Cortical Spreading Depression Closes Paravascular Space and Impairs Glymphatic Flow: Implications for Migraine Headache

Abstract

Functioning of the glymphatic system, a network of paravascular tunnels through which cortical interstitial solutes are cleared from the brain, has recently been linked to sleep and traumatic brain injury, both of which can affect the progression of migraine. This led us to investigate the connection between migraine and the glymphatic system. Taking advantage of a novel in vivo method we developed using two-photon microscopy to visualize the paravascular space (PVS) in naive uninjected mice, we show that a single wave of cortical spreading depression (CSD), an animal model of migraine aura, induces a rapid and nearly complete closure of the PVS around surface as well as penetrating cortical arteries and veins lasting several minutes, and gradually recovering over 30 min. A temporal mismatch between the constriction or dilation of the blood vessel lumen and the closure of the PVS suggests that this closure is not likely to result from changes in vessel diameter. We also show that CSD impairs glymphatic flow, as indicated by the reduced rate at which intraparenchymally injected dye was cleared from the cortex to the PVS. This is the first observation of a PVS closure in connection with an abnormal cortical event that underlies a neurological disorder. More specifically, the findings demonstrate a link between the glymphatic system and migraine, and suggest a novel mechanism for regulation of glymphatic flow.

Perivascular spaces, glymphatic dysfunction, and small vessel disease

“…CAA and CADASIL) characterized by protein aggregation and deposition. Glymphatic function has been assessed in several highly relevant processes to SVD including aging(28) and diseases such as microinfarction (29, 30), stroke (31), Alzheimer’s disease (AD)(32), migraine(33), and diabetes(34). Extrapolating from the current literature, we will focus on the effects that altered PVS structure and function, arterial pulsatility, and clearance have on glymphatic function.…”

Intranasally administered IGF-1 inhibits spreading depression in vivo

“…First, Schain et al (2017) recently showed that SD induces transient closing of the paravascular spaces, impairing glymphatic flow. This transient closing of paravascular spaces would potentially impair IGF-1 access to areas of brain affected by the SD we induced immediately prior to intranasal administration (Fig.…”

Significance of Understanding Function of Glymphatic System to Manage Practical Clinical Problems of the Elderly

“…Just like Alzheimer's disease, glaucoma might be caused by an imbalance between the production and clearance of neurotoxins, including amyloid-β [24]. Schain et al argue that impairment of the glymphatic system can be involved in the pathogenesis of migraine [28]. Hitscherich et al consider the possibilities of so-called "osteopathic manipulative treatment" to improve the function of the glymphatic system.…”

“…Hitscherich et al consider the possibilities of so-called "osteopathic manipulative treatment" to improve the function of the glymphatic system. They note that these manipulations could concentrate on opening myofascial transition areas, maximalization of diaphragmatic movement and augmenting lymphaticovenous outflow [28].…”

“…They maintain that "it is conceivable, then, that aspiratory thoracic pressure may also contribute to glymphatic transport activity." [28] …”