Tinnitus and insomnia: Is hyperarousal the common denominator?

Sleep Medicine Reviews 17 (2013) 65e74

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Sleep Medicine Reviews journal homepage: www.elsevier.com/locate/smrv

THEORETICAL REVIEW

Tinnitus and insomnia: Is hyperarousal the common denominator? Elisabeth Wallhäusser-Franke a, *, Michael Schredl b, Wolfgang Delb a a b

Medical Faculty Mannheim, Heidelberg University, Department of Phoniatrics and Audiology, Tridomus House C, Ludolf-Krehl-Str. 13-17, 68167 Mannheim, Germany Central Institute of Mental Health, Sleep Research, J 5, 68159 Mannheim, Germany

a r t i c l e i n f o

s u m m a r y

Article history: Received 7 February 2012 Received in revised form 12 April 2012 Accepted 13 April 2012 Available online 30 June 2012

Tinnitus is an auditory sensation that is generated by aberrant activation within the auditory system. Sleep disturbances are a frequent problem in the tinnitus population. They are known to worsen the distress caused by the tinnitus which in turn worsens sleep quality. Beyond that, disturbed sleep is a risk factor for mental health problems and distressing tinnitus is often associated with enhanced depressivity, anxiety, and somatic symptom severity. Moreover there is evidence that therapies which alleviate tinnitus-related distress have a positive influence on sleep quality and help interrupt this vicious cycle. This suggests that distressing tinnitus and insomnia may both be promoted by similar physiological mechanisms. One candidate mechanism is hyperarousal caused by enhanced activation of the sympathetic nervous system. There is increasing evidence for hyperarousal in insomnia patients, and animal models of tinnitus and insomnia show conspicuous similarities in the activation pattern of limbic and autonomous brain regions. In this article we review the evidence for this hypothesis which may have implications for therapeutic intervention in tinnitus patients with comorbid insomnia. Ó 2012 Elsevier Ltd. All rights reserved.

Keywords: Tinnitus Sleep Insomnia Hyperarousal Depressivity Anxiety Somatic symptom severity Sympathetic nervous system Hypothalamus-pituitary-adrenal (HPA) axis Ageing

Background Sleep disturbances are the second most frequent comorbid condition among tinnitus patients.1 Tinnitus and insomnia tend to intensify one another, and successful tinnitus therapies often improve insomnia complaints.2 Studies exploring the relation between tinnitus and insomnia are sparse, however.1,3e7 In this review, we put forward the hypothesis that hyperactivity of the sympathetic nervous system might promote the emergence of a distressing tinnitus and at the same time might be the underlying etiologic factor in primary insomnia. In addition, we include data about sleep quality in persons with tinnitus from a survey with 4705 participants and discuss physiological evidence for an association of hyperactivity in the sympathetic nervous system with distressing tinnitus and insomnia, respectively. Tinnitus Tinnitus is the perception of a sound that originates from selfgenerated abnormal neural activity in the auditory system, and * Corresponding author. Tel.: þ49 621 383 6919; fax: þ49 621 383 6923. E-mail addresses: [email protected] (E. Wallhäusser-Franke), [email protected] (M. Schredl), wolfgang.delb@ medma.uni-heidelberg.de (W. Delb). 1087-0792/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.smrv.2012.04.003

that is heard only by the affected person. Tinnitus is rather common,8 it is considered to be a symptom that is associated with various diseases and that may be a side effect of medications. The majority habituate to their tinnitus, but about 10e20% of the tinnitus patients feel severely handicapped.9 The prevalence of tinnitus increases with age and more men than women are affected.8 Although tinnitus is usually accompanied by cochlear impairment,10 and its perceived frequency is usually located within the frequency range of the hearing impairment,11 tinnitus is not an automatic consequence of hearing impairment. Tinnitus complaints can be classified into a category associated with its perception like persistence of awareness, perceived loudness and pitch, and into a category reflecting reactions to this percept, i.e., the distress associated with it. The subjective loudness which is a relevant tinnitus feature for the affected individual can be derived only from subjective rating, because physiological loudness measures deviate substantially.12 Likewise auditory features are not correlated well with tinnitus-related distress.13 On the contrary, highly distressing tinnitus is often accompanied by depressive symptoms (depressivity), anxiety, somatic symptom severity, and insomnia.14e16 Several ways of interaction between tinnitus and insomnia have been proposed. For example reduced masking by environmental sounds because of low external noise levels during sleep onset may

