Received: 19 July 2020 Revised: 4 September 2020 Accepted: 29 September 2020

DOI: 10.1002/hbm.25238

RESEARCH ARTICLE

Alterations of brain activity and functional connectivity in

transition from acute to chronic tinnitus

Liping Lan1,2† | Jiahong Li1,2† | Yanhong Chen1,2 | Wan Chen3 |

Wenrui Li1,2 | Fei Zhao4,5 | Guisheng Chen1,2 | Jiahao Liu1,2 | Yuchen Chen6 |
Yuanqing Li7 | Chang-Dong Wang8 | Yiqing Zheng1,2 | Yuexin Cai1,2
1
Department of Otolaryngology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou City, Guangdong Province, China
2
Institute of Hearing and Speech-Language Science, Sun Yat-sen University, Guangzhou City, Guangdong Province, China
3
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
4
Department of Speech and Language Therapy and Hearing Science, Cardiff Metropolitan University, Cardiff, UK
5
Department of Hearing and Speech Science, Xinhua College, Sun Yat-Sen University, Guangzhou, China
6
Department of Radiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
7
School of Automation Science and Engineering, South China University of Technology, Guangzhou, China
8
School of Data and Computer Science, Sun Yat-sen University, Guangzhou, China

Correspondence
Yuexin Cai and Yiqing Zheng, Department of Abstract
Otolaryngology, Sun Yat-sen Memorial The objective of this study was to investigate alterations to brain activity and func-
Hospital, Sun Yat-sen University, 107 West
Yanjiang Road, Guangzhou City, Guangdong tional connectivity in patients with tinnitus, exploring neural features in the transition
Province, China. from acute to chronic phantom perception. Twenty-four patients with acute tinnitus,
Email: [email protected] (Y. C.) and
[email protected] (Y. Z.) 23 patients with chronic tinnitus, and 32 healthy controls were recruited. High-
density electroencephalography (EEG) was used to explore changes in brain areas
Funding information
Key R&D Program of Guangdong Province, and functional connectivity in different groups. When compared with healthy sub-
China, Grant/Award Number: jects, acute tinnitus patients had a significant reduction in superior frontal cortex
2018B030339001; the Fundamental Research
Funds for the Central Universities, Grant/ activity across all frequency bands, whereas chronic tinnitus patients had a significant
Award Number: 20ykpy91; the Medical reduction in the superior frontal cortex at beta 3 and gamma frequency bands as well
artificial intelligence project of Sun Yat-sen
Memorial Hospital, Grant/Award Number: as a significant increase in the inferior frontal cortex at delta-band and superior tem-
YXYGZN201904; Sun Yat-Sen Clinical poral cortex at alpha 1 frequency band. When compared to the chronic tinnitus
Research Cultivating Program, Grant/Award
Number: SYS-Q-20190; National Natural group, the acute tinnitus group activity was significantly increased in the middle fron-
Science Foundation of China, Grant/Award tal and parietal gyrus at the gamma-band. Functional connectivity analysis showed
Number: 82071062
that the chronic tinnitus group had increased connections between the
parahippocampus gyrus, posterior cingulate cortex, and precuneus when compared
with the healthy group. Alterations of local brain activity and connections between
the parahippocampus gyrus and other nonauditory areas appeared in the transition
from acute to chronic tinnitus. This indicates that the appearance and development

†
Liping Lan and Jiahong Li contributed equally to this work.

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,
provided the original work is properly cited.
© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.

Hum Brain Mapp. 2021;42:485–494. wileyonlinelibrary.com/journal/hbm 485

486 LAN ET AL.

of tinnitus is a dynamic process involving aberrant local neural activity and abnormal
connectivity in multifunctional brain networks.

KEYWORDS
acute tinnitus, chronic tinnitus, local neural activity, multifunctional brain network, transition

1 | I N T RO DU CT I O N scores. The abnormal connectivity of ACC and other cortical regions

may contribute to tinnitus induced depression.
Tinnitus is the perception of a phantom sound lacking any external or Although a number of previous studies on chronic tinnitus have been
internal sound stimulation. As a common clinical symptom tinnitus is published and many pathophysiological models have been developed, few
experienced constantly by 10–15% of the adult population (Langguth, studies have investigated central plasticity in acute tinnitus (Cai et al., 2020;
Kreuzer, Kleinjung, & De, 2013). It is generally believed that tinnitus is Stolzberg et al., 2013), especially the dynamic changes to neural processing
not only the result of a cochlear lesion, but also a symptom involving during transition from acute to chronic tinnitus. This issue is crucial to clari-
plasticity of the central nervous system (Chen et al., 2016; Lanting, De, & fying the central neural characteristics of acute and chronic tinnitus, which
Van, 2009; Loo et al., 2009). Recent studies have found that abnormal is important in identifying neural predictors for the development of tinnitus
central reorganization in subjective chronic tinnitus involves auditory and prevention of transition from acute to chronic tinnitus.
and nonauditory brain areas such as the frontal cortex, parahippocampal A study by Vanneste et al. (Vanneste, van de Heyning, & De
gyrus, caudate nucleus, cingulate cortex, and insula (Araneda et al., 2018; Ridder, 2011) aimed to identify neural generator or neural network
Besteher et al., 2019; De et al., 2014; Elgoyhen, Langguth, Ridder, & change over time with tinnitus by comparing EEG responses in chronic
Vanneste, 2015; Henderson-Sabes et al., 2019; Schlee et al., 2009; tinnitus patients with different durations (< 4 years and > 4 years). Differ-
Vanneste, Alsalman, & De Ridder, 2018; Xu et al., 2019), and that these ences were found in auditory and nonauditory areas (anterior cingulate,
central neural changes were possible contributors to the clinical symp- insula and medial premotor cortex). In the present study, we aimed to
toms of tinnitus, for example, impairment of perception, cognition, atten- explore neural generator and dynamic development of tinnitus by com-
tion, memory, and emotion (Besteher et al., 2019; Chen et al., 2017; De, paring tinnitus patients between acute (< 1 months) and chronic stages
Elgoyhen, Romo, & Langguth, 2011; Husain, 2016; Joos, Vanneste, & De (> 6 months). A number of different functional techniques have been used
Ridder, 2012; Pattyn et al., 2016; Vanneste, To, & De Ridder, 2019). For to study central processing in tinnitus; electroencephalography (EEG),
example, Schlee et al. (Schlee et al., 2009) found that abnormal activation functional magnetic resonance imaging (fMRI), magnetoencephalography
of the frontal cortex was related to a conscious perception of subjective (MEG), and positron emission tomography (PET). Each approach has its
chronic tinnitus and Vanneste et al. (Vanneste & De Ridder, 2016) found strengths and weakness. For example, fMRI is known to have good spatial
that the parahippocampal area was significantly activated in chronic tin- resolution. However, fMRI produces aversive scanner noise which inter-
nitus patients with severe hearing loss. In addition, a positive correlation feres with auditory processing in the human brain. The resting state neural
was found between neural activity in the parahippocampal area and response in tinnitus patients can be affected by the fMRI scan because
averaged hearing thresholds. As the parahippocampal area has been central neural processing is activated by scanner noise even when ear
hypothesized to play a crucial role in memory recollection, sending infor- plugs, or headphones with active noise reduction are worn (Logothetis
mation from the hippocampus to the association areas, such a correlation et al., 2009). EEG has the advantage of high temporal resolution, time effi-
might indicate its involvement in the generation of tinnitus. ciency, and noise avoidance, and is widely used in source localization and
Chen et al. (Chen et al., 2017) investigated aberrant amygdala- functional connectivity analysis (Van Diessen et al., 2015).
cortical functional connectivity using a seed-based whole-brain corre- Therefore, to verify the hypothesis and explore the underlying
lation method in chronic tinnitus patients with depression and found mechanism of subjective tinnitus, this study investigated aberrant
abnormal resting-state functional connectivity between the amygdala central changes between acute and chronic tinnitus patients and
and prefrontal-cingulate-temporal circuit. These aberrant functional healthy controls using resting-state EEG. These finding may be impor-
couplings may explain the depressive symptoms of chronic tinnitus. A tant to identify the central processing network and neural predictors
review by Pattyn et al. (Pattyn et al., 2016) concluded that interac- for the development of tinnitus.
tions between auditory networks and the limbic system also appeared
in tinnitus patients with anxiety and depression. Chen et al. (Chen
et al., 2018) also found abnormal connections between the anterior 2 | METHODS
cingulate cortex (ACC) and auditory cortex, prefrontal cortex, visual
cortex, and default mode network in chronic tinnitus patients. These 2.1 | Participants
abnormally increased connections between the rostral ACC and left
precuneus as well as dorsal ACC and right inferior parietal lobe were Twenty-four patients with acute tinnitus (duration less than 1 month)
positively correlated with Tinnitus Handicap Questionnaire (THQ) and 23 patients with chronic tinnitus (duration more than 6 months)
LAN ET AL. 487

