TNF-α Treatment of Blast-Induced Tinnitus

Portland VA Medical Center, University of Miami, United States Naval Medical Center, San Diego, Michigan Ear Institute

This study evaluates the therapeutic effects of Etanercept (Enbrel) on the treatment of blast/noise induced tinnitus in adults. Half of the participants will receive 2 x 25mg/ Entanercept injections, and the other half will receive placebo injections.

The primary objectives are to test if: 1) Etanercept significantly reduces tinnitus distress as measured by Tinnitus Functional Index (TFI); and 2) Etanercept improves hearing. In addition, the investigators will test if: 1) Etanercept treatment leads to sustained therapeutic effects over time; The secondary objective is to test if: 1) Etanercept reduces tinnitus loudness measured by visual numeric scale (VNS) rating.

Subjects with tinnitus associated with blast and/or noise exposure will receive 12 consecutive weekly treatments of Etanercept. Tinnitus Functional Index (TFI) questionnaire will be administered at baseline, and weeks 1, 4, 8 and 12, with the primary end point at 12 weeks. Following the 12 weeks of Etanercept treatment, each subject will undergo post-treatment outcome assessments at 4, 8, 12 and 24 weeks after the final administration of Etanercept, this will be the same as study schedule week 16, 20, 24 and 36 respectively. A seven-point decrease on the TFI score will be considered clinically significant. Scores range from 0 to 100; A higher score means more severe and a lower score means less severe in tinnitus. Mean score of 21 (range 18-31) small problem. Mean score of42 (range 32-53) moderate problem. Mean score of 65 (range 54-72) big problem. Mean score of 78 (range 73-100) very big problem.

Subjects with tinnitus associated with blast and/or noise exposure will receive 12 consecutive weekly treatments of Etanercept. Tinnitus Functional Index (TFI) questionnaire will be administered at baseline, and weeks 12, with the primary end point at 12 weeks. Following the 12 weeks of Etanercept treatment, each subject will undergo post-treatment outcome assessments at 12 and 24 weeks after the final administration of Etanercept, this will be the same as study schedule week 24 and 36 respectively. Scores range from 0 to 100; A higher score means more severe and a lower score means less severe in tinnitus. Mean score of 21 (range 18-31) small problem. Mean score of42 (range 32-53) moderate problem. Mean score of 65 (range 54-72) big problem. Mean score of 78 (range 73-100) very big problem. A 13% decrease on the TPF will be considered clinically significant.

Pure tone audiometric air conduction testing is performed by presenting a pure tone to the ear through an earphone and measuring the lowest intensity in decibels (dB) at which this tone is perceived 50% of the time. This measurement is called threshold. The testing procedure is repeated at specific frequencies from 150 to 8000 hertz (Hz, or cycles per second) for each ear, and the thresholds are recorded on a graph called an audiogram. It ranges from 0 to 110 dB Hearing Level. The lower dB level, the better hearing sensitivity is. Subjects with tinnitus will receive 12 consecutive weekly treatments of Etanercept. Tpure-tone audiometric threshold will be tested at baseline, and weeks nd weeks 1, 4, 8 and 12, with the primary end point at 12 weeks. Following the 12 weeks of Etanercept treatment, each subject will undergo post-treatment outcome assessments at 12 20, 24 and 36 weeks after the final administration ofEtanercept.

Subjects with tinnitus associated with blast and/or noise exposure will receive 12 consecutive weekly treatments of Etanercept. Visual Numerical Scale (VNS) for self-rated tinnitus loudness. On the scale of 0-10, a subject is required to rate the loudness of his/her tinnitus. 0 means no tinnitus and 10 as very loud tinnitus. A score of at least 5 out of 10 for tinnitus loudness is required for participation in the study VNS questionnaire will be administered at baseline, and weeks 1, 4, 8 and 12, with the primary end point at 12 weeks. Following the 12 weeks of Etanercept treatment, each subject will undergo post-treatment outcome assessments at 4, 8, 12 and 24 weeks after the final administration of Etanercept, this will be the same as study schedule week 16, 20, 24 and 36 respectively.

