EngineeringBAP · Engineering brain activity patterns for therapeutics of neuropsychiatric and neurological disorders

Neuropsychiatric and neurological disorders are complex dysfunctions of neuronal circuits. Their treatmenthas been limited by the lack of non-invasive methods for measuring the underlying circuit dysfunctions, andfor direct and localized modifications of these circuits. We propose minimally invasive technologies formeasuring brain activity and functional connectivity patterns, and for manipulating them directly in vivo tocorrect the abnormal behavioural phenotypes (in rodents with potential scalability to non-human primates andhumans). First, we present a proof-of-principle study on mutant zebrafish, in which we correct whole-brainlevel abnormal activity patterns and behaviours by using large-scale single-neuron resolution measurements,and by simultaneously modulating multiple sub-networks via neuromodulator cocktails. Next, we presentstrong preliminary data in rodents and our plan: (1) For manipulating brain circuits in rodents/primates noninvasively,we will develop technologies that can deliver receptive-specific neuromodulators to spatiallyprecise brain targets without opening/damaging the blood brain barrier. These methods will employ engineeredultrasound pulses and drug carrying microparticles we designed. (2) For reading out the brain circuits inrodents/primates, we will develop flexible low-power neuromorphic μECoG circuits that can detect singleneuron signals from superficial cortical layers of many cortical areas simultaneously. (3) Finally, these noveltechnologies will be comprehensively evaluated on a mouse model of obsessive compulsivity and anxietyusing a battery of behavioural tasks to reverse the pathological symptoms (beyond what is achievable byexisting approaches). This project constitutes a major step towards the development and testing of minimallyinvasiveand high-precision technologies for manipulating brain activity patterns, which can impact both ourunderstanding of the brain and treatment of intractable brain disorders.