The objective of this experiment is to determine the effects of an analog of long-duration space flight on neural structural alterations and assess associated impacts on cognitive and behavioral performance. This experiment proposes to perform structural and functional MR brain imaging (fMRI)to identify the relationship between changes in participants neurocognitive function and neural structural alterations following 60 days of head-down tilt bed rest. The central hypotheses are that measures of brain structure, function, and network integrity will change from pre to post bed rest to a greater extent than in control participants over the same time period.
Specific Aim 1: It is predicted that these changes will correlate with indices of cognitive, sensory, and motor function in a structurally selective fashion.
Specific Aim 2: This work complements the ongoing NASA funded flight study, NNX11AR02G “Space flight Effects on Neurocognitive Performance: Extent, Longevity, and Neural Bases”. The current proposal will be able to determine the neural and neurocognitive effects of unloading, reduced sensory inputs, and increased cephalic fluid distribution. This enables the parsing out of multiple mechanisms contributing to any space flight induced neural structural and behavioral changes that are observed.
This is an interdisciplinary approach which utilizes cutting edge neuro-imaging techniques and a broad battery of sensory, motor, and cognitive assessments to investigate neuroplastic and maladaptive brain changes following long- duration bed rest. Success in this endeavor would 1) aid in identification of the underlying neural mechanisms and operational risks of space flight-induced changes in behavior using a well-established space flight analog, and 2) identify whether a return to normative behavioral function following recovery from prolonged bed rest is associated with a restitution of brain structure and function or instead is supported by substitution with compensatory brain processes.
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Specific relationships will be assessed between structural and functional brain changes as well as subject’s performance. A broad-ranging battery of sensorymotor and cognitive assessments will be administered pre, during, and post bed rest.
Several laboratory tests of behavior will be performed outside of the MRI scanner to supplement those conducted during the neuroimaging measurements. Some of these assessments will only be performed during the pre and post bed rest time points. That is, subjects will not be required to stand for the interim bed rest assessments. Participants can remain head down tilt for the neuroimaging assessments and most of the behavioral assessments, with the exception of the computerized dynamic posturography (CDP) and functional mobility tests (FMT). Behavioral assessments will include measures of cognitive abilities such as spatial working memory capacity and processing speed; measures of hand motor function such as bimanual coordination; measures of posture and locomotor control which are known to be sensitive to both space flight and bed rest changes; and measures of vestibular sensory function.
The neuroimaging test sessions pre, during, and post bed rest will include passive structural and functional scans (during which participants do not perform a task) as well as some task-based fMRI scans. Behavioral tests that will be conducted during fMRIs include a test of spatial working memory; a manual motor learning task that measures sensorimotor adaptation and motor control; dual tasking of cognitive and motor behaviors; and measures of vestibular and proprioceptive function. During the MRI scan, the participant’s head will be restrained with soft padding. Participants will don MRI compatible mirrored glasses to view stimuli on a rear projection screen.
The study design is a two-group cross sectional comparison by time. During this study, non-invasive brain structural and functional imaging and behavioral assessments at each time point on bed rest and control participants will be conducted. A high resolution structural MRI scan, will measure volumetric measurements of brain structures such as the cerebellum and the motor cortex that are likely to exhibit unloading-related changes. Functional MRI will be conducted while participants perform a variety of cognitive and sensorimotor tasks.
Recent approaches in resting state functional connectivity MRI (fcMRI) and diffusion tensor imaging (DTI) have been used to assess brain functional (fcMRI) and structural (DTI) network connectivity, allowing for more integrative assessments of distributed neural systems than in the past. Data acquisition for both techniques is rapid and noninvasive. Moreover, because participants are not performing a task, there are no confounds of the effects of fatigue, attention, or task difficulty that often complicate interpretation of task-driven fMRI studies.
Specific MRI scan test include:
- Structural MRI scan: High-resolution anatomical images covering the whole brain including the cerebellum will be acquired using a T1-weighted gradient-echo pulse sequence with the following parameters: 3D T1 axial overlay (TR=8.9 ms, TE=1.8 ms, flip angle=15°, FOV=260 x 260 mm, slice thickness=1.4 mm, 124 slices; matrix=256 × 160).
