Cerebellar Gray Matter Volume in Tinnitus.

Tinnitus is the perception of sound without an external source. The flocculus (FL) and paraflocculus (PFL), which are small lobules of the cerebellum, have recently been implicated in its pathophysiology. In a previous study, the volume of the (P)FL-complex correlated with tinnitus severity in patients that had undergone cerebellopontine angle (CPA) tumor removal. In this study, the relation between tinnitus and gray matter volume (GMV) of the (P)FL-complex, GMV of the other cerebellar lobules and GMV of the cerebellar nuclei is investigated in otherwise healthy participants. Data was processed using the SUIT toolbox, which is dedicated to analysis of imaging data of the human cerebellum. GMV of all cerebellar lobules and nuclei were similar between tinnitus and non-tinnitus participants. Moreover, no relation was present between tinnitus severity, as measured by the Tinnitus Handicap Inventory, and (P)FL-complex GMV, tonsil GMV, or total cerebellar cortical GMV. These results suggest that in otherwise healthy participants, in contrast to participants after CPA tumor removal, no relation between the GMV of neither the (P)FL-complex nor other cerebellar lobules and tinnitus presence and severity exists. These findings indicate that a relation only exists when the (P)FL-complex is damaged, for instance by a CPA tumor. Alternatively, it is possible that differences in (P)FL-complex GMVs are too small to detect with a voxel-based morphometry study. Therefore, the role of the (P)FL-complex in tinnitus remains to be further studied.

Neuroanatomical Alterations in Tinnitus Assessed with Magnetic Resonance Imaging.

Previous studies of anatomical changes associated with tinnitus have provided inconsistent results, with some showing significant cortical and subcortical changes, while others have found effects due to hearing loss, but not tinnitus. In this study, we examined changes in brain anatomy associated with tinnitus using anatomical scans from 128 participants with tinnitus and hearing loss, tinnitus with clinically normal hearing, and non-tinnitus controls with clinically normal hearing. The groups were matched for hearing loss, age and gender. We employed voxel- and surface-based morphometry (SBM) to investigate gray and white matter volume and thickness within regions-of-interest (ROI) that were based on the results of previous studies. The largest overall effects were found for age, gender, and hearing loss. With regard to tinnitus, analysis of ROI revealed numerous small increases and decreases in gray matter and thickness between tinnitus and non-tinnitus controls, in both cortical and subcortical structures. For whole brain analysis, the main tinnitus-related significant clusters were found outside sensory auditory structures. These include a decrease in cortical thickness for the tinnitus group compared to controls in the left superior frontal gyrus (SFG), and a decrease in cortical volume with hearing loss in left Heschl's gyrus (HG). For masked analysis, we found a decrease in gray matter volume in the right Heschle's gyrus for the tinnitus group compared to the controls. We found no changes in the subcallosal region as reported in some previous studies. Overall, while some of the morphological differences observed in this study are similar to previously published findings, others are entirely different or even contradict previous results. We highlight other discrepancies among previous results and the increasing need for a more precise subtyping of the condition.

Tinnitus- and Task-Related Differences in Resting-State Networks.

We investigated tinnitus-related differences in functional networks in adults with tinnitus by means of a functional connectivity study. Previously it was found that various networks show differences in connectivity in patients with tinnitus compared to controls. How this relates to patients' ongoing tinnitus and whether the ecological sensory environment modulates connectivity remains unknown.Twenty healthy controls and twenty patients suffering from chronic tinnitus were enrolled in this study. Except for the presence of tinnitus in the patient group, all subjects were selected to have normal or near-normal hearing. fMRI data were obtained in two different functional states. In one set of runs, subjects freely viewed emotionally salient movie fragments ("fixed-state") while in the other they were not performing any task ("resting-state"). After data pre-processing, Principal Component Analysis was performed to obtain 25 components for all datasets. These were fed into an Independent Component Analysis (ICA), concatenating the data across both groups and both datasets, to obtain group-level networks of neural origin, each consisting of spatial maps with their respective time-courses. Subject-specific maps and their time-course were obtained by back-projection (Dual Regression). For each of the components a mixed-effects linear model was composed with factors group (tinnitus vs. controls), task (fixed-state vs. resting state) and their interaction. The neural components comprised the visual, sensorimotor, auditory, and limbic systems, the default mode, dorsal attention, executive-control, and frontoparietal networks, and the cerebellum. Most notably, the default mode network (DMN) was less extensive and shows significantly less connectivity in tinnitus patients than in controls. This group difference existed in both paradigms. At the same time, the DMN was stronger during resting-state than during fixed-state in the controls but not the patients. We attribute this pattern to the unremitting engaging effect of the tinnitus percept.