The word recognition score (WRS) test requires a list of single syllable words unknown to the patient to be presented at the speech recognition threshold. The number of correct words is scored out of the number of presented words to give the WRS. The range of the score is 0-100%, with 0% is the worst and 100% is the best. WRS will be administered at baseline, and weeks 12. Following the 12 weeks of Etanercept treatment, each subject will undergo post-treatment outcome assessments at 24 weeks after the final administration of Etanercept.

Hospital Anxiety and Depression Scale (HADS) is used to determine the levels of anxiety and depression that a person is experiencing. The HADS is a fourteen item scale that generates ordinal data. Seven of the items relate to anxiety and seven relate to depression. HADS will be administered at baseline, and weeks12. Following the 12 weeks of Etanercept treatment, each subject will undergo post-treatment outcome assessments at 24 and 36 weeks after the final administration of Etanercept. Each item on the questionnaire is scored from 0-3 and this means that a person can score between 0 and 21 for either anxiety or depression. A cut-off point for anxiety or depression is f 8/21.

This test involves going into a sound booth and having foam earphones inserted into ear canals by the audiologist. The audiologist will then play a 1 kHz pure-tone presented to the ear contralateral to the side of the tinnitus perception. In cases of bilateral tinnitus that does not lateralize to one side or is perceived "in the head" the contralateral ear will be selected based on whichever ear has the better pure-tone hearing threshold at 1 kHz. The goal is to find the intensity level of a 1 kHz pure-tone that best matches the loudness of his/her tinnitus. This test will be conducted at Baseline and during the treatment phase at weeks 1, 4, 8, and 12 and also during the post-treatment follow-up phase at 16, 20, 24 and 36 weeks. Tinnitus is usually matched in loudness by a sound with a low Sensation Level, typically in the range 0-30+ dB SL, with 0 dB SL repressing soft and 30+ dB SL as loud tinnitus.

After obtaining the 1 kHz tinnitus loudness match, the audiologist will obtain hearing thresholds for a band of noise for each ear separately. Next, the noise will be presented at the same sensation level binaurally until the participant states the tinnitus is completely or partially masked. The goal is for a subject to tell the audiologist the softest intensity level of noise that will cover (or "mask") the sound of the subject's tinnitus. This test will be conducted at Baseline and during the treatment phase at weeks 1, 4, 8, and 12 and also during the post-treatment follow-up phase at 16, 20, 24 and 36 weeks. During administration of MML, increase the level of the masking noise gradually in 1 dB steps until the tinnitus is no longer detectable in that ear. MML is expressed in dB Sensation Level (SL), relative to the Masking Noise Threshold. In most cases the MML ranges from 2 to 30+ dB SL, with a smaller number indicating soft loudness.

Exploratory Aim Identify contributing factors that influence the therapeutic effects of Etanercept on blast-induced tinnitus - Age

Conduct exploratory investigations to if AGE influences the therapeutic effects of Etanercept on blast-induced tinnitus, and leads lead to subgrouping of subjects.

Exploratory Aim Identify contributing factors that influence the therapeutic effects of Etanercept on blast-induced tinnitus - Hearing sensitivity

Conduct exploratory investigations to if "Hearing sensitivity" influences the therapeutic effects of Etanercept on blast-induced tinnitus, and leads lead to subgrouping of subjects.

Exploratory Aim Identify contributing factors that influence the therapeutic effects of Etanercept on blast-induced tinnitus - History of noise exposure, which can be captured with questionnaires

Conduct exploratory investigations to if "History of noise exposure, which can be captured with questionnaires" influences the therapeutic effects of Etanercept on blast-induced tinnitus, and leads lead to subgrouping of subjects.

