The real-world economic impact of home-based video electroencephalography: the payer perspective.

Aims: Electroencephalography (EEG) is an established method to evaluate and manage epilepsy; video EEG (VEEG) has significantly improved its diagnostic value. This study compared healthcare costs and diagnostic-related outcomes associated with outpatient vs inpatient VEEG among patients with epilepsy in the US. Materials and methods: This study used Truven MarketScan Commercial and Medicare Supplemental claims databases. Patients with a VEEG between July 1, 2013 and December 31, 2016 were identified. Index event was the first VEEG claim, which was used to determine inpatient and outpatient cohorts. Continuous health plan enrollment 6 months pre- and 12 months post-index VEEG was required. Primary outcomes were costs during the index event and 12 months post index. A generalized linear model with gamma distribution and a log link was used to estimate adjusted index and post-index costs. Results: Controlling for baseline differences, epilepsy-related cost of index VEEG was significantly lower for the outpatient ($4,098) vs the inpatient cohort ($13,821; p < 0.0001). The cost differences observed at index were maintained in the post-index period. The 12-month post-index epilepsy-related costs were lower in the outpatient cohort ($6,114 vs $12,733, p < 0.0001). Time from physician referral to index VEEG was significantly shorter in the outpatient cohort (30.6 vs 42.5 days). Patients in the inpatient cohort were also more likely to undergo an additional subsequent follow-up inpatient VEEG (p < 0.0001). Limitations: Administrative claims data have limitations, including lack of data on clinical presentation, disease severity, and comprehensive health plan information. Generalizability may be limited to a US insured population of patients who met study criteria. Conclusions: Index VEEG was less costly in an outpatient vs inpatient cohort, and costs were lower during the follow-up period of 12 months, suggesting that outpatient VEEG can be provided to appropriate patients as a less costly option. There were fewer follow-up tests in the outpatient cohort with similar pre- and post-index diagnoses.

Circadian integration of inflammation and glucocorticoid actions: Implications for the cochlea.

Auditory function has been shown to be influenced by the circadian system. Increasing evidence point towards the regulation of inflammation and glucocorticoid actions by circadian rhythms in the cochlea. Yet, how these three systems (circadian, immune and endocrine) converge to control auditory function remains to be established. Here we review the knowledge on immune and glucocorticoid actions, and how they interact with the circadian and the auditory system, with a particular emphasis on cochlear responses to noise trauma. We propose a multimodal approach to understand the mechanisms of noise-induced hearing loss by integrating the circadian, immune and endocrine systems into the bearings of the cochlea. Considering the well-established positive impact of chronotherapeutic approaches in the treatment of cardiovascular, asthma and cancer, an increased knowledge on the mechanisms where circadian, immune and glucocorticoids meet in the cochlea may improve current treatments against hearing disorders.

Identification of a Circadian Clock in the Inferior Colliculus and Its Dysregulation by Noise Exposure.

UNLABELLED: Circadian rhythms regulate bodily functions within 24 h and long-term disruptions in these rhythms can cause various diseases. Recently, the peripheral auditory organ, the cochlea, has been shown to contain a self-sustained circadian clock that regulates differential sensitivity to noise exposure throughout the day. Animals exposed to noise during the night are more vulnerable than when exposed during the day. However, whether other structures throughout the auditory pathway also possess a circadian clock remains unknown. Here, we focus on the inferior colliculus (IC), which plays an important role in noise-induced pathologies such as tinnitus, hyperacusis, and audiogenic seizures. Using PER2::LUC transgenic mice and real-time bioluminescence recordings, we revealed circadian oscillations of Period 2 protein in IC explants for up to 1 week. Clock genes (Cry1, Bmal1, Per1, Per2, Rev-erbα, and Dbp) displayed circadian molecular oscillations in the IC. Averaged expression levels of early-induced genes and clock genes during 24 h revealed differential responses to day or night noise exposure. Rev-erbα and Dbp genes were affected only by day noise exposure, whereas Per1 and Per2 were affected only by night noise exposure. However, the expression of Bdnf was affected by both day and night noise exposure, suggesting that plastic changes are unlikely to be involved in the differences in day or night noise sensitivity in the IC. These novel findings highlight the importance of circadian responses in the IC and emphasize the importance of circadian mechanisms for understanding central auditory function and disorders. SIGNIFICANCE STATEMENT: Recent findings identified the presence of a circadian clock in the inner ear. Here, we present novel findings that neurons in the inferior colliculus (IC), a central auditory relay structure involved in sound processing, express a circadian clock as evidenced at both the mRNA and protein levels. Using a reporter mouse that expresses a luciferase protein coupled to the core clock protein PERIOD2 (PER2::LUC), we could observe spontaneous circadian oscillations in culture. Furthermore, we reveal that the mRNA profile of clock-related genes in the IC is altered differentially by day or night noise exposure. The identification of a clock in the IC is relevant for understanding the mechanisms underlying dysfunctions of the IC such as tinnitus, hyperacusis, or audiogenic seizures.

