Stress and Tinnitus; Transcutaneous Auricular Vagal Nerve Stimulation Attenuates Tinnitus-Triggered Stress Reaction.

TLDR: TRMS is an example of a stress condition in which patients may benefit from taVNS, and as revealed by HRV, test-taVNS improved parasympathetic function, most efficiently in patients with a low starting HRV level.

Abstract: Introduction Tinnitus can become a strong stressor for some individuals, leading to imbalance of the autonomous nervous system with reduction of parasympathetic activity. It can manifest itself as sleep disturbances, anxiety and even depression. This condition can be reversed by bioelectrical vagal nerve stimulation (VNS). Conventional invasive VNS is an approved treatment for epilepsy and depression. Transcutaneous VNS (taVNS) stimulating the auricular branch of the vagus nerve has been shown to activate the vagal pathways similarly as an implanted VNS. Therefore, taVNS might also be a therapeutic alternative in health conditions such as tinnitus-related mental stress (TRMS). This retrospective study in 171 TRMS patients reports the clinical features, psychophysiological characteristics, and results of the heart rate variability (HRV) tests before and after test-taVNS. This study also reports the therapy outcomes of 113 TRMS patients treated with taVNS, in combination with standard tinnitus therapy. Methods Diagnostic tinnitus and hearing profiles were defined. To detect possible cardiac adverse effects, test-taVNS with heart rate monitoring as well as pre- and post-stimulation HRV tests were performed. Daily taVNS home therapy was prescribed thereafter. To assess therapeutic usefulness of taVNS, 1-year follow-up outcome was studied. Results of HRV tests were retrospectively analyzed and correlated to diagnostic data. Results The large majority of patients with TRMS suffer from associated symptoms such as sleep disturbances and anxiety. Baseline HRV data showed that more than three quarters of the 171 patients had increased sympathetic activity before test-taVNS. Test-taVNS shifted mean values of different HRV parameters toward increased parasympathetic activity in about 80% of patients. Test-taVNS did not cause any cardiac or other side effects. No significant adverse effects were reported in follow-up questionnaires. Conclusion TRMS is an example of a stress condition in which patients may benefit from taVNS. As revealed by HRV, test-taVNS improved parasympathetic function, most efficiently in patients with a low starting HRV level. Our tinnitus treatment program, including taVNS, effectively alleviated tinnitus stress and handicap. For wider clinical use, there is a great need for more knowledge about the optimal methodology and parameters of taVNS.

Figures

TABLE 1 | Mean HRV test data of 171 patients with TRMS.

FIGURE 6 | (A) Summary of the hypothesis. Noise exposure (most commonly music) causes dysfunction/damage in the high-frequency (>6.0 kHz) region of the cochlea) in >85% of patients. This leads to high-pitched tinnitus, most commonly at about 8.0 kHz. Bioelectrical impulse flow from the damaged cochlear region toward auditory cortex diminishes or ceases (”dead” region). This leads to reduced (inhibitory) regulation with subsequent neuronal hyperactivity in the central auditory pathway, first in the auditory nuclei of brainstem, later in the auditory cortex. The normal (spontaneous) alpha activity (in EEG) changes to gamma activity. (Continued)

TABLE 2 | Correlations between HRV parameters and scores of sleep and anxiety between age groups.

TABLE 3 | Comparison between taVNS responses and questionnaire-based clinical data in super-responders and non-responders.

FIGURE 6 | (A) Summary of the hypothesis. Noise exposure (most commonly music) causes dysfunction/damage in the high-frequency (>6.0 kHz) region of the cochlea) in >85% of patients. This leads to high-pitched tinnitus, most commonly at about 8.0 kHz. Bioelectrical impulse flow from the damaged cochlear region toward auditory cortex diminishes or ceases (”dead” region). This leads to reduced (inhibitory) regulation with subsequent neuronal hyperactivity in the central auditory pathway, first in the auditory nuclei of brainstem, later in the auditory cortex. The normal (spontaneous) alpha activity (in EEG) changes to gamma activity. (Continued)

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This article has been accepted for publication and undergone full peer review but has not been through the
copyediting, typesetting, pagination and proofreading process, which may lead to differences between this
version and the Version of Record. Please cite this article as doi: 10.1111/aji.13195
This article is protected by copyright. All rights reserved
DR SETH GULLER (Orcid ID : 0000-0003-0651-8241)
PROFESSOR GIL MOR (Orcid ID : 0000-0002-5499-3912)
Article type : Short Communication
Corresponding author mail-id: gil.mor@yale.edu
IL-10 to TNFα ratios throughout early first trimester can discriminate healthy pregnancies
from pregnancy losses
Janina Kaislasuo*
1,2
, Samantha Simpson
1
, Jesper F Petersen
3
, Gang Peng
4
, Paulomi Aldo
1
, Ellen
Lokkegaard
3
, Michale Paidas
5
, Lubna Pal
1
, Seth Guller
1
, Gil Mor
1,6
1
Department of Obstetrics, Gynecology and Reproductive Sciences, Division of Reproductive
Sciences, Yale School of Medicine, New Haven, CT, USA.
2
Department of Obstetrics and
Gynecology, University of Helsinki and the Helsinki University Hospital, Helsinki, Finland.
3
Department of Obstetrics and Gynecology, North Zealand Hospital, Hilleroed, Denmark.
4
Department of Biostatistics, School of Public Health, Yale University, New Haven, CT, USA.
5
Department of Obstetrics, Gynecology and Reproductive Sciences, University of Miami Miller
School of Medicine, Miami, Fl, USA.
6
C.S. Mott Center for Human Growth and Development,
Department of Obstetrics, Gynecology, Wayne State University, Detroit, MI, USA.
*Kaislasuo and Simpson should be considered joint first author
Accepted Article

