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

研究神经行为问题和催产素在下丘脑-垂体轴异常儿童中的作用

• 批准号: MR/V038060/1
• 负责人: Ritika R Kapoor
• 金额: $ 17.09万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FV038060%2F1
• 关键词: Investigating; Neurobehavioural; Problems; Role; Oxytocin

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

下丘脑和脑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协调生长和生殖的中心。HP轴在调节生理功能中也起着不可或缺的作用，如心率、血压、体温、口渴、食欲、能量代谢和睡眠。视隔发育不良（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。SOD患儿存在认知、视力和激素功能缺陷。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，在患有SOD的儿童中，自闭症谱系障碍（ASD）的患病率也很高。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，儿童和家庭往往发现更难以科普比激素替代，既没有很好地理解，也没有很好地确定或治疗。神经行为问题在儿童颅咽管瘤（一种源自脑垂体的良性肿瘤）中的患病率也不成比例地高。这支持了HP轴的作用和已知的激素缺乏症或可能是尚未确定的激素缺乏症导致的社会和行为缺陷。催产素（OT）是一种由下丘脑产生并由脑垂体分泌的激素。它在哺乳和分娩中的作用已经得到很好的证实。然而，OT具有更广泛的影响，包括调节社会联系，记忆，认知和社会行为的关键因素。因此，OT系统的中断在神经行为障碍即ASD和精神分裂症的机械理解中引起了兴趣。鼻内OT的治疗试验报告了ASD儿童的社交能力改善。研究还报告了继发于颅咽管瘤的垂体功能减退症的低OT水平，并强调了颅咽管瘤单个病例中鼻OT的亲社会行为的改善。因此，针对OT缺乏症是HP轴异常和神经行为问题儿童的有吸引力的治疗可能性。该研究项目是国王儿科内分泌学，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，催产素能系统失调的儿童和青少年SOD或颅咽管瘤，并发挥了重要作用，在神经行为和神经认知缺陷，这些队列的患者。我们的项目将研究这一假设作为疾病类型（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函数，从而开辟了令人兴奋的治疗途径，包括外源性OT的管理，以提高生活质量，在这个具有挑战性的患者队列。预期产出和未来方向：1）详细描述患有HP轴障碍的儿童的神经行为/神经认知概况，作为障碍类型、HP轴损伤发展时的发育阶段、神经解剖学和内分泌概况以及血浆OT水平的函数2）为鼻内催产素作为治疗的功效的可行性研究奠定基础，3）此外，CIPPRD将在当地CCG的支持下，开发一个专门的诊所，提供重大神经行为问题的评估和治疗

项目成果

Neurodevelopmental impairments in children with septo-optic dysplasia spectrum conditions: a systematic review.

• DOI: 10.1186/s13229-023-00559-0
• 发表时间: 2023-07-25
• 期刊: Molecular autism
• 影响因子: 6.2

Neurobehavioural impairments in children with septo-optic dysplasia: a scoping review

视神经间隔发育不良儿童的神经行为障碍：范围审查

• 发表时间: 2022
• 作者: Mann A