Conceived and designed the experiments: FTH NMP BH. Performed the experiments: FTH NMP JFS HJK SR CZ CB. Analyzed the data: FTH NMP JFS. Wrote the paper: FTH NMP BH. Screening and detailed audiological testing: CZ CB. Otolaryngological consulting and screening: HJK. Medical, general health consulting, testing, and screening: SR.
The authors have declared that no competing interests exist.
We investigated auditory perception and cognitive processing in individuals with chronic tinnitus or hearing loss using functional magnetic resonance imaging (fMRI). Our participants belonged to one of three groups: bilateral hearing loss and tinnitus (TIN), bilateral hearing loss without tinnitus (HL), and normal hearing without tinnitus (NH). We employed pure tones and frequency-modulated sweeps as stimuli in two tasks: passive listening and active discrimination. All subjects had normal hearing through 2 kHz and all stimuli were low-pass filtered at 2 kHz so that all participants could hear them equally well. Performance was similar among all three groups for the discrimination task. In all participants, a distributed set of brain regions including the primary and non-primary auditory cortices showed greater response for both tasks compared to rest. Comparing the groups directly, we found decreased activation in the parietal and frontal lobes in the participants with tinnitus compared to the HL group and decreased response in the frontal lobes relative to the NH group. Additionally, the HL subjects exhibited increased response in the anterior cingulate relative to the NH group. Our results suggest that a differential engagement of a putative auditory attention and short-term memory network, comprising regions in the frontal, parietal and temporal cortices and the anterior cingulate, may represent a key difference in the neural bases of chronic tinnitus accompanied by hearing loss relative to hearing loss alone.
Subjective tinnitus is the phantom perception of sound in the absence of an external source. The annoyance and distress associated with tinnitus range from mild to severe, with the latter type having a major impact on a person's life, making sleep difficult and intellectual work challenging
We used two tasks to investigate the neural bases of short-term memory and auditory processing in individuals with hearing loss without tinnitus, participants with hearing loss accompanied by tinnitus and normal hearing control subjects without tinnitus. Both tasks used identical non-speech stimuli; they differed only in the tasks: passive listening or active discrimination. We had previously used similar tasks and stimuli to investigate short-term memory and auditory processing in young normal-hearing adults
We wanted to test differences in behavior and neural response of those with hearing loss with and without tinnitus, for sounds they could hear and discriminate well. Both of these groups would be compared to a control group of normal hearing participants without tinnitus. We ensured that all participants could hear the sounds equally well by (a) recruiting only those with either normal hearing for octave frequencies 0.25–8 kHz (control group) or normal hearing through 2 kHz (i.e. they have bilateral high-frequency sensorineural hearing loss) and (b) creating stimuli that included frequencies only up to 2 kHz. Our prediction was that the response of a distributed set of regions in the frontal, parietal and temporal cortices would be enhanced for those with hearing loss and would be increased further for those with hearing loss and tinnitus compared to normal hearing controls during these tasks. Such increased response would be more apparent for the discrimination task relative to the passive listening task because of the greater engagement of a distributed cortical network in the former, possibly due to attentional and short-term memory processing. The prediction was based on our previous fMRI study of young normal hearing adults using similar stimuli and a discrimination task. However, because all participants could hear the sounds and if their behavior did not differ significantly, the null hypothesis would be that there would be no appreciable difference in the response of the auditory processing network between the normal hearing and hearing impaired group without tinnitus; the group with tinnitus would differ due to the additional distracting factor of chronic tinnitus.
Three groups of participants were recruited in the study from the greater Washington, D.C. metropolitan area. All participants gave written informed consent. The National Institutes of Health/National Institute of Neurological Disorders and Stroke-National Institute on Deafness and Other Communication Disorders Institutional Review Board approved the study (protocol 06-DC-0218) and all participants were suitably compensated.
