Diffusion Weighted Magnetic Resonance Imaging of in utero and ex utero Human Brain Development

The primary objective of this thesis was to establish quantitative measurements of normal fetal brain tissue across gestation using diffusion magnetic resonance imaging (MRI); the secondary aim was to compare diffusion metrics in fetuses with normal brain development to those with isolated ventriculomegaly (VM), congenital heart disease and in infants born preterm. Fetal diffusion weighted imaging (DWI) was optimised, and a motion-corrected diffusion tensor imaging (DTI) technique was utilized to produce apparent diffusion coefficient (ADC) and fractional anisotropy (FA) values across gestation in normal fetal cohorts. Tract-based spatial statistics (TBSS) was utilised to analyse DTI in neonates with isolated VM compared to controls. Diffusion and volumetric MR data in preterm infants were analysed using an objective segmentation approach to characterise ex utero neurodevelopment, and to establish the effects of perinatal clinical factors on brain development. Normative ADC values were established in the fetal brain (n=52) across a large gestational age range. Increased ADC values were found in fetuses (n=24) and neonates (n=22) with isolated VM compared to controls; decreased FA was also demonstrated in neonates with VM. In preterm neonates (n=208), white and deep grey matter exhibited significantly increasing FA, and decreasing ADC, axial and radial diffusivity measures with increasing age at scan. DTI measures in the cortex significantly decreased with increasing age at scan; volume measures increased in all brain regions. Clinical factors including respiratory support and age at birth affected regional DTI and volumetric measures in preterm infants. FA values from a normal fetal cohort using motion-corrected DTI (n=26) were compared to preterm neonates (n=32) and significant differences were found. This thesis produced normal fetal diffusion data comparable to that produced in neonates. Quantifiable MR techniques can be used to explore the relationship between in utero and ex utero brain development and study alterations of normal fetal maturation.Open Acces

Barriers to Autism Spectrum Disorder diagnosis for young women and girls: a systematic review

There is increased recognition that women and girls with autism spectrum disorders (ASD) are underserved by the clinical criteria and processes required to receive a diagnosis. This mixed-methods systematic review aimed to identify key barriers to obtaining an ASD diagnosis in girls and young women under 21 years. Six themes were identified that focused on perceived gendered symptoms, namely behavioural problems, social and communication abilities, language, relationships, additional diagnoses/ difficulties and restricted and repetitive behaviours and interests. Five themes were identified as (parental) perceived barriers to diagnosis, namely compensatory behaviours, parental concerns, others’ perceptions, lack of information/resources and clinician bias. This review highlights the importance of enhancing widespread understanding and recognition of ASD presentation in females across development. PROSPERO Centre for Reviews and Dissemination (ID 2018 CRD42018087235)

Attention control in autism: Eye-tracking findings from preschool children in a low- and middle-income country setting

Alterations in the development of attention control and learning have been associated with autism and can be measured using the ‘antisaccade task’, which assesses a child’s ability to make an oculomotor response away from a distracting stimulus, and learn to instead anticipate a later reward. We aimed to assess these cognitive processes using portable eye-tracking in an understudied population of pre-school children with and without a diagnosis of autism spectrum disorder in community settings in New Delhi, India. The eye-tracking antisaccade task was presented to children in three groups (n=104) (children with a clinical diagnosis of autism spectrum disorder or intellectual disability and children meeting developmental milestones). In accordance with findings from high-income, laboratory- based environments, children learnt to anticipate looks towards a reward, as well as inhibit eye-movements towards a distractor stimulus. We also provide novel evidence that while differences in inhibition responses might be applicable to multiple developmental conditions, a reduced learning to anticipate looks towards a target in this age group may be specific to autism. This eye-tracking task may, therefore, have the potential to identify and assess autism specific traits across development, and be used in longitudinal research studies such as investigating response to intervention in low-resource settings

Young pregnant women and risk for mental disorders: findings from an early pregnancy cohort

BACKGROUND:Young women aged 16-24 are at high risk of common mental disorders (CMDs), but the risk during pregnancy is unclear.AimsTo compare the population prevalence of CMDs in pregnant women aged 16-24 with pregnant women ≥25 years in a representative cohort, hypothesising that younger women are at higher risk of CMDs (depression, anxiety disorders, post-traumatic stress disorder, obsessive-compulsive disorder), and that this is associated with low social support, higher rates of lifetime abuse and unemployment. METHOD:Analysis of cross-sectional baseline data from a cohort of 545 women (of whom 57 were aged 16-24 years), attending a South London maternity service, with recruitment stratified by endorsement of questions on low mood, interviewed with the Structured Clinical Interview DSM-IV-TR. RESULTS:Population prevalence estimates of CMDs were 45.1% (95% CI 23.5-68.7) in young women and 15.5% (95% CI 12.0-19.8) in women ≥25, and for 'any mental disorder' 67.2% (95% CI 41.7-85.4) and 21.2% (95% CI 17.0-26.1), respectively. Young women had greater odds of having a CMD (adjusted odds ratio (aOR) = 5.8, 95% CI 1.8-18.6) and CMDs were associated with living alone (aOR = 3.0, 95% CI 1.1-8.0) and abuse (aOR = 1.5, 95% CI 0.8-2.8). CONCLUSIONS:Pregnant women between 16 and 24 years are at very high risk of mental disorders; services need to target resources for pregnant women under 25, including those in their early 20s. Interventions enhancing social networks, addressing abuse and providing adequate mental health treatment may minimise adverse outcomes for young women and their children.Declaration of interestNone

