Bi-modal stimulation in the treatment of tinnitus: a study protocol for an exploratory trial to optimise stimulation parameters and patient subtyping

Introduction: Tinnitus is the perception of sound in the absence of a corresponding external acoustic stimulus. Bi-modal neuromodulation is emerging as a promising treatment for this condition. The main objectives of this study are to investigate the relevance of inter-stimuli timing and the choice of auditory stimuli for a proprietary bi-modal (auditory and somatosensory) neuromodulation device and to explore whether specific subtypes of patients are differentially responsive to this novel intervention for reducing the symptoms of chronic tinnitus. Methods and analysis: This is a two-site, randomised, triple-blind, exploratory study of a proprietary neuromodulation device with a pre-post and 12-month follow-up design. Three different bi-modal stimulation parameter sets will be examined. The study will enrol 342 patients, split 80:20 between two sites (Dublin, Ireland and Regensburg, Germany), to complete 12 weeks of treatment with the device. Patients will be allocated to one of three arms using a step-wise stratification according to four binary categories: tinnitus tonality, sound level tolerance (using Loudness Discomfort Level of <60 dB SL as an indicator for hyperacusis), hearing thresholds, and presence of a noise-induced audiometric profile. The main indicators of relative clinical efficacy for the three different parameter sets are two patient-reported outcomes measures, the Tinnitus Handicap Inventory and the Tinnitus Functional Index, after 12 weeks of intervention. Clinical efficacy will be further explored in a series of patient subtypes, split by the stratification variables and by presence of a somatic tinnitus. Evidence for sustained effects on the psychological and functional impact of tinnitus will be followed up for 12 months. Safety data will be collected and reported. A number of feasibility measures to inform future trial design include: reasons for exclusion, completeness of data collection, attrition rates, patient’s adherence to the device usage as per manufacturer’s instructions and evaluation of alternative methods for estimating tinnitus impact and tinnitus loudness. Ethics and dissemination: This study protocol is approved by the Tallaght Hospital / St. James’s Hospital Joint Research Ethics Committee in Dublin, Republic of Ireland, and by the Ethics Committee of the University Clinic Regensburg, Germany. Findings will be disseminated to relevant research, clinical, health service and patient communities through publications in peer-reviewed and popular science journals and presentations at scientific and clinical conferences. Trial registration number; the trial is registered on ClinicalTrials.gov (NCT02669069). The sponsor is Neuromod Devices, Dublin, Republic of Ireland. STRENGTHS AND LIMITATIONS OF THIS STUDY • The main strength of this study is that it is a large two-site, triple-blinded, randomised trial that will provide exploratory evidence of the relevance of stimulation parameters on the clinical efficacy of different bi-modal stimulation parameters and will inform future trial design. • The study comprehensively characterises patients for subtyping and this will refine candidature for the intervention. • Among the limitations of this study are the variability in duration between screening and enrolment and the selection of the investigated stimulation parameters. • The online recruitment process may inadvertently introduce participant selection bias

Phase diagram of the lattice SU(2) Higgs model

We perform a detailed study of the phase diagram of the lattice Higgs SU(2) model with fixed Higgs field length. Consistently with previsions based on the Fradkin Shenker theorem we find a first order transition line with an endpoint whose position we determined. The diagram also shows cross-over lines: the cross-over corresponding to the pure SU(2) bulk is also present at nonzero coupling with the Higgs field and merges with the one that continues the line of first order transition beyond the critical endpoint. At high temperature the first order line becomes a crossover, whose position moves by varying the temperature.Comment: 18 pages, 15 figure

Accessing directly the properties of fundamental scalars in the confinement and Higgs phase

The properties of elementary particles are encoded in their respective propagators and interaction vertices. For a SU(2) gauge theory coupled to a doublet of fundamental complex scalars these propagators are determined in both the Higgs phase and the confinement phase and compared to the Yang-Mills case, using lattice gauge theory. Since the propagators are gauge-dependent, this is done in the Landau limit of 't Hooft gauge, permitting to also determine the ghost propagator. It is found that neither the gauge boson nor the scalar differ qualitatively in the different cases. In particular, the gauge boson acquires a screening mass, and the scalar's screening mass is larger than the renormalized mass. Only the ghost propagator shows a significant change. Furthermore, indications are found that the consequences of the residual non-perturbative gauge freedom due to Gribov copies could be different in the confinement and the Higgs phase.Comment: 11 pages, 6 figures, 1 table; v2: one minor error corrected; v3: one appendix on systematic uncertainties added and some minor changes, version to appear in EPJ

