Tinnitus distress: a paradoxical attention to the sound?

Tinnitus, the perception of sound in the absence of external stimuli, is often a disturbing symptom for which the underlying functional neuroanatomy still remains poorly understood. Most studies have focused solely on functional connectivity changes in the auditory cortex of tinnitus patients. The aim of this study was to investigate whether a correlation exists between tinnitus behavioural scores and functional brain connectivity of five resting-state networks comprising the auditory, the default mode, the external control left and right, and the salience network. For this purpose, a large sample of one hundred and thirty-five subjects underwent resting-state functional magnetic resonance imaging and their behavioural scores were obtained using clinical evaluations. Networks were extracted using independent component analysis, and functional connectivity patterns in the extracted networks were evaluated by a graph theoretical approach. The effects of tinnitus for each network were investigated by correlating the graph strength of all the regions with the tinnitus behavioural scores using stepwise fit regression analysis. Results indicated that alterations of functional interactions between key neural circuits of the brain are not limited to one single network. In particular, tinnitus distress showed a strong correlation with the connectivity pattern within and between the right executive control network and the other four resting-state networks, indicating that tinnitus distress is probably the consequence of a hyperactive attention condition. Among the behavioural scores, the strongest correlation was observed between age and hearing loss, while the tinnitus objective loudness was not correlated with any behavioural scores.

Differential electrophysiological correlates of panic disorder in non-pulsatile tinnitus.

AIMS: The prevalence of panic disorder (PD) reportedly is up to fivefold higher in people with tinnitus than it is in the general population. The brain networks in the two conditions overlap but the pathophysiological link remains unclear. In this study the electrophysiological brain activity is investigated in adults with non-pulsatile tinnitus with and without concurrent PD. METHODS: Resting-state EEGs of 16 participants with non-pulsatile tinnitus and PD were compared with those of 16 peers with non-pulsatile tinnitus without PD and as many healthy controls. The sLORETA technique was used to identify group-specific electrophysiological frequencies in the brain and to approximate the brain regions where differences occurred. The influence of distress was investigated and functional connectivity charted using the Region-of-Interest (ROI) approach (amygdala, anterior cingulate cortex (ACC), insula, precuneus). RESULTS: The comorbid group showed significantly diminished theta activity (p < 0.05) in the precuneus (BA7) compared to the tinnitus group without PD as well as in another region of the precuneus (BA31) as compared to the controls. Higher levels of distress influenced results in the tinnitus group without PD, while in those with PD a diminished connectivity was observed between the dorsal ACC and the other three ROIs as contrasted to the controls. CONCLUSIONS: Adults with non-pulsatile tinnitus and concurrent PD show differential brain activity patterns to tinnitus only sufferers and healthy controls. Higher levels of distress may modulate brain activity in the absence of PD. Screening for distress is recommended in both clinical and research settings.

Tinnitus and anxiety disorders: A review.

BACKGROUND: The most common form of tinnitus is a subjective, auditory, and distressing phantom phenomenon. Comorbidity with depression is high but other important psychiatric disorders such as anxiety disorders have received less attention. The current paper reviews the literature on the associations between tinnitus and anxiety disorders and the underlying pathophysiology, and discusses the clinical implications. METHODOLOGY: PubMed and Web of Science were searched for all articles published up until October 2014 using combinations of the following search strings "Tinnitus", "Anxiety disorder", "Panic Disorder", "Generalized Anxiety Disorder", "Post traumatic stress disorder", "PTSD" "Social Phobia", "Phobia Disorder", "Obsessive Compulsive Disorder", "Agoraphobia". RESULTS: A total of 117 relevant papers were included. A 45% lifetime prevalence of anxiety disorders is reported in tinnitus populations, while an important overlap in associated (sub)cortical brain areas and cortico-subcortical networks involved in attention, distress, and memory functions is suggested. A disturbed hypothalamic-pituitary-adrenal axis function can be found in tinnitus and in anxiety disorders but, in comorbidity, the direction of the dysfunction is unclear. CONCLUSION: Comorbidity is high and screening for and treatment of anxiety disorders is recommended in moderate to severe tinnitus, as, given the overlap in the structural and functional brain circuitries involved, theoretically, their management could improve (subjective) levels of tinnitus although further empirical research on this topic is required.

