The Behavioral Neuroscience of Tinnitus

Preface
	References
Contents
Part I: Tinnitus in Humans
Prevalence, Incidence, and Risk Factors for Tinnitus
	1 Measures of Frequency
		1.1 Prevalence
		1.2 Incidence
		1.3 Variability in the Estimates of Tinnitus Frequency
		1.4 Estimates of Frequency for ``Any Tinnitus´´
		1.5 Distinguishing ``Severe Tinnitus´´ from ``Any Tinnitus´´
	2 Measures of Effect
	3 Observational Study Designs to Measure Frequency and Effect
		3.1 Cross-Sectional Studies for Estimating Prevalence
			3.1.1 Strengths and Limitations
		3.2 Cohort Studies for Estimating Incidence and Risk
			3.2.1 Strengths and Limitations
		3.3 Case-Control Studies for Estimating Risk
			3.3.1 Strengths and Limitations
	4 Some Examples of Risk Factors for Developing Tinnitus
		4.1 Hearing Loss or Hearing Difficulty
		4.2 Age
		4.3 Sex
		4.4 Lifestyle
	5 Future Directions
	6 Synopsis of Key Points
	References
Genetic Inheritance and Its Contribution to Tinnitus
	1 Introduction to Human Genetics
		1.1 Molecular Genetics
		1.2 Genetic Variation
		1.3 Genetic Inheritance
		1.4 Genetic Disorders: Testing and Research
			1.4.1 Assessment of Genetic Risk
			1.4.2 Genetic Testing Strategies
			1.4.3 Pharmacogenomics
	2 Evidence on Tinnitus Heritability
		2.1 Familial Aggregation
		2.2 Adoptees-Based Studies
		2.3 Twins-Based Studies
	3 Genetic Contribution to Tinnitus
		3.1 Neurotrophic Factors BDNF, GDNF
		3.2 Regulation of Serotonin Transporter
		3.3 Potassium Channels
	4 Strategies for Designing Tinnitus Genetic Studies
		4.1 Well-Defined Tinnitus Phenotype with a Homogenous Profile
		4.2 Extreme Phenotype Studies
		4.3 Tinnitus Extreme Phenotype in Meniere Disease
		4.4 Limitations and Future Directions
	References
Part II: Preclinical and Clinical Models of Tinnitus
Pharmacological Evaluation of Drugs in Animal Models of Tinnitus
	1 Animal Models of Tinnitus
	2 Current Drug Evaluation in Animal Models of Tinnitus
		2.1 Drugs Enhancing GABA-Mediated Inhibitory Neurotransmission
		2.2 Drugs Reducing Glutamate-Mediated Excitatory Neurotransmission
		2.3 Drugs Modulating Other Neurotransmitter Systems
		2.4 Drugs Modulating Ion Channels
		2.5 Drugs Modulating Neuroinflammatory Pathways
		2.6 Herbal Medicines
	3 Advantages and Limitations of Drug Evaluation Using Animal Models
	4 Future Directions in Tinnitus Drug Discovery
	References
Animal Models of Tinnitus Treatment: Cochlear and Brain Stimulation
	1 Significance of Developing Animal Models
	2 Cochlear Stimulation to Suppress Tinnitus
		2.1 Cochlear Electrical Stimulation
			2.1.1 Intra-cochlear Electrical Stimulation
			2.1.2 Extra-cochlear Electrical Stimulation
			2.1.3 CES to Normalize Spontaneous Firing in the Auditory Nerve
			2.1.4 CES and Modulation of Brain Plasticity
			2.1.5 Directions of Future Studies with Cochlear Electrical Stimulation
		2.2 Optogenetic Cochlear Stimulation
	3 Intraparenchymal Brain Electrical Stimulation
		3.1 Targets in the Brain Network and Modalities of Stimulation
			3.1.1 Brain Network Dysfunction and Informatics
			3.1.2 Lemniscal vs. Extra-lemniscal and Their Associated Neural Network
		3.2 Auditory Brainstem Implant (ABI)
		3.3 Auditory Midbrain Implant (AMI)
		3.4 Thalamocortical Modulation
			3.4.1 Thalamic Modulation and Deep Brain Stimulation (DBS)
			3.4.2 Auditory Cortex Electrical Stimulation (ACES)
		3.5 The Basal Ganglion and Deep Brain Stimulation (DBS)
			3.5.1 Subthalamic Nucleus (STN)-DBS
			3.5.2 Nucleus Accumbens (NAc)-DBS
	4 Transcranial Brain Stimulation
		4.1 Transcranial Magnetic Stimulation (TMS)
		4.2 Transcranial (TES) and Epi-Cranial Electrical Stimulation (ECS)
	5 Bottom-Up and Top-Down Modulations
	6 Summary, Limitations, and Future Directions
	References
Part III: Developing Biomarkers for Tinnitus
Functional Neuroanatomy of Salicylate- and Noise-Induced Tinnitus and Hyperacusis
