Plasticity in the Primary Auditory Cortex, Not

Georgiewa et al., Otolaryngology 2012, S:3 Otolaryngology http://dx.doi.org/10.4172/2161-119X.S3-003

ResearchResearch Article Article OpenOpen Access Access Affective Processing in Tinnitus Patients Assessed by Functional Magnetic Resonance Imaging Petra Georgiewa1, Georg Bohner2, Yvonne Rothemund1, Randolf Klingebiel2, Heidi Olze3, Burghard F. Klapp1 and Birgit Mazurek4* 1Department of Medicine, Division of Psychosomatic Medicine and Psychotherapy, Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Berlin, Germany 2Neuroradiology Section, Department of Radiology, Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Berlin, Germany 3Department of Otorhinolaryngology, Campus Virchow Klinikum, Charité - Universitätsmedizin Berlin, Berlin, Germany 4Department of Otorhinolaryngology, Tinnitus Centre, Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Berlin, Germany

Abstract Background: Brain imaging studies suggested that the functional connectivity of various limbic, prefrontal, and temporal brain structures may play an important role in tinnitus. Methods: We evaluated in affective processing of tinnitus patients by functional Magnetic Resonance Imaging (fMRI). Patients with tinnitus and healthy controls underwent fMRI (1.5 T scanner) during 4 blocks of auditory stimuli of different emotional quality: 1) unpleasant beep tones, 2) pleasant sounds of chimes, 3) neutral words, 4) words with affective valence, alternating with off-periods. Results: The comparison of activation patterns (Statistical Parametric Mapping SPM 99) revealed significant differences in the limbic system, in prefrontal regions, temporal association cortices and striatal regions independent of affective relevance of stimuli. Conclusion: Our results underline a differing affective perception of acoustic stimuli in tinnitus patients.

Keywords: Tinnitus; Affective processing; fMRI; Limbic system concept, EEG studies performed in tinnitus patients have demonstrated alterations in the dorsal anterior cingulated cortex overlapping with the Abbreviations: BA: Brodmann Area; BDI: Beck’s Depression emotional component of pain matrix and distress-related areas [4]. Inventory; fMRI: functional Magnetic Resonance Imaging; SPM: Statistical Parametric Mapping; TQ: Tinnitus Questionnaire Here, using functional Magnetic Resonance Imaging (fMRI), we examined cerebral processes devoted to perception and emotional Introduction processing (including distress symptoms) in tinnitus patients and in control subjects. Previous imaging studies [2,10,13-15] have Subjective tinnitus is a hyperactive hearing disorder commonly demonstrated functional deficits in primary and secondary auditory defined as a phantom sound perceived solely by the affected person cortex, dorsolateral prefrontal cortex and limbic system, occurring in without an external acoustic stimulus. The pathogenesis of subjective tinnitus patients. Based on these findings, we hypothesized that the tinnitus is poorly understood; certain forms of subjective tinnitus perception of tinnitus and different grades of distress could involve are described and believed to involve both peripheral and central functional linkage of the brain areas mentioned above and may auditory pathways [1-5]. Neuronal plasticity was recently recognized correlate with the complexity and the affective burden of the auditory as accountable for the restructuring of tonotopic maps in primary and stimuli. secondary auditory regions [6-8]. Occasionally, tinnitus can cause a considerable amount of distress [1,4]. It has been suggested that subjects Materials and Methods with tinnitus have elevated neuronal response to sound in the inferior colliculi [9]. Functional connectivity of various limbic, prefrontal, and Subjects temporal brain structures was proposed as a basis for tinnitus-related Twenty-three subjects (10 tinnitus patients and 13 healthy control negative non-auditory symptoms such as stress, insomnia, anxiety, subjects) participated in this study. The tinnitus group consisted of tension and depression (tinnitus-related distress) [3,4,10]. Moreover, 5 men and 5 women with a mean age of 44 years; the control group functional connectivity between the auditory and somatosensory, included 5 men and 8 women, mean age 33 years (Tables 1 and 2). attention, cognitive and emotional neural networks were suggested to Tinnitus patients were examined by Otorhinolaryngologists. To be relevant for the pathogenesis of tinnitus [2,4,11,12]. The data has demonstrated the existence of a tinnitus network with long-range cortical connections extending beyond the central auditory system and including cingulate cortex, the insula, parahippocampal area, *Corresponding author: Birgit Mazurek, MD, PhD, Department of Otorhinolaryngology, Tinnitus Centre, Campus Charité Mitte, Charité - precuneus and amygdala. Such expansion of tinnitus network could Universitätsmedizin Berlin, Charitéplatz 1, D-10117 Berlin, Germany; Tel: +49-30- be crucial for the continuous perception of tinnitus tone and distress- 450555009; Fax: +49-30-450555942; E-mail: [email protected] related processes. Received March 27, 2012; Accepted May 23, 2012; Published May 28, 2012