were recruited from the Ear, Nose and Throat clinic, Sun Yat-sen handicap scale. Participants completed the THI prior to the
Memorial Hospital, Sun Yat-sen University. experiment.
The selection criteria for subjects with tinnitus were:

• Patients had sought clinical help for their tinnitus. 2.5 | EEG data collection
• Patients with conductive or mixed hearing loss were excluded
• Patients had no history of use of ototoxic drugs A high-density EEG with 128channels (EGI, Eugene) and a NetAmps
• Subjects with middle ear surgery, pulsatile tinnitus, Ménière's dis- 200 amplifier was applied to collect resting-state EEG data from all
ease, autoimmune hearing loss, acoustic neurinoma, central ner- participants. Subjects were instructed to sit in a comfortable chair and
vous system disorders, and head trauma were excluded. remain calm. Subjects were then required to keep their eyes open and
fixate a cross mark in front of them. The EEG recording lasted 7 min.
Thirty-two healthy controls without tinnitus were also recruited. The CZ electrode was used as reference. The sampling rate was
None of participants was reported comorbid conditions alongside tinni- 1,000 Hz. Impedances were kept to less than 50 kΩ.
tus such as hypertension, hyperacusis, depression, epilepsy. Acute tin-
nitus patient data were collected prior to receiving any therapeutic
intervention. All participants were provided with information about this 2.6 | Preprocessing of EEG data
study and signed a written consent form. This research was approved
by the Institution Review Board of The Sun Yat-sen Memorial Hospital. EEGLAB for v13.0.0 toolbox in MATLAB for R2013a was used to pre-
process the raw EEG data. Firstly, the data were re-referenced against
the mean reference for all electrodes. The sampling rate was adjusted
2.2 | Audiological investigations to 0.5 kHz. A notch filter was implemented at 50 Hz and the signals
were band-pass-filtered from 0.5 to 100 Hz. Gross artifacts were
All participants were interviewed to obtain a thorough case history manually removed by visual inspection. Artifacts originating from one
including; age, duration of tinnitus, side of tinnitus and any other or a few distinct sources or a limited volume of space were removed.
pathologies. This was followed by otoscopic examination, pure tone In addition, other artifacts characterized by a particular temporal pat-
audiometry and a tinnitus matching test. The hearing threshold was tern such as exponential decay were removed using an independent
determined using pure tone audiometry: air conduction hearing component analysis (ICA) algorithm.
thresholds were measured at frequencies between 125 and 8,000 Hz The advantages of the ICA algorithm can be viewed in the litera-
with an octave interval. In addition, bone conduction hearing thresh- ture (Onton, Westerfield, Townsend, & Makeig, 2006), the artifacts
olds were measured at 250, 500, 1,000, 2000, and 4,000 Hz. Mean can be separated as independent components, and the other features
hearing threshold was calculated as the average of hearing thresholds of the original EEG signal can be effectively retained. Other artifacts,
at 500, 1000, 2000, and 4,000 Hz (Bing et al., 2018; Dispenza such as eye movement, muscle artifacts, and heart beats, could be also
et al., 2011). removed by ICA correction. The EEG data were segmented into 2 s
blocks. Finally, average Fourier cross-spectral matrices were com-
puted for the frequency bands, including delta (0.5–3.5 Hz), theta
2.3 | Tinnitus pitch and loudness matching tests (4–7.5 Hz), alpha1 (8–10 Hz), alpha2 (10–12 Hz), beta1 (13–18 Hz),
beta2 (18.5–21 Hz), beta3 (21.5–30 Hz), gamma 1 (30.5–44 Hz), and
At first, nine audiometric frequencies between 125 and 8.0 kHz gamma 2 (55–100 Hz).
(125, 250, 500 Hz and 1.0, 2.0, 3.0, 4.0, 6.0, and 8.0 kHz) were used
to approximately match the tinnitus pitch. Subjects were asked to
compare their perceived tinnitus pitch with different matching tones 2.7 | Data analysis
until the tone exactly matching their tinnitus was obtained. If no pure
tone was obtained, narrowband noise was used. After confirming tin- 2.7.1 | Source localization
nitus pitch, the level was set 5 dB above the measured audiometric
threshold to give an approximate tinnitus loudness level, which was Standardized low-resolution brain electromagnetic tomography
then adjusted in 1 dB step until the subject reported that the tone (sLORETA) was used to explore the activity of brain areas in three
matched the loudness of their tinnitus (Kim et al., 2016). groups and find any abnormal activity of brain areas in acute and
chronic tinnitus patients. After mean reference transformation was
applied, the sLORETA algorithm was used to calculate neuronal activ-
2.4 | Tinnitus handicap inventory ity as current density (A/m2) (Pascual-Marqui, 2002). The LORETA-
Key software was used to investigate solution space and lead field
A tinnitus handicap inventory (THI) was used to evaluate tinnitus matrix. sLORETA is a method employed to resolve the EEG inverse
severity and level of tinnitus handicap, according to 0–100 increasing problem and localize the sources of EEG activity using a three-shell
488 LAN ET AL.