Numerical Simulations and the Strength of the Electroweak Phase Transition

Numerical simulations are performed to study the finite temperature phase transition in the SU(2) Higgs model on the lattice. The strength of the first order phase transition is investigated by determining the latent heat and the interface tension on $L_t=2$ lattices. The values of the Higgs boson mass presently chosen are below 50 GeV. Our results are in qualitative agreement with two-loop resummed perturbation theory.Comment: (Only a few minor changes compared to the original version.) 9 pages and 2 figures, DESY-94-08

Anti-Suicidal Efficacy of Repetitive Transcranial Magnetic Stimulation in Depressive Patients: A Retrospective Analysis of a Large Sample

Background: Suicide is a major public health problem. About 90% of suicide victims have one or more major psychiatric disorder, with a reported 20-fold increased risk for suicide in patients with affective disorders in comparison with healthy subjects. Repetitive transcranial magnetic stimulation (rTMS) has been established as an effective alternative or adjunctive treatment option for patients with depressive disorders, but little is known about its effects on suicide risk. Objective: For the assessment of the effectiveness of rTMS on suicidal ideation and behaviors, we performed a retrospective analysis of a large sample of patients with depressive disorders, who were treated with rTMS. Methods: We analyzed the records of 711 TMS in- and out-patients with depressive affective disorders in a tertiary referral hospital between 2002 and 2017. Out of these patients we were able to collect Hamilton depression rating scale (HAMD) data of 332 patients (180 females, 152 males; age range 20 to 79 years; mean age 47.3 ± 12.3) for which we analyzed the change of suicidal ideation by using item 3 (suicidality) of HAMD. Results: Out of all 711 patients treated with rTMS for their depression, one patient (0.1%) committed suicide during the TMS treatment. In the statistical analysis of the subsample with 332 patients there was an overall amelioration of depressive symptoms accompanied by a significant decrease in the suicidality item with a medium effect size. Decrease in suicidality was not inferior to changes in other items as indicated by effect sizes. Forty-seven percent of patients showed an amelioration in suicidality, 41.3% of patients did not show a change in their suicidality’s scores, and 11.7% of patients showed an increase in suicidality’s scores from baseline to final rating. Correlation of item 3 (suicidality) and item 7 (drive) demonstrated a significant positive association, revealing improved drive with a parallel decreased suicidality. Conclusion: Based on the proposed data, there is no evidence that rTMS increases the risk for suicide during the course of the treatment. Conversely, rTMS tends to reduce suicidal ideation. Our findings call for further rTMS controlled studies using large sample sizes and specific suicidality assessment measures to obtain more conclusive results

Emerging pharmacotherapy of tinnitus

Tinnitus, the perception of sound in the absence of an auditory stimulus, is perceived by about 1 in 10 adults, and for at least 1 in 100, tinnitus severely affects their quality of life. Because tinnitus is frequently associated with irritability, agitation, stress, insomnia, anxiety and depression, the social and economic burdens of tinnitus can be enormous. No curative treatments are available. However, tinnitus symptoms can be alleviated to some extent. The most widespread management therapies consist of auditory stimulation and cognitive behavioral treatment, aiming at improving habituation and coping strategies. Available clinical trials vary in methodological rigor and have been performed for a considerable number of different drugs. None of the investigated drugs have demonstrated providing replicable long-term reduction of tinnitus impact in the majority of patients in excess of placebo effects. Accordingly, there are no FDA or European Medicines Agency approved drugs for the treatment of tinnitus. However, in spite of the lack of evidence, a large variety of different compounds are prescribed off-label. Therefore, more effective pharmacotherapies for this huge and still growing market are desperately needed and even a drug that produces only a small but significant effect would have an enormous therapeutic impact. This review describes current and emerging pharmacotherapies with current difficulties and limitations. In addition, it provides an estimate of the tinnitus market. Finally, it describes recent advances in the tinnitus field which may help overcome obstacles faced in the pharmacological treatment of tinnitus. These include incomplete knowledge of tinnitus pathophysiology, lack of well-established animal models, heterogeneity of different forms of tinnitus, difficulties in tinnitus assessment and outcome measurement and variability in clinical trial methodology. © 2009 Informa UK Ltd.Fil: Langguth, Berthold. Universitat Regensburg; AlemaniaFil: Salvi, Richard. State University of New York; Estados UnidosFil: Elgoyhen, Ana Belen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentin