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Physiological and anatomical changes associated with tinnitus Since tinnitus often persists after auditory nerve transsection,17 processes in the central auditory system supposedly play a major role in its maintenance even though the primary cause for tinnitus is very likely to be associated with cochlear impairments.10 As a conscious and often continuous percept, tinnitus is thought to require continued activation of cortical networks engaged in conscious perception.18 In accordance with that assumption, brain imaging studies reported changes in the activation patterns of cortical and subcortical auditory areas as well as in areas related to emotion and attention (review in19). In support of a crucial role of attention for the tinnitus perception is the observation that activity levels in the auditory cortex of tinnitus patients are reduced by cognitive distraction,20 and that attention to the tinnitus is more pronounced in patients with severe tinnitus-related distress.21 In addition to activation of the auditory cortex, activation of the amygdala22 as well as the anterior cingulate and insular cortices were shown (review in19). Morphometric alterations associated with chronic tinnitus are gray-matter increases in the auditory thalamus as well as gray-matter decreases in the auditory cortex, and in the subcallosal region including nucleus accumbens23e25 Cortical gray matter decreases may, however, be a consequence of the hearing loss that is usually accompanying tinnitus and not of the tinnitus itself.26 Besides that functional connectivity between anterior cingulate cortex and right frontal lobe was found to be correlated with tinnitus-related distress,18 and functional connectivity was increased between auditory cortex and the amygdala.27 Finally, magnetoencephalography (MEG) and electroencephalography (EEG) recordings suggest that tinnitus is associated with decreased alpha and increased delta and gamma-oscillatory brain activity.28e31

normal auditory input. This is thought to be a consequence of reduced lateral inhibition in this area of auditory cortex (edge effect). Changes in oscillatory brain activity are observed in MEG and EEG recordings of tinnitus patients (e.g.,29e31,40), and there is direct evidence that certain gamma oscillations relate to the tinnitus percept.28 Tinnitus-related distress, i.e., the reaction on the tinnitus percept, appears to be associated with activation of cortical and subcortical areas concerned with the processing of emotions and with brainstem centres of the autonomic nervous system.41 The neurophysiological tinnitus model41,42 proposes that tinnitus-related distress is the result of a conditioning process by which a stressful, unconditioned stimulus is linked to the tinnitus signal. This process is supposed to be under control of the amygdala which in turn controls the autonomic nervous system. Activation in this system supposedly prevents habituation to the tinnitus signal.13 This model is supported by the observation that the amygdala a crucial structure for the emotional evaluation of sensory stimuli as well as for emotional learning and conditioning43 is highly active during tinnitus induction in animals,33,44 and that temporarily sedating the amygdala in patients may temporarily reduce the tinnitus.22 In accord with the neurophysiological model, a decrease of autonomic reactions to the tinnitus during the initial stages of habituation therapy is observed and a decrease in the level of tinnitus-related distress can be achieved without changes in tinnitus loudness.45,46 A recent model integrates and extends the major aspects of the neurophysiological and the TCD model. It is based on observations in tinnitus patients of altered activation in the auditory cortex and in striatal areas that belong to a general appraisal network.24 In this model the cortio-striatal interaction is thought to act as a noisecancellation system tuning out uninformative background noise by dampening abnormal activity in auditory brain centres. For some as yet unknown reason, tinnitus-related oscillatory brain activity which is thought to arise as described by the TCD model and fed into this system via the amygdala escapes cancellation.

