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“Prescriptive Tinnitus Treatment” Components: Evaluation - Tinnitus Evaluation Program (TEP™) *Full description is described in another document Acoustic Program - Tinnitus Modulation Program (TMP™) *Description of concepts are described in this document Cognitive/Behavioral Program - Tinnitus Adaptation Program (TAP™) *Full description is described in another document David W. Holmes, Ph.D. Board Certified in Audiology CEO & Senior Scientist Melmedtronics Holdings, LLC Dallas, Texas USA [email protected] Viber #: 1-817-201-6791 Introduction Prevalence of Tinnitus Tinnitus is a disorder that affects 15% (1/6) of the general population. Severity ratings appear to follow a bellshaped curve with some individuals reporting very mild tinnitus and some (~20%) who find it devastating. Approximately 20% of those with tinnitus report their tinnitus to be severe to profound. Nearly 90% of patients with tinnitus also have a concomitant hearing loss. Unfortunately there is no cure for benign tinnitus (not related to an active medical condition). However, there are some treatments that do provide partial relief for certain individuals. This means that 97% of those with tinnitus are faced with a disorder that is not curable. To put this into perspective, there are 50 million individuals with tinnitus in the U.S. and 135 million in Europe. Tinnitus location Tinnitus is described as a sound that is not externally generated. Until recently, it was perceived as an “ear” problem. However, in 1998 (Lockwood & Salvi) discovered areas of the brain that represented activity in individuals with tinnitus and absent in individuals without tinnitus. This seminal paper literally transformed our attention from the ear to the brain as the locus of tinnitus. Since 1998, there have been numerous studies that have confirmed their findings. There is now great interest among many disciplines (pharmacology, radiology, neurotology, audiology, neurophysiology and bioengineering) to develop new methods of treatment and perhaps an ultimate cure. The limbic system is a system of the brain that has connections to various areas of the cortex that may be affected by tinnitus. It is hypothosized that this system of the brain may control how patients perceive thir tinnitus. Figure 1. Anatomy of the cortex and EEG activity of tinnitus activity (Langguth, B., 2011). Figure 2. It has been found that there is stronger connectivity between the auditory and non-auditory regions in tinnitus patients when compared to controls. (Schlee et al. BMC, Neuroscience, 2009). A study conducted by Holmes (2007), utilized Quantitave EEG to record the pre and post effects of ultrasound, and found similar changes, in not only the limbic area, but also other areas of the cortex. Figure 3. EEG power spectrum changes before and after treatment using ultrsound (Holmes, 2007). Acoustic Signals Used in Tinnitus Treatments Frequency Modulation There is evidence that low frequencies (40-100 Hz) may “modulate” the information that is sent to the brain. “CR treatment was safe, well-tolerated and caused a significant decrease of tinnitus loudness and symptoms. Placebo treatment did not lead to any significant changes. Effects gained in 12 weeks of treatment persisted through a preplanned 4-week therapy pause and showed sustained long-term effects after 10 months of therapy: Response, i.e. a reduction of at least 6 TQ points, was obtained in 75% of patients with a mean TQ reduction of 50% among responders. CR therapy significantly lowered tinnitus frequency and reversed the tinnitus related EEG alterations.” (Tass, et a, 2012) Some of the current tinnitus treatment devices (Sound Cure’s Seranade, Neuromonics’ Oasis, Widex’s Zen2Go, Phonak’s Audeo Q, Starkey’s Xino, GN ReSound’s Altera TC, Siemens’ Life, and General Hearing ’s Tranquil ) appear to offer some relief for some patients. These approaches have provided varying relief to tinnitus patients that is administered over a period of months. Zwicker Effect “The 'Zwicker tone' (ZT) is an auditory after-image that can be evoked most effectively when a bandsuppressed noise (relative width of gap 1/3 octave) presented for a certain period of time has been switched off. The sensation of this purely monaural phenomenon is that of a pure tone with a frequency corresponding to the center frequency of the gap and an equivalent level of 10-15 dB above auditory threshold. The sensation decays gradually; it may last as long as 10 s depending on how long the evoking noise was presented. The search for a physiological correlate has been futile so far, probably because the search was confined to more peripheral levels of the auditory system (inferior colliculus). A neuromagnetic study was performed in normal-hearing subjects in order to look for a neurophysiological correlate of the ZT in the auditory cortex. With a stimulation