Exploratory Aim Identify contributing factors that influence the therapeutic effects of Etanercept on blast-induced tinnitus - Time since blast exposure (and number of blast exposures)

Conduct exploratory investigations to if "Time since tinnitus started (tinnitus duration)" influences the therapeutic effects of Etanercept on blast-induced tinnitus, and leads lead to subgrouping of subjects.

Exploratory Aim Identify contributing factors that influence the therapeutic effects of Etanercept on blast-induced tinnitus - Time since military service ended

Conduct exploratory investigations to if "Time since military service ended" influences the therapeutic effects of Etanercept on blast-induced tinnitus, and leads lead to subgrouping of subjects.

Exploratory Aim Identify contributing factors that influence the therapeutic effects of Etanercept on blast-induced tinnitus - History of traumatic brain injury (TBI)

Conduct exploratory investigations to if "History of traumatic brain injury (TBI)" influences the therapeutic effects of Etanercept on blast-induced tinnitus, and leads lead to subgrouping of subjects.

Inclusion Criteria: Tinnitus of at least a moderate severity as defined by a score of ≥ 25 points or higher on the Tinnitus Functional Index (TFI) questionnaire associated with one or more of the following: Blast or noise exposure Traumatic brain injury (TBI) and/or concussion diagnosed by a health care provider. Able to provide written informed consent. Age: Minimum 18 years of age at the time of enrollment. Other concurrent treatments: A four-week washout from any other tinnitus treatment or management program is required prior to entering this study. Psychological status: Stable enough to complete this study per the opinion of the research team. Hearing function: All degrees of hearing function can be included, recognizing that individuals with profound, bilateral hearing loss will not be able to perform tinnitus evaluations and hearing tests but will be able to rate subjective tinnitus loudness, annoyance and impact on life. This is an important sub-population because of the challenges in treating them with acoustic therapy and the need for a medical intervention. Additional tinnitus characteristics: a) Tinnitus history: Onset associated with blast and/or noise exposure or associated with diagnosed TBI and/or concussion. Subjects will have blast exposure, noise exposure, traumatic brain injury (TBI), and/or concussion impact, defined as exposure/impact less than or longer than six months at time of enrollment. (i) Participants enrolled with tinnitus associated with TBI and/or concussion must have received a diagnosis of TBI and/or concussion by a health care provider. b) Stability: Constant (not pulsatile, intermittent, varying to a high degree in loudness or changing in location of perception). Fluctuating tinnitus reduces the reliability of test-retest measures for loudness. c) Location of tinnitus perception: Unrestricted. Tinnitus may be unilateral, bilateral, or perceived in the head. Exclusion Criteria: History or evidence of significant brain malformation, cerebral vascular events (such as strokes), neurodegenerative disorders affecting the brain (such as Parkinson's disease, ALS, Huntington's disease or Multiple sclerosis), or prior brain surgery. History of Guillain-Barré syndrome. Active neoplasm such as lymphoma or solid tumors. History of neoplasm, excluding successfully treated squamous cell carcinoma or basal carcinoma of the skin or cervical cancer. Diagnosis of congestive heart failure. History of seizures or epileptic activity. Subjects with cardiac pace makers, other electronic implants (including cochlear implants), or intracranial or intraocular metallic particles. Subjects who currently have an active infection, including tuberculosis, HIV, hepatitis B, and/or chicken pox. Scheduled to receive a live vaccine during study participation or received a live vaccine within 2 weeks prior to screening visit/procedures. Diagnosis of active neurologic disease, auto-immune disease, diabetes, or a weak immune system. For the purposes of this protocol, "active neurologic disease" is defined as multiple sclerosis or any other disease involving demyelination disorder or any finding suggesting a demyelination disease or disorder. Migraines/migraine headaches are not a condition that would exclude a potential patient from participation in the study unless associated with a demyelination disease or disorder. Autoimmune thyroid disease is not considered an exclusionary autoimmune disease for participation in this study. Ongoing treatment with one of the following contraindicated medications: abatacept or any other biologic therapy, cyclophosphamide or sulfasalazine. Subjects who cannot communicate reliably with research team members or who are not likely to cope with the requirements of the trial. Subjects who have participated in a drug clinical trial within the last 30 days before the start of this one. Current substance abuse (defined as a score of 2 or greater on the CAGE Substance Abuse Screening Tool). Pregnancy or planned pregnancy during the study. Women who are lactating or are of child-bearing-age without use of contraception. Participation in greater than two previous clinical drug-trials for tinnitus. MMSE score < 24. Clinically significant out of range laboratory values (contact medical monitor to discuss).