Plasmonic Band Structure Controls Single-Molecule Fluorescence

A chieving a complete manipulation of the generally weak optical signal from a single quantum emitter is a key objective in nanophotonics. To this end, two major routes have been investigated: plasmonic metal nanostructures 1À11 and dielectric photonic crystals. 12À21 Both routes have demonstrated breakthrough results in tailoring the photoluminescence intensity, spectrum, or directionality of single emitters. The plasmonic approach has put the most emphasis on the nanoscale antenna element to control single-emitter radiation 1,2,22À24 via the strong electromagnetic enhancement in the near field of metals. In contrast, the photonic crystal approach centers on the use of coherent scattering to boost the interaction strength of intrinsically weakly scattering building blocks. State-of-the-art structures use thin highindex membranes perforated by nanoapertures, in which the guided modes fold into a complex band structure. Spontaneous emission control then revolves around the targeted coupling of an emitter to select Bloch modes, with well-controlled outcoupling characteristics. Very recently, interest has emerged in the interplay between these two approaches, implying the use of a coherent array of plasmonic resonators to shape the luminescence emission properties. Two key examples are provided on one hand by the use of diffractive modes in 2D arrays of plasmon particles to shape emission of thin emissive layers 10,11,25À27 and on the other hand by the demonstration of YagiÀUda antennas with a single quantum dot emitter in the optical regime, 3 where coherent near -field coupling between scattering nanoparticles is determinant to achieve directional emission. 6 Here, we investigate the emergence of coherent antenna array effects to shape the fluorescence emission of single molecules in finite-sized bidimensional arrays of apertures milled into a metal film that supports surface plasmon guided modes. Transmission properties of quasi-infinite aperture arrays and single holes have been thoroughly investigated in the framework of extraordinary optical transmission. Henzie. Received for review June 28, 2013 and accepted September 10, 2013. Published online 10.1021/nn4033008 ABSTRACT Plasmonics and photonic crystals are two complementary approaches to tailor singleemitter fluorescence, using strong local field enhancements near metals on one hand and spatially extended photonic band structure effects on the other hand. Here, we explore the emergence of spontaneous emission control by finite-sized hexagonal arrays of nanoapertures milled in gold film. We demonstrate that already small lattices enable highly directional and enhanced emission from single fluorescent molecules in the central aperture. Even for clusters just four unit cells across, the directionality is set by the plasmonic crystal band structure, as confirmed by full-wave numerical simulations. This realization of plasmonic phase array antennas driven by single quantum emitters opens a flexible toolbox to engineer fluorescence and its detection

Matching conditions and Higgs mass upper bounds revisited

Matching conditions relate couplings to particle masses. We discuss the importance of one-loop matching conditions in Higgs and top-quark sector as well as the choice of the matching scale. We argue for matching scales $\mu_{0,t} \simeq m_t$ and $\mu_{0,H} \simeq max[ m_t, M_H ]$. Using these results, the two-loop Higgs mass upper bounds are reanalyzed. Previous results for $\Lambda\approx$ few TeV are found to be too stringent. For $\Lambda=10^{19}$ GeV we find $M_H < 180 \pm 4\pm 5$ GeV, the first error indicating the theoretical uncertainty, the second error reflecting the experimental uncertainty due to $m_t=175\pm6$ GeV.Comment: 20 pages, 6 figures; uses epsf and rotate macro