Criticism of earlier studies has been predominantly based on the Citation: Georgiewa P, Bohner G, Rothemund Y, Klingebiel R, Olze H, et al. audiometric differences between the groups. Tinnitus patients were (2012) Affective Processing in Tinnitus Patients Assessed by Functional Magnetic often hearing impaired whereas the control subjects were not. In spite Resonance Imaging. Otolaryngology S3:003. doi:10.4172/2161-119X.S3-003 of this criticism, the concept of a positive correlation between changes Copyright: © 2012 Georgiewa P, et al. This is an open-access article distributed in perception or reporting of tinnitus volume and the brain activity under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the in the auditory cortex remains dominant [13]. Corroborating this original author and source are credited.

Otolaryngology Auditory Neuro-Plasticity ISSN:2161-119X Otolaryngology an open access journal Citation: Georgiewa P, Bohner G, Rothemund Y, Klingebiel R, Olze H, et al. (2012) Affective Processing in Tinnitus Patients Assessed by Functional Magnetic Resonance Imaging. Otolaryngology S3:003. doi:10.4172/2161-119X.S3-003

Page 2 of 6 be included in the study, the patients had to have normal hearing the exception of the most superior frontal and superior parietal lobe, (maximal mean hearing loss of 20 dB over 0.5 to 6 kHz). inferior temporal pole, and cerebellum (most superior z about 60 and most inferior z about -25 according to Talairach and Tournoux Tinnitus-related distress was assessed by a standard German [20] were obtained. Structural 3D data sets were acquired using a T1- Tinnitus Questionnaire (TQ) [16], an adaptation of Hallam’s TQ weighted sagittal sequence with isotropic voxels (TR/TE 11.4/4.4 ms; [17]. According to Hiller et al. [18], tinnitus is considered to be flip angle 15 degrees; number of slices 160, matrix 256 x 256, field of ‘compensated’ at a TQ level of ≤46 (no secondary symptoms) and view 256 mm, voxel size 1 mm3). ‘decompensated’ at a TQ level of >46 (permanent annoyance and psychological strain; accompanied by complaints like depression, MRI-Analysis anxiety, impaired sleep and concentration). Both groups were matched for depressive symptoms using the Beck’s Depression Inventory (BDI) The fMRI scans were analyzed using Statistical Parametric [19]. None of the subjects with tinnitus or control group had a history Mapping (SPM) 99 [21]. In order to remove effects of head movements, of neurological or psychiatric diseases. Immediately after the scanning, subsequent scans of each subject were first realigned using a ‘least the subjects estimated the affective value of the acoustic stimuli by squares’ approach with reference to the first scan. Motion artifact paper-pencil rating on a 10 cm visual analogue scale with the pools: 0 corrections were based on 3 parameters: translation x, translation y, and cm = negative, 5 cm = neutral, 10 cm = positive. rotation α. In the next step, all images were transformed into a standard space [20] using a 2D affine transformation and then smoothed with a 5 Stimuli mm FWHM (Full Width at Half Maximum) isotropic kernel to match lattice assumptions made by the SPM program. Images were re-sliced In order to visualize brain regions associated with acoustic, to 2 x 2 x 2 mm within stereotactic space and a high-pass frequency emotional and complex cognitive processing with emotional impact, filter (128 s) was applied to remove low-frequency drifts. subjects were asked to listen to blocks of 4 different acoustic stimuli. One block was designed of one of four different acoustic stimuli with In order to cope with the considerable inter-individual variance different emotional impact: (A) acoustic stimulation with unpleasant that usually arises from cognitive tasks, the random effects toolkit