J Am Acad Audiol 26:408-422 (2015)

Alterations in Auditory Change Detection Associated with Tinnitus Residual Inhibition Induced by Auditory Electrical Stimulation DOI: 10.3766/jaaa.26.4.8 Saeid Mahmoudian*t Mohammad Farhadi* Mehrnaz Mohebbi* Farshid Alaeddini$ Mojtaba Najafi-Koopaie§ Ehsan Darestani Farahani** Hamidreza Mojallalf Ronak Omrani* Ahmad Daneshi* Thomas Lenarzt

Abstract Background: Residual inhibition (Rl) is a temporary phenomenon that happens following offset of appro­ priate complete or partial acoustical and electrical masking stimulations in people who experience tinni­ tus. The biologic mechanisms associated with Rl are not yet fully understood. Few studies have been focused on Rl. Auditory mismatch negativity (MMN) as a change-detection tool may be an appropriate tool to explore the processing changes because of tinnitus and Rl. Purpose: The purpose of this study was to investigate alterations in auditory change detection and auditory sensory memory related to Rl induced by auditory electrical stimulation (AES) using MMN brain mapping in participants with tinnitus. Research Design: This investigation was a single-blind randomized controlled clinical trial study. Participants were randomly assigned into two groups: AES and placebo electrical stimulation (PES). Study Sample: Twenty-eight participants with chronic subjective tinnitus aged 22- to 45-yr-old participated in the study. Intervention: After randomization, all participants received both AES and PES for 1 min in different sessions. Data Collection and Analysis: Brain mapping of multifeature MMN paradigm was recorded from 29 scalp electrodes pre- and post-AES and PES. Following AES, participants were categorized into two groups: Rl and nonresidual inhibition (NRI). The grand average MMN waveforms and isopotential topo­ graphic maps were obtained in Rl, NRI, and PES groups. Results: Three MMN parameters for five deviants of frequency, intensity, duration, location, and silent gap were compared among three groups of Rl, NRI, and PES. Statistical analyses revealed significant between-subject effects for AES on MMN amplitude of frequency and duration deviant, MMN area under the curve of frequency, intensity, and duration deviants. Conclusions: Presence of Rl can reestablish change-detection mechanisms in the central auditory pathways. It is suggested that MMN is reliable for assessment of change-detection system in people with tinnitus. It can be a useful technique in monitoring effects of treatments and rehabilitation.

*ENT and Head and Neck Surgery Research Center, Iran University of Medical Sciences, Tehran, Iran; +Department of Otorhinolaryngology, Hannover Medical University (MHH), Hannover, Germany; +Academy of Medical Sciences, Tehran, Iran; §Electronics Group, Faculty of Engineering, Shahed University, Tehran, Iran; * 'Biomedical Engineering Faculty, Amir Kabir University of Technology, Tehran, Iran Corresponding author: Mehrnaz Mohebbi, Laboratory for Auditory Neuroscience and Tinnitus, ENT and Head and Neck Surgery Research Center, Iran University of Medical Sciences, Tehran, Iran; E-mail: [email protected], [email protected]

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A ltera tio n s in A u d itory C h an ge D e te c tio n R ela te d to R I/M ahm oudian et al

Key Words: tinnitus, residual inhibition, auditory MMN, change detection, sensory memory Abbreviations: AES = auditory electrical stimulation; ANOVA = analysis of variance; dB SL = dB sensation level; EEG = electroencephalography; ERP = event-related potential; IUMS = Iran University of Medical Sciences; LMT = loudness matching of tinnitus; MCL = most comfortable level; MML = minimal masking level; MMN = mismatch negativity; NBN = narrowband noise; NRI = nonresidual inhibition; PES = placebo electrical stimulation; PMT = pitch matching of tinnitus; PTA = pure-tone average; Rl = residual inhibition; ROI = region of interest; SD = standard deviation; TSL = tinnitus suppression level; VAS = visual analogue scale

INTRODUCTION ubjective idiopathic tinnitus is the conscious ex­ perience of a sound without an external or mechani­ cal source that originates in an involuntary manner in the head of its owner or may appear to him or her to do so (McFadden, 1982). It can be considered as an audi­ tory phantom perception. One of the fundamental properties of tinnitus that some people may experience is th at it can be inhibited by stimulation of the auditory system by stimuli such as acoustical, electrical, and magnetic. Previous studies showed th at following offset of appropriate acoustical or electrical masking stimulations, tinnitus may tempo­ rarily remain inhibited or eliminated for a period of time (Hazell and Wood, 1981; Meikle et al, 2004; Savastano, 2004). This phenomenon is known as “residual inhibi­ tion” (RI). The effect of RI can last from seconds or minutes up to hours or even a day or more in a small proportion of people (Hazell and Wood, 1981; Meikle et al, 2004). More than 75% of patients with tinnitus indicate some degree of RI consisting of either complete or partial RI (Vernon and Meikle, 2003; Roberts et al, 2006). The biologic mechanisms associated with RI are not yet fully understood. Evidence from many studies sug­ gests that most forms of tinnitus result from a loss of inhibition secondary to cochlear damage in central audi­ tory structures. This loss of inhibition disrupts the normal synchronized neural activity constrained by feed-forward inhibition to acoustic features of stimulus. In this model of tinnitus, it is hypothesized th at related brain regions are abnormally underactive and to compensate this under­ activity, function of neural networks are aberrantly in­ creased when tinnitus is present (Kadner et al, 2002; Eggermont and Roberts, 2004; Weisz et al, 2007). Norena (2011) suggested that neural activity may increase at all levels of the central auditory system because of sensory deprivation in the auditory system. Central neural gain increases to adapt neural sensitivity to the reduced sen­ sory inputs, preserving a stable mean firing and neural coding efficiency. Maintaining neural homeostasis can be done with amplifying “neural noise” because of the overall increase of gain (or sensitivity). Tinnitus can result from a trade-off between a central gain increase and neural noise. Other studies reported that tinnitus