Using mobile health technology to assess childhood autism in low-resource community settings in India: an innovation to address the detection gap

A diagnosis of autism typically depends on clinical assessments by highly-trained professionals. This high resource demand poses a challenge in low-resource settings. Digital assessment of neurodevelopmental symptoms by non-specialists provides a potential avenue to address this challenge. In this study, we provide the proof of principle for such a digital assessment, with a cross-sectional case control field study using mixed methods. We developed and tested an app, START, that can assess autism phenotypic domains (social, sensory, motor) through child performance and parent reports. N=131 children (2-7 years old; 48 autistic, 43 intellectually disabled, and 40 non-autistic typically developing) from low-resource settings in India were assessed using START in home settings by non-specialist health workers. The two groups of children with neurodevelopmental disorders manifested lower social preference, higher sensory sensitivity, and lower fine-motor accuracy compared to their typically developing counterparts. Machine-learning analysis combining all START-derived measures demonstrated 78% classification accuracy for the three groups. Qualitative analysis of the interviews with health workers and families of the participants demonstrated high acceptability and feasibility of the app. These results provide feasibility, acceptability, and proof of principle for START, and demonstrate the potential of a scalable, mobile tool for assessing neurodevelopmental conditions in low-resource settings

Mapping the link between socio-economic factors, autistic traits and mental health across different settings

Autistic individuals experience higher rates of externalising and internalising symptoms that may vary with environmental factors. However, there is limited research on variation across settings that may highlight common factors with globally generalisable effects. Data were taken from two cohorts: a multinational European sample (n = 764; 453 autistic; 311 non-autistic; 6–30 years), and a South African sample (n = 100 non-autistic; 3–11 years). An exploratory factor analysis aggregated clinical (Verbal Comprehension and Perceptual Index), adaptive traits (Vineland Adaptive Behaviour Scale) and socio-economic variables (parental employment and education, home and family characteristics) in each cohort separately. With regression, we investigated the effect of these factors and autistic traits on internalising and externalising scores (measured with the Strengths and Difficulties Questionnaire). Cohorts showed similar four-factor structures (Person Characteristics, Family System, Parental and Material Resources). The ‘Family System’ factor captured family size and maternal factors and was associated with lower internalising and externalising symptoms in both cohorts. In the European cohort, high autistic traits reduced this effect; the opposite was found in the South Africa cohort. Our exploratory findings from two separate analyses represent consistent evidence that Family System is associated with internalising and externalising symptoms, with a context-specific impact in persons with high autism traits

White and grey matter development in utero assessed using motion-corrected diffusion tensor imaging and its comparison to ex utero measures

Fetal brain diffusion tensor imaging (DTI) offers quantitative analysis of the developing brain. The objective was to 1) quantify DTI measures across gestation in a cohort of fetuses without brain abnormalities using full retrospective correction for fetal head motion 2) compare results obtained in utero to those in preterm infants. Motion-corrected DTI analysis was performed on data sets obtained at 1.5T from 32 fetuses scanned between 21.29 and 37.57 (median 31.86) weeks. Results were compared to 32 preterm infants scanned at 3T between 27.43 and 37.14 (median 33.07) weeks. Apparent diffusion coefficient (ADC) and fractional anisotropy (FA) were quantified by region of interest measurements and tractography was performed. Fetal DTI was successful in 84% of fetuses for whom there was sufficient data for DTI estimation, and at least one tract could be obtained in 25 cases. Fetal FA values increased and ADC values decreased with age at scan (PLIC FA: p = 0.001; R  = 0.469; slope = 0.011; splenium FA: p < 0.001; R  = 0.597; slope = 0.019; thalamus ADC: p = 0.001; R  = 0.420; slope = - 0.023); similar trends were found in preterm infants. This study demonstrates that stable DTI is feasible on fetuses and provides evidence for normative values of diffusion properties that are consistent with aged matched preterm infants

Thailand's national universal developmental screening programme for young children: action research for improved follow-up

Introduction In low-income and middle-income countries, it is estimated that one in every three preschool-age children are failing to meet cognitive or socioemotional developmental milestones. Thailand has implemented a universal national developmental screening programme (DSPM) for young children to enable detection of developmental disorders and early intervention that can improve child health outcomes. DSPM implementation is being hampered by low attendance at follow-up appointments when children fail the initial screening. Methods Action research, using qualitative methods was conducted with 19 caregivers, 5 health workers and 1 chief at two Health Promotion Hospitals to explore the factors affecting attendance at follow-up appointments. Transcripts and notes were analysed using descriptive content analysis. Findings were then discussed with 48 health workers, managers, researchers and policymakers. Results The high workload of health workers during busy vaccination clinics, and inadequate materials prevented clear communication with caregivers about the screening, how to stimulate child development and the screening result. Caregivers, particularly grandparents, had a lack of understanding about how to stimulate child development, and did not fully understand failed screening results. Caregivers felt blamed for not stimulating their child’s development, and were either worried that their child was severely disabled, or they did not believe the screening result and therefore questioned its usefulness. This led to a lack of attendance at follow-up appointments. Conclusion Task-sharing, mobile health (mhealth), community outreach and targeted interventions for grandparent caregivers might increase awareness about child development and screening, and allow health workers more time to communicate effectively. Sharing best practices, communication training and mentoring of DSPM workers coupled with mhealth job aids could also improve caregiver attendance at follow-up. Engagement of caregivers in understanding the barriers to attendance at follow-up and engagement of stakeholders in the design and implementation of interventions is important to ensure their effectiveness