Effects of Residual Inhibition Phenomenon on Early Auditory Evoked

University of Veterinary Medicine Hannover
Hannover Medical University
Department of Otorhinolaryngology
Center for Systems Neuroscience
Effects of Residual Inhibition Phenomenon on Early Auditory Evoked Potentials and
Topographical Maps of the Mismatch Negativity Obtained With the Multi-Feature
Paradigm in Tinnitus
THESIS
Submitted in partial fulfillment of the requirements for the degree
DOCTOR OF PHILOSOPHY
(Ph.D.)
Awarded by the University of Veterinary Medicine Hannover
By
Saeid Mahmoudian
Tehran, Iran
Hannover, Germany 2015
Supervisor:
Prof. Prof. h. c. Dr. med. Thomas Lenarz
Supervision Group:
Prof. Prof. h. c. Dr. med. Thomas Lenarz
Prof. Dr. med. Reinhard Dengler
P.D. Dr. rer. nat. Karl-Heinz Esser
Prof. Dr. Christoph Herrmann
1st Evaluation:
Prof. Prof. h. c. Dr. med. Thomas Lenarz
Department of Otorhinolaryngology
Hannover Medical University
Prof. Dr. med. Reinhard Dengler
Department of Neurology
Hannover Medical University
P.D. Dr. rer. nat. Karl-Heinz Esser
Auditory Neuroethology and
Neurobiology Lab, Institute of Zoology
University of Veterinary Medicine Hannover
2nd Evaluation:
Prof. Dr. Uwe Baumann
University of Frankfurt/Main
Date of final exam:
13.03.2015
Dedicated
To my loving wife for her utmost efforts to make impossible, possible
To my kids and my parents
Parts of the thesis have been published previously in:
Brain Research journal (2013) and International Tinnitus Journal (2013).
AUTHOR’S PEER REVIEWED ARTICLES

Mahmoudian S, Farhadi M, Mohebbi M, Alaeddini F, Najafi-Koopaie, Darestani
Farahani E, Mojallal H, Omrani R, Daneshi A, Lenarz T. Alterations in auditory
change detection associated with tinnitus residual inhibition induced by auditory
electrical stimulation. J Am Acad Audiol. 2014; 26 (5), Accepted to publish.

Mohebbi M, Mahmoudian S, Sharifian Alborzi M, Najafi-Koopaie M, Darestani
Farahani E, Farhadi M. Auditory middle latency responses differ in right- and lefthanded subjects: An evaluation through topographic brain mapping. Am J Audiol.
2014; 23(3): 273-81. doi: 10.1044/2014_AJA-13-0059.

Mahmoudian S, Farhadi M, Gholami S, Saddadi F, Jalesi M, Karimian AR,
Darbeheshti M, Momtaz S, Fardin S. Correlation between brain cortex metabolic
and perfusion functions in subjective idiopathic tinnitus. Int Tinnitus J. 2013; 18 (1):
20-8. doi: 10.5935/0946-5448.20130004.

Najafi-Koopaie M, Sadjedi H, Mahmoudian S, Darestani-Farahani E, Mohebbi M.
Wavelet Decomposition-Based Analysis of Mismatch Negativity Elicited by a
Multi-Feature Paradigm. Neurophysiology. 2014; 46 (4): 361-69.
doi.org/10.1007/s11062-015-9487-0.

Mahmoudian S, Farhadi M, Gholami S, Saddadi F, Karimian AR, Mirzaei M,
Ghoreyshi E, Ahmadizadeh M, Lenarz T. Pattern of brain blood perfusion in tinnitus
patients using technetium-99m SPECT imaging. J Res Med Sci. 2012; 17(3): 24247.

Mahmoudian S, Shahmiri E, Rouzbahani M, Jafari Z, Keyhani MR, Rahimi F,
Mahmoudian G, Akbarvand L, Barzegar G, Farhadi M. Persian language version of
the Tinnitus Handicap Inventory: translation, standardization, validity and
reliability. Int Tinnitus J. 2011; 16(2): 93-103.

Farhadi M, Mahmoudian S, Saddadi F, Ahmadizadeh M, Karimian AR,
Ghasemikian K, Mirzaee M, Beyty S, Shamshiri A, Madani S, Bakaev V, Raeisali
GR. Functional brain abnormalities localized in 55 chronic tinnitus patients: fusion
of SPECT coincidence imaging and MRI. J Cereb Blood Flow Metab. 2010; 30(4):
864-70. doi: 10.1038/jcbfm.2009.254. Epub 2010 Jan 13.
Table of Contents
ABBREVIATIONS
I
1
GENERAL INTRODUCTION
1
1.1
Definitions
1
1.2
Pathophysiology of Tinnitus
1
1.3
Residual Inhibition (RI)
5
1.4
Some of the Theories Corresponding to RI
8
1.5
Auditory Evoked Potentials (AEPs)
12
1.6
Auditory Electrical Stimulation (AES)
19
1.6.1 Characteristics of AES
20
1.7
21
Diagnostic Approach to Tinnitus
1.7.1 Tinnitus Psychoacoustic Assessments
21
1.7.2 Tinnitus Questionnaires
23
1.8
Aim of the Thesis
23
2
PAPER I. Alterations in Early Auditory Evoked Potentials and
Brainstem Transmission Time Associated With Tinnitus Residual Inhibition
Induced By Auditory Electrical Stimulation
26
Abstract
27
3
PAPER II. Central Auditory Processing During Chronic Tinnitus
As Indexed by Topographical Maps of the Mismatch Negativity Obtained
With the Multi-Feature Paradigm
28
Abstract
29
4
COMPREHENSIVE DISCUSSION
30
4.1
Alterations in Neuro- Electric Potentials Associated with Tinnitus RI
31
4.2
The Effects of Chronic Tinnitus on Central Auditory Processing
33
5
SYNOPSIS OF RESEARCH
36
6
REFERENCES
39
7
SUMMARY
58
ZUSAMMENFASSUNG
60
Acknowledgments
63
Declaration
65
Abbreviations
ABR
Auditory Brain Stem Response
AEPs
Auditory Evoked Potentials
AERPs
Auditory Event Related Potentials
AES
Auditory Electrical Stimulation
ALLR
Auditory Late Latency Response
AMLR
Auditory Middle Latency Response
AMPA receptor
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
receptor
ANOVA
analysis of variance
ASSR
Auditory Steady State Response
BTT
Brainstem Transmission Time
CAP
Compound Action Potential
CAS
Central auditory system
CI
Cochlear implant
CNS
Central Nervous System
CRI
Complete Residual Inhibition
CT
Computerized Tomography
dB
Decibel
DS
Deviant Stimuli
DW
Difference Waves
ECochG
Electrocochleography
EEG
Electroencephalography
ENT
Ear, Nose, Throat
EOG
Electro-oculogram
ERPs
Event Related Potentials
ES
Electrical Stimulation
fMRI
Functional Magnetic Resonance Imaging
HL
Hearing Level
5-HT receptor
5-Hydroxytryptamine Receptors
IC
Inferior colliculus
IPL
Inter Peak Latency
LLRs
Late Latency Responses
I
MEG
Magnetoencephalography
MLRs
Middle Latency Responses
MMN
Mismatch Negativity
MTL
Medio-Temporal Lobe
MRI
Magnetic Resonance Imaging
NH
Normal Hearing
NMDA receptor
N-methyl-D-Aspartate Receptor
NRI
Non-Residual Inhibition
PES
Placebo Electrical Stimulation
PET
Positron Emission Tomography
PRI
Partial Residual Inhibition
QEEG
Quantitative Electroencephalography
RI
Residual Inhibition
ROI
Region-of-Interest
rTMS
Repetitive Transcranial Magnetic Stimulation
SL
Sensation Level
SS
Standard Stimuli
SIT
Subjective Idiopathic Tinnitus
SPECT
Single-Photon Emission Computed Tomography
SPSS
The Statistical Package for Social Science
THI-P
Persian Version of Tinnitus Handicap Inventory
TAFC
Two-Alternative first choice method
TinnED®
Tinnitus Evaluation Device
TQ-P
Persian version of Tinnitus Questionnaire
TTS
Temporary Threshold Shift
II
1
General Introduction
1.1
Definitions
Tinnitus is “the conscious experience of a sound that originates in an involuntary manner in the
head of its owner or may appear to him to be so” (McFadden, 1982). It can be considered also as
an auditory phantom perception. People who are suffering from tinnitus usually complain
significant accompanied morbidities such as sleep deprivation, lifestyle detriment, emotional
disturbances, depression, work difficulties, social interaction problems, and decreased overall
health. With regard to epidemiological view, Tinnitus affects 10–30% of the population and tends
to increase in frequency with age (Davis et al., 2000).
1.2
Pathophysiology of Tinnitus
The fact that tinnitus is consciously perceived as a sound suggests that central auditory neural
networks activity must be involved (Eichhammer, 2007; Shulman et al., 2006; Eggermont &
Roberts, 2004; Eggermont, 2003; Lockwood et al., 2002; Reyes, 2002; Jastreboff, 1990).