of beep tones (2 kHz), (B) pleasant sounds of chimes, (C) hearing of the SPM 99 program package was used to perform the statistical data neutral words and (D) hearing of affectively-important words. The analysis. First, integrated pooled images of each experimental condition emotional word impact has been evaluated in a pilot experiment (A-D) were derived for each subject by computing the weighted with 20 healthy volunteers to save the affective difference of stimulus mean of smoothed images from the separate experimental blocks in material. The acoustic stimuli were presented via headphones that conjunction with an intra-subject global normalization. Second, the passively protected the subjects from a noise generated by scanner. integrated images were entered into a multi-subject study (factor Environmental noise was used as baseline condition (rest). experimental condition, within subject analysis) and into a multi- session study (factor experimental group: tinnitus patients vs. controls, Task between-subjects analysis). Resulting SPM scores (value of variance Subjects were scanned during 2 experimental runs. All 4 acoustic analyses of the statistical parametric mapping) were thresholded at p = stimuli were included twice in each run in a pseudo-randomized order 0.05 for height (u) and p = 0.05 for the spatial extent (k). Single subject (Figure 1), resulting in 4 repetitions of each stimulus during the whole studies were performed to derive patterns of individual activation for experiment (total duration about 35 min, one block consists of only each experimental condition. Obtained data were used to compute one type of stimulus, TR of 4 s). After 10 s of baseline (= 5 volumes), the regressions (Spearman’s correlation with highest statistical significance acoustic stimuli were presented for 20 s each and were always separated as regions of interest) between brain activities and the tinnitus or by 10 s baseline phases (Figure 1). Twenty volumes were acquired affective impairment assessed by TQ and BDI. during each acoustic condition (block) leading to a total of 80 volumes The study was approved by a local Ethics Committee and adhered in addition to 40 baseline volumes. Two hundred and twenty volumes to the Declaration of Helsinki regarding the use of human subjects. per run were acquired. The subjects were asked to silently listen to the stimuli with their eyes open. Results It is known that MRI scanner noise can affect non-auditory brain The scores of the individual subscales of TQ (indicating tinnitus- areas; however, these effects were equalized since all subjects were related distress) are presented for individual patients in Table 1 and exposed to the same experimental conditions. The time of testing was summarized in Table 2. Eight patients suffered from compensated identical for all subjects. tinnitus (TQ ≤46) and 2 patients from decompensated tinnitus (TQ ≥ 47). MRI-Method Magnetic resonance images were collected using 1.5 T whole body scanner (Siemens Magnetom Vision, Erlangen, Germany) with a standard head coil. A vacuum pad was used to minimize head movements. First, a T1-weighted localizer scan was recorded. Next, T2-weighted oblique scans were obtained (TR/TE 4500/128 ms, field of view 230 mm), primarily to aid Talairach transformation for data analysis. For the functional scans, an echo-planar sequence (TR/TE 4000/66 msec; flip angle 90 degrees; field of view 230 mm; matrix 128 x 128; slice thickness 6 mm, interslice gap 0.6 mm; in-plane resolution 1.8 x 1.8 mm) was used. Sixteen slices per volume adjusted at a transverse- Figure 1: Schematic representation of the experimental design. Shown is an to-coronal angle of approximately 20° covering the whole brain with experimental run composed of the acoustic stimulation blocks.