Functional specialization of the male insula during taste perception.

The primary gustatory area is located in the insular cortex. Although the insular cortex has been the topic of multiple parcellation studies, its functional specialization regarding taste processing received relatively little attention. Studies investigating the brain response to taste suggested that the insular cortex is involved in processing multiple characteristics of a taste stimulus, such as its quality, intensity, and pleasantness. In the current functional magnetic resonance study, younger and older adult male subjects were exposed to four basic tastes in five increasing concentrations. We applied a data-driven analysis to obtain insular response maps, which showed that the insular cortex processes the presence of taste, its corresponding pleasantness, as well as its concentration. More specifically, the left and right insular cortices are differentially engaged in processing the aforementioned taste characteristics: representations of the presence of a taste stimulus as well as its corresponding pleasantness dominate in the left insular cortex, whereas taste concentration processing dominates in the right insular cortex. These results were similar across both age groups. Our results fit well within previous cytoarchitectural studies and show insular lateralization in processing different aspects of taste stimuli in men.

Tinnitus-related abnormalities in visual and salience networks during a one-back task with distractors.

Tinnitus is highly prevalent in the general population. Tinnitus sufferers often report having difficulties focusing on a task at hand and ignoring the tinnitus percept. Behavioral studies have shown evidence for impairments in attention, interference inhibition, and various other executive functions in tinnitus. However, few neuroimaging studies have directly addressed this issue. In the present functional Magnetic Resonance Imaging (fMRI) study we employed a 1-back task, requiring subjects to monitor relevant auditory and visual information. Additionally, interfering stimuli were presented to investigate selection of relevant information and inhibition of irrelevant information. Significant behavioral group differences were not found, although performance worsened for increasing tinnitus severity. Significant group differences in evoked neural activation neither occurred in the central auditory system, nor in the attentional fronto-parietal network. However, the anterior insula and the vermis of the cerebellum showed significantly stronger task-related activation in the tinnitus group when compared to the controls. Furthermore, deactivation in the primary visual cortex that occurred in the control group for various combinations of modalities and distractors was significantly less in the tinnitus group. These results are consistent with previous studies that showed the involvement of various networks in tinnitus, particularly the salience and visual networks, which are also implicated in attention. Although we did not demonstrate cognitive impairment in tinnitus, significantly different evoked responses were found in various brain regions that we attribute to an abnormal involvement of attention control mechanisms in tinnitus.

Unilateral tinnitus: changes in connectivity and response lateralization measured with FMRI.

Tinnitus is a percept of sound that is not related to an acoustic source outside the body. For many forms of tinnitus, mechanisms in the central nervous system are believed to play a role in the pathology. In this work we specifically assessed possible neural correlates of unilateral tinnitus. Functional magnetic resonance imaging (fMRI) was used to investigate differences in sound-evoked neural activity between controls, subjects with left-sided tinnitus, and subjects with right-sided tinnitus. We assessed connectivity patterns between auditory nuclei and the lateralization of the sound-evoked responses. Interestingly, these response characteristics did not relate to the laterality of tinnitus. The lateralization for left- or right ear stimuli, as expressed in a lateralization index, was considerably smaller in subjects with tinnitus compared to that in controls, reaching significance in the right primary auditory cortex (PAC) and the right inferior colliculus (IC). Reduced functional connectivity between the brainstem and the cortex was observed in subjects with tinnitus. These differences are consistent with two existing models that relate tinnitus to i) changes in the corticothalamic feedback loops or ii) reduced inhibitory effectiveness between the limbic system and the thalamus. The vermis of the cerebellum also responded to monaural sound in subjects with unilateral tinnitus. In contrast, no cerebellar response was observed in control subjects. This suggests the involvement of the vermis of the cerebellum in unilateral tinnitus.