spherical model (skin, skull, cortex) registered to the Talairach human TABLE 1 The regions of interest in this study
brain atlas provided by the Montreal Neurological Institute (MNI)
Centroid voxela
(Dümpelmann, Ball, & Schulze-Bonhage, 2012). The software revisited
Regions of interest BA X y z
realistic electrode coordinates (Jurcak, Tsuzuki, & Dan, 2007) and the
lead field (Fuchs, Kastner, Wagner, et al., 2002), applying the bound- Auditory cortices 41L −46 −29 10

ary element on the MMI-152 (Mazziotta et al., 2001). The solution 41R 47 −29 10
space had a total of 6,239 voxels at 5-mm spatial resolution 42L −62 −23 12
(Lancaster et al., 2015). 42R 63 −24 12
21L −57 −18 −15
21R 58 −17 −15
2.7.2 | Functional connectivity measurements 22L −56 −25 5
22R 56 −22 3
When two brain areas oscillate coherently with a phase lag, cross talk
Insula 13L −39 −8 9
can be interpreted as information sharing by axonal transmission.
13R 40 −7 9
Phase synchronization was defined as synchronization of the phases
Dorsal anterior cingulate cortex 24L −8 2 36
of two coupled neural oscillatory activities, that is, the phase differ-
24R 7 1 36
ence of two activities does not change with time, and there is a fixed
Pregenual anterior cingulate cortex 32L −9 29 21
phase difference. The linear (i.e., coherence) and nonlinear depen-
dence (i.e., phase synchronization) between the multivariate time 32R 8 30 20

series were measured (Pascual-Marqui, 2007). The results were Subgenual anterior cingulate cortex 25L −8 18 −17
expressed as the sum of lagged dependence and instantaneous 25R 5 14 −14
dependence. The measures were non-negative, and took the value Posterior cingulate cortex 31L −11 −50 32
zero only when the result showed independence, that is, lagged, 31R 9 −48 33
instantaneous, or both. In the meantime, the measures were defined Parahippocampus 27L −19 −33 −4
in the following frequency domains: delta (0.5–3.5 Hz), theta 27R 18 −33 −4
(4–7.5 Hz), alpha1 (8–10 Hz), alpha2 (10–12 Hz), beta1 (13–18 Hz),
29L −7 −50 7
beta2 (18.5–21 Hz), beta3 (21.5–30 Hz), gamma 1 (30.5–44 Hz), and
29R 6 −50 8
gamma 2 (55–100 Hz).
Orbitofrontal cortex 10L −22 54 9
Based on this principle, the lagged linear (nonlinear) connectivity
10R 22 54 9
was calculated. After filtering the EEG data, the instantaneous phase
11L −18 43 −17
was calculated using the Hilbert transform. More precisely, the data
11R 19 43 −17
was decomposed into a limited number of cosine and sine waves at
the Fourier frequencies using the discrete Fourier transform. Precuneus 7L −17 −63 50

sLORETA was applied to extract current density for regions of interest 7R 15 −63 49
(ROI) over time. Power in all voxels was normalized to a power of Abbreviations: BA, Brodmann area; L, left; R, right.
a
1 and log transformed at each time point. As a result, ROI values Coordinates are described in MNI coordinates.
reflect the log transformed fraction of total power across all voxels for
specific frequencies. ROI was confirmed based on a previous study, as
shown in Table 1 (Carpenterthompson, Schmidt, & Husain, 2015). differences between the chronic tinnitus and healthy control groups,
between the chronic tinnitus and acute tinnitus groups and between
the acute tinnitus and healthy control groups for each contrast using
2.8 | Statistical analysis the t statistic for independent groups with a corrected threshold of
p < .05. The significance threshold was based on a permutation test
A non-parametric statistical analysis of LORETA-KEY images (statisti- with 5,000 permutations.
cal non-parametric mapping; SnPM) was used to compare differences
in resting-state EEG activity between the patient groups using
LORETA-KEY's built-in voxel-wise randomization tests (5,000 permu- 3 | RE SU LT S
tations) and a t statistic for independent groups with a threshold of
p < .01 (corrected for multiple comparison). A correction for multiple The characteristics of acute and chronic tinnitus patients were sum-
comparisons in SnPM using random permutation has been shown to marized in Table 2. There were no significant differences in the score
yield similar results with those acquired from a statistical parametric of THI, hearing threshold, and tinnitus laterality between acute and
mapping approach using a general linear model with multiple compari- tinnitus groups. Regression analysis showed that there were no signif-
sons corrections. For lagged connectivity differences, we compared icant correlations between the activity of EEG frequency bands and
LAN ET AL. 489

TABLE 2 The demographic information and tinnitus characteristics of acute and chronic tinnitus patients

Acute tinnitus patients (n = 24) Chronic tinnitus patients (n = 23) p-value

Age (years) 47.17 ± 15.22 49.09 ± 13.78 .877
Gender (male: female) M: F = 9:15 M: F = 8:15 .974
THI score 37.83 ± 16.71 40.61 ± 26.52 .675
Hearing thresholds (healthy side) 17.29 ± 7.54 23.60 ± 4.76 .099
Hearing thresholds (tinnitus side) 40.02 ± 10.83 43.13 ± 13.19 .391

Note: Data are represented as mean ± SD.

Abbreviation: THI, tinnitus handicap inventory.

