Increased glymphatic influx is correlated with high EEG delta power and low heart rate in mice under anesthesia

Hablitz, Lauren M.; Vinitsky, Hanna S.; Sun, Qian; Stæger, Frederik Filip; Sigurðsson, Björn; Mortensen, Kristian Nygaard; Lilius, Tuomas

doi:10.1126/sciadv.aav5447

Cited by 394 publications

(473 citation statements)

References 39 publications

(43 reference statements)

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“…In order to better understand the mechanism behind VNS-induced CSF penetrance, we attempted to correlate the degree of CSF penetrance with the physiological responses recorded during stimulation. The CSF influx hypothesized to occur in the glymphatic model is driven by cerebral arterial pulsation and it was recently reported that increased glymphatic influx was correlated with a reduced HR in mice under anesthesia (24,26,38). Although no direct experiments have been undertaken to assess the effect of VNS on cerebral arterial pulsation, several studies detail the systemic cardiovascular and respiratory responses of VNS (12,13).…”

Section: Vns-induced Csf Penetrance Could Not Be Directly Linked To Cmentioning

confidence: 99%

“…Thus, it has been suggested that improvement or rescue of clearance function in these pathologies may be of potential therapeutic benefit. Importantly, aspects of the brain clearance systems are sensitive to both changes in noradrenergic signaling associated with sleep/arousal states and to cerebral arterial pulsatility which is hypothesized to drive CSF penetrance into the parenchyma (18,(24)(25)(26). Given the well-known noradrenergic, cardiovascular, and respiratory effects induced by VNS, we theorized that VNS may be able to increase CSF penetrance, thereby providing a previously unknown and unexplored therapeutic mechanism of the reported beneficial outcomes of VNS (4,12,27,28).…”

Section: Introductionmentioning

confidence: 99%

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Is Vagus Nerve Stimulation Brain Washing?

Cheng

Brodnick

Blanz

et al. 2019

Preprint

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Authors contributed equally to this work One Sentence Summary: Cervical vagus nerve stimulation using clinically derived parameters enhances movement of cerebrospinal fluid into the brain parenchyma presenting a previously unreported effect of vagus nerve stimulation with potential clinical utility.Abstract: Vagal nerve stimulation (VNS) is an FDA approved treatment method for intractable epilepsy, treatment resistant depression, cluster headaches and migraine with over 100,000 patients having received vagal nerve implants to date. Moreover, evidence in the literature has led to a growing list of possible clinical indications, with several small clinical trials applying VNS to treat conditions ranging from neurodegenerative diseases to arthritis, anxiety disorders, and obesity. Despite the growing list of therapeutic applications, the fundamental mechanisms by which VNS achieves its beneficial effects are poorly understood and an area of active research. In parallel, the glymphatic and meningeal lymphatic systems have recently been proposed and experimentally validated to explain how the brain maintains a healthy homeostasis without a traditionally defined lymphatic system. In particular, the glymphatic system relates to the interchange of cerebrospinal fluid (CSF) and interstitial fluid (ISF) whose net effect is to wash through the brain parenchyma removing metabolic waste products and misfolded proteins from the interstitium. Of note, clearance is sensitive to adrenergic signaling, and a primary driver of CSF influx into the parenchyma appears to be cerebral arterial pulsations and respiration. As VNS has well-documented effects on cardiovascular and respiratory physiology as well as brain adrenergic signaling, we hypothesized that VNS delivered at clinically derived parameters would increase CSF influx in the brain. To test this hypothesis, we injected a low molecular weight (3 kD) lysine-fixable fluorescent tracer (TxRed) into the CSF system of mice with a cervical vagus nerve cuff implant and measured the amount of CSF penetrance following VNS. We found that the clinical VNS group showed a significant increase in CSF dye penetrance as compared to the naïve control and sham groups. This study demonstrates that VNS therapeutic strategies already being applied in the clinic today may induce intended effects and/or unwanted side effects by altering CSF/ISF exchange in the brain. This may have broad ranging implications in the treatment of various CNS pathologies.

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Section: Vns-induced Csf Penetrance Could Not Be Directly Linked To Cmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Is Vagus Nerve Stimulation Brain Washing?

Cheng

Brodnick

Blanz

et al. 2019

Preprint

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“…The demonstrated AQP4-haplotype modulation of SWE documents an association between the intensity of deep NREM sleep and the expression of the AQP4-water channel, a relationship that may be central for CSF driven brain pulsations. Given how recent preclinical evidence show that the intensity of slow waves is directly linked to glymphatic influx (10), and that the complete removal of AQP4 in mice results in brain impairments after sleep deprivation (8), this suggest an important role of AQP4-mediated clearance during sleep. The results match our initial hypothesis suggesting that in an attempt to compensate for a reduced AQP4 expression (23), AQP4 HtMi-carriers have a stronger parenchymal CSF flow and increased SWE in NREM sleep ( Figure 1A).…”

