Dilatation of the bridging cerebral veins in multiple sclerosis correlates with fatigue and suggests an increase in pressure.

BACKGROUND: There is a significant increase in the parenchymal microvessel blood volume in the earliest forms of multiple sclerosis (MS) which may be due to venular dilatation. Increased cortical venous pressure could account for this finding. Venous pressure is also implicated in the physiology of fatigue. The purpose of this study is to discover if there is dilatation of the veins within the subarachnoid space in multiple sclerosis and to estimate the pressures required to maintain any enlargement found. These findings will be correlated with the fatigue symptoms found in MS. METHODS: 103 patients with MS were compared with a control group of 50 patients. Post contrast 3DT1 images were used. The cross-sectional area of the bridging cortical veins and the vein of Galen were measured. RESULTS: In MS, the superficial territory cortical veins were 29% larger and the veins of Galen were 25% larger than the controls. CONCLUSION: There is evidence of a significant increase in the bridging vein transmural pressure in MS, estimated to be approximately 6.5 mmHg in the superficial cortical veins. MS patients with significant fatigue have larger cortical veins than those who are not significantly fatigued.

Intracranial pressure and veins.

This review summarizes the relationship between intracranial pressure and the venous system as far as ultrasound methods are concerned. Although the pressure in cortical veins is tightly and linearly coupled to the intracranial pressure, venous flow velocities in the basal veins are not. However, venous flow velocities reflect better the local cerebral blood flow than measurements in arteries. Therefore, they correlate better with clinical outcome in head trauma and subarachnoid hemorrhage. Transorbital sonography with measurement of the optic nerve sheath diameter and optic disk elevation has evolved to a valuable point of care diagnostic tool in idiopathic intracranial hypertension. In cerebral vein and sinus thrombosis ultrasound is at best a supplementary diagnostic tool, which may have a value in patient follow-up.

Reverse blood flow in cervicofacial veins after venous ligations: Potential implications in microsurgery.

INTRODUCTION: The consequences on the cervicofacial venous circulation of major cervicofacial vein ligations are poorly known. We aimed to highlight by using Doppler Ultrasound flow differences in the cervicofacial venous network in the case of unilateral or bilateral ligation of main venous collector trunks (external jugular vein [EJV] and internal jugular vein [IJV]) METHODS: A Doppler ultrasound was performed on 10 healthy volunteers, 8 patients with previous bilateral ligation of the EJV, 8 with a unilateral ligation of the EJV, and 8 with a unilateral ligation of the EJV and IJV, after modified radical neck dissection. The diameter, the flow direction and the peak systolic velocity (PSV) of the superficial temporal vein, the facial vein (FV) and the IJV were measured. RESULTS: Healthy patients had a similar right and left PSV for all the veins studied, with always antegrade flows. Patients with previous ligations had some significant right/left differences and retrograde flows. CONCLUSION: A redistribution of venous blood flow on the contralateral side of the face and neck seems to take place in the case of unilateral ligation of the EJV and/or IJV. Retrograde flows are sometimes observed in the case of previous ligation of the EJV and/or IJV and might compromise the success of venous microanastomoses.

Brain deep medullary veins on 3-T MRI in a population-based cohort.

Our aim is to investigate whether vascular risk factors are associated with cerebral deep medullary veins (DMVs) and whether DMVs are associated with MRI markers of cerebral small vessel disease (CSVD) or risk of stroke. In a community-based cohort of 1056 participants (mean age 55.7 years), DMVs were identified on susceptibility-weighted imaging (SWI) and counted in periventricular regions. Neuroimaging markers including lacunes, whiter matter hyperintensity (WMH), microbleeds, enlarged perivascular space, and brain atrophy were evaluated. The number of DMVs decreased with age (p = 0.007). After adjusting for age and sex, the number of DMVs was not associated with traditional vascular risk factors. Fewer DMVs was associated with increase of WMH and lacunes, but the association vanished after adjustment for vascular risk factors. However, fewer DMVs were independently associated with brain atrophy (p < 0.001). DMVs were not associated with three-year risk of stroke. Our results suggest that DMV is significantly different from other MRI markers of CSVD regarding risk factors, association with other CSVD markers, and risk of stroke. Nonetheless, the significant association between DMV and brain atrophy suggested the potential role of venules in age-related neurodegenerative process, which deserves further investigation.

Endovascular deep brain stimulation: Investigating the relationship between vascular structures and deep brain stimulation targets.