	1 Introduction
		1.1 Consistent Induction of Tinnitus and Hyperacusis
		1.2 Tinnitus Evaluated with Schedule-Induced Polydipsia Avoidance Conditioning (SIPAC)
		1.3 How Much Salicylate Is Required to Induce Tinnitus?
		1.4 Using SIPAC to Screen Drugs to Suppress Tinnitus
		1.5 Two-Alternative Forced Choice Paradigm to Assess Tinnitus
		1.6 Noise-Induced Tinnitus Measured with 2AFC Paradigm
		1.7 Does Salicylate Induce Hyperacusis?
		1.8 Noise-Induced Hyperacusis
		1.9 Noise-Induced Avoidance Hyperacusis
		1.10 Salicylate-Induced Hyperexcitability
		1.11 Salicylate-Induced Upshifts and Downshifts in Neural Tuning
		1.12 Brain Imaging of Salicylate-Induced Tinnitus and Hyperacusis
		1.13 Salicylate-Induced Increases in Functional Connectivity
		1.14 Sound-Evoked Hyperactivity Measured by fMRI
		1.15 Synopsis
	References
Neuroinflammation and Tinnitus
	1 Introduction
	2 TNF-α Signaling Pathway in Tinnitus
	3 Calpain Signaling Pathway in Tinnitus
	References
Using Big Data to Develop a Clinical Decision Support System for Tinnitus Treatment
	1 Introduction
	2 Decision Support System
		2.1 Requirements for the Underlying Database
		2.2 Requirements for the Underlying Knowledge Base
		2.3 Requirements for the Algorithms
	3 Decision Support System Within the UNITI Project
	4 Privacy and Ethical Concerns
	5 Summary
	References
Part IV: Pharmacotherapy and Neuromodulation of Tinnitus
Pharmacotherapy of Tinnitus
	1 Introduction
	2 Rationale for Pharmacotherapy
	3 Acute Tinnitus
	4 Chronic Tinnitus
	5 Objective Tinnitus
	6 Medications that Can Cause Tinnitus
	7 Conclusion and Outlook
	References
Sense and Sensibility: A Review of the Behavioral Neuroscience of Tinnitus Sound Therapy and a New Typology