paradigm especially designed for this study, we have been able to isolate poststimulus activity which appears to be related to the ZT and which originates in the supratemporal auditory cortex. It is a sustained neuromagnetic activity that shows a clear-cut dipolar field distribution, and it appears that this activity has certain similarities with the tone-evoked auditory sustained response. The hypothesis is put forward that during the sensation of the ZT a process takes place in the auditory cortex which is similar to that underlying the sustained response, and which gives rise to the sensation of the ZT. In contrast to the sustained response, however, which is due to neural activity evoked by an external acoustic stimulus, the sustained activity associated with the ZT is due to a temporary absolute or relative reduction of neural activity originating from those regions in which the ZT exciting stimulus caused an adaptation. These differences in neural activity cannot be distinguished by the auditory system from a corresponding external acoustic signal. Preliminary studies in patients suffering from tonal tinnitus yielded results which exhibit a certain similarity with those obtained in the ZT experiment.” (Hoke, Hoke and Ross, 1996). Figure 5. Mean variation of tinnitus loudness over time in the three sound therapy groups. Decibel units on the yaxis are mean values (+1 SE) of ∆dBt computed for three subsequent temporal classes using dBt measurements in subsequent control visits of the same patient. See Methods for details. (WN = broadband noise; WWN = notched broadband noise Marco Lugli1; Romano Romani1; Stefano Ponzi2; Salvatore Bacciu2; Stefano Parmigiani1Wa = water noise.) Marco Lugli1; Romano Romani1; Stefano Ponzi2; Salvatore Bacciu2; Stefano Parmigiani1 (2009) Music “Chronic tinnitus, one of the most common disorders in ENT medicine, requires comprehensive and interdisciplinary treatment. An innovative music therapy approach, developed at the German Center for Music Therapy Research in cooperation with the ENT clinic of the University of Heidelberg ("Heidelberg Model"), strives to integrate the tinnitus sound into a musically controllable acoustic process. The aim of the present study is to evaluate the effectiveness of this current treatment. We carried out a prospective, two-armed (music therapy group vs control group) study with 20 patients (10 males, 10 females; mean age 51+/-7 years), suffering from decompensated chronic tinnitus (mean score in the Tinnitus Questionnaire TQ=46.8+/-9.6). The target variables involved TQ values, pre- and post-measurements, and follow-up after 3 and 6 months. Group comparison yields a highly statistically and clinically significant decrease in mean TQ-scores pre- and post in the music therapy group by 25 points or 52% on average as compared to 2 points (4%) in the control group [univariate ANOVA: (F(1,31)=14.19, P=0.001), effect size d=1.73]. Logarithmic regression analysis reveals a fast onset and long lasting effect of music therapy (B=-8.9; F(1,125)=32.11, P=0.000). The effectiveness of this highly economic approach was proven as the innovative music therapy concept yields statistically and clinically significant results which remain stable throughout follow-up. Further investigations with larger sample sizes and using brain imaging should strengthen these findings.” (Argstatter H, Plinkert P, Bolay HV., 2007). Fractals According to Sweetow (2013): “The potential application of fractal tones delivered via high-fidelity hearing aids was explored in an experiment to determine if the presence of various acoustic stimuli, including fractal tones, would (1) be perceived as relaxing to tinnitus patients, (2) reduce short term tinnitus annoyance, and (3) lower subjective tinnitus handicap and reaction scores in a 6 month field trial. [45] The experimental protocol allowed for a comparison of fractal tones alone, fractal tones combined with amplification, broadband (white) noise alone, white noise mixed with amplification, and fractal tones along with amplification and white noise. Results indicated that fractal tones were effective in promoting relaxation and reducing annoyance from tinnitus. Similar results were also reported by others. [46],[47] Both fractal tones and white noise reduced tinnitus annoyance (white noise to a greater degree than the fractal tones, likely due to greater masking effects), but the fractal tones were preferred by subjects for longer term use for reasons discussed below. In addition, while the majority of subjects selected slower tempos for relaxation and long-term wear, this choice was not unanimous. This underscores the benefit of providing the individual listener with choices. [48] Individual preferences for certain types of acoustic stimuli were also emphasized in the Henry et al., [49] study in which they reported most, but not all, of their participants clearly