- “Resting state” functional MRI scan: FMRI data will be collected using a single-shot gradient-echo (GRE) reverse spiral pulse sequence to acquire 240 T2* - weighted BOLD images (TR = 2 s, TE = 30 ms, flip angle =90°, FOV = 220 x 220 mm, voxel size = 3.4 x 3.4 x 3.2 mm, 40 axial slices). Participants will be instructed to keep their eyes closed but to remain awake and to not think about anything in particular. A pressure belt will be used to record the respiratory signal and a pulse oximeter will be placed on the participant’s finger to record the cardiac signal, both of which will be regressed out prior to data analyses.
- Diffusion tensor imaging (DTI) scan: Diffusion tensor images will be collected using a single shot echo planar sequence (39 slices, slice thickness: 3 mm; TE/TR: 82.8 ms/9000 ms, field of view: 220 mm x 220 mm). Diffusion gradients will be applied in 30 directions (b = 800 s/mm2) (4 averages). Eight reference images (b = 0 s/mm2) will be acquired and averaged. The diffusion tensor will be calculated using the averaged images with b = 0 and b = 800 s/mm2.
- Functional MRI during auditory click-induced VEMP: We will follow the methods of two recent fMRI investigations of the vestibular cortex using click-induced VEMP or we will provide vestibular stimulation via vibrotactile stimulation to the head. Previous investigators used an approximately 12 minute scan comprising alternating 30 seconds periods of on and off stimulation. They provided stimulation to both the left and the right ear, as well as control auditory stimulation of a lower intensity. During fMRI, the investigator will use video-based measures that can be correlated with the VEMP responses obtained outside of the scanner using both video and EMG. Participants will lie passively during stimulation.
- Functional MRI during finger tapping under single and dual task (while performing a secondary cognitive task) conditions: Stimulus-driven finger tapping will be used to produce activation of the motor and somatosensory regions of the brain (primary motor cortex, primary sensory cortex, premotor cortex, cerebellum, etc.). Participants will be visually cued to tap fingers at a paced rate. Stimuli will be presented randomly so that learning will not play a role across test sessions. For some blocks, subjects will perform the tapping task in combination with a secondary, distractor task. This task requires subjects to view another stimulus box centered directly above those just described. This box changes color at a rate of 3 Hz and subjects are instructed to keep track of the number of times that their target color appears. The incidence of the target color is kept quite low (1-3%), forcing the subjects to remain vigilant. This dual tasking requirement will determine whether the predicted compensatory activation (and/or spread of activation due to remapping of the sensorimotor cortex during bed rest) results in compromised availability of neural resources for dual tasking. Subjects will perform the tapping and distractor tasks in isolation as well as simultaneously, in a counterbalanced order across participants and test sessions. One example sequence is 30 second control (view static display while not moving), 30 second motor, 30 second control, 30 second dual, 30 second control, 30 second distractor task (tracking target color), 30 second control. This block design will be repeated three times, resulting in nine minutes of image acquisition.
- Functional MRI during the sensorimotor adaptation task: Participants move an MRI-compatible joystick to targets presented on a computer display screen, with real-time feedback of the joystick location presented as a cursor on the screen. The adaptive stimulus will be a 45° rotation of the visual feedback display about the central start location. Participants will first perform a block of trials under normal visual feedback, followed by several blocks of trials under the rotated feedback condition, and then an additional block of normal feedback to measure the aftereffects of learning. Each block will have a 20 second visual fixation period at the beginning of the run, and periods of the motor task will alternate with fixation every 30 second (block design protocol). The control blocks at the beginning and end of the experiment are important for separating learning-related activation from scanner signal drift over the course of the experiment.
- Functional MRI during the spatial working memory task: This task requires participants to memorize a 3-target set (solid circles) in a 500 millisecond period. Participants are instructed to mentally “connect the dots” of the target set and then mentally rotate the resulting shape 30°clockwise during a 3000 millisecond retention interval. They are then asked to indicate whether a subsequently presented probe set of circles forms the same configuration as the rotated target shape. The ratio of match to non-match trials will be 70:30. The control task involves visual processing and making a manual response in the absence of working memory demands. Comparison of the two conditions reveals brain regions actively involved in spatial working memory.