This article is protected by copyright. All rights reserved
Acknowledgments The authors thank A Cunha and D Leonard for assistance with patient
recruitment and sample collection, and J Shaw and R Cortes and S Nichols-Burns for assistance
with sample processing and storage (Yale University Fertility Center).
Key words (3-8): pregnancy loss, embryo implantation, TNFα, interleukin-10, inflammation,
infertility.
Abstract
Problem: Embryo implantation and placentation require a careful immunological balance. Cytokines
such as IL-10 and TNFα have been implicated as markers of dysregulation, but have only been
studied at a single time point or after a pregnancy lost. Our objective was to determine normative
patterns of serum levels of IL-10 and TNFα and their ratio throughout the first trimester in healthy
pregnancies, and to determine if this pattern differs from pregnancy loss.
Methods: Two prospective longitudinal cohorts of gravidae including in vitro fertilization (IVF) and
naturally conceived pregnancies with serial blood draws. Cytokines were assayed using SimplePlex.
In the IVF cohort we monitored from the implantation day up to 6 weeks of gestation; whereas in the
naturally conceived cohort, sample collection began at 4 weeks and throughout the whole first
trimester.
Results: IL-10 concentrations in normal pregnancies were significantly higher than in pregnancies
ending in a loss starting at 6-8 weeks of gestation while TNFα concentrations were significantly lower
in normal than in pregnancies ending in a loss starting at 3-5 of gestation weeks. The IL-10 to TNFα
ratio in normal pregnancies was significantly higher from 4 to 9 weeks compared to pregnancies that
were lost (t-test, p<0.05). Changes were observed before any symptoms of miscarriage were
present.
Accepted Article

This article is protected by copyright. All rights reserved
Conclusions: We provide evidences of differences in early immunomodulation in healthy pregnancies
versus those destined to end in first trimester loss. The ratio of IL-10 to TNFα rises significantly
higher in viable pregnancies as early as 4.5 weeks compared to pregnancies loss.
STUDY FUNDING/COMPETING INTEREST(S)
The authors received no specific funding for this work and disclose no conflicts of interest
TRIAL REGISTRATION NUMBER
N/A
Accepted Article

This article is protected by copyright. All rights reserved
Introduction
The implantation of a semi-allogenic embryo and its ongoing development requires careful
checks and balances in the maternal immune system. Cellular and humoral immunity are an ongoing
area of study owing to their critical role in normal pregnancy. Alteration of cellular and humoral
immunity might be associated with pregnancy complications, specifically recurrent implantation
failure (RIF) and recurrent pregnancy loss (RPL)
1,2
. Immunologic explanations have also been
implicated as an important reason behind early pregnancy loss in women without this history
3
.
Cytokines and chemokines are a family of secreted immune modulators controlling the
function and differentiation of both immune and non-immune cells. During pregnancy, cytokines and
chemokines have been shown to be critical for the success of implantation, trophoblast invasion, and
immune regulation of the maternal immune system
4-6
. At five days after fertilization, the process of
implantation depends on the preparation of the uterine surface epithelium to allow a dialogue with
and subsequent attachment of the embryonic trophectoderm. The preparation of the epithelium
requires an inflammatory process that removes the mucin layer covering the epithelium, and the
exposure of adhesion molecules that facilitate the attachment of the embryo
7,8
. After attachment, the
blastocyst begins migration into the underlying decidua. This process is tightly regulated by immune
cells present in the decidua, which secrete pro-inflammatory cytokines and chemokines to attract the
blastocyst
8,9
. This presence is critical and depletion of any of the immune cell types has shown to be
detrimental, resulting in fetal loss or impaired growth in animal studies
10
.
Excessive inflammation can also be detrimental
1
. Therefore, the success of implantation and
pregnancy in general depends on the maintenance of a balance between pro-and anti-inflammatory
signals. This balance is defined as the ratio of pro- and anti-inflammatory cytokines, and is a process
regulated by both the maternal local environment and the implanting blastocyst. The blastocyst
secrets immunomodulatory factors to dampen inflammation and gradually switch the environment to
an anti-inflammatory profile as placentation is established
9,11
.
Various cytokines have been examined as markers of immune dysregulation in early
pregnancy loss, with findings of prolonged upregulation of T-helper 1(Th1) mediated pro-
inflammatory responses compared to T-helper 2 (Th2) mediated anti-inflammatory responses being
associated with complications
3,12-14
. Anti-inflammatory Interleukin-10 (IL-10) and pro-inflammatory
Tumor Necrosis Factor alpha (TNFα), both key cytokines in the cascade of immune signaling, have
Accepted Article