S

might be the consequence of the underlying neural re­ organization of the tonotopic areas induced by auditory deafferentation (De Ridder et al, 2012). Studies have shown th at RI effects might temporarily return the impaired synchronized neural activity to normal healthy levels and therefore stop the perception of tinnitus (Kahlbrock and Weisz, 2008; Sedley et al, 2012). The experiment reported in this article was guided by the belief th at alterations in activity through the central auditory system associated with RI induced by auditory electrical stimulation (AES) can tend to return the abnormal neural activity to normal levels. It has been suggested th at the brain keeps a prior pat­ tern of sensory inputs and compares any new input to th at pattern (Knill and Pouget, 2004; Friston, 2010). The brain detects what is different from what is expected. This process of comparison involves memory functions (De Ridder et al, 2012). Studying tinnitus and RI revealed that cortical networks of auditory higher-order processing, memory, and attention are related to tinnitus and RI because pitch and duration of sounds are stored in the memory for the recognition (Osaki et al, 2005). Although by no means certain, the mechanisms which underlie RI may overlap those that generate tin­ nitus. If this is accepted, efforts to understand RI can be a clue for advancing our knowledge of the mechanisms underlying tinnitus. Despite the fact th at RI phenom­ enon is among few procedures effective in reduction of tinnitus for brief periods, few studies have been focused on RI (Roberts et al, 2008). Recent advances in signal processing and electrophysiological approaches have led to improved objective studies of tinnitus by providing quantitative information and determining neural mechanisms of tinnitus. A very fruitful approach to studying auditory information pro­ cessing and the underlying neurophysiology involves recording of the mismatch negativity (MMN). MMN ena­ bles one to reach a biological understanding of central auditory perception, auditory sensory memory, change detection, and involuntary auditory attention (Naatanen et al, 2007). As previously mentioned, tinnitus and RI can be considered as the forms of alteration in neural activity and auditory information processing. Therefore, MMN as a change-detection tool may be appropriate to explore the processing changes because of tinnitus and RI. The newly developed and fast multifeature MMN responses

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allow for the focused recording of the most widely reported MMN deviants (frequency, intensity, duration, location, and silent gap) within an efficient and time-saving paradigm among individuals with tinnitus. We hypothesized th at maladaptive cortical reorgan­ izations following long-term tinnitus would be adjusted by inducing RI. The main purpose of this study was to investigate alterations in auditory change detection and auditory sensory memory related to RI induced by AES, using MMN brain mapping in participants with subjec­ tive tinnitus METHODS P a rtic ip a n ts

Twenty-eight participants with chronic subjective tinni­ tus (18 males, 10 females) aged 22-45 yr old (mean = 35.33, standard deviation [SD] = 7.01 yr) enrolled in this study. They were referred to ENT and Head and Neck Research Center of Rasoul-e-Akram Hospital (Tehran, Iran) for assessment and treatm ent from July 2012 to April 2013. Tinnitus was present for 2-228 mo (mean = 56.55, SD = 67.77 mo) in left (6 participants), right (7 participants), or both ears (15 participants). There was no evidence of evoked tinnitus and partic­ ipants had various senses of tinnitus including ringing, whistling, hissing, cricket sound, single high-pitch tone, or noise. All participants were right-handed as revealed by the Edinburgh Handedness Inventory (Oldfield, 1971). All participants had bilateral normal external and middle-ear functions as assessed by otoscopy and tympanometry. The behavioral pure-tone thresholds in both ears were 44% in P ersian T innitus Q uestionnaire, >39% in P ersian Tin­ nitus H andicap Inventory, LMT > 6 dB SL, and > 6 of 10 points in VAS were enrolled in the study. P ro ced u res P articipants sat on a comfortable chair in an electro­ m agnetic and soundproof chamber. One pillow was placed behind the p articipant’s neck to reduce muscle contractions. P articipants were asked to rem ain re­ laxed and not pay attention to the MMN auditory stim ­ uli, stay awake, and avoid eye and body movements during recording, b u t not to try h ard to suppress blinks. Electrodes were connected to a well-sized electroence­ phalography (EEG) cap w ith 29 electrodes. A scrubbing gel was used to clean and scrub the areas of scalp under each electrode. A conducting gel was injected into each electrode using a blunt needle. A subtitled silent movie (Planet E arth , BBC Docum entary production, 2006) was played for participants via a m onitor in front of them to m aintain alertness and distract from the audi­ tory stim uli during the experim ent. Each EEG record­ ing session, including preparation and recording, lasted approxim ately 60 min. Prior to perform ing the electrical stim ulation, partici­ pan ts were allocated random ly into two sessions of AES and placebo electrical stim ulation (PES). D uring re ­ cording sessions, MMN, LMT, and VAS for loudness were prim arily recorded pre-AES or -PES presentation. P articipants were in structed to report if they felt any changes in quality (pitch) and loudness of th eir tin n itu s during the procedure. AES or PES was presented for 60 sec. MMN, LMT, and VAS were recorded again imme­ diately following AES or PES. The additional session of PES was considered as a control to obtain the real ef­ fects of tin n itu s RI induced by AES. A sim ilar procedure as th a t used in AES was repeated in the PES session, except th a t the AES device was tu rn ed off. P articipants were asked to report four levels of AES, including lowest cu rren t level (including sound sensation in subjects), term ed as auditory sensation level; tinnitus suppression

