NOTE: End date changed to 9/30/2020 per NSSC information (Ed., 2/3/2020)

Sleep is a central physiological regulator of cognitive / behavioral, neurophysiological, and immune functions. The study of sleep quality and duration on orbit may thus yield important insights into etiology and mechanisms of adverse cognitive/behavioral, Spaceflight Associated Neuro-ocular Syndrome (SANS), and immunological responses during long duration deep space exploration missions. We will investigate these relationships via an integrated approach combining assessments of (1) sleep duration and quality, (2) cognitive performance, and (3) immunological response. We will collect data on crewmembers participating in the integrated one-year mission project (CIPHER), including flyers on short-duration (<3 months), nominal-duration (~6 months) and long-duration (~12 months) missions aboard the International Space Station (ISS). We also plan to study demographically matched control subjects in Earth-based analogs (e.g., the Human Exploration Research Analog/HERA) during missions of similar duration. Our specific aims are: (SA1) Characterize behavioral performance changes during the integrated one-year mission project (CYPHER) on the ISS; (SA2) Characterize changes in brain and systemic physiology as a function of mission duration on the ISS; (SA3) Characterize the relationship between sleep duration and quality on cerebral physiology on the ISS. and (SA4) Characterize the relationship between sleep duration and quality on immune response on the ISS. The outcomes of the study will contribute to quantification of crew health and performance risks associated with human spaceflight, and aid in development of technologies for monitoring and mitigating crew health and performance. [Ed. Note: CIPHER is the short title for a set of 14 studies sponsored by NASA and international partner agencies ( https://www.nasa.gov/feature/experiments-to-unlock-how-human-bodies-react-to-long-space-journeys ). CIPHER stands for "Complement of Integrated Protocols for Human Exploration Research".]

In addition to the primary project, a Psycho-Neuro-Immunological supplement to this project seeks to investigate the influence of headward fluid shifts on facial expressiveness, ability to convey non-verbal affective cues, and compromised cognitive and immune functioning.

TASK PROGRESS

As we approach the end of year 3 of this project, the following milestones have been achieved: • We completed CIPHER integration and timeline revisions. This involved—for all CIPHER investigators—significant reductions in the number of testing days as well as reductions in measurement times to meet the collective flight and crew-time requirements. • Full Institutional Review Board (IRB) approval (from NASA, Massachusetts General Hospital, and partnering space agencies) was obtained. • Subject recruitment was initiated as part of the integrated CIPHER complement informed consent briefing process. • In coordination with NASA Research Operations and Integration (ROI), we completed the design and development of three complete NINscan-ISS (v4) systems. These systems are fully functional, including associated sensor harnesses. • Due to timeline and budgetary issues, we are now initiating a rescope in our project to remove the physiological sleep and functional brain imaging measures from the study. This will have two consequences: (i) the data for sleep quality will become subjective instead of objective, and (ii) the relationship between sleep parameters and cerebral physiology (Aim 3) will need to shift to investigating the relationship between sleep and operationally-relevant behavioral performance. • We completed preparations for the PsychoNeuroImmunological (PNI) supplement data collection process and developed a novel data processing pipeline for analyzing 3D scans of individuals at multiple head-up and head-down tilt angles. • The project provided educational activities for 10 Bachelor's degree and 4 graduate students on both the CIPHER and PNI supplement projects. This included learning how to develop research procedures and protocols, and how to conduct pilot testing and data quality control, as well as writing up and presenting the research at the 2022 NASA Human Research Program Investigators' Workshop.

NOTE: End date changed to 9/30/2020 per NSSC information (Ed., 2/3/2020)

Sleep is a central physiological regulator of cognitive / behavioral, neurophysiological, and immune functions. The study of sleep quality and duration on orbit may thus yield important insights into etiology and mechanisms of adverse cognitive/behavioral, Spaceflight Associated Neuro-ocular Syndrome (SANS), and immunological responses during long duration deep space exploration missions. We propose to investigate these relationships via an integrated approach combining assessments of (1) sleep quality and duration, (2) intracranial physiology, (3) cognitive performance, and (4) immunological response. We will collect data on crewmembers participating in integrated one-year mission project (CIPHER), including flyers on short-duration (<3 months), nominal-duration (~6 months), and long-duration (~12 months) missions aboard the International Space Station (ISS). We also plan to study demographically matched control subjects in Earth-based analogs (e.g., the Human Exploration Research Analog, or HERA) during missions of similar duration. Our specific aims are: (SA1) Characterize cognitive task performance changes during the integrated 1 Year Mission Project (1YMP) on the ISS; (SA2) Characterize brain and systemic physiology changes during 1YMP on the ISS; (SA3) Characterize the effects of sleep duration and quality on cerebral hemodynamics on ISS and in HERA; and (SA4) Quantify the effects of sleep duration and quality on immune response. The outcomes of the study will contribute to quantification of crew health and performance risks associated with human spaceflight, and aid in development of technologies for monitoring and mitigating crew health and performance.

Our CIPHER project seeks in particular to provide a wide range of brain-related measures for all subjects in all study arms. These include changes in (i) blood flow in/out of the brain, (ii) cerebral blood flow, (iii) brain perfusion and oxygenation, (iv) blood distribution along the body axis, (v) intracranial pulsatility, (vi) sagittal sinus imaging of potential, (vii) intracranial water concentration, (xiii) functional brain activation, (ix) electrical brain activity, as well as (x) cognitive performance data (Cognition). We also plan to compare these measures with measures from other groups including ocular measures, mood and sleep, 1-carbon single nucleotide polymorphisms, and MRI.