The tinnitus group (TIN) consisted of 8 male volunteers (age range = 42–64 yr, mean = 56.13 yr, SD = 7.04 yr) with bilateral, mild to moderately-severe high-frequency sensorineural hearing loss and chronic subjective tinnitus that had persisted for between 3–38 years at the time of their scan (
Variables | Normal HearingN = 11 | Hearing LossN = 7 | TinnitusN = 8 |
Age (M/SD) | 48.09/10.42 | 51.38/11.45 | 56.13/7.04 |
Sex N (M/F) | 11/0 | 7/0 | 8/0 |
BDI-II (M/SD) | 0.75/2.81 | 0.57/0.73 | 1.45/1.49 |
THI (M/SD) | n/a | n/a | 17.25/5.01 |
Duration of tinnitus (M/SD) in years | n/a | n/a | 14.43/12.56 |
BDI = Beck Depression Inventory, THI = Tinnitus Handicap Inventory.
The second group (HL) (n = 7) was matched in age (age range = 31–64 yr, mean = 51.38 yr, SD = 11.45 yr), gender and hearing loss and had bilateral, mild to moderately-severe hearing loss but did not have tinnitus. The third group (NH) (n = 11) was age (age range = 32–63 yr, mean = 48.09 yr, SD = 10.42 yr) and gender-matched and had normal hearing with no tinnitus. All subjects scored in the minimal depression range on the Beck Depression Inventory (BDI-II)
All participants underwent full audiologic evaluation before and after the scanning session at the NIH Clinical Center. The audiologic examination, including speech recognition and pure-tone air- and bone-conduction thresholds (0.25–8 kHz), was conducted in a double-walled audiometric test suite using ER-3A transducers in accordance with American National Standards Institute standards (American National Standards Institute, S3.1-1999 American National Standard Maximum Permissible Ambient Noise Levels for Audiometric Test Rooms (Standard S3.1), New York, NY: American National Standards Institute, 2003, and S3.1-1996 American National Standard Specification for Audiometers (Standard S3.6). New York, NY: American National Standards Institute; 2004). Additional audiometric measures, including distortion product otoacoustic emissions, tympanometry, and acoustic reflex thresholds and decay, were conducted to ensure that there were no audiometric signs of conductive or retrocochlear pathology. Loudness tolerance evaluation using recorded samples of scanner noise was also conducted to ensure that each participant's loudness discomfort levels were sufficiently high to permit scanning without loudness discomfort. We excluded potential participants who exhibited symptoms of hyperacusis, either via loudness tolerance evaluation or subjective questionnaire. All participants in the NH group had pure-tone thresholds of 25 dB HL or less for all of the test frequencies. Participants in the TIN and HL groups had pure-tone thresholds of 25 dB HL or less for 0.25–2 kHz, and sensorineural hearing loss in the mild to moderately-severe range (no greater than 70 dB as defined by
Stimuli used in the study consisted of pure tones and frequency modulated sweeps. There were three pure tones: 3 low frequency tones (0.5, 0.6, 0.7 kHz) and 3 high frequency tones (1.5, 1.7, 1.9 kHz). There were two types of frequency modulated sweep stimuli: “down-up” and “up-down”. The up-down stimuli consisted of a 200 ms up sweep, a 100 ms pure tone and a 200 ms down sweep. The three segments were concatenated such that each complete stimulus was continuous and the total duration was 500 ms. For both the up-down and the down-up stimuli, the 100 ms pure tone frequency was 1 kHz. There were 3 up-down stimuli with varying frequencies. The starting frequencies of the up-down stimuli were 0.65, 0.55, 0.45 kHz. The initial 200 ms up sweep always ended at 1 kHz (the frequency of the pure tone) regardless of the starting frequency. The down sweep then started at a frequency of 1 kHz and dropped in frequency to 0.65, 0.55 and 0.45 kHz to match each beginning frequency. The down-up stimuli were identical to the up-down in duration and segmentation but consisted of a concatenated down sweep, pure tone (with frequency at 1 kHz) and up sweep. There were 3 down-up stimuli with starting and ending frequencies of 2.0, 1.8, 1.6 kHz. Each stimulus-pair (either ‘same’ or ‘different’) was presented 5 times in pseudo-random order with 10 silent (rest) trials mixed amongst the listening trials. Thus, there were 30 trials with pure tones and 30 trials with the sweeps, with equal distribution of same and different trials. The tones and sweeps were generated using Audition 2.0 (Adobe Systems Inc., San Jose, CA). None of the stimuli overlapped the hearing loss range of the listeners who had normal hearing at frequencies less than 2 kHz. The sounds were further low-pass filtered with a cut-off point at 2 kHz and were normalized to have the same root-mean-square amplitude. Sounds were played at most comfortable level for the participants, during the ‘silent’ portion of the sparse sampling acquisition. Post-hoc measurements revealed that this was between 70–80 dB SPL.
