Otto_ILIR_Statement of Work.pdf

Statement of Work (SOW) Project: Investigating the Effects of Acute Hypoxia on Neuroinflammation and Signal

Transduction: A Combined Diffusion MRI and EEG Approach

GENERAL INFORMATION

1.0 Scope of Work:

2.0

The Naval Medical Research Unit – Dayton (NAMRU-D) is conducting a funded study that includes research support from a team with a strong background in advanced magnetic resonance imaging (MRI) techniques. This study requires implementing a novel and innovative research approach that combines magnetic resonance imaging (MRI) with electroencephalography (EEG) to identify and characterize neuroinflammatory consequences of acute hypoxia exposure. Funding will be provided to NAMRU-D from the Office of Naval Research under the FY24 In-House Laboratory Independent Research (ILIR) program, of which $137,106 is budgeted for the support Team.

The project discussed is titled: Investigating the Effects of Acute Hypoxia on Neuroinflammation and Signal Transduction: A Combined Diffusion MRI and EEG Approach – Period of performance beginning with receipt of funds and ending 30

SEP 2026.

The objectives of this effort are to 1) determine if neural transfer times are altered as a response to acute hypoxic exposure, 2) characterize any neuroinflammatory features associated with acute hypoxia and, 3) evaluate whether these impairments correlate with the observed signal transfer times. The desired outcome is a knowledge product describing the results of the study, which may take the form of conference abstract(s), technical report(s), or peer-reviewed publication(s).

3.0 Background:

The human brain must consume a considerable amount of oxygen to operate effectively. In the absence of oxygen, metabolic processes involved in maintaining brain functionality become perturbed. This can have devastating consequences on sensory and cognitive functioning and can impact operational and safety-critical military aviation tasks. The relationship between acute hypoxia exposure, neuroinflammation, and their impact on the transmission speed of neural information remains unknown. Thus, the current effort will examine neuroinflammation using electroencephalography (EEG) and diffusion magnetic resonance imaging (dMRI) under acute hypoxic conditions.

In Experiment 1 of this funded effort (base year), we will evaluate the interhemispheric transfer time (IHTT) of visual and tactile sensory information both before and after exposure to acute hypoxia. Using EEG, we will calculate the differences in signal transmission times between ipsi- and contralateral pathways.

The study involves quantifying the structural connectivity within subsections of the corpus callosum (CC) using dMRI. Specifically, we will calculate the average streamline length of CC pathways to assess axon diameter distribution within the CC's body and splenium, in conjunction with event related potential (ERP) data. We plan to perform whole-brain quantification of apparent diffusion coefficient (ADC) measures, comparing global ADC values for each subject before and after AH exposure to assess changes in brain tissue diffusion characteristics.

In Experiment 2 of this funded effort (option year) we will seek to identify in vivo biomarkers of neuroinflammation following acute hypoxia exposure. To accomplish this, we will use magnetic resonance spectroscopy (MRS) to measure changes in peak levels of brain metabolites known to be associated with glial cell-mediated neuroinflammation. We will also investigate changes to peripheral levels of proinflammatory cytokines. The combination of these measures will provide a more robust biomarker for future use in evaluating hypoxia-induced neuroinflammation.

3.0 Technical Requirements/Tasks:

To successfully execute the project, the support team would need to fulfill the following requirements within the period of performance described above:

Set up MRI acquisition protocol with different contrasts to study change in brain tissues after exposure to hypoxia. These protocols will be set up in research MRI scanners located in CIR (Soref imaging facilities) at MCW. These acquisitions may include (proposed scans will be reviewed by Dr. Otto of NAMRL and finalized before MRI scans begin):

• Must have peer-reviewed journal publications in the fields of MAP-MRI and neuroinflammatory conditions, demonstrating expertise in these areas.

• Advanced diffusion MRI (such as Mean Apparent Propagator).

• High resolution T1 weighted MRI (such as MPRAGE).

