Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2015 Aug 5;35(31):11034-44.
doi: 10.1523/JNEUROSCI.1625-15.2015.

The Effect of Body Posture on Brain Glymphatic Transport

Hedok Lee  1 , Lulu Xie  2 , Mei Yu  3 , Hongyi Kang  2 , Tian Feng  4 , Rashid Deane  2 , Jean Logan  5 , Maiken Nedergaard  2 , Helene Benveniste  6
Affiliations

The Effect of Body Posture on Brain Glymphatic Transport

Hedok Lee et al. J Neurosci. .

Abstract

The glymphatic pathway expedites clearance of waste, including soluble amyloid β (Aβ) from the brain. Transport through this pathway is controlled by the brain's arousal level because, during sleep or anesthesia, the brain's interstitial space volume expands (compared with wakefulness), resulting in faster waste removal. Humans, as well as animals, exhibit different body postures during sleep, which may also affect waste removal. Therefore, not only the level of consciousness, but also body posture, might affect CSF-interstitial fluid (ISF) exchange efficiency. We used dynamic-contrast-enhanced MRI and kinetic modeling to quantify CSF-ISF exchange rates in anesthetized rodents' brains in supine, prone, or lateral positions. To validate the MRI data and to assess specifically the influence of body posture on clearance of Aβ, we used fluorescence microscopy and radioactive tracers, respectively. The analysis showed that glymphatic transport was most efficient in the lateral position compared with the supine or prone positions. In the prone position, in which the rat's head was in the most upright position (mimicking posture during the awake state), transport was characterized by "retention" of the tracer, slower clearance, and more CSF efflux along larger caliber cervical vessels. The optical imaging and radiotracer studies confirmed that glymphatic transport and Aβ clearance were superior in the lateral and supine positions. We propose that the most popular sleep posture (lateral) has evolved to optimize waste removal during sleep and that posture must be considered in diagnostic imaging procedures developed in the future to assess CSF-ISF transport in humans.

Significance statement: The rodent brain removes waste better during sleep or anesthesia compared with the awake state. Animals exhibit different body posture during the awake and sleep states, which might affect the brain's waste removal efficiency. We investigated the influence of body posture on brainwide transport of inert tracers of anesthetized rodents. The major finding of our study was that waste, including Aβ, removal was most efficient in the lateral position (compared with the prone position), which mimics the natural resting/sleeping position of rodents. Although our finding awaits testing in humans, we speculate that the lateral position during sleep has advantage with regard to the removal of waste products including Aβ, because clinical studies have shown that sleep drives Aβ clearance from the brain.