F I G U R E 1 Standardized low-resolution brain electromagnetic tomography (p < .05). (a) Compared with the control group, the superior frontal
cortex (BA 6) of acute tinnitus patients was significantly reduced across the whole frequency band. (b) Compared with the control group, the
inferior frontal gyrus (BA 47) of chronic tinnitus patients was significantly enhanced in the delta frequency band. (c) Compared with the control
group, the superior temporal gyrus (BA 13) of chronic tinnitus patients was significantly enhanced in the alpha 1 frequency band. (d) Compared
with the control group, the superior frontal cortex (BA 6) of chronic tinnitus patients was significantly decreased in the beta 3 and gamma
frequency bands. (e) Compared with the chronic tinnitus group, the middle temporal gyrus and parietal gyrus (BA 6, BA 7) of acute tinnitus
patients were significantly increased in the gamma frequency band

tinnitus pitch and intensity of acute and chronic groups separately (BA 47) for the delta-band and the superior temporal cortex (BA 13)
(p > .05). In addition, no significant difference was found between for alpha 1 frequency band when compared with the healthy subjects
patient groups in terms of age (F = 0.132, df = 2, p = .877) and gender (see Figure 1b–d; p < .05). The acute tinnitus group activity was how-
(x2 = 0.052, df = 2, p = .974). ever significantly increased in the middle frontal gyrus and the parietal
Acute tinnitus patients had a significant reduction in superior gyrus (BA 6, BA 7) for gamma-band when compared to the chronic
frontal cortex (BA 6) activity across all frequency bands when com- tinnitus group (see Figure 1e; p < .05). No significant difference was
pared with the healthy subjects (see Figure 1a; p < .05). In contrast, found in other brain areas and frequencies.
compared with the healthy subjects, chronic tinnitus patients had When compared with the healthy group, significantly increased
reduced brain activity in the superior frontal cortex (BA 6) for beta functional connections were shown in chronic tinnitus patients
3 and gamma frequency bands. In addition, chronic tinnitus subjects between the parahippocampus gyrus (BA 21) and the posterior cingu-
had a significant increase brain activity in the inferior frontal cortex late cortex (PCC) (BA 18) as well as between the parahippocampus
490 LAN ET AL.

F I G U R E 2 Functional connectivity in chronic tinnitus patients (p < .05). According to the lagged phase synchronization analysis, the
significantly enhanced connections were found between the parahippocampus gyrus (BA 21) and the posterior cingulate cortex (BA 18) as well as
between the parahippocampus gyrus (BA 22) and precuneus (BA 28) in chronic tinnitus patients

gyrus (BA 22) and precuneus (BA 28) under the lagged phase synchro- patients had aberrant neural activity in the superior frontal cortex
nization analysis (see Figure 2; p < .05). However, no significant con- when compared to the control group. Respectively, increasing
nectivity change was found in acute tinnitus patients when compared gamma-band activity in the middle frontal gyrus and the parietal gyrus
with healthy subjects or chronic tinnitus patients. was observed for the acute tinnitus group. In contrast, an increase in
the inferior frontal cortex for the delta-band and the superior tempo-
ral cortex for alpha 1 frequency band was detected in patients with
4 | DISCUSSION chronic tinnitus. Functional connectivity analysis showed the chronic
tinnitus group to have increased connections between the
To our knowledge, this is the first study to identify the central parahippocampus gyrus and other nonauditory areas (PPC and
processing network and neural predictors for the development of tin- precuneus) when compared with the control group. Abnormalities
nitus by using source localization and functional connectivity within the frontal, parietal, and temporal cortex identify the changed
methods. Although a number of previous studies on chronic tinnitus neural target in the dynamic development of tinnitus. In addition,
have been published and many pathophysiological models have been aberrant connections imply that the parahippocampus gyrus is likely a
developed (Chen et al., 2017; Chen et al., 2018; Vanneste, Song, & De major hub in the transition from acute to chronic tinnitus.
Ridder, 2018; Vanneste, To, & De Ridder, 2019), few studies have
investigated central plasticity in acute tinnitus (Cai et al., 2019; Cai
et al., 2020), especially the dynamic changes to neural processing in 4.1 | Reduction of activity in superior frontal
the transition period from acute to chronic tinnitus. This issue is cru- cortex in both acute and chronic tinnitus
cial to clarify central neural characteristics of acute and chronic tinni-
tus, which is important in identifying neural predictors for the A significant reduction of activity in the superior frontal cortex (SFC)
development of tinnitus and prevent transition from acute to chronic. could be detected in patients with either acute or chronic tinnitus.
A major finding of this study was that both acute and chronic tinnitus The SFC has been regarded as the integrative hub of tinnitus that
LAN ET AL. 491

organizes efferent impulses to ensure coordination of the central ner- parietal regions could imply that patients with acute tinnitus might pay
vous system (Chen et al., 2016; Mathew et al., 2007). The SFC is more attention to auditory stimuli and message processing.
related to various cognitive and executive control tasks. Li et al.
(Li et al., 2013) divided the human SFC into anteromedial (SFCam),
dorsolateral (SFCdl) and posterior (SFCp) subregions based on diffu- 4.3 | Increased brain activity in inferior frontal
sion tensor imaging. Furthermore, it has been shown that the SFCam cortex and superior temporal cortex in chronic tinnitus
and SFCdl are anatomically and functionally correlated with the exec-
utive control network (ECN) and default mode network (DMN) and In the patients with chronic tinnitus there was significantly enhanced
the SFCp is correlated with sensorimotor-related brain areas. Thus, low frequency (Delta and alpha bands) activity in the inferior frontal
reduced SFC activity might suggest decreased use of the ECN in tinni- cortex (IFC) and superior temporal cortex (STC). IFG acts as an execu-
tus patients, possibly related to the attention paid to the phantom tive control component in the attention system that regulates dorsal
noise and its influence on their cognitive control. This is also in line and ventral attention networks (Sebastian et al., 2016). The STC is the
with a dysfunctional top-down noise-canceling mechanism for tinni- center of the primary auditory cortex and related to auditory percep-
tus. Previous studies have postulated that the frontal cortex is tion. The STC is considered to be an important multisensory func-
involved in top-down modulation in a frequency-specific manner tional brain region, which integrates visual, auditory and language
(Helfrich, Huang, Wilson, & Knight, 2017; Vanneste, Alsalman, & De information (Zevin, 2009). It has been argued that low-frequency neu-
Ridder, 2019). In the context of the existing literature, the default ronal oscillations might serve as a cortical mechanism for sensory
mode alpha activity represents a functional top-down control system selection, attention allocation, and evidence updating (Schroeder &
that actively blocks disturbing noise in tinnitus (Joos et al., 2012). The Lakatos, 2009). Analogous to deep-sleep states or neuronal dysfunc-
alpha activity within the superior frontal cortex decreased only in tion, low frequency oscillations might hinder active processing in
acute tinnitus subjects, whereas alpha activity in chronic tinnitus sub- patients with chronic tinnitus. Because of their control of neuronal
jects was not significantly different in comparison to the healthy con- excitability and sensory processing, low-frequency oscillations could
trols. It might imply enhanced alpha activity during the move from play a role in attention selection. Previous studies have shown a link
acute to chronic tinnitus. Normally, alpha waves are recorded from between low neuronal oscillations in the frontal regions and conscious
the auditory cortex during the resting state. Thus, the altered alpha perception (Mathew et al., 2007) and frontal delta activity with visual
activity in the superior frontal cortex might indicate plasticity and perception (Helfrich et al., 2017). In summary, delta and alpha activity
adaptation to offset the phantom noises in the development of observed in the frontal and temporal cortex might reflect an involve-
tinnitus. ment of emotion, perception, and attention in the transition from
acute to chronic tinnitus.