level (TSL); m ost comfortable level (MCL); and uncom ­ fortable current level; regardless of w hether they felt any sensations associated w ith AES or PES. Therefore, the participants were advised th a t they m ight or m ight not feel any sensations of AES. VAS and LMT were m easured four tim es (before and after each MMN and each intervention) to m onitor changes of tinnitu s loudness during the procedure (Figure 1). LMT was m easured based on the loudness obtained during the first session of assessm ent for participants. Following AES, participants were categorized into two groups (NRI and R I) based on the VAS and LMT score changes (score changes > 3 scales decrem ent were considered as RI and < 3 scales decrem ent were considered as NRI). T hirteen participants w ere RI and 15 participants were NRI. Because different participants m ay have various durations of RI, a w ashout interval was considered between the sessions of AES and PES. The washout period for the crossover study was at least 5 days following the first session. MMN S tim u li MMN was recorded using the new paradigm proposed by N aatanen et al (2004), with a small change in the num ber of stim uli to decrease the tim e of the recordings. In this paradigm compared with the traditional oddball condition, five auditory features can be recorded in a considerably shorter time. In this new paradigm , every other tone is a standard and the deviants are presented once after each standard, m eaning th a t the deviants occur w ith the probability of 50% relative to standards (Pstd = 0.5, P Dev = 0.5/5 = 0.1). The stim uli were con­ structed digitally using MATLAB. S tandard stim uli were composed of three sinusoidal tones of 500, 1000, and 1500 Hz w ith a total duration of 75 msec including 5 msec rise and fall times. The intensity of the second and th ird tones was 3 and 6 dB lower th a n th a t of the Screening Tests

Inclusion

r ~ E n ro llm e n t an d C o n sen t

| Randomization

...................

j

Allocation iVAS-l,LMT-l

(VAS-l, LMT-lj

M ultifeature MMN mapping

M ultifeature MMN mapping PES

S-3, LMT^ >

Multifeature MMN mapping

$AS-3,LMT-3I

Multifeature MMN mapping I

......

Figure 1. Flowchart of the study procedure. Following randomi­ zation, a session of either AES or PES was performed. Participants were crossed over for the second session of recording, after a 5-day washout period. VAS and LMT were administered at four time points during each session to assess tinnitus loudness changes.

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Journal of the American Academy of Audiology/Volume 26, Number 4, 2015

first tone, respectively. The stimuli were presented binaurally via ER-3A insert earphones with an intensity level of 85 dB SPL and equal phase in both ears. The deviant tones consisted of five auditory features includ­ ing frequency, intensity, duration, perceived sound source location, and a gap in the middle of the tone. Fre­ quency, intensity, and location deviants had two types. Half of the frequency deviants had tones 10% higher (550, 1100, 1650 Hz) and the other half had tones 10% lower (450, 900, 1350 Hz) than the standard. Half of the intensity deviants were -1 0 dB and the other half +10 dB compared to the standard. To change the loca­ tion of the perceived sound source, an interaural time difference of 800 |xs was applied for half of the deviants to the right channel and the other half to the left chan­ nel. The perceived difference between the standard stimulus and the location deviant was approximately 90°. The duration deviant was 25 msec in duration (5 msec rise and fall times). To make the gap deviant, 7 msec (including 1 msec rise and fall times) was cut from the middle of the standard stimulus, creating a silent gap there. The stimuli were presented in three 5-min blocks with 500-msec onset asynchrony. In each block, the first 15 tones were standards and the devi­ ants were presented pseudorandomized within a block so that in an array of five deviants, each deviant was presented once and two of the same types of deviants never directly followed each other (Figure 2). The total number of stimuli was 1,845, and the recording lasted 15 min for the five deviants. To present the stimuli, we used the Presentation software (version 0.71; NeuroBehavioral Systems, Berkeley, CA), a stimulus delivery and exper­

imental control program for neuroscientific research purposes. The stimuli intensity was 70 dB SPL, which was at least 35 dB above the pure-tone averages (PTAs) of 500,1000, and 2000 Hz in all study participants. This presentation level could provide enough intensity for evoking MMN. AES AES was delivered by a stimulation system (Promon­ tory Stimulator; Cochlear Company, Australia), which is used to evaluate cochlear implant candidates. Using this system, an active surface tympanic membrane elec­ trode (tymptrode) was inserted through the external auditory canal and placed adjacent to the posterior infe­ rior part of tympanic membrane, with the ground elec­ trode on the forehead. A saline solution was put in the ear canal to improve electrical conductivity. Bipolar bursts of alternating current (square pulses) with 500-msec duration were applied to the tinnitus ear (a pulse rate of 1 Hz) and a frequency modulation of 50 Hz. In bila­ teral tinnitus, AES was delivered to the ear which tin­ nitus was perceived as more severe. The stimulation was presented for 60 sec. Four current levels of AES were measured: auditory sensation level, TSL, MCL, and the uncomfortable current level at which patients felt pain. Because the intensity level of electrical stim­ ulation for generating RI differed among the participants, AES was applied slightly above TSL at the MCL, which could be between 50 and 500 p.A for different participants. The normal saline solution was removed from the ear canal after presenting AES.

7.5 sec 15 Standard

5 min 300 Standard 5X60 Devaint A

7.5 sec 15 Standard

5 min 300 Standard 5X60 Devaint

Figure 2. Schematic illustration of the new MMN paradigm used in this study. As indicated, each array consisted of five different devi­ ant types which were presented pseudorandomized so that each deviant type was presented once, and two of the same types of deviants never followed each other. Stimulus-onset-asynchrony was 500 msec in three 5-min blocks (1,845 stimuli in total), with total recording time for the five types of deviants = 15 min. S = standard tone; D = deviant tone.

