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

下丘脑和脑垂体腺位于大脑的中部。下丘脑-垂体(HP)轴是生长和生殖的中心协调者，通过产生各种激素。HP轴在调节心率、血压、温度、口渴、食欲、能量代谢和睡眠等生理功能方面也发挥着不可或缺的作用。隔-视神经发育不良(SOD)是一种罕见的先天性疾病，影响大脑特定部分的发育，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、社交和睡眠-觉醒周期(昼夜节律)困难。据报道，患有自闭症谱系障碍(ASD)的儿童中也有很高的患病率。这些神经行为问题的存在严重影响了生活质量，并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学，儿童和家庭经常发现比激素替代更难处理，既没有很好的理解，也没有很好的识别或治疗。神经行为问题在儿童颅咽管瘤中的患病率也不成比例地高，颅咽管瘤是一种源自脑下垂体的良性肿瘤。这支持了HP轴的作用，以及已知的激素缺乏或可能是一种尚未确定的激素缺乏，导致社会和行为缺陷。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有更广泛的含义，包括调节社会纽带、记忆、认知和社会行为的关键因素。因此，OT系统的破坏一直是人们对神经行为障碍的机制理解的兴趣，即。自闭症和精神分裂症。鼻腔催产素的治疗试验报告说，ASD儿童的社交能力得到了改善。研究还报道了颅咽管瘤继发的垂体功能低下症的低OT水平，并强调了单例颅咽管瘤患者在接受鼻腔OT治疗后亲社会行为的改善。因此，对于患有HP轴异常和神经行为问题的儿童，靶向OT缺乏症是一种有吸引力的治疗可能性。这项研究项目是金氏儿科内分泌学、发育神经精神病学和精神药理学以及OT心理力学和神经成像之间的合作试点项目。我们的假设是，患有SOD或颅咽管瘤的儿童和青少年的催产素能系统失调，并在这些患者的神经行为和神经认知缺陷中发挥主要作用。我们的项目将研究这一假说作为疾病类型(超氧化物歧化酶、颅咽管瘤)、神经发育阶段和潜在的神经解剖和内分泌缺陷的函数，从而开辟涉及外源性OT的令人兴奋的治疗途径，以改善这一具有挑战性的患者队列的生活质量。预期成果和未来方向：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轴受损时的发育阶段、神经解剖和内分泌特征以及血浆催产素水平的函数。2)为鼻内催产素作为治疗方法的有效性研究奠定基础，随后进行多中心随机对照试验。3)此外，CIPPRD将在当地CCG的支持下，开发一家专门的诊所，对重大神经行为问题进行评估和治疗

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