Periodic Reporting for period 4 - EngineeringBAP (Engineering brain activity patterns for therapeutics of neuropsychiatric and neurological disorders)
Periodo di rendicontazione: 2024-04-01 al 2024-09-30
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 project, we developed minimally invasive technologies for measuring brain activity and functional connectivity patterns, and for manipulating them directly in vivo to correct the abnormal behavioral phenotypes. To this end we pursued 3 aims: (1) For manipulating brain circuits in noninvasively, we developed technologies that can deliver receptive-specific neuromodulators to spatially precise brain targets without opening/damaging the blood brain barrier. (2) For reading out the brain circuits in rodents/primates, we developed flexible low-power circuits that can detect single neuron signals from cortical layers across many cortical areas simultaneously. (3) Finally, we evaluated these novel technologies on mouse models of chronic anxiety to reverse the pathological symptoms with minimal side effects, thanks to the precision targeting of only the pathological brain circuits. 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.
The two big breakthrough neurotechnologies developed and advanced during the funding period of “EngineeringBAP” are:
1. Non-invasive hyper-concentrated focal drug delivery to brain using Aggregation-Uncaging Focused Ultrasound (AU-FUS) technology.
Our technology makes use of FUS-sensitive drug carriers in combination with AU-FUS sequences we engineered to deliver drugs to small brain volumes with millimeter resolution and without disrupting the Blood-Brain-Barrier. Our technology achieves focal drug concentration levels (100x-1000x higher than any other technology) and has tremendous medical potential for treating diverse neurological and neuropsychiatric disorders. Based on the achievements made during “EngineeringBAP”, we are preparing the clinical study plans for the first-in-human clinical trials.
2. Ultra-Flexible Tentacle Electrodes (UFTE) for chronic and minimally invasive intracranial brain recordings
We developed electrodes and implantation technologies for BMI which achieve highest biocompatibility with brain tissue and can resolve the activity of single neurons with highest SNR reported to date. Besides the electrodes can record from single neurons for many months, they can be placed deep into the brain and many different areas. We are currently testing them in preclinical large-animal models and we are going through the regulatory approval process for clinical tests.
Under the first subproject, we succeeded in manipulating focal brain circuits by combining molecular specificity of drugs with simultaneous millimeter-resolution targeting accuracy of ultrasound waves (Ozdas et. al. Nature Comm. 2020). We modified the drug packaging into ultrasound-controlled drug carriers for Focused-Ultrasound (FUS) triggered focal drug delivery such that we can package an anxiolytic drug with reliably high yield into FUS-controlled carriers and deliver them non-invasively to the mouse prefrontal cortex involved in chronic anxiety. Additionally, we established a microfluidic platform and new chemistries for fabricating FUS-sensitive drug carriers with high purity at larger volumes (10x) and increased stability (at least 1 week). For translating our AU-FUS technology into the clinic, we developed a closed-loop control system for automatic pressure-intensity adjustments and shifted the frequency range from 2.5 MHz to clinically relevant 500 kHz.
During the second subproject, our goal has been to perform high-resolution readouts of entire brain activity patterns at neuronal resolution as they guide treatment decisions better than purely behavioral assessment as we recently shown in vertebrates (Rezaie et. al. Nature Comm. 2019). To extend these measurements to mammals, we developed minimally-invasive electrodes (UFTE, Yasar et al., 2024). These electrodes allow chronic, high density single neuron recordings from multiple brain structures which we use for analyzing the connectivity of brain networks under different brain states. They can be implanted without any detectable histological damage , allow the chronic recording for at least 10 months (longest duration tested) and have an outstanding SNR (the best in the world by far). We engineered an integrated, high-channel count (up to 3x 1024-channel MEA chips bonded to UFTEs) neurophysiology system that allows wireless single neuron recordings from multiple brain areas in freely moving subject.
During the third subproject, our objective was to normalize brain activity patterns and behavior in a rodent model of chronic anxiety (SAPAP3). We have applied our FUS-technology to this anxiety animal model. Specifically, we delivered an anxiolytic to the prefrontal cortex and demonstrated significantly reduced anxiety, without any motor side effects (in contrast to systemic administration). Using UFTEs, we simultaneously recorded single-neuron activity from groups of neurons within the medial prefrontal cortex and ventrolateral orbitofrontal cortex while rats performed an inference-based decision-making task which can be used to identify compulsive behaviors. We also developed AI technology to analyze animal behavior in complex environments for behavioral assessments, which is significantly better than the existing state of the art for complex behaviors (Marks et. al. Nature Mach. Intel. 2022).
1. Non-invasive hyper-concentrated focal drug delivery to brain using Aggregation-Uncaging Focused Ultrasound (AU-FUS) technology.
Our technology makes use of FUS-sensitive drug carriers in combination with AU-FUS sequences we engineered to deliver drugs to small brain volumes with millimeter resolution and without disrupting the Blood-Brain-Barrier. Our technology achieves focal drug concentration levels (100x-1000x higher than any other technology) and has tremendous medical potential for treating diverse neurological and neuropsychiatric disorders. Based on the achievements made during “EngineeringBAP”, we are preparing the clinical study plans for the first-in-human clinical trials.
