Structural correlates of the audiological and emotional components of chronic tinnitus.

The objective is to investigate white matter tracts, more specifically the arcuate fasciculus and acoustic radiation, in tinnitus and assess their relationship with distress, loudness and hearing loss. DTI images were acquired for 58 tinnitus patients and 65 control subjects. Deterministic tractography was first performed to visualize the arcuate fasciculus and acoustic radiation tracts bilaterally and to calculate tract density, fractional anisotropy, radial diffusivity, and axial diffusivity for tinnitus and control subjects. Tinnitus patients had a significantly reduced tract density compared to controls in both tracts of interest. They also exhibited increased axial diffusivity in the left acoustic radiation, as well as increased radial diffusivity in the left arcuate fasciculus, and both the left and right acoustic radiation. Furthermore, they exhibited decreased fractional anisotropy in the left arcuate fasciculus, as well as the left and right acoustic radiation tracts. Partial correlation analysis showed: (1) a negative correlation between arcuate fasciculus tract density and tinnitus distress, (2) a negative correlation between acoustic radiation tract density and hearing loss, (3) a negative correlation between acoustic radiation tract density and loudness, (4) a positive correlation between left arcuate fasciculus and tinnitus distress for radial diffusivity, (5) a negative correlation between left arcuate fasciculus and tinnitus distress for fractional anisotropy, (6) a positive correlation between left and right acoustic radiation and hearing loss for radial diffusivity, (7) No correlation between any of the white matter characteristics and tinnitus loudness. Structural alterations in the acoustic radiation and arcuate fasciculus correlate with hearing loss and distress in tinnitus but not tinnitus loudness showing that loudness is a more functional correlate of the disorder which does not manifest structurally.

Virtual brain grafting: Enabling whole brain parcellation in the presence of large lesions.

Brain atlases and templates are at the heart of neuroimaging analyses, for which they facilitate multimodal registration, enable group comparisons and provide anatomical reference. However, as atlas-based approaches rely on correspondence mapping between images they perform poorly in the presence of structural pathology. Whilst several strategies exist to overcome this problem, their performance is often dependent on the type, size and homogeneity of any lesions present. We therefore propose a new solution, referred to as Virtual Brain Grafting (VBG), which is a fully-automated, open-source workflow to reliably parcellate magnetic resonance imaging (MRI) datasets in the presence of a broad spectrum of focal brain pathologies, including large, bilateral, intra- and extra-axial, heterogeneous lesions with and without mass effect. The core of the VBG approach is the generation of a lesion-free T1-weighted image, which enables further image processing operations that would otherwise fail. Here we validated our solution based on Freesurfer recon-all parcellation in a group of 10 patients with heterogeneous gliomatous lesions, and a realistic synthetic cohort of glioma patients (n = 100) derived from healthy control data and patient data. We demonstrate that VBG outperforms a non-VBG approach assessed qualitatively by expert neuroradiologists and Mann-Whitney U tests to compare corresponding parcellations (real patients U(6,6) = 33, z = 2.738, P < .010, synthetic-patients U(48,48) = 2076, z = 7.336, P < .001). Results were also quantitatively evaluated by comparing mean dice scores from the synthetic-patients using one-way ANOVA (unilateral VBG = 0.894, bilateral VBG = 0.903, and non-VBG = 0.617, P < .001). Additionally, we used linear regression to show the influence of lesion volume, lesion overlap with, and distance from the Freesurfer volumes of interest, on labeling accuracy. VBG may benefit the neuroimaging community by enabling automated state-of-the-art MRI analyses in clinical populations using methods such as FreeSurfer, CAT12, SPM, Connectome Workbench, as well as structural and functional connectomics. To fully maximize its availability, VBG is provided as open software under a Mozilla 2.0 license (https://github.com/KUL-Radneuron/KUL_VBG).

Brain activation during non-habitual speech production: Revisiting the effects of simulated disfluencies in fluent speakers.