BACKGROUND: Endovascular delivery of current using 'stentrodes' - electrode bearing stents - constitutes a potential alternative to conventional deep brain stimulation (DBS). The precise neuroanatomical relationships between DBS targets and the vascular system, however, are poorly characterized to date. OBJECTIVE: To establish the relationships between cerebrovascular system and DBS targets and investigate the feasibility of endovascular stimulation as an alternative to DBS. METHODS: Neuroanatomical targets as employed during deep brain stimulation (anterior limb of the internal capsule, dentatorubrothalamic tract, fornix, globus pallidus pars interna, medial forebrain bundle, nucleus accumbens, pedunculopontine nucleus, subcallosal cingulate cortex, subthalamic nucleus, and ventral intermediate nucleus) were superimposed onto probabilistic vascular atlases obtained from 42 healthy individuals. Euclidian distances between targets and associated vessels were measured. To determine the electrical currents necessary to encapsulate the predefined neurosurgical targets and identify potentially side-effect inducing substrates, a preliminary volume of tissue activated (VTA) analysis was performed. RESULTS: Six out of ten DBS targets were deemed suitable for endovascular stimulation: medial forebrain bundle (vascular site: P1 segment of posterior cerebral artery), nucleus accumbens (vascular site: A1 segment of anterior cerebral artery), dentatorubrothalamic tract (vascular site: s2 segment of superior cerebellar artery), fornix (vascular site: internal cerebral vein), pedunculopontine nucleus (vascular site: lateral mesencephalic vein), and subcallosal cingulate cortex (vascular site: A2 segment of anterior cerebral artery). While VTAs effectively encapsulated mfb and NA at current thresholds of 3.5 V and 4.5 V respectively, incremental amplitude increases were required to effectively cover fornix, PPN and SCC target (mean voltage: 8.2 ± 4.8 V, range: 3.0-17.0 V). The side-effect profile associated with endovascular stimulation seems to be comparable to conventional lead implantation. Tailoring of targets towards vascular sites, however, may allow to reduce adverse effects, while maintaining the efficacy of neural entrainment within the target tissue. CONCLUSIONS: While several challenges remain at present, endovascular stimulation of select DBS targets seems feasible offering novel and exciting opportunities in the neuromodulation armamentarium.

Contractile pericytes determine the direction of blood flow at capillary junctions.

The essential function of the circulatory system is to continuously and efficiently supply the O2 and nutrients necessary to meet the metabolic demands of every cell in the body, a function in which vast capillary networks play a key role. Capillary networks serve an additional important function in the central nervous system: acting as a sensory network, they detect neuronal activity in the form of elevated extracellular K+ and initiate a retrograde, propagating, hyperpolarizing signal that dilates upstream arterioles to rapidly increase local blood flow. Yet, little is known about how blood entering this network is distributed on a branch-to-branch basis to reach specific neurons in need. Here, we demonstrate that capillary-enwrapping projections of junctional, contractile pericytes within a postarteriole transitional region differentially constrict to structurally and dynamically determine the morphology of capillary junctions and thereby regulate branch-specific blood flow. We further found that these contractile pericytes are capable of receiving propagating K+-induced hyperpolarizing signals propagating through the capillary network and dynamically channeling red blood cells toward the initiating signal. By controlling blood flow at junctions, contractile pericytes within a functionally distinct postarteriole transitional region maintain the efficiency and effectiveness of the capillary network, enabling optimal perfusion of the brain.

Analysis and manegement of laminar blood flow inside a cerebral blood vessel using a finite volume software program for biomedical engineering.

BACKGROUND AND OBJECTIVE: Hemodynamic blood flow analysis in the cerebrovascular is has become one of the important research topics in the bio-mechanic in recent decades. The primary duty of the cerebral blood vessel is supplying Glucose and oxygen for the brain. METHODS: In this investigation, the non-Newtonian blood flow in the cerebral blood vessels studied. For modeling the geometry of this problem, we used Magnetic Resonance Image (MRI) approach to take Digital Imaging and Communications in Medicine (DICOM) images and using an open-source software package to construct the geometry, which is a complicated one. The power-law indexes, heat flux, and Reynolds number range in the investigation are 0.6 ≤ n ≤ 0.8, 5 ≤ q ≤ 15Wm-2 and 160≤Re≤310. Effects of Reynolds number, power-law indexes and heat fluxes are investigated. RESULTS: We found that the pressure drop increase with increasing the Reynolds number and power-law index. The maximum Nusselt number in the cerebral blood vessels accrued in the running position of the body in n = 0.8. Also, the highest average wall shear stress occurs in maximum power-law indexes and Reynolds number. CONCLUSION: By increasing the power-law index and Reynolds number, the wall shear stress increases.