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Alterations in Auditory Change D etection R elated to RI/Mahmoudian et al

S u b jectiv e E v a lu a tio n s F o llo w in g AES

A few minutes following AES, the inhibitory effects of AES on perceived tinnitus loudness (RI) were measured using VAS and LMT. VAS and LMT are important for quantification of severity and for understanding the annoyance caused by tinnitus. Changes in tinnitus loudness were classified into three groups: (a) tinnitus reduced or became inaudible (complete or partial RI), (b) tinnitus did not change (NRI), and (c) tinnitus became worse than before AES (rebound effect). In this study, the participants were grouped in RI and NRI, which included (a) and (b, c), respectively. The subjective criteria for evaluating tinnitus after AES using a psychoacoustic tinnitus assessment included dimin­ ishing or worsening of tinnitus loudness by at least 2 dB SL in LMT. Participants were categorized into groups of RI and NRI, based on their LMT and VAS scores. Increased, unchanged, or reduced 3 scales in VAS and decreased tinnitus loudness by a 2 dB SL in LMT were considered as RI. EEG R eco rd in g

A 32-channel Micromed BRAIN QUICK system was used to record electrical brain activities. Twenty-nine scalp sites (FP1, FPz, FP2, F7, F3, Fz, F4, F8, FT7, FC3, FCz, FC4, FT8, T7, C3, Cz, C4, T8, TP7, CP3, CPz, CP4, TP8, P3, Pz, P4, POz, M l, and M2) were chosen according to the International 10-10 system, and Ag/AgCl electrodes were connected to an EEG cap placed on the scalp (Oostenveld and Praam stra, 2001). Common reference is placed on the tip of the nose and the ground electrode on the forehead. Electroocu­ lography was recorded by placing two electrodes below and at the outer canthus of the left eye to monitor vertical and horizontal eye movements. Electrode impedance was kept below 5 Kfl during the recordings. EEG signals were filtered with an online 0.00-100 Hz band-pass filter. Sampling rate for digitalization was 1024 Hz. In addition, a custom-designed microcontroller device received digital interface events and triggered stimulus event marking on the computerized EEG record. EEG D ata P re p r o cessin g

The EEG data were analyzed offline using EEGLAB 11.02 (Delorme and Makeig, 2004) toolboxes running in MATLAB software. EEG signals were offline-filtered with a 0.5-40 Hz filter. Individual epochs were marked from 100 msec prestimulus to 400 msec poststimulus, based on the triggered stimulus events made by the microcontroller device EEG. Eye blinks, electrocardio­ graphies, and other muscular artifacts were removed from epochs by visual inspection. Any epochs with

amplitudes >80 |xV were omitted from the averaging. Epochs were separately averaged and extracted for the standard and for the five types of deviants. The first 15 standards of each block were rejected from the averaging. EEG D ata A n alysis

The standard event-related potentials (ERPs) were subtracted from the corresponding deviant ERPs to delineate the MMN, resulting in five different types of MMN. Amplitude, latency, and area under the curve were computed for each participant in the frontocentral region of interest (ROI) consisting of F3, F4, Fz, FC3, FC4, FCz, and Cz. These electrode sites were chosen because the largest MMN amplitude is typically ob­ tained from those sites. Amplitudes and latencies were calculated according to the most negative peak in the averaged MMN in a time window of 100-250 msec post­ stimulus. Amplitude was calculated from baseline to maximum negative peak of MMN. The area under the curves was calculated as the mean voltage in the negativity of extracted MMN waveform. MMN validity was confirmed by checking polarity reversals at channels M l and M2 occurring at the 100-250 msec poststimulus period. The grand average waveforms and isopotential topographic maps were obtained in the RI and NRI groups. Checking polarity reversals at channels M l and M2 occurring at the 100-250 msec poststimulus period confirmed the MMN waveforms validity. S ta tistic a l A n alysis

Five different procedures were used to analyze and describe the data: the first procedure was an analysis of variance (ANOVA) to analyze the differences be­ tween the RI, NRI, and PES controls for auditory PTAs. The second procedure used an independent f-test to determine if there was any significant alteration in mean differences of amplitudes, latencies, and area under the curves of MMN responses between PES controls and the AES group. The third procedure was a repeated measure ANOVA to analyze the measured amplitudes, latencies, and area under the curves of MMN responses across fac­ tors group and deviants, pre- and post-AES. The fourth procedure permitted visualization of the data using trendline graphs, and the fifth procedure was another visualization of MMN data using topographic brain maps. Statistical analyses was performed using the Statistical Package for Social Science (SPSS V.21; Chicago, IL). The significance level for assessment of the main effect was 0.05. RESULTS

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verall, 13 of 28 participants with problem tinnitus (46.42%) indicated RI after receiving AES. Five

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Jo u rn a l o f th e A m erican A cad em y o f A u d io lo g y /Volume 26, Number 4, 2015

participants reported a complete inhibition (complete RI) of tinnitus, and eight participants reported a signifi­ cant attenuation of tinnitus (partial RI). Tinnitus did not become worse in any of the participants. The duration of RI induced by AES and the length of poststimulus inhibition ranged from 30 to 2,880 min (mean = 583.85, SD = 802.37 min). AES current inten­ sity levels differed from 125 to 500 pA. (mean = 247.85, SD = 124.31 pA.) in the RI group, and from 92.5 to 500 p.A (mean = 266.33, SD = 124.71 pA.) in the NRI group. The mean stimulus intensity difference in both groups was not significant. A u d ito ry PTAs, VAS, and L ou d n ess M atch in g