Abnormal increase in function of neural networks or enhancement of stimulatory synapses
function and/or decreased function of inhibitory synapses may be responsible for impairing
pathways. Subjective idiopathic tinnitus (SIT) may occur during a malfunctioning of feedback
loops or hyperactivity in the peripheral auditory system (cochlea and eighth cranial nerves) (Coles,
1997; Zenner and Ernst, 1993). In the recent years, it has been widely accepted that maladaptation
of central information processing are mainly responsible in tinnitus perception and generation
(Plewnia et al, 2007). Meanwhile abnormal activity at higher levels of the auditory pathways
(auditory nuclei, auditory cortex, associative cortices) may contribute significantly to the
generation of tinnitus. This abnormal auditory signal is interpreted as a troublesome tinnitus. This
1
processed auditory conscious sound could also create unpleasant and distress feeling in the chronic
tinnitus subjects due to its relation to limbic system. Memory, attention, and the emotional state of
the patients are important factors that may be involved in this reaction. Thus, this
neurophysiological process may not be detected by an evaluation of the cerebral function in
tinnitus subjects (Mirz et al., 1999). Tinnitus is not a single pathology, but rather a multiform
symptom (Guitton, 2006). This symptom can be associated with other disorders such as hearing
loss, presbycusis, drug ototoxicity, neurinoma and other pathologies. Thus, various origins could
be considered as various forms of tinnitus. However, despite of this variation, the final result is the
tinnitus sensation and the transmission of an abnormal message through the central auditory
pathways. It was suggested that, at least for some forms of tinnitus, a common biological bases
could be considered (Guitton, 2012).
Clinical evidence suggested a peripheral origin for the majority of tinnitus (Guitton, 2006;
Nicolas-Puel et al., 2002; Loeb and Smith, 1967). The cochlea as primary auditory organ is the
first place for generating tinnitus (Guitton, 2012). Tinnitus which is an abnormal message,
perceived in the earlier neural pathways should originate in the same area. Thus, the synapse
between the sensory inner hair cells and the primary auditory neuron and the primary auditory
neurons themselves are highlighting candidates for the site of initiation of tinnitus (Guitton, 2012).
Guitton and Dudai (2007) reported that local intra-cochlear application of NMDA receptor
antagonists was able to prevent the initiation of tinnitus induced by noise over exposure in 100%
of animal subjects, when applied around the time of induction of tinnitus by noise over exposure.
These authors also reported that AMPA receptor antagonists and 5-HT receptors antagonists did
2
not prevent the onset of tinnitus and this blockade was specific to NMDA receptors. Furthermore,
in the case of noise-induced tinnitus, the sensitivity of this process to NMDA receptor blockade
remains for several days after the initial noise over exposure (Guitton and Dudai, 2007). Thus, the
initial phase of both salicylate-induced and noise-induced tinnitus is dependant on NMDA receptor
activity in primary auditory neurons.
The involvement of central parts of the auditory system does not contradict with the evidence
that tinnitus originates from single synapses in the auditory peripheral system. Sensory messages
originate from the peripheral organs, but perception itself is a phenomenon carried out by system
activity such as subcortical and cortical neural networks. Nonetheless, Tinnitus is not different
from other sensory phenomena (Guitton, 2012).
The long-term remaining of tinnitus is critical as defined by Guitton, 2012. According to his
study there are two possible factors are important in tinnitus: (1) a possibility would be that tinnitus
“stays” in the peripheral auditory system, but under the dependency of other molecular pathways,
(2) by passing time, tinnitus progressively recruits several anatomical structures in auditory (the
peripheral and central auditory systems) and non-auditory (the limbic system and higher order
brain structures) systems (Guitton and Dudai, 2007; Eggermont, 2006; Guitton, 2006; Eggermont
and Roberts, 2004) (Fig 1.1). Guitton’s (2012) results pointed out that “the distribution of the
tinnitus engram from one location to multiple locations strongly echoes the process of systemlevel consolidation which appears in memory (Dudai, 2004, Dudai, 2006). The engram moves
forward from an initial location (cochlea) and the medio-temporal lobe for different forms of
memory (Dudai, 2004), to the other complex network structures of the brain (Dudai, 2004).
3
The translocation of the engram corresponding to tinnitus may be the result of significant
plasticity observed along the auditory structures after acoustic trauma measured at the molecular
level (Mahlke and Wallhäusser-Franke, 2004; Wallhäusser-Franke et al., 2003; Milbrandt et al.,
2000) and electrophysiological recordings (Eggermont, 2006; Noreña et al., 2006, Kaltenbach et
al., 2004; Kimura and Eggermont, 1999; Willott and Lu,1982). This comparison between tinnitus
and those of memory could also be extended with another phenomenon such as chronic pain
(Guitton, 2012) shown in Fig. 1.1.
Memory
Tinnitus
Acquisition
Sensory organ
Consolidation-like
process
Complex cortical
networks
Molecular level
NMDA-dependent
process
Long-term
maintenance
System level
Long-term
plasticity
Medio-temporal
lobe (MTL)
Consolidation
Complex cortical
networks
Fig. 1.1
Tinnitus and memory. Analogies between the consolidation process occurring in memory and the
translocation of the engram from the medio-temporal lobe to complex cortical networks; and the putative
consolidation-like process which may lead to the translocation of tinnitus from the cochlea to complex neuronal
networks. (Similarities of tinnitus with memory, Guitton, 2012).
Although the psychophysical characteristics of tinnitus have been described in some details, the
neural locations and mechanisms that cause tinnitus and associated with disabilities are poorly
4
understood in the absence of suitable techniques for assessment of the abnormal neural activation
in human of being (Murai et al., 1992). Progress in brain electrophysiology and function imaging
techniques have made it possible to identify the specific brain regions interacting in the production
and processing of transient subjective sensations such as phantom pain, hallucination and also
perception and processing of sound and tinnitus (Plewnia et al., 2007; Shulman et al., 2004;
Lockwood et al., 1998, 2001; Mirz et al., 1999; Giraud et al., 1999; Lockwood et al., 1998; Flor et
al., 1995; Silbersweig et al., 1995). It could be an important step in the task of defining the factors
creates these phantom sensations and accordingly suitable treatments for this chronic and disabling
condition (Lockwood et al., 1998, 2001).
1.3
Residual Inhibition (RI)
Following an appropriate masking stimulus, tinnitus may remain suppressed for a period. This
phenomenon is known as “residual inhibition” (RI). After deactivating the stimulation, one of the
following results may occur. These results include Complete Residual Inhibition (CRI), Partial
Residual Inhibition (PRI), Non-Residual Inhibition (NRI) and finally Rebound Effect (facilitated
tinnitus) leading to some aggravation in tinnitus loudness reported by the patients.
When tinnitus remains inaudible, even after disengaging the masking stimulus, it is called CRI
(Fig. 1.2-A). The term PRI refers to the situation in which the tinnitus is reduced but still heard by
the patient (Fig. 1.2-A). While tinnitus is remained unchanged, after switching off the masking
stimulation, it is called NRI. In few tinnitus patients some increase may occur in loudness of
tinnitus after presenting masking stimuli, which is called rebound phenomenon (Fig. 1.2-B).
5
(A)
(B)
Fig.1.2
Hypothetical model of tinnitus RI. Figure illustrates complete residual inhibition (CRI), partial residual
inhibition (PRI) and rebound effect (facilitating tinnitus loudness). CRI is measured normally from the cutoff point of
masking stimulus (60 second) as long as tinnitus loudness reappears (120 second). From this time till the loudness of
tinnitus gradually reach to its initial level called PRI (Kitahara, 1988).
RI can also be generated by auditory electrical stimulation (AES) (Daneshi et al., 2005; Kim et
al., 1998; Balkany et al., 1987; Graham and Hazell, 1977), repetitive transcranial magnetic
stimulation (rTMS) (Kleinjung et al., 2009; Lee et al., 2008; Plewnia et al., 2007; Smith et al.,
2007). Although these procedures act in different ways, all of them can reduce tinnitus by
interrupting abnormal synchronous activity among networks of neurons generating tinnitus
(Roberts, 2007). Treatments that induce tinnitus suppression utilizing these methods have been
6
reported to reduce tinnitus distress by processes that are not well understood. We know that
implication of electrical/acoustical stimulation in tinnitus subjects can cause improvement. The
neural origin and mechanisms of tinnitus RI by different stimuli are largely unclear.
It could be possible (with no certainty) that the neural mechanisms which are involved in RI
phenomenon, are similar to (or overlap with) those that cause generation of tinnitus (Roberts,
2007). By accepting aforesaid hypothesis, understanding neural mechanisms involved in RI can
create a new horizon to understand the essential mechanisms in tinnitus. Feldman (1971) in his
classic studies on tinnitus masking observed that a considerable number of tinnitus subjects
experienced a brief reduction in their tinnitus following the cutoff masker. This phenomenon has
come to be called as RI. Till now and in spite of its importance, RI has not been thoroughly
investigated and understanding its involved neural mechanisms. This indeed can improve our
knowledge about tinnitus neural mechanisms. While RI phenomenon is one of the few procedures
that may cause the reduction of tinnitus for a short period of time, it is amazing that there is no
adequate quantity of published studies and researches in this subject (Henry and Meikle, 2000).