Identifying tinnitus-related genes based on a side-effect network analysis.

Tinnitus, phantom sound perception, is a worldwide highly prevalent disorder for which no clear underlying pathology has been established and for which no approved drug is on the market. Thus, there is an urgent need for new approaches to understand this condition. We used a network pharmacology side-effect analysis to search for genes that are involved in tinnitus generation. We analyzed a network of 1,313 drug-target pairs, based on 275 compounds that elicit tinnitus as side effect and their targets reported in databases, and used a quantitative score to identify emergent significant targets that were more common than expected at random. Cyclooxigenase 1 and 2 were significant, which validates our approach, since salicylate is a known tinnitus generator. More importantly, we predict previously unknown tinnitus-related targets. The present results have important implications toward understanding tinnitus pathophysiology and might pave the way toward the design of novel pharmacotherapies.CPT Pharmacometrics Syst. Pharmacol. (2014) 3, e97; doi:10.1038/psp.2013.75; published online 29 January 2014.

[Neuromodulation as an intervention for addiction: overview and future prospects]. / Neuromodulatie als interventie voor verslaving: stand van zaken en toekomstperspectief.

BACKGROUND: In recent years several neuromodulation techniques have been introduced as interventions for addiction. AIM: To review and discuss studies that have investigated the effects of treating addiction by means of electroencephalography (EEG) neurofeedback, real-time functional magnetic resonance imaging (rt-fMRI) neurofeedback, transcranial magnetic stimulation/transcranial direct current stimulation (TMS/tDCS) and deep brain stimulation (DBS). METHOD: We reviewed the literature, focusing on Dutch studies in particular. RESULTS: Studies using EEG neurofeedback were shown to have positive effects on drug use, treatment compliance, and cue reactivity in patients with cocaine and alcohol dependence. A pilot study investigating the effects of rt-fMRI neurofeedback on nicotine dependent patients showed that modulation of the anterior cingulate cortex can decrease smokers' craving for nicotine. In several studies decreased craving was found in alcohol dependent patients after TMS or tDCS stimulation of the anterior cingulate cortex or the dorsolateral prefrontal cortex. The first DBS pilot studies suggest that the nucleus accumbens is a promising target region for the treatment of alcohol and heroin dependence. CONCLUSION: Neuromodulation provides us with a unique opportunity to directly apply neuroscientific knowledge to the treatment of addiction. However, more research is needed to ensure the efficacy, safety and feasibility of the various neuromodulation techniques that are now available.

Surgical brain modulation for tinnitus: the past, present and future.

Tinnitus treatment has traditionally been restricted to ENT surgeons, audiologists, psychologists and psychiatrists. Recently, both basic and clinical research has focused on the brain's involvement in the generation of tinnitus, opening the tinnitus field up to neurologists and neurosurgeons specialized in the field of tinnitus. Non-pulsatile tinnitus can be considered an auditory phantom phenomenon, analogous to phantom pain, both with regards to pathophysiological mechanisms, clinical characteristics, and treatment approaches. Thus the understanding of tinnitus has benefited a lot from translating available knowledge of the somatosensory (pain) system to the auditory system. A literature review of neuromodulatory approaches to tinnitus is integrated in a single center's experience with invasive neuromodulation treatments for tinnitus. This is compared to findings from neuromodulatory treatment of chronic pain syndromes. The past, present and future options for functional neurosurgical approaches are outlined. In the past only destructive approaches were used, consisting of nerve lesions and frontal lobotomies. Presently neurostimulation trials are ongoing evaluating the effect of auditory cortex stimulation, frontal cortex stimulation, thalamic (VIM) and caudate stimulation as well as amygdalohippocampal stimulation, yielding suppression rates between 10 and 70%. Further potentially promising targets include the anterior cingulate, the medial geniculate bodies (MGB), the periaqueductal gray/ tectal longitudinal column (PAG/TLC), the dorsal cochlear nucleus, as well as the C2 and trigeminal nerve. Understanding tinnitus and its potential neuromodulation treatments is relatively simple for a neurosurgeon specialized in pain or a pain physician, based on the pathophysiological and clinical analogies. Similarly to pain a multidisciplinary approach can be advocated, and in view of the epidemiology and amount of suffering associated with this enigmatic symptom further investment in possible neuromodulation treatments is warranted.

