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

下丘脑和脑下垂体位于大脑的中部。下丘脑-垂体（HP）轴是通过产生各种激素来调节生长和繁殖的中心协调器。HP轴在调节心率、血压、体温、口渴、食欲、能量代谢和睡眠等生理功能方面也起着不可或缺的作用。中隔-视神经发育不良（SOD）是一种罕见的先天性疾病，影响大脑特定部位的发育，包括HP轴。患有SOD的儿童在认知、视力和激素功能方面存在缺陷。这些儿童还患有各种神经行为、社会和睡眠-觉醒周期（昼夜节律）困难。据报道，患有超氧化物歧化酶的儿童患自闭症谱系障碍（ASD）的比例也很高。这些神经行为问题的出现严重影响了生活质量，对儿童及其家庭构成了巨大的挑战。这些神经行为问题的病因，孩子和家庭往往发现比激素替代疗法更难应对，既没有得到很好的理解，也没有得到很好的识别和治疗。神经行为问题在儿童颅咽管瘤（一种源自脑下垂体的良性肿瘤）中的患病率也高得不成比例。这支持了HP轴和已知激素缺乏的作用，或者可能是一种尚未确定的导致社会和行为缺陷的激素缺乏。催产素（OT）是一种在下丘脑产生并由脑下垂体分泌的激素。它在哺乳和分娩中的作用已经得到了很好的证实。然而，OT具有更广泛的含义，包括调节社会联系、记忆、认知和社会行为的关键因素。因此，对神经行为障碍（即ASD和精神分裂症）的机制理解对OT系统的破坏很感兴趣。鼻内OT治疗试验报告了ASD患儿社交能力的改善。研究还报道了颅咽管瘤继发的垂体功能低下患者的低OT水平，并强调了在颅咽管瘤的单个病例中，鼻OT对亲社会行为的改善。因此，针对OT缺乏是一种有HP轴异常和神经行为问题的儿童有吸引力的治疗可能性。该研究项目是King's儿科内分泌学、发育神经精神病学和精神药理学以及OT精神药理学和神经影像学之间的合作试点项目。我们的假设是，在患有SOD或颅咽管瘤的儿童和青少年中，催产素系统失调，并在这些患者的神经行为和神经认知缺陷中起主要作用。我们的项目将研究这一假说与疾病类型（SOD、颅咽管瘤）、神经发育阶段和潜在的神经解剖学和内分泌缺陷的关系，从而开辟令人兴奋的治疗途径，包括外源性OT的管理，以改善这一具有挑战性的患者群体的生活质量。预期结果和未来方向：1)详细描述HP轴障碍儿童的神经行为/神经认知特征，作为障碍类型、HP轴损伤发生时的发育阶段、神经解剖学和内分泌特征以及血浆OT水平的函数。2)为鼻内催产素作为治疗效果的可行性研究奠定基础，随后进行多中心随机对照试验。3)此外，CIPPRD将开发一个特定的诊所，在当地CCG的支持下，提供重大神经行为问题的评估和治疗

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 levels2) 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