Subjects performed (a) a passive listening task (PL) where they listened to pairs of stimuli without responding and (b) a discrimination task (DT) in which they responded whether a pair of tones or a pair of sweeps was ‘same’ or ‘different’. Responses were collected via button-presses. Subjects performed a brief training session for 5–10 minutes to familiarize them with the tasks and stimuli. The training sounds were similar to but not identical to the stimuli used in the experiment. Subjects began the actual experiment once they achieved a threshold of 85% accuracy on the task.
Participants were scanned in a 3 Tesla GE Excite scanner using an eight-channel receive-only coil. Subjects were scanned using an Echo Planar Imaging (EPI) sparse sampling technique (shown in
PL = passive listening, DT = discrimination task.
Statistical parametric software (SPM5, Wellcome Trust Centre for Neuroimaging,
There were no statistically significant differences between the three groups for the discrimination task, either in accuracy or response times. Behavioral responses of two normal hearing participants were excluded in the analysis: the button responses of one were inadvertently not recorded for all trials and the other only performed at 55% accuracy. We had set the inclusion criterion at 75% accuracy. All included participants, regardless of group, performed at or near ceiling; the lowest individual score was 87% accuracy. The group scores were as follows: normal hearing (N = 9, mean = 92, standard deviation = 5.75), hearing loss (N = 7, mean = 91.8, standard deviation = 4.65), tinnitus (N = 8, mean = 91.0, standard deviation = 4.25).
As shown in
Statistical parametric maps of the passive listening task (PL>Rest) rendered on a template brain for (a) normal hearing, (b) hearing loss and (c) tinnitus with hearing loss groups. Results of the NH>TIN comparison showed greater response in the left middle/inferior frontal gyri are depicted in (d). All reported clusters are p<0.05 FWE corrected for multiple comparisons at the voxel or cluster-level. Some clusters are highlighted in the figure - MFG: middle frontal gyrus, IFG: inferior frontal gyrus, STG: superior temporal gyrus.
Contrast | MNI coordinates | Z score | Clustersize | Gyrus(Brodmann Area) | ||
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NH groupPL>Rest | −50 | −20 | 2 | 6.09 *# | 597 | L superior temporal gyrus (21/22) |
66 | −16 | −2 | 5.69*# | 888 | R superior and middle temporal gyri, superior temporal sulcus (21/22) | |
−50 | 10 | 32 | 4.87*# | 634 | L inferior and middle frontal gyri (44/6) | |
40 | 26 | 4 | 4.08* | 150 | R inferior and middle frontal gyri (45/46) | |
44 | 0 | 40 | 3.84* | 173 | R middle frontal gyrus (9) | |
HL groupPL>Rest | −46 | −32 | 12 | 5.62*# | 455 | L transverse and superior temporal gyri, superior temporal sulcus (41/42/22) |
46 | −20 | 2 | 4.41* | 293 | R superior temporal gyrus (22) | |
TIN groupPL>Rest | 60 | −28 | 2 | 5.13*# | 623 | R superior and middle temporal gyri, superior temporal sulcus (42/22/21) |
−52 | −12 | −2 | 4.23* | 358 | L superior and middle temporal gyrus, superior temporal sulcus (42/22/21) | |
NH>TIN | −50 | 10 | 32 | 4.17* | 300 | L inferior and middle frontal gyri (44,6,9) |
All reported clusters are p<0.05 FWE corrected for multiple comparisons at the voxel (indicated by * next to the Z-score) or cluster-level (indicated by #), cluster extent is 50 voxels.