Neuroimaging paradigms for tonotopic mapping (II): the influence of acquisition protocol.

Numerous studies on the tonotopic organisation of auditory cortex in humans have employed a wide range of neuroimaging protocols to assess cortical frequency tuning. In the present functional magnetic resonance imaging (fMRI) study, we made a systematic comparison between acquisition protocols with variable levels of interference from acoustic scanner noise. Using sweep stimuli to evoke travelling waves of activation, we measured sound-evoked response signals using sparse, clustered, and continuous imaging protocols that were characterised by inter-scan intervals of 8.8, 2.2, or 0.0 s, respectively. With regard to sensitivity to sound-evoked activation, the sparse and clustered protocols performed similarly, and both detected more activation than the continuous method. Qualitatively, tonotopic maps in activated areas proved highly similar, in the sense that the overall pattern of tonotopic gradients was reproducible across all three protocols. However, quantitatively, we observed substantial reductions in response amplitudes to moderately low stimulus frequencies that coincided with regions of strong energy in the scanner noise spectrum for the clustered and continuous protocols compared to the sparse protocol. At the same time, extreme frequencies became over-represented for these two protocols, and high best frequencies became relatively more abundant. Our results indicate that although all three scanning protocols are suitable to determine the layout of tonotopic fields, an exact quantitative assessment of the representation of various sound frequencies is substantially confounded by the presence of scanner noise. In addition, we noticed anomalous signal dynamics in response to our travelling wave paradigm that suggest that the assessment of frequency-dependent tuning is non-trivially influenced by time-dependent (hemo)dynamics when using sweep stimuli.

Neuroimaging paradigms for tonotopic mapping (I): the influence of sound stimulus type.

Although a consensus is emerging in the literature regarding the tonotopic organisation of auditory cortex in humans, previous studies employed a vast array of different neuroimaging protocols. In the present functional magnetic resonance imaging (fMRI) study, we made a systematic comparison between stimulus protocols involving jittered tone sequences with either a narrowband, broadband, or sweep character in order to evaluate their suitability for the purpose of tonotopic mapping. Data-driven analysis techniques were used to identify cortical maps related to sound-evoked activation and tonotopic frequency tuning. Principal component analysis (PCA) was used to extract the dominant response patterns in each of the three protocols separately, and generalised canonical correlation analysis (CCA) to assess the commonalities between protocols. Generally speaking, all three types of stimuli evoked similarly distributed response patterns and resulted in qualitatively similar tonotopic maps. However, quantitatively, we found that broadband stimuli are most efficient at evoking responses in auditory cortex, whereas narrowband and sweep stimuli offer the best sensitivity to differences in frequency tuning. Based on these results, we make several recommendations regarding optimal stimulus protocols, and conclude that an experimental design based on narrowband stimuli provides the best sensitivity to frequency-dependent responses to determine tonotopic maps. We forward that the resulting protocol is suitable to act as a localiser of tonotopic cortical fields in individuals, or to make quantitative comparisons between maps in dedicated tonotopic mapping studies.

Neuroanatomical abnormalities in chronic tinnitus in the human brain.

In this paper, we review studies that have investigated brain morphology in chronic tinnitus in order to better understand the underlying pathophysiology of the disorder. Current consensus is that tinnitus is a disorder involving a distributed network of peripheral and central pathways in the nervous system. However, the precise mechanism remains elusive and it is unclear which structures are involved. Given that brain structure and function are highly related, identification of anatomical differences may shed light upon the mechanism of tinnitus generation and maintenance. We discuss anatomical changes in the auditory cortex, the limbic system, and prefrontal cortex, among others. Specifically, we discuss the gating mechanism of tinnitus and evaluate the evidence in support of the model from studies of brain anatomy. Although individual studies claim significant effects related to tinnitus, outcomes are divergent and even contradictory across studies. Moreover, results are often confounded by the presence of hearing loss. We conclude that, at present, the overall evidence for structural abnormalities specifically related to tinnitus is poor. As this area of research is expanding, we identify some key considerations for research design and propose strategies for future research.

Tinnitus-related dissociation between cortical and subcortical neural activity in humans with mild to moderate sensorineural hearing loss.

