Effects of Sound Interventions on the Permeability of the Blood–Brain Barrier and Meningeal Lymphatic Clearance

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Effects of Sound Interventions on the Permeability of the Blood–Brain Barrier and Meningeal Lymphatic Clearance 

by

Sean Sachdeva

¹,

Sushmita Persaud

¹,

Milani Patel

¹,

Peyton Popard

¹,

Aaron Colverson

² and

Sylvain Doré

^1,3,*

¹

Department of Anesthesiology, Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, FL 32610, USA

²

Musicology/Ethnomusicology Program, School of Music, College of the Arts, University of Florida, Gainesville, FL 32603, USA

³

Departments of Pharmaceutics, Psychology, and Neuroscience, McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL 32610, USA

^*

Author to whom correspondence should be addressed.

Brain Sci. 2022, 12(6), 742; https://doi.org/10.3390/brainsci12060742

Received: 2 March 2022 / Revised: 28 May 2022 / Accepted: 31 May 2022 / Published: 5 June 2022

(This article belongs to the Section Neurosurgery and Neuroanatomy)

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Abstract

The meningeal lymphatic, or glymphatic, system is receiving increasing attention from the scientific community. Recent work includes noninvasive techniques to demonstrate relationships between blood–brain barrier (BBB) activity and the glymphatic system in the human central nervous system. One potential technique is the use of music/sound to enhance BBB permeability regarding the movement of small molecules in and out of the brain. However, there is minimal knowledge regarding the methodical investigation(s) of the uses of music/sound on BBB permeability and glymphatic clearance and the outcomes of these investigation(s). This review contains evidence discussing relationships between music/sound, BBB permeability, and meningeal lymphatic clearance. An overview of the anatomy and physiology of the system is presented. We discuss the uses of music/sound to modulate brain and body functions, highlighting music’s effects on mood and autonomic, cognitive, and neuronal function. We also propose implications for follow-up work. The results showed that music and sound interventions do, in fact, contribute to the opening of the BBB and subsequently increase the function of the meningeal lymphatic system. Evidence also suggests that music/sound has the ability to reduce the collateral effects of brain injuries. Unfortunately, music/sound is rarely used in the clinical setting as a medical intervention. Still, recent research shows the potential positive impacts that music/sound could have on various organ systems.

Keywords:

elimination; glymphatic system; meninges; music; noise; opening

1. Introduction

The glymphatic system was discovered relatively recently; however, the existence of the lymphatic system/vessels has been known for centuries. Re-discoveries of different portions of the system since the 1950s have led researchers to identify the overall role of the lymphatic pathway. This pathway serves as a connection between the interstitial space and the peripheral tissues; it was soon determined that this connection allowed molecules to drain from cells of vital organs throughout the body [1,2]. In the past decade, researchers characterized a waste clearance system that relies on perivascular channels sourced from astroglial cells in the brain, allowing metabolites and soluble proteins to be eliminated from the central nervous system [3]. This pathway was categorized as the glymphatic system because of its association with the brain’s glial cells and brain meninges. In addition to waste clearance, the glymphatic system diffuses crucial molecules such as glucose, neurotransmitters, lipids, and amino acids throughout the brain [3]. This is visualized in Figure 1, in which the pathway of waste metabolites is shown in terms of the anatomical view of the glymphatic/meningeal lymphatic system (MLS). Of interest, its flow or pulse wave appears to be activated during regular sleep patterns. For example, various theories have been proposed to better understand and accelerate the clearance of these toxic Aβ splicing fragments from the brain [3]. The glymphatic system exists in the perivascular space and is now considered to contribute to approximately 60% of the brain’s Aβ drainage to the cervical lymph nodes and further downstream [4]. However, because of new technologies, this is being rigorously re-evaluated and independently validated; much remains unknown.

