Transient Reset Of The Pathological Brain

许多神经发育和神经精神回路障碍的特征是在没有明显结构病理的情况下大脑功能异常。电休克疗法、氯胺酮或迷幻药等急性干预措施的中期治疗效果意味着，有可能将大脑回路“重置”到更接近基态。然而，这些治疗方法都是钝器，并不是基于对抑郁症的机械理解。相反，在癫痫的情况下，针对引起癫痫发作的基本机制（神经元和回路兴奋性）的基因疗法在临床前模型中非常有效。这种治疗的成功是否代表了基因治疗的持续效果，或者是大脑重新回到了基态？我最近开发了一些工具，以闭环方式修改神经元的兴奋性，从而开始解决这个问题。通过评估短暂疗法在病理演变的不同阶段的效果，该提案还将使我们对生理和病理发育过程中大脑特性的理解发生一步变化。改变的脑动力学与许多难治性脑疾病有关，这意味着我们的发现将为适应不良的脑可塑性的基本机制提供深刻的新见解。该项目也有可能为许多给患者、其家庭和社会造成巨大负担的疾病开发短暂有效的治疗方法。

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.