A dynamical model of the laminar BOLD response.

High-resolution functional magnetic resonance imaging (fMRI) using blood oxygenation dependent level-dependent (BOLD) signal is an increasingly popular tool to non-invasively examine neuronal processes at the mesoscopic level. However, as the BOLD signal stems from hemodynamic changes, its temporal and spatial properties do not match those of the underlying neuronal activity. In particular, the laminar BOLD response (LBR), commonly measured with gradient-echo (GE) MRI sequence, is confounded by non-local changes in deoxygenated hemoglobin and cerebral blood volume propagated within intracortical ascending veins, leading to a unidirectional blurring of the neuronal activity distribution towards the cortical surface. Here, we present a new cortical depth-dependent model of the BOLD response based on the principle of mass conservation, which takes the effect of ascending (and pial) veins on the cortical BOLD responses explicitly into account. It can be used to dynamically model cortical depth profiles of the BOLD signal as a function of various baseline- and activity-related physiological parameters for any spatiotemporal distribution of neuronal changes. We demonstrate that the commonly observed spatial increase of LBR is mainly due to baseline blood volume increase towards the surface. In contrast, an occasionally observed local maximum in the LBR (i.e. the so-called "bump") is mainly due to spatially inhomogeneous neuronal changes rather than locally higher baseline blood volume. In addition, we show that the GE-BOLD signal laminar point-spread functions, representing the signal leakage towards the surface, depend on several physiological parameters and on the level of neuronal activity. Furthermore, even in the case of simultaneous neuronal changes at each depth, inter-laminar delays of LBR transients are present due to the ascending vein. In summary, the model provides a conceptual framework for the biophysical interpretation of common experimental observations in high-resolution fMRI data. In the future, the model will allow for deconvolution of the spatiotemporal hemodynamic bias of the LBR and provide an estimate of the underlying laminar excitatory and inhibitory neuronal activity.

Collapsibility of the internal jugular veins in the lateral decubitus body position: A potential protective role of the cerebral venous outflow against neurodegeneration.

Recent research has revealed that patients with neurodegenerative disease sleep longer in the supine position, while healthy controls prefer sleeping in the lateral decubitus position. Thus, sleeping in the lateral position seems to be protective against neurodegeneration. It has also been suggested that a protective role of this body position could be associated with better cerebral venous drainage in this body position, which results in more active glymphatic system of the brain (the system responsible for clearance of the cerebral tissue from waste products, e.g. amyloid-ß). Since no published evidence exists regarding venous outflow from the cranial cavity in the lateral decubitus position, we performed a pilot sonographic study of the internal jugular veins in 3 young healthy volunteers and 2 patients presenting with abnormal jugular valves. In all healthy volunteers both internal jugular veins were opened in the supine position and collapsed in the sitting one. In the right lateral decubitus position the right internal jugular vein was opened, while the left one was partially collapsed; and-vice versa-in the left lateral decubitus position the right internal jugular vein was partially collapsed and the left one opened. In patients with abnormal jugular valves both internal jugular veins were opened in both lateral decubitus body positions. We hypothesize that in the lateral decubitus body position, because of decreased flow resistance in the extracranial veins, cerebral venous outflow is optimal, which in turn optimizes the activity of the glymphatic system. Therefore, people intuitively prefer this body position during sleep, while other positions are associated with a higher risk of neurodegenerative disorders. Yet, it should be emphasized that our results need to be interpreted with caution, since only a few individuals have been assessed and this discovery should be confirmed in more patients and healthy controls, and by precise quantitative measurements.

Does the prone sleeping position affect the intracranial dural venous flow?

PURPOSE: There are few studies documenting the effect of posture on intracranial dural venous flow. The aim of the present study was to explore alterations caused by the prone position using magnetic resonance (MR) venography. METHODS: A total of eight patients (five men and three women) underwent non-contrast MR venography in both supine and prone positions. RESULTS: In the prone position, an increase in intracranial dural venous flow was found in all patients in the non-dominant transverse and sigmoid sinuses. An increase in venous flow to the straight sinus was observed in 75% of the patients. Flow to the superior ophthalmic vein decreased in three patients. No postural flow alterations were observed in any of the patients in the superior sagittal, dominant transverse, and sigmoid sinuses. CONCLUSION: Based on results of the study, in the prone sleeping position, part of the intracranial venous flow may be preferentially drained through the straight and non-dominant transverse sinuses.