The proportion of tinnitus patients who report some degrees of RI (complete or partial RI) are
more than 75% (Vernon and Meikle, 2003; Roberts et al., 2006).
There is, however, considerable variability amongst tinnitus subjects in the RI depth and duration
of tinnitus inhibition. Therefore, different types of RI such as CRI, PRI and NRI and the related
recurrent time are restricted to each case. This mentioned point should be considered as a separated
issue for further researches.
7
1.4
Some of the Theories Corresponding to RI
In 2008, Nina Kahlbrock from Konstanz University and Nathan Weisz from INSERM completed
a whole-brain Magnetoencephalography (MEG) imaging study on tinnitus subjects who showed
RI (Kahlbrock and Weisz, 2008). Their main finding was that brain activity in the delta frequency
band (i.e. 1.5 to 4 Hertz) was decreased during RI, in temporal regions. They put forward a theory
that RI is caused by a temporary return of normal activity in the brain’s auditory system. Other
previous MEG study showed an increased activity in the 2 to 8 hertz frequency band. Those authors
stated that RI involves some unusual extra brain activity which was not seen in their control
subjects (Kristeva-Feige et al., 1995).
In 2012 a research group from University College London and Newcastle University, led by
William Sedley, published another whole-brain MEG study on 17 patients with chronic tinnitus
(Sedley et al., 2012). 14 tinnitus subjects exhibited RI, and 4 showed the reverse response which
was termed as “residual excitation”. The study reported that auditory cortex gamma power
positively correlates with RI, and in residual excitation it shows the opposite correlation. The team
also looked at lower frequency activity in the auditory cortex (in the delta band, from 1.5 to 4 Hz;
and the theta band, from 4 to 8 Hz). Again, this activity consistently decreased during RI. During
residual excitation however, no significant change in auditory cortex lower frequency activity was
seen. Regarding a theory for RI, the authors propose that, “RI is achieved by a transient and partial
normalization of the deafferentation of auditory thalamus that leads to the generation of tinnitus.”
This agrees with the theory of Kahlbrock and Weisz, with the added detail of the normalization
occurring in the auditory thalamus – this following from an earlier “thalamocortical dysrhythmia
8
model” cited by the Sedley team. They propose that auditory cortex gamma oscillations act to
suppress the perception of tinnitus.
In addition to brain-imaging studies, the following theories concerning RI have been also
published in the past years:
Harald Feldmann in 1971 stated that tinnitus masking and RI occurred in the brain rather than
the ear; meanwhile he proposed that this indeed might be due to neural inhibition (Feldmann,
1971). He based his thought on evidence from the unusual frequency characterized in tinnitus
masking.
Mark Terry and colleagues from UWIST in Wales spread over a theory in 1983 for RI based on
an unusual form of temporary threshold shift (TTS) that they had found associated with RI (Terry
et al., 1983). TTS is a temporary hearing loss, which normally occurs after exposure to loud sound.
However, the UWIST team noticed that a small TTS occurred during RI, in the frequency region
of the tinnitus. They suggested that RI may occur because “the tinnitus ‘signal’ drops below the
temporarily raised threshold.”
In 1987, Juergen Tonndorf from Columbia University declares a theory for RI based on the
neuroscience of pain (Tonndorf, 1987). In this theory, he pointed out that mechanism of subjective
tinnitus (for many patients) was assumed to be in the cochlea. Since Tonndorf wrote his paper,
evidence and argument has grown for the mechanism (typically) being based in the brain, even if
the tinnitus started as a result of cochlear damage. Tonndorf outlines the situation for most cochlear
damage associated with tinnitus: the stronger inner hair cells (with large diameter nerve fibers)
9
remain relatively undamaged, while the delicate outer hair cells (with small diameter nerve fibers)
are destroyed. This leaves the small diameter nerve fibers input-starved (“deafferented”), which is
known to increase spontaneous activity in the nerve. This extra activity is the supposed source of
the ongoing tinnitus. Making an analogy with a neural theory regarding chronic intractable pain,
Tonndorf then suggests that, “Acoustic masking with its relatively short ‘residual inhibition’
(typically measuring in minutes) might mechanically re-activate the large diameter, inner-hair-cell
fibers in largely the same manner as the large-diameter pain fibers are temporarily re-activated by
scratching or by vibratory stimulation.” Then, by a “gate control theory” for pain (first proposed
in 1965), the activity of the large diameter, inner-hair-cell fibers act to shut-off (for a time) the
aberrant signaling from the small diameter, outer-hair-cell fibers. Thus perception of the tinnitus
is stopped for a period of time. Similarly, in 1981 Jack Vernon and Mary Meikle speculated that
the mechanism of RI may be related to mechanisms that suppress pain for a period of time after
electrical stimulation (Vernon and Meikle, 1981).
Pawel Jastreboff and Jonathan Hazell, the pioneers of tinnitus retraining therapy, suggested in a
2004 book on the subject that RI can “be easily explained by the rebound phenomenon”. The
rebound phenomenon is well recognized in neurophysiology. If the activity of a neuron, as the
result of sound stimulation, is increased, cessation of the signal frequently results in activity
decreasing below the previous level of spontaneous activity occurring before stimulation. If
stimulation was causing inhibition of neuronal activity, then switching off the sound results in an
enhancement of spontaneous activity for some time. Then the neuronal activity returns to the prestimulus level” (Jastreboff and Hazell, 2004).
10
In a plenty of papers between 2004 and 2008, Larry Roberts and colleagues published their
observations and arguments supporting a particular theory for the mechanism of tinnitus, along
with ideas for the mechanism highlighting RI (Roberts et al., 2008; Roberts, 2007; Roberts et al.,
2006; Henry et al., 2007). They observed that the frequency region of hearing loss related to the
range of tinnitus pitch, and also to the frequency region that stimulates the deepest and longest RI.
Based on this, and previous research, they argued that the primary auditory cortex is starved of
nerve signal inputs in the frequency region of hearing-loss, and groups of neurons associated with
that region then start to spontaneously “self-fire” in synchronous fashion (hypersynchrony). The
team suggested a number of more detailed mechanisms by which that might occur, one of which
is the breakdown of a system of feed-forward neural inhibition that normally keeps neurons
switched off in frequency regions corresponding to silence (Roberts et al., 2008). If this mechanism
fails, the perception of silence could be broken at those frequencies, causing tinnitus. When a
masking sound is played at these frequencies, this may inject new states of excitation or inhibition
into the region, thus disrupting the overactive synchronous neurons responsible for tinnitus. Then,
“RI could reflect a temporary adaptation of neurons involved in synchronous activity,” or a
“rebalancing” of the inputs to those neurons, or “other mechanisms that subside” over the same
durations as RI.
When inhibitory deficits occur, synchronous neural activity that is normally constrained by feed
forward inhibition to acoustic features in the stimulus (normal auditory perception) may develop
spontaneously among networks of neurons in the affected auditory cortical regions, giving rise to
the sensation of tinnitus (Weisz et al., 2007; Eggermont and Roberts, 2004). Synchronous activity
in the auditory cortex appears to recruit via intercortical or corticothalamic pathways a distributed
11
network involving other brain regions (Schlee et al., 2007), some of which have been identified by
anatomical (Mühlau et al., 2006) and functional brain imaging studies (Plewnia et al., 2007;
Lockwood et al., 2001; Melcher et al., 2000).
1.5
Auditory Evoked Potentials (AEPs)
Subjective tinnitus is a symptom with no reflections on routine lab tests and/or X-ray of brain so
the assessment of tinnitus subjects is a complicated task. Meanwhile lack of a standard protocol
make assessments and following treatments more complicated. Functional imaging such as
positron emission tomography (PET), single positron emission computerized tomography
(SPECT) and functional magnetic resonance imaging (fMRI), also electrophysiological tests like
event
related
potentials
(ERPs),
auditory evoked
potentials
(AEPs)
consisting
of
electrocochleography (ECochG), auditory brain stem responses (ABR), middle latency responses
(MLR), late latency responses (LLR), auditory steady state responses (ASSRs) etc. as well as
psycho-acoustical evaluations are amongst the tools that could be used to objectify tinnitus. High
temporal resolution (< 1 ms) of ERPs creates an appropriate technique to record electrical brain
activities which is time locked to the auditory events. Since the duration of RI has been short in
most tinnitus subjects so using of AEPs and ERP can be considered as an appropriate technique to
detect tinnitus in the brain.
It has been shown that there is a relationship between the auditory evoked potentials (AEPs) and
tinnitus (Gerken et al., 2001). By using electrophysiological approaches we may achieve the
appointed goals including diagnosis, reliable modes of treatment, determining functional locations
of tinnitus. Recent studies revealed that both tinnitus and its RI involved a number of regions of
12
the auditory system (Melcher et al., 2000; Giraud et al., 1999; Mirz et al., 1999; Lockwood et al.,
1998; Mühlnickel et al., 1998; Arnold et al., 1996; Mäkelä et al., 1994; Møller et al., 1992a; Hoke
et al., 1991; Attias et al., 1996). Other previous studies have also reported that the tinnitus was
associated with abnormally high neural activity in the auditory system by means of AEPs
measuring and functional imaging (Jastreboff, 1990; Jastreboff and Hazell, 1993; Chen and
Jastreboff, 1995; Melcher et al., 2000). Existence of such alterations was considered in the
occurrence of uncommon increased or decreased amplitude and latency of waves in the AEPs.