Contralateral parahippocampal gamma-band activity determines noise-like tinnitus laterality: a region of interest analysis.

Tinnitus is described as an auditory perception in the absence of any external sound source. Tinnitus loudness has been correlated to sustained high frequency gamma-band activity in auditory cortex. It remains unknown whether unilateral tinnitus is always generated in the left auditory cortex, irrespective of the side on which the tinnitus is perceived, or in the contralateral auditory cortex. In order to solve this enigma source localized electroencephalographic (EEG) recordings of a homogenous group of unilateral left and right-sided tinnitus patients presenting with noise-like tinnitus was analyzed. Based on a region of interest analysis, the most important result of this study is that tinnitus lateralization depended on the gamma-band activity of the contralateral parahippocampal area. As for the auditory cortex no differences were found between left-sided and right-sided tinnitus patients. However, in comparison to a control group both left and right-sided tinnitus patients had an increased gamma-band activity in both the left and right primary and secondary auditory cortex. Thus whereas in tinnitus the primary and secondary auditory cortices of both sides are characterized by increased gamma-band activity, the side on which the tinnitus is perceived relates to gamma-band activity in the contralateral parahippocampal area.

Insular lateralization in tinnitus distress.

Tinnitus affects 15% of the population. Of these 1-2% are severely disabled by it. The role of the autonomic system in tinnitus is hardly being investigated. The aim of this study is to investigate the relationship between tinnitus distress and lateralization of the anterior insula, known to be involved in interoceptive awareness and (para)sympathetic changes. For this, Tinnitus Questionnaire scores are correlated to Heart Rate Variability markers, and related to neural activity in left and right anterior insula. Our results show that tinnitus distress is related to sympathetic activation, in part mediated via the right anterior insula.

Validation of the Mini-TQ in a Dutch-speaking population: a rapid assessment for tinnitus-related distress.

OBJECTIVE: Up to 30% of the adult population experiences tinnitus at some point in life. The aim of the present study was to validate the Mini-Tinnitus Questionnaire (TQ) in a Dutch-speaking population for measuring tinnitus-related distress and compare it with the extended version normally used in clinical practice and research. METHODOLOGY: We assessed 181 patients at the Tinnitus Research Initiative clinic of Antwerp University Hospital. Twelve items from the TQ chosen by Hiller and Goebel based on the optimal combination of high item correlation, reliability, and sensitivity were selected and correlated to the different subscale and global scores of the TQ. Internal consistency was evaluated using Cronbach's alpha coefficient, and the Guttman split-half coefficient was used to confirm reliability. RESULTS: Correlation to the global TQ score was .93, internal consistency was .87, and reliability was .89. This study further revealed that the Mini-TQ correlates better with the different subscales of the TQ in the Dutch-speaking population. The convergence validity was confirmed, ensuring that this new instrument measures distress. In addition, the norms suggested by Hiller and Goebel were verified and established. CONCLUSION: Based on these results, the Mini-TQ is recommended as a valid instrument for evaluating tinnitus-related distress in Dutch-speaking populations for a compact, quick, and economical assessment.

The psychometric properties of the Tinnitus Handicap Questionnaire in a Dutch-speaking population.

