Investigating Neurobehavioural Problems and The Role of Oxytocin in Children with Abnormalities of the Hypothalamo-Pituitary Axis

The hypothalamus and pituitary gland are situated in the mid-part of the brain. The Hypothalamo-Pituitary (HP) Axis is the central co-ordinator of growth and reproduction via production of various hormones. The HP axis also plays an integral part in regulating physiological functions such as heart rate, blood pressure, temperature, thirst, appetite, energy metabolism and sleep.
Septo-optic dysplasia (SOD) is a rare congenital condition affecting the development of particular parts of the brain, including the HP axis. Children with SOD have defects in cognition, vision and hormonal function. These children also suffer from various neurobehavioural, social and sleep-wake cycle (circadian) difficulties. A high prevalence of Autistic Spectrum Disorder (ASD) has also been reported in children with SOD. The presence of these neurobehavioural problems significantly affects the quality of life and poses a formidable challenge for the child and their family. The aetiology of these neurobehavioural problems, which the child and the family often find more difficult to cope with than the hormone replacement, is neither well understood nor well identified or treated.
Neurobehavioural problems are also disproportionately high in prevalence in childhood craniopharyngioma, a benign tumour derived from the pituitary gland. This supports the role of the HP axis and known hormone deficiencies or possibly a yet unidentified hormone deficiency leading to social and behavioural deficits.
Oxytocin (OT) is a hormone that is produced in the hypothalamus and secreted by the pituitary gland. It's role in lactation and parturition has been well established. However, OT has wider implications, including a key factor in modulating social bonding, memory, cognition and social behaviour. The disruption of the OT system has hence been of interest in the mechanistic understanding of neurobehavioural disorders viz. ASD and schizophrenia. Treatment trials of intranasal OT have reported improved sociability in children with ASD. Studies also report on low OT levels in hypopituitarism secondary to craniopharyngioma and have highlighted improvements in pro-social behaviour in response to nasal OT in single cases of craniopharyngioma. Targeting OT deficiency is hence an attractive therapeutic possibility in children with abnormalities of the HP axis and neurobehavioural problems.
This research project is a collaborative pilot project between King's Paediatric Endocrinology, Developmental Neuropsychiatry and Psychopharmacology and OT Psychopharmachology and Neuroimaging . Our hypothesis is that the oxytocinergic system is dysregulated in children and adolescents with SOD or craniopharyngioma and plays a major role in the neurobehavioural and neurocognitive deficits that characterise these cohorts of patients. Our project will investigate this hypothesis as a function of disorder type (SOD, craniopharyngioma), neurodevelopmental stage and underlying neuroanatomical and endocrine deficits, and hence open up exciting therapeutic avenues involving the administration of exogenous OT to improve the quality of life in this challenging patient cohort.
Expected Outputs and Future direction: 1) Detailed characterisation of the neurobehavioural/ neurocognitive profile of children with HP axis disorders, as a function of disorder type, developmental stage when the insult to the HP axis developed, neuroanatomical and endocrine profile and plasmatic OT levels
2) Lay the groundwork for a feasibility study on the efficacy of intranasal oxytocin as a treatment, followed by a multicentre randomised controlled trial.
3) Additionally, the CIPPRD will develop a specific clinic to provide assessment and treatment of significant neurobehavioural problems, with local CCG support

Objectives: 1. To define the neurobehavioural and neurocognitive phenotype of children with HP axis defects (SOD or craniopharyngioma).
2. To characterise the underlying neuroanatomical and endocrine deficits in these patients.
3. To investigate potential differences in the pattern of neurobehavioural and neurocognitive deficits as a function of disorder type (SOD, craniopharyngioma), neuroanatomical and endocrine deficits and developmental stage when the insult to the HP axis developed.
3. To assess plasma oxytocin (OT) levels as a potential marker for the deficiency the OTergic system, characterise the stability of plasmatic levels of OT in this cohort over a 6 month interval, and investigate plasma OT level deficits as a function of disorder type, underlying neuroanatomical deficits, developmental stage when the insult to the HP axis developed
4. To investigate the association between plasma OT levels and severity of neurobehavioural/neurocognitive deficits.
Methodology:
Patient Population: Prospective cohort analysis of patients with SOD and craniopharyngioma attending King's Paediatric Endocrinology service.
Intervention: the neurobehavioural phenotype of both our patient and control groups will be characterised twice over a 6 month interval using the HealthTrackerTM platform-based Profile Of Neuropsychiatric Symptoms, the HowRU, and the Assessment of Concerning Behaviours. We will assess their neurocognitive profile using a battery of tasks to assess intellectual ability, empathy, social cognition and attachment style. Finally, we will use gold-standard practices in the field to assay plasma OT concentrations using radioimmunoassay in extracted samples that we will obtain at the same time as the neurobehavioural/neurocognitive assessments. We will use existing neuroimaging and clinical data from the patient group to characterise neuroanatomical/ endocrine deficits and associate them to neurobehavioural/neurocognitive profiles and OT levels.