SBIR-STTR Award

This Lab to Marketplace project describes the development of HyperAxon™, highly innovative software for performing automated segmentation, tracing, reconstruction and quantitative analysis of all axonal fibers visible in three-dimensional (3D) microscopic images of central nervous system (CNS) areas, even those with extremely high axonal fiber density. Accurate and rigorous analysis of all axonal fibers visible in 3D microscopic images of CNS tissue of non-transgenic and transgenic animal models as well as in human post mortem CNS tissue holds the promise of novel insights into physiological neural network connectivity patterns as well as into the neuropathological underpinnings of alterations in connectivity associated with human neuropsychiatric and neurological disorders. However, this cannot be achieved with contemporary, computer-assisted tracing and reconstruction methods, which currently are the gold standard for investigating axonal fibers, because these methods primarily address tracing and reconstruction of only a limited number of individual axonal fibers. HyperAxon will be based on the highly innovative artificial intelligence technology Learning-based Tracing of Dense Axonal Fibers (LTDAF) that was recently developed at MIT Lincoln Laboratory (MIT LL) (Lexington, MA). This project will build upon the original, lab-built LTDAF technology to create commercial software for wide- spread dissemination of this important new technology. Dissemination of this technology via a Lab to Marketplace commercial product is consistent with NIMH goals and will result in the technology having a significant impact on neuroscience research. The game-changing innovation in HyperAxon is the ability to automatically (i) segment, trace and reconstruct all axonal fibers visible in 3D microscopic images of CNS areas with high axonal fiber density, (ii) identify axonal branch points, (iii) resolve axonal fibers of passage from axonal fibers that make presumptive synapses in target regions, (iv) identify axonal fibers showing acute axonal injury and (v) precisely quantify alterations in number and density of axonal fibers in CNS tissue. Based on published pilot work performed at MIT LL, we are convinced that HyperAxon will be impactful in the field of neuroscience research and will enable substantial advancements in research on alterations in CNS circuitry associated with neurodevelopmental, neuropsychiatric, neurodegenerative and neurological disorders. Ultimately, this will result in an improved basis for developing novel treatment strategies for a wide spectrum of complex brain diseases. In Phase I we will demonstrate feasibility of this novel technology by developing prototype software; work in Phase II will focus on creating the full functionality of HyperAxon for commercial release. We will perform extensive feasibility studies, product validation and usability studies of HyperAxon in close collaboration with MIT LL and our academic collaboration partners. A competing technology is not available. Public Health Relevance Statement Narrative Accurate and rigorous analysis of all visible axonal fibers in 3D microscopic images of central nervous system (CNS) tissue of non-transgenic and transgenic animal models as well as in human postmortem CNS tissue holds the promise of novel insights into physiological neural network connectivity patterns as well as into the neuropathological underpinnings of alterations in connectivity associated with human neurodevelopmental, neuropsychiatric, neurodegenerative and neurological disorders. Our proposed product will be a transformative technology, using a number of technical innovations that, for the first time, will enable researchers to perform such studies automatically and in a comprehensive manner. This system will allow researchers to make new discoveries based on new studies that are currently not feasible, ultimately providing the basis for developing novel treatments to prevent and fight complex brain diseases.

Project Terms:
Transgenic Animals ; Artificial Intelligence ; AI system ; Computer Reasoning ; Machine Intelligence ; Autopsy ; necropsy ; postmortem ; Axon ; Biotechnology ; Biotech ; Brain Diseases ; Brain Disorders ; Encephalon Diseases ; Intracranial CNS Disorders ; Intracranial Central Nervous System Disorders ; Classification ; Systematics ; Communities ; Feasibility Studies ; Goals ; Gold ; Human ; Modern Man ; Laboratories ; Learning ; Logic ; Methods ; National Institute of Mental Health ; NIMH ; nervous system disorder ; Nervous System Diseases ; Neurologic Disorders ; Neurological Disorders ; neurological disease ; Pharmacology ; Publishing ; Research ; research and development ; Development and Research ; R & D ; R&D ; Research Personnel ; Investigators ; Researchers ; Societies ; Computer software ; Software ; Synapses ; Synaptic ; synapse ; Technology ; Time ; Tissues ; Body Tissues ; Work ; base ; density ; image processing ; improved ; Area ; Acute ; Phase ; Physiological ; Physiologic ; Fiber ; insight ; Individual ; Collaborations ; Morphology ; Nature ; machine learned ; Machine Learning ; Knowledge ; fighting ; Complex ; Pattern ; System ; 3-D ; 3D ; three dimensional ; 3-Dimensional ; Degenerative Neurologic Diseases ; Degenerative Neurologic Disorders ; Nervous System Degenerative Diseases ; Neural Degenerative Diseases ; Neural degenerative Disorders ; Neurodegenerative Diseases ; Neurologic Degenerative Conditions ; degenerative diseases of motor and sensory neurons ; degenerative neurological diseases ; neurodegenerative illness ; Neurodegenerative Disorders ; Animal Models and Related Studies ; model of animal ; model organism ; Animal Model ; high-end computing ; High Performance Computing ; novel ; novel technologies ; new technology ; CNS Nervous System ; Central Nervous System ; Neuraxis ; preventing ; prevent ; Address ; Detection ; Neurosciences Research ; Validation ; Development ; developmental ; Neurodevelopmental Disorder ; Neurological Development Disorder ; Image ; imaging ; reconstruction ; Computer Assisted ; computer aided ; next generation ; innovation ; innovate ; innovative ; usability ; prototype ; treatment strategy ; operation ; axon injury ; axon damage ; axonal damage ; axonal injury ; microscopic imaging ; microscope imaging ; microscopy imaging ; neuropsychiatric disorder ; neuropsychiatric disease ; terabyte ; neural network ; convolutional neural network ; ConvNet ; convolutional network ; convolutional neural nets ; automated segmentation ; auto-segmentation ; automatic segmentation ; autosegmentation ;

