THE NEUROSCIENCE OF TINNITUS AND A RATIONALE FOR TREATMENT Pim van Dijk, PhD University of Groningen, University Medical Center Groningen The Netherlands AudiologyNow, 5 April 2013, Anaheim, CA Rosemarie Arnold, PhD Kris Boyen, PhD Emile de Kleine, PhD RolienFree, PhD, MD LeontienGeven, MD Amarins Heeringa Karin Heijneman, MD RutgerHofman, PhD, MD Gijs Hoskam Francka Kloostra, MD Dave Langers, PhD Cris Lanting, PhD Hans Segenhout Margriet van Gendt Esther Wiersinga, PhD Acknowledgments 3/92 1
Acknowledgments Heinsius Houbolt Foundation www.huizingastichting.nl Dorhout Mees Family Foundation Gratama-Stichting 4/92 Overview Introduction Tinnitus: characteristics and neurophysiology Neuroimaging Treatments: interplay between audiological rehabilitation and counseling 5/92 Groningen lon ams ber par 6/92 2
Groningen Population: 190,000 Students: 40,000 University: founded 1614 7/92 History of Audiology in Groningen 1929-1969: Hendrik C. Huizing, PhD 1969-1986: Roel J. Ritsma, PhD 1987-2006: Hero P. Wit, PhD 8/92 Overview Introduction Tinnitus: characteristics and neurophysiology Neuroimaging Treatments: interplay between audiological rehabilitation and counseling 9/92 3
Discovering the source of tinnitus (or the Nile) We can only tell that we are on the right track, once we found the source There may be multiple sources Both these statements imply that people may have different opinions on tinnitus. (An opinion is just an opinion.) A relevant question from patients: when will you find the source? Answer: we do not know, since we don t know how far away it is. Picture: wikipedia 10/92 Definition Tinnitus: A (meaningless) sound percept No acoustic source outside the body 11/92 Tinnitus: An old disease Babylonian Talmud, 5 th century A.C. 12/92 4
Titus s curse A gnat entered his nostril and pecked at his brain for seven years. One day Titus was passing by a blacksmith. He heard the noise of the sledgehammer and the gnat became silent. Titus thus said: Here is the remedy. Every day he brought a blacksmith to bang in his presence. [ ] For thirty days this worked fine but then the gnat became accustomed [to the banging] and it resumed pecking (Babylonian Talmud). Dan (2005) J. Hist. Neurosci. 13/92 Tinnitus en hearing loss: prevalence Tinnitus 6 per 100 Hearing loss 20 per 100 Lockwood et al., 2002 14/92 Objective and subjective tinnitus Tinnitus: A (meaningless) sound percept No acoustic source outside the body Objective tinnitus internal acoustic source Subjective tinnitus a phantom sound 15/92 5
Objective tinnitus (not a complete overview) Myoclonus Palatum Middle ear muscles Vascular origin Vascular malformation Carotic stenosis Sinodural fistula 16/92 Pulsatile tinnitus (not a complete list) Not synchronous to heartbeat Modulating subjective tinnitus (?) Pulsing subjective tinnitus (e.g. typewriter, Levine, 2006) Synchronous to heartbeat Carotic stenosis Sinodural fistula Cardiac condition 17/92 Central auditory system Peripheral auditory system Langers (2006) 18/92 6
Tinnitus as a condition of the central auditory system Sectioning the auditory nerve gave no relief of tinnitus in 35-85% of patients Sectioning of the auditory nerve resulted in tinnitus in 50% of the patients (House & Brackman, 1981; Dandy, 1941; Silverstein, 1976; Gardner, 1984; Berliner et al. 1992) 19/92 Tinnitus spontaneous neural activity Neural activity Response to stimulus Spontaneous activity tinnitus Time 20/92 Tinnitus and spontaneous activity Increase of firing rate? Normal Increased Firing rate Increase of bursts? Bursts Increase of synchrony? Normal Eggermont, 2007 Increased synchrony Time 21/92 7