However, emphasis just in measurement of AEPs parameters (amplitude and latency) for
assessment of tinnitus can be misleading. Previous studies have reported using other alternative
measurements of time interval between certain waves (Fabiani et al., 1984; Sohmer and Student
1978; Starr 1977; Salamy et al., 1976) Meanwhile the transmission time-interval is a demonstration
of progress of excitation from the distal portion of acoustic nerve to the inferior colliculus of the
brainstem; this interval indeed has been called brainstem transmission time (BTT). It has been
shown that BTT is stable feature in assessment of neurotological conditions (Fabiani et al., 1984).
These researchers have found that BTT to be significantly more stable and it is independent from
intensity and frequency of stimulus. BTT is also constant in relating to stimulus rates below 20/sec,
as well as conductive hearing-loss.
In one study, Kim et al., (1998) evaluated the ABR and ECochG parameters before and after the
electrical stimulation (ES) in guinea pigs. These guinea pigs were split into two groups; (A) the
group which were stimulated by ES and (B) control group. ABR and ECochG results were obtained
under four experimental conditions, before tinnitus and 1, 6, 12 hours after tinnitus induction using
salicylate. ES were applied to the group A, and the alterations of ABR/ECochG correlations were
13
observed. Results showed that ES brings ABR waveforms back to the normal state in group (A)
compared to group (B), and this proved the effectiveness of above stimulation. Watanabe et al.,
(1997) measured the compound action potentials (CAP) in tinnitus subjects using ECochG before
and after ES. They found that CAP amplitudes were significantly increased in those that tinnitus
were inhibited whereas the latencies had no remarkable change. In the 1930s, the discovery of a
scalp-recorded electrical rhythm results showed that ES brings ABR waveforms back to the normal
state (Shulman et al., 2006). Aran et al., (1981) used the ECochG test to study the effect of tinnitus
inhibition induced by ES. Results showed that amplitudes of CAP were increased significantly.
Other previous study evaluated ABR parameters before and after induced by ES amongst tinnitus
subjects (de Lavernhe-Lemaire et al., 1987). 10 out of 30 tinnitus subjects revealed significant
inhibition in their tinnitus after applying ES. After ES the left delta I-V latency is considerably
prolonged and wave I latency is shortened in the inhibition group. They concluded that ABR
appears to be a suitable predictive tool for inhibition induced by ES. In the field of evoked
potentials (EPs), researchers are motivated to study short, middle and long latencies potentials by
measuring amplitude and latency recovery after some sort of stimulations.
Based on the model proposed by Hazell and Jastreboff (1990), the tinnitus associated with signal
passes from the source, e.g., the cochlea, through subcortical filters and detection stages until it is
perceived and evaluated in the auditory and other cortical areas. In this processing system, there is
an emotional weighting (Jastreboff et al., 1996; Jastreboff, 1990) of the signal which either results
in its habituation or amplification. Attias et al., (1996) observed N1 amplitude as well as latency
differences between tinnitus and non-tinnitus subjects. Norena et al., (1999) found significant
14
amplitude differences with respect to N1–P2 amplitudes at higher stimulus intensities when
comparing the tinnitus and non-tinnitus ear in subjects with unilateral tinnitus.
Recent progresses in signal processing and electrophysiological approaches have caused to
improve objectifying tinnitus and facilitating to understand quantitative information and
determining neural mechanisms of tinnitus. These facilitating approaches enable us to record
mismatch negativity (MMN) responses by study auditory information processing and related
involved foundations of neurophysiology aspects. MMN has opened a unique window to the
central auditory processing and the foundations of neurophysiology, affected a large number of
different clinical conditions. MMN as a change-specific component of the auditory ERPs is elicited
by any discriminable changes in auditory stimulation (Näätänen, 1995). MMN enables us to reach
a biological understanding of central auditory perception, auditory sensory memory, change
detection and involuntary auditory attention (Näätänen, 2007). As previously mentioned, tinnitus
can be considered a kind of alteration in neural activity and subsequently an alteration in auditory
information processing. Therefore, MMN as a change detection tool could be sufficient to explore
the processing changes due to tinnitus and RI. The new and fast multi-feature MMN paradigm
allows for the focused recording of the MMN deviants (frequency, intensity, duration, location
and silent gap) within an efficient and time-saving paradigm in tinnitus subjects.
MMN responses are seen as a negative displacement in particular at the frontocentral and central
scalp electrodes relative to mastoid or nose reference (Näätänen, 2007). The new multi-feature
paradigm was proposed by Näätänen et al., (2004) enable us to obtain MMN responses for multifeature auditory attributes in a short time.
15
In the current study we applied standard stimulus and five different deviant stimuli during the
experiment in tinnitus subjects. Fig. 1.3 and Fig. 1.4 show the waveforms and specifications of
standard and 5 types of deviant stimuli in summary.
A
B
C
D
A
E
Fig. 1.3 The waveforms of standard stimuli (A), frequency deviant (B), duration deviant (C), location deviant (D)
and silent gap deviant (E), (Näätänen et al., 2004).
16
MMN
15 minute
15
SS
MMN
5 minute
P (standard) = 0.5
P (deviant) = 0.5
s
MMN
5 minute
15
SS
s
d2
d1
s
d4
MMN
5 minute
15
SS
s
d3
s
d5
s
d4
...
500 ms
(SS)
Standard Stimuli
frequency
Composed of 3 sinusoidal
partials of 500, 1000, 1500Hz
Intensity
First partial at 60dB above the
individual subject’s hearing threshold
duration
75ms including 5ms rise and fall times
location
Equal phase and intensity at both ears
The second and third partials was lower
than that of the first partial by 3 and 6 dB,
respectively
Deviant Stimuli (DS)
Frequency deviants (d1)
Intensity deviants
(d2)
Duration deviants (d3)
Location deviants (d4)
Gap deviants
(d5)
A half of the frequency deviants were 10% higher (partials: 550, 1100,
1650Hz) And the other half 10% lower (450, 900, 1350)
A half of the intensity deviant were -10dB and the other half +10dB compared
with the standard
25ms including 5ms rise and fall times
An interaural time difference of 800us, for a half of the deviants to the right
channel and for the other half to the left channel
Cutting out 7ms (1ms fall and rise times included) from the middle of the
standard stimulus
Fig.1.4 Specifications of standard and 5 types of deviant stimuli in summary (Näätänen et al., 2004).
17
Data extraction is important in MMN studies. Generally, after artifact rejection, recordings
belong to each type of stimulus are averaged to obtain an ERP waveforms. Response to standard
stimuli is typically subtracted from the ERP elicited by infrequently presented deviant stimulus.
The resulting wave is called the difference waves (DW) which indicates MMN (Näätänen et al.,
1992). Peak amplitude and peak latency of MMN were usually obtained from the DW. This is the
most typically process for MMN recording.
Quantitative electroencephalography (QEEG) is a simple method for measurement of regional
brain activity and various EEG abnormalities in temporal lobe and other areas which have been
described in tinnitus subjects (Shulman et al., 2006; Shulman and Goldstain 2002; Weiler and
Brill, 2004; Weiler et al., 2000).
Previous studies proposed that MEG alterations in the pathological patterns of spontaneous
neural brain activity, particularly a reduction of delta activity are associated with RI (Kahlbrock et
al., 2009). Auditory cortex gamma oscillations decreases associated with RI and auditory cortex
gamma activity acts to inhibit the perception of tinnitus (Sedley et al., 2012).
Studying tinnitus and RI by using PET in patients with cochlear implants revealed that cortical
networks of auditory higher-order processing, memory and attention are integrated to RI (Osaki et
al., 2005).
18
1.6
Auditory Electrical Stimulation (AES)
The effectiveness of ES for tinnitus suppression was investigated by many authors (Graham and
Hazell, 1977; Matsushima et al., 1994; Okusa et al., 1993; Portman, 1983). Many researchers have
been looking for the effects of ES as an alternative therapy in treating severe tinnitus (Mielczarek
et al., 2005). Daneshi et al., (2005) evaluated the effectiveness of tinnitus suppression induced by
AES in two sample groups of chronic severe tinnitus subjects (with and without implants) and
compared the effectiveness of AES and the role of cochlear implant (CI) for the suppression or
abolition of the perception of tinnitus. The degree of disability owing to tinnitus was evaluated
using standard tinnitus questionnaires. The pulse rate of the ES for tinnitus suppression has
reported variably by many authors from 22 (Graham and Hazell, 1977) to 66 (Portman et al., 1983)
pulses per second. It is widely believed that continued use of tinnitus masking can promote a
neurological process resulting in habituation to tinnitus. In fact, habituation of tinnitus is a
neurophysiological process which involves neuronal remapping in the auditory cortex of the brain
leading to desensitization of tinnitus. Investigators in recent research believe that tinnitus is closely
related to functional alterations of the central auditory and non-auditory systems in terms of
sensation processing (Farhadi and Mahmoudian et al, 2010; Weisz, 2005; Rauschecker, 1999).