OBJECTIVE: The aim of the study is to translate and validate the tinnitus handicap questionnaire (THQ) for a Dutch-speaking population. The factor structure of the questionnaire, the reliability and the validity is determined. Furthermore, a statistical comparison with the original English version of the tinnitus handicap questionnaire is performed. METHODOLOGY: We assessed 101 patients at the Tinnitus Research Initiative clinic of Antwerp University Hospital. Twenty-seven Dutch items from the tinnitus handicap questionnaire by Kuk et al. [(1990), Ear Hear11:434-45.] were obtained by the process of translation and back translation. The factor structure, internal consistency, was evaluated using Cronbach's alpha coefficient and item correlations were used to confirm reliability. The construct validity was confirmed with a visual analogue scale for loudness and distress, awareness, annoyance, the Tinnitus Questionnaire (TQ), the mini-Tinnitus Questionnaire, the Hospital Anxiety and Depression Scale (HADS), the Beck Depression Inventory (BDI) and the Profile of Mood State (POMS), ensuring that this new instrument measures the tinnitus handicap. RESULTS: This study demonstrates that the Dutch version of the tinnitus handicap questionnaire is a reliable (Cronbach's alpha coefficient α = 0.93) and valid measure of self-perceived tinnitus-related distress [with visual analogue scale for loudness (r = 0.39) and distress (r =0.45), awareness (r = 0.39), annoyance (r = 0.57), the Tinnitus Questionnaire (r = 0.82), the mini-Tinnitus Questionnaire (r = 0.79), the Hospital Anxiety and Depression Scale (r = 0.62) and the Beck Depression Inventory (r = 0.32)]. The psychometric properties are in line with previous findings on the English version with regard to reliability and validity. However, the items in the subscales differ from the English version. While the English version has three subscales, our version has only two subscales. Yet, the English version reports that for the three factors, there is a low internal consistency and low correlation among the different items. For the Dutch-speaking version, both factors show a very high reliability and validity. CONCLUSIONS: The tinnitus handicap questionnaire is suitable for assessing the handicapping effects of tinnitus among a Dutch-speaking population in both clinical and research settings.

Mindreading in individuals with an empathizing versus systemizing cognitive style: An fMRI study.

Our fMRI study compares the neural correlates of face-based mindreading in healthy individuals with an empathizing (n=12) versus systemizing cognitive style (n=12). The empathizing group consists of individuals that score high on empathizing and low on systemizing, while the systemizing group consists of individuals with an opposite cognitive pattern. We hypothesize that the empathizing group will show stronger simulation-type neural activity (e.g., in mirror neuron areas, medial prefrontal cortex, anterior cingulate cortex) or simulation-related neural activity (e.g., in areas involved in perspective taking and experiential processing) compared to the systemizing group. As hypothesized, our study reveals that the empathizing group shows significantly stronger activity in mirror neuron areas of the brain, such as the left inferior frontal gyrus and inferior parietal lobe, and in temporal areas involved in perspective taking and autobiographical memory. Moreover, the empathizing group, but not the systemizing group, shows activity in the medial prefrontal cortex and anterior cingulate cortex which have been related to simulation-type neural activity in the brain and are central to mindreading. Also, the systemizing group shows significantly stronger activity in the left parahippocampal gyrus. In conclusion, both the empathizing and systemizing individuals show simulation-type and simulation-related neural activity during face-based mindreading. However, more neural activity indicative of simulation-based processing is seen in the empathizing individuals, while more neural activity indicative of non-simulation-based processing is seen in the systemizing individuals.

Burst transcranial magnetic stimulation: which tinnitus characteristics influence the amount of transient tinnitus suppression?

