Modern cerebrospinal fluid flow research and Heinrich Quincke's seminal 1872 article on the distribution of cinnabar in freely moving animals.

Abstract

The discovery of the ‘glymphatic’ pathway has shed new light on the cerebrospinal (CSF)–brain interstitial fluid (ISF) exchange process (Iliff et al., 2012). In new anatomically defined terms, the glymphatic pathway now represents a brain-wide pathway where CSF flows through the brain and spinal cord parenchyma and exchanges with ISF from periarterial to perivenous spaces in a route interconnected by aquaporin 4 water channels present on glial cells (Iliff et al., 2012). The new concept of the glymphatic pathway has evolved from the older concept of bulk flow of ISF from brain parenchyma to the ventricular CSF referred to as the “ependymal pathway” (Brightman, 1965a,b). The glymphatic pathway is important for detoxification of the brain (and spinal cord), a cleaning process that appears to be driven by adrenergic tone (Xie et al., 2013), arterial pulsatility (Iliff et al., 2013b), level of arousal (Xie et al., 2013), and aging (Kress et al., 2014). For decades, brain pulsations have been observed directly during neurosurgical procedures. Pulsation of the CSF was first qualitatively described in vivo using fluoroscopy (Du Boulay, 1966) and then validated using non-invasively using magnetic resonance imaging (MRI) (Sherman and Citrin, 1986; Sherman et al., 1986). A comprehensive review of this topic by Wagshul and coworkers was recently published (Wagshul et al., 2011). Phase-contrast MRI was later used to quantify CSF pulsation in selected parts of the ventricular CSF spaces, followed by quantitative flow visualization in the entire subarachnoid and ventricular spaces through computational flow reconstruction from phase-contrast MRI data (Gupta et al., 2010; Cheng et al., 2012; Siyahhan et al., 2014). Major aspects of CSF flow dynamics and outflow pathways are now more fully characterized (Wagshul et al., 2006; Oreskovic and Klarica, 2010; Bulat and Klarica, 2011). All of these experimental and mathematical modeling studies have led the conclusion that for example ‘pressure pulsatility’ in the brain functions as an internal biosensor of intracranial compliance (Wagshul et al., 2011) which is heightened in chronic hydrocephalus (Greitz, 2004). CSF reabsorption via the arachnoid villi into the dural sinuses to the blood or through the nasal lymphatics have been previously documented in seminal papers (Boulton et al., 1996; Abbott, 2004; Johnston et al., 2004). Nevertheless, important questions pertaining to CSF drainage remain unanswered. For example, the exact anatomy of the subarachnoid spaces along cranial and spinal nerves, the functional (quantitative and directional) relationship between influx of CSF into the brain and lymphatic drainage of CSF-ISF, and the potentially fluctuating outflow volumes at the various exit points along the complex outflow pathways, which under normal conditions may be dependent on posture, activity and state of consciousness. The influence of body posture and respiration on CSF outflow and transport has been characterized; and continues to be investigated using MRI techniques with improved temporal resolution (Bradbury et al., 1981; Bradbury and Westrop, 1983; Alperin et al., 2005; Yamada et al., 2013). However, another exceedingly important area that is only partially understood is how physiological movement and various motor activities affects CSF movements and outflow patterns. This lack of information is paradoxical because the influence of motor activity is clearly playing a prominent role on CSF-ISF exchange and clearance (Bechter, 2011). For example, local muscle tone change associated with yawning changes CSF dynamics (Walusinski, 2014). To our knowledge, one of the best studies on CSF flow and outflow pathways have been performed by Heinrich Quincke and described in a paper he published in “Archiv fur Anatomie, Physiologie und wissenschaftliche Medicin” in 1872 (Quincke, 1872). In his studies, Quincke experimented with freely moving animals, injecting the particulate dye cinnabar (Mercury(II) sulfide, HgS) into the intrathecal spaces of dogs, cats, and rabbits, all animals with high motor activity, and analyzed the dye’s distribution throughout the body after days, weeks or months postmortem.