Physical Activity and Cerebral Small Vein Integrity in Older Adults.

Identifying promoters of cerebral small vein integrity is important to counter vascular contributions to cognitive impairment and dementia. PURPOSE: In this preliminary investigation, the effects of a randomized 24-month physical activity (PA) intervention on changes in cerebral small vein integrity were compared to those of a health education (HE) control. METHODS: Cerebral small vein integrity was measured in 24 older adults (n = 8, PA; n = 16, HE) using ultra-high field MRI before and at the end of the 24-month intervention. Deep medullary veins were defined as straight or tortuous; percent change in straight length, tortuous length, and tortuosity ratio were computed. Microbleed count and white matter hyperintensities were also rated. RESULTS: Accelerometry-based values of PA increased by 17.2% in the PA group but declined by 28.0% in the HE group. The PA group, but not the HE group, had a significant increase in straight vein length from baseline to 24-month follow-up (P = 0.02 and P = 0.21, respectively); the between-group difference in percent change in straight length was significant (increase: median, 93.6%; interquartile range, 112.9 for PA; median, 28.4%; interquartile range, 90.6 for HE; P = 0.07). Between group differences in other markers were nonsignificant. CONCLUSIONS: Increasing PA in late-life may promote cerebral small vein integrity. This should be confirmed in larger studies.

Transclival Venous Circulation: Anatomic Study.

INTRODUCTION: The clivus is a small, central area of the basal cranium with limited surgical access and high morbidity associated with pathologies of its surrounding structures. Therefore thorough knowledge and understanding of the anatomy in this region are crucial for the success of treatments and interpretation of imaging. As to our knowledge, there is no extant cadaveric examination of the transclival veins, so the present study was performed. METHODS: Fifteen lightly embalmed adult heads underwent blue latex injection of the left and right internal jugular veins. Special attention was given to the presence or absence of transclival vessels. When transclival veins were identified, their intracranial source, point of penetration of the clivus and anterior connections were documented. RESULTS: Ten (66.7%) specimens were found to have transclival veins. These connected the basilar venous plexus to the retropharyngeal venous plexus on all specimens. Eight of the 10 specimens had multiple transclival veins, and 2 had only 1 vessel. The majority of the transclival veins were found penetrating the clivus at its lower one third. However, 2 specimens also had transclival veins that pierced the clivus at its upper one third. CONCLUSIONS: An improved understanding of the skull base and its venous drainage can assist clinicians and surgeons in better understanding normal, pathologic, and variant anatomy in this region.

Fluid-structure Interaction in the Cerebral Venous Transverse Sinus.

The biomechanics of the cerebral venous system plays an important role in determining blood flow to the brain. Computational approaches to help elucidate the role of the cerebral venous system in health and disease have largely focused on lumped-parameter models and one-dimensional computational fluid dynamics simulations. To expand upon the prior work, and to investigate the possible role of cerebral venous collapse in normal physiology and pathological conditions, we developed a fluid-structure interaction (FSI) model of the cerebral venous transverse sinus (TS), coupled to a lumpedparameter representation of the upstream cerebral circulation to provide boundary conditions for the FSI simulation. We simulated the effects of local venous hemodynamics on the TS distention and investigated TS vascular collapse under increased intracranial pressure, as has been hypothesized in the pathogenesis of idiopathic intracranial hypertension. Our baseline simulations reproduced pressures and flows in the cerebral venous system that compared favorably with what has been reported in the literature. The FSI simulations under increased intracranial pressure showed a decreased venous flow through and progressive collapse of the TS veins. Our simulations captured the dynamic behavior of the vascular collapse and may help shed light on the interactions between the cerebrovascular and cerebrospinal fluid spaces in health and disease.

Contribution of systemic vascular effects to fMRI activity in white matter.