	1 Introduction to the Sense and Sensibility of Sound Therapy
	2 A Modern History of Sound Therapy
		2.1 Hearing Aids
		2.2 Masking
		2.3 Tinnitus Retraining Therapy (TRT)
		2.4 Modified Tinnitus Retraining Therapy
		2.5 Tinnitus Activities Treatment (TAT)
		2.6 Music Therapy
		2.7 Neuromonics
		2.8 Notched: Noise, Music, and Amplification
		2.9 Fractal Sounds
		2.10 Acoustic CR Neuromodulation: Desyncra
		2.11 The Levo System: Otoharmonics
		2.12 Timed Bimodal and Multimodal Stimulation
		2.13 Active Auditory Perceptual Training
	3 Treatment Frameworks and Protocol Strategy
	4 Typology: Evidence from Behavioral Neuroscience
		4.1 Presence of Sound Effect
			4.1.1 Masking
			4.1.2 Residual Inhibition
			4.1.3 Entrainment and Desynchronization
			4.1.4 Lateral Inhibition
			4.1.5 Peripheral Re-afferentation and Change in Gain
		4.2 Context of Sound Effect
			4.2.1 Informational Masking
			4.2.2 Attention and Categorization Retraining
		4.3 Reaction to Sound Effect
			4.3.1 Gating
			4.3.2 Affect
			4.3.3 Relaxation
			4.3.4 Clinical Implications of Reaction to Sound
		4.4 Adaptation
	5 Sound Therapy with Precision
	6 Is Sound Therapy Harmful?
	7 Conclusion
	References
Tinnitus and Brain Stimulation
	1 Introduction
	2 History and Evolution of the Pathophysiology of Tinnitus
	3 A Theory of Symptom Generation in the Brain
		3.1 Neuromodulation as Targeted Neuroplasticity
		3.2 Mechanism of Action of Cortex Stimulation
			3.2.1 Brain Stimulation Techniques in the Treatment of Tinnitus
			3.2.2 TMS for Treating Tinnitus
				The Regimen, Parameter, and Efficacy of TMS
				Single Sessions
				Repeated Sessions
				tES for Treating Tinnitus
			3.2.3 Transcranial Direct Current Stimulation (tDCS)
				Conventional tDCS
				High-Definition tDCS
			3.2.4 Transcranial Alternating Current Stimulation (tACS)
			3.2.5 Transcranial Random Noise Stimulation (tRNS)
			3.2.6 Vagus Nerve Stimulation (VNS) and Transcutaneous Vagal Nerve Stimulation (tVNS)
			3.2.7 Bimodal (Auditory and Sensory) Stimulation
			3.2.8 Invasive Brain Stimulation for Tinnitus
				Auditory Cortex Stimulation
				Deep Brain Stimulation
	4 Conclusion
	References
Bimodal Auditory Electrical Stimulation for the Treatment of Tinnitus: Preclinical and Clinical Studies