All three groups, on average, showed greater response of the bilateral superior and middle temporal cortex when discriminating sounds compared to rest (see
Statistical parametric maps of the discrimination task (DT>Rest) rendered on a template brain for (a) normal hearing, (b) hearing loss and (c) tinnitus with hearing loss groups are shown on the left. The sagittal sections shown are located at
Contrast | MNI coordinates | Z score | Clustersize | Gyrus (Brodmann Area) | ||
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NH groupDT>Rest | 58 | −12 | 2 | Inf*# | 681 | R superior and middle temporal gyrus (22,21) |
−44 | −42 | 24 | 8.62*# | 898 | L transverse and superior temporal gyrus, inferior parietal lobule (42,22,40) | |
54 | 4 | −8 | 7.6*# | 249 | R superior and middle temporal gyrus (22,21) | |
−40 | −20 | −12 | 6.5*# | 112 | L hippocampus | |
12 | −10 | 10 | 6.44*# | 528 | R thalamus, putamen | |
−52 | 2 | 30 | 6.39*# | 123 | L inferior and middle frontal gyrus (44, 6) | |
−52 | −20 | 2 | 6.34*# | 274 | L superior and middle temporal gyrus (22,21) | |
36 | −48 | 38 | 6.25*# | 128 | L inferior parietal lobule (40) | |
0 | −34 | 26 | 6.16*# | 110 | posterior cingulate (23) | |
−34 | −10 | 62 | 6.12*# | 86 | L precentral gyrus, middle frontal gyrus (4,6) | |
−26 | −66 | −36 | 5.99*# | 51 | L cerebellum | |
−22 | 14 | −2 | 5.82*# | 88 | L putamen | |
48 | −54 | 52 | 5.79*# | 92 | R inferior parietal lobule (40) | |
8 | 26 | 40 | 5.46*# | 54 | R anterior cingulate, dorsomedial frontal gyrus (32, 8) | |
36 | 44 | 26 | 5.32*# | 60 | R middle and superior frontal gyrus (10) | |
44 | −24 | 58 | 5.23*# | 36 | L thalamus, putamen | |
HL groupDT>Rest | 60 | −28 | 8 | Inf*# | 2804 | R superior temporal gyrus (42, 22) |
−54 | −44 | 22 | Inf*# | 4318 | L postcentral gyrus, inferior parietal lobule (1, 2, 3, 40) | |
0 | 10 | 58 | Inf | 1039 | Dorsomedial frontal gyrus, anterior cingulate (6, 8, 32) | |
−36 | 50 | 10 | 6.89*# | 232 | L middle frontal gyrus (10,44) | |
−54 | −40 | −4 | 6.5*# | 129 | L superior and middle temporal gyrus (22, 21) | |
2 | −62 | −10 | 6.5*# | 98 | R cerebellum | |
34 | 52 | 14 | 6.49*# | 345 | R middle and inferior frontal gyrus (10, 46) | |
8 | −76 | −24 | 6.15*# | 104 | R cerebellum | |
24 | 14 | 0 | 6.11*# | 389 | R putamen | |
16 | −2 | 10 | 6.11*# | 129 | R putamen, caudate | |
−6 | 34 | 28 | 5.97*# | 54 | L anterior cingulate, dorsomedial frontal gyrus (32, 9) | |
−18 | −58 | −32 | 5.91*# | 65 | L cerebellum | |
54 | 4 | 36 | 5.87*# | 56 | R inferior frontal gyrus (44) | |
−10 | −20 | 4 | 5.86*# | 76 | L thalamus | |
−30 | −60 | 46 | 5.4*# | 56 | L inferior parietal lobule (40) | |
TIN groupDT>Rest | −58 | −22 | 4 | Inf*# | 2372 | L superior temporal gyrus (22) |
54 | −26 | 10 | Inf*# | 2806 | R superior temporal gyrus (42, 22) | |
36 | −22 | 70 | Inf*# | 260 | R precentral gyrus, superior frontal gyrus (4, 6) | |
−2 | 12 | 44 | 6.69*# | 846 | L dorsomedial frontal gyrus, anterior cingulate (6, 32) | |
−22 | 6 | 6 | 6*# | 356 | L putamen | |
−40 | −14 | 64 | 5.97*# | 133 | Left precentral and postcentral gyri (4, 1, 2, 3) | |
60 | 4 | 16 | 5.86*# | 91 | R inferior frontal gyrus (44, 6) | |
34 | −52 | 64 | 5.74*# | 56 | R postcentral gyrus, superior parietal lobule (5, 7) | |
24 | 6 | 4 | 5.63*# | 164 | R putamen | |
56 | −30 | 44 | 5.55*# | 57 | R postcentral gyrus (1, 2, 3) | |
−38 | −58 | 56 | 5.38*# | 56 | L inferior and superior parietal lobule (40, 5, 7) |
All reported clusters are p≤0.05 FWE corrected for multiple comparisons at the voxel (indicated by * next to the Z-score) or cluster-level (indicated by #).