TrkB-mediated protection against circadian sensitivity to noise trauma in the murine cochlea.

Noise-induced hearing loss (NIHL) is a debilitating sensory impairment affecting 10%-15% of the population, caused primarily through damage to the sensory hair cells or to the auditory neurons. Once lost, these never regenerate [1], and no effective drugs are available [2, 3]. Emerging evidence points toward an important contribution of synaptic ribbons in the long-term coupling of the inner hair cell and afferent neuron synapse to maintain hearing [4]. Here we show in nocturnal mice that night noise overexposure triggers permanent hearing loss, whereas mice overexposed during the day recover to normal auditory thresholds. In view of this time-dependent sensitivity, we identified a self-sustained circadian rhythm in the isolated cochlea, as evidenced by circadian expression of clock genes and ample PERIOD2::LUCIFERASE oscillations, originating mainly from the primary auditory neurons and hair cells. The transcripts of the otoprotecting brain-derived neurotrophic factor (BDNF) showed higher levels in response to day noise versus night noise, suggesting that BDNF-mediated signaling regulates noise sensitivity throughout the day. Administration of a selective BDNF receptor, tropomyosin-related kinase type B (TrkB), in the night protected the inner hair cell's synaptic ribbons and subsequent full recovery of hearing thresholds after night noise overexposure. The TrkB agonist shifted the phase and boosted the amplitude of circadian rhythms in the isolated cochlea. These findings highlight the coupling of circadian rhythmicity and the TrkB receptor for the successful prevention and treatment of NIHL.

Estradiol treatment and hormonal fluctuations during the estrous cycle modulate the expression of estrogen receptors in the auditory system and the prepulse inhibition of acoustic startle response.

Estrogens' effects on hearing are documented across species, but the responsible molecular mechanisms remain unknown. The presence of estrogen receptors (ER) throughout the auditory system offers a potential pathway of direct estrogenic effects on auditory function, but little is known about how each ER's expression is regulated by the overall hormonal status of the body. In the present study, we determined the effects of ovariectomy and chronic 17ß-estradiol treatment on mRNA and protein expression of ERα and ERß in peripheral (cochlea) and central (inferior colliculus) auditory structures of mice, as well as on auditory-related behavior using the acoustic startle response (ASR), prepulse inhibition (PPI), and habituation of the startle response. 17ß-Estradiol treatment down-regulated ERα but not ERß and increased PPI and latency of the ASR. Neither the magnitude nor the habituation of ASR was affected. Furthermore, ER's mRNA and protein expression in the inner ear were analyzed throughout the estrous cycle (proestrus, estrus, metestrus, and diestrus), revealing a negative correlation of circulating estrogens with ERα expression, whereas ERß was stable. Our findings show that ER not only are present in both the peripheral and central auditory system but also that circulating estrogen levels down-regulate ERα expression in the auditory system and affect PPI and the latency of ASR, suggesting a key role of ERα as a hormone-induced modulator of the auditory system and behavior.

Protecting the auditory system with glucocorticoids.

Glucocorticoids are hormones released following stress-related events and function to maintain homeostasis. Glucocorticoid receptors localize, among others, to hair cells, spiral ligament and spiral ganglion neurons. Glucocorticoid receptor-induced protection against acoustic trauma is found by i) pretreatment with glucocorticoid agonists; ii) acute restraint stress; and iii) sound conditioning. In contrast, glucocorticoid receptor antagonists exacerbate hearing loss. These findings have important clinical significance since synthetic glucocorticoids are commonly used to treat hearing loss. However, this treatment has limited success since hearing improvement is often not maintained once the treatment has ended, a fact that reduces the overall appeal for this treatment. It must be realized that despite the widespread use of glucocorticoids to treat hearing disorders, the molecular mechanisms underlying this treatment are not well characterized. This review will give insight into some physiological and biochemical mechanisms underlying glucocorticoid treatment for preventing hearing loss.

The expression of mitogen-activated protein kinases and brain-derived neurotrophic factor in inferior colliculi after acoustic trauma.

Acoustic trauma is well known to cause peripheral damage with subsequent effects in the central auditory system. The inferior colliculus (IC) is a major auditory center for the integration of ascending and descending information and is involved in noise-induced tinnitus and central hyperactivity. Here we show that the early effects of acoustic trauma, that eventually result in permanent damage to auditory system, lead to a transient activation of BDNF and mitogen-activated protein kinases (MAPK) including extracellular signal-regulated kinase (ERK), c-jun N-terminal kinase (JNK), and p38 in the IC. In contrast, the early effects of acoustic trauma that result in a temporary damage produced a reversible activation only of p38. The transient activation of MAPK and BDNF in the IC after permanent acoustic trauma is attributed to the plastic changes triggered by a decreased signal input from the damaged periphery. The pattern of MAPK and BDNF activation in the IC is different from that previously described for the cochlea from this laboratory. The differences in the pattern of MAPK and BDNF expression in the IC highlight unique molecular mechanisms underlying temporary and permanent acoustic damage to the central auditory system.