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None of the control subjects had relevant depression symptoms, as group analysis: beep tones vs. baseline (scanner-noise), chimes vs. per standardized clinical test. Two tinnitus patients reached a threshold baseline, neutral words vs. baseline and affective wordsvs. baseline. relevant for depressive disease, prior to our investigations. There were significant differences in depression between tinnitus patients and Beep tones caused significant activation differences of nucleus control subjects (BDI), but the absolute depression value in the tinnitus caudatus, anterior part of gyrus cingulum and prefrontal regions group was lower than the threshold level indicating clinically relevant (Brodmann areas 9 and 10), when comparing tinnitus group with the depression (Table 3). The affective evaluation of stimuli was different controls. The comparison of controls with tinnitus patients indicated for chimes. activation differences of thalamus and posterior part of gyrus cingulum, in right prefrontal and frontal areas (Brodmann areas 6 and 10), and in The fMRI data analysis revealed different activation patterns somatosensory area (Brodmann area 2). between tinnitus patients and control subjects. Principal spatial distribution of voxel clusters showing significant SPM Z-scores is In the tinnitus group, the individual patterns of brain activation illustrated in Figure 2. The x-, y-, and z-coordinates of local voxel were correlated to the results of the TQ (tinnitus-evoked distress) and maxima with reference to the standardized space of Talairach and the depression score. Significant correlation coefficients were revealed Tournoux [20] are summarized in Table 4. Z-scores are reported that between depression scores and activations of caudatus, thalamus, reach significance on an uncorrected voxel level. According tothe superior temporal gyrus (Brodmann area 28) and inferior frontal gyrus paradigm, the following contrasts are reported only for the between- (Brodmann area 47) (r = 0.79; p < 0.001 for caudatus). Significant age localization of tinnitus gender tinnitus distress emotional distress cognitive distress intrusiveness hearing problems sleeping problems somatic complaints depression score 23 Bilateral m 18 6 5 4 0 2 1 10 53 Right f 31 8 4 8 3 2 0 15 34 Right f 10 4 3 1 0 0 2 2 41 Bilateral f 25 9 3 10 4 3 2 50 58 Left f 55 15 12 12 6 5 5 32 42 Bilateral m 50 13 7 14 8 6 2 55 36 Bilateral m 23 5 4 9 3 2 0 18 50 Bilateral m 24 6 7 7 3 4 1 27 64 Bilateral m 30 7 5 9 5 2 3 8 42 Bilateral f 33 5 2 10 7 5 4 20 Table 1: Individual patient’s characteristics and tinnitus impairment scores.

Scale Mean ± SD Range Tinnitus questionnaire 29.9 ± 13.7 10.0 – 55.0 Emotional distress 7.8 ± 3.6 4.0 – 15.0 Cognitive distress 5.2 ± 2.9 2.0 – 12.0 Intrusiveness 8.4 ± 3.7 1.0 – 14.0 Auditory perceptual difficulties 3.0 ± 2.7 0 – 8.0 Sleep disturbances 3.1 ± 1.9 0 – 6.0 Somatic complaints 2.0 ± 1.6 0 – 5.0 Beck’s depression inventory 23.7 ± 17.6 2.0 – 55.0

SD: standard deviation Table 2: Tinnitus impairment and depressive symptoms – mean scores for the tinnitus group. Given are the scores of the tinnitus questionnaire and its subscales and of the Beck’s depression inventory.

Parameter Controls Patients Gender (female/male) 8/5 5/5 Depression score 7 24* Stimulus rating (VAS, range 0 neutral – 10 highly affective): Beep tones 1.6 2.0 Chimes 8.8 7.1* Neutral words 5.1 5.2 Affective words 8.0 6.6 *p < 0.05 vs. controls

Table 3: Depression score and stimulus rating of healthy controls and tinnitus patients.