4.2 | Enhanced brain activity of middle frontal

gyrus and parietal gyrus in acute tinnitus 4.4 | Connectivity between the parahippocampus
gyrus and other nonauditory areas
Increased gamma-band activity was found in the middle frontal gyrus
(MFG) and the parietal gyrus of the acute tinnitus group when com- Significantly increased connections between the parahippocampus gyrus
pared to the chronic tinnitus patients. The parietal gyrus is traditionally and other nonauditory areas (PCC and precuneus) were found only when
considered to be involved with attention, perceptual decision making the chronic tinnitus group was compared to the control group. Based on
and sensorimotor transformations (Freedman & Ibos, 2018; Sestieri, a hypothesis (De Ridder et al., 2006), increased activity in para-
Shulman, & Corbetta, 2017). The posterior part of the parietal gyrus has hippocampal areas might reflect the constant updating of tinnitus per-
functions in feature-independent coding, enhancement of activity by ception, preventing habituation by means of its sensory gating function.
attention and representation of task-related signals. The MFG is The cells in the human hippocampus and parahippocampal areas increase
involved in the frontoparietal attention network (Ptak, 2012). In tinni- their firing in response to new stimuli. The number of cells responding to
tus patients, the processing of phantom noise can cause cognitive inter- stimulation in the parahippocampal region decreased sharply, suggesting
ference. Consequently, networks that enable focusing of attention that rapid adaptation. In contrast to the rapid auditory habituation of the
prevent the unconscious conversion of phantom to salient noises col- parahippocampal region, a large number of neurons in the hippocampus
lide (Schmidt, Akrofi, Carpenterthompson, & Husain, 2013). showed inhibitory responses (Viskontas, Knowlton, Steinmetz, &
Thus, tinnitus might deplete cognitive resources and compromise Fried, 2006). Dysfunction of this mechanism has been hypothesized to
attending to visual tasks such as reading. Prior behavioral evidence indi- explain complex auditory experiences such as tinnitus perception
cates that tinnitus disrupts the allocation of attention to nonauditory (Diederen et al., 2010). In addition the parahippocampus has also been
stimuli (Burton et al., 2012). It has been proposed that tinnitus conflicts hypothesized to contribute to auditory memory, sending information
sufficiently with nonauditory sensory processes to alter concentration, from the hippocampus to the relative areas (Leaver et al., 2016).
thereby lowering accuracy on attention demanding tasks. In this Vanneste et al. (Vanneste & De Ridder, 2016) explored the mechanisms
research, increased beta 3 and gamma activity found in the frontal and of different amounts of hearing loss in tinnitus and found tinnitus with
492 LAN ET AL.

little or no hearing loss to be more related to auditory cortex activity, development of tinnitus is a dynamic process from abnormal local
whereas tinnitus with more severe hearing loss seemed to be related to neural activity to abnormal connectivity in multifunctional brain net-
parahippocampal activity. This supports the idea of a compensation works. Particularly, the present results suggest that alterations of local
mechanism where, as tinnitus can be seen to result from persistent para- brain activity and connections between the parahippocampus gyrus
hippocampal activity, to fill the missing auditory information it constantly and other nonauditory areas may predict the transition from acute to
sends stored auditory information from the hippocampus to the auditory chronic tinnitus and the parahippocampus gyrus appears a key hub in
and other nonauditory areas. the central mechanism of tinnitus.
The PCC and precuneus are important structures of the default
mode network DMN, which is most active at rest and shows reduced ACKNOWLEDG MENTS
activity when entering a task-based state involving attention and goal- We would like to acknowledge Dr. Christopher Wigham for the proof
directed behavior (Mantini, Perrucci, Gratta, Romani, & Corbetta, 2007; reading.
Raichle et al., 2001). Another study (Husain & Schmidt, 2014) has shown
decreased connectivity in the (DMN), involving the precuneus and PCC CONFLIC T OF INT ER E STS
in tinnitus patients. Previous fMRI studies found abnormal functional The authors declare that the research was conducted in the absence
connectivity within the DMN related to tinnitus distress (Burton of any commercial or financial relationships that could be construed
et al., 2012; Schmidt et al., 2013). A positive association has also been as a potential conflict of interest.
found between THI score and beta values of the posterior cingulate as
well as the precuneus region (Maudoux et al., 2012). Brain regions in the DATA AVAILABILITY STAT EMEN T
PCC/precuneus (Krick, Argstatter, Grapp, Plinkert, & Reith, 2017) and There is no other available data. However, the data related to the
parahippocampus (Kim et al., 2016) were also reported to have signifi- results of the study can be obtained by emailing [email protected].
cantly altered functional activity with improvement of distress after tin- edu.cn.
nitus therapy. In addition, frontal brain areas (SFG, MFG), the PCC,
parahippocampal gyrus and precuneus are included within the frontal– OR CID
parietal-limbic network, which has been regarded as a specific distress Liping Lan https://orcid.org/0000-0002-6093-1443
network in tinnitus and more active in tinnitus patients with serious dis- Yuchen Chen https://orcid.org/0000-0002-8539-7224
tress and high THI scores (Golm, Schmidtsamoa, Dechent, & Yuanqing Li https://orcid.org/0000-0002-6583-3797
Kronerherwig, 2013; Husain, 2016; Husain & Schmidt, 2014). Our find-
ings support the view that alterations within these areas in the transition RE FE RE NCE S
from acute to chronic tinnitus may also be a reflection of the distress that Araneda, R., Renier, L., Dricot, L., Decat, M., Ebner-Karestinos, D.,
accompanies the development of tinnitus. We suggest that connectivity Deggouj, N., … De Volder, A. G. (2018). A key role of the prefrontal
cortex in the maintenance of chronic tinnitus: An fMRI study using a
between parahippocampus gyrus and other nonauditory cortex may play
Stroop task. NeuroImage: Clinical, 17(C), 325–334. https://doi.org/10.
a crucial role in the development and maintenance of chronic tinnitus. 1016/j.nicl.2017.10.029
Limitations must be acknowledged in this study. This is a cross- Besteher, B., Gaser, C., Ivanšic, D., Guntinas-Lichius, O., Dobel, C., …
sectional study with a limited sample size. Due to patient compliance, Nenadic, I. (2019). Chronic tinnitus and the limbic system: Reappraising
it is difficult to longitudinally analyze the move from acute to chronic brain structural effects of distress and affective symptoms. NeuroImage:
Clinical, 24, 101976. https://doi.org/10.1016/j.nicl.2019.101976
onset with tinnitus subjects. In addition, we mainly investigated differ-
Bing, D., Ying, J., Miao, J., Lan, L., Wang, D., Zhao, L., … Wang, Q. (2018).
ences in cortical activity and connectivity between acute and chronic Predicting the hearing outcome in sudden Sensorineural hearing loss
tinnitus. Although there were mild to moderate hearing loss on the via machine learning models. Clinical Otolaryngology, 43(3), 868–874.
tinnitus side, no significant differences were found in the hearing https://doi.org/10.1111/coa.13068
thresholds and laterality of tinnitus between two groups, hearing Burton, H., Wineland, A., Bhattacharya, M., Nicklaus, J., Garcia, K. S., …
Piccirillo, J. F. (2012). Altered networks in bothersome tinnitus: A func-
threshold and tinnitus laterality effect on brain network were not fur-
tional connectivity study. BMC Neuroscience, 13(1), 3. https://doi.org/
ther explored in the present study. It would be interested to explore 10.1186/1471-2202-13-3
the influence of various factors on the central neural alterations in Cai, Y., Li, J., Chen, Y., Chen, W., Dang, C., Zhao, F., … Zheng, Y. (2019). Inhibi-
patients with tinnitus by categorizing them on the basis of the tinnitus tion of brain area and functional connectivity in idiopathic sudden Senso-
characteristics (e.g., tinnitus laterality and hearing thresholds). rineural hearing loss with tinnitus, based on resting-state EEG. Frontiers in
Neuroscience, 13, 851. https://doi.org/10.3389/fnins.2019.00851
Cai, Y., Xie, M., Su, Y., Tong, Z., Wu, X., Xu, W., … Zheng, Y. (2020). Aber-
rant functional and causal connectivity in acute tinnitus with Sensori-
5 | C O N CL U S I O N neural hearing loss. Frontiers in Neuroscience, 14(592), 1–11. https://
doi.org/10.3389/fnins.2020.00592
With increase in tinnitus duration neural activity in the frontal, parietal Carpenterthompson, J. R., Schmidt, S. A., & Husain, F. T. (2015). Neural
plasticity of mild tinnitus: An fMRI investigation comparing those
and temporal cortices changed continuously and connectivity
recently diagnosed with tinnitus to those that had tinnitus for a long
between the parahippocampus gyrus and other nonauditory areas period of time. Neural Plasticity, 2015(1), 161478–161411. https://
appeared gradually. This study indicates that the occurrence and doi.org/10.1155/2015/161478
LAN ET AL. 493