The mean of auditory PTAs across three frequencies (500, 1000, and 2000 Hz) was 6.53 ± 3.75 dB HL in the RI group, 5.66 ± 3.19 dB HL in the NRI group, and 6.07 ± 3.43 dB HL in the PES control group. A one-way ANOVA was used to assess the statistical sig­ nificance between the RI, NRI, and PES controls for the auditory PTAs. Overall, there were no significant differ­ ences in thresholds of PTAs among the study groups, p > 0.05. Participants rated their average tinnitus loudness pre-AES as >6 on a 10-point VAS. A repeated measures ANOVA was used to test for the loudness rating dif­ ferences using VAS and psychoacoustical LMT among the groups pre- and post-AES (Table 1). The results revealed that the loudness rating using VAS differed significantly among RI, NRI, and PES control groups; •^(2,53) = 17.18, p < 0.05. Post hoc comparisons using a Bonferroni test indicated th at the mean VAS scores for the RI group (from mean = 6.38, SD = 1.26 to mean = 2.92, SD = 1.75) was significantly different from that for the NRI group (from mean = 7.00, SD = 1.25 to mean = 6.73, SD = 1.03) and PES controls (from mean = 7.00, SD = 1.21 to mean = 6.75, SD = 1.23), p < 0.05. There were no significant differences between the NRI and PES control groups. Loudness rating using LMT showed significant differences among the RI, NRI, and PES control groups; Fi2,5 3 ) = 4.02, p < 0.05. Post hoc comparisons using a Bonferroni test indicated that the mean LMT scores for the RI group (from mean = 6.53, SD = 1.99 to mean = 3.38, SD = 2.09) were sig­ nificantly different from those for the PES controls

(from mean = 6.78, SD = 2.23 to mean = 6.78, SD = 2.23),p < 0.05. The mean LMT and VAS scores showed that the severity and annoyance of tinnitus decreased after AES intervention in the RI group. There was no significant difference between the NRI group compared to the other two groups. None of the participants reported any differences in the pitch of their tinnitus, so no statistical analysis was performed for PMT. C om p arison s o f MMN F ea tu r es Pre- to Post-A ES

The grand average of ERPs was generated for the standard stimuli and for the five types of deviants (Figure 3). An independent /-test was used to determine whether there was any significant alteration in mean differences of amplitudes, latencies, and area under the curves of MMN responses from pre- to post-AES and PES between the PES control group and the AES group. Statistical analyses showed that mean dif­ ferences of amplitudes of intensity, location, and silent gap were significantly larger in the AES group (inten­ sity: mean = 0.70, SD = 1.18; location: mean = 0.99, SD = 1.62; silent gap: mean = 0.57, SD = 1.51) compared to the PES control group (intensity: mean = —0.32, SD = 1.14; location: mean = 0.08, SD = 1.48; silent gap: mean = -0.17, SD = 1.23). Also, mean differences of area under the curves of frequency and intensity deviants were signi­ ficantly larger in the AES group (frequency: mean = 65.46, SD = 88.51; intensity: mean = 77.96, SD = 114.65) than the PES control group (frequency: mean = —2.18, SD = 105.20; intensity: mean = -10.16, SD = 66.08). Associated results are presented in Table 2. A repeated measure ANOVA was used with group (RI, NRI, and PES) as the between variable and time as the within variable. Statistical analyses revealed sig­ nificant between-participant effects for AES on MMN amplitude of frequency deviant F(2t53) = 4.70, p < 0.05, and duration deviant F(2j53) = 8.01, p < 0.05; MMN area under the curve of frequency E(2,5 3) = 3.37, p < 0.05; inten­ sity F(2,53) = 3.69,p < 0.05; and duration F(2;5 3) = 4.35,p < 0.05 deviants (Table 3). To perform pairwise comparisons among the groups, a post hoc Bonferroni test was con­ ducted. The results of the Bonferroni test showed that MMN amplitudes of frequency and duration deviants were significantly larger (p < 0.05) in the RI than in the NRI group. MMN area under the curves of intensity

Table 1. Statistical Results for Repeated Measure ANOVA with VAS and LMT (Between-Subject Variables) and Groups as Repeated Variable (Within-Subject Variable) Variable VAS

M ode Pre Post

LMT

Control Group

RI Group

NRI Group

Mean ± SD

Mean ± SD

Mean ± SD

7 ± 1.27

6.38 ± 1.26

7 ± 1.25

6.75 ± 1.23

2.93 ± 1.75

6.73 ± 1.03

Pre

5.78 ± 2.23

5.53 ± 1.99

5.70 ± 1.64

Post

5.78 ± 2.23

2.38 ± 2.09

5.50 ± 1.21

N o te : Values in b oldface indicate p values less than 0.05.

414

p Value

P(2,53)

0.00

17.18

0.02

4.02

Alterations in Auditory Change D etection R elated to RI/Mahmoudian et al

RI Group (Pre-AES)

RI Group (Post-AES) NRI Group (Pre-AES) NRI Group (Post-AES)

,.\r

uV

Time (ms)

Time (ms)

11V

Time (ms)

Standard (frontocentral)

----------- Difference wave (frontocentral)

Deviant (frontocentral)

----------- Difference wave (mastoid)

Time (ms)

Figure 3. The grand mean average of AEPs recorded in the RI and NRI groups. AEPs to standards (blue or dark gray line) and deviants (red or light gray line) are shown for a frontocentral ROI (F3, F4, Fz, FC3, FC4, FCz, and Cz) for each type of deviant, averaged across all deviations. Difference waves are given for a frontocentral ROI (black solid line) and for the electrode mastoid (black dotted line), which shows MMN polarity inversion. Topographies at MMN peak maximum are illustrated for each group of participants and for each type of deviant. Difference waves were computed by subtracting AEPs to standards from AEPs to deviants, averaged across all deviation mag­ nitudes. The approximate latency of the MMN response is indicated next to the maps. (This figure appears in color in the online version of this article.)

