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Recent data suggest that interactions between systems involved in higher order knowledge and associative learning drive responses during value-based learning. However, it is unknown how these systems impact subjective responses, such as pain. We tested how instructions and reversal learning influence pain and pain-evoked brain activation. Healthy volunteers (n=40) were either instructed about contingencies between cues and aversive outcomes or learned through experience in a paradigm where contingencies reversed three times. We measured predictive cue effects on pain and heat-evoked brain responses using functional magnetic resonance imaging. Predictive cues dynamically modulated pain perception as contingencies changed, regardless of whether participants received contingency instructions. Heat-evoked responses in the insula, anterior cingulate, and other regions updated as contingencies changed, and responses in the prefrontal cortex mediated dynamic cue effects on pain, whereas responses in the brainstem's rostroventral medulla (RVM) were shaped by initial contingencies throughout the task. Quantitative modeling revealed that expected value was shaped purely by instructions in the Instructed Group, whereas expected value updated dynamically in the Uninstructed Group as a function of error-based learning. These differences were accompanied by dissociations in the neural correlates of value-based learning in the rostral anterior cingulate, thalamus, and posterior insula, among other regions. These results show how predictions dynamically impact subjective pain. Moreover, imaging data delineate three types of networks involved in pain generation and value-based learning: those that respond to initial contingencies, those that update dynamically during feedback-driven learning as contingencies change, and those that are sensitive to instruction. Together, these findings provide multiple points of entry for therapies designs to impact pain., Competing Interests: LA, TD, EP, QY, RR, LB, SG, DP No competing interests declared

Astronauts on board the International Space Station (ISS) must adapt to several environmental challenges including microgravity, elevated carbon dioxide (CO 2 ), and isolation while performing highly controlled movements with complex equipment. Head down tilt bed rest (HDBR) is an analog used to study spaceflight factors including body unloading and headward fluid shifts. We recently reported how HDBR with elevated CO 2 (HDBR+CO 2 ) affects visuomotor adaptation. Here we expand upon this work and examine the effects of HDBR+CO 2 on brain activity during visuomotor adaptation. Eleven participants (34 ± 8 years) completed six functional MRI (fMRI) sessions pre-, during, and post-HDBR+CO 2 . During fMRI, participants completed a visuomotor adaptation task, divided into baseline, early, late and de-adaptation. Additionally, we compare brain activity between this NASA campaign (30-day HDBR+CO 2 ) and a different campaign with a separate set of participants (60-day HDBR with normal atmospheric CO 2 levels, n = 8; 34.25 ± 7.9 years) to characterize the specific effects of CO 2 . Participants were included by convenience. During early adaptation across the HDBR+CO 2 intervention, participants showed decreasing activation in temporal and subcortical brain regions, followed by post- HDBR+CO 2 recovery. During late adaptation, participants showed increasing activation in the right fusiform gyrus and right caudate nucleus during HDBR+CO 2 ; this activation normalized to baseline levels after bed rest. There were no correlations between brain changes and adaptation performance changes from pre- to post HDBR+CO 2 . Also, there were no statistically significant differences between the HDBR+CO 2 group and the HDBR controls, suggesting that changes in brain activity were due primarily to bed rest rather than elevated CO 2 . Five HDBR+CO 2 participants presented with optic disc edema, a sign of Spaceflight Associated Neuro-ocular Syndrome (SANS). An exploratory analysis of HDBR+CO 2 participants with and without signs of SANS revealed no group differences in brain activity during any phase of the adaptation task. Overall, these findings have implications for spaceflight missions and training, as ISS missions require individuals to adapt to altered sensory inputs over long periods in space. Further, this is the first study to verify the HDBR and elevated CO 2 effects on the neural correlates of visuomotor adaptation., Competing Interests: NB, IK, YD, and AM were employed by the company KBR. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Salazar, Hupfeld, Lee, Banker, Tays, Beltran, Kofman, De Dios, Mulder, Bloomberg, Mulavara and Seidler.)

Aboard the International Space Station (ISS), astronauts must adapt to altered vestibular and somatosensory inputs due to microgravity. Sensorimotor adaptation on Earth is often studied with a task that introduces visuomotor conflict. Retention of the adaptation process, known as savings, can be measured when subjects are exposed to the same adaptive task multiple times. It is unclear how adaptation demands found on the ISS might interfere with the ability to adapt to other sensory conflict at the same time. In the present study, we investigated the impact of 30 days' head-down tilt bed rest combined with elevated carbon dioxide (HDBR + CO 2 ) as a spaceflight analog on sensorimotor adaptation. Eleven subjects used a joystick to move a cursor to targets presented on a computer screen under veridical cursor feedback and 45° rotated feedback. During this NASA campaign, five individuals presented with optic disk edema, a sign of spaceflight-associated neuro-ocular syndrome (SANS). Thus, we also performed post hoc exploratory analyses between subgroups who did and did not show signs of SANS. HDBR + CO 2 had some impact on sensorimotor adaptation, with a lack of savings across the whole group. SANS individuals showed larger, more persistent after-effects, suggesting a shift from relying on cognitive to more implicit processing of adaptive behaviors. Overall, these findings suggest that HDBR + CO 2 alters the way in which individuals engage in sensorimotor processing. These findings have important implications for missions and mission training, which require individuals to adapt to altered sensory inputs over long periods in space. NEW & NOTEWORTHY This is the first bed rest campaign examining sensorimotor adaptation and savings in response to the combined effect of HDBR + CO2 and to observe signs of spaceflight-associated neuro-ocular syndrome (SANS) in HDBR participants. Our findings suggest that HDBR + CO2 alters the way that individuals engage in sensorimotor processing. Individuals who developed signs of SANS seem to rely more on implicit rather than cognitive processing of adaptive behaviors than subjects who did not present signs of SANS.