Noise trauma & spontaneous activity Cortex 4 Thalamus 3 Brainstem 1. Liberman and Kiang(1978) 2. Kaltenbach et al. (1989) 3. Bauer et al. (2008) 4. Noreña and Eggermont (2003) 2 1 Oor 22/92 Spontaneous neural activity and induced hearing loss Peripheral hearing loss reduced afferent excitation changes in spontaneous activity Eggermont and Roberts (2004) 23/92 Frequency specific hearing loss and hyperactivity 5 khz trauma 10 khz trauma Robertson et al., 2012 24/92 8
How does hyperactivity develop after acoustic trauma? Mulders and Robertson, 2013 25/92 What happens in cochlear ablation? 26/92 Spontaneous rate, synchronicity, bursting in the cortex, post trauma Rate Bursting Synchronicity Norena and Eggermont, 2003 27/92 9
Spontaneous rate, synchronicity, bursting in the cortex post trauma, summary Immediate After a few hours Spontaneous rate Synchronicity Bursting activity = = Norena and Eggermont, 2003 28/92 Spontaneous activity summery Spontaneous activity in auditory brain areas changes after peripheral trauma These change involve Increases in spike rate Increases in synchronicity across neurons Increases in bursting activity These changes may relate to different forms of tinnitus Chronic Acute 29/92 Which of these factors influence your tinnitus? If so, how do they influence your tinnitus? Tinnitus (%) Tinnitus =(%) Tinnitus (%) Loud sound 38 42 20 Stress 48 51 1 Background music 13 60 28 Lack of sleep 36 62 2 Movement of head/neck/jaw 29 65 6 Afternoon na 12 76 12 Alcohol 8 87 5 Medication 3 94 3 Coffee 4 96 1 Smoking 3 97 1 30/92 10
Thalamus-cortex-amygdala Non-classical auditory system, Diffuse system Classical auditory system, Tonotopic system From: Møller, SensorySystems 31/92 Somatosensorymodulationof tinnitus Auditory cortex Limbic system, Amygdala Thalamus 32/92 Overview Introduction Tinnitus: characteristics and neurophysiology Neuroimaging of tinnitus Introduction to fmri Tonotopy in the human auditory cortex (a little detour) Tonotopy and tinnitus Brain connectivity in tinnitus A special case: gaze-modulated tinnitus Treatments: interplay between audiological rehabilitation and counseling 33/92 11
Functional Magnetic Resonance Imaging (fmri) Lanting, 2009 34/92 The response of a voxel Task Task Task 35/92 The hemodynamic response Backes and Van Dijk, 2002 36/100 12
The hemodynamic response Backes and Van Dijk, 2002 37/92 Comparing fmri and ABR www.audiologieboek.nl 38/92 Methodological issues Functional MRI measures the hemodynamic response, which is an indirect measure of neural activity in the brain Issues to deal with: Poor signal-to-noise: statistical methods, averaging across voxel (Region-of-interest, ROI analysis) Scanner noise Tinnitus: measuring spontaneous neural activity? 39/92 13
Sparse imaging (Hall et al., 2001) to reduce the effect of scanner noise Scan Experimental stimulus Voxel response TR=10 s time 40/92 fmri responses down to the behavioral threshold 41/92 Overview Introduction Tinnitus: characteristics and neurophysiology Neuroimaging of tinnitus Introduction to fmri Tonotopyin the human cortex (a little detour) Tonotopy and tinnitus Brain connectivity in tinnitus A special case: gaze-modulated tinnitus Treatments: interplay between audiological rehabilitation and counseling 42/92 14
Tonotopy in the cochlea: Relation between sound frequency and place Sound frequency in Hertz (Hz) 43 43/92 Tonotopy in the auditory nerve 30.000 nerve cells Kiang, 1965 44/92 Tonotopy in the cortex Multiple abutting tonotopic gradients were demonstrated in auditory cortex Marmoset Bendor & Wang, 2008 Kaas & Hackett, 2000 45/92 15
