Periodic Reporting for period 3 - EngineeringBAP (Engineering brain activity patterns for therapeutics of neuropsychiatric and neurological disorders)
Reporting period: 2022-10-01 to 2024-03-31
Neuropsychiatric and neurological disorders are complex dysfunctions of neuronal circuits. Their treatment has been limited by the lack of non-invasive methods for measuring the underlying circuit dysfunctions, and for direct and localized modifications of these circuits. In this ERC Consolidator Grant, we are using minimally invasive technologies for measuring brain activity and functional connectivity patterns, and for manipulating them directly in vivo to correct the abnormal behavioral phenotypes (in rodents with potential scalability to non-human primates and humans). To this end we pursue 3 aims: (1) For manipulating brain circuits in rodents/primates noninvasively, we are developing technologies that can deliver receptive-specific neuromodulators to spatially precise brain targets without opening/damaging the blood brain barrier. These methods will employ engineered ultrasound pulses and drug carrying microparticles we designed. (2) For reading out the brain circuits in rodents/primates, we are developing flexible low-power circuits that can detect single neuron signals from cortical layers across many cortical areas simultaneously. (3) Finally, these novel technologies are being comprehensively evaluated on mouse models of obsessive compulsivity and anxiety using a battery of behavioral tasks to reverse the pathological symptoms (beyond what is achievable by existing approaches). This project constitutes a major step towards the development and testing of minimally invasive and high-precision technologies for manipulating brain activity patterns, which can impact both our understanding of the brain and treatment of intractable brain disorders.
All subprojects addressing the three central aims of this grant are by now fully established and operational at the end of the first reporting period. At the core of this project is to measure the abnormal whole brain activity patterns at single-neutron resolution in a mouse brain disorder model, and then use a novel non-invasive focal drug delivery to the brain to correct abnormal brain activity patterns and behaviour.
In the first subproject, we succeeded in manipulating individual brain circuits by combining molecular/receptor specificity of drugs with simultaneous millimeter-resolution targeting accuracy of ultrasound waves (Ozdas et. al. Nature Comm. 2020). As the first step, we had to modify the drug packaging into ultrasound-controlled drug carriers for Focused-Ultrasound (FUS) triggered focal drug delivery. We are now able to successfully package the anxiolytic drug alprazolam and similar lipophilic drugs with reliably high yield (as much as 2.8 µg per dose) into ultrasound-controlled carriers and deliver them non-invasively to the mouse prefrontal cortex (namely infralimbic and prelimbic cortices) involved in anxiety behaviour. This is a critical achievement as the medial prefrontal cortex is not directly at the brain's outer surface requiring us to fine-tune the FUS-parameters for delivering the drugs to a deeper structure without opening the blood-brain barrier.
In the second subproject, we are performing high-resolution readouts of neural activity and brain activity patterns as they guide treatment decisions better than purely behavioural assessment as we recently demonstrated in small animal model (Rezaie et. al. Nature Comm. 2019). To extend these measurements to rodents and primates, we have been developing minimally-invasive ultraflexible electrodes that currently allow us to record intracortical activity for up to a year from the same single units/neurons. We design and fabricate these electrodes in house and customize for brain areas, so that single neuron activity in multiple brain areas can be recorded and used for analysing the connectivity and entropy of the brain network under different conditions. In a first group of mice exhibiting an anxiety phenotype (SAPAP3), we performed such recordings in the medial prefrontal cortex and the hippocampus, both critically involved in anxiety behavior.
The objective of the third subproject is to normalize brain activity patterns and behavior in a rodent model of anxiety (SAPAP3). Here, we established the basic behavioral test (elevated maze) to assess the anxiety phenotype of our mouse model. We achieved a major milestone in a pilot experiment with SAPAP3 mice, where we reduced anxiety-like behavior to a similar level of wild-type animals by FUS-mediated delivery of alprazolam to the prefrontal cortex (to be published). We are currently consolidating these findings in a larger group and combining with recordings from multiple brain areas. We also developed a state of the art AI technology to analyse rodent/primate behaviour in complex environments for behavioural assessments (Marks et. al. Nature Mach. Intel. 2022).
Overall, all subprojects achieved already major milestones. However, the effects of the Covid-19 situation could not be mitigated altogether, resulting in an overall project delay of approximately 6-9 months.