Keywords: CSF; brain; posture; sleep; unconsciousness; waste removal.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
A, Two-compartment model used for characterizing transport of Gd-DTPA contrast into and out of the brain. The compartment model use the defined TSCs from the CM and whole brain (excluding CSF spaces) to calculate retention and loss. Compartments C1 and C2 are assumed to occupy the same space. The main input (K1) is represented by TSC from the CM. Tracer “retention” can be described as k3/k4 and “loss” (or clearance) as the parameter k2/(1 + k3/k4). Examples of raw data (blue) and fitted data derived from the two-compartment model (red) from representative rats in supine (B), prone (C), and RLD (D) positions. As can be seen, the calculated parameter for “retention” is highest for the rat in prone position and “loss” is most pronounced in the rat positioned in RLD.
Figure 2.
Figure 2.
TSCs from the CM of rats in different body positions. A, T1-weighted MRI of rat brain at the level of the CM ∼30 min after infusion of Gd-DTPA. Note that the CM catheter can be appreciated as a straight, high-signal-intensity line (white arrow). B, Average TSCs associated with infusion of Gd-DTPA into the CM for rats positioned in prone (blue, n = 7), supine (red, n = 9), and RLD (n = 8) body posture. Data are presented as mean ± SD. As can be observed, the TSCs from the three groups are identical and statistical analysis confirmed this statement (Table 1).
Figure 3.
Figure 3.
Effect of posture on brain transport of Gd-DTPA. Gd-DTPA transport/uptake for the cerebellum (A), hippocampus (B), midbrain (C), and orbital frontal cortex (D) represented by VT derived from executing the Logan plot. The data are presented as box-and-whisker plots (median, first quartile, third quartile, minimum, and maximum values); red: prone; blue: lateral, and black: supine. For each box-and-whisker plot, the corresponding 3D volume rendered brain region is shown: cerebellum (dark blue), hippocampus (light blue), midbrain (pink), and orbitofrontal cortices (turquoise). The VTs were compared between the three groups [prone (n = 7*), lateral (n = 8), supine (n = 9)] via the K–W test, which demonstrated positional dependence (p < 0.05) for all brain regions. The Wilcoxon rank-sum test was performed as a post hoc test to compare VTs between each of two groups with correction for multiple comparisons via FDR. This analysis showed that rats in prone position had significantly lower uptake of Gd-DTPA in the cerebellum (p < 0.05), hippocampus (p < 0.05), and midbrain (p < 0.03) compared with rats in the RLD position. *For the orbital frontal cortex, one rat's time activity curve in the prone group failed in the Logan-plot-fitting routine for estimation of VT and was excluded from the group analysis.
Figure 4.
Figure 4.
Anatomical key points of interest for Gd-DTPA efflux. Horizontal sections from T1-weighted MRIs at the level of the cochlea from rat brain before (A) and after (B) infusion of Gd-DTPA. The cochlea (Co) can be easily identified on the T1-weighted anatomical MRIs because it is shaped like a snail shell (A). The vagus nerve exits together with the glossopharyngeal (IX) nerve from the medulla oblongata below the vestibulocochlear nerve (VIII); the large nerve believed to be the vagus nerve is marked “X.” Note that part of the anatomy is obscured by susceptibility artifacts (dark spots marked by * in A and B). When contrast is infused into the CM, Gd-DTPA transport can be detected as an increase in signal intensity on the T1-weighted MRIs (brightness in B), which can be seen surrounding the cochlea 60 min after infusion start. (At later time points contrast is also seen inside the cochlea.) The exit points of the vagal nerve are also associated with Gd-DTPA contrast (B). C, D, 3D surface-rendered whole brains from a rat illustrating the spatial positions of the CM, cochlea (Co, blue), vagus nerve (X, black), and ICA (red). Only part of the ICA can be identified because its passage is partly obscured on the MRIs due to susceptibility artifacts and bony structures. E, 3D surface-rendered images of the cranium of a rat head acquired by CT to delineate all cranial components. The cranium is clearly visualized, including the squamosal (SQA), occipital (OCC), basis-phenoid (BAS), tympanic (TYM), pterygoid (PPI), paramastoid processes (PMP), and the foramen ovale (FOV). The temporal-mandibular joint (data not shown) and part of the PPI are causing the susceptibility artifacts on the MRIs obscuring the ICA as it enters the skull. Furthermore, part of the ICA runs through the bony carotid canal (CCA) shown as a dashed red line (E). F, G, Sagittal T1-weighted MRIs of a rat head at the level of the ICA shown before (F) and 80 min after (G) infusion