In cases where the human subject could possibly benefit medically or otherwise from the information, explain whether or not the results of screening and/or study participation will be shared with human subjects or their primary care provider, to include results from any screening or diagnostic tests performed as part of the study. The PI plans to disseminate abstracts in National and International Conferences, and the PI plans to publish manuscripts in peer-reviewed journals (national and international) to share the knowledge obtained from the study's data with the research team of this study. Any research team member planning to disseminate results from this study needs the permission of the PI and must follow FDA guidelines.Additionally, data collected during the proposed study period will be shared with the NIH, the Department of Veterans Affairs, the National Science Foundation, and the Department of Health Human.

Meikle MB, Henry JA, Griest SE, Stewart BJ, Abrams HB, McArdle R, Myers PJ, Newman CW, Sandridge S, Turk DC, Folmer RL, Frederick EJ, House JW, Jacobson GP, Kinney SE, Martin WH, Nagler SM, Reich GE, Searchfield G, Sweetow R, Vernon JA. The tinnitus functional index: development of a new clinical measure for chronic, intrusive tinnitus. Ear Hear. 2012 Mar-Apr;33(2):153-76. doi: 10.1097/AUD.0b013e31822f67c0. Erratum In: Ear Hear. 2012 May;33(3):443.

Lew HL, Jerger JF, Guillory SB, Henry JA. Auditory dysfunction in traumatic brain injury. J Rehabil Res Dev. 2007;44(7):921-8. doi: 10.1682/jrrd.2007.09.0140.

VBA. VA Annual Benefits Report: Fiscal Year 2012. In: VA US, ed. 810 Vermont Avenue N. W. , Washington, D.C., 20420: Veterans Benefits Administration, 2013:82.

Hesser H, Westin V, Hayes SC, Andersson G. Clients' in-session acceptance and cognitive defusion behaviors in acceptance-based treatment of tinnitus distress. Behav Res Ther. 2009 Jun;47(6):523-8. doi: 10.1016/j.brat.2009.02.002. Epub 2009 Feb 10.

Crocetti A, Forti S, Ambrosetti U, Bo LD. Questionnaires to evaluate anxiety and depressive levels in tinnitus patients. Otolaryngol Head Neck Surg. 2009 Mar;140(3):403-5. doi: 10.1016/j.otohns.2008.11.036.

Hasson D, Theorell T, Wallen MB, Leineweber C, Canlon B. Stress and prevalence of hearing problems in the Swedish working population. BMC Public Health. 2011 Feb 23;11:130. doi: 10.1186/1471-2458-11-130.

Hebert S, Fullum S, Carrier J. Polysomnographic and quantitative electroencephalographic correlates of subjective sleep complaints in chronic tinnitus. J Sleep Res. 2011 Mar;20(1 Pt 1):38-44. doi: 10.1111/j.1365-2869.2010.00860.x.

Stevens C, Walker G, Boyer M, Gallagher M. Severe tinnitus and its effect on selective and divided attention. Int J Audiol. 2007 May;46(5):208-16. doi: 10.1080/14992020601102329.

Rossiter S, Stevens C, Walker G. Tinnitus and its effect on working memory and attention. J Speech Lang Hear Res. 2006 Feb;49(1):150-60. doi: 10.1044/1092-4388(2006/012).