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Table 2, Statistical Results for Independent f-test Comparing Mean Differences of Latency, Amplitude, and Area under the Curve for Five MMN Deviants between PES and AES Groups PES Group (Mean ± SD)

MMN Features MMN-Frequency

MMN-Intensity

MMN-Duration

MMN-Location

MMN-Silent Gap

N o te :

Amplitude Latency Area under the Curve Amplitude Latency Area under the Curve Amplitude Latency Area under the Curve Amplitude Latency Area under the Curve Amplitude Latency Area under the Curve

0.22 -12.07 -2.18 -0.32 -13.71 -10.16 0.03 5.50 32.47 0.08 5.14 29.36 -0.17 -6.10 11.27

0.60 1.04 -16.21 37.11 65.46 88.51 0.70 1.18 -1.14 + 66.32 77.96 + 114.65 0.27 1.49 -3.14 48.64 74.54 129.54 0.99 1.62 3.20 34.77 56.78 145.95 0.57 1.51 -2.25 40.46 23.75 124.20

p Value 0.20 0.71

0.01 0.002 0.49

0.001 0.56 0.48 0.24

0.03 0.87 0.59

0.04 0.76 0.69

Values In boldface indicate p values less than 0,05.

and duration deviants were larger in the RI th an in the PES group. The MMN area under the curve of fre­ quency deviant was larger in the RI th an in the NRI group. No significant differences were seen in the PES group pre- to post-PES (Figure 4). G raphic D isp la y o f th e MMN D ata As repeated m easure ANOVA yielded statistically sig­ nificant results, the MMN data exhibited differences between- and within-groups. In Figure 5, we used a graphic method to display trends of the results. The ampli­ tude, latency, and area under the curve for the five devi­ ants of MMN are depicted in a linear scheme, with each line representing pre- and post-means for the RI, NRI, and PES groups. Results from the PES group were used as a reference for all of the comparisons in each graph. In addi­ tion to these significant differences, some other features of MMN tended to show significant differences. As demon­ strated in Figure 5, the mean am plitude and area under the curve for MMN of the intensity deviant, as well as the area under the curve for MMN of silent gap deviant, tended to increase pre- to post-AES in the RI group com­ pared with the NRI and PES groups. D isp la y o f T o p ograp h ic M aps As illustrated in Figures 3 and 4, the fast m ultifea­ tu re paradigm produced distinct MMNs for all deviants: frequency (PES group: 178 msec, RI group: 158 msec, NRI group: 168 msec), duration (PES group: 132 msec, RI group: 130 msec, NRI group: 153 msec), intensity (PES group: 170 msec, RI group: 204 msec, NRI group: 170 msec), location (PES: 133 msec, RI group: 140 msec, NRI group: 134 msec), and silent gap (PES: 136 msec, RI group: 143 msec, NRI group: 159 msec). The visual inspection

416

1.18 47.00 105.20 1.14 69.29 66.08 1.58 + 43.76 139.38 + 1.48 -+- 42.62 + 225.93 1.23 55.94 108.63

AES Group (Mean ± SD)

of the distribution m aps suggests th a t the MMN wave­ forms were best evoked in the RI group after AES. The scalp distribution of MMN for all deviants differed between pre- and post-AES in the RI group, except for the location deviant. The distribution of MMN was wider, more robust, and more anteriorly distributed post-AES in the RI group. In the NRI group, the scalp distribution of MMN for all deviants did not differ between pre- and postAES, except for the duration deviant. The visual inspec­ tion of the distribution maps suggests th a t the MMN for the intensity deviant tone had a more anterior distribu­ tion over temporal areas, as compared to the duration and frequency conditions which had more frontocentral distributions. DISCUSSIO N his study investigated preattentive central audi­ tory processing associated w ith tin n itu s RI induced by AES as shown by m ultifeature MMN. We postulated th a t RI induced by AES could recover MMN am plitudes and area under the curves as an index of autom ated auditory sensory memory and change-detection func­ tion. The hypothesis th a t the MMN would be changed in participants w ith a tin n itu s problem from pre- to post-AES was supported by d ata collected in this study. The statistical analysis revealed significant group ef­ fects for MMN am plitude and area under the curve of frequency, duration, and intensity deviants. O ur previous study indicated a possible deficit in autom ated central auditory processing m echanism s supported by the MMN findings involved in p re atten ­ tive change detection in individuals w ith tinnitu s (M ahmoudian et al, 2013). O ther studies also exhibited im paired m echanism s involved in cortical netw orks of

T

A ltera tio n s in A u d itory C h an ge D e te c tio n R ela ted to R I/M ahm oudian et al

Table 3. Statistical Results for Repeated Measure ANOVA with Latency, Amplitude, and Area under the Curve as Factors (Between-Subject Variables) and Groups as Repeated Variable (Within-Subject Variable) Variable/Deviant MMN-Frequency

Feature Amplitude Latency Area under the Curve

MMN-Intensity

Amplitude Latency Area under the Curve

MMN-Duration

Amplitude Latency Area under the Curve

MMN-Location

Amplitude Latency Area under the Curve

MMN-Silent Gap

Amplitude Latency Area under the Curve

Mode Pre Post Pre Post Pre Post Pre Post Pre Post Pre Post Pre Post Pre Post Pre Post Pre Post Pre Post Pre Post Pre Post Pre Post Pre Post

Control Group Mean ± SD -1 .9 9 ± 0.72 -2.21 ± 0.76 178.07 166.00 168.30 166.11 -1 .6 3

± ± ± ± ±

24.62 35.26 50.27 88.11 1.00

-1 .3 0 195.21 181.50 69.18

± ± ± ±

0.79 41.26 48.30 58.54

59.02 -2 .4 2 -2 .4 5 163.35 168.85

± 68.08 ± 0.86 ± 1 .1 1 ± 38.07 ± 41.79

134.63 162.50 -2 .1 4 -2 .2 2 139.04 144.17 142.37 140.84 -2 .0 5 -1 .8 8 161.60

± ± ± ± ± ± ± ± ± ± ±

85.68 105.14 0.97 1.27 24.28 32.48 119.28 117.64 0.99 0.91 36.41

155.50 ± 35.75 102.08 ± 79.13 113.36 ± 94.07

RI Group Mean ± SD —1.96 ± 0.57 -3 .2 0 ± 0.56 176.54 ± 29.27 161.00 132.50 252.48 -1 .1 4 -2 .4 9 179.46 195.92 35.67