of Gd-DTPA. The Gd-DTPA-induced signal changes appear as a bright signal that follow a well defined path along the ICA (sometimes along the ECA as well). H, I, Horizontal sections of T1-weighted MRIs from a rat head at the level of the SS sinus before (H) and 80 min after (I) infusion of Gd-DTPA into the CM. The SS sinus appears as a dark line in the middle of the two hemispheres (arrow, H) and, after infusion of contrast, areas adjacent to the SS sinus appear bright (arrows, I). J, Sagittal section from T1-weighted MRI before infusion of contrast at the level of the ICA and ECA showing more detail with regard to branching vessels including the occipital artery (aOCC) arising from the ECA and the pterygopalatine artery (aPTP) arising from the ICA.
Figure 5.
Figure 5.
Analysis of the effect of posture on efflux of Gd-DTPA. Average TSCs obtained from anatomical areas associated with efflux of Gd-DTPA from the three different groups (prone, n = 7; supine, n = 9; lateral, n = 8). The kinetics of the TSCs are different and dependent on anatomical point of interest. A, TSCs extracted from with areas along the SS sagittal sinus are characterized by a steady increase over time. B, C, Anatomical landmarks and illustration of the ROI measured along the SS sinus. Note that the SS sinus itself appears dark on the T1-weighted MRIs. Scale bars in B and C, 2 mm. D, TSCs extracted from the ROI-associated acoustic–cochlea complex (anatomical position illustrated in E and F; scale bar, 3 mm) are also characterized by a steady increase over time. G, TSCs associated with the vagus (Xth) nerve are characterized by a peak. H, I, Position of the vagus nerve (X) on a T1-weighted MRI in the sagittal plane at the level of the ICA and external carotid artery (ECA) before (H) and after (I) Gd-DTPA administration. Note that the path of the X nerve appears to be toward the ICA; the ROI associated with the vagal nerve is also indicated. Scale bar, 3 mm. J, TSCs derived from the areas along the ICA are characterized by a steady but variable signal change rising over time. An example of a ROI associated with this signal is shown in I. In general, CSF efflux associated with the vagus nerve was more pronounced compared with the other efflux pathways (G). Rats in prone position appear to have the largest amount of Gd-DTPA exiting along the ICA compared with the two other body positions (J).
Figure 6.
Figure 6.
Effect of posture on glymphatic transport using fluorescent and radiolabeled tracers. A, Small MW (Texas Red-conjugated dextran, 3 kDa) and large MW tracer (FITC-conjugated dextran, 2000 kDa) were injected intracisternally in mice placed in the prone, lateral, and supine position. B, Thirty minutes after injection, animals were perfusion fixed and whole-slice fluorescence was evaluated. Representative coronal sections are shown. CSF tracer influx in brain was significantly reduced in prone brain compared with lateral and supine brain (*p < 0.05, one-way ANOVA; for prone, n = 8, for lateral and supine, n = 6). C, Radiolabeled 125I-amyloid β1-40 was injected into cortex in mice in the same positions. Thirty minutes after injection, radiolabeled clearance was evaluated by gamma counting. 125I-Aβ1-40 clearance was significantly more efficient in the supine than in the lateral and prone positions (*p < 0.05; one-way ANOVA; for prone, n = 6; for lateral and supine, n = 7). D, Fluorescent tracer intensity was significantly higher in prone spinal cord compared with lateral and supine spinal cord. (*p < 0.05, one-way ANOVA; for prone, n = 6; for lateral, n = 5; and for supine, n = 6).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Børgesen SE, Westergård L, Gjerris F. Isotope cisternography and conductance to outflow of CSF in normal pressure hydrocephalus. Acta Neurochirurgica. 1981;57:67–73. doi: 10.1007/BF01665115. - DOI - PubMed
    1. Brightman MW. The distribution within the brain of ferritin injected into cerebrospinal fluid compartments. II. Parenchymal distribution. Am J Anat. 1965a;117:193–219. doi: 10.1002/aja.1001170204. - DOI - PubMed
    1. Brightman MW. The distribution within the brain of ferritin injected into cerebrospinal fluid compartments. I. Ependymal distribution. J Cell Biol. 1965b;26:99–123. doi: 10.1083/jcb.26.1.99. - DOI - PMC - PubMed
    1. Brosnan RJ, Steffey EP, LeCouteur RA, Imai A, Farver TB, Kortz GD. Effects of body position on intracranial and cerebral perfusion pressures in isoflurane-anesthetized horses. J Appl Physiol. 2002;92:2542–2546. doi: 10.1152/japplphysiol.00055.2002. - DOI - PubMed
    1. Bushey D, Tononi G, Cirelli C. Sleep and synaptic homeostasis: structural evidence in Drosophila. Science. 2011;332:1576–1581. doi: 10.1126/science.1202839. - DOI - PMC - PubMed

Publication types

Substances