This Phase II project describes the commercial development of HyperAxon™, highly innovative software forperforming automated segmentation, tracing, reconstruction and quantitative analysis of all axonal fibers (withand without signs of acute axonal injury) visible in two- and three-dimensional (2D and 3D) microscopy imagesof central nervous system (CNS) areas, even those with extremely high axonal fiber density. Accurate andrigorous analysis of all axonal fibers visible in 3D and 2D microscopy images of CNS tissue of non-transgenicand transgenic animal models as well as in human post mortem CNS tissue promises to enable researchers togain novel insights into physiological neural network connectivity patterns as well as into the neuropathologicalunderpinnings of alterations in connectivity associated with human neuropsychiatric and neurological disorders.However, this cannot be achieved with contemporary, computer-assisted tracing and reconstruction methods,which currently are the gold standard for investigating axonal fibers, because these methods primarily addresstracing and reconstruction of only a limited number of individual axonal fibers. During Phase I we createdHyperAxon prototype software by leveraging the original, lab-built technology Learning-based Tracing of DenseAxonal Fibers created at MIT Lincoln Laboratory (MIT LL) (Lexington, MA) and extending this technology withseveral new, specialized deep neural networks. Furthermore, we validated that our approach will be successfulin research applications. All specific aims of Phase I were fully completed, demonstrating feasibility ofsuccessfully developing HyperAxon. The game-changing innovation in HyperAxon is the ability to automatically(i) segment, trace and reconstruct all axonal fibers visible in 3D and 2D microscopy images of CNS areas withhigh axonal fiber density, (ii) identify axonal branch points, (iii) resolve axonal fibers of passage in fiber tractsfrom those in axonal terminal fields, (iv) identify axonal fibers showing acute axonal injury and (v) preciselyquantify alterations in number and density of axonal fibers in CNS tissue. For widespread dissemination of thisimportant new technology we plan to commercialize the HyperAxon software at the end of Phase II as both acloud-based "software as a service" running on Amazon Web Services (AWS) and traditional softwareapplication running on local institutional computers. We are convinced that HyperAxon will be impactful in thefield of neuroscience research and will enable substantial advancements in research on alterations in CNScircuitry associated with neurodevelopmental, neuropsychiatric, neurodegenerative and neurological disorders.Ultimately, this will result in an improved basis for developing novel treatment strategies for a wide spectrum ofcomplex brain diseases. In Phase I we demonstrated feasibility of this novel technology by developing prototypesoftware; work in Phase II will focus on creating the full functionality of HyperAxon for commercial release. DuringPhase II we will perform extensive product validation and usability studies of HyperAxon in close collaborationwith MIT LL and our academic collaboration partners. A competing technology is not available.

Public Health Relevance Statement:
Narrative Accurate and rigorous analysis of all visible axonal fibers (with and without signs of acute axonal injury) in 2D and 3D microscopy images of central nervous system (CNS) tissue of non-transgenic and transgenic animal models as well as in human postmortem CNS tissue holds the promise of enabling novel insights into physiological neural network connectivity patterns as well as into the neuropathological underpinnings of alterations in connectivity associated with human neurodevelopmental, neuropsychiatric, neurodegenerative and neurological disorders. Our proposed product will be a transformative technology, using a number of technical innovations that, for the first time, will enable researchers to perform such studies automatically and in a comprehensive manner. This system will allow researchers to make new discoveries based on new studies that are currently not feasible, ultimately providing the basis for developing novel treatments to prevent and fight complex brain diseases.

Project Terms:
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