Collaborative Tinnitus Research at Washington University

This will be a cross-over randomized trial. The order of the treatments received will be randomly selected and the participant will not be told which treatment they are receiving. Subjects will fall into one of the four treatment groups described below:

1. 2 weeks of active rTMS treatment followed by washout and then by 2 weeks sham
2. 2 weeks of sham followed by washout and then 2 weeks of active rTMS treatment
3. 4 weeks of active rTMS treatment followed by washout and then 4 weeks of sham
4. 4 weeks of sham followed by washout and then 4 weeks of active rTMS treatment

For the washout period between the two interventions, we will plan a minimum of 2 weeks to avoid the problem of carryover effects. Prior to starting the next intervention after the washout period, we will re-assess subject's tinnitus severity. To ensure no carryover effect, the washout period will be extended for those subjects whose tinnitus severity, as defined by the THI, is more than 20 points different than their baseline THI score.

• rTMS (Device), also known as Neuronetics 2100 device: Stimulation Settings: Frequency -- 1Hz on 330 sec (5 min 30 sec.) per train for the first 5 trains with the last train 350 sec. (5 min. 50 sec.) in duration Off -- 90 sec (1 min. 30 sec.) Intensity -- 110% of motor threshold Duration -- 42½ minutes (total 2000 pulses in 6 trains)

Primary outcomes

• Change in THI (Tinnitus Handicap Inventory) [baseline at the start of each treatment period, end of each treatment period (2 or 4 weeks)]: Tinnitus Handicap Inventory (THI) is a measure of bother from tinnitus. THI is measured as a score in a scale ranging from 0=No bother to 100=Extremely Bothered. THI score post active rTMS treatment minus THI score pre active rTMS treatment will provide the change in THI score due to active treatment. THI score post rTMS sham minus THI score pre rTMS sham will provide change in THI due to sham. The difference of THI change due to active treatment minus THI change due to sham will provide the THI change that is our primary outcome measure.

Secondary outcomes

• Perceived Global Impression of Change (PGIC: Number of Participants With Perceived Global Impression of Change (PGIC) of 1 or Greater [End of each treatment period (2 or 4 weeks)]: PGIC is a 7 point scale ranging from -3 to +3,with 0 meaning no change,negative values reporting worsening of symptoms(Tinnitus), and values of +1 or above reporting perceived improvement of Tinnitus. PGIC score post active rTMS treatment treatment will provide subject's impression of change in tinnitue due to active treatment.PGIC score post rTMS sham will provide subject's impression of change in tinnitus due to sham. Number of subjects with scores of 1 or above are recorded to perceive improvement due to treatment of the corresponding study arm.

Sex: All, ages: 18 Years to 60 Years

On-line eligibility screening:

https://tinnitus.wustl.edu/

Inclusion Criteria:

* Men and women between the ages of 18 and 60 years.
* Subjective, unilateral or bilateral, non-pulsatile tinnitus of 6 month's duration or greater.
* Tinnitus Handicap Inventory (THI) score of 38 or greater.
* Subjects of child-bearing potential using an appropriate form of birth control acceptable to the research team and with a negative urine pregnancy test or undergone sterilization procedure.
* Able to give informed consent.
* Available for once daily therapy, during working hours, Mon.-Fri.
* English-speaking.

Exclusion Criteria:

* Patients experiencing tinnitus related to cochlear implantation, retrocochlear lesion, or other known anatomic/structural lesions of the ear and temporal bone.
* Patients with hyperacusis or misophonia (hyper-sensitivity to loud noises).
* History of seizures, history of loss of consciousness requiring medical care, any other CNS pathology that increases a subject's risk for treatment with rTMS.
* Patients with cardiac pacemakers, intracardiac lines, implanted medication pumps, implanted electrodes in the brain, other intracranial metal objects with the exception of dental fillings, or any other contraindication for MRI scan.
* Any contraindication for receiving FDG PET, as determined by established clinical criteria.
* Patients with an acute or chronic unstable medical condition which, in the opinion of the investigator, would require stabilization prior to initiation of magnetic stimulation.
* Patients with any active ear disease that, in the opinion of the PI, needs to be further evaluated.
* Patients with symptoms of depression as evidenced by a score of 14 or greater on the Beck Depression Inventory or, in the opinion of the psychiatric sub-investigator demonstrates active mood symptoms that meet DSM-IV-TR criteria for Major Depressive Disorder.
* Any psychiatric co-morbidity that, in the opinion of the psychiatric sub-investigator, may complicate the interpretation of study results.
* Pregnancy
* Currently breast-feeding
* Previous treatment with rTMS
* Patients with tinnitus related to Workman's Compensation claim or litigation-related event.
* Patients with a history of diabetes.
* Fasting glucose > 150mg/Dl.
* Patients taking any medication(s), in the opinion of the investigator, that is(are) deemed to be etiologically related to the development of tinnitus.
* Unable to elicit a motor threshold with rTMS.
* A Mini-Mental Status Exam score less than 27.
* Untreated or newly diagnosed hypertension, (systolic blood pressures above 140 mm or diastolic pressure above 90 mm).
* Patients with a history of claustrophobia.
* Inability to lay flat for 2 hours.
* Active alcohol and/or drug dependence or history of alcohol and/or ETOH dependence within the last year.
* Any medical condition that, in the opinion of the investigators, confounds study results or places the subject at greater risk.
* Unable to provide informed consent.
* Any exclusions from radiology screening for MRI or PET scanning.

Participant flow

Outcome results

• Change in THI (Tinnitus Handicap Inventory) (Primary), Median, units on a scale: 2-weeks rTMS Active Treatment -5 (-14 to 0); 2-Weeks Sham rTMS Treatment -6 (-12 to -2); 4-weeks rTMS Active Treatment -10 (-12 to 3); 4-weeks rTMS Sham Treatment -6 (-12 to 4) (p 0.944)
• Perceived Global Impression of Change (PGIC: Number of Participants With Perceived Global Impression of Change (PGIC) of 1 or Greater (Secondary), Number, participants: 2-Weeks Active rTMSTreatment 1; 2-Weeks Sham rTMS Treatment 3; 4-Weeks Active rTMSTreatment 3; 4-Weeks Sham rTMS Treatment 5

Adverse events

Time frame: Up to 6 months.Minimum of 10 weeks in 2wk treatment, or 14 weeks in 4 week treatment.

Other adverse events by term

Limitations and caveats: Excluding subjects with Beck Depression Index of above 14 we treated an exclusive group of the Very bothered tinnitus patients, which may not be representative of the tinnitus population as a whole.

• Results publication: Piccirillo JF, Garcia KS, Nicklaus J, Pierce K, Burton H, Vlassenko AG, Mintun M, Duddy D, Kallogjeri D, Spitznagel EL Jr. Low-frequency repetitive transcranial magnetic stimulation to the temporoparietal junction for tinnitus. Arch Otolaryngol Head Neck Surg. 2011 Mar;137(3):221-8. doi: 10.1001/archoto.2011.3. PMID 21422304
• Results publication: Pierce KJ, Kallogjeri D, Piccirillo JF, Garcia KS, Nicklaus JE, Burton H. Effects of severe bothersome tinnitus on cognitive function measured with standardized tests. J Clin Exp Neuropsychol. 2012;34(2):126-34. doi: 10.1080/13803395.2011.623120. Epub 2011 Dec 14. PMID 22168528
• Results publication: Burton H, Wineland A, Bhattacharya M, Nicklaus J, Garcia KS, Piccirillo JF. Altered networks in bothersome tinnitus: a functional connectivity study. BMC Neurosci. 2012 Jan 4;13:3. doi: 10.1186/1471-2202-13-3. PMID 22217183
• Results publication: Piccirillo JF, Kallogjeri D, Nicklaus J, Wineland A, Spitznagel EL Jr, Vlassenko AG, Benzinger T, Mathews J, Garcia KS. Low-frequency repetitive transcranial magnetic stimulation to the temporoparietal junction for tinnitus: four-week stimulation trial. JAMA Otolaryngol Head Neck Surg. 2013 Apr;139(4):388-95. doi: 10.1001/jamaoto.2013.233. PMID 23599075

• Jay F Piccirillo, MD, CPI, Principal investigator, Washington University School of Medicine

NIH grants: R01DC009095