Tinnitus mechanisms The psychoacoustical approach associates the emergence of tinnitus with alterations in the auditory system which are related to a hearing deficit. It concentrates on the psychophysical tinnitus characteristics and is substantiated by a vast body of animal data.11,32e35 In this context, tinnitus is thought to be heard, if spontaneous neural activity exceeds the level that is perceived as silent or if spontaneous activity is excessively synchronized giving rise to patterned activity. As tinnitus may persist after sectioning of the auditory nerve17 continuing tinnitus was furthermore supposed to be a consequence of central gain adaptation which is observed following acute hearing loss.11 Aberrant activation should be present at the cortical level since conscious perceptions such as tinnitus presumably arise cortically (review in15). Eggermont and Roberts36 propose that peripheral damage causes a loss of central inhibition, and that this leads to increased excitation and reorganization in auditory cortex. This is supported by the finding of a down-regulation of inhibitory amino acid neurotransmission in the central auditory pathway of animals in response to cochlear hearing impairment.37 According to the thalamocortical dysrhythmia (TCD) model38,39 loss of auditory input into the thalamocortical auditory feedback loop via the ascending auditory pathway results in excessive thalamic cell membrane hyperpolarization which causes lowfrequency oscillations. This kind of activity is normal during delta sleep, but is seen as pathological when occurring continuously and with large scale coherence during wake.38 Since the ascending auditory system is topographically organized, fast frequency gamma oscillations are thought to arise at the boundary between locations receiving reduced auditory input and locations with

Current tinnitus therapies Essentially, there exist two different therapeutic approaches that are combined in some of the current tinnitus therapies.47 One approach focuses on the reduction of the tinnitus percept, whereas the other focuses on a reduction of the reaction to this percept. Evaluation of therapeutic success and comparison of different approaches is complicated by the circumstance that there is no universally used measure to scale tinnitus severity. Several measures are currently being used and a modified scaling has just been proposed.48 Many tinnitus patients benefit from stimulation of the auditory system either by sound or electrically, and the tinnitus perception is often diminished by the use of hearing aids or cochlear implants (49 review in50). Therapeutic sound comprises either the whole audible frequency spectrum,47 the region of impaired hearing excluding the tinnitus frequencies (notch filtering51), or the frequency spectrum of the sound deprived regions including the tinnitus frequencies.52 Notch filtering the energy spectrum of auditory stimuli around the individual tinnitus frequency is thought to silence the auditory neurons involved in tinnitus perception by means of lateral inhibition.51 The alternative approach, stimulating the frequency range affected by the hearing impairment is motivated by the hypothesis that hyperactivity of neurons with characteristic frequencies at the tinnitus pitch is caused by a loss of input resulting in a compensatory increase in gain, and that hyperactivity of these neurons can be reduced by stimulating them.11 Though auditory stimulation suppresses the conscious perception of tinnitus in a substantial portion of the tinnitus patients, the exact mechanism and consequently the most effective type of stimulation still has to be

increase awareness of the tinnitus sensation. Furthermore anxious focussing on the tinnitus sound and worries about the tinnitus before falling asleep or following awakening during the night might prolong the time that is needed to return to sleep.13