Figure 1. Glymphatic/Meningeal Lymphatic System Process. Illustration of the glymphatic/meningeal lymphatic system in terms of the cerebrospinal fluid (CSF) and the movement of solutes in and out of the brain. An expanded view is provided to allow for a better understanding of the process involved with the meningeal lymphatic vessels in reference to the blood–brain barrier and the flow of CSF. (A) Music/sound exposure in the scope of brain structure in terms of the CSF as paravascular influx is involved in the meningeal lymphatic system exchange from arteries to veins. A deep cervical lymph node representation is shown in which meningeal lymphatic vessels originate from within the neck. Nodes are involved with waste elimination based on lymph flow and perivenous efflux pathways. (B) A zoomed-in representation of brain meninges in which the meningeal lymphatic vessels are located in the subarachnoid space containing the CSF. A clear separation of meningeal lymphatic anatomy and its process is depicted compared to its counterpart, the glymphatic system residing in vessels in the brain tissue, as shown in panel C. (C) A zoomed-in representation of the glymphatic system based on the perivascular space in brain tissue. Brain circulation in terms of periarterial influx and perivenous efflux provides a pathway for solute waste clearance. The pia mater layer is tied with astrocytes and aquaporin-4 channels (AQP4). CSF influx through periarterial space into arteries allows AQP4 water pump function to drive CSF/interstitial fluid (ISF) exchange within the brain parenchyma. The convective flow of CSF/ISF exchange drives interstitial solutes through opposite AQP4 channels and through paravenous spaces into venous vessels as efflux essentially clears solutes/waste from the brain.

1.1. Music and Body and Brain Function Health

Music is receiving increasing attention for its beneficial effects on a variety of health outcomes. One area of recent attention is severe mental illness [5]. Golden and colleagues conducted a global scoping review of evidence on the uses of music to treat or mitigate symptoms of severe mental illness. Their results point to the significant benefits of using music to manage symptoms of major mental disorders, with over two-thirds of included studies reporting positive effects. The study, however, concluded that the heterogeneity of the study design limited the replicability and transferability of the findings to various populations of interest, and the authors provided five recommendations for follow-up work [5]. A separate study examined the effects of music on preoperative anxiety and incorporated 26 trials (2051 participants). Music exposure resulted in an average reduction in anxiety by 5.72 units of measure compared to the standard control group [6]. Studies examining the effects of music on anxiety reduction in patients with coronary heart disease have reported similar results [6]. Similar decreases have also been reported in mechanically ventilated patients [7] and cancer patients [8]. Music, in this instance, can function similarly to anxiety-reducing medications, indicating the need for research on how music can affect the brain in terms of nervous system function and response.

1.2. Music and Autonomic Function

There is substantial research on the effects of music on autonomic nervous system (ANS) activity. The ANS is the main driving force in regulating homeostasis and adaptation of the body based on external circumstances. Incorporating music can have positive effects that have yet to be explored. Extensive research has shown that music affects physiological variables associated with blood pressure, heart rate, respiratory rate, body temperature, and various biochemical parameters. In addition to these findings, similar effects have been reported for the cardiac ANS. Music stimulus increases parasympathetic activity associated with increased heart rate variability, which is the variation of time intervals between successive heartbeats [9]. Across 29 studies with varying populations and music therapies, all but three groups showed initial results of a positive impact of music on heart rate variability (p = 0.05). Thus, data in this specific field are consistent and could form a foundation for researching the effects of music on the glymphatic system.

1.3. Music and Cognitive Function

Research shows positive effects of engagement with music and healthy cognitive function. For example, one study showed that music improvisation significantly improved memory [10]. One hundred and thirty-two individuals aged 60 to 90 years old participated in the study, 51 of whom were musicians who had 5 or more years of formal music training. After acquiring neural or emotional information, the experimental and control groups were exposed to music imitation or improvisation. Memory was evaluated based on free recall and recognition using immediate and deferred measurements. The results suggested that a focal musical activity can help enhance memory in older adults. In addition, other studies have shown that listening to music advances cognitive skills such as recognition memory [11], working memory [12], and fluency [13]. Furthermore, another study found an effect of musical training on verbal memory and visual memory in older adults [14]. The study consisted of 24 people, with a median age of 77 years and 3 months. Participants were randomly assigned to music, literature, or untrained groups. The musically trained individuals remembered more words from a list than both control groups, along with symbol sequences. However, this study did not coincide with the influence of music training on working memory.