Namas R, Ghuma A, Hermus L, Zamora R, Okonkwo DO, Billiar TR, Vodovotz Y. The acute inflammatory response in trauma / hemorrhage and traumatic brain injury: current state and emerging prospects. Libyan J Med. 2009 Sep 1;4(3):97-103. doi: 10.4176/090325.

Eyre H, Baune BT. Neuroplastic changes in depression: a role for the immune system. Psychoneuroendocrinology. 2012 Sep;37(9):1397-416. doi: 10.1016/j.psyneuen.2012.03.019. Epub 2012 Apr 21.

Beattie EC, Stellwagen D, Morishita W, Bresnahan JC, Ha BK, Von Zastrow M, Beattie MS, Malenka RC. Control of synaptic strength by glial TNFalpha. Science. 2002 Mar 22;295(5563):2282-5. doi: 10.1126/science.1067859.

Steinmetz CC, Turrigiano GG. Tumor necrosis factor-alpha signaling maintains the ability of cortical synapses to express synaptic scaling. J Neurosci. 2010 Nov 3;30(44):14685-90. doi: 10.1523/JNEUROSCI.2210-10.2010.

Stellwagen D, Malenka RC. Synaptic scaling mediated by glial TNF-alpha. Nature. 2006 Apr 20;440(7087):1054-9. doi: 10.1038/nature04671. Epub 2006 Mar 19.

Schaette R, Kempter R. Computational models of neurophysiological correlates of tinnitus. Front Syst Neurosci. 2012 May 8;6:34. doi: 10.3389/fnsys.2012.00034. eCollection 2012.

Yang S, Bao S. Homeostatic mechanisms and treatment of tinnitus. Restor Neurol Neurosci. 2013;31(2):99-108. doi: 10.3233/RNN-120248.

Yang S, Weiner BD, Zhang LS, Cho SJ, Bao S. Homeostatic plasticity drives tinnitus perception in an animal model. Proc Natl Acad Sci U S A. 2011 Sep 6;108(36):14974-9. doi: 10.1073/pnas.1107998108. Epub 2011 Sep 6.

Weinberg MS, Blake BL, McCown TJ. Opposing actions of hippocampus TNFalpha receptors on limbic seizure susceptibility. Exp Neurol. 2013 Sep;247:429-37. doi: 10.1016/j.expneurol.2013.01.011. Epub 2013 Jan 16.

Kaneko M, Stellwagen D, Malenka RC, Stryker MP. Tumor necrosis factor-alpha mediates one component of competitive, experience-dependent plasticity in developing visual cortex. Neuron. 2008 Jun 12;58(5):673-80. doi: 10.1016/j.neuron.2008.04.023.

Stellwagen D, Beattie EC, Seo JY, Malenka RC. Differential regulation of AMPA receptor and GABA receptor trafficking by tumor necrosis factor-alpha. J Neurosci. 2005 Mar 23;25(12):3219-28. doi: 10.1523/JNEUROSCI.4486-04.2005. Erratum In: J Neurosci. 2005 Jun 1;25(22):1 p following 5454.

Ogoshi F, Yin HZ, Kuppumbatti Y, Song B, Amindari S, Weiss JH. Tumor necrosis-factor-alpha (TNF-alpha) induces rapid insertion of Ca2+-permeable alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA)/kainate (Ca-A/K) channels in a subset of hippocampal pyramidal neurons. Exp Neurol. 2005 Jun;193(2):384-93. doi: 10.1016/j.expneurol.2004.12.026.

Llano DA, Turner J, Caspary DM. Diminished cortical inhibition in an aging mouse model of chronic tinnitus. J Neurosci. 2012 Nov 14;32(46):16141-8. doi: 10.1523/JNEUROSCI.2499-12.2012.

Middleton JW, Kiritani T, Pedersen C, Turner JG, Shepherd GM, Tzounopoulos T. Mice with behavioral evidence of tinnitus exhibit dorsal cochlear nucleus hyperactivity because of decreased GABAergic inhibition. Proc Natl Acad Sci U S A. 2011 May 3;108(18):7601-6. doi: 10.1073/pnas.1100223108. Epub 2011 Apr 18.