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significant regression scores between fMRI activation pattern and scores in depression inventory resulted in the lingual and fusiform gyrus, in the superior and medial temporal gyrus (Brodmann area 22), in the inferior frontal gyrus and the parahippocampal gyrus and the cerebellum. The correlation coefficient of depression score and activation in the lingual gyrus was r = 0.677 (p < 0.001). Affective words induced significantly different activation only in the left prefrontal brain in comparing tinnitus group vs. controls. Controls had significant changes in activation of the left inferior frontal gyrus (Broca’s area, Brodmann area 46), prefrontal (Brodmann area 10) and temporal regions (gyrus temporalis medius), of the limbic cortex: parahippocampal gyrus, cingulate gyrus, in the precuneus, substantia nigra and pons, as compared to the tinnitus patients. Significant correlation was found only with significant deactivation. Depression scores (BDI) correlated with deactivation in caudate, putamen, cingulum, precuneus, middle and superior frontal gyrus (Brodmann area 9 and 10) and the insula. For example, the correlation coefficient between BDI scores and deactivation in caudate was 0.692 (p < 0.001). Tinnitus-related distress (TQ) correlated with deactivation in the anterior cingulum, Brodmann areas 4 and 40. Discussion The results of our study are partially in line with several other imaging studies that likewise found abnormal activation in the auditory cortex and the limbic system of tinnitus sufferers or healthy controls exposed to aversive noise [4,5,15,22-24]. Taken together, these studies suggest that the auditory cortex and limbic areas are always involved in the sounds processing by tinnitus patients, also the frontal Figure 2: Representative differences in auditory stimuli-activated brain areas between tinnitus patients and healthy subjects. The brain responses to and parietal cortex. The temporal regions and parietal association different auditory stimuli are compared to baseline each: (A) beep, (B) chimes, cortices are mainly involved in perceptual issues (loudness etc.) and in (C) neutral words and (D) affective words. secondary processing concerning the character of the sound whereas the frontal regions are involved in with motivational attention of correlation was found between the depression score and significant tinnitus (i.e., the tinnitus becoming a signal of high importance, so that deactivation in middle frontal gyrus (Brodmann area 10) (r = 0.85; p it draws executive top-down attention) [25]. Prefrontal areas are seen < 0.001). as a “candidate for the integration of sensory and emotional aspects of tinnitus” [26]. Structures of the limbic system are involved in emotional Chimes induced significantly different activation pattern between aspects of tinnitus and in conjunction with frontal brain regions may tinnitus patients and control subjects in following brain structure be responsible for emotional distress and negative feedback loops seen regions: (a) caudatus, thalamus and insula, (b) limbic structures: in tinnitus [4,12,15]. It remains to be determined to what extend the gyrus cinguli anterior, (c) prefrontal areas left (gyrus frontalis medius, tinnitus-related brain network is a cause or consequence of the problem. Brodmann area 11) and (d) superior temporal areas (Brodmann Bulk of published literature suggests that tinnitus-related sound area 38). In the between-group comparison of controls vs. tinnitus, perception and distress correlate with two separate mechanisms in the significant activation differences were found in the left precuneus and brain [4]. Our data suggest possible integration of several mechanisms the Brodmann area 39 (gyrus temporalis medius). into one network for acoustic processing and development of tinnitus- For the tinnitus group, the regressions of subjective impairment related distress. and fMRI activation pattern were significant in thalamus, superior The major methodical limitation of our paper is small sample temporal gyrus (Brodmann area 22), medial frontal gyrus (Brodmann size. Unfortunately, extensive costs of fMRI reduced the possibility of area 10) and Gyrus precentralis. The correlation coefficient between extending the number of patients. Another drawback of our work is a depression score and activation in thalamus was r = 0.67 (p < 0.001). lack of balance between the non-verbal auditory stimuli (negative and Significant correlations with Tinnitus-Distress-Syndromes were found positive) and the verbal stimuli (emotional and neutral). These stimuli inferior parietal (Brodmann area 40). Significant correlation scores were chosen based on set-ups existing at that time and, unfortunately, for depression and significant deactivation were found in the anterior cannot be redone. cingulum. In our study, we have not found differences between tinnitus Neutral words induced relative over-activation in the tinnitus patients and healthy subjects in the activation of primary and group in left frontal regions, in medial and inferior temporal regions secondary acoustic cortices (Brodmann areas 41 and 42). This could (GTM, GTI), in the thalamus, gyrus lingualis, limbic regions: gyrus be due to the large variability of AC morphology. However, we found parahippocampi, gyrus cingulus and cerebellum in comparing both the differences in the acoustic association areas and areas included in experimental groups. No significant effect was found for the between- (episodic) memory processing (temporo-parietal association-cortex: group analysis controls vs. tinnitus patients. In the tinnitus group, angular gyrus, precuneus or posterior part of cingular gyrus; fronto-