BACKGROUND: Transcranial Magnetic Stimulation (TMS) is a method capable of temporarily suppressing tinnitus by delivering tonic or burst stimuli. Burst TMS has a high interindividual variability and low effect size. Tinnitus type and laterality, tinnitus-related distress, and tinnitus duration might contribute to this large individual variation. METHODS: The effect of burst TMS on the auditory cortex in 100 male individuals is evaluated with coil placed over the auditory cortex. For unilateral tinnitus, this coil was placed contralaterally to the tinnitus, whilst for bilateral tinnitus the coil was placed over the right auditory cortex. The site of maximal tinnitus suppression is determined using 1-Hz stimulation with five pulses per burst (intensity of the stimulation set at 90% of the motor threshold). When tinnitus suppression is noted, the patients are asked to estimate the decrease in tinnitus in percentage using the numeric rating scale. The procedure is repeated with stimulations at 5, 10 and 20 Hz, each stimulation session consisting of 200 pulses. RESULTS: Results demonstrate that burst stimulation can decrease the perceived tinnitus intensity transiently in 57.83% of the patients. Patients with bilateral tinnitus respond better to burst TMS than patients with unilateral tinnitus and highly distressed patients presenting with unilateral pure tone tinnitus fail to bust TMS. CONCLUSIONS: Burst TMS modulates both unilateral and bilateral tinnitus, both high and low distress and both pure tones and narrow band tinnitus. However, the suppression effect is moderated by tinnitus type and laterality, tinnitus-related distress, and tinnitus duration.

An easy and versatile embedding method for transverse sections.

In several research areas, transverse sections are indispensable for studying structural aspects of specimens. However, the oriented embedding of small cylindrical samples can become problematic, especially when transverse sections at right angles to the main axis of the object are desired. Here, we describe an easy and low-cost technique for oriented embedding of small (psi < 500 micro m) as well as of larger specimens (psi > 500 micro m). The usefulness of the technique is demonstrated for roots and stamens of Arabidopsis thaliana and for adventitious roots of Asplenium demerkense, as examples of small and larger cylindrical samples, respectively. Furthermore, several types of resin (glycol methacrylate, epoxy and acrylic resins) were successfully tested, showing the applicability of the technique for light and electron microscopy and for immunolocalizations. In conclusion, the principle of the technique can be extended to several resins and a wide variety of specimen types, such as stems, leaves and textile fibres. The originality of the technique lies in its simplicity combined with its high efficiency to produce well-oriented transverse sections.

Temporal control of rhythmic performance: a comparison between young and old adults.

Young (20-30-year-old) and older (60-76-year-old) adults were tested on two measures of rhythmic performance. The first involved tapping at the subject's own preferred rate, a measure of so-called internal tempo. Over five sessions of testing, tapping rates were consistently and significantly slower on average in the older subjects than the younger ones, but rates were not relatively more variable in older subjects (i.e., coefficients of variation, standard deviation/mean, did not differ between the older and young people). In addition, both old and younger subjects performed on a synchronized-tapping and continuation task of the type used by Wing and Kristofferson (1973, Perception and Psychophysics, 14, 3-12). Target interresponse times were 300, 400, 500, 600, and 700 ms, and in all cases interresponse intervals produced by both the old and young adults matched the target times very closely. Wing and Kristofferson's analytical procedure was used to decompose tapping variance into that attributable to timing processes and that resulting from motor implementation of the timing signal. Both sorts of variance increased with increasing target interresponse time (with timer variance increasing most markedly), but no difference was found in either type of variance in comparisons between the old and younger subjects. If the internal tempo measure directly reflects the speed of internal timing processes, the data suggest that such processes are slower, but not relatively more variable, in older than younger subjects (consistent with some previous evidence and speculation), but that the calibration of performance forced by the synchronization task will make such an age-related difference in "internal clock speed" unobservable on synchronized-tapping tasks.

Timing in aging: the role of attention.