Variable results in humans L L Tonotopy in humans H H EEG/MEG and PET/fMRI consistently reveal a gradient along Heschl s Gyrus (HG) Low f: anterolaterally High f: posteromedially Less consistent additional gradients reported in adjacent cortex Formisanoet al, 2003 Talavageet al, 2004 46/92 Methods 20 healthy subjects with normal hearing Sound stimuli presented at Frequencies: 0.25, 0.5, 1, 2, 4, or 8 khz Intensity levels: soft (~10-30 db SL), or loud (~30-50 db SL) 47/92 Methods fmri paradigm: While subjects performed three 8-minute blocks of an engaging visual/emotional task, 100-ms tones were presented at a 5-Hz rate Sound stimuli presented at Frequencies: 0.25, 0.5, 1, 2, 4, or 8 khz Intensity levels: soft (~10-30 db SL), or loud (~30-50 db SL) instruction crosshair picture reply crosshair picture reply crosshair picture reply Video Audio fmri Time t (m:s) start 0 s 12 s 24 s Etc trial #1 trial #2 trial #3 trial #40 0:00 0:12 0:24 8:00 48/92 16
Results Activated voxels Omnibus F-test FWE threshold p< 0.05 Cluster sizek> 100 1613 activatedvoxelsin the temporal lobe 49/92 Results 3D rendering a mixture of the first two principal components togethers Mixture of components high +.50 frequency 250 Hz 8000 Hz Langers& Van Dijk, 2011 low frequency -.50 50/92 Discussion: tonotopic fields in AC LF HF HF Langers& Van Dijk, 2011 51/92 17
Langers& Van Dijk, 2011 R A1 Kaas& Hackett, 2000 52/92 Conclusion on tonotopy Multiple tonotopic fields across Heschl s gyrus/temporal lobe Low frequencies are represented laterally, andhigh frequencies are represented medially, both anterior and posterior to HG Primary/core cortical fieldsai/r do notextendmediolaterally alonghg, but rostrocaudally across HG, similar to primates Consistency acrossseveralrecent studies: Woods et al., 2000; Humphries, 2010; Langers andvan Dijk, 2011; Moerel et al, 2012. 53/92 Overview Introduction Tinnitus: characteristics and neurophysiology Neuroimaging of tinnitus Introduction to fmri Tonotopyin the human cortex (a little detour) Tonotopy and tinnitus Brain connectivity in tinnitus A special case: gaze-modulated tinnitus Treatments: interplay between audiological rehabilitation and counseling 54/92 18
Tonotopic re-mapping of the cortex Low f Cortex High f Low f Cochlea Hearing loss High f 55/92 Comparison of subjects with and without tinnitus 56/92 Tonotopy in tinnitus 57/92 19
Conclusion tonotopy Tinnitus does not require tonotopicreorganization of the auditory cortex Is this conclusive? What are alternative models? 58/92 Alternative to tonotopic reorganization: upregulation along the auditory path Low f Cortex High f Low f Cochlea Hearing loss High f 59/92 Low f Alternative to tonotopic reorganization: local upregulation Cortex High f Low f Cochlea Hearing loss High f 60/92 20
Boyen, 2013 61/92 Functional connectivity Pearson correlation 62/92 Functional connectivity Differences associated with tinnitus 63/92 21
Conclusion on connectivity Tinnitus is associated with reduced functional connectivity of the brainstem and cortex This suggest that tinnitus may arise as a result of abnormal spontaneous activity in the cortex due to abnormal reduced drive from lower levels (e.g. thalamus and brainstem) Low f Cortex High f Hearing loss 64/92 Gaze evoked/modulated tinnitus A rare kind of tinnitus (Whitaker, 1982, 1983), relatively common in patients that underwent acoustic neuroma surgery (36%-19%, Biggs and Ramsden, 2002) Monaural deafness, tinnitus in the deaf ear, modulated by gaze Earlier imaging studies (Cacace et al., 1995; Giraud et al., 1999; Lockwood et al., 2001) 65/92 A so-called uniform group of tinnitus subjects Van Gendt et al., 2012 66/92 22
A so-called uniform group of tinnitus subjects 67/92 Response to bilateral sound AC MGB IC C TIN C TIN C TIN C TIN C TIN C TIN Van Gendt, Boyen et al., 2012 68/92 Response to gaze AC MGB IC C 0 1-5 >5dB C 0 1-5 >5dB C 0 1-5 >5dB Van Gendt, Boyen et al., 2012 69/92 23