• High resolution T2 weighted MRI (such as 3D FSE).

• High resolution fluid attenuated inversion recovery (FLAIR).

• Perfusion or BOLD fMRI acquisitions to study brain function.

• Process and pay for MRI scan charges for this project. Note that CIR may charge a fee if a booking is canceled. Details of fees and cancellation policies can be found in this link:

• https://www.mcw.edu/departments/center-for-imaging-research/policies-and-procedures

• MCW CIR will provide certified scanner operators to place the subject in the MRI scanner and run the MRI scans.

• Set up secure data transfer protocols in coordination with NAMRL team to deliver acquired MRI scans and other related data.

• Coordinate with CIR to book rooms for participant interviews, cognitive tests and preparations.

https://www.mcw.edu/departments/center-for-imaging-research/policies-and-procedures https://www.mcw.edu/departments/center-for-imaging-research/policies-and-procedures

• Coordinate with TRU to draw blood samples from participants and ship them to NAMRL (if needed).

• Work with NAMRL team to submit IRB reliance application to MCW IRB.

• Meet regularly using virtual meeting tools to discuss progress and challenges and protocol improvements.

• Furnish resources to administer aid in case of adverse reactions to acute hypoxia or MRI.

4.0 Government Furnished:

Resources to be furnished to the subcontractor by NAMRL team:

The NAMRL team has established workflows, equipment, and expertise to run acute hypoxia experiments. The NAMRL team will provide the following for this study:

• Hypoxia device

• Study participants.

• Team of experts on site (MCW imaging center) to safely administer and monitor acute hypoxia condition.

• Coordinate participant recruitment, MRI scheduling and participant preparations (MRI safety screening and consenting participants, administering cognitive tests, administering acute hypoxia, etc).

• NAMRL will be responsible for the travel arrangements of the participants to the imaging center at MCW and financial compensation of the participants for their travel expenses and stipends (if required).

• Maintain all study related documents such as signed consent forms, MRI safety questionnaires, etc.

• Furnishing all consumable supplies for EEG and hypoxia exposures

• Participant compensation

Reporting Requirements and/or Other Deliverables:

• All MRI data (this may include unprocessed digital MRI signals, reconstructed images in DICOM format and digital recordings of physiological signals such as cardiac or respiratory recordings from the scanner).

• Python software codes to process and reconstruct diffusion MRI parameter maps and provide training on those software.

• Consultation about processing the data and various analysis methods.

• Intellectual contributions to write conference abstracts, white papers, reports and peer-reviewed papers.

5.0 Deliverables / Schedule:

Key Deliverables

Item No.

Deliverable

Objective

Due

1 Proposed Project Plan

Defining the responsibilities, timeline, risks, and milestones of contract objectives.

No later than thirty (30) business days after contract award

2 Periodic Status Meetings

Discuss status, barriers to progress, and research planning

As needed.

Meetings will be held virtually.

Updates and discussions may occur over e-mail

3 Final Report Document contributions, including any unique design and/or data analysis contributions

No later than thirty (30) business days after end of period of performance

6.0 Travel: Data collection will occur at the Medical College of Wisconsin (MCW) in Milwaukee, WI. The support team is responsible for any of their staff (or team) related travel costs. The NAMRU-D is responsible for any government/contractor related travel costs. During active data collection, Dr. Otto and a research assistant will travel to MCW once per month to oversee data collection until all in-person data has been collected. Regular communication via e-mail, phone, or video will ensure successful execution of the project. The leader of the support team is expected to attend a conference where the results of the study will be presented.

7.0 Support Team Key Personnel:

Key personnel must have research experience and expertise in the areas of MRI physics, computational modeling of diffusion MRI data (e.g. MAP-MRI), and interpretation of results from any MRI data collected, evidenced by a history of publications involving the subject matter.

Positions key to successful performance of the contract include: professor/research faculty, postdoctoral research fellow, MRI technicians, and research assistants.