Tinnitus is a phantom sound percept that is strongly associated with peripheral hearing loss. However, only a fraction of hearing-impaired subjects develops tinnitus. This may be based on differences in the function of the brain between those subjects that develop tinnitus and those that do not. In this study, cortical and sub-cortical sound-evoked brain responses in 34 hearing-impaired chronic tinnitus patients and 19 hearing level-matched controls were studied using 3-T functional magnetic resonance imaging (fMRI). Auditory stimuli were presented to either the left or the right ear at levels of 30-90 dB SPL. We extracted neural activation as a function of sound intensity in eight auditory regions (left and right auditory cortices, medial geniculate bodies, inferior colliculi and cochlear nuclei), the cerebellum and a cinguloparietal task-positive region. The activation correlated positively with the stimulus intensity, and negatively with the hearing threshold. We found no differences between both groups in terms of the magnitude and lateralization of the sound-evoked responses, except for the left medial geniculate body and right cochlear nucleus where activation levels were elevated in the tinnitus subjects. We observed significantly reduced functional connectivity between the inferior colliculi and the auditory cortices in tinnitus patients compared to controls. Our results indicate a failure of thalamic gating in the development of tinnitus.

Abnormal visual field maps in human cortex: a mini-review and a case report.

Human visual cortex contains maps of the visual field. Much research has been dedicated to answering whether and when these visual field maps change if critical components of the visual circuitry are damaged. Here, we first provide a focused mini-review of the functional magnetic resonance imaging (fMRI) studies that have evaluated the human cortical visual field maps in the face of retinal lesions, brain injury, and atypical retinocortical projections. We find that there is a fair body of research that has found abnormal fMRI activity, but also that this abnormal activity does not necessarily stem from cortical remapping. The abnormal fMRI activity can often be explained in terms of task effects and/or the uncovering of normally hidden system dynamics. We then present the case of a 16-year-old patient who lost the entire left cerebral hemisphere at age three for treatment of chronic focal encephalitis (Rasmussen syndrome) and intractable epilepsy. Using an fMRI retinotopic mapping procedure and population receptive field (pRF) modeling, we found that (1) despite the long period since the hemispherectomy, the retinotopic organization of early visual cortex remained unaffected by the removal of an entire cerebral hemisphere, and (2) the intact lateral occipital cortex contained an exceptionally large representation of the center of the visual field. The same method also indicates that the neuronal receptive fields in these lateral occipital brain regions are extraordinarily small. These features are clearly abnormal, but again they do not necessarily stem from cortical remapping. For example, the abnormal features can also be explained by the notion that the hemispherectomy took place during a critical period in the development of the lateral occipital cortex and therefore arrested its normal development. Thus, caution should be exercised when interpreting abnormal fMRI activity as a marker of cortical remapping; there are often other explanations.

Tonotopic mapping of human auditory cortex.

Since the early days of functional magnetic resonance imaging (fMRI), retinotopic mapping emerged as a powerful and widely-accepted tool, allowing the identification of individual visual cortical fields and furthering the study of visual processing. In contrast, tonotopic mapping in auditory cortex proved more challenging primarily because of the smaller size of auditory cortical fields. The spatial resolution capabilities of fMRI have since advanced, and recent reports from our labs and several others demonstrate the reliability of tonotopic mapping in human auditory cortex. Here we review the wide range of stimulus procedures and analysis methods that have been used to successfully map tonotopy in human auditory cortex. We point out that recent studies provide a remarkably consistent view of human tonotopic organisation, although the interpretation of the maps continues to vary. In particular, there remains controversy over the exact orientation of the primary gradients with respect to Heschl's gyrus, which leads to different predictions about the location of human A1, R, and surrounding fields. We discuss the development of this debate and argue that literature is converging towards an interpretation that core fields A1 and R fold across the rostral and caudal banks of Heschl's gyrus, with tonotopic gradients laid out in a distinctive V-shaped manner. This suggests an organisation that is largely homologous with non-human primates. This article is part of a Special Issue entitled Human Auditory Neuroimaging.

Assessment of tonotopically organised subdivisions in human auditory cortex using volumetric and surface-based cortical alignments.