To investigate a potential contribution of systemic physiology to recently reported BOLD fMRI signals in white matter, we compared photo-plethysmography (PPG) and whole-brain fMRI signals recorded simultaneously during long resting-state scans from an overnight sleep study. We found that intermittent drops in the amplitude of the PPG signal exhibited strong and widespread correlations with the fMRI signal, both in white matter (WM) and in gray matter (GM). The WM signal pattern resembled that seen in previous resting-state fMRI studies and closely tracked the location of medullary veins. Its temporal cross-correlation with the PPG amplitude was bipolar, with an early negative value. In GM, the correlation was consistently positive. Consistent with previous studies comparing physiological signals with fMRI, these findings point to a systemic vascular contribution to WM fMRI signals. The PPG drops are interpreted as systemic vasoconstrictive events, possibly related to intermittent increases in sympathetic tone related to fluctuations in arousal state. The counter-intuitive polarity of the WM signal is explained by long blood transit times in the medullary vasculature of WM, which cause blood oxygenation loss and a substantial timing mismatch between blood volume and blood oxygenation effects. A similar mechanism may explain previous findings of negative WM signals around large draining veins during both task- and resting-state fMRI.

Hemodynamics of cerebral bridging veins connecting the superior sagittal sinus based on numerical simulation.

BACKGROUND: The physiological and hemodynamic features of bridging veins involve wall shear stress (WSS) of the cerebral venous system. Based on the data of cadavers and computational fluid dynamics software pack, the hemodynamic physical models of bridging veins (BVs) connecting superior sagittal sinus (SSS) were established. RESULTS: A total of 137 BVs formed two clusters along the SSS: anterior group and posterior group. The diameters of the BVs in posterior group were larger than of the anterior group, and the entry angle was smaller. When the diameter of a BV was greater than 1.2 mm, the WSS decreased in the downstream wall of SSS with entry angle less than 105°, and the WSS also decreased in the upstream wall of BVs with entry angle less than 65°. The minimum WSS in BVs was only 63% of that in SSS. Compared with the BVs in anterior group, the minimum WSS in the posterior group was smaller, and the distance from location of the minimum WSS to the dural entrance was longer. CONCLUSION: The cerebral venous thrombosis occurs more easily when the diameter of a BV is greater than 1.2 mm and the entry angle is less than 65°. The embolus maybe form earlier in the upstream wall of BVs in the posterior part of SSS.

Spatial distribution of flow and oxygenation in the cerebral venous drainage system.

PURPOSE: To investigate the venous oxygenation and flow in the brain, and determine how they might change under challenged states. MATERIALS AND METHODS: Eight healthy human subjects (24-37 years) were studied. T2 -relaxation under spin tagging (TRUST) magnetic resonance imaging (MRI) and phase-contrast MRI were performed to measure venous oxygenation and venous blood flow, respectively, in the superior sagittal sinus (SSS), the straight sinus (SS), and the internal jugular veins (IJVs). Venous oxygenation was assessed at room air (0.03%CO2 , 21%O2 ) and under hyperoxia (O%CO2 , 95%O2 , and 5%N2 ) conditions. Venous blood flow was assessed at room air and under hypercapnia (5%CO2 , 21%O2 , and 74%N2 ) conditions. Whole-brain blood flow was also measured at the four feeding arteries of the brain using phase-contrast MRI. The changes in venous oxygenation and blood flow from room air to hyperoxia or hypercapnia conditions were tested using paired t-tests. RESULTS: Venous oxygenation in the SSS, the SS, and the IJVs was 61 ± 4%, 64 ± 4%, and 62 ± 4%, respectively, at room air, and increased to 70 ± 3% (P < 0.01 compared to room air), 71 ± 5% (P = 0.59), and 68 ± 5% (P < 0.05) under hyperoxic condition. The SSS, SS, and IJV drained 46 ± 9%, 16 ± 4%, and 79 ± 1% of whole-brain blood flow, respectively, and this flow distribution did not change under hypercapnic condition (P > 0.5). CONCLUSION: The results found in this study provide insight into the venous oxygenation and venous flow distribution and its heterogeneity among different venous structures. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;47:1091-1098.

Investigation of cerebral venous outflow in microgravity.