Over the past decades, brain imaging studies in fluently speaking participants have greatly advanced our knowledge of the brain areas involved in speech production. In addition, complementary information has been provided by investigations of brain activation patterns associated with disordered speech. In the present study we specifically aimed to revisit and expand an earlier study by De Nil and colleagues, by investigating the effects of simulating disfluencies on the brain activation patterns of fluent speakers during overt and covert speech production. In contrast to the De Nil et al. study, the current findings show that the production of voluntary, self-generated disfluencies by fluent speakers resulted in increased recruitment and activation of brain areas involved in speech production. These areas show substantial overlap with the neural networks involved in motor sequence learning in general, and learning of speech production, in particular. The implications of these findings for the interpretation of brain imaging studies on disordered and non-habitual speech production are discussed.

Functional connectivity analysis of fMRI data collected from human subjects with chronic tinnitus and varying levels of tinnitus-related distress.

The data presented here are functional connectivity analyses based on fMRI scans from a clinical sample of the chronic tinnitus population (n = 75). All data were obtained during an experiment in which subjects listened to auditory stimuli via headphones while undergoing fMRI scanning. The stimuli consisted of tones and bandpass noise presented at different frequencies. Stimulus frequency was the experimental factor, which was set (1) at each subject's tinnitus percept frequency (TF) and (2) at an unrelated control frequency (CF) at least one octave away from the TF stimuli. All subjects were presented with stimuli at these two frequencies. We refer the reader to our original research article "Functional brain changes in auditory phantom perception evoked by different stimulus frequencies" (Hullfish et al., 2018) for further discussion. Here, we present data specifically from group-level analyses where the subjects were divided according to their level of tinnitus-related distress. The high-distress (HD) group comprised 43 subjects with Tinnitus Questionnaire (TQ) scores greater than or equal to 47, out of a possible 82 points. The low-distress (LD) group comprised the remaining 32 subjects with TQ score less than 47. The data presented include contrasts of functional connectivity elicited by TF and CF stimuli in each group as well as contrasts between the two groups.

Functional brain changes in auditory phantom perception evoked by different stimulus frequencies.

Bayesian models of brain function such as active inference and predictive coding offer a general theoretical framework with which to explain several aspects of normal and disordered brain function. Of particular interest to the present study is the potential for such models to explain the pathology of auditory phantom perception, i.e. tinnitus. To test this framework empirically, we perform an fMRI experiment on a large clinical sample (n = 75) of the human chronic tinnitus population. The experiment features a within-subject design based on two experimental conditions: subjects were presented with sound stimuli matched to their tinnitus frequency (TF) as well as similar stimuli presented at a control frequency (CF). The responses elicited by these stimuli, as measured using both activity and functional connectivity, were then analyzed both within and between conditions. Given the Bayesian-brain framework, we hypothesize that TF stimuli will elicit greater activity and/or functional connectivity in areas related to the cognitive and emotional aspects of tinnitus, i.e. tinnitus-related distress. We conversely hypothesize that CF stimuli will elicit greater activity/connectivity in areas related to auditory perception and attention. We discuss our results in the context of this framework and suggest future directions for empirical testing.

Resting-State Functional Magnetic Resonance Imaging for Language Preoperative Planning.

Functional magnetic resonance imaging (fMRI) is a well-known non-invasive technique for the study of brain function. One of its most common clinical applications is preoperative language mapping, essential for the preservation of function in neurosurgical patients. Typically, fMRI is used to track task-related activity, but poor task performance and movement artifacts can be critical limitations in clinical settings. Recent advances in resting-state protocols open new possibilities for pre-surgical mapping of language potentially overcoming these limitations. To test the feasibility of using resting-state fMRI instead of conventional active task-based protocols, we compared results from fifteen patients with brain lesions while performing a verb-to-noun generation task and while at rest. Task-activity was measured using a general linear model analysis and independent component analysis (ICA). Resting-state networks were extracted using ICA and further classified in two ways: manually by an expert and by using an automated template matching procedure. The results revealed that the automated classification procedure correctly identified language networks as compared to the expert manual classification. We found a good overlay between task-related activity and resting-state language maps, particularly within the language regions of interest. Furthermore, resting-state language maps were as sensitive as task-related maps, and had higher specificity. Our findings suggest that resting-state protocols may be suitable to map language networks in a quick and clinically efficient way.

Dorsolateral prefrontal cortex transcranial magnetic stimulation and electrode implant for intractable tinnitus.