± 28.01 ± 6 3 .1 2 ± 34.08 ± 0.53 ± 0.87 ± 43.29 ± 42.34 ± 29.64

188.04 -2 .8 3 -3 .3 8 161.15 156.76 174.44 255.62 -1 .9 8 -3 .7 6 133.07 129.61 136.48 263.20 — 1.79 -2 .7 8 162.53 162.07 117.74 181.08

± ± ± ± ±

± ± ± ± ± ± ± ± ± ± ± ±

± ±

92.79 1.15 0.79 31.54 34.65 83.27 52.84 0.72 1.50 17.61 17.90 85.38 109.66 0.45 0.41 34.29 35.38 49.57 49.48

NRI Group Mean ± SD -1 .7 9 ± 1.16 -1 .8 5 186.53 169.73 117.82

± ± ± ±

1.12 40.45 40.03 102.36

142.53 -1 .4 6 -1 .6 0 183.66 167.20

± ± ± ± ±

108.46 0.99 0.61 52.94 35.85

71.10 ± 64.12 77.25 ± 75.68 -2 .1 7 ± 1.08 -2 .2 0 ± 0.89 159.86 ± 34.85 170.46 ± 39.40 125.37 194.18 -2 .4 0 -2 .7 7 138.07 147.13 151.47 147.60 -1 .9 7

± 1 1 1 .7 4 ± 117.07 ± 1.46 ± 1.45 ± 14.99 ± 30.26 ± 112.25 ± 1 0 4 .1 9 ± 1.35

-2 .2 0 ± 1.16 159.13 ± 34.01 155.20 ± 29.65 114.85 ± 110.63 104.30 ± 101.82

p Value

F(2.53)

0.01

4.70

0.59

0.52

0.04

3.37

0.27

1.32

0.35

1.05

0.03

3.69

0.001

8.01

0.79

0.22

0.01

4.35

0.11

2.29

0.12

2.17

0.13

2.05

0.37

0.99

0.84

0.16

0.13

2.05

Note: Values in boldface indicate p values less than 0.05.

auditory higher-order processing, memory, and a tte n ­ tion in individuals w ith tinnitus (Osaki et al, 2005; De Ridder et al, 2006; Weisz et al, 2007). Findings of this study are consistent with the notion th a t autom ated auditory sensory memory and change detection is recov­ ered by inducing RI. Additionally, as revealed in MMN responses and th eir topographical maps, the scalp dis­ tribution of MMN increased pre- to post-AES in the RI group. Therefore, it seems th a t the presence of RI may have an im portant role in recovering MMN am plitudes. T innitus is a phantom auditory experience which is detected as an error signal in the brain (Joos et al, 2014). Sensory m essages originate from the peripheral organs, b u t perception itself is a phenom enon carried out by system activity such as subcortical and cortical n eu ral networks. Nonetheless, tinnitus is not different from other sensory phenom ena (Guitton, 2012). The sensation of tin n itu s, irrespective of its possible etiolo­ gies, is generated from loss of inhibitory m echanism s in central auditory stru ctures or abnorm al reorganization throughout the central auditory system th a t also extends into nonauditory brain regions. Synchronous neural

activity is norm ally lim ited by feed-forward inhibition to acoustic features of the stim ulus, bu t tin n itu s alters brain electrical activities and feed-forward inhibition networks (Terry et al, 1983; Engelberg and Bauer, 1985). Based on the new proposed Bayesian brain model (Knill and Pouget, 2004; Friston, 2010), the brain keeps a prior p attern of w hat it anticipates to encounter in the environm ent. It m akes a prediction, which is updated by active sam pling of the environm ent. This continuous updating p attern becomes the new reference for the next inform ation-seeking cycle. This m eans th a t the brain compares sensory input to the prior p attern and detects w hat is different th a n w hat is expected. In au d ito ry system , th is m odel is su p p o rted by change-detection m echanism s indexed by P50, N100, MMN, and P300 (Itti and Baldi, 2009; Baldi and Itti, 2010; Joos et al, 2014). Auditory MMN is a m ulticellular representation of auditory sensory memory a t a single-cell level in the auditory cortex (Ulanovsky et al, 2003). It reflects the process of autom atic error detection, i.e., the neural expression of a conflicting in tern al representation of

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J o u rn a l o f th e A m erican A cad em y o f A udiology/Volum e 26, N um ber 4, 2015

Frequency Deviant

Intensity Deviant

F ig u re 4. The grand m ean average of AEPs recorded in th e PES group. AEPs to stan d ard s (blue or d ark gray line) and deviants (red or light gray line) are dem onstrated for a frontocentral ROI (F3, F4, Fz, FC3, FC4, FCz, and Cz) for each type of deviant, averaged across all deviations. Difference waves are given for a frontocentral ROI (black solid line) and for the electrode m astoid (black dotted line), which shows MMN polarity inversion. Topographies a t MMN peak m aximum are illu strated for each group of participants and for each type of deviant. Difference waves were computed by subtracting AEPs to stan d ard s from AEPs to deviants, averaged across all deviation m ag­ nitudes. The approxim ate latency of the MMN response is indicated n ext to the maps. (This figure appears in color in th e online version of this article.)

41 S

A ltera tio n s in A u d itory C h an ge D e te c tio n R ela te d to R I/M ahm oudian et al

F ig u re 5. Trendline charts showing tren d s of alterations in MMN features pre- to post-AES and pre- to post-PES in th ree groups of the study. (This figure appears in color in the online version of this article.)