Brozoski T, Odintsov B, Bauer C. Gamma-aminobutyric acid and glutamic acid levels in the auditory pathway of rats with chronic tinnitus: a direct determination using high resolution point-resolved proton magnetic resonance spectroscopy (H-MRS). Front Syst Neurosci. 2012 Feb 24;6:9. doi: 10.3389/fnsys.2012.00009. eCollection 2012.

Isaacson JE, Moyer MT, Schuler HG, Blackall GF. Clinical associations between tinnitus and chronic pain. Otolaryngol Head Neck Surg. 2003 May;128(5):706-10. doi: 10.1016/S0194-59980300227-4.

Tonndorf J. The analogy between tinnitus and pain: a suggestion for a physiological basis of chronic tinnitus. Hear Res. 1987;28(2-3):271-5. doi: 10.1016/0378-5955(87)90054-2.

De Ridder D, Elgoyhen AB, Romo R, Langguth B. Phantom percepts: tinnitus and pain as persisting aversive memory networks. Proc Natl Acad Sci U S A. 2011 May 17;108(20):8075-80. doi: 10.1073/pnas.1018466108. Epub 2011 Apr 18.

Ignatowski TA, Covey WC, Knight PR, Severin CM, Nickola TJ, Spengler RN. Brain-derived TNFalpha mediates neuropathic pain. Brain Res. 1999 Sep 11;841(1-2):70-7. doi: 10.1016/s0006-8993(99)01782-5.

Covey WC, Ignatowski TA, Knight PR, Spengler RN. Brain-derived TNFalpha: involvement in neuroplastic changes implicated in the conscious perception of persistent pain. Brain Res. 2000 Mar 17;859(1):113-22. doi: 10.1016/s0006-8993(00)01965-x.

Hess A, Axmann R, Rech J, Finzel S, Heindl C, Kreitz S, Sergeeva M, Saake M, Garcia M, Kollias G, Straub RH, Sporns O, Doerfler A, Brune K, Schett G. Blockade of TNF-alpha rapidly inhibits pain responses in the central nervous system. Proc Natl Acad Sci U S A. 2011 Mar 1;108(9):3731-6. doi: 10.1073/pnas.1011774108. Epub 2011 Jan 18.

Widomski D, Fretland DJ, Gasiecki AF, Collins PW. The prostaglandin analogs, misoprostol and SC-46275, potently inhibit cytokine release from activated human monocytes. Immunopharmacol Immunotoxicol. 1997 May;19(2):165-74. doi: 10.3109/08923979709007656.

Briner W, House J, O'Leary M. Synthetic prostaglandin E1 misoprostol as a treatment for tinnitus. Arch Otolaryngol Head Neck Surg. 1993 Jun;119(6):652-4. doi: 10.1001/archotol.1993.01880180068013.

Akkuzu B, Yilmaz I, Cakmak O, Ozluoglu LN. Efficacy of misoprostol in the treatment of tinnitus in patients with diabetes and/or hypertension. Auris Nasus Larynx. 2004 Sep;31(3):226-32. doi: 10.1016/j.anl.2004.03.005.

Page TH, Turner JJ, Brown AC, Timms EM, Inglis JJ, Brennan FM, Foxwell BM, Ray KP, Feldmann M. Nonsteroidal anti-inflammatory drugs increase TNF production in rheumatoid synovial membrane cultures and whole blood. J Immunol. 2010 Sep 15;185(6):3694-701. doi: 10.4049/jimmunol.1000906. Epub 2010 Aug 16.

Hwang JH, Chen JC, Yang SY, Wang MF, Chan YC. Expression of tumor necrosis factor-alpha and interleukin-1beta genes in the cochlea and inferior colliculus in salicylate-induced tinnitus. J Neuroinflammation. 2011 Apr 9;8:30. doi: 10.1186/1742-2094-8-30.