Although orderly representations of sound frequency in the brain play a guiding role in the investigation of auditory processing, a rigorous statistical evaluation of cortical tonotopic maps has so far hardly been attempted. In this report, the group-level significance of local tonotopic gradients was assessed using mass-multivariate statistics. The existence of multiple fields on the superior surface of the temporal lobe in both hemispheres was shown. These fields were distinguishable on the basis of tonotopic gradient direction and may likely be identified with the human homologues of the core areas AI and R in primates. Moreover, an objective comparison was made between the usage of volumetric and surface-based registration methods. Although the surface-based method resulted in a better registration across subjects of the grey matter segment as a whole, the alignment of functional subdivisions within the cortical sheet did not appear to improve over volumetric methods. This suggests that the variable relationship between the structural and the functional characteristics of auditory cortex is a limiting factor that cannot be overcome by morphology-based registration techniques alone. Finally, to illustrate how the proposed approach may be used in clinical practice, the method was used to test for focal differences regarding the tonotopic arrangements in healthy controls and tinnitus patients. No significant differences were observed, suggesting that tinnitus does not necessarily require tonotopic reorganisation to occur.

Mapping tonotopy in human auditory cortex.

Tonotopy is arguably the most prominent organizational principle in the auditory pathway. Nevertheless, the layout of tonotopic maps in humans is still debated. We present neuroimaging data that robustly identify multiple tonotopic maps in the bilateral auditory cortex. In contrast with some earlier publications, tonotopic gradients were not found to be collinearly aligned along Heschl's gyrus; instead, two tonotopic maps ran diagonally across the anterior and posterior banks of Heschl's gyrus, set at a pronounced angle. On the basis of the direction of the tonotopic gradient, distinct subdivisions of the auditory cortex could be clearly demarcated that suggest homologies with the tonotopic organization in other primates. Finally, we applied our method to tinnitus patients to show that - contradictory to some pathophysiological models - tinnitus does not necessarily involve large-scale tonotopic reorganization. Overall, we expect that tonotopic mapping techniques will significantly enhance our ability to study the hierarchical functional organization of distinct auditory processing centers in the healthy and diseased human brain.

The relevance of task-irrelevant sounds: hemispheric lateralization and interactions with task-relevant streams.

The effect of unattended task-irrelevant auditory stimuli in the context of an auditory task is not well understood. Using human functional magnetic resonance imaging (fMRI) we compared blood oxygenation level dependent (BOLD) signal changes resulting from monotic task-irrelevant stimulation, monotic task-relevant stimulation and dichotic stimulation with an attended task-relevant stream to one ear and an unattended task-irrelevant stream to the other ear simultaneously. We found strong bilateral BOLD signal changes in the auditory cortex (AC) resulting from monotic stimulation in a passive listening condition. Consistent with previous work, these responses were largest on the side contralateral to stimulation. AC responses to the unattended (task-irrelevant) sounds were preferentially contralateral and strongest for the most difficult condition. Stronger bilateral AC responses occurred during monotic passive-listening than to an unattended stream presented in a dichotic condition, with attention focused on one ear. Additionally, the visual cortex showed negative responses compared to the baseline in all stimulus conditions including passive listening. Our results suggest that during dichotic listening, with attention focused on one ear, (1) the contralateral and the ipsilateral auditory pathways are suppressively interacting; and (2) cross-modal inhibition occurs during purely acoustic stimulation. These findings support the existence of response suppressions within and between modalities in the presence of competing interfering stimuli.

Gray matter in the brain: differences associated with tinnitus and hearing loss.

Tinnitus, usually associated with hearing loss, is characterized by the perception of sound without an external sound source. The pathophysiology of tinnitus is poorly understood. In the present study, voxel-based morphometry (VBM) was employed to identify gray matter differences related to hearing loss and tinnitus. VBM was applied to magnetic resonance images of normal-hearing control subjects (n = 24), hearing-impaired subjects without tinnitus (n = 16, HI group) and hearing-impaired subjects with tinnitus (n = 31, HI + T group). This design allowed us to disentangle the gray matter (GM) differences related to hearing loss and tinnitus, respectively. Voxel-based VBM analyses revealed that both HI and HI + T groups, relative to the controls, had GM increases in the superior and middle temporal gyri, and decreases in the superior frontal gyrus, occipital lobe and hypothalamus. We did not find significant GM differences between both patient groups. Subsequent region-of-interest (ROI) analyses of all Brodmann Areas, the cerebellum and the subcortical auditory nuclei showed a GM increase in the left primary auditory cortex of the tinnitus patients compared to the HI and control groups. Moreover, GM decreases were observed in frontal areas and mainly GM increases in limbic areas, both of which occurred for hearing loss irrespective of tinnitus, relative to the controls. These results suggest a specific role of the left primary auditory cortex and the additional involvement of various non-auditory brain structures in tinnitus. Understanding the causal relation between these GM changes and tinnitus will be an important next step in understanding tinnitus mechanisms.

