Transient Reset Of The Pathological Brain

许多神经发育和神经精神回路障碍的特点是在没有明显的结构病理的情况下，大脑功能异常。急性干预的中期治疗效果，如电休克疗法、氯胺酮或迷幻药物，意味着有可能“重置”大脑回路，使其更接近基态。然而，这些治疗方法都是生硬的工具，并不是基于对重度抑郁症的机械理解。相比之下，在癫痫的情况下，针对引起癫痫发作的基本机制（神经元和电路兴奋性）的基因疗法在临床前模型中非常有效。这些治疗的成功是否代表了基因治疗的持续效果，还是将大脑重置为基态？我最近开发了一种工具，以闭环的方式修改神经元的兴奋性，从而开始解决这个问题。在不同的病理发展阶段评估瞬时治疗的效果，这一建议也将为我们在生理和病理发展过程中对大脑特性的理解提供一个台阶。大脑动力学的改变与许多顽固性脑部疾病有关，这意味着我们的发现将为大脑可塑性不良的基本机制提供深刻的新见解。该项目也有可能开发出短期有效的治疗方法，以治疗给患者、其家庭和社会带来沉重负担的许多疾病。

Many neurodevelopmental and neuropsychiatric circuit disorders are characterized by abnormal function of the brain in the absence of overt structural pathology. The medium-term therapeutic effect of acute interventions such as electroconvulsive therapy, ketamine or psychedelic drugs implies that it is possible to 'reset' brain circuits closer to a ground state. However, these treatments are blunt tools that are not based on a mechanistic understanding of major depression. In the case of epilepsy, in contrast, gene therapies aimed at fundamental mechanisms giving rise to seizures (neuronal and circuit excitability) have been highly effective in preclinical models. Does the success of such treatments represent a continuous effect of the gene therapy or a resetting of the brain to a ground state? I have recently developed tools to modify neuronal excitability in a closed loop manner, allowing to begin to address this question. Assessing the effect of transient therapies at different stages of evolution of the pathologies, this proposal will also deliver a step change in our understanding of brain properties during physiological and pathological development. Altered brain dynamics has been implicated in many intractable brain diseases, implying that our findings will provide profound new insights into fundamental mechanisms of maladaptive brain plasticity. The project also has the potential to develop transient effective treatments for many pathologies that account for substantial burdens to patients, their families and society.