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determined. Moreover this effect is present predominantly during stimulation therefore it often resembles masking and should not be confounded with constant elimination of the tinnitus. Reductions of tinnitus loudness have also been achieved by electrical stimulation paradigms aiming at the dorsolateral prefrontal cortex.53 Moreover deep brain stimulation placed in subcortical forebrain or thalamic regions,54 as well as direct electrical stimulation of the auditory cortex55 successfully reduced the perceived tinnitus loudness. The latter approaches are very invasive and therefore can only be accepted as a last chance but not as standard therapy. For most tinnitus patients treatments to reduce the tinnitus perception are not successful, whereas attempts to reduce the reaction to the tinnitus, i.e., the tinnitus-related distress are more promising. Though there are a number of experimental approaches reported in the literature (review in15), at present therapies such as tinnitus retraining therapy (TRT) and cognitive-behavioural therapy (CBT) are most successful in reducing tinnitus-related distress.13,45,46 Notwithstanding the popularity of the TRT method as a treatment for tinnitus, there exist an insufficient number of controlled clinical trials that ascertain its effectiveness.56 TRT is based on the neurophysiological tinnitus model outlined above and combines psychoeducative counselling with broad band auditory stimulation. Counselling aims to reduce the emotional significance of the tinnitus signal which is thought to lessen coupling between the tinnitusrelated activation within the auditory system and activation of the limbic and autonomic nervous systems. This should lead to eased physiological responses which represent stressors by themselves, it brings forth habituation of the emotionalephysiological reaction on the tinnitus signal and eventually also habituation to the tinnitus signal.13 CBT aims at replacing negative thoughts about the tinnitus with more positive thoughts and combines this with behavioural and relaxation training, thereby aiming to reduce the emotional autonomous response to the tinnitus signal. The results of various studies indicate a positive overall effect of CBT not only for tinnitusrelated distress but also on mood measures.45 Although CBT is among the most validated treatment approaches used in tinnitus management, not every patient receiving this treatment shows clinically significant improvement (e.g.,46). At present, there is no generally accepted drug therapy for the treatment of tinnitus. Although pharmacological treatments of chronic tinnitus are not uncommon as indicated by a recent review among general practioners and otolaryngologists in several European countries and the US.57 This survey furthermore indicates offlabel use of a wide variety of therapeutic drugs and it indicates country-specific prescription preferences. Various comprehensive reviews on the pharmacological treatment of tinnitus have been published recently (review32,58,59), therefore only a few aspects and very recent literature will be described here. Lidocaine, a local anaesthetic so far appears to be the only compound that reliably eliminates the tinnitus percept. Though, lidocaine is not suitable for therapy, because it has to be injected intravenously, it has frequent serious side effects and its effects on tinnitus loudness are of very short duration (review in60). Some antidepressants are beneficial for tinnitus patients with comorbid depressivity (review in58,61), likewise some benzodiazepines are effective for tinnitus associated with anxiety (review in58,62). Recently, the centrally acting muscle relaxant cyclobenzaprine which has structural similarity to the antidepressant amitryptiline was shown to reduce tinnitus severity.62 Furthermore, several studies indicate that acamprosate, originally used to treat alcohol dependence,63,64 the nicotinergic and N-methyl-D-aspartate (NMDA) antagonist neramexane,65 and the neurohormone melatonine66 may reduce tinnitus severity. Moreover combinations of various pharmaceuticals such as the combination of an antidepressant, an antipsychotic and the

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benzodiazepine clonazepam,67 or the combination of melatonin with an antidepressant68 or an enhancer of microcirculation69 reduced tinnitus severity. In particular the success of melatonin is interesting in the present context. Melatonin possibly has an antidepressant effect, it improves sleep, and it is thought to be protective against exaggerated sympathetic drive.70 Not surprisingly, all melatonin studies report improvement in sleep quality66,68,69 which by itself is known to reduce tinnitus-related distress.2 Currently auditory stimulation therapies that aim at reducing tinnitus loudness and behavioural therapies that aim at reducing tinnitus-related distress are the therapies that appear to specifically address the tinnitus perception or the related distress with notable success, and they are low in potential complications. Insomnia Similar to the diagnostic criteria of tinnitus, insomnia is defined as being chronic after about six months and often leads to substantial impairments in life quality. Sleep problems are a frequent symptom of many psychiatric and medical disorders, but they can also exist as a separate symptom, then called primary insomnia (International classification of sleep disorders - 2nd edition, ICSD-271). Typical in primary insomnia, the focus of this review, is prolonged sleep onset latency, increased wake time after sleep onset and reduced slow wave sleep.72 Subjects usually experience non-restorative sleep, they underestimate the time that was actually spent asleep, and subjective symptoms are often perceived as being more severe than deviations detected by polysomnographic recordings.73 Insomnia negatively affects attention, concentration, and mood during waking, resulting in day-time fatigue and increased irritability.72 Data of several population-based studies from different countries agree that approximately 30% of the adults report one or more of the symptoms of insomnia with an increased prevalence in women and older adults.74 It is estimated that the majority of people with insomnia have an increased risk for comorbid medical disorders, and similar to tinnitus there is a high comorbidity between insomnia and depressivity as well as anxiety.75 Longitudinal studies indicate that sleep disturbances rather precede than follow the occurrence of mood disorder, and that insomnia can independently predict the development of a new depressive episode one to three years later,75 whereas anxiety disorders preceded insomnia in most instances.76 Insomnia-related brain changes Whereas sleep architecture in general is largely intact, insomnia is associated with signs of physiological arousal such as abnormal hormone secretion, increased whole body and brain metabolic activation, elevated heart rate and sympathetic nervous system activation (ICSD-2,71). Moreover the spectral content of the sleep EEG is shifted towards elevated beta and gamma power which also is taken as a sign of enhanced physiological arousal.76 More specifically, increased beta-activity was associated directly with the severity of sleep difficulties,77 and animal studies showed that inappropriate arousals can be blocked by lesions in the limbic and arousal systems.78 Neuroimaging studies during sleep in insomniacs are rare. While Smith et al.79 reported lower overall blood flow during non-rapid eye movement (NREM) sleep in insomniacs than in healthy controls, Nofzinger et al.80 showed that metabolism in the brain’s arousal systems and in cortical and subcortical limbic areas such as in the amygdala exhibited a less marked reduction between wake and NREM sleep in insomniacs in comparison to healthy sleepers. In contrast, in insomniacs brain metabolism was lower in several cortical areas and in the brainstem reticular formation during the waking state. Another functional magnetic resonance imaging (fMRI) study corroborated frontal hypoactivation during waking in insomniacs.81 Taken together, the