When the pathology in the peripheral auditory system acts as an initiating change for inducing
tinnitus, it can cause the sustained plastic changes and aberrant activity residing in the subcortical
and cortical structures of the auditory and non-auditory nervous systems. These changes can cause
the sensation of tinnitus.
19
1.6.1 Characteristics of AES
In this thesis bipolar burst current (Square waves) was applied in the tinnitus ear with a duration
of 500 ms (repetition rate of 1 Hz) and a pulse rate of 50 Hz delivered by a stimulation system
(Promontory Stimulator; Cochlear Company, Australia) shown in Figure 1.5.
Characteristics of Electrical Stimulation
Bipolar burst currents (Square waves)
Pulse duration: 500 ms on / 500 ms off
Time of stimulation: 60 second
Repetition rate: 1 Hz
Fig. 1.5 Specifications of auditory electrical stimulation used in current study (Mahmoudian et al., 2013).
Fig. 1.6 Two channel electrical stimulator
20
1.7
Diagnostic Approach to Tinnitus
1.7.1 Tinnitus Psychoacoustic Assessments
Tinnitus identification parameters subjectively were estimated as follows. The test ear is
contralateral to the ear with predominant or louder tinnitus, if there is a difference between the two
sides. If the tinnitus is equally loud on both sides, or localized to the head, the test ear is the one
with better hearing. A two-alternative forced-choice (TAFC) method is used, in which pairs of
tones are presented and subjects asked to identify which one best matched the pitch of their tinnitus
(Henry et al., 2007; Holgers et al., 2003; American Academy of Audiology 2000; Watanabe et al.,
1997; Jastreboff et al., 1994). We gave different pairs of pitch sounds from a 6-channel tinnitus
evaluation device (TinnED®; designed in ENT-Head and Neck Research Center of Iran University
of Medical Sciences) to reconstruct the most troublesome tinnitus with a similar frequency and
intensity. Test frequencies are typically multiples of 1 kHz. Before each tone pair is presented,
each tone is adjusted to a loudness level equivalent to that of the tinnitus. Once the dB settings for
a given pair of tones are established, the two tones are then presented in an alternating manner
until the subject indicates which one is closest to the pitch of the tinnitus.
Example procedure
Comparison Tones (Hz)
Tone Judged Like Tinnitus (Hz)
Trial 1
1000 vs 2000
2000
Trial 2
2000 vs 3000
3000
Trial 3
3000 vs 4000
Trial 4
4000 vs 5000
4000
4000
21
Care is taken to randomize the selection of which tone is presented first in each trial, so that the
lower of the two frequencies is not always the one presented first. Using the same 2AFC procedure,
a test for “octave confusion” is then performed:
Comparison Tones (Hz)
Trial 5
Tone Judged Like Tinnitus (Hz)
4000 vs 8000
4000
Because the majority of subjects have high-pitched tinnitus, there is seldom a need to include
tones below 1 kHz. Subsequently, with the auditory threshold level (a) at that frequency, the sound
was increased by 1-dB steps until a patient reported that the external tone equaled the loudness of
the tinnitus. The sound level matching that of the tinnitus (b) and the sound level a little louder
than that of the tinnitus (c) were obtained by TinnED® (loudness balance test). The mean level of
loudness between points (b) and (c) as the representative loudness of tinnitus was used. The
formula of the loudness (expressed as decibels of sensation level [dB SL]) is as follows:
Loudness of tinnitus = [(b + c)/2 – a] [dB SL]
The criteria of objective methods for evaluating tinnitus after AES using tinnitus identification
parameters were such that the change seen as a diminishing or worsening of tinnitus loudness
match or changes in the pitch of tinnitus occurred when reduced or increased by at least 1,000 Hz
and loudness was reduced or increased by at least 2 dB SL.
22
The lowest level at which a standard band of noise "covered" the tinnitus (i.e. rendered it inaudible)
was recorded and termed the minimum masking level; also, the duration of tinnitus loudness
reduction after AES was termed the electrical RI.
1.7.2 Tinnitus Questionnaires
We administered the Persian version of the Tinnitus Handicapped Inventory (THI-P)
(Mahmoudian et al., 2011) that was firstly designed by Newman et al., 1996, and tinnitus
questionnaire (TQ-P) (Daneshi et al., 2005) which was developed by Hallam (1996), to measure
the dimensions of associated tinnitus complaints and severity of tinnitus. The THI-P (25 items)
and TQ-P (52 items) assess the subjective psychological effects of tinnitus as described by
subjects. The dimensions for THI-P include functional, emotional and catastrophic subscales. The
TQ-P evaluates the other dimensions of tinnitus consisting emotional, cognitive, emotional and
cognitive, auditory perceptual difficulties, intrusiveness and sleep disturbances. Subjects with
chronic severe tinnitus having scores more than 44% in TQ-P and 38% in THI-P were enrolled in
the study.
1.8
Aim of the Thesis
The fact that tinnitus is consciously perceived as a sound meaning that auditory neural networks
activity must be involved (Eichhammer, 2007; Shulman, 2006; Eggermont and Roberts, 2004;
Eggermont, 2003; Lockwood et al, 2002; Reyes, 2002; Llinás, 1999; Jeanmonod, 1996; Jastreboff,
1990; Shulman, 1981). Nevertheless the pathophysiology of chronic tinnitus as well as neural
mechanism involved in RI is not yet fully understood, meanwhile the assumption is that in certain
forms of subjective tinnitus both peripheral and central auditory pathways are involved (Vanneste
23
et al., 2010; Smits et al., 2007; Georgiewa et al., 2006; Cacace, 2003; Baguley et al., 2002).
However, there are not enough studies to indicate the effects of tinnitus on brain electrical activities
and its effects on auditory signal processing inside central auditory pathways.
The overall purpose of this thesis was to evaluate the effect of tinnitus RI induced by AES on
early auditory evoked potentials as well as determining the topographical maps of the mismatch
negativity responses in central auditory processing of chronic tinnitus quantitatively. This research
work is important because it increases our knowledge about pathophysiology of tinnitus and raises
possibilities for further research into possible treatments.
Take into consideration, that in order to obtain the above mentioned aim, the study at first
approached toward tinnitus RI and its effect on short latency AEPs consisting of ECochG and
ABR) and then we were focused on the topographical maps of the mismatch negativity obtained
with the multi-feature paradigm in subjects with chronic tinnitus. All mentioned methods will be
discussed in more details later (ECochG, ABR and MMN obtained with the multi-feature
paradigm).
This study basically can guide us to (i) objectify abnormal auditory signal processing in the
brain due to tinnitus perception and (ii) determining the manner of abnormal brain electrical
activity through the auditory pathways and (iii) to provide quantitative information about chronic
tinnitus and RI phenomenon.
24
In the first part of the study it was assumed that the BTT and other specific features of early
AEPs can be altered associated with RI induced by AES. Short latency AEP measurements
including ECochG and ABR were applied to assess neural changes that are associated with RI
phenomenon. In the next part of the study it was hypothesized that the central auditory processing
is affected due to chronic tinnitus compared to normal hearing (NH) controls. The aim of this study
was to compare the neural correlation of acoustic stimulus representation in the auditory sensory
memory on an automatic basis as well as auditory discrimination in tinnitus subjects and normal
hearing (NH) controls.
25
2
PAPER I. Alterations in early auditory evoked potentials and brainstem transmission
time associated with tinnitus residual inhibition induced by auditory electrical
stimulation
Published in Int. Tinnitus J. 2013; 18(1): 63-74. DOI: 10.5935/0946-5448.20130009.
Saeid Mahmoudian
1,2*,
Minoo Lenarz 3, Karl-Heinz Esser 4, Behrouz Salamat 1, Farshid
Alaeddini 5, Reinhard Dengler 6, Mohammad Farhadi 2, Thomas Lenarz 1.
1
Department of Otorhinolaryngology, Medical University of Hannover, Hannover, Germany
2
ENT, Head and Neck Research Center, Iran University of Medical Sciences, Tehran, Iran
3
Department of Otolaryngology, Charité – Medical University of Berlin, Berlin, Germany
4
Auditory Neuroethology and Neurobiology Lab, Institute of Zoology, University of Veterinary
Medicine Hannover, Hannover, Germany
5
Academy of Medical Sciences, Tehran, Iran
6
Department of Neurology, Hannover Medical University, Hannover, Germany
*Corresponding author:
Otorhinolaryngology Department, Hannover Medical University,
Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
Phone: +49-511-532-9494, Fax: +49-511-532-5558
E-mail address: mahmoudian.saeid@mh-hannover.de
26
Abstract
Introduction: Residual inhibition (RI) is the temporary inhibition of tinnitus by use of masking
stimuli when the device is turned off. Objective: The main aim of this study was to evaluate the
effects of RI induced by auditory electrical stimulation (AES) in the primary auditory pathways
using early auditory-evoked potentials (AEPs) in subjective idiopathic tinnitus (SIT) subjects.
