Neural Abnormalities Underlying Tinnitus and Hyperacusis MASSACHUSETTS INSITUTE OF TECHNOLOGY by JUN 0 8 2011 Jianwen Wendy Gu LIBRARIES Bachelor of Science in Physics, MIT, 2003 Master of Engineering in Biomedical Engineering, MIT, 2004 Submitted to the ARCHNES Harvard-MIT Division of Health Sciences and Technology in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Health Sciences and Technology at the MASSACHUSETTS INSTITUTE OF TECHNOLOGY June 2011 © Massachusetts Institute of Technology 2011. All rights reserved. Author .. .... Halvard-MIT Division of Heilth Sciences and Technology May 17, 2011 Certified b, Jennifer R. Melcher, PhD AssociateIrof)or of Otology and Laryngology and HST Thesis Supervisor Accepted by .................... Ram Sasisekharan, PhD Edward Hood Taplin Professor of HST and Biological Engineering Director, Harvard-MIT Division of Health Sciences and Technology 2 Neural Abnormalities Underlying Tinnitus and Hyperacusis by Jianwen Wendy Gu Submitted to the Harvard-MIT Division of Health Sciences and Technology on May 17, 2011, in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Health Sciences and Technology Abstract Tinnitus, the ongoing perception of sound in the absence of a physical stimulus, and hyperacusis, the intolerance of sound intensities considered comfortable by most peo- ple, are two often co-occurring clinical conditions lacking effective treatments. This thesis identified neural correlates of these poorly understood disorders using func- tional magnetic resonance imaging (fMRI) and auditory brainstem responses (ABRs) to measure sound-evoked activity in the auditory pathway. Subjects with clinically normal hearing thresholds, with and without tinnitus, underwent fMRI or ABR test- ing and behavioral assessment of sound-level tolerance (SLT). The auditory midbrain, thalamus, and primary auditory cortex (PAC) showed elevated fMRI activation re- lated to reduced SLT (i.e. hyperacusis). PAC, but not midbrain or thalamus, showed elevated fMRI activation related to tinnitus, perhaps reflecting undue attention to the auditory domain. In contrast to fMRI activation, ABRs showed relationships only to tinnitus, not SLT. Wave I of the ABR, which reflects auditory nerve activity, was reduced in tinnitus subjects, while wave V, reflecting input activity to the midbrain, was elevated. Wave I reduction in tinnitus subjects suggests that auditory nerve dysfunction apparent only above threshold is a factor in tinnitus. Because ABRs re- flect activity in only one of multiple pathways from cochlear nucleus to midbrain, the wave V elevation implicates this particular pathway in tinnitus. The results directly link tinnitus and hyperacusis to hyperactivity within the central auditory system. Because fMRI and ABRs reflect different aspects of neural activity, the dependence of fMRI activation on SLT and ABR activity on tinnitus in the midbrain raises the possibility that tinnitus and hyperacusis arise in parallel from abnormal activity in separate brainstem pathways. Thesis Supervisor: Jennifer R. Melcher, PhD Title: Associate Professor of Otology and Laryngology and HST 4 Acknowledgements My advisor Jennifer Melcher has been a wonderful mentor in every sense of the word: scientifically, professionally, and personally. My committee members have given me many helpful comments and suggestions: Charlie Liberman, Barb Herrmann, Joe Mandeville, and Bob Levine. Special thanks to Bob for recruiting his tinnitus pa- tients to participate in my studies. I am very grateful to my co-workers, Barbara Kiang and Inge Knudson, for their kindness, support, and help. I have truly enjoyed their company. I thank Nelson Kiang for his advice and books, and for many in- teresting conversations. Chris Halpin taught me a lot about working with human subjects. Chris Shera gave me useful data analysis suggestions and let me borrow his oscilloscope for the ABR study. Previous members of the group, Eui-Cheol Nam, Dave Langers, and Elif Ozdemir, helped me collect data for the fMRI study. The Eaton-Peabody Laboratory would not function nearly as well without the staff, and I am particularly grateful to Dianna Sands, Jess Cunha, Ish Stefanov, and Frank Car- darelli for effectively and efficiently addressing my questions and issues. John Guinan and Nik Francis graciously allowed me to use Chamber 3b for the ABR study. I thank the study participants, especially the tinnitus patients who knew that they would not benefit directly from participating but wanted to help others with the condition by supporting science. My previous advisors, Denny Freeman and A.J. Aranyosi, laid the foundation for my scientific growth and have continued to help me to this day. I am deeply grateful to my family and friends whose love and encouragement have sustained my spirit. 