Seizures & Amydala-Based Socioemotional Dysfunction

癫痫发作

• 批准号: 7154364
• 负责人: Ludise Malkova
• 金额: $ 17.46万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-18 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7154364
• 关键词: Primates; amygdala; human; partial seizure

DESCRIPTION (provided by applicant): A large proportion of subjects with autism exhibit seizure disorders and epilepsy. This co morbidity has been reported to be in the range of 30-40%. Epilepsy and abnormal EEG patterns occur at a significantly higher rate in individuals in the more impaired range of the autism spectrum. Seizures in the autistic population often include complex partial seizures involving the temporal lobe. The limbic network supporting these seizures is composed of the amygdala, hippocampus, medio-dorsal thalamus, piriform, rhinal, and orbitofrontal cortices. Recurrent and/or prolonged complex partial seizures alter the functional connectivity of this network in a manner that can impact both cognitive function and socio-emotional regulation. Importantly, this is the same network implicated in autistic pathophysiology and therefore these seizures may pose the greatest risk for adverse psychiatric outcomes in this population. Dysfunction (often in the absence of structural abnormalities) in the network anchored in the amygdala, and interconnected with the orbital frontal cortex, has been found in many cases of autism. This dysfunction is likely to be exacerbated by the aberrant plasticity induced in response to repeated seizure discharge. The goal of this application is to determine if a history of repeated seizure activity changes the responsiveness of this network and whether it predisposes this network to amygdala-mediated behavioral disturbances. Our recent findings showed that reversible manipulations of the GABAA receptors within the basolateral amygdala (BLA) by focal intracerebral infusions of GABAA receptor agonists or antagonists resulted in profound changes in social interactions and reward evaluation in nonhuman primates. The Specific Aims will determine whether a history of complex partial seizures, focally-evoked from the piriform cortex in one hemisphere, result in an increased vulnerability to disinhibition within BLA in nonhuman primates. This shift in sensitivity will be probed by evaluating specific behavioral responses to focal manipulations of GABAA transmission within BLA: Social interactions (Aim 1), reinforcer devaluation (Aim 2), and emotional conditioning (Aim 3). The studies will address a recognized comorbidity, not yet studied in pre-clinical animal models, for which clinical studies cannot sort out the extent to which seizures may exacerbate the autistic symptomatology. The combination of co-investigators provides a unique blend of expertise in experimental epilepsy models, nonhuman primate models of socio-emotional disturbances, and neural substrates of human disorders of affect and psychopathy. The team is ideally suited to approach the analysis of comorbidity of seizures and autistic-like symptoms evoked from amygdala and to permit a translationally meaningful analysis of the animal data.

描述（由申请人提供）：大部分自闭症受试者表现出癫痫症和癫痫症。据报道，这种合并症的发生率为 30-40%。在自闭症谱系受损程度较高的个体中，癫痫和异常脑电图模式的发生率明显更高。自闭症人群的癫痫发作通常包括涉及颞叶的复杂部分性癫痫发作。支持这些癫痫发作的边缘网络由杏仁核、海马、丘脑内侧背侧、梨状皮质、鼻皮质和眶额皮质组成。反复和/或长期的复杂部分性癫痫发作会改变该网络的功能连接，从而影响认知功能和社会情绪调节。重要的是，这与自闭症病理生理学涉及的网络相同，因此这些癫痫发作可能对该人群造成不良精神结果的最大风险。在许多自闭症病例中都发现了锚定于杏仁核并与眶额皮质相互连接的网络功能障碍（通常没有结构异常）。这种功能障碍可能会因反复发作放电而引起的异常可塑性而加剧。该应用的目标是确定重复癫痫活动的历史是否改变了该网络的反应性，以及是否使该网络容易受到杏仁核介导的行为障碍的影响。我们最近的研究结果表明，通过局部脑内注射 GABAA 受体激动剂或拮抗剂对基底外侧杏仁核 (BLA) 内的 GABAA 受体进行可逆操作，导致非人灵长类动物的社会互动和奖励评估发生深刻变化。具体目标将确定非人类灵长类动物中，由一侧半球梨状皮层局部诱发的复杂部分性癫痫发作史是否会导致 BLA 内抑制解除的脆弱性增加。这种敏感性的转变将通过评估 BLA 内 GABAA 传输焦点操纵的具体行为反应来探讨：社交互动（目标 1）、强化物贬值（目标 2）和情绪调节（目标 3）。这些研究将解决尚未在临床前动物模型中研究的公认的合并症，临床研究无法弄清楚癫痫发作可能加剧自闭症症状的程度。共同研究人员的结合提供了实验性癫痫模型、社会情绪障碍的非人类灵长类动物模型以及人类情感障碍和精神病的神经基础方面的独特专业知识融合。该团队非常适合分析杏仁核引起的癫痫发作和自闭症样症状的共病，并允许对动物数据进行具有翻译意义的分析。