OBJECTIVE: The gravitational gradient is the major component to face when considering the physiology of venous return, and there is a growing interest in understanding the mechanisms ensuring the heart filling, in the absence of gravity, for astronauts who perform long-term space missions. APPROACH: The purpose of the Drain Brain project was to monitor the cerebral venous outflow of a crew member during an experiment on the International Space Station (ISS), so as to study the compensatory mechanisms that facilitate this essential physiological action in subjects living in a microgravity environment. Such venous function has been characterized by means of a novel application of strain-gauge plethysmography which uses a capacitive sensor. MAIN RESULTS: In this contribution, preliminary results of our investigation have been presented. In particular, comparison of plethysmography data confirmed that long duration spaceflights lead to a redistribution of venous blood volume, and showed interesting differences in the amplitude of cardiac oscillations measured at the level of the neck veins. SIGNIFICANCE: The success of the experiment has also demonstrated that thanks to its easy portability, non-invasiveness, and non-operator dependence, the proposed device can be considered as a novel tool for use aboard the ISS. Further trials are now under way to complete the investigation on the drainage function of the neck veins in microgravity.

Relationship between cerebral arterial inflow and venous outflow during dynamic supine exercise.

The regulation of cerebral venous outflow during exercise has not been studied systematically. To identify relations between cerebral arterial inflow and venous outflow, we assessed the blood flow (BF) of the cerebral arteries (internal carotid artery: ICA and vertebral artery: VA) and veins (internal jugular vein: IJV and vertebral vein: VV) during dynamic exercise using ultrasonography. Nine subjects performed a cycling exercise in supine position at a light and moderate workload. Similar to the ICA BF, the IJV BF increased from baseline during light exercise (P < 0.05). However, the IJV BF decreased below baseline levels during moderate exercise, whereas the ICA BF returned near resting levels. In contrast, BF of the VA and VV increased with the workload (P < 0.05). The change in the ICA or VA BF from baseline to exercise was significantly correlated with the change in the IJV (r = 0.73, P = 0.001) or VV BF (r = 0.52, P = 0.028), respectively. These findings suggest that dynamic supine exercise modifies the cerebral venous outflow, and there is coupling between regulations of arterial inflow and venous outflow in both anterior and posterior cerebral circulation. However, it remains unclear whether changes in cerebral venous outflow influence on the regulation of cerebral arterial inflow during exercise.

Failure and Fatigue Properties of Immature Human and Porcine Parasagittal Bridging Veins.

Tearing of the parasagittal bridging veins (BVs) is thought to be a source of extra-axial hemorrhage (EAH) associated with abusive traumatic brain injuries (TBIs) in children. However, the pediatric BV mechanical properties are unknown. We subjected porcine adult, porcine newborn, and human infant BVs to either a low rate pull to failure, a high rate pull to failure, or 30 s of cyclic loading followed by a pull to failure. An additional subset of human infant BVs was examined for viscoelastic recovery between two cycling episodes. We found that human infant BVs are stronger than porcine BVs, and BV mechanical properties are rate dependent, but not age dependent. Successive cyclic loading to a uniform level of stretch softened BVs with decaying peak stresses, and shifted their stress-stretch relationship. These data are critical in understanding BV tissue behavior in accidental and abusive trauma scenarios, which in turn may clarify circumstances that may be injurious to young children.

An international collaboration studying the physiological and anatomical cerebral effects of carbon dioxide during head-down tilt bed rest: the SPACECOT study.

Exposure to the microgravity environment results in various adaptive and maladaptive physiological changes in the human body, with notable ophthalmic abnormalities developing during 6-mo missions on the International Space Station (ISS). These findings have led to the hypothesis that the loss of gravity induces a cephalad fluid shift, decreased cerebral venous outflow, and increased intracranial pressure, which may be further exacerbated by increased ambient carbon dioxide (CO2) levels on the ISS. Here we describe the SPACECOT study (studying the physiological and anatomical cerebral effects of CO2 during head-down tilt), a randomized, double-blind crossover design study with two conditions: 29 h of 12° head-down tilt (HDT) with ambient air and 29 h of 12° HDT with 0.5% CO2 The internationally collaborative SPACECOT study utilized an innovative approach to study the effects of headward fluid shifting induced by 12° HDT and increased ambient CO2 as well as their interaction with a focus on cerebral and ocular anatomy and physiology. Here we provide an in-depth overview of this new approach including the subjects, study design, and implementation, as well as the standardization plan for nutritional intake, environmental parameters, and bed rest procedures.NEW & NOTEWORTHY A new approach for investigating the combined effects of cephalad fluid shifting and increased ambient carbon dioxide (CO2) is presented. This may be useful for studying the neuroophthalmic and cerebral effects of spaceflight where cephalad fluid shifts occur in an elevated CO2 environment.