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imaging studies suggest hyperarousal during sleep together with hypoarousal during waking and a less pronounced difference in brain activation patterns between sleep and waking in insomniacs. Orbitofrontal and parietal gray-matter and hippocampal volume are reduced in chronic insomnia.82 Furthermore, reductions in hippocampal volume which according to animal data might be a consequence of decreased neurogenesis and dendritic branching83 correlate with the subjectively perceived severity of insomnia.82 Experimentally inducing sleep deficits in normal sleepers by repeatedly waking them up during consecutive nights reproduced some of the alterations seen in insomnia like an increase of metabolic rate during the night as well as increased fatigue and decreased vigour during the day.76 Other changes common in patients with insomnia such as increased metabolic rate and body temperature during the day, false estimation of actual sleeping time, or an increase in depressivity and anxiety scores, were not found and reflect different symptomatology in persons suffering from insomnia compared to sleep deprived healthy controls.76 Moreover, a further reduction of sleeping time in insomniacs did not change their physiological or mental measures.76 These findings indicate that insomnia might be associated with a distinctly altered physiological state which is quite independent of the actual sleep duration. Insomnia mechanisms The neurocognitive model of insomnia84 proposes that excessive arousal prevents attenuation of sensory and cognitive activity during the wake/sleep transition in insomniacs and thereby indirectly produces sleep discontinuities. It is assumed that such arousal is the result of classical conditioning. Increased arousal together with increased short-term memory formation is held responsible for the common misperception insomniacs have about their sleeping time, as they mistake actual sleep for wakefulness.84 Reduced homeostatic drive to sleep or alternatively physiological hyperarousal have been suggested as physiological insomnia mechanisms.72 These mechanisms are not mutually exclusive, but in particular the hyperarousal hypothesis has been corroborated by empirical research.76,83,85 It was proposed that excessive activation of the sympathetic part of the autonomous nervous system results in a state of hyperarousal. Behavioural and a multitude of physiologic data concordantly support this hypothesis. At the behavioural level, frequent negatively toned cognitive activity during the day, excessive and uncontrollable worry and intrusive thoughts interfering with sleep onset,86 as well as enhanced dream recall with dream contents reflecting current stressors87 were reported. Enhanced sympathetic activation is supported by ample evidence about increased cardiovascular activation,76,88,89 and increased nocturnal norepinephrine90 in insomniacs. In addition, elevated urinary cortisol levels in the evening and in the first half of the night indicate a hyperactive hypothalamus-pituitary-adrenal (HPA) axis.91 Moreover higher arousal is suggested by altered auditory evoked potential amplitudes (review in76), by the higher EEG-beta activation during wake and sleep (e.g.,77,92,93), and less EEG delta activity when falling asleep.94 Additionally, during waking lower theta power correlated negatively whereas higher beta power correlated positively with scores in a hyperarousal questionnaire,93 and CBT reduced the previously elevated beta-activity during sleeping.95 Finally, a neuroimaging study provided evidence for elevated global brain metabolism during sleep and waking, less activity reduction between wake and sleep in thalamic and frontal cortical areas together with hypoactivity in several cortical and subcortical areas during waking in insomniacs as compared to good sleepers.80 In animals the alternation between sleep and wake states is controlled by a series of brain nuclei promoting interacting mechanisms that control the timing, structure, depth and duration of