Glucocorticoid receptor and mitogen-activated protein kinase activity after restraint stress and acoustic trauma.

Restraint stress (RS) protects auditory function against acoustic trauma by activating glucocorticoid receptors (GR) in the cochlea. In a search for the signaling pathways downstream to GR that may be involved in RS-induced protection we report here (1) a downregulation of phosphorylated extracellular signal-regulated kinases 1 and 2 (pERK 1/2) after the combined treatment of RS and acoustic trauma; (2) activation of phospho-p38 in the auditory nerve after RS; (3) the abolition of these two effects by pretreatment with metyrapone (an inhibitor of corticosterone synthesis) and RU486 (a GR antagonist); and (4) no activation of c-jun-N-terminal kinases 1 and 2 (JNK 1/2), ERK, or p38 after acoustic trauma alone. Thus we demonstrate a GR-dependent ERK-mediated pathway that modulates auditory function after RS and acoustic trauma. These findings reveal new mechanisms that underlie hearing loss and will have implications for the development of pharmacological strategies for protecting against acoustic trauma.

Functional responses of estrogen receptors in the male and female auditory system.

Recently significant progress was made in understanding the mechanisms by which the two estrogen receptors (alpha and beta) are involved in different pathways of estrogen action in a wide variance of tissues. Divergent responses of cells and tissues to estrogens or their ligands have been attributed to various isoforms and signaling pathways of estrogen receptors. Both subtypes of estrogen receptors have been identified in the cochlea and there are indications that they have neuroprotective effects but there is still limited information on the role and specific mechanisms of these two receptors in the auditory system. This review will examine the molecular and functional actions of the two estrogen receptor subtypes, the pivotal role they play in the auditory system and their therapeutic strategies for protecting against hearing loss.

Estrogen receptor beta protects against acoustic trauma in mice.

The hormone estradiol affects the auditory system both by itself and by its interaction with neuroprotective factors. In this study, we examined the role of estrogen receptors (ERs) in response to auditory trauma. We found a ligand-dependent protective role for ERbeta in the auditory system by investigating mice deficient in ERalpha (ERKO mice), ERbeta (BERKO mice), and aromatase (ARKO mice). Basal auditory brainstem response (ABR) thresholds were similar in all animals. An acoustic trauma causing a temporary hearing loss raised ABR thresholds in male and female BERKO and ARKO mice compared with WT and ERKO mice. The ERalpha-selective agonist, propyl(1H) pyrazole-1,3,5-triyl-trisphenol (PPT), partially protected ARKO mice from trauma, while the ERbeta-selective agonist, 2,3-bis (4-hydroxyphenyl)-propionitrile (DPN), protected WT and ARKO mice. Immunohistochemistry and western blotting confirmed the expression of ERbeta in cochlea of WT males and females. Levels of brain-derived neurotrophic factor (BDNF), a neuroprotective peptide that can be induced by estrogen, was lower in BERKO and ARKO mice compared with WT. DPN treatment increased BDNF expression in ARKO mice. These data indicate ERbeta-mediated neuroprotection involving BDNF in the auditory system of males and females.

Glucocorticoid receptors modulate auditory sensitivity to acoustic trauma.

Glucocorticoids are widely used to treat different hearing disorders yet the exact mechanisms of glucocorticoid action on the inner ear are not known. The inner ear of both humans and experimental animals demonstrate an abundance of glucocorticoid receptors (GRs) in both neuronal and non-neuronal tissues. In this review, we discuss how activation of the hypothalamic-pituitary-adrenal axis can directly modulate hearing sensitivity. Recent findings indicate that several factors define the responsiveness of the peripheral auditory system to glucocorticoids including the concentration of agonist, availability of the GR, and the activation of GR and NF-kappaB. These findings will further our understanding of individual glucocorticoid responsiveness to steroid treatment, and will help improve the development of pharmaceuticals to selectively target GR in the inner ear for individuals with increased sensitivity to acoustic trauma.

Sound conditioning protects hearing by activating the hypothalamic-pituitary-adrenal axis.