	1 Introduction
		1.1 Animal Model Development of Tinnitus Treatments
			1.1.1 Dorsal Cochlear Nucleus Plasticity as a Basis for Tinnitus Treatment
				Dorsal Cochlear Nucleus Fusiform Cells Integrate Multisensory Information
				Tinnitus-Linked Neural Plasticity First Arises in the Cochlear Nucleus
				Toward a Tinnitus Treatment
				Noise Overexposure Alters Excitability Throughout the Auditory Pathway
			1.1.2 Cortical Plasticity as a Basis for Tinnitus Treatment
				Treating Tinnitus by Reversing Pathological Cortical Plasticity in Animals
		1.2 Translating Animal Studies to Humans
			1.2.1 Bimodal Auditory-Somatosensory Stimulation to Reduce Tinnitus in Humans
			1.2.2 Bimodal Auditory VNS to Treat Tinnitus in Humans
			1.2.3 Open-Label Pilot Studies Using Bimodal Auditory Electrical Stimulation
	2 Discussion
	References
Part V: Cognitive and Affective Aspects of Tinnitus
Neurobiology of Stress-Induced Tinnitus
	1 Introduction
	2 Stressors
	3 Neurobiological Mechanisms Associated with Tinnitus Induction
	4 Stress-Induced Responses
		4.1 The Hypothalamus-Pituitary-Adrenal Axis (HPA Axis)
		4.2 Potential Involvement of the Stress-Activated HPA Axis in Tinnitus Generation
			4.2.1 Mitochondrial Damage and ROS Formation
			4.2.2 Glucocorticoid-Modified Expression of Genes
			4.2.3 Influence of HPA Axis on Glutamate Signaling
		4.3 The Sympathetic-Adreno-Medullar (SAM) Axis
		4.4 Potential Involvement of the Stress-Activated SAM Axis in Tinnitus Generation
			4.4.1 Arterial Hypertension
			4.4.2 Catecholamines
		4.5 The Immune Axis
		4.6 Potential Involvement of the Stress-Activated Immune Axis in Tinnitus Generation
			4.6.1 A Direct Influence of Stress on the Immune Cells in the Cochlea
			4.6.2 Influence of Cytokines
	5 Summary and Conclusions
	References
Psychological Comorbidities of Tinnitus
	1 Introduction
	2 Diagnosis and Assessment of Tinnitus
	3 Stress, Anxiety, and Depression Are Frequent Comorbidities of Tinnitus
	4 Depression or Severe Tinnitus?
	5 Therapeutic Avenues for Decreasing Comorbidities of Tinnitus
	6 Final Remarks
	References
Psychosocial Variables That Predict Chronic and Disabling Tinnitus: A Systematic Review
	1 Introduction
	2 Methods
		2.1 Search Procedure
		2.2 Study Selection
		2.3 Eligibility Criteria
	3 Results
		3.1 Predictors of the Transition from Acute to Chronic, Disabling Tinnitus
		3.2 Predictors of Tinnitus Outcomes in Individuals with Chronic Tinnitus: Longitudinal Studies with 2 Data Collection Points
		3.3 Predictors of Tinnitus Outcomes in Individuals with Chronic Tinnitus: Ecological Momentary Assessment (EMA) and Diary Stud...
	4 Discussion
	References
Part VI: Clinical Assessment of Tinnitus
Momentary Analysis of Tinnitus: Considering the Patient
	1 Introduction: Momentary Assessment
		1.1 Designing an Ecological Assessment
		1.2 Precision Medicine and Ecological Data Sampling
	2 Analytical Approaches to Ecological Data
	3 Use and Utility of Momentary Assessment in Other Fields
	4 Tinnitus
		4.1 Tinnitus as an Ecological Entity
		4.2 Current Assessment
		4.3 Examples of EMA
		4.4 Where We Are
		4.5 Limitations of Momentary Assessment
	5 Future Directions
	6 Conclusion
	References
Tinnitus Questionnaires for Research and Clinical Use
	1 Introduction
		1.1 Characteristics of Questionnaires
		1.2 Item Wording and Measurement Scales
	2 Psychometric Properties
	3 Assessment
		3.1 Tinnitus Case History
		3.2 Performing a Needs Assessment
		3.3 Screening Tools and Outcome Measures
		3.4 Permission for Use
	4 Summary
	References
Principles and Methods for Psychoacoustic Evaluation of Tinnitus
	1 Introduction
		1.1 Overview of Clinical Characteristics of Tinnitus
		1.2 The Historic Foundations of Tinnitus Matching
	2 Psychoacoustic Measures: Pitch
		2.1 Methodologies of Tinnitus Pitch Matching
			2.1.1 Test Ear
			2.1.2 Matching Method
		2.2 Tinnitus Pitch and Hearing Loss
		2.3 Reliability of Pitch-Matching Measures
	3 Psychoacoustic Measures: Loudness
		3.1 Tinnitus Loudness Matching and Choice of Units
		3.2 Tinnitus Loudness, Recruitment, and Hyperacusis
		3.3 Tinnitus Loudness: Annoyance and Severity
		3.4 Tinnitus Loudness, Magnitude, and the Adaptation Level Theory
	4 Confusion of Pitch and Loudness: The Circular Problem
	5 The Minimum Masking Level
	6 Auditory Residual Inhibition
		6.1 Cautions and Application
	7 The Future of Psychoacoustic Measures: Methods and Application to Therapy
		7.1 Methods
		7.2 Application to Treatment
	8 Summary
	References
Emerging Topics in the Behavioral Neuroscience of Tinnitus
	1 Introduction
	2 Tinnitus Is, What Tinnitus Is
	3 The Pathway to Precision in Assessment
		3.1 Biomarkers of Tinnitus
		3.2 Acute, Chronic, Bothersome, and Disabling Tinnitus
		3.3 Psychoacoustic Measures
		3.4 Standardized Outcome Measures
		3.5 Predicting Success
	4 The Research Pathway to Precision Therapy
		4.1 Network-Based Models
			4.1.1 Polytherapeutics
			4.1.2 From Polypharmacology to Multimodal Treatment
	5 Improving Research to Improve Outcomes
		5.1 Diversity
		5.2 Clinical Research Design and Methods
		5.3 Tinnitus Research Community and Cooperation
	6 Summary
	References
Correction to: Prevalence, Incidence, and Risk Factors for Tinnitus
	Correction to:Chapter ``Epidemiology of Tinnitus´´ in: Roshni Biswas and Deborah A. Hall, Curr Topics Behav Neurosci, https://...
Correction to: Emerging Topics in the Behavioral Neuroscience of Tinnitus
	Correction to: Chapter ``Emerging Topics in the Behavioral Neuroscience of Tinnitus´´ in: Grant D. Searchfield et al., Curr To...