sleep.96 The homeostatic drive increases in relation to the time span since the last sleep, it diminishes with subsequent sleep, and it is controlled by an interaction between wake- and sleep-promoting brain regions. Wake-promoting regions belong to the brain’s arousal system such as the reticular formation, pedunculopontine and laterodorsal tegmental nuclei, locus coeruleus (LC), the dorsal and medial raphe nuclei, the ventral periaqueductal gray (vPAG), and the tuberomamillary nucleus (TMN). These interact with the sleep-promoting hypothalamic ventrolateral preoptic nucleus (VLPO). The transition between wake and sleep states appears to be regulated by reciprocal inhibitory projections between the sleeppromoting VLPO and the wake-promoting TMN reminding of a flipflop switch that produces sharp transitions between the two states but also has the property of potentially undergoing unwanted state transitions when becoming unstable. Orexin neurons in the lateral thalamus appear to stabilize the system by reinforcing arousal.97 Additionally, activity of neurons on both sides of the switch is influenced by the brain’s main circadian pacemaker, the hypothalamic suprachiasmatic nucleus (SCN) which has indirect connections via other hypothalamic nuclei to these areas.97 The SCN displays a self-sustaining oscillatory activity pattern that is driven by a transcriptional-translational feedback loop which is under control of the external lightedark cycle through a special class of light-sensitive retinal ganglion cells that contain melanopsin.98 The pathways controlling the homeostatic and circadian drives are in addition modulated by emotional and cognitive influence. Limbic areas such as infralimbic cortex, the lateral septum, the central nucleus of the amygdala (CeA), the bed nucleus of the stria terminalis (BNST), and the ventral subiculum project to the VLPO and to the orexin neurons in lateral hypothalamus. These inputs may be able to override the normal homeostatic and circadian circuitry through their influence on the arousal system.97 Although such input is needed to overcome homeostatic sleep pressure if necessary, inappropriate activation of emotional and cognitive circuits is a potential mechanism in the aetiology of insomnia. In this framework, stress-induced insomnia represents a state during which neither the sleep- nor the wake-regulating circuitry is able to overcome the other because both receive strong excitatory input. This is thought to generate a novel intermediate state in which the dominant mode is sleep but with wake-related neuronal groups still active, and which is characterized by high frequency activity in the EEG during NREM sleep. This suggests that shutting down the residual activity of the limbic-arousal system might be a promising approach to treat stress-induced insomnia.97 Current therapies for primary insomnia Effective nonpharmacologic treatments for the management of insomnia such as CBT include behavioural and cognitive techniques that focus on changing poor sleep habits, promoting better sleep hygiene practices and by challenging negative thoughts, attitudes and beliefs about sleep.86 CBT significantly reduced beta EEG activity in insomniacs.95 Moreover, neurofeedback reduced a significant proportion of high levels of delta and beta power which coincided with a reduction of excessive sleepiness.99 Although the most widely used treatments for insomnia are mild sedative and hypnotic pharmaceutical agents like z-drugs (positive allosteric modulators of the gamma aminobutyric acid (GABA)-A receptor) and antidepressants, which are effective as short-term therapies, but often insomnia returns when these therapies are discontinued.100 Tinnitus, insomnia and hyperarousal Hyperarousal represents a state of increased psychological and physiological tension.76 On the behavioural level it is marked by anxiety, exaggerated startle responses, reduced pain tolerance,

