Problems to be Solved by h.o.p.e.

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No medical imaging or research group can currently calculate the amount of cell loss, scar tissue burden, or cellular network loss after a neurological injury. Furthermore, no brain atlas, publication, or research group has achieved a comprehensive cell atlas capable of calculating the amount of cell loss for a specific injury. Without this knowledge, it is impossible to accurately dose any therapeutic. A “damage report” needs to exist to quantify how much missing tissue needs to be regrown.

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Technology to be Orchestrated 

Central Nervous System Atlases 

Neuroanatomical atlases are ever increasing in their understanding of the exact cellular composition of the central nervous system. The Automated Anatomical Labeling Atlas, Pubbrain, Brain Parser, Segmentation Validation Engine, Statistical Parametric Mapping, Human Connectome Project, Yale Neuro library, Allen Brain Atlas, and Montreal Neurological Institute - all combined with a novel, global comprehensive cell biology team - will allow worthwhile calculations of the number of cell types missing from each region after the patient’s injury. 

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Current MRI Image Analysis Technology

Current medical imaging technology provides a gross structural view of the damaged brain, an accomplishment that revolutionized the field of diagnosing neurological pathology. To date, medical imaging of the central nervous system is similar to other organs. A typical MRI scan of the brain shows the injured area of the brain and shows evidence to help diagnose why the brain was injured.

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Volumetric analysis is the ability to examine a region of the brain based on its size, and it has been a critical field of neuroscience for over a century. This involves regions of the brain being segmented out by researchers to further examine the interface among anatomy, function, and injury. The computing software, mathematics, and imaging technology are rapidly improving to further refine calculations of cell loss. The field is striving toward a goal of rapid, reproducible, and automated calculations of tissue loss, but has not yet incorporated comprehensive cell biology calculations. 

Advanced imaging can now render a patient’s MRI, not just in 2D, but in more sophisticated 3D images called diffusion tensor images. This technology calculates the ease of water flow through a neuron. Given neurons extend great distances, this technology allows scientists to see the distant cellular network the brain relies on for rapid communication. This is especially important after a neurological injury because neuronal networks die back if their connections are not used in a process called Wallerian degeneration. This die back is significant and must be quantified to understand what needs accurate regrowth on the network scale. Currently, no cellular network quantification is performed clinically. However, a recent tool, called the NeMo Tool (network modification tool), quantifies losses in the brain connectivity network by mapping a specific patient’s lesions onto 116 regions of the brain, compared with 70 healthy, digitized MRI scans at the Montreal Neurological Institute. This will allow a more sophisticated approach for calculating the number of missing networks to be reconnected.

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Stereology, the science of calculating particles in 3D space, has been applied to the field of neuroscience over previous decades to provide necessary rigor to our understanding of the cellular composition of each brain region. Stereology, the quantification of objects in space, was initially developed to ensure that materials such as cement were correctly composed. For example, if cement has the wrong ratio of water to limestone and other oxides, it will cause structures such as bridges and buildings to collapse. When this is applied to the brain, it allows new levels of rigor in the calculations of cell loss. Technologies, such as StereoTool, are beginning to perform computer-based simulations and are being tested against the rigor of the stereological vertical sections method, thereby calculating the patient’s missing amount of tissue. 

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Advanced imaging techniques - partial least-squares regression, bootstrapping, change in connectivity, NetMo, network modification, similar lesion dysfunction mapping, voxel-based morphometry, tract-based spatial statistics, vascular tree influence on connectivity, goodness of fit, and Akaike Information Criterion - are all advanced imaging analysis tools integrating brain atlases with a patient’s MRI images to produce a render of the lost cellular network following an injury. The techniques can be performed on any region of the brain and allow an understanding of the network loss. All of these are academic pursuits, but none yet have clinical applications. 

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Goal of h.o.p.e. 

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The input for calcutating the 3D missing tissue hologram is the patient’s available medical imaging (X-ray, CT, MRI, angiogram). The image analysis team then determine the negative space of missing tissue, the injury cavity, the absent networks, and the amount of scar tissue. Cell biology experts, equipped with the most sophisticated knowledge graphs, anatomy atlases, and stereology algorithms, will calculate how much scar tissue is present and how many cells and cellular networks are missing per specific cell type. This output will be transformed into a 3D hologram to then be imported into the regrowth simulation as the beginning of repair calculations, as well as lab clinical trials as the template for the regrowth experiments.

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We will enhance current advanced imaging technologies in conjunction with the comprehensive cell biology section to include the calculations answering the following questions:

1. How big is the negative space of the acellular cavity per volumetric analysis?

2. How much scar tissue (chondroitin sulfate proteoglycans, reactive astrocytes, immune cells, etc.) is surrounding the patient’s injury cavity?

3.  How many cells (neurons, astrocytes, oligodendrocytes, pericytes, vasculature, lymphatics, ependymal, cerebrospinal, extracellular matrix and microglia cells) were lost?

4. How extensive is the cellular network loss (neuronal, astrocytic, oligodendrocytic, pericyte, vasculature, lymphatic, ependymal, cerebrospinal, extracellular matrix, and microglia networks) in meters both for efferent (exiting) and afferent (incoming) connections?

Impact of h.o.p.e. 

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Applying comprehensive cell biology expertise will dramatically enhance the sophistication of every brain atlas, connectome project, and image analysis technique. It will demonstrate to the field the rigor necessary to calculate the unique injury of a single person. By solving one injury at a time, an algorithm will be built to integrate into all future imaging, allowing all future patients to know the extent, prognosis, and required interventions for their unique neurological injury.

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For the first time, we will actually know the number of cells needed to replace the missing part of the individual’s damaged CNS. This will have a clarifying effect on the entire field of basic neuroscience by showing how overly simplistic monotherapy rationales are toward repairing the vast number of missing cells. For clinical trials, this new information will finally allow the correct dosing of therapeutics. 

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All neurological disorders need these calculations applied to them in the future. As funding agencies and advocacy groups have their particular disease of interest, these analyses will set an accurate benchmark for future grants, lab research, and clinical trials, so that their research questions will actually match the disease burden to be overcome.