Section: Aqp4-haplotype Modulates Slow Waves In Nrem Sleepmentioning

confidence: 99%

“…Mice lacking AQP4 show a strong reduction in parenchymal CSF influx (5,6) and increased interstitial beta-amyloid depositions (7), which is ameliorated by sleep deprivation (8). Thirdly, the inward flow of CSF through AQP4 channels mainly occurs during non-rapid eye-movement (NREM) sleep (9) and in preclinical studies, glymphatic flow is known to be positively correlated with slow wave production (10).…”

Section: Introductionmentioning

confidence: 99%

Haplotype of the astrocytic water channel AQP4 modulates slow wave energy in human NREM sleep

Smu

Landolt

Berger

et al. 2019

Preprint

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Cerebrospinal fluid (CSF) flow through the brain parenchyma is facilitated by the astrocytic water channel aquaporin 4 (AQP4). Homeostatically regulated electroencephalographic (EEG) slow waves are a hallmark of deep non-rapid-eye-movement (NREM) sleep and have been implicated in the regulation of parenchymal CSF flow and brain clearance. The human AQP4 gene harbors several single nucleotide polymorphisms (SNPs) associated with AQP4 expression, brain-water homeostasis and neurodegenerative diseases. To date, their role in sleep-wake regulation is unknown. To investigate whether functional variants in AQP4 modulate human sleep, nocturnal EEG-recordings and cognitive performance were investigated in 123 healthy participants genotyped for a common eight-SNP AQP4-haplotype. We show that this AQP4-haplotype is associated with distinct modulations of NREM slow wave energy, strongest in early sleep and mirrored by changes in sleepiness and reaction times during extended wakefulness. The study provides the first human evidence for a link between AQP4, deep NREM sleep and cognitive consequences of prolonged wakefulness.

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“…Indeed, experimental studies and computer simulations have demonstrated that not only SWA reflects experience-dependent changes in regional synaptic density/strength, but also have indicated that slow waves may play a direct role in cellular and systems restoration and in the consolidation of newly acquired memories (Tononi and Cirelli, 2014). Recent evidence also suggested a possible implication of sleep slow waves in the clearance of neurotoxic metabolic products that accumulate during wakefulness (Xie et al, 2013;Hablitz et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Integrity of corpus callosum is essential for the cross-hemispheric propagation of sleep slow waves: a high-density EEG study in split-brain patients

Avvenuti¹,

Handjaras²,

Betta³

et al. 2019

Preprint

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400)The slow waves of NREM-sleep (0.5-4Hz) reflect experience-dependent plasticity and play a direct role in the restorative functions of sleep. Importantly, slow waves behave as traveling waves and their propagation is assumed to reflect the structural properties of white matter connections. Based on this assumption, the corpus callosum (CC) may represent the main responsible for cross-hemispheric slow wave propagation. To verify this hypothesis, here we studied a group of patients who underwent total callosotomy due to drug-resistant epilepsy.Overnight high-density (hd)-EEG recordings (256 electrodes) were performed in five totally callosotomized in-patients (CP; 40-53y, 2F), in three control non-callosotomized neurological in-patients (NP; 44-66y, 2F, 1M epileptic), and in an additional sample of 24 healthy adult subjects (HS; 20-47y, 13F). Data were inspected to select NREM-sleep epochs and artefactual or non-physiological activity was rejected. Slow waves were detected using an automated algorithm and their properties and propagation patterns were computed. For each slow wave parameter and for each patient, the relative z-score and the corresponding p-value were calculated with respect to the distribution represented by the HS-group. Group differences were considered significant only when a Bonferroni corrected P < 0.05 was observed in all the CP and in none of the NP. A regression-based adjustment was used to exclude potential confounding effects of age. Slow wave density, amplitude, slope and propagation speed did not differ across CP and HS. In all CP slow waves displayed a significantly reduced probability of cross-hemispheric propagation and a stronger inter-hemispheric asymmetry. Moreover, we found that the incidence of large slow waves tended to differ across hemispheres within individual NREM epochs, with a relative predominance of the right over the left hemisphere in both CP and HS. The absolute magnitude of this inter-hemispheric difference was significantly greater in CP relative to HS. This effect did not depend on differences in slow wave origin within each hemisphere across groups. Present results indicate that the integrity of the CC is essential for the cross-hemispheric traveling of sleep slow waves, supporting the assumption of a direct relationship between white matter structural integrity and cross-hemispheric slow wave propagation. Our findings also imply a prominent role of cortico-cortical connections, rather than cortico-subcortico-cortical loops, in slow wave cross-hemispheric synchronization.Finally, this data indicate that the lack of the CC does not lead to differences in sleep depth, in terms of slow wave generation/origin, across brain hemispheres.

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Increased glymphatic influx is correlated with high EEG delta power and low heart rate in mice under anesthesia

Cited by 394 publications

References 39 publications

Is Vagus Nerve Stimulation Brain Washing?

Is Vagus Nerve Stimulation Brain Washing?

Haplotype of the astrocytic water channel AQP4 modulates slow wave energy in human NREM sleep

Integrity of corpus callosum is essential for the cross-hemispheric propagation of sleep slow waves: a high-density EEG study in split-brain patients

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