Wang HT, Luo B, Zhou KQ, Xu TL, Chen L. Sodium salicylate reduces inhibitory postsynaptic currents in neurons of rat auditory cortex. Hear Res. 2006 May;215(1-2):77-83. doi: 10.1016/j.heares.2006.03.004. Epub 2006 Apr 24.

Satoh H, Firestein GS, Billings PB, Harris JP, Keithley EM. Tumor necrosis factor-alpha, an initiator, and etanercept, an inhibitor of cochlear inflammation. Laryngoscope. 2002 Sep;112(9):1627-34. doi: 10.1097/00005537-200209000-00019. Erratum In: Laryngoscope. 2003 Jun;4(2):291.

Wang X, Truong T, Billings PB, Harris JP, Keithley EM. Blockage of immune-mediated inner ear damage by etanercept. Otol Neurotol. 2003 Jan;24(1):52-7. doi: 10.1097/00129492-200301000-00012.

Matteson EL, Choi HK, Poe DS, Wise C, Lowe VJ, McDonald TJ, Rahman MU. Etanercept therapy for immune-mediated cochleovestibular disorders: a multi-center, open-label, pilot study. Arthritis Rheum. 2005 Jun 15;53(3):337-42. doi: 10.1002/art.21179.

Rahman MU, Poe DS, Choi HK. Etanercept therapy for immune-mediated cochleovestibular disorders: preliminary results in a pilot study. Otol Neurotol. 2001 Sep;22(5):619-24. doi: 10.1097/00129492-200109000-00010.

Van Wijk F, Staecker H, Keithley E, Lefebvre PP. Local perfusion of the tumor necrosis factor alpha blocker infliximab to the inner ear improves autoimmune neurosensory hearing loss. Audiol Neurootol. 2006;11(6):357-65. doi: 10.1159/000095897. Epub 2006 Sep 21.

Scherer EQ, Yang J, Canis M, Reimann K, Ivanov K, Diehl CD, Backx PH, Wier WG, Strieth S, Wangemann P, Voigtlaender-Bolz J, Lidington D, Bolz SS. Tumor necrosis factor-alpha enhances microvascular tone and reduces blood flow in the cochlea via enhanced sphingosine-1-phosphate signaling. Stroke. 2010 Nov;41(11):2618-24. doi: 10.1161/STROKEAHA.110.593327. Epub 2010 Oct 7.

Hiller W, Goebel G. A psychometric study of complaints in chronic tinnitus. J Psychosom Res. 1992 May;36(4):337-48. doi: 10.1016/0022-3999(92)90070-i.

Falkenberg ES, Wie OB. Anxiety and depression in tinnitus patients: 5-year follow-up assessment after completion of habituation therapy. Int J Otolaryngol. 2012;2012:375460. doi: 10.1155/2012/375460. Epub 2012 Mar 28.

Halford JB, Anderson SD. Anxiety and depression in tinnitus sufferers. J Psychosom Res. 1991;35(4-5):383-90. doi: 10.1016/0022-3999(91)90033-k.

Harrop-Griffiths J, Katon W, Dobie R, Sakai C, Russo J. Chronic tinnitus: association with psychiatric diagnoses. J Psychosom Res. 1987;31(5):613-21. doi: 10.1016/0022-3999(87)90040-7.

Henry JL, Wilson PH. Coping with Tinnitus: Two Studies of Psychological and Audiological Characteristics of Patients with High and Low Tinnitus-Related Distress. Int Tinnitus J. 1995;1(2):85-92.

Seydel C, Haupt H, Olze H, Szczepek AJ, Mazurek B. Gender and chronic tinnitus: differences in tinnitus-related distress depend on age and duration of tinnitus. Ear Hear. 2013 Sep;34(5):661-72. doi: 10.1097/AUD.0b013e31828149f2.

Tyler RS, Gogel SA, Gehringer AK. Tinnitus activities treatment. Prog Brain Res. 2007;166:425-34. doi: 10.1016/S0079-6123(07)66041-5.