The relation between perception and brain activity in gaze-evoked tinnitus.

Tinnitus is a phantom sound percept that can be severely disabling. Its pathophysiology is poorly understood, partly due to the inability to objectively measure neural correlates of tinnitus. Gaze-evoked tinnitus (GET) is a rare form of tinnitus that may arise after vestibular schwannoma removal. Subjects typically describe tinnitus in the deaf ear on the side of the surgery that can be modulated by peripheral eye gaze. This phenomenon offers a unique opportunity to study the relation between tinnitus and brain activity. We used functional magnetic resonance imaging in humans to show that in normal-hearing control subjects, peripheral gaze results in inhibition of the auditory cortex, but no detectable response in the medial geniculate body (MGB) and inferior colliculus (IC). In patients with GET, peripheral gaze (1) reduced the cortical inhibition, (2) inhibited the MGB, and (3) activated the IC. Furthermore, increased tinnitus loudness is represented by increased activity in the cochlear nucleus (CN) and IC and reduced inhibition in the auditory cortex (AC). The increase of CN and IC activity with peripheral gaze is consistent with models of plastic reorganization in the brainstem following vestibular schwannoma removal. The activity decrease in the MGB and the reduced inhibition of the AC support a model that attributes tinnitus to a dysrhythmia of the thalamocortical loop, leading to hypometabolic theta activity in the MGB. Our data offer the first support of this loop hypothesis of tinnitus, independent of the initial experiments that led to its formulation.

Tinnitus does not require macroscopic tonotopic map reorganization.

The pathophysiology underlying tinnitus, a hearing disorder characterized by the chronic perception of phantom sound, has been related to aberrant plastic reorganization of the central auditory system. More specifically, tinnitus is thought to involve changes in the tonotopic representation of sound. In the present study we used high-resolution functional magnetic resonance imaging to determine tonotopic maps in the auditory cortex of 20 patients with tinnitus but otherwise near-normal hearing, and compared these to equivalent outcomes from 20 healthy controls with matched hearing thresholds. Using a dedicated experimental paradigm and data-driven analysis techniques, multiple tonotopic gradients could be robustly distinguished in both hemispheres, arranged in a pattern consistent with previous findings. Yet, maps were not found to significantly differ between the two groups in any way. In particular, we found no evidence for an overrepresentation of high sound frequencies, matching the tinnitus pitch. A significant difference in evoked response magnitude was found near the low-frequency tonotopic endpoint on the lateral extreme of left Heschl's gyrus. Our results suggest that macroscopic tonotopic reorganization in the auditory cortex is not required for the emergence of tinnitus, and is not typical for tinnitus that accompanies normal hearing to mild hearing loss.

Mapping the tonotopic organization in human auditory cortex with minimally salient acoustic stimulation.

Despite numerous neuroimaging studies, the tonotopic organization in human auditory cortex is not yet unambiguously established. In this functional magnetic resonance imaging study, 20 subjects were presented with low-level task-irrelevant tones to avoid spread of cortical activation. Data-driven analyses were employed to obtain robust tonotopic maps. Two high-frequency endpoints were situated on the caudal and rostral banks of medial Heschl's gyrus, while low-frequency activation peaked on its lateral crest. Based on cortical parcellations, these 2 tonotopic progressions coincide with the primary auditory field (A1) in lateral koniocortex (Kl) and the rostral field (R) in medial koniocortex (Km), which together constitute a core region. Another gradient was found on the planum temporale. Our results show the bilateral existence of 3 tonotopic gradients in angulated orientations, which contrasts with colinear configurations that were suggested before. We argue that our results corroborate and elucidate the apparently contradictory findings in literature.