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脑功能异常，没有明显的结构病理。电休克治疗、氯胺酮或迷幻药物等急性干预措施的中期疗效表明，有可能将大脑回路重新设置为更接近基态的状态。然而，这些治疗都是生硬的工具，并不是基于对严重抑郁症的机械性理解。相反，在癫痫的情况下，针对导致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一直非常有效。这种治疗的成功是否代表了基因治疗的持续效果，还是将大脑重新设置为基础状态？我最近开发了一些工具，以一种封闭的方式修改神经元的兴奋性，从而开始解决这个问题。评估暂时性治疗在病理演变的不同阶段的效果，这一建议也将使我们对生理和病理发育过程中大脑属性的理解发生阶段性变化。脑动力学改变与许多难治性脑疾病有关，这意味着我们的发现将为研究适应不良大脑可塑性的基本机制提供深刻的新见解。该项目还有可能为给患者、他们的家人和社会带来巨大负担的许多病理疾病开发暂时有效的治疗方法。

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.