OBJECTIVE: Tinnitus is a distressing symptom that affects up to 15% of the population; no satisfactory treatment exists. We present a novel surgical approach for the treatment of intractable tinnitus based on electrical extradural stimulation of the dorsolateral prefrontal cortex via an electrode implant. Tinnitus can be considered an auditory phantom phenomenon similar to deafferentation pain in the somatosensory system. It is characterized by gamma-band activity in the frontal cortex that can be visualized with the use of electroencephalography, magnetoencephalography, and functional magnetic resonance imaging (fMRI). CASE DESCRIPTION: Transcranial magnetic stimulation (TMS) is a noninvasive technique capable of modulating the ongoing activity of the human brain. When linked with a neuronavigation system, fMRI-guided frontal cortex TMS can be performed in a placebo-controlled way. If it is successful in suppressing tinnitus, this focal and temporary effect can be maintained in perpetuity by implanting a cortical electrode. A neuronavigation-based auditory fMRI-guided frontal cortex TMS session was performed in a patient experiencing intractable tinnitus, yielding 50% tinnitus suppression. Two extradural electrodes were subsequently implanted, also based on auditory fMRI-guided navigation. Postoperatively the tinnitus has improved by 66.67% and progressively continues to improve for more than one year. CONCLUSION: Focal extradural electrical stimulation of the dorsolateral prefrontal cortex at the area of cortical plasticity is capable of suppressing contralateral tinnitus partially. TMS might be a possible method for noninvasive studies of surgical candidates for implantation of stimulating electrodes for tinnitus suppression.

Central effects of occipital nerve electrical stimulation studied by functional magnetic resonance imaging.

OBJECTIVE: To study the central effects of occipital nerve stimulation (ONS) using functional magnetic resonance imaging (fMRI). MATERIALS AND METHODS: After phantom measurements, blocked design fMRI scanning was performed during intermittent ONS in a healthy volunteer with implanted electrodes connected to an external generator. To assess the effect of frequency and stimulation mode, seven different frequencies in either tonic or burst mode were generated by a neurostimulator. RESULTS: A qualitative analysis of the main effect of ONS demonstrated significantly decreased activity within the bilateral primary visual, auditory, and somatosensory cortices and in the amygdala. Significant increased activity was observed bilaterally in the thalamus, frontal, and parietal areas and the cerebellum. Subsequently, quantitative analysis revealed that, unlike tonic mode stimulation, burst mode stimulation appeared to be frequency-dependent. CONCLUSIONS: This study demonstrates the feasibility and safety of fMRI studies with simultaneous ONS in a subject with externalized electrodes. The activation and deactivation pattern induced by ONS depends on stimulation mode and frequency.

Transient alcohol craving suppression by rTMS of dorsal anterior cingulate: an fMRI and LORETA EEG study.

It has recently become clear that alcohol addiction might be related to a brain dysfunction, in which a genetic background and environmental factors shape brain mechanisms involved with alcohol consumption. Craving, a major component determining relapses in alcohol abuse has been linked to abnormal activity in the orbitofrontal cortex, dorsal anterior cingulated cortex (dACC) and amygdala. We report the results of a patient who underwent rTMS targeting the dACC using a double cone coil in an attempt to suppress very severe intractable alcohol craving. Functional imaging studies consisting of fMRI and resting state EEG were performed before rTMS, after successful rTMS and after unsuccessful rTMS with relapse. Craving was associated with EEG beta activity and connectivity between the dACC and PCC in the patient in comparison to a healthy population, which disappeared after successful rTMS. Cue induced worsening of craving pre-rTMS activated the ACC-vmPFC and PCC on fMRI, as well as the nucleus accumbens area, and lateral frontoparietal areas. The nucleus accumbens, ACC-vmPFC and PCC activation disappeared on fMRI following successful rTMS. Relapse was associated with recurrence of ACC and PCC EEG activity, but in gamma band, in comparison to a healthy population. On fMRI nucleus accumbens, ACC and PCC activation returned to the initial activation pattern. A pathophysiological approach is described to suppress alcohol craving temporarily by rTMS directed at the anterior cingulate. Linking functional imaging changes to craving intensity suggests this approach warrants further exploration.

Theta-gamma dysrhythmia and auditory phantom perception.