8.0 Data Rights:

Each Collaborator shall have title to all de-identified Subject Data generated by that Collaborator. Each Collaborator agrees to provide all de-identified Subject Data to the other Collaborator and hereby grants Unlimited Rights in de-identified Subject Data that does not contain Proprietary Information.

For Subject Data that contains the Non-Navy Collaborators’ Proprietary Information, the Government has rights to: 1) Use, modify, reproduce, release, perform, display, or disclose Technical Data within the Government without restriction; and 2) Release or disclose Subject Data outside the Government and authorize persons to whom release or disclosure has been made to use, modify, reproduce, release, perform, display, or disclose that Subject Data for any U.S.

Government purpose (purposes where the U.S. Government is a Collaborator) including competitive procurement.

For Subject Data that contains NAMRU-D’s Proprietary Information, Non-Navy Collaborators have rights to use, modify, reproduce, release, perform, display, or disclose Technical Data within the Non-Navy Collaborators’ organization, in whole or in part, and in any manner, for any internal purpose excluding commercial purposes. If Non-Navy Collaborators are subsequently awarded a Government contract that entails deliverables that incorporate NAMRU-D’s Proprietary Information, such deliverables must be delivered with at least Government Purpose Rights, as defined in the DFARS § 252.227-7013.

The Non-Navy Collaborators shall have a Limited Right to use, reproduce, or disclose Subject Data that may describe one or more Inventions in which the Government owns or may own a right, title, or interest, if such Subject Data are provided by NAMRU-D under this Agreement. This Limited Right does not grant the Non-Navy Collaborators any License to any Invention in which the Government owns or may own a right, title, or interest. In accordance with Article 7.5 below, such Subject Data are to be held in confidence.

The Collaborators shall have Unlimited Rights in any Non-Subject Data that are not Proprietary Information or protected under 35 U.S. Code § 205 provided under this Agreement.

NAMRU-D have a Limited Right to use, reproduce, and disclose only to Government employees for use in support of the Cooperative Work any Non- Subject Data that are properly marked as Proprietary Information and are provided by the Non-Navy Collaborators under this Agreement. Such Proprietary Information can be used only for the purpose of performing the Cooperative Work unless written consent to other use or disclosure is obtained from the Non-Navy Collaborators.

The Non-Navy Collaborators shall have a Limited Right to use, reproduce, or disclose Non-Subject Data that may describe one or more Inventions in which the Government owns or may own a right, title, or interest, if such Non-Subject Data are provided by NAMRU-D under this Agreement. Such Non-Subject Data shall be properly marked by NAMRU-D.

Except for the rights granted in Article 7.1 and Article 7.2, Data shall be protected in accordance with the proper markings of its owner and as provided by, at a minimum, the requirements of 15 U.S. Code § 3710a. Proprietary Information will be protected only if it is properly marked as such. Information provided in intangible form that is Proprietary Information must be designated Proprietary Information at the time it is provided, followed within fifteen (15) days by a writing summarizing the exact information to be protected. The Collaborator receiving Information in an intangible form that is designated as Proprietary Information shall be responsible for protecting the Information as Proprietary Information during the fifteen (15) day notification. After the fifteen (15) day period, if no written summary has been received, the receiving Collaborator need not continue to protect the Information received in intangible form.

Data that is provided by the Non-Navy collaborator in the performance of this Agreement, and is appropriately marked as a trade secret or commercial or financial information that is privileged or confidential under 5 U.S. Code § 552(b)(4), shall not be disclosed by NAMRU-D. The Parties shall agree to not disclose, for up to five (5) years, Data that is produced by the NAMRU-D and that would have been considered a trade secret or commercial or financial information that is privileged or confidential if it had been produced by the Non-Navy collaborator.

CI, CUI, or otherwise restricted information shall be protected in accordance with the security laws of the U.S.