preferred certain stimuli over others. The Sweetow and Sabes results [45] agreed with the Henry et al., [49] data in that their subjects showed a preference for stimuli that were modulated in both the spectral and temporal domains. In the latter study, subjects were presented with a variety of noises and environmental sounds that were filtered and modulated. They found that most, but not all, of their subjects had clear preferences for certain stimuli over others, and most preferred were those that were modulated or temporally varying as opposed to steady state (i.e., pure tones, or filtered or broad band-noise) signals. Modulated signals are characteristic of fractal and other musical stimuli. Reavis, et al., [50] indicated that electrical and acoustic suppression was achieved most effectively using dynamically modulated signals. Their results confirmed the conclusions of others. [51],[52] that temporally patterned sounds such as amplitude and frequency modulated signals may produce highly synchronized and robust cortical responses as opposed to steady state sounds, which produce mostly onset and offset responses in the cortex, and thus may be a more attractive stimulus for this cortical effect. Zeng et al. [53] also suggested that the temporal characteristics of an electrically generated signal are critical to suppression. Sounds that are too slow produce bursts of activity and those that are too fast show no synchronization, but within a specific range the neurons fire synchronously to the sound stimulus and can produce synchronized, robust neural activity in the auditory cortex. It is possible that there are also optimal properties for an acoustical signal designed for tinnitus relief, though this has yet to be verified.” (Sweetow, 2013). Adaptation/Habituation Therapy Jastreboff is known for Tinnitus Retraining Therapy, Henry for Progressive Tinnitus Management and Holmes & Cozort for Tinnitus Adaptation Therapy. These approaches have yielded effective results in the maanagement of tinnitus, but results vary from one clinical setting to another for a variety of reasons (skill of clinician, concomitant use of a variety of devices, psycho/social variables of patients and a host of other variables). These methods are enhaced when used in conjunction with some form of accoustic device. Figure 4. Results of cognitive therapy used in conjunction with broad-band noise. (Holmes Cozort, 1999). Issues One of the problems faced with all current treatment approaches is, that the patients’ tinnitus may change and fluctuate over time. If the treatment is partially effective, it may change the perception of the frequency and/or the intensity of the patient’s tinnitus for a variety of reasons (additional insults, age, body physiology, medications and treatment effects). If a tinnitus treatment program is effective for a portion of the tinnitus spectrum and those characteristics change, then it is possible that the treatment is no longer suitable for the residual tinnitus components. The solution should then be, to either apply an alternative method of treatment, or modify the existing treatment in a manner that will focus on the remaining components of the tinnitus spectrum. A second problem, effecting positive patient outcomes, is that of compliance. Patients expect quick results and if they are not obtained, then they abandon the treatment and look for a replacement therapy, in hopes of finding the “silver-bullet”. Solution The solution would be to develop a “modifiable” treatment program, that would respond to changes in the patient’s tinnitus. The use of “intelligent” algorithms could then be used to predict which program had the highest probability of success, based on variables that had been identifed through ongoing diagnostic information. Variables Clinicians who see patients with tinnitus share a common axiom, “If you’ve seen one tinnitus patient, you’ve seen one tinnitus patient.” Patients with tinnitus are very complex for more reasons than can possibly be listed, but here are a few examples: Causes 1. 2. 3. 4. 600+ prescription drugs have a tinnitus side effect Tinnitus effects of interactions among multiple drugs are unknown 200+ known medical conditions Variety of frequency and intensity parameters of noise induced tinnitus Effects 1. Personality Type Reactions a. Sensing-Judging b. Sensing-Perceiving c. Intuitive-Feelers d. Intuitive-Thinkers 2. Anxiety 3. Depression 4. Hyperacusus 5. Misophonia 6. Phonophobia Assessments 1. Patient Information a. Demographics b. History (detailed) c. Description of tinnitus i. Type i. Tonal a. Frequency b. Minimum masking level c. Residual inhibition ii. Noise a. intensity b. Minimum masking level c. Residual inhibition ii. Etiology iii. Date of onset iv. Location i. L, R, C d. Psycho/Social measures i. Tinnitus Handicap inventory ii. Tinnitus Reaction Quotient iii. Tinnitus Severity Scale iv. Depression