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Activation in the tinnitus patients compared to controls Stimulus Lobe Structure Side BA Z-score x y z P A Caudatus 2.46 -6 8 0 0.007 limbic G. cinguli anterior L 32 2.18 -2 26 38 0.015 prefrontal G. frontalis inferior L 9 2.19 -44 2 -22 0.014 prefrontal G. frontalis medius L 9 2.14 -48 18 38 0.016 prefrontal G. frontalis superior R 10 1.97 30 52 2 0.024 B Caudatus L 2.81 0 2 6 0.003 sublobar Thalamus L 2.84 -2 -30 4 0.002 sublobar Insula L 13 3.20 -44 -6 0 0.001 limbic G. cinguli anterior 32 2.65 0 42 -6 0.004 frontal G. frontalis medius R 11 3.10 2 54 -14 0.001 temporal G. temporalis superior R 38 3.39 32 12 -22 0 C frontal G. frontalis inferior L 47 3.45 -38 30 -18 0 frontal G. frontalis medius L 11 2.47 -8 42 -8 0.007 limbic G. parahippocampi L 35 3.19 -22 -24 -30 0.001 limbic G. cinguli posterior 31 1.98 14 -24 44 0.024 G. lingualis R 18 3.91 12 -74 0 0 sublobar Thalamus 1.97 -14 -18 -2 0.024 Cerebellum 2.14 -6 -46 -34 0.016 D prefrontal G. frontalis superior L 10 2.01 -16 56 20 0.022 Activation in controls compared to tinnitus patients Stimulus Lobe Structure Side BA Z-score x y z P A sublobar Thalamus 2.18 36 -53 -12 0.003 limbic G. cinguli posterior L/R 31 1.84 -14 -30 36 0.001 prefrontal G. frontalis inferior R 10 2.38 40 50 4 0.009 frontal G. precentralis/frontalis* R 6 1.92 -28 -12 52 0.027 G. postcentralis L 2 2.20 -40 -30 36 0.014 B parietal Precuneus L 7 2.90 -22 -70 26 0.002 temporal G. temporalis medius L 39 2.72 -36 -68 26 0.003 D frontal G. frontalis inferior L 46 3.83 -46 36 16 0 prefrontal G. frontalis superior L 10 3.07 -26 58 6 0.001 limbic G. cinguli posterior 23 3.17 -8 -58 -24 0.001 limbic G. parahippocampi L 35 3.80 -22 -12 -26 0 temporal G. temporalis medius L 20 2.79 -44 -20 -16 0.003 parietal Precuneus 7 3.00 -6 -60 32 0.001 midbrain Substantia nigra 2.89 -12 -26 -8 0.002 Brainstem Pons 3.21 -4 -40 -32 0.001 A: beep; B: chimes; C: neutral words; D: affective words; G.: gyrus; L: left; R: right; BA: Brodman area; *gyrus frontalis medialis

