s Hospital in Calgary), Alberta Children’s Services, parent/caregiver support groups for FASD, community groups (eg, Calgary and Edmonton Fetal Alcohol Networks), as well as online advertisements and word of mouth.
Participants in the PAE group must have a diagnosis of FASD or confirmed heavy PAE at levels consistent with Canadian FASD diagnostic guidelines (≥7 drinks/week or ≥2 binge episodes at some point during pregnancy).
Controls must have confirmed absence or minimal PAE (≤5 drinks total in pregnancy, with no binge episodes) via biological maternal report, no diagnosis of genetic or neurological disorders and no contraindications to MRI scanning. Controls will be recruited through online advertisements, parent groups in Edmonton and Calgary and word of mouth. Controls must not have significant intellectual or developmental impairments, but will not be excluded for neurodevelopmental disorders such as ADHD or learning disabilities.
MRI scanning at baseline and 2-year follow-up will take place at the Alberta Children’s Hospital (Calgary) on a research-dedicated General Electric 3T MR750w system, or at the Peter S Allen MRI Centre (Edmonton) on a research-dedicated Siemens 3T Prisma. The imaging protocol is detailed in
MRI protocol. Parameters are given for GE MR750w before Siemens Prisma; if only one set of parameters is given, they were the same for both scanners
Sequence | Scan time (min:s) | Resolution (mm3) | Slices | Field-of-view(cm) | Reptetition Time (TR) (ms) | Echo Time (TE) (ms) | Other information |
Passive viewing fMRI (ss-EPI) | 8:10 | 3.6×3.6×3.6 | 36 | 23 | 2000 | 30 | Acquired while watching a clip from Planet Earth |
ASL (3D) | 5:01 | 3.5×3.5×3.5 / | 34 | 23/24 | 4600/4845 | 15.6/10.1 | TI 1990/2025 ms |
DTI | 7:08/14:12 | 2.2×2.2×2.2 | 57 | 22/24.2 | 6300/12000 | 55/98 | 5/10 b0, 30 dir b900, |
3D T1 | 4:57 | 0.8×0.8×0.8 | 192 | 25.6/24 | 1880/8.25 | 2.9/3.16 | Flip angle 10, |
QSM | 5:16 | 1.0×1.0×2.0 / | 80 | 24 | 42/44.8 | 3.8–36.8/4.1–37.9 | 7/8 echoes, flip angle 17/15 |
ihMT | 3:09 | 0.9×0.9×5.0 | 30 | 22 | 8500/15000 | 85/103 |
ASL, arterial spin labelling; DTI, diffusion tensor imaging; EPI, echo planar imaging; fMRI, functional MRI; FSPGR, fast spoiled gradient; ihMT, inhomogeneous magnetisation transfer; MP-RAGE, magnetisation prepared rapid acquisition gradient echo; QSM, quantitative susceptibility mapping; SPGR, spoiled gradient; ss-EPI, single shot echo planar imaging.
T1-weighted images will be processed using FreeSurfer’s
Diffusion data will be quality checked, brain extracted and corrected for eddy currents and head motion. FA and MD maps will be generated for each subject. Tractography (FA >0.2, angle <30∘) will be used to reconstruct white matter fibres connecting frontal and limbic regions (uncinate fasciculus, cingulum, fornix). FA and MD will be assessed within each white matter fibre bundle as primary variables of interest. The dual b-value scan also allows for more advanced diffusion models and analysis,
Assessment of rs-fMRI data will use AFNI and FSL tools.
Mental health assessments will occur at baseline, a subset of tests will be administered online at 1-year follow-up, and the full set will be administered again at 2-year follow-up (see
Questionnaires and assessments
Time 1 (in person) | Time 2 (online) | Time 3 (in person) | Age limits | |
Child Depression Index | Caregiver report | Caregiver report | Caregiver report | Beck Depression Inventory used for youth >17 years |
Multidimensional Anxiety Scale for Children | Caregiver report | Caregiver report | Caregiver report | MASC-2 not used in children aged 7 years; PROMIS Anxiety Short Form used for young adults 20 years |
Behaviour Assessment System for Children | Caregiver report | Caregiver report Self-report | Caregiver report | Self-report only completed by children ≥12 years |
Kiddie Scale of Affective Disorders and Schizophrenia | Caregiver interview | Caregiver interview | Child interview only conducted with children ≥12 years | |
Adaptive Behaviour Assessment System | Caregiver report | Caregiver report | ||
Pain questionnaire | Caregiver report | |||
Sensory Profile | Caregiver report | Caregiver report | Only used for children <15 years | |
Wechsler Abbreviated Scale of Intelligence 2-subtest form | Matrix reasoning, vocabulary | |||
Rey-Osterrieth Complex Figure Test | Child | Child | ||
Wechsler Individual Achievement Test | Word reading, pseudo-word reading, oral reading fluency, reading comprehension, numerical operations | Word reading, pseudo-word reading, oral reading fluency, reading comprehension, numerical operations | ||
NEPSY-II | Inhibition, word generation | Inhibition, word generation | Only conducted with children <17 years | |
California Verbal Learning Task - Child | Child | Child | CVLT-3 used for youth ≥17 years | |
Wisconsin Card Sort Task | Child | Child | ||
Demographic questionnaire | Caregiver | Caregiver | Caregiver | |
Prenatal and postnatal exposure assessment | Caregiver; medical, legal, children’s services records | |||
Puberty questionnaire | Caregiver, child | Caregiver, child | Caregiver, child | |
Gender identity questionnaire | Caregiver, child | |||
Adverse childhood experiences | Caregiver on behalf of child |
Questionnaire and assessments are listed below for each study time point. Caregiver refers to a parent or guardian who regularly cares for the child. Study personnel support younger children in completing the questionnaires if necessary.
