Transient Reset Of The Pathological Brain

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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.