Tyler R, Ji H, Perreau A, Witt S, Noble W, Coelho C. Development and validation of the tinnitus primary function questionnaire. Am J Audiol. 2014 Sep;23(3):260-72. doi: 10.1044/2014_AJA-13-0014.

Scott B, Lindberg P, Melin L, Lyttkens L. Predictors of tinnitus discomfort, adaptation and subjective loudness. Br J Audiol. 1990 Feb;24(1):51-62. doi: 10.3109/03005369009077842.

Herbert TB, Cohen S. Stress and immunity in humans: a meta-analytic review. Psychosom Med. 1993 Jul-Aug;55(4):364-79. doi: 10.1097/00006842-199307000-00004.

Kiecolt-Glaser JK, Marucha PT, Malarkey WB, Mercado AM, Glaser R. Slowing of wound healing by psychological stress. Lancet. 1995 Nov 4;346(8984):1194-6. doi: 10.1016/s0140-6736(95)92899-5.

Huerta PT, Kowal C, DeGiorgio LA, Volpe BT, Diamond B. Immunity and behavior: antibodies alter emotion. Proc Natl Acad Sci U S A. 2006 Jan 17;103(3):678-83. doi: 10.1073/pnas.0510055103. Epub 2006 Jan 4.

Andrews JA, Neises KD. Cells, biomarkers, and post-traumatic stress disorder: evidence for peripheral involvement in a central disease. J Neurochem. 2012 Jan;120(1):26-36. doi: 10.1111/j.1471-4159.2011.07545.x. Epub 2011 Nov 17.

Hansel A, Hong S, Camara RJ, von Kanel R. Inflammation as a psychophysiological biomarker in chronic psychosocial stress. Neurosci Biobehav Rev. 2010 Sep;35(1):115-21. doi: 10.1016/j.neubiorev.2009.12.012. Epub 2009 Dec 22.

Steptoe A, Hamer M, Chida Y. The effects of acute psychological stress on circulating inflammatory factors in humans: a review and meta-analysis. Brain Behav Immun. 2007 Oct;21(7):901-12. doi: 10.1016/j.bbi.2007.03.011. Epub 2007 May 1.

Bob P, Raboch J, Maes M, Susta M, Pavlat J, Jasova D, Vevera J, Uhrova J, Benakova H, Zima T. Depression, traumatic stress and interleukin-6. J Affect Disord. 2010 Jan;120(1-3):231-4. doi: 10.1016/j.jad.2009.03.017.

Szczepek AJ, Haupt H, Klapp BF, Olze H, Mazurek B. Biological correlates of tinnitus-related distress: an exploratory study. Hear Res. 2014 Dec;318:23-30. doi: 10.1016/j.heares.2014.10.007. Epub 2014 Oct 28.

Weber C, Arck P, Mazurek B, Klapp BF. Impact of a relaxation training on psychometric and immunologic parameters in tinnitus sufferers. J Psychosom Res. 2002 Jan;52(1):29-33. doi: 10.1016/s0022-3999(01)00281-1.

Arck PC, Rose M, Hertwig K, Hagen E, Hildebrandt M, Klapp BF. Stress and immune mediators in miscarriage. Hum Reprod. 2001 Jul;16(7):1505-11. doi: 10.1093/humrep/16.7.1505.

Folstein MF, Folstein SE, McHugh PR. "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975 Nov;12(3):189-98. doi: 10.1016/0022-3956(75)90026-6. No abstract available.

Andersson G. Tinnitus loudness matchings in relation to annoyance and grading of severity. Auris Nasus Larynx. 2003 May;30(2):129-33. doi: 10.1016/s0385-8146(03)00008-7.

Andersson G, Lyttkens L, Larsen HC. Distinguishing levels of tinnitus distress. Clin Otolaryngol Allied Sci. 1999 Sep;24(5):404-10. doi: 10.1046/j.1365-2273.1999.00278.x.