Conjunction analysis, which was used to identify commonalities between HL and TIN groups, revealed widespread activations in the bilateral superior temporal cortex and in the central regions of anterior cingulate and in the medial frontal gyri (
Statistical parametric maps for (a) conjunction of HL and TIN rendered on a template brain and sagittal slice at
We next determined the effect of hearing loss alone without the confounding factor of tinnitus, by comparing HL and NH groups (
Contrast | MNI coordinates | Z score | Clustersize | Gyrus (Brodmann Area) | ||
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HL>NH | 58 | −26 | 48 | 6.37*# | 203 | R postcentral gyrus (1,2) |
60 | −28 | 8 | 5.66*# | 286 | R superior temporal gyrus (42, 22) | |
−56 | −30 | 38 | 5.64*# | 276 | R postcentral gyrus, inferior parietal lobule (1, 2, 40) | |
−46 | −18 | 60 | 5.15# | 106 | L precentral gyrus (4) | |
−44 | −28 | 12 | 5.02*# | 312 | L transverse and superior temporal gyrus (42, 22) | |
−32 | −26 | 72 | 4.79# | 29 | L superior frontal gyrus (6) | |
−50 | −22 | −4 | 4.75# | 68 | L superior and middle temporal gyri (21) | |
−2 | 10 | 56 | 4.61*# | 203 | R dorsomedial frontal gyrus, anterior cingulate (8, 6,32) | |
NH>HL | −28 | −44 | −12 | 4.7# | 54 | L parahippocampal gyrus (37, 36) |
−4 | −28 | 24 | 4.69# | 113 | L posterior cingulate (23) | |
−52 | −48 | 36 | 4.67# | 86 | L inferior parietal lobule, supramarginal gyrus (40) | |
HL>TIN | −54 | −44 | 22 | 6.07# | 88 | L superior temporal gyrus (42, 22) |
−36 | 52 | 10 | 5.03# | 163 | L superior and middle frontal gyri (10) | |
54 | 22 | 26 | 4.71# | 73 | R inferior frontal gyrus (44, 46) | |
−50 | −34 | 42 | 4.52# | 152 | L inferior parietal lobule (40) | |
−50 | 10 | 36 | 4.2* | 150 | L inferior frontal gyrus (44) | |
6 | −78 | −24 | 4.14* | 182 | R cerebellum | |
−42 | −68 | 4 | 4.09* | 164 | L middle temporal gyrus (22, 37) | |
TIN>HL | No significant differences | |||||
TIN>NH | −50 | −38 | 8 | 5.62*# | 979 | L transverse and superior temporal gyrus (41, 42, 22) |
54 | −26 | 8 | 5.26*# | 451 | R superior and middle temporal gyrus (42, 22, 21) | |
36 | −22 | 70 | 5.04# | 34 | R superior frontal gyrus (6) | |
NH>TIN | No significant differences |
All reported clusters are p≤0.05 FWE corrected for multiple comparisons at the voxel (indicated by * next to the Z-score) or cluster-level (indicated by #).
We contrasted the activation patterns for the TIN group separately against the NH and HL groups (
Statistical parametric maps rendered on a template brain for the contrasts (a) TIN>NH and (b) HL>TIN, showing increased and decreased response, respectively, due to tinnitus. The contrasts NH>TIN and TIN>HL did not result in any suprathreshold voxels. All reported clusters are p<0.05 FWE corrected for multiple comparisons at the voxel or cluster-level. Some clusters are highlighted in the figure – STG: superior temporal gyrus, IPL: inferior parietal lobule, MTG: middle temporal gyrus.