Materials and Methods: A randomized placebo-controlled study was conducted on forty-four
tinnitus subjects. All enrolled subjects based on the responses to AES, were divided into two
groups of RI and Non-RI (NRI). The results of the electrocochleography (ECochG), auditory brain
stem response (ABR) and brain stem transmission time (BTT) were determined and compared preand post-AES in the studied groups. Results: The mean differences in the compound action
potential (CAP) amplitudes and III/V and I/V amplitude ratios were significantly different between
the RI, NRI and control group. BTT was significantly decreased associated with RI. Conclusion:
The observed changes in AEP associated with RI suggested some peripheral and central auditory
alterations. Synchronized discharges of the auditory nerve fibers and inhibition of the abnormal
activity of the cochlear nerve by AES may play important roles associated with RI. Further
comprehensive studies are required to determine the mechanisms of RI more precisely.
Keywords: auditory, auditory brain stem, evoked potentials, tinnitus.
27
3
PAPER II. Central auditory processing during chronic tinnitus as indexed by
topographical maps of the mismatch match negativity obtained with the multi-feature
paradigm
Published in Brain Res, 2013 Aug 21; 1527:161-73. doi: 10.1016/j.brainres.2013.06.019. Epub
2013 Jun 26.
Saeid Mahmoudiana,b,*, Mohammad Farhadib, Mojtaba Najafi-Koopaiec, Ehsan DarestaniFarahanid, Mehrnaz Mohebbib, Reinhard Denglere, Karl-Heinz Esserf, Hamed Sajedic, Behrouz
Salamata, Ali A. Daneshg, Thomas Lenarza
a
Department of Otorhinolaryngology, Hannover Medical University (MHH), Hannover,
Germany
b
ENT and Head & Neck Research Center, Iran University of Medical Sciences (IUMS), Tehran,
Iran
c
Electronics Group, Faculty of Engineering, Shahed University, Tehran, Iran
d
Biomedical Engineering Faculty, Amirkabir University of Technology, Tehran, Iran
e
Department of Neurology, Hannover Medical University (MHH), Hannover, Germany
f
Auditory Neuroethology & Neurobiology Lab, Institute of Zoology, School of Veterinary
Medicine Hannover, Hannover, Germany
g
Department of Communication Sciences and Disorders, Florida Atlantic University, Boca
Raton, Florida, USA
*Corresponding author:
Saeid Mahmoudian, Carl-Neuberg-Str. 1, 30625 Hannover, Department of Otorhinolaryngology,
Hannover Medical University (MHH), Hannover, Germany. Phone: ++49-511-532-9494, Fax:
++49-511-532-5558; Email address: mahmoudian.saeid@mh-hannover.de
28
Abstract:
This study aimed to compare the neural correlates of acoustic stimulus representation in the
auditory sensory memory on an automatic basis between tinnitus subjects and normal hearing (NH)
controls, using topographical maps of the MMNs obtained with the multi-feature paradigm. A new
and faster paradigm was adopted to look for differences between 2 groups of subjects. 28 subjects
with chronic subjective idiopathic tinnitus and 33 matched healthy controls were included in the
study. Brain electrical activity mapping of multi-feature MMN paradigm was recorded from 32
surface scalp electrodes. Three MMN parameters for five deviants consisting frequency, intensity,
duration, location and silent gap were compared between the two groups. The MMN amplitude,
latency and area under the curve over a region of interest comprising: F3, F4, Fz, FC3, FC4, FCz,
and Cz were computed to provide better signal to noise ratio. These three measures could
differentiate the cognitive processing disturbances in tinnitus sufferers. The MMN topographic
maps revealed significant differences in amplitude and area under the curve for frequency, duration
and silent gap deviants in tinnitus subjects compared to NH controls. The current study provides
electrophysiological evidence supporting the theory that the pre-attentive and automatic central
auditory processing is impaired in individuals with chronic tinnitus. Considering the advantages
offered by the MMN paradigm used here, these data might be a useful reference point for the
assessment of sensory memory in tinnitus patients and it can be applied with reliability and success
in treatment monitoring.
Keywords: MMN; Central Auditory Processing; ERP; Tinnitus
29
4
Comprehensive Discussion
What lies in front of us is a challenging puzzle filled with bits and pieces of knowledge and
different fields of sciences involved in diagnosis and treatment of tinnitus which require to be
studied more and more in order to discover the ambiguities. The aim of this doctoral thesis was to
find evidences to objectify chronic tinnitus as well as RI phenomenon through the central auditory
pathways.
In the first hypothesis, it was assumed that early AEPs as well as BTT show changes associated
with tinnitus RI. The second hypothesis stated that tinnitus can cause a deficit in pre-attentive
central auditory processing mechanisms. In order to clarify these hypotheses we systematically
evaluated the effects of tinnitus RI using early AEPs (ECochG and ABR) and followed by preattentive central auditory processing (MMN responses) were measured in chronic tinnitus subjects
(Fig. 4.1).
The present part summarizes the primary findings of this thesis and discusses possible future
work on the basis of these results. The experimental work, described in papers I and II involves a
progression in the understanding of the neural circuitry that is involved in tinnitus perception. The
present results implicate electrophysiological alterations involved in tinnitus pathophysiology. For
clarity, this part is divided into a few sections that describe the following topics: alterations in
neuro- electric potentials associated with RI functions in relation to tinnitus, the effects of chronic
tinnitus on central auditory processing, synopsis of research and the conclusions.
30
Fig. 4.1
4.1
The study plan for identifying BTT and AEPs alterations during chronic tinnitus and RI
(Mahmoudian et al., 2013).
Alterations in neuro- electric potentials associated with tinnitus RI
In part one, the effects of tinnitus as well as RI phenomenon on primary auditory pathways was
studied to investigate the neuro- electric potentials change associated with RI function in relation
to tinnitus using ECochG and ABR tests. Using short-latency AEPs, the distal portion of auditory
nerve and auditory brainstem function were revealed to be involved in the pathophysiological
mechanism of tinnitus perception. Obtaining results in current study showed significant alterations
in ECochG and ABR recordings associated with RI induced by AES in tinnitus subjects. It could
be concluded that AES, through the effects on distal proportion of auditory nerve fibers, play an
important role in RI. This conclusion was based on an observed increase in the CAP amplitude
and decrease in the brainstem transmission time (BTT) in subjects with tinnitus compared to the
controls. These findings are consistent with previous study (Shulman and Kisiel, 1987). They used
electrical stimulation for tinnitus suppression and concluded that the morphology of ABR waves
31
in tinnitus ear convert to the normal state, interferential influence of tinnitus decreased, amplitude
of wave III decreased and amplitude of wave V became close to the normal value
The observed changes in early AEPs associated with RI suggested some peripheral and central
auditory alterations including auditory nerve fibers, cochlear nucleus, inferior colliculus and
consequently modification of cortical activities. RI phenomenon induced by AES, might be
explained by interference with tinnitus generating circuits. Our results revealed interference of
distal portion of auditory nerve in generating tinnitus and with the same basis it could induce RI
phenomenon by means of AES. Synchronizing discharges of the auditory nerve fibers can cause
inhibition of the abnormal activities of cochlear nerve induced by AES and may play an important
role associated with RI. Take into consideration that as BTT is an expression of progress of neural
excitation from the distal portion of auditory nerves to the inferior colliculus of the brainstem,
decrease of BTT after AES could be explained as an increase in auditory nerve conductive velocity.
Also decrease of BTT following AES could be explained as an increase of neural synchronization
in auditory system. The alterations seen in the peak V, amplitude ratios of III/V and BTT are
consistent with the noise-cancellation mechanism (Rauschecker et al., 2010) and stated that not
only serotonergic projections from the Raphe Nuclei could be able to change tinnitus perception,
but also serotonergic projections in the inferior colliculus, both meeting at the thalamic level
(Cartocci et al., 2012). It seems that early AEPs to be influenced by serotonin in an excitatory
manner mainly. In addition, the inferior colliculus, the main generator of wave V, receives
serotonergic input from the dorsal Raphe nucleus (Hurley et al., 2002). Also serotonin often
coexists with GABA in the inferior colliculus and both acting in the suppression of fearful and
aversive behaviour (Peruzzi et al., 2004). Furthermore, descending serotonergic projections from
32
Raphe nucleus may also modulate superior olive neurons (Shulman and Kisiel, 1987), the
generators of ABR wave III (Hashimoto, 1982).
The current results suggest that changes of tinnitus intensity associated with RI are mediated by
alterations in the pathophysiological patterns of spontaneous brain activity. This means that RI
effects might reflect the transient reestablishment of balance between excitatory and inhibitory
neuronal assemblies, via reafferentation, which might be damaged.
4.2
The Effects of chronic tinnitus on central auditory processing
In part one, we used MMN recording to investigate the central auditory processing in subjects
with tinnitus. According to the results obtained from the present study, we faced a question that
whether alteration caused by tinnitus in early AEPs (low and high brain stem areas) could affect
pre-attentive central auditory processing in higher order of auditory pathways. In order to reach
the answer in the next step, the study targeted to evaluate higher portions of auditory pathways
consisting of neural structures in the primary and secondary associative auditory cortices in brain
using MMN recording.