Conclusion neuroimaging 70/92 Tinnitus as a failure to adapt to peripheral loss (after Singer et al., 2012; Rüttiger et al., 2013) ARC 3 ABR 2 = failure to adapt => leads to tinnitus Ribbons 1 71/92 Overview Introduction Tinnitus: characteristics and neurophysiology Neuroimaging of tinnitus Treatments: interplay between audiological rehabilitation and counseling 72/92 24
Thalamus-cortex-amygdala Non-classical auditory system, Diffuse system Classicalauditory system, Tonotopic system From: Møller, SensorySystems 73/92 Audiograms: mild sensory neural hearing loss (n=40) Preliminary analysis 74/92 Effect of hearing aids on tinnitus in cases with mild hearing loss after 6 weeksand 6 months (Heijneman, De Kleine, Van Dijk) better 2 41% 23% better Preliminary analysis 75/92 25
Logistic regression analysis with 4 factors to predict outcome Factors Initial THI, p=0.69 Initial HADS Tinnitus frequency match Hearing loss Significance p=0.69 p=0.78 P=0.28 P=0.03 Preliminary analysis 76/92 Relation to audiogram Preliminary analysis 77/92 Effect of cochlear implantation on tinnitus Groningen population (Kloostra et al.) 100% Number of patients 50 45 40 35 30 25 20 15 10 5 0 45 No tinnitus 11 Tinnitus onset 8% 5 Tinnitus worse 22 23 No effect tinnitus less 56% 11 Tinnitus stopped 78/92 26
CI in monaural tinnitus+deafness (Kleine Punte et al. 2011, n=26) 100% 79/92 Neuromodulation with cuff electrode 80/92 Cuff electrode 81/92 27
Placement around the 8th nerve 82/92 Results of the cuff electrode (Holm et al. 2005; Bartels et al.,2007) THI-score 100 90 80 70 60 50 40 30 20 10 0 Voor 3 maanden 3,5 jaar 1 2 3 4 5 83/92 Results after 10 years 1 patient no effect, explanted 1 patient no effect 1 patient, reasonably satisfied at 3 years. No longer uses device, as it causes instability 3 patients very satisfied Long-term success rate: 50% Preliminary analysis 84/92 28
Conclusion peripheral stimulation Reported success rates between 25% and 100% Electrical stimulation seems somewhat more effective than acoustic stimulation But: There is probably a selection bias in subject inclusion in the electrical studies! Small number of subjects 85/92 Diagnostic protocol UMCG 3 rd -level referral clinic WEEK 0 WEEK 1 WEEK 2 - Information - Questionnaire I Day 1 (±3 hours): - Intake - Audiometry - ENT examination - Questionnaire II - team meeting Day 2 (±2 hours): - Tinnitus masking - Residual inhibition - Final consult 86/92 Final advising consult 30-45 minutes Explanation of the outcome of Medical diagnostics Audiological diagnostics Psychological diagnostics Possible follow up diagnostics (e.g. MRI, CT) Explanation of the pathophysiology of tinnitus Treatment options Rarely a medical treatment Rarely referral to neurosurgeon, cardiologist, TMD specialist, other specialist 70% advise to try hearing aids 19% a form of psychological counselling(1% psychiatric follow-up) 87/92 29
Changes within treatment groups THI Depression (HADS) Anxiety (HADS) * p <.05; p =.075 mean SD mean SD mean SD Hearing aids (N=90) Counselling / therapy (N=10) Hearing aids + counselling (N=9) T1 T2 T1 T2 T1 T2 34.9 19.8 4.5 3.8 4.9 3.2 36.9 21.7 5.5 4.4 5.3 3.7 64.8 17.3 8.8 5.1 11.0 4.6 53.1 21.4 7.2 4.1 7.9* 5.1 49.5 14.2 5.8 3.9 5.5 3.2 38.0* 15.6 5.8 3.9 5.0 2.6 88/92 Comparable results in a TRT trial (Henry et al., 2006) TM=tinnitus masking TRT=tinnitus retraining therapy 89/92 Conclusion Peripheral stimulation may (partially) inhibit tinnitus Counseling may ameliorate tinnitus handicap It is unclear why these interventions have are differentially effect across tinnitus patients These interventions do not cure tinnitus 90/92 30
And finally. Introduction Tinnitus: characteristics and neurophysiology Neuroimaging Treatments: interplay between audiological rehabilitation and counseling 91/92 92/100 31