In addition, a Psycho-Neuro-Immunological (PNI) supplement to this project seeks to investigate the influence of headward fluid shifts on facial expressiveness, ability to convey non-verbal affective cues, and compromised cognitive and immune functioning.

SUMMARY TO DATE

We are reaching the end of year 2 of this project, and by that time we will have achieved the following milestones:

• Full IRB (Institutional Review Board) approval (NASA and Massachusetts General Hospital) was obtained and we initiated subject recruitment as part of the integrated CIPHER complement informed consent process. Final approvals from partnering space agencies are expected by the end of year 2.

• Integration of NINscan-sleep project measurements with other CIPHER complement investigators was completed, involving numerous decisions regarding data- and sample-sharing arrangements to ensure maximal science with a minimal crew-time footprint.

• Overall CIPHER integration and timeline revision was completed. This involved—for all CIPHER investigators—significant reductions in the number of testing days as well as reductions in measurement times to meet the collective flight and crew-time requirements.

• In coordination with NASA Research Operations and Integration (ROI) Human Research Program element, we completed the design and development of v3, and subsequently v4, of our NINscan physiological monitoring hardware (NINscan systems). Changes were required in electrical, interface, and shielding components to achieve flight certification. We expect to have a finalized version of NINscan (v4)—including control hardware, enclosure, and sensors—completed by the end of year 2.

• We sought and received approval to expand serum cytokine measurements using Multiplex technology, providing a more comprehensive assessment of immunological status of the astronauts.

• We sought and gained approval for the PNI supplement project and have initiated preliminary work including pilot work collecting 3D scans of individuals at multiple head-up and head-down tilt angles.

• The project also provided numerous educational activities for six bachelor’s and three graduate students on both the CIPHER and PNI supplement projects. This included learning how to develop research procedures and protocols, how to conduct pilot testing and data quality control, as well as writing up summaries and abstracts and poster presentations of the research for the 2021 NASA Human Research Program’s Investigators' Workshop.

NOTE: End date changed to 9/30/2020 per NSSC information (Ed., 2/3/2020)

1) NINscan device modifications: The majority of the Definition Phase work focused on making sure the NINscan devices would be suitable for flight. This work has included the following:

* Battery management: we tested numerous batteries and configurations and found one that matches device needs with previously-approved or readily available batteries onboard the ISS. The main challenge is having sufficient battery power for the device to last the nominal overnight (sleep) recording periods (ideally >10 hrs continuous recording time, to provide some time-buffer).

* Laser safety: the device lasers were confirmed to be safe (effective Class I).

* Device Housing and EMI (electromagnetic interference): began coordinating with ISSMP [ISS Medical Project; as of May 2019, element is now Research Operations and Integration (ROI)--ed., Dec 2020] regarding the final housing of the NINscan devices to address in-flight concerns

* Sterilization: benzalkonium chloride (BZK) confirmed to be fully compatible with our system.

* Electrodes: we confirmed any wet-style stick-on (Ag/AgCl) electrodes will be suitable for our use.

* Constraints document. We provided a detailed spreadsheet describing all study constraints.

* Hardware modifications. Given device size is closely related to the upmass cost, flight certification user experience, we have been redesigning the device to reduce its form factor and improve its user interface. The new devices will have approximately 50% of the size and weight of the previous device, with numerous hardware enhancements to improve performance and reliability.

* Flight requirements: Many device housing requirements, such as “no sharp edges; rounded corners preferred”, are implemented in the new enclosure design with smaller form factor and more friendly user interface. We have built 4 enclosures and now testing the 5th version of the housing design; and will provide ISSMP with the final schematic for metal housing. In addition, other flight certification requirements include “no small loose pieces,” as well as wiring changes. The current NINscan device has numerous manually soldered wires to connect the from the probe plug to the circuit boards, which can be unreliable during space flight. In order to improve and meet the flight need, we designed a new adaptor board structure to reduce the use of wires and manual assembly, which will significantly improve the systems reliability and signal quality.

In summary, corresponding to the tasks of the SOW (statement of work), we completed our adaptation of the NINscan-SE next-generation (v3) design, based on ISSMP  input/requests, and we have gone through two rounds of NINscan-SE V3 board design, fabrication, debugging and testing, including analog boards, digital boards, battery management, and device enclosure. The circuit design is 90% finalized and firmware design is 70% finalized. Fabrication and testing of all NINscan-SE components (i.e., analog boards, digital boards, probe "boards")

* We have fabricated/re-fabricated two rounds and a total of 18 sets of analog, digital, and sensor adaptor boards, and prepared the lasers, connectors, and other key components for the four devices used for this project. Assembly and testing of 4 NINscan-SE v3 devices and probes, suitable for final NASA preflight testing

* We expect to complete the assembly of two functional devices with probes by the end of May 2020.

In addition to the above, we continued coordination with the Portfolio Manager, Flight Analogs Project (FAP), and ISSMP to develop clear, firm, and feasible baseline data collection (BDC), pre-, in-, and post-flight plans. These activities and achieved milestones included project presentations, timeline and scheduling coordination and modifications, blood and saliva sampling coordination with other 1YMP investigators, data share coordination, discussions regarding BDC support for the BHP (behavioral health & performance) and DST Laboratory (Cognition/ROBoT-r testing), IRB (Institutional Review Board) submissions with MGH, LSU, and NASA (awaiting confirmation on whether MGH or NASA (or neither) will be the IRB of record for this study)), and coordinating plans for sample-retrieval post-flight.

In all, progress to date keeps us in line with other CIPHER studies to meet the projected flight timelines.

NOTE: End date changed to 9/30/2020 per NSSC information (Ed., 2/3/2020)