This paper questions the issue of attentional capacity in changes in time processing with aging. Performances of young and old subjects were compared in a task involving an attentional sharing between three concurrent estimations of durations (6, 8, or 10 s). Depending upon the experimental condition, the subjects were instructed to simultaneously focus their attention onto one, two, or three target stimuli. The results showed that increased difficulty of the task, that is the increased number of concurrent temporal targets to monitor at a time, led to a greater disruption of timing performance in elderly people than in young adults. Temporal judgments of elderly were less accurate and more variable than those of young adults in the attentional sharing conditions (two or three target durations). The greater sensitivity to interference effects observed in the elderly is discussed in terms of age-related reduction of attentional resources and working-memory deficits.

Polyarteritis nodosa type vasculitis in a patient with familial Mediterranean fever treated with cyclosporin A.

Patients with amyloidosis secondary to familial Mediterranean fever (FMF) are known to tolerate cyclosporin A poorly. We report a case of severe cyclosporin toxicity in a patient with FMF amyloidosis who underwent kidney transplantation. The clinical syndrome consisted of severe gastrointestinal, neuromuscular, and psychiatric disturbances. Histological examination of the transplanted kidney revealed vasculitis of the polyarteritis nodosa type. We hypothesize that FMF patients are more vulnerable to the acute vascular toxicity of cyclosporin due to defective inhibition of complement activation, leading to a widespread vasculitis of the polyarteritis nodosa type.

Salivary gland involvement as initial presentation of Wegener's disease.

We describe a case of Wegener's disease with massive painful bilateral submandibular gland enlargement as the presenting symptom. The diagnosis was based on histologically documented nasal mucosa involvement, focal necrotizing glomerulonephritis, episcleritis and anti-neutrophil cytoplasmic antibody.

Fever of unknown origin in the 1980s. An update of the diagnostic spectrum.

OBJECTIVE: To determine the relative proportions of the diagnostic categories in patients with fever of unknown origin who were examined in the 1980s. STUDY DESIGN: Prospective case series. SETTING: General Internal Medicine Service based at University Hospital, Leuven, Belgium. PATIENTS: One hundred ninety-nine consecutive patients meeting the classic criteria of fever of unknown origin who were treated in the 1980s. MAIN OUTCOME MEASUREMENT: The final diagnosis established at discharge or during follow-up. RESULTS: Infections were found in 45 patients (22.6%), tumors were found in 14 (7%), multisystem diseases were found in 42 (21.5%), drug-related fever was found in six (3%), factitious fever was found in seven (3.5%), habitual hyperthermia was found in five (2.5%), miscellaneous diseases were found in 29 (14.5%), and no diagnosis was reached in 51 (25.6%). CONCLUSIONS: Tumors were a less important cause of fever of unknown origin in the 1980s. The same holds true for some infectious diseases, such as abscesses and hepatobiliary disorders. Multisystem diseases were more frequently found, and the number of undiagnosed cases increased. Although these shifts in the disease spectrum in fever of unknown origin most probably resulted from a constellation of factors, we suspect that these changes are mainly due to easy and early diagnosis by new diagnostic modalities, such as ultrasonography and computed tomography, of previously common causes of fever of unknown origin.

SLE and acute Addisonian crisis due to bilateral adrenal hemorrhage: association with the antiphospholipid syndrome.

This report describes a 68-year-old woman with SLE and positive antiphospholipid antibodies who developed an acute Addisonian crisis due to bilateral adrenal hemorrhage. We suggest that adrenal bleeding can be part of the thrombo-embolic complications seen in the secondary antiphospholipid syndrome.

Occult tuberculous postpneumonectomy space empyema four years after lung resection.

We describe a patient in whom a tuberculous postpneumonectomy empyema developed 4 years after resection for lung cancer. The clinical presentation was dominated by non-specific constitutional symptoms, without any chest complaints. A computed tomographic scan of the chest suggested inflammation in the postpneumonectomy space. Ultimately Mycobacterium tuberculosis was cultured from material aspirated by needle thoracocentesis. To our knowledge this is the first report of a tuberculous postpneumonectomy empyema complicating resection for cancer.