Sound conditioning primes the auditory system to low levels of acoustic stimuli and reduces damage caused by a subsequent acoustic trauma. This priming activates the HPA axis resulting in the elevation of plasma corticosterone with a consequent upregulation of glucocorticoid receptors (GR) in the cochlea and the paraventricular nucleus (PVN) of the hypothalamus in the mouse. This protective effect is blocked by adrenalectomy or pharmacological treatment with RU486 + metyrapone. Sound conditioning prevents GR down-regulation induced by acoustic trauma and subsequently enhances GR activity in spiral ganglion neurons. Increased SRC-1 expression, triggered by sound conditioning, positively correlates with the upregulation of GR in the cochlea. These findings will help to define the cellular mechanisms responsible for protecting the auditory system from hearing loss by sound conditioning.

Glucocorticoid receptor and nuclear factor-kappa B interactions in restraint stress-mediated protection against acoustic trauma.

The role of glucocorticoid receptors (GRs) in the protective effect of restraint stress (RS) before acoustic trauma was studied in spiral ganglion neurons of CBA mice. RS increased corticosterone and protected against elevated auditory brain stem thresholds caused by acoustic trauma. This protection was inhibited by the pretreatment with a corticosterone synthesis inhibitor, metyrapone (MET), and a GR antagonist (RU486). RS followed by acoustic trauma caused an immediate increase in corticosterone that triggered nuclear translocation of GR, without a change in the expression of GR protein. RU486 + MET before RS and acoustic trauma caused an immediate increase in GR mRNA followed by increased GR protein expression (24 h after trauma). GR signaling was further characterized by analyzing nuclear factor-kappaB (NF kappaB) nuclear translocation and protein expression. NF kappaB nuclear translocation was reduced after acoustic trauma or pretreatment with RU486 + MET before RS and acoustic trauma. On the contrary, RS protected against the trauma-induced NF kappaB reduction of its nuclear translocation in inhibitory-kappaB (I kappaB)-dependent manner. RU486 + MET caused a simultaneous decreased I kappaB expression and NF kappaB nuclear translocation, demonstrating an interference with the I kappaB-mediated activation of NF kappaB. In summary, RS protects the cochlea from acoustic trauma by increasing corticosterone and activating GRs. These results emphasis how GR activity modulates hearing sensitivity and its importance for the rationale use of glucocorticoids in inner ear diseases.

Restraint stress modulates glucocorticoid receptors and nuclear factor kappa B in the cochlea.

The regulation of glucocorticoid receptors and nuclear factor kappaB was evaluated in the spiral ganglion neurons after 4 h of restraint stress in the mouse cochlea. Immediately after restraint stress, glucocorticoid receptor protein expression was not altered in spiral ganglion neurons even though both the plasma corticosterone levels and glucocorticoid receptor nuclear translocation increased. By 24 h after restraint stress, the protein expression of glucocorticoid receptors was decreased in spiral ganglion neurons. Pre-treatment with RU486 and metyrapone prevented nuclear translocation of glucocorticoid receptors and nuclear factor kappaB. Moreover, the synthesis of nuclear factor kappaB protein (p65) and inhibitory factor kappaBalpha decreased when RU486 and metyrapone treatment was given before restraint stress. These findings suggest that restraint stress modulates glucocorticoid receptor and nuclear factor kappaB activity in the spiral ganglion neurons, resulting in an altered response to stress.

NF-kappaB mediated glucocorticoid response in the inner ear after acoustic trauma.

The inner ear of humans and experimental animals demonstrate an abundance of glucocorticoid receptors (GR). Glucocorticoids (GC) are widely used to treat different hearing disorders; yet the mechanisms of GC action on the inner ear are unknown. We demonstrate how GR can directly modulate hearing sensitivity in response to a moderate acoustic trauma that results in a hearing loss (10-30 dB). The GC agonist (dexamethasone) and the drugs (metyrapone + RU 486) showed opposing effects on hearing threshold shifts. GC agonist (dexamethasone) decreased the hearing threshold whereas pre-treatment with a GC synthesis inhibitor (metyrapone) in combination with a GR antagonist (RU 486) exacerbated auditory threshold shifts (25-60 dB) after acoustic trauma with statistically significant increase in GR mRNA and GR protein compared with the vehicle and acoustic trauma group. Acoustic trauma caused a significant increase in the nuclear transport of NF-kappaB, whereas pre-treatment with the drugs (metyrapone and RU 486) blocked NF-kappaB nuclear transport into spiral ganglion nuclei. An NF-kappaB inhibitor, pyrrolidine dithiocarbamate ammonium blocked the trauma-induced translocation of NF-kappaB and resulted in a hearing loss (45-60) dB. These results indicate that several factors define the responsiveness of the inner ear to GC, including the availability of ligand or receptor, and the nuclear translocation of GR and NF-kappaB. These findings will further our understanding of individual GC responsiveness to steroid treatment, and will help improve the development of pharmaceuticals to selectively target GR in the inner ear for individuals with increased sensitivity to acoustic trauma.