6 Contents 1 Introduction 2 Tinnitus, diminished sound-level tolerance, and elevated auditory activity in humans with clinically normal hearing sensitivity 2.1 Introduction..... . . . . . . . . . . . . . . . . . . . . . . . . . 19 2.2 M ethods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 2.2.1 Subjects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 2.2.2 Hearing threshold . . . . . . . . . . . . . . . . . . . . . . . . . 21 2.2.3 Measuring loudness discomfort level . . . . . . . . . . . . . . . 22 2.2.4 Assessment of behavioral tinnitus characteristics . . . . . . . . 23 2.2.5 Questionnnaires . . . . . . . . . . . . . . . . . . . 24 2.2.6 Acoustic stimulation and visual task . . . . . . . . . . . . . . 25 2.2.7 Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 2.2.8 Image processing . . . . . . . . . . . . . . . . . . . . . . . . . 26 2.2.9 Quantification of activation . . . . . . . . . . . . . . . . . . . 27 2.3 Results . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . 29 2.3.1 Behavioral data: Measurements of sound-level tolerance . . . . 29 2.3.2 Activation in the auditory midbrain and thalamus: Dependen- cies on sound-level tolerance, not tinnitus . . . . . . . . . . . . 29 2.3.3 Activation in auditory cortex: Dependencies on both sound- level tolerance and tinnitus . . . . . . . . . . . . . . . . . . . . 32 2.4 Discussion . . . . .. . . .... . . . . . . . . . . . . . . . . . . . . . 33 2.4.1 A physiological correlate of hyperacusis . . . . . . . . . . . . . 34 2.4.2 Re-interpretation of previous fMRI studies of tinnitus patients 2.4.3 Dependence of PAC activation on tinnitus: Possible role of at- tention . . . . . . . . . . . . . . . . . .... - -. .. . . . 2.4.4 Cortical activation dependencies on SLT and tinnitus: Core vs belt . . . . . . . . . . . . . . . . . . . . . . . . - -. ... . 2.4.5 Relationship to animal work . . . . . . . . . . . . . . . . . . . 2.4.6 Relationship to previous studies relating auditory cortical acti- vation and loudness . . . . . . . . . . . 2.4.7 Clinical implications . . . . . . . . . . 3 Threshold-matched tinnitus and non-tinnitus subjects differ in au- ditory nerve and brainstem function 39 3.1 Introduction . . . . . . . . . . . . .................... 39 3.2 Methods . . . . . . . . . . . . . . . . . . - - . - - - - - . . . . 42 3.2.1 Behavioral testing . . . . . .... ................ 43 3.2.2 Electrode placement . . . ... ................. 43 3.2.3 Stimuli . . . . . . . . . . . .................... 43 3.2.4 Data acquisition . . . . . . ..... ..............- 44 3.2.5 Data processing . . . . . . .... ................ 45 3.2.6 Stimulus artifact removal . .... ................ 46 3.3 Results . .... .- - - - .- - - - - .- - - - 47 3.3.1 Normal ABRs in young non-tinnitus subjects (all male) . . . . 3.3.2 Reduced ABR amplitudes in older non-tinnitus subjects (all ma le) . . . . . . . . . . . . . . . . . . . . . .. ... ... . . 3.3.3 Reduced wave I amplitude but elevated wave V amplitude in tinnitus subjects (all male) . . . . . . . . . . . . . . . ... . . 3.3.4 Elevated wave V/I and III/I amplitude ratios in tinnitus subjects 3.3.5 Effects of variables other than tinnitus . . . . . . . . . . . . . 3.3.6 Relation to tinnitus characteristics . . . . . . . . . . . . ... 3.4 Discussion . . . . . . . . . . . . . . . . . . . . . . . -. . .. . . 3.4.1 Extent and pattern of auditory nerve dysfunction may be a factor in tinnitus . . . . . . . . . . . . . . . . . . . . . . . . . 51 3.4.2 Spherical bushy cell pathway implicated in tinnitus . . . . . . 52 3.4.3 Possible mechanisms underlying brainstem hyperactivity . . . 53 3.4.4 Comparison to previous ABR studies of tinnitus . . . . . . . . 54 3.4.5 Comparison of ABR and fMRI results: Tinnitus and abnormal SLT may be arise in parallel brainstem pathways . . . . . . . 55 4 Conclusion 57 4.1 Clinical implications . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 4.2 Future work . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 A Figures 61 B Tables 73 10