Chen, Y., Bo, F., Xia, W., Liu, S., Wang, P., Su, W., … Yin, X. (2017). Amyg- Husain, F. T. (2016). Neural networks of tinnitus in humans: Elucidating
dala functional disconnection with the prefrontal-cingulate-temporal severity and habituation. Hearing Research, 334, 37–48. https://doi.
circuit in chronic tinnitus patients with depressive mood. Progress in org/10.1016/j.heares.2015.09.010
Neuro-Psychopharmacology and Biological Psychiatry, 79, 249–257. Husain, F. T., & Schmidt, S. A. (2014). Using resting state functional con-
https://doi.org/10.1016/j.pnpbp.2017.07.001 nectivity to unravel networks of tinnitus. Hearing Research, 307(1),
Chen, Y., Liu, S., Lv, H., Bo, F., Feng, Y., Chen, H., … Gu, J. (2018). Abnormal 153–162. https://doi.org/10.1016/j.heares.2013.07.010
resting-state functional connectivity of the anterior cingulate cortex in Joos, K., Vanneste, S., & De Ridder, D. (2012). Disentangling depression
unilateral chronic tinnitus patients. Frontiers in Neuroscience, 12, 9. and distress networks in the tinnitus brain. [journal article]. PLoS One,
https://doi.org/10.3389/fnins.2018.00009 7(7), e40544. https://doi.org/10.1371/journal.pone.0040544
Chen, Y. C., Feng, Y., Xu, J. J., Mao, C. N., Xia, W., Ren, J., … Yin, X. (2016). Jurcak, V., Tsuzuki, D., & Dan, I. (2007). 10/20, 10/10, and 10/5 systems
Disrupted brain functional network architecture in chronic tinnitus revisited: Their validity as relative head-surface-based positioning sys-
patients. Frontiers in Aging Neuroscience, 8, 174. https://doi.org/10. tems. NeuroImage, 34(4), 1600–1611. https://doi.org/10.1016/j.
3389/fnagi.2016.00174 neuroimage.2006.09.024
De, R. D., Elgoyhen, A. B., Romo, R., & Langguth, B. (2011). Phantom percepts: Kim, S. H., Jang, J. H., Lee, S. Y., Han, J. J., Koo, J. W., Vanneste, S., …
Tinnitus and pain as persisting aversive memory networks. Proceedings of Song, J. (2016). Neural substrates predicting short-term improvement
the National Academy of Sciences of the United States of America, 108(20), of tinnitus loudness and distress after modified tinnitus retraining
8075–8080. https://doi.org/10.1073/pnas.1018466108 therapy. Scientific Reports, 6(1), 29140. https://doi.org/10.1038/
De, R. D., Vanneste, S., Weisz, N., Londero, A., Schlee, W., Elgoyhen, A. B., srep29140
… Langguth, B. (2014). An integrative model of auditory phantom per- Kim, T. S., Yoo, M. H., Lee, H. S., Yang, C. J., Ahn, J. H., Chung, J. W., …
ception: Tinnitus as a unified percept of interacting separable subnet- Park, H. J. (2016). Short-term changes in tinnitus pitch related to
works. Neuroscience and Biobehavioral Reviews, 44, 16–32. https://doi. audiometric shape in sudden sensorineural hearing loss. Auris Nasus
org/10.1016/j.neubiorev.2013.03.021 Larynx, 43(3), 281–286. https://doi.org/10.1016/j.anl.2015.10.001
De Ridder, D., Fransen, H., Francois, O., Sunaert, S., Kovacs, S., … De Krick, C., Argstatter, H., Grapp, M., Plinkert, P. K., & Reith, W. (2017). Hei-
Heyning, P. V. (2006). Amygdalohippocampal involvement in tinnitus delberg Neuro-music therapy enhances task-negative activity in tinni-
and auditory memory. Acta Oto-Laryngologica, 126(556), 50–53. tus patients. Frontiers in Neuroscience, 11(384), 1–9. https://doi.org/
https://doi.org/10.1080/03655230600895580 10.3389/fnins.2017.00384
Diederen, K. M. J., Neggers, S. F. W., Daalman, K., Blom, J. D., Lancaster, J. L., Woldorff, M. G., Parsons, L. M., Liotti, M., Freitas, C. S.,
Goekoop, R., Kahn, R. S., … Sommer, I. E. (2010). Deactivation of the Rainey, L., … Fox, P. T. (2015). Automated Talairach atlas labels for
parahippocampal gyrus preceding auditory hallucinations in schizo- functional brain mapping. Human Brain Mapping, 10(3), 120–131.
phrenia. American Journal of Psychiatry, 167(4), 427–435. https://doi. https://doi.org/10.1002/1097-0193(200007)10:3<120::AID-
org/10.1176/appi.ajp.2009.09040456 HBM30>3.0.CO;2-8
Dispenza, F., Amodio, E., Stefano, A. D., Gallina, S., Marchese, D., Langguth, B., Kreuzer, P. M., Kleinjung, T., & De, R. D. (2013). Tinnitus:
Mathur, N., … Riggio, F. (2011). Treatment of sudden sensorineural Causes and clinical management. Lancet Neurology, 12(9), 920–930.
hearing loss with transtympanic injection of steroids as single therapy: https://doi.org/10.1016/S1474-4422(13)70160-1
A randomized clinical study. European Archives of Oto-Rhino-Laryngol- Lanting, C. P., De, K. E., & Van, D. P. (2009). Neural activity underlying tin-
ogy, 268(9), 1273–1278. https://doi.org/10.1007/s00405-011- nitus generation: Results from PET and fMRI. Hearing Research, 255(1),
1523-0 1–13. https://doi.org/10.1016/j.heares.2009.06.009
Dümpelmann, M., Ball, T., & Schulze-Bonhage, A. (2012). sLORETA allows Leaver, A. M., Turesky, T. K., Seydellgreenwald, A., Morgan, S., Kim, H. J.,
reliable distributed source reconstruction based on subdural strip and … Rauschecker, J. P. (2016). Intrinsic network activity in tinnitus inves-
grid recordings. Human Brain Mapping, 33(5), 1172–1188. https://doi. tigated using functional MRI. Human Brain Mapping, 37(8),
org/10.1002/hbm.21276 2717–2735. https://doi.org/10.1002/hbm.23204
Elgoyhen, A. B., Langguth, B., Ridder, D. D., & Vanneste, S. (2015). Erra- Li, W., Qin, W., Liu, H., Fan, L., Wang, J., Jiang, T., … Yu, C. (2013). Subre-
tum: Tinnitus: Perspectives from human neuroimaging. Nature Reviews gions of the human superior frontal gyrus and their connections.
Neuroscience, 16, 632–642. https://doi.org/10.1038/nrn4003 NeuroImage, 78, 46–58. https://doi.org/10.1016/j.neuroimage.2013.
Freedman, D. J., & Ibos, G. (2018). An integrative framework for sensory, 04.011
motor, and cognitive functions of the posterior parietal cortex. Neuron, Logothetis, N. K., Murayama, Y., Augath, M., Steffen, T., Werner, J., …
97(6), 1219–1234. https://doi.org/10.1016/j.neuron.2018.01.044 Oeltermann, A. (2009). How not to study spontaneous activity. NeuroImage,
Fuchs, M., Kastner, J., Wagner, M., … John, S. (2002). A standardized 45(4), 1080–1089. https://doi.org/10.1016/j.neuroimage.2009.01.010
boundary element method volume conductor model. Clinical Neuro- Loo, E. V. D., Gais, S., Congedo, M., Vanneste, S., Plazier, M., Menovsky, T.,
physiology: Official Journal of the International Federation of Clinical … Ridder, D. D. (2009). Tinnitus intensity dependent gamma oscilla-
Neurophysiology, 113(5), 702–712. https://doi.org/10.1016/S1388- tions of the contralateral auditory cortex. PLoS One, 4(10), e7396.
2457(02)00030-5 https://doi.org/10.1371/journal.pone.0007396
Golm, D., Schmidtsamoa, C., Dechent, P., & Kronerherwig, B. (2013). Neu- Mantini, D., Perrucci, M. G., Gratta, C. D., Romani, G. L., & Corbetta, M.
ral correlates of tinnitus related distress: An fMRI-study. Hearing (2007). Electrophysiological signatures of resting state networks in the
Research, 295, 87–99. https://doi.org/10.1016/j.heares.2012.03.003 human brain. Proceedings of the National Academy of Sciences of the
Helfrich, R. F., Huang, M., Wilson, G., & Knight, R. T. (2017). Prefrontal cor- United States of America, 104(32), 13170–13175. https://doi.org/10.
tex modulates posterior alpha oscillations during top-down guided 1073/pnas.0700668104
visual perception. Proceedings of the National Academy of Sciences of Mathew, L., Evans, A., Ouriadov, A., Etemad-Rezai, R., Fogel, R., Santyr, G.,
the United States of America, 114(35), 9457–9462. https://doi.org/10. … Parraga, G. (2007). Synchronization of neural activity across cortical
1073/pnas.1705965114 areas correlates with conscious perception. Journal of Neuroscience:
Henderson-Sabes, J., Shang, Y., Perez, P. L., Chang, J. L., Pross, S. E., The Official Journal of the Society for Neuroscience, 27(11), 2858–2865.
Findlay, A. M., … Cheung, S. W. (2019). Corticostriatal functional con- https://doi.org/10.1523/JNEUROSCI.4623-06.2007
nectivity of bothersome tinnitus in single-sided deafness. Scientific Maudoux, A., Lefebvre, P., Cabay, J. E., Demertzi, A., Vanhaudenhuyse, A.,
Reports, 9(1), 19552. https://doi.org/10.1038/s41598-019-56127-1 Laureys, S., … Soddu, A. (2012). Connectivity graph analysis of the
494 LAN ET AL.

