A single dose of ketamine or a course of electroconvulsive therapy can lift severe depression for weeks, even though the drug or electricity leaves the body within hours. This suggests that the brain can be temporarily “reset” to a healthier state, but no one understands how that reset works or why it lasts. The researcher has built a tool that can briefly tweak the excitability of specific neurons in a living brain, then switch off—allowing, for the first time, a direct test of whether a transient intervention can permanently shift a diseased circuit back toward normal. If the answer is yes, it would transform how we think about treating epilepsy, depression, and other brain disorders: instead of lifelong medication or permanent gene therapy, a short, precisely timed treatment might suffice. The project is fundamentally curiosity-driven—it asks whether the brain has a hidden ground state that can be restored—but the answer could open a new class of therapies for conditions that currently carry a huge burden for patients, families, and society.
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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.
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