DIAMOND, Diagnostic Interview for Anxiety and Mood, and OCD and Related Neuropsychiatric Disorders; NEPSY-II, A Developmental NEuroPSYchological Assessment, 2nd Edition.
To determine whether an individual meets diagnostic criteria for anxiety or depression, youth ≥12 years of age and all caregivers will complete a diagnostic assessment of internalising mental health disorders with a trained and reliable clinician using the mood and affective disorders subscales of Kiddie Schedule for Affective Disorders and Schizophrenia – Lifetime Version (K-SADS-PL).
We also examine the frequency, chronicity and location of pain of children and youth in the past 30 days.
IQ will be assessed using the Wechsler Abbreviated Scale of Intelligence – Second Edition
Adverse postnatal exposures are assessed using questions adapted from the National Crittenton Foundation ACEs survey,
Caregivers will complete a comprehensive demographic survey that includes information about other individuals in the house, household income, parent education and ethnicity. Caregivers will be asked if youth have other diagnoses or are taking medications. Depending on the age and abilities of the youth, they and/or their caregiver will be asked to complete a short questionnaire about puberty. Youth will be asked to self-report their sex and gender. Sex will be included as a covariate in all analyses, and sex-by-age or sex-by-anxiety/depression interaction terms will be included where appropriate. Gender and its interaction terms will be used as additional covariates if numbers permit.
Statistical analysis will occur in SPSS (IBM), R (
Key grey matter regions (A) and white matter connections (B) related to anxiety and/or depression symptoms. Volume of the regions in A, functional connectivity between pairs of regions in A and structural connectivity (diffusion metrics) of tracts in B will be measured. dACC, dorsal anterior cingulate cortex; dlPFC, dorsolateral prefrontal cortex; mPFC, medial prefrontal cortex.
For Aim 2, mediation will be carried out by testing the first pathway from the main predictor (PAE) to each brain measure (volume, structural or functional connectivity), controlling for age and sex of participants, and then testing the second pathway from each brain measure to each mental health measures (anxiety or depression symptoms), with age, sex and postnatal adversity as covariates. The overall mediation effect will be tested using percentile-based bootstrap CIs, computed from 5000 simulations.
For Aim 3, change in anxiety and depression symptoms will be calculated by subtracting the
We collected preliminary data, including MRI, mental health assessments and postnatal adversity on 17 children with FASD and 19 controls without PAE aged 7–15 years. Control subjects (part of a different study)
CT (co-investigator on the project) was an Associate Director of Alberta Children’s Services and was involved in study design. She has since moved on to a role as Assistant Professor at Mount Royal University and remains involved with the project. We continue to involve staff from Children’s Services in the design and execution of the study, and will involve them in interpretation and dissemination of findings. We also have active relationships with organisations serving individuals with FASD and their families, including the Calgary and Edmonton Fetal Alcohol Networks and CanFASD (co-investigator JP is Senior Research Lead/Intervention Lead at CanFASD). These organisations have provided study feedback and support and will assist with interpretation and dissemination of findings.
Research on children and youth with FASD is complex due to confounding prenatal and postnatal exposures, missing information and behavioural difficulties. If recruitment or retention are lower than anticipated, we will recruit participants outside Calgary and Edmonton (eg, through the other 10 FASD Networks across Alberta). The strict diagnostic criteria used here will ensure that all participants have a minimum level of PAE, though exact amounts may not be known. We will use all available sources to characterise other risks and diagnoses in our participants and will statistically control for these in our analyses.
FASD is a common disorder (~4% of Canadians) with a very high societal cost (>$17B annually). Most individuals with FASD experience co-occurring mental health issues throughout their lifespan, but effective treatments are hindered by a lack of understanding of the neurobiological basis for these problems. The use of quantitative MRI to understand the brain abnormalities and atypical development patterns underlying mental health problems in youth with FASD is critical to early identification and appropriate intervention strategies to improve outcomes. This study will reveal developmental patterns of brain connectivity, identify the underlying neurological correlates of anxiety and depression symptoms in youth with FASD and identify baseline brain features that can predict the worsening of anxiety and depression symptoms. This knowledge is crucial for advancing research and identifying prevention and early intervention strategies, which will have substantial benefits for children and youth with FASD, their families and the public health system and society. This innovative project will address significant gaps in the literature, inform prevention strategies and promote early detection and intervention of internalising issues in children and youth with FASD.
This study has been approved by the University of Calgary Conjoint Health Research Ethics Board (REB17-0663) and the University of Alberta Health Research Ethics Board (Pro00093230). Data collection takes 4–6 hours for youth, and 2–3 hours for caregivers (
Communication of our findings to other researchers will occur via publications in peer-reviewed journals and presentations at relevant conferences (eg, Organization for Human Brain Mapping, Canadian Academy of Child & Adolescent Psychiatry). As we publish our research findings, we will produce lay summaries and infographics for distribution to stakeholders via our website, our Twitter accounts, Kids Brain Health Network’s website (researchimpact.ca), social media (including Kids Brain Health Network’s YouTube, Facebook and Twitter accounts), and email.
Knowledge translation to the wider community will include direct communication (via reports, presentations, meetings) with diagnostic clinics and Children’s Services. Results will be presented at policy and practice meetings (eg, International Conference on Child and Family Maltreatment, Canadian Association of Pediatric Health Centres, Canadian Pediatric Society, Alberta College of Social Workers).