Tinnitus is considered an auditory phantom percept analogous to phantom pain. Thalamocortical dysrhythmia has been proposed as a possible pathophysiological mechanism for both tinnitus and pain. Thalamocortical dysrhythmia refers to a persistent pathological resting state theta-gamma coupling that is spatially localized at an area where normally alpha oscillations predominate. Auditory cortex stimulation via implanted electrodes has been developed to treat tinnitus, targeting an area of activation on functional MR imaging elicited by tinnitus-matched sound presentation. The authors describe a case in which clinical improvement was correlated with changes in intracranial recordings. Maximal tinnitus suppression was obtained by current delivery exactly at the blood oxygen level-dependent activation hotspot, which colocalizes with increased gamma and theta activity, in contrast to the other electrode poles, which demonstrated a normal alpha peak. These spectral changes normalized when stimulation induced tinnitus suppression, both on electrode and source-localized electroencephalography recordings. These data suggest that thetagamma coupling as proposed by the thalamocortical dysrhythmia model might be causally related to a conscious auditory phantom percept.

Transcranial magnetic stimulation and extradural electrodes implanted on secondary auditory cortex for tinnitus suppression.

OBJECT: Tinnitus is a prevalent symptom, with clinical, pathophysiological, and treatment features analogous to pain. Noninvasive transcranial magnetic stimulation (TMS) and intracranial auditory cortex stimulation (ACS) via implanted electrodes into the primary or overlying the secondary auditory cortex have been developed to treat severe cases of intractable tinnitus. METHODS: A series of 43 patients who benefited transiently from 2 separate placebo-controlled TMS sessions underwent implantation of auditory cortex electrodes. Targeting was based on blood oxygen level-dependent activation evoked by tinnitus-matched sound, using functional MR imaging-guided neuronavigation. RESULTS: Thirty-seven percent of the patients responded to ACS with tonic stimulation. Of the 63% who were nonresponders, half benefited from burst stimulation. In total, 33% remained unaffected by the ACS. The average tinnitus reduction was 53% for the entire group. Burst stimulation was capable of suppressing tinnitus in more patients and was better than tonic stimulation, especially for noise-like tinnitus. For pure tone tinnitus, there were no differences between the 2 stimulation designs. The average pure tone tinnitus improvement was 71% versus 37% for noise-like tinnitus and 29% for a combination of both pure tone and noise-like tinnitus. Transcranial magnetic stimulation did not predict response to ACS, but in ACS responders, a correlation (r = 0.38) between the amount of TMS and ACS existed. A patient's sex, age, or tinnitus duration did not influence treatment outcome. CONCLUSIONS: Intracranial ACS might become a valuable treatment option for severe intractable tinnitus. Better understanding of the pathophysiological mechanisms of tinnitus, predictive functional imaging tests, new stimulation designs, and other stimulation targets are needed to improve ACS results.

Lateralization of functional magnetic resonance imaging (fMRI) activation in the auditory pathway of patients with lateralized tinnitus.

INTRODUCTION: Tinnitus is hypothesized to be an auditory phantom phenomenon resulting from spontaneous neuronal activity somewhere along the auditory pathway. We performed fMRI of the entire auditory pathway, including the inferior colliculus (IC), the medial geniculate body (MGB) and the auditory cortex (AC), in 42 patients with tinnitus and 10 healthy volunteers to assess lateralization of fMRI activation. METHODS: Subjects were scanned on a 3T MRI scanner. A T2*-weighted EPI silent gap sequence was used during the stimulation paradigm, which consisted of a blocked design of 12 epochs in which music presented binaurally through headphones, which was switched on and off for periods of 50 s. Using SPM2 software, single subject and group statistical parametric maps were calculated. Lateralization of activation was assessed qualitatively and quantitatively. RESULTS: Tinnitus was lateralized in 35 patients (83%, 13 right-sided and 22 left-sided). Significant signal change (P(corrected) < 0.05) was found bilaterally in the primary and secondary AC, the IC and the MGB. Signal change was symmetrical in patients with bilateral tinnitus. In patients with lateralized tinnitus, fMRI activation was lateralized towards the side of perceived tinnitus in the primary AC and IC in patients with right-sided tinnitus, and in the MGB in patients with left-sided tinnitus. In healthy volunteers, activation in the primary AC was left-lateralized. CONCLUSION: Our paradigm adequately visualized the auditory pathways in tinnitus patients. In lateralized tinnitus fMRI activation was also lateralized, supporting the hypothesis that tinnitus is an auditory phantom phenomenon.