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J o u rn a l o f th e A m erican A cad em y o f A udio logy /'Volume 26, Number 4, 2015

the environment with the incoming sensory stimulus, and it is even present in states of impaired conscious­ ness (Escera et al, 1998, 2003). The auditory MMN automatically compares the auditory inputs with the prior representation of the environment. If incoming information does not match the prior expectations, a cortical error response is induced that can be repre­ sented by MMN (Langers and Melcher, 2011). Presence of auditory deafferentation in individuals with tinnitus restricts change detection related to memory-based tem­ poral or spatial incongruity. This means that the func­ tion of comparing auditory input with sensory memory is impaired in individuals with tinnitus. This leads to constant updating of the tinnitus percept from memory, thereby preventing habituation (De Ridder et al, 2006, 2012). As a consequence of impaired change-detection mechanisms, the tinnitus signal is continuously identi­ fied as an inconsistent signal, i.e., there is less habitu­ ation of irrelevant stimuli of tinnitus. This is confirmed by studies which have shown the elicited N 1 response, a marker for late sensory gating in individuals with tinnitus, was less decreased when repetitive auditory stimuli were presented (Kadner et al, 2002; Walpurger et al, 2003). Our study results supported the hypothesis th at RI induced by AES reflects the temporary reestablishment of automated auditory change detection in individuals with tinnitus. Subsequently, excitatory-inhibitory bal­ ance is recovered in neuronal assemblies (Kahlbrock and Weisz, 2008). Because comparing auditory input with sensory memory is recovered in individuals with tinnitus, tinnitus is not detected as an error signal and may be filtered out by related inhibitory mecha­ nisms and does not reach the perceptual levels of the auditory cortex. RI caused by a temporary return of nor­ mal activity in the auditory system results in reducing the effects of tinnitus by providing a temporary normal habituation mechanism. Wider and more frontal distribution of MMNs in the RI group from pre- to post-AES may be due to improving neural inhibition and temporary adaptation of neurons involved in synchronous activity of tinnitus, or a “reba­ lancing” of the inputs to those neurons (Feldmann, 1971) th at have a separate neural representation in auditory sensory memory. Also, the prefrontal cortex, which serves as a storage of automated short memory, may have affected in wider and more frontal distribu­ tion of MMNs maps in the RI group. Uncompensated tinnitus is defined as a repeated con­ tinuous error signal. In recent years, it has been widely accepted th at maladaptation of central information pro­ cessing is mainly responsible in tinnitus perception and generation (Plewnia et al, 2007). When tinnitus is expe­ rienced over a long term, memory, attention, and the emotional state of individuals with tinnitus may be in­ volved in this reaction. Normal function of auditory MMN responses is required to provide appropriate neural

4SO

information for higher-order processing centers in the brain. Normal sensory gating diminishes evoked res­ ponses to repeated auditory stimuli (Kadner et al, 2002). In this process, the repeated stimuli are considered as the brain’s prior pattern from the environment, so habi­ tuation to that repeated stimuli occurs in the brain. According to our findings in this study, MMN is an indicator of automated change-detection deficits in indi­ viduals with tinnitus. This deficit prevents the normal habituation mechanisms in the higher order of neural networks. This is what occurred in the NRI group, and is likely related to uncompensated tinnitus processes (Joos et al, 2014). In the RI group, presentation of AES could temporary reestablish the normal habituation to the tinnitus signal. But in the NRI group, AES could not recover the change-detection process and could not activate the habituation processes. The reason tinnitus is not suppressed by AES in some patients is not well rec­ ognized, but this may be related to the underlying neural reorganization of the tonotopic areas induced by auditory deafferentation. Sensory memory deficit may cause the constant updating of the tinnitus percept from memory, and this prevents habituation in NRI participants. In this study we looked for electrophysiological changes associated with RI, and not for its treatm ent effects. It is possible th at neural mechanisms involved in RI phenomenon overlap with those th at cause generation of tinnitus (Roberts, 2007); however, this is not an abso­ lute fact. Accepting the abovementioned hypothesis, the mechanisms involved in RI and its essentiality in tinnitus mechanisms are highlighted. Our study revealed that the change-detection process is impaired in individuals with tinnitus. Therefore, tinnitus as a frequent error signal could not be detected and inhibited by relative neural networks. Inducing RI in clinical treatm ent plans could restore the excitatory-inhibitory balance in the sub­ cortical level. Additionally, it can be speculated that recovering automated change detection following RI may prove overlapping RI and tinnitus mechanisms.

CONCLUSIONS he hypothesis th at change detection (indexed by MMN) would be sensitive to detecting neurophy­ siological changes and its reestablishment associated with RI induced by AES in individuals with tinnitus was supported by the data collected in this study. According to the results, it can be concluded that:

T

1. The presence of auditory deafferentiation in individ­ uals with tinnitus restricts change-detection mecha­ nisms (indexed by MMN) in the brain. 2. Constant updating of the tinnitus percept (as an incon­ sistent signal) from memory prevents habituation. 3. RI induced by AES reflects the temporary reestab­ lishment of automated auditory change detection

Alterations in Auditory Change D etection R elated to RI/Mahmoudian et al

in individuals with tinnitus. Subsequently, excitatoryinhibitory balance is recovered in neural assemblies. 4. MMN can be considered a useful technique in moni­ toring the effects of treatment and rehabilitation. The rehabilitation and treatment methods should be designed in a way to improve auditory change detec­ tion and sensory memory to develop normal habitua­ tion to the tinnitus signal in the brain.

A cknowledgm ents. This study was methodologically ap­ proved by the ENT and Head and Neck Surgery Research Center of IUMS, MT/2435/1391.06.14, collaborated with Otorhinolaryn­ gology Departm ent of Hannover Medical University (MHH).

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