In the first subproject, we succeeded in manipulating individual brain circuits by combining molecular/receptor specificity of drugs with simultaneous millimeter-resolution targeting accuracy of ultrasound waves (Ozdas et. al. Nature Comm. 2020). As the first step, we had to modify the drug packaging into ultrasound-controlled drug carriers for Focused-Ultrasound (FUS) triggered focal drug delivery. We are now able to successfully package the anxiolytic drug alprazolam and similar lipophilic drugs with reliably high yield (as much as 2.8 µg per dose) into ultrasound-controlled carriers and deliver them non-invasively to the mouse prefrontal cortex (namely infralimbic and prelimbic cortices) involved in anxiety behaviour. This is a critical achievement as the medial prefrontal cortex is not directly at the brain's outer surface requiring us to fine-tune the FUS-parameters for delivering the drugs to a deeper structure without opening the blood-brain barrier.
In the second subproject, we are performing high-resolution readouts of neural activity and brain activity patterns as they guide treatment decisions better than purely behavioural assessment as we recently demonstrated in small animal model (Rezaie et. al. Nature Comm. 2019). To extend these measurements to rodents and primates, we have been developing minimally-invasive ultraflexible electrodes that currently allow us to record intracortical activity for up to a year from the same single units/neurons. We design and fabricate these electrodes in house and customize for brain areas, so that single neuron activity in multiple brain areas can be recorded and used for analysing the connectivity and entropy of the brain network under different conditions. In a first group of mice exhibiting an anxiety phenotype (SAPAP3), we performed such recordings in the medial prefrontal cortex and the hippocampus, both critically involved in anxiety behavior.
The objective of the third subproject is to normalize brain activity patterns and behavior in a rodent model of anxiety (SAPAP3). Here, we established the basic behavioral test (elevated maze) to assess the anxiety phenotype of our mouse model. We achieved a major milestone in a pilot experiment with SAPAP3 mice, where we reduced anxiety-like behavior to a similar level of wild-type animals by FUS-mediated delivery of alprazolam to the prefrontal cortex (to be published). We are currently consolidating these findings in a larger group and combining with recordings from multiple brain areas. We also developed a state of the art AI technology to analyse rodent/primate behaviour in complex environments for behavioural assessments (Marks et. al. Nature Mach. Intel. 2022).
Overall, all subprojects achieved already major milestones. However, the effects of the Covid-19 situation could not be mitigated altogether, resulting in an overall project delay of approximately 6-9 months.
During this first reporting period significant efforts were invested to assemble the project team and to set up the three subprojects. Independent of this, we already made progress beyond the state of the art by alleviating an anxiety phenotype using our technology in the SAPAP3 mouse model. This is the first time, such a drug delivery, that correct a brain disorder, is achieved non-invasively with receptor- and brain-area specificity.
The development of our focal drug delivery technology has been so successful that we are now planning for preclinical and clinical trials with a team of neurosurgeons and neurologists in Zurich.
During the first half of ERC grant, we already published 3 papers in Nature journals among others.
By the end of this ERC project, we are aiming to be able to detect signatures of abnormal brain activity using multi-areal single-neuron-resolution recordings and how these brain signals evolve as a function our non-invasive focal drug targeting. We are also developing specialized MRI sequences to aid positioning of intracortical electrodes with high precision and to detect the loci of ultrasound drug uncaging in real time to adapt beam distortions during ultrasound propagation through the brain. Finally, we are trying to microrobotically position the penetrating ultra-flexible electrodes in desired brain regions with the assistance of functional MRI.
The development of our focal drug delivery technology has been so successful that we are now planning for preclinical and clinical trials with a team of neurosurgeons and neurologists in Zurich.
During the first half of ERC grant, we already published 3 papers in Nature journals among others.
By the end of this ERC project, we are aiming to be able to detect signatures of abnormal brain activity using multi-areal single-neuron-resolution recordings and how these brain signals evolve as a function our non-invasive focal drug targeting. We are also developing specialized MRI sequences to aid positioning of intracortical electrodes with high precision and to detect the loci of ultrasound drug uncaging in real time to adapt beam distortions during ultrasound propagation through the brain. Finally, we are trying to microrobotically position the penetrating ultra-flexible electrodes in desired brain regions with the assistance of functional MRI.