auditory resting state network in tinnitus. Brain Research, 1485(47), oscillatory neural activity. Journal of Neuroscience Methods, 219(2),
10–21. https://doi.org/10.1016/j.brainres.2012.05.006 224–232. https://doi.org/10.1016/j.jneumeth.2013.07.021
Mazziotta, J., Toga, A., Evans, A., Fox, P., Lancaster, J., Zilles, K., … Van Diessen, E., Numan, T., Van Dellen, E., Der Kooi, A. W. V.,
Mazoyer, B. (2001). A probabilistic atlas and reference system for the Boersma, M., Hofman, D., … Hillebrand, A. (2015). Opportunities and
human brain: International consortium for brain mapping (ICBM). Phil- methodological challenges in EEG and MEG resting state functional
osophical transactions. Biological Sciences, 356(1412), 1293–1322. brain network research. Clinical Neurophysiology, 126(8), 1468–1481.
https://doi.org/10.1098/rstb.2001.0915 https://doi.org/10.1016/j.clinph.2014.11.018
Onton, J., Westerfield, M., Townsend, J., & Makeig, S. (2006). Imaging Vanneste, S., Alsalman, O., & De Ridder, D. (2018). COMT and the neu-
human EEG dynamics using independent component analysis. Neuro- rogenetic architecture of hearing loss induced tinnitus. Hearing
science and Biobehavioral Reviews, 30(6), 808–822. https://doi.org/10. Research, 365, 1–15. https://doi.org/10.1016/j.heares.2018.05.020
1016/j.neubiorev.2006.06.007 Vanneste, S., Alsalman, O., & De Ridder, D. (2019). Top-down and bottom-
Pascual-Marqui, R. D. (2002). Standardized low-resolution brain electro- up regulated auditory phantom perception. The Journal of Neurosci-
magnetic tomography (sLORETA): Technical details. Methods and Find- ence, 39(2), 364–378. https://doi.org/10.1523/JNEUROSCI.0966-18.
ings in Experimental and Clinical Pharmacology, 24 Suppl D(Suppl D), 5. 2018
https://doi.org/10.1002/med.10000 Vanneste, S., & De Ridder, D. (2016). Deafferentation-based pathophysio-
Pascual-Marqui, R. D. (2007). Instantaneous and lagged measurements of logical differences in phantom sound: Tinnitus with and without hear-
linear and nonlinear dependence between groups of multivariate time ing loss. NeuroImage, 129, 80–94. https://doi.org/10.1016/j.
series: frequency decomposition. neuroimage.2015.12.002
Pattyn, T., Van, D. E. F., Vanneste, S., Cassiers, L., Veltman, D. J., Vanneste, S., Song, J. J., & De Ridder, D. (2018). Thalamocortical dysrhyth-
Van, D. H. P., … Sabbe, B. C. (2016). Tinnitus and anxiety disorders: A mia detected by machine learning. Nature Communications, 9(1), 1103.
review. Hearing Research, 333, 255–265. https://doi.org/10.1016/j. https://doi.org/10.1038/s41467-018-02820-0
heares.2015.08.014 Vanneste, S., To, W. T., & De Ridder, D. (2019). Tinnitus and neuropathic
Ptak, R. (2012). The Frontoparietal attention network of the human brain. pain share a common neural substrate in the form of specific brain
The Neuroscientist, 18(5), 502–515. https://doi.org/10.1177/ connectivity and microstate profiles. Progress in Neuro-
1073858411409051 Psychopharmacology & Biological Psychiatry, 88, 388–400. https://doi.
Raichle, M. E., Macleod, A. M., Snyder, A. Z., Powers, W. J., Gusnard, D. A., org/10.1016/j.pnpbp.2018.08.015
… Shulman, G. L. (2001). A default mode of brain function. Proceedings Vanneste, S., van de Heyning, P., & De Ridder, D. (2011). The neural net-
of the National Academy of Sciences of the United States of America, 98 work of phantom sound changes over time: A comparison between
(2), 676–682. https://doi.org/10.1073/pnas.98.2.676 recent-onset and chronic tinnitus patients. The European Journal of
Schlee, W., Mueller, N., Hartmann, T., Keil, J., Lorenz, I., … Weisz, N. Neuroscience, 34(5), 718–731. https://doi.org/10.1111/j.1460-9568.
(2009). Mapping cortical hubs in tinnitus. BMC Biology, 7(1), 1–14. 2011.07793.x
https://doi.org/10.1186/1741-7007-7-80 Viskontas, I. V., Knowlton, B. J., Steinmetz, P. N., & Fried, I. (2006). Differ-
Schmidt, S. A., Akrofi, K., Carpenterthompson, J. R., & Husain, F. T. (2013). ences in mnemonic processing by neurons in the human hippocampus
Default mode, dorsal attention and auditory resting state networks and Parahippocampal regions. Journal of Cognitive Neuroscience, 18
exhibit differential functional connectivity in tinnitus and hearing loss. (10), 1654–1662. https://doi.org/10.1162/jocn.2006.18.10.1654
PLoS One, 8(10), 1–12. https://doi.org/10.1371/journal.pone.0076488 Xu, J., Cui, J., Feng, Y., Yong, W., Chen, H., Chen, Y., … Wu, Y. (2019).
Schroeder, C. E., & Lakatos, P. (2009). Low-frequency neuronal oscillations Chronic tinnitus exhibits bidirectional functional dysconnectivity in
as instruments of sensory selection. Trends in Neurosciences, 32(1), frontostriatal circuit. Frontiers in Neuroscience, 13, 1299. https://doi.
9–18. https://doi.org/10.1016/j.tins.2008.09.012 org/10.3389/fnins.2019.01299
Sebastian, A., Jung, P., Neuhoff, J., Wibral, M., Fox, P. T., Lieb, K., … Zevin, J. (2009). Word recognition. In L. R. Squire (Ed.), Encyclopedia of neu-
Mobascher, A. (2016). Dissociable attentional and inhibitory networks roscience (pp. 517–522). Oxford: Academic Press.
of dorsal and ventral areas of the right inferior frontal cortex: A com-
bined task-specific and coordinate-based meta-analytic fMRI study.
Brain Structure and Function, 221(3), 1635–1651. https://doi.org/10.
1007/s00429-015-0994-y
Sestieri, C., Shulman, G. L., & Corbetta, M. (2017). The contribution of the How to cite this article: Lan L, Li J, Chen Y, et al. Alterations
human posterior parietal cortex to episodic memory. Nature Reviews. of brain activity and functional connectivity in transition from
Neuroscience, 18(3), 183–192. https://doi.org/10.1038/nrn.2017.6
acute to chronic tinnitus. Hum Brain Mapp. 2021;42:485–494.
Stolzberg, D., Hayes, S. H., Kashanian, N., Radziwon, K. E., Salvi, R., …
Allman, B. L. (2013). A novel behavioral assay for the assessment of https://doi.org/10.1002/hbm.25238
acute tinnitus in rats optimized for simultaneous recording of