Our study employed passive listening and active discrimination tasks to investigate differences in the neural bases of hearing loss and chronic tinnitus. We found bilateral superior temporal cortex response for passive listening of sounds across all three groups (hearing loss, hearing loss with tinnitus, and normal hearing without tinnitus). There were no regions of significant difference for the passive listening task between the three groups, except participants in the NH group activated the left inferior/middle frontal gyrus to a greater extent relative to those in the hearing loss groups with and without tinnitus (TIN and HL). The patterns of response across the three groups varied more for the discrimination task compared to the passive listening task. In the discrimination task compared to rest, we found an elevated response in the frontal and parietal cortices in addition to the temporal cortex for the normal hearing and hearing impaired without tinnitus participants. This is not surprising because the discrimination task is a short-term memory task. The activation patterns seen in the normal hearing control group are similar to those seen in our previous study of young normal hearing adults
One of the surprising results of our study was that high-frequency hearing loss affected perception and discrimination of low-frequency sounds, not in terms of behavior, but in terms of the response of the auditory, frontal and parietal cortices. Because the sounds were low-pass filtered at 2 kHz to be within the normal hearing range of all participants, the null hypothesis was that there would be no difference in the response of brain for the participants regardless of their hearing status (disregarding tinnitus). This was mostly true for the passive listening task; however, we observed differential involvement of a distributed set of brain regions in the three groups for the discrimination task, varying both on hearing and tinnitus status.
The distributed set of regions (prefrontal cortex, inferior parietal cortex, anterior cingular cortex) highlighted in our results have been proposed previously to play an important role in auditory attention and working memory. Although our study did not employ tasks that require attention explicitly, the short-term memory task uses attention implicitly. Studies investigating attention in the auditory modality have reported on the involvement of the following cortical and subcortical structures: prefrontal cortex, parietal cortex, superior temporal gyrus, temporoparietal junction, anterior cingulate gyrus, basal ganglia, thalamus and inferior colliculus (for reviews, see
Cognitive scientists and neuroscientists have suggested that cognitive function may be affected by sensory difficulties in older adults
We interpret the differential response of the AASM network as follows. The hearing loss group likely engages attentional resources to a greater extent compared to normal hearing participants in order to compensate for their hearing impairment. The hearing loss group activates superior temporal, superior frontal, inferior parietal, and anterior cingular cortices significantly more than the normal hearing group (
The role of the attentional network in mediating chronic tinnitus has been inferred from a number of whole-brain imaging studies. Use of lidocaine allowed
Neurophysiological studies employing electroencephalography (EEG) have also implicated the involvement of the attentional network in tinnitus perception; however, for the most part they have not taken into account the effect of hearing loss and have reported disparate findings. Jacobson and colleagues
Although we found brain activation pattern differences between the groups, we did not find any statistically significant behavioral differences. Behavioral studies have noted attentional deficits in selective and divided attention in chronic tinnitus sufferers, specifically in the form of slower response times. In one such study
We compared TIN and HL groups in order to understand better the neural correlates of tinnitus, however, the interaction between hearing loss and tinnitus may not be linear. The TIN and HL comparison gave us greater understanding of the brain regions most affected by hearing loss and those that may be most influenced by tinnitus, within the context of simple listening tasks. The relation between hearing loss and tinnitus is complex and includes other cortical and subcortical networks such as those subserving emotion or somatosensory processing
We collected structural MR and diffusion tensor imaging (DTI) data on the same group of participants in the current study
We chose to perform a fixed-effects analysis because of the limited number of participants in our study and additionally, the patients belonged to a subset (bilateral hearing loss with mild tinnitus) of a complex heterogeneous population. Fixed-effects analysis also lends itself to conjunction analysis
In conclusion, our study suggests the differential involvement of a putative AASM network in hearing loss with and without tinnitus. This network consisted of regions in the frontal, parietal and temporal cortices and the anterior cingulate. In participants with hearing loss without tinnitus, the attentional network response was enhanced relative to normal hearing controls. In individuals with tinnitus and hearing loss, the response of some nodes of the attentional network was diminished with respect to hearing loss only group, whereas response of other nodes was enhanced. This suggests a complex role for the attentional network in those with chronic tinnitus and studies are needed that will elaborate on the functioning of this network.
We are grateful to Dr. Allen Braun of the Language Section, NIDCD, NIH, for his assistance with patient evaluation.