scale v. Anxiety scale vi. Personality Index vii. Acoustic Parameters There are several methods that can be used to create/modify an acoustic signal: Frequency o Sinusoidal o Noise o Modulate FM AM o Filter o Notch These are the possible modifications that could be applied to a patient’s matched tinnitus: 2. Acoustic Treatment Options a. (tones, NB noise, Zwicker, music and fractals) Tonal i. ii. iii. iv. v. vi. Non-modulated frequency Frequency Modulated (40 Hz) Frequency Modulated (Sweep 40-100 Hz) Amplitude Modulated (+/- 5 dB) Combined Modulated (AM & 40 Hz) Combined Modulated (AM & sweep 40-100 Hz) Noise vii. viii. ix. x. xi. xii. Non-modulated Notched band Modulated notched band (40 Hz) Modulated notched band (sweep 40-100 Hz) Notched band (AM +/- 5 dB) Combined notched band (AM and 40 Hz) Combined notched band (AM and sweep 40-100 Hz) NB Zwicker xiii. xiv. xv. xvi. xvii. xviii. Non-modulated notched Zwicker band Modulated notched Zwicker band (40 Hz) Modulated notched Zwicker band (sweep 40-100 Hz) Notched band (AM +/- 5 dB) Combined notched band Zwicker (AM and 40 Hz) Combined notched band Zwicker (AM and sweep 40-100 Hz) xix. xx. xxi. xxii. xxiii. xxiv. Non-modulated Notched band Modulated notched band (40 Hz) Modulated notched band (sweep 40-100 Hz) Notched band (AM +/- 5 dB) Combined notched band (AM and 40 Hz) Combined notched band (AM and sweep 40-100 Hz) Music Fractals xxv. xxvi. xxvii. xxviii. xxix. xxx. Non-modulated Notched band Modulated notched band (40 Hz) Modulated notched band (sweep 40-100 Hz) Notched band (AM +/- 5 dB) Combined notched band (AM and 40 Hz) Combined notched band (AM and sweep 40-100 Hz) Common Tasks Registration 1. 2. 3. 4. 5. 6. 7. Name Date of birth Sex Social Security (last four digits) Unique I.D. Login (email address) Password Data 1. Data logging a. Login/logout date and time b. Treatment assigned 2. Data collection 3. Analyses Task Sequences for Matching Tinnitus and Treatment Stimuli 1. Develop code to: a. Match tone frequencies b. Match narrowband noise c. Modulate frequency d. Modulate amplitude e. Filter out notched frequencies 2. Selected Treatments a. Amplitude modulation +/- 5 dB of threshold b. Frequency modulation 40 Hz – 100 Hz c. Zwicker Development Stages 1. Intellectual Property a. Identify all possible combinations of treatment options b. Search patents for prior art i. Widex patents that exist ii. Widex patents that could be enhanced iii. New applications that could be filed 2. Identify a. All possible treatment conditions b. Rank order development stages c. Determine platforms d. Identify delivery systems 3. Program Variables a. Frequency modulation b. Amplitude modulation c. Notched filters d. Combinations of the above 4. Clinical Trials a. List variables for analyses b. Identify existing cohorts for potential subjects c. Develop inclusion/exclusion criteria for all conditions d. Recruit subjects e. Collect data f. Analyze data with multivariate analysis g. Identify factors that have the highest predictability of success Partial References Bao SW, Chan VT, Merzenich MM (2001) Cortical remodelling induced by activity of ventral tegmental dopamine neurons. Nature 412:79–83. Blood AJ, Zatorre RJ (2001) Intensely pleasurable responses to music correlate with activity in brain regions implicated in reward and emotion. Proc Natl Acad Sci USA 98: 11818–11823. Diesch E, et al. 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Appendix B Project Management Plan To be completed by: Deadline: Team Leaders As indicated Phase 1 Q4 and Q1-Q4, 2013-14 % done Items Status Notes 100% 100% 50% 25% 5% Federal Supply Schedule GSA Identify Potential Funding Sources Secure Round 1 funding Program beta version of software Contract Awarded 11-15-2011 Uploaded to GSA and GSA Advantage 75% 75% 10% 25% Identify clinical trial sites Identify Multivatiate loadings Phase 2 clinical trials Identify treatment delivery options 15-Nov-11 21-Nov-11 23-Nov-13 23-Dec-14 12-Feb-14 15-Mar14 30-Jun-14 15-Jul-14 15-Sep-14 75% 75% Begin discussions with potential Distributors Hire Sales Reps 15-Nov-14 1-Dec-14 Widex, Oticon, Phonak, GN ReSound, Starkey and Seim Phase Due By Notes 25% 50% 75% 25% Complete ISO:13485 and CE Mark File FDA 510(k) File U.S. and International Patents Schedule Demonstrations 15-Jan-15 15-Feb-15 15-Mar-15 ongoing Embargo and BSI 25% 50% Trade Journal Advertising Trade Show monthly 8-Mar-15 Hearing Review and The Hearing Journal (print and eB JDVAC 50% 25% 25% Trade Shows Develop CEU courses R&D ongoing ongoing ongoing US, Europe, Middle East and India Develop CEU courses Ongoing data analyses Meet with researchers (US, India and Germany) Phase 2 Q1 - Q4, 20115 % done Phase 3 Q1 - 4, 2016 % done Phase Due By 0% 50% Expand Marketing and Advertising Trade Shows Ongoing Ongoing 0% Begin discussions with possible Acquisition sources Ongoing New Sales Reps begin demonstrations in VA clinics