Amygdalohippocampal involvement in tinnitus and auditory memory.

CONCLUSION: The preliminary results suggest that in chronic unilateral tinnitus the contralateral amygdalohippocampal complex does seem to be involved in tinnitus perception of pure tones. OBJECTIVES: Functional neuroimaging studies have revealed that the hippocampus and amygdala are involved in tinnitus perception. The amygdala and hippocampus are supplied by the anterior choroidal artery. Selective amobarbital injections in the anterior choroidal artery result in a non-functional amygdalohippocampal area for 10 min. The aim of this study was to assess the influence of this procedure on tinnitus perception. PATIENTS AND METHODS: Amobarbital (80 mg in total) was injected selectively in two sessions in the left and right anterior choroidal artery in six male patients with tinnitus: four with unilateral tinnitus, two with bilateral tinnitus. Of the patients with unilateral tinnitus, three had right-sided tinnitus and one had left-sided tinnitus. The average age was 57.3 years (range 43-69). Average tinnitus duration was 5.3 years (range 1-10). The differences in visual analogue scale (VAS) scores before and after the amytal tests were analysed. RESULTS: Amytal injection ipsilateral to the side where the tinnitus was perceived resulted in a maximum of 30% tinnitus suppression, whereas amytal injection contralateral to the tinnitus side yielded a 60-70% tinnitus suppression in three patients with unilateral chronic tinnitus (>4 years). Only pure tone tinnitus was suppressed, white noise was not. Two patients with bilateral tinnitus had no suppression, irrespective of the tinnitus type. A third patient without clinical tinnitus suppression had tinnitus of more recent origin (1.5 years).

Primary and secondary auditory cortex stimulation for intractable tinnitus.

INTRODUCTION: Recent research suggests tinnitus is a phantom phenomenon based on hyperactivity of the auditory system, which can be visualized by functional neuroimaging, and transiently modulated by transcranial magnetic stimulation (TMS). We present the results of the first implanted electrodes on the primary and secondary auditory cortex after a successful TMS suppression. METHODS AND MATERIALS: Twelve patients underwent an auditory cortex implantation, 10 for unilateral and 2 for bilateral tinnitus, based on >50% suppression applying TMS. Results were analyzed for pure tone tinnitus and white noise tinnitus. RESULTS: TMS results in 77% pure tone tinnitus and 67% white noise reduction. Electrical stimulation via an implanted electrode results in a mean of 97% pure tone tinnitus and 24% white noise suppression. Mean Visual Analogue Scale score decreases from 9.5 to 1.5 for pure tone and from 8.8 to 6.8 for white noise postoperatively. DISCUSSION: Pure tone tinnitus might be the conscious percept of focal neuronal hyperactivity of the auditory cortex. Once visualized, this hyperactivity can be modulated by neurostimulation. CONCLUSION: The preliminary results of the first implantations suggest that patients with unilateral pure tone tinnitus are good surgical candidates for electrode implantation and permanent electrical stimulation of the auditory cortex, provided that the tinnitus is of recent origin and can be suppressed by TMS.

Activation of cortical and subcortical auditory structures at 3 T by means of a functional magnetic resonance imaging paradigm suitable for clinical use.

OBJECTIVES: Visualization of functional magnetic resonance imaging (fMRI) activation of subcortical auditory structures remains challenging because of the cardiac-related pulsatile movement of both the brainstem and the cerebrospinal fluid and involved, until now, special scanning, pre- and postprocessing techniques, which are not convenient in clinical settings. The aim of this study is to examine the activation in both cortical and subcortical auditory structures by means of an fMRI paradigm, which is suitable for clinical use. MATERIALS AND METHODS: Twenty subjects (13 volunteers and 7 patients) were examined on a 3 T imaging system with binaural musical stimulation. RESULTS: Both cortical and subcortical auditory structures are successfully visualized in volunteers and patients. CONCLUSIONS: Activation of both the cortical and subcortical auditory structures can be visualized by means of an appropriate fMRI setup at 3 T. This paradigm can easily be used in patients with tumors and/or hearing disorders.