- Functional MRI during foot movement: Participants will move the dominant foot and wrist in isolation and in combination, paced by an auditory metronome. Participants will alternate between 20 seconds of movement and 20 seconds of rest within runs. MRI compatible encoders will be used to track movement.
- Functional MRI during ankle muscle proprioceptive stimulation: Investigator will compare foot
tendon vibration to vibration of a nearby bone to map proprioceptive
representations. Proprioceptive activation in the parietal, frontal, and insular cortices has
been shown to be correlated with balance performance measured outside the scanner. This experiment will determine whether bed rest-induced changes in proprioceptive maps correlate with
balance changes. Participants will lie in the scanner during alternating 20 second blocks of
80 Hertz tendon or bone vibration.
The investigators are in the process of analyzing data. However, preliminary results are available.
Investigators have fifteen participants enrolled in the bed rest arm of this study; eleven of these have completed all seven of the test sessions. To summarize, the measures acquired can be categorized into behavioral assessments and brain imaging assessments. The behavioral tests measured outside of the scanner include: card and cube rotation tests of spatial working memory; digit symbol substitution test of processing speed; rod and frame test of visual bias; pegboard test of bimanual coordination; sensory organization test of vestibular-mediated balance; functional mobility test of obstacle course navigation; vestibular evoked myogenic potential to assess vestibular function. The neuroimaging tests of brain structure and function include: structural MRI to measure regional brain volumes and relative gray matter density; diffusion weighted scans (often referred to as DTI) to measure structural connectivity integrity; resting state functional MRI to measure functional connectivity integrity; functional MRI to measure brain networks engaged during the performance of various tasks. The latter tasks include imaging of the functional vestibular cortex; brain regions engaged during single and dual tasking of cognitive and motor behaviors; brain regions engaged during adaptation of pointing movements to perturbed visual feedback; brain regions engaged for spatial working memory, and for foot tapping.
Investigators initiated the data collection for normative control subjects and have obtained complete data for six subjects so far. Also, they added an extra structural MRI measure (i.e., T2-weighted image) to the MRI protocols of the normative and bed rest subjects. T2-weighted imaging is better able in visualizing fluid, and thus could be a more sensitive method to detect fluid redistribution as a result of space flight/bed rest that could induce increased intracranial pressure. The analyses of brain structure have revealed focal and global changes in frontal, temporal, and parietal regions of the brain. Furthermore, investigators observed increases in third ventricle volume with accumulating time in bed rest.
Koppelmans V, Erdeniz B, De Dios YE, Wood SJ, Reuter-Lorenz PA, Kofman I, Bloomberg JJ, Mulavara AP, and Seidler RD. Study protocol to examine the effects of spaceflight and a spaceflight analog on neurocognitive performance: extent, longevity, and neural bases. BMC Neurology.
2013. December 18; 13:205. [
Koppelmans V, Pasternak O, Bloomberg JJ, Dios YE, Wood SJ, Riascos R, Reuter-Lorenz PA, Kofman IS, Mulavara AP, and Seidler RD. Intracranial fluid redistribution but no white matter microstructural changes during a spaceflight analog. Science Report.
2017. June 9; 7(1):3154.
Computerized dynamic posturography - CDP
Diffusion tensor imaging - DTI
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Functional mobility test - FMT
Functional MRI - during auditory click-induced VEMP
Functional MRI - during finger tapping under single and dual task
Functional MRI - during ankle muscle proprioceptive stimulation
Functional MRI - during foot movement
Functional MRI - during the sensorimotor adaptation task
Functional MRI - during the spatial working memory task
Hand motor function
Posture and locomotor control
Sensorimotor and cognitive assessments
Spatial working memory capacity
Structural and functional brain changes
Vestibular evoked myogenic potentials - VEMP
Crew health and performance is critical to successful human exploration beyond low Earth orbit.
The Human Research Program (HRP) investigates and mitigates the highest risks to human health
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Risks include physiological and performance effects from hazards such as radiation, altered gravity,
and hostile environments, as well as unique challenges in medical support, human factors,
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