Table 4: Significant signal differences in the between-group contrasts. Given are the responses to different auditory stimuli. vs. baseline. lateral association-cortex; basal ganglia and cerebellum). Other studies Each of the striatal nuclei serves as an input point for signal circuits suggested that the amount of distress in tinnitus patients is related to that originate in the cerebral cortex, pass through other basal ganglia the activation of amygdala-ACC-insula-parahippocampal area [4]. and then return to the cerebral cortex via the thalamus. Previously This distress network is also seen to be involved in affective aspects of performed fMRI studies confirm the involvement of (left) parietal pain [24]. and frontal sites in alerting (monitoring and regulation performance and arousal levels, especially left after a warning cue und usual right In the controls and in the tinnitus group, we found activation of hemisphere activation as phasic and tonic influences) [29]. left parahippocampal gyrus during listening to the affective words and the neutral words. The parahippocampal gyrus is one of the Furthermore, our data demonstrated stronger involvement of areas preferentially active during encoding (relative to retrieval [27]), limbic structures of tinnitus patients in response to any auditory distinguishing unpleasant from neutral or pleasant emotion [28] and stimuli, as compared to the control subjects. Acoustic stimulation with seems to be coupled with a noise-like character of the acoustic stimuli. tinnitus-like aversive beep tones had equally high emotional impact Possibly in association with the tinnitus tone, tinnitus patients failed in both groups. However, the sound of pleasant chimes has activated the limbic, prefrontal and association areas significantly stronger in to distinguish between pleasant and unpleasant (affective and neutral). the tinnitus group than in healthy subjects. Also neutral words have The higher involvement of striatum (caudate, putamen, gyrus significantly activated whole emotion-processing brain network in frontalis medius, gyrus frontalis inferior) seen in our study in tinnitus the tinnitus but not in the control group. This over activation seen in patients corroborates the hypothesis of Jastreboff, who suggested tinnitus patients could be associated with their general negative distress involvement of prefrontal cortex in the auditory attention directed [30]. Interestingly, we have demonstrated activation of affective- towards tinnitus and in the emotional emphasizing of tinnitus [26]. processing network of limbic, prefrontal and association-cortices in

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8. Møller AR (2007) The role of neural plasticity in tinnitus. Prog Brain Res 166: 37-45. Submit your next manuscript and get advantages of OMICS

9. Melcher JR, Levine RA, Bergevin C, Norris B (2009) The auditory midbrain of Group submissions people with tinnitus: abnormal sound-evoked activity revisited. Hear Res 257: Unique features: 63-74. • User friendly/feasible website-translation of your paper to 50 world’s leading languages 10. Lockwood AH, Salvi RJ, Coad ML, Towsley ML, Wack DS, et al. (1998) The • Audio Version of published paper functional neuroanatomy of tinnitus: evidence for limbic system links and neural • Digital articles to share and explore plasticity. Neurology 50: 114-120. Special features:

11. Levine RA (1999) Somatic (craniocervical) tinnitus and the dorsal cochlear • 200 Open Access Journals nucleus hypothesis. Am J Otolaryngol 20: 351-362. • 15,000 editorial team • 21 days rapid review process 12. Schlee W, Weisz N, Bertrand O, Hartmann T, Elbert T (2008) Using auditory • Quality and quick editorial, review and publication processing steady state responses to outline the functional connectivity in the tinnitus • Indexing at PubMed (partial), Scopus, DOAJ, EBSCO, Index Copernicus and Google Scholar etc brain. PLoS One 3: e3720. • Sharing Option: Social Networking Enabled • Authors, Reviewers and Editors rewarded with online Scientific Credits 13. Melcher JR, Sigalovsky IS, Guinan JJ Jr, Levine RA (2000) Lateralized • Better discount for your subsequent articles tinnitus studied with functional magnetic resonance imaging: abnormal inferior Submit your manuscript at: www.omicsonline.org/submission/ colliculus activation. J Neurophysiol 83: 1058-1072.

Otolaryngology Auditory Neuro-Plasticity ISSN:2161-119X Otolaryngology an open access journal