The results revealed significant decrease of amplitude, area under the curve for multi-feature of
MMN frequency, duration and silent gap deviants among tinnitus subjects. Therefore, it was
concluded that a deficit occurred in auditory sensory memory mechanisms involved in preattentive change detection in tinnitus subjects comparing to NH controls. Larger amplitudes, area
under the curves and significant MMN responses for five deviants in the NH control group were
33
found. The AEPs alterations which were found in chronic tinnitus subjects associated with RI can
also affect the automated auditory sensory memory mechanisms in tinnitus subjects.
Since MMN responses evaluate the neural correlates of auditory discrimination and sensory
memory, therefore they can be used to study the cerebral processes in tinnitus subjects which occur
during auditory perception and cognition. In the other words, MMN may provide novel insights
into discriminative capabilities in subjects with cognitive impairment (Heinze et al., 1999) and the
pathophysiology of neuropsychiatric conditions (Gené-Cos et al., 1999). Furthermore, there is a
deep gap between sensitivity and specificity of MMN in classification of particular disorders or
diseases and this gap may be improved by introducing new comprehensive measures. The current
study focused on the assessment of auditory processing in tinnitus subjects using modified multifeature MMN paradigm. It is believed that, the present study is the first to assess the MMNs in
tinnitus subjects using a modified version of the multi-feature MMN paradigm. Decrement of
MMN amplitude as well as the area under the curves among tinnitus subjects in this study is
coincident with Weisz et al., 2004 findings, and supports this assumption that the mechanisms
involved in pre-attentive sensory memory might be impaired in tinnitus subjects.
The mismatch negativity ERP component is especially valuable in such studies as it reflects preattentive detection of occasional changes in an auditory sequence irrespective to direction of the
subject’s attention or task (Rinne et al. 2000), so this process is assumed to be automatic. It
provides objective index about the encoding of deviant events and also about encoding of the
previous stimulus events which form the bases of change detection.
34
The statistical analyses indicated that the silent gap MMN was significantly smaller in amplitude
and area under the curve in the tinnitus subjects comparing to NH control group. The silent gap
MMN could be mostly affected by tinnitus signal. An interruption in a sound stimulus (such as a
gap in the middle of standard stimulus) is perceived as discontinuous by the auditory cortex. Based
on the current study, it was indicated that the NH control group’s brains could detect the silent gap
better than the tinnitus group. It means that the human’s brain always detect silence in a normal
condition. For this reason, the MMN change-detection responses for silence gap are well detected
by the normal subjects. Whereas, the patterns of silence in the human’s brain can be affected by
receiving any abnormal coding, this will be decoded as an aberrant sound and interpreted in the
brain as tinnitus.
There is increasing evidence that tinnitus, is a consequence of neuroplastic alterations in the
central auditory pathways (Eggermont and Roberts, 2012). The MMN has appeared as a tool for
determining how a pre-conscious sensory process reaches to the level of conscious perception. The
results of present study are interpreted as evidences of abnormalities in the central information
processing mechanisms of tinnitus subjects. These results also provide electrophysiological
evidence supporting the theory that the central sound-change detection and also the remaining of
sensory memory are impaired in individuals with chronic tinnitus. It can therefore be concluded
that the MMN alterations observed in this study can cause neuroplastic changes in the brain of
tinnitus subjects.
We believe that the mechanisms involved in tinnitus perception may be caused by reduction in
sensory memory. This reduction might lead to decreased MMN amplitude and area under the
35
curve. These alterations result from an unbalance of excitatory and inhibitory mechanisms on
many levels of the auditory pathways which are due to disturbed auditory input. There is still
uncertainty whether any other factors contributing in decrease of amplitude and area under the
curve of MMN responses in tinnitus subjects or not. However, all the mentioned theories require
more systematic studies corresponding to other neurophysiological findings, functional imaging
and behavioral evidence.
Considering the advantages offered by the early AEPs and MMN responses used here, these data
might be a useful reference point for the assessment of sensory memory in tinnitus subjects and it
can be applied with reliability and follow up success in treatment of tinnitus.
4.3
Synopsis of research
Considering all of the above results, it should be noted that the observed neuronal activity
changes that are associated with tinnitus perception overlap in two primary brain regions: the
auditory brainstem and the neural structures in the primary and secondary associative auditory
cortices. The observed neuroelectrical alterations are characterized by an increased BTT and
decreased CAP amplitude in tinnitus subjects and may indicate underlying neuronal activity
lesions, which manifest as auditory deafferentation. Regarding to extraction of whatever
mentioned in part one, “it was assumed that BTT and other specific features of early AEPs altered
associated with RI induced by AES”. Based on results of this study, we came into this point that
some of the features of early AEPs and particularly BTT changed associated with RI and therefore
our main hypothesis was confirmed.
36
The reduced integrity of the brainstem auditory nuclei and centrifugal pathways in tinnitus
subjects (as indexed by ECochG and ABR recordings) and the neural structures in the primary and
secondary associative auditory cortices (as indexed by MMN) with other cortical and subcortical
structures, all together may indicate a primary lesion that underlies tinnitus pathogenesis. A
consequence of such deficits may cause a secondary defect that is characterized by abnormal
functionality in these regions. As mentioned in part two “the study hypothesized that the central
auditory processing was affected from chronic tinnitus compared to normal hearing (NH) controls.
Also the main aim of the study was to compare the neural correlation of the automatic auditory
sensory memory and auditory discrimination in tinnitus subjects and normal hearing (NH)
controls”. The results revealed smaller amplitude and area under the curve for multi-feature of
MMN responses consisting of frequency, duration and silent gap deviants in the tinnitus subjects
(refer to page 80-83). The study concluded that there was a deficit in automatic central auditory
processing mechanisms in tinnitus subjects (as supported by the MMN findings).
The following results were extracted from the part one of study:
1- CAP amplitude significantly increased associated with RI in tinnitus subjects.
2- BTT significantly decreased associated with RI in tinnitus subjects.
3- Amplitude ratio of waves III/V and I/V decreased associated with RI in tinnitus subjects.
And the following evidences were concluded from the part two of the study:
1- MMN amplitude and area under the curve decreased for three deviants of frequency,
duration and silent gap in tinnitus subjects.
37
2- The patterns of silence in the brain of chronic tinnitus subjects were potentially affected by
abnormal silence code.
The following issues were concluded in chronic tinnitus subjects:
1- Neuro-electrical alterations in early AEPs induced by RI and some changes in peripheral
and central auditory functions including auditory nerve fibres, the cochlear nucleus and
inferior colliculus and finally modification of cortical activity
2- The roles of synchronizing discharges in auditory nerve fibers and inhibition of abnormal
activity of cochlear nerve during RI
3- Subjects with chronic tinnitus indicated a deficit in pre-attentive central auditory
processing and auditory sensory memory mechanisms.
4- Possible neuroplastic changes in brain caused by abnormal central auditory activity.
5- Transient and partial normalization of abnormal auditory neural activities associated with
RI
This thesis was highlighted the neuro-electrical substrates caused by tinnitus RI using early AEPs
and also disclosed that pre-attentive central auditory processing was affected in chronic tinnitus
(as indexed by topographical maps of the mismatch negativity responses). Hopefully this study
could extend our insight to neurophysiological and pathophysiological aspects corresponding to
tinnitus and RI. Meanwhile investigation of pathophysiology of tinnitus and related neural
mechanisms through more precise studies with other methods is fully recommended.
38
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7
Summary
Title: Effects of Residual Inhibition Phenomenon on Early Auditory Evoked Potentials and
Topographical Maps of the Mismatch Negativity Obtained With the Multi-Feature Paradigm in
Tinnitus
Author: Saeid Mahmoudian
Based on McFadden (1982), tinnitus is the “conscious experience of a sound that originates in
an involuntary manner in the head of its owner or may appear to him to be so”. This phantom
sound can be inhibited by external masking stimuli. The term of residual inhibition (RI) refers to
the temporary suppression and/or disappearance of tinnitus following such a period of masking.
The effects of tinnitus are not limited to the ear. There is also evidence that tinnitus can lead to
changes in the cortical function and organization. However, the exact pathophysiology of chronic
tinnitus as well as the RI phenomenon remains unclear. In this thesis, alterations occurring in early
auditory evoked potentials (AEPs) and brainstem transmission time (BTT) associated with RI
induced by auditory electrical stimulation (AES) in chronic tinnitus subjects were investigated.
Furthermore, the effects of chronic tinnitus on central auditory processing were characterized.
In the first part of the thesis, it was hypothesized that the BTT and early AEP features can be
altered by the application of electrical stimulation in subjects with chronic tinnitus. To investigate
the effects of AES in the primary auditory pathway, early AEP tests consisting of
electrocochleography (ECochG) and auditory brain stem responses (ABR) were performed and
evaluated. Since it is known that RI can be modulated by AES, the BTT was measured and used
as a considerably more stable and invariant parameter for evaluation of this (RI) phenomenon.