Previous studies have shown a relationship between music training and central executive processing [15]. Bugos (2019) examined the effects of bimanual coordination in piano performance on cognitive performance in healthy older adults. The study was composed of 135 healthy older adults between the ages of 60 and 80 years who experienced music training interventions. Participants were evaluated using the Wechsler Abbreviated Scale of Intelligence, and their Verbal Intelligence Quotient was measured. In addition, the Advanced Measures of Music Audiation aptitude test was completed to measure musical aptitude. The results suggested that dynamic music performance can benefit working memory, and the extent of the benefit relies on coordination demands. Specifically, the Group Piano Instruction (GPI) and Group Percussion Instruction (GPeI) groups had significantly enhanced performance in visual scanning and working memory compared to the Music Listening Instruction (MLI) group. The GPI group also had an increased processing speed.

1.4. Music and Neuronal Function/Health

The existing experimental literature demonstrates that music substantially affects neuronal function and body health. Exposure to learning music enhances specific brain areas, such as the premotor and cerebral cortex, cerebellum, and left Heschl’s gyrus [16]. Heschl’s gyrus is the human primary auditory cortex and an area of acoustic processing. Findings suggest that professional musicians have greater gray matter volume than non-musicians in Heschl’s gyrus [16]. By studying exposure to music in Heschl’s gyrus, new insight may be provided into how music can affect secondary structures. An example is how exposure to music could decrease blood pressure via dynamic interactions between calcium-dependent dopamine synthesis and calmodulin [17]. Music exposure has been shown to positively affect the body by stimulating the development of axonal and dendritic growth and regulating blood pressure.

1.5. Relationships between Music, Body/Brain, and Glymphatic Clearance

The relationship between music/sound and glymphatic clearance has seldom been studied because of its novelty. Figure 2 demonstrates the potential overall outcomes of music/sound on the MLS. However, music/sound has the potential effect of permeating the BBB, allowing specific solutes to pass into the brain at a more efficient rate and reach the intended tissue. This passage creates optimal results with a lower dose of medication in a shorter amount of time. Sound-based interventions, specifically ultrasound, have proved successful in increasing the permeability of the blood–brain vasculature. This is because the pores and intracellular gaps within the BBB endothelium are highly dependent on acoustic pressure [18].

Figure 2. Relationship between music/sound exposure on meningeal lymphatic system/glymphatic system and blood–brain barrier function. The illustration depicts important outcomes that arise from music/sound exposure on the meningeal lymphatic/glymphatic system. The bullets emphasize the main points of these studies and this review.

An example of how music/sound affects the permeability of the BBB is reported by Semyachkina-Glushkovskaya et al. [19]. Upon intravenously injecting Evans blue (EB) dye into mice, audible sound exposure was applied at 100 dB and 370 Hz. Leakage of the EB through the BBB increased 19.7-fold compared to the group with no exposure to sound (p < 0.05). EB is a common macromolecule used to analyze the permeability of the BBB. Because of the dye’s high affinity to serum albumin, essentially all EB is bound to albumin, which does not readily cross the BBB. In a usual permeability scenario, the neural tissue will remain unstained with EB bound to albumin; however, with compromised permeability of the BBB, EB is found in the brain tissue. In terms of fluorescein isothiocyanate (FITC)-dextran, its reaction with primary amines allows it to readily cross the BBB. It is also helpful in analyzing the extravasation of neurological pathways.

Another study exposed mice to Scorpions’ “Still Loving You” at 100 dB [20]. One hour after music exposure, BBB permeability increased 17.3-fold. Importantly, however, this permeability increase was induced only at 90-dB and 100-dB sound levels. The experimental group exposed to music at 70 dB experienced the same rise in BBB permeability as controls.