2. Ultra-Flexible Tentacle Electrodes (UFTE) for chronic and minimally invasive intracranial brain recordings
We developed electrodes and implantation technologies for BMI which achieve highest biocompatibility with brain tissue and can resolve the activity of single neurons with highest SNR reported to date. Besides the electrodes can record from single neurons for many months, they can be placed deep into the brain and many different areas. We are currently testing them in preclinical large-animal models and we are going through the regulatory approval process for clinical tests.
Under the first subproject, we succeeded in manipulating focal brain circuits by combining molecular specificity of drugs with simultaneous millimeter-resolution targeting accuracy of ultrasound waves (Ozdas et. al. Nature Comm. 2020). We modified the drug packaging into ultrasound-controlled drug carriers for Focused-Ultrasound (FUS) triggered focal drug delivery such that we can package an anxiolytic drug with reliably high yield into FUS-controlled carriers and deliver them non-invasively to the mouse prefrontal cortex involved in chronic anxiety. Additionally, we established a microfluidic platform and new chemistries for fabricating FUS-sensitive drug carriers with high purity at larger volumes (10x) and increased stability (at least 1 week). For translating our AU-FUS technology into the clinic, we developed a closed-loop control system for automatic pressure-intensity adjustments and shifted the frequency range from 2.5 MHz to clinically relevant 500 kHz.
During the second subproject, our goal has been to perform high-resolution readouts of entire brain activity patterns at neuronal resolution as they guide treatment decisions better than purely behavioral assessment as we recently shown in vertebrates (Rezaie et. al. Nature Comm. 2019). To extend these measurements to mammals, we developed minimally-invasive electrodes (UFTE, Yasar et al., 2024). These electrodes allow chronic, high density single neuron recordings from multiple brain structures which we use for analyzing the connectivity of brain networks under different brain states. They can be implanted without any detectable histological damage , allow the chronic recording for at least 10 months (longest duration tested) and have an outstanding SNR (the best in the world by far). We engineered an integrated, high-channel count (up to 3x 1024-channel MEA chips bonded to UFTEs) neurophysiology system that allows wireless single neuron recordings from multiple brain areas in freely moving subject.
During the third subproject, our objective was to normalize brain activity patterns and behavior in a rodent model of chronic anxiety (SAPAP3). We have applied our FUS-technology to this anxiety animal model. Specifically, we delivered an anxiolytic to the prefrontal cortex and demonstrated significantly reduced anxiety, without any motor side effects (in contrast to systemic administration). Using UFTEs, we simultaneously recorded single-neuron activity from groups of neurons within the medial prefrontal cortex and ventrolateral orbitofrontal cortex while rats performed an inference-based decision-making task which can be used to identify compulsive behaviors. We also developed AI technology to analyze animal behavior in complex environments for behavioral assessments, which is significantly better than the existing state of the art for complex behaviors (Marks et. al. Nature Mach. Intel. 2022).
The two technologies developed during the project “EngineeringBAP” (1. Aggregation-Uncaging Focused Ultrasound and 2. Ultra-Flexible Tentacle Electrodes) are breakthroughs i.e. far better than comparable technologies in the world.
The four most significant publications of the project so far are:
1. Engineering brain activity patterns by neuromodulator polytherapy for treatment of disorders. Nature Comm.2019.
2. Non-invasive molecularly-specific millimeter-resolution manipulation of brain circuits by ultrasound-mediated aggregation and uncaging of drug carriers. Nature Comm. 2020. Patent filed.
3. Deep-learning-based identification, tracking, pose estimation and behavior classification of interacting primates and mice in complex environments. Nature Machine Intel. 2022.
4. Months-long tracking of neuronal ensembles spanning multiple brain areas with Ultra-Flexible Tentacle Electrodes. Nature Comm. 2024. Patent submitted.
Five more high-profile publications are in preparation. All these publications were highlighted as major breakthroughs in various media outlets. To translate these technologies into pre-clinical and ultimately clinical tests, we recently received significant funding from the Swiss National Science Foundation (Sinergia, with Prof. Javad Nazarian and Prof. Sebastian Waszak), the Swiss Innovation Hub Innosuisse (BRIDGE Discovery, with neurosurgeon Dr. Hugelshofer and Dr. Richter), the ETH Pioneer fellowship (Dr. Yasar) for commercialization and Novartis FreeNovation Award.
The four most significant publications of the project so far are:
1. Engineering brain activity patterns by neuromodulator polytherapy for treatment of disorders. Nature Comm.2019.
2. Non-invasive molecularly-specific millimeter-resolution manipulation of brain circuits by ultrasound-mediated aggregation and uncaging of drug carriers. Nature Comm. 2020. Patent filed.
3. Deep-learning-based identification, tracking, pose estimation and behavior classification of interacting primates and mice in complex environments. Nature Machine Intel. 2022.
4. Months-long tracking of neuronal ensembles spanning multiple brain areas with Ultra-Flexible Tentacle Electrodes. Nature Comm. 2024. Patent submitted.
Five more high-profile publications are in preparation. All these publications were highlighted as major breakthroughs in various media outlets. To translate these technologies into pre-clinical and ultimately clinical tests, we recently received significant funding from the Swiss National Science Foundation (Sinergia, with Prof. Javad Nazarian and Prof. Sebastian Waszak), the Swiss Innovation Hub Innosuisse (BRIDGE Discovery, with neurosurgeon Dr. Hugelshofer and Dr. Richter), the ETH Pioneer fellowship (Dr. Yasar) for commercialization and Novartis FreeNovation Award.