AES in tinnitus subjects resulted in a significant increase in amplitude of compound action
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potential (CAP), a significant decrease in amplitude ratios of waves III/V and I/V as well as in a
significant decrease in BTT associated with RI. The observed neuroelectrical changes indicate that
peripheral and central auditory alterations may occur in tinnitus subjects.
In the second part of the thesis it was hypothesized that central auditory processing is different
in subjects with chronic tinnitus when compared to normal hearing (NH) control. While presenting
distinct auditory stimuli (varying in frequency, intensity, duration, location, and silent gaps),
electrical activity of the brain was recorded and maps of voltage changes of the mismatch
negativity (MMN) responses were plotted. The new and fast multi-feature paradigm was adopted
to analyze differences of the MMN between the two groups: significant differences in amplitude
and area under the curve for frequency, duration and silent gap deviants could be detected in
tinnitus subjects compared to NH control group. These results indicate a possible deficit in central
auditory processing mechanisms involved in pre-attentive change detection in chronic tinnitus
subjects.
In conclusion, the present electrophysiological results of both studies support the theory that
encoding of stimuli as well as central auditory processing are impaired in individuals suffering
from chronic tinnitus.
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8
Zusammenfassung
Titel: Der Einfluss der Residualen-Inhibition auf frühen auditiv-evozierte Potentiale sowie
topographische Karten der mit einem Multi-Feature Paradigma gewonnenen MismatchNegativity Antworten bei Tinnitus.
Verfasst von: Saeid Mahmoudian
Nach der Definition von McFadden (1982) ist Tinnitus die bewusste Empfindung eines
Geräusches, welches in einer unwillkürlichen Art und Weise im Kopf des Betroffenen
entsteht. Dieses Phantomgeräusch kann durch externe, maskierende Stimuli unterdrückt
werden. Residuale-Inhibition (RI) bezeichnet die vorübergehenden Unterdrückung bzw. das
vollständige Verschwinden des Tinnitus im Anschluss an eine solche Maskierung. Die
Auswirkungen von Tinnitus sind nicht auf das Ohr beschränkt. Vielmehr gibt es Hinweise,
dass chronischer Tinnitus ebenso zu Veränderungen des Kortex sowohl in dessen Funktion
als auch Organisation führen kann. Die zugrundeliegenden pathophysiologischen
Mechanismen des chronischen Tinnitus sowie der Residualen-Inhibition sind jedoch unklar.
Gegenstand dieser Arbeit war daher zum einen die Untersuchung des Effekts von
elektrischer Stimulation der Hörbahn (auditory electrical stimulation, AES) auf die RI bei
Personen mit chronischem Tinnitus. Der Fokus lag hierbei insbesondere auf Veränderungen
in den frühen akustisch-evozierten Potentialen (auditory evoked potentials, AEP) sowie in
der Hirnstamm-Transmissionszeit (brainstem transmission time, BTT). Weiterhin wurden
die Effekte von chronischem Tinnitus auf die zentral-auditorischen Verarbeitung
untersucht.
Im ersten Teil der Arbeit wurde die Hypothese geprüft, ob bei Personen mit chronischen
Tinnitus die BTT und frühen AEP durch elektrische Stimulation beeinflusst werden können.
Um die Auswirkungen von chronischem Tinnitus und RI auf die Hörbahn beurteilen zu
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können, wurden während elektrischer Stimulation Untersuchungen bestehend aus
Elektrocochleographie (ECochG) und auditorischen Hirnstamm-Antworten (auditory
brainstem responses, ABR) zur Beurteilung der frühen AEPs abgeleitet und ausgewertet.
Da bekannt ist, dass die RI durch elektrische Stimulation moduliert werden kann, wurde die
BBT gemessen und als stabiler und unveränderlicher Parameter zur Evaluation des RIPhänomens eingesetzt. Die Ergebnisse zeigten während der RI eine signifikante
Amplitudensteigerung des Summenaktionspotentials (compound action potential, CAP),
signifikant absteigende Amplitudenverhältnisse der Wellen III/V und I/V (der ABR) sowie
eine signifikante Abnahme der Hirnstamm-Transmissionszeit. Die beobachteten
neuroelektrischen Veränderungen lassen den Schluss zu, dass periphere und zentrale
Veränderungen bei Tinnitus-Patienten auftreten können.
Im zweiten Teil wurde untersucht, inwieweit sich die zentral-auditorische Verarbeitung
zwischen Tinnitus-Patienten und einer normalhörenden (NH) Kontrollgruppe unterscheidet.
Während der Präsentation unterschiedlicher auditorische Stimuli (mit Variation in
Frequenz, Intensität, Dauer, Auftreten und dem Vorkommen von Pausen) wurde die
elektrische Aktivität des Gehirns aufgenommen und topographischen Karten resultierend
aus den Potentialveränderungen - basierend auf den Mismatch-Negativity (MMN)
Antworten - erstellt. Mithilfe des neuen und schnellen Multi-Feature Paradigmas wurde die
Unterschiede zwischen den beiden Gruppen analysiert: Signifikante Unterschiede in der
Amplitude und Integralfläche unter den Kurven für Frequenz, Dauer und den „silent gap
deviants“ bei Tinnitus-Probanden im Vergleich zur NH-Kontrollgruppe konnten
verzeichnet werden. Diese festgestellten Veränderungen weisen auf ein mögliches Defizit
zentral
auditorischer
Verarbeitungsmechanismen
hin,
die
in
„präattentiver
Änderungserkennung“ (pre-attentive change detection) bei Patienten mit chronischem
Tinnitus beteiligt sind.
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Zusammenfassend unterstützen die elektrophysiologisch gewonnen Ergebnisse die
Theorie, dass die Kodierung von Reizen und auch die zentral-auditorische Verarbeitung bei
Personen mit chronischem Tinnitus beeinträchtigt sind.
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Acknowledgements
At the first, I would like to thank the ENT and Head & Neck Research Center and the
office of vice-chancellor for global strategies and international affairs, Iran University of
Medical Sciences (IUMS) for the fellowship stipend. The work presented in this thesis
would not have been accomplished without the support of many people. I would like to
express my deepest appreciation to my supervisors, Prof. Dr. Thomas Lenarz for providing
me the opportunity of being a member of the ENT-family in Hannover Medical School, and
for his support and encouragement during these three years. I would like also to express my
sincere thanks to my supervisor, Prof. Dr. Mohammad Farhadi in Iran for the fellowship
stipend and providing me the opportunity of Ph.D. education in Germany and his support. I
am thankful to both Prof. Farhadi and Prof. Lenarz for providing me a platform to carry out
independent research. I would also like to thank Dr. Ali A. Danesh, Associated Professor of
Florida Atlantic University in USA for his scientifically support and constructive comments
on this thesis. Many thanks to my co-supervisors, Prof. Dr. Reinhard Dengler, P.D. Dr. KarlHeinz Esser, Prof. Dr. Christoph Herrmann, my colleagues and all the staff of MHH for
their supports, helps and constructive advices.
My special thanks extended to P.D. Dr. Minoo Lenarz for her great supports, proper
guidance and for giving me the motivation and constructive comments during my study
journey. I am delighted also to thank Mr. Hessam Emamjomeh for his voluntary and very
sincerely support, for his cooperation during my Ph.D. project. For their overwhelming help
and support, I extend my sincere gratitude to my dear friends and colleagues; Dr. Behrouz
Salamat, Dr. Pooyan Aliuos, Dr. Lydia Timm, Mehrnaz Mohebbi (M.Sc.), Dr. Farshid
Alaeddini, Mojtaba Najafi-Koopaie (M.Sc., Eng.) and Ehsan Darestani- Farahani (M.Sc.,
Eng.).
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Last but not least, with loved I’m debited to my wife and my parents for their supports,
encouragement and love extended to me during my study journey. Thank you for that
support, without it I would not be able to continue. Moreover, my whole heartily thanks to
my lovely sister, my dear brothers and my special thanks and appreciation to my mother in
low, I should confess that without these people success in preparing this thesis would not
be possible.
I owe also to extend my deepest appreciations to Dr. Behzad Salamat, Dr. Thorsten
Schweizer, Dr. Dagmar Esser, Prof. Dr. Beatrice Grummer, Dr. Tina Selle and Ms. Saskia
Günter from the Ph.D. coordination office for their supports and guidance during the last
years.
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Declaration
I hereby declare that I have autonomously carried out my Ph.D. thesis entitled:
“Effects of Tinnitus and Residual Inhibition Phenomenon on Early Auditory Evoked
Potentials and Topographical Maps of the Mismatch Negativity Responses Obtained
With Multi-Feature Paradigm in Tinnitus”
I did not receive any assistance from in return for payment by consulting agencies or any
other person. No one received any kind of payment for direct or indirect assistance in
correlation to the content of the submitted thesis.
I conducted the project at the following collaborated institutions:
1- Department of Otorhinolaryngology, Hannover Medical School, Hannover,
Germany
2- ENT and Head & Neck Research Center, Iran University of Medical Sciences,
Tehran, Iran
The thesis has not been submitted elsewhere for an exam, as thesis or for evaluation in a
similar context.
I hereby affirm the above statements to be complete and true to the best of my knowledge.
Saeid Mahmoudian, Hannover 20.07.2013
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