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insomnia, fatigue, and accentuation of personality traits. As reviewed above, hyperarousal has been discussed as potential mechanism in the aetiology of insomnia (e.g.,76,85), but has not been considered as a potential tinnitus mechanism e with the exception of the neurophysiological tinnitus model by Jastreboff.41 As the symptoms of tinnitus and insomnia may be triggered by stressful events, and stress has been associated with symptom severity,83,101 it may be hypothesized that stress promotes a conditioning process to increase arousal in insomnia84 and to associate the tinnitus signal with distress.41 Stress management is considered to be an essential part of psychological tinnitus therapies,46,102 and psychosocial stress is more common in patients with severely distressing tinnitus than in patients with mild tinnitus.14 Often patients with a severely distressing tinnitus exhibit enhanced irritability and anxiousness that is associated with heightened attention towards internal signals indicating increased vegetative reactivity.21 Maladaptive stress reactivity as has been observed in tinnitus patients102,103 may lead to hyperarousal and continued hyperreactivity in the main stressresponsive systems, the sympathetic-adrenal-medullary (SAM) and HPA axes. Both systems are modulated by corticotropinreleasing factor (CRF) that is seen as a link between stressful life events and an increased vulnerability for affective and anxiety disorders.104 In accordance, tinnitus subjects express a blunted and delayed cortisol response to psychosocial stress which indicates deregulation of the negative feedback loop in the HPA system.105 Some evidence for hyperreactivity in the stress systems can also be derived from studies addressing the role of abnormal physiological stress reactions during the onset and maintenance of tinnitus symptoms. In stress tests tinnitus patients reported more subjective strain than healthy controls, but only few physiological reactivity patterns differed significantly from controls.106 Therefore this study did only partly confirm the hypothesis of increased arousal in tinnitus patients. Besides altered activation in auditory brain regions, there is evidence that tinnitus is associated with increased activity in regions associated with emotion processing and the control of autonomic bodily functions such as prefrontal cortex and the amygdala.22,24 This is thought to be a feature that is common to many disorders that are associated with unexplained functional somatic symptoms and that show high comorbidities with depressivity and anxiety such as tinnitus or sleep disorders.55 Age effects The prevalence of tinnitus and insomnia increases with age and the underlying mechanisms may therefore be related to fundamental ageing processes. Since hearing impairments that constitute an important risk factor for tinnitus augment with age, it is not surprising that the prevalence of tinnitus does also increase with advancing age. In addition, persons with later tinnitus onset express higher tinnitus-related distress.107 Animal studies suggest agerelated changes in auditory processing which are larger at the cortical than at the brainstem level suggesting that central alterations exacerbate peripheral impairments.108 Sleep patterns change with age and sleep efficiency decreases. At older age sleep is earlier, shorter, lighter and more fragmented compared to young sleepers.109 Sympathetic drive (SAM-axis: review in110) and reactivity of the HPA system ( HPA axis: review in91) increase with age. Increased activation in the SAM-axis with advancing age is reflected by a gradual increase of systolic and diastolic blood pressure across the adult life span until about the age of 70, and a gradual decrease in maximum heart rate in relation to a fairly stable resting heart rate (e.g.,111). Plasma norepinephrine concentrations increase by 10e15% per decade over the adult age range, whereas tonic epinephrine secretion from the adrenal medulla is markedly reduced, diurnal

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changes are blunted and sympatho-adrenal responsiveness to acute stress is substantially attenuated in older men (review in91,110). Intra-neural recordings of post-ganglionic nerve activity to skeletal muscle are considered to be a measure of sympathetic nervous system discharge generated in the central nervous system. This activity essentially doubles between the ages of 25 and 65 years even in healthy adults suggesting a primary effect of physiological ageing.112 Furthermore there is evidence that visceral adiposity is associated with increased levels of sympathetic activity, and even in the absence of weight gain ageing is associated with increases in body fatness.112 The neurophysiological mechanisms underlying the observed age associated increases in sympathetic nervous system activity have not been established, but data are consistent with an increased subcortical central nervous system sympathetic drive (review in110). A possible explanation for increased sympathetic drive is the loss of central inhibitory pathways in the brainstem, since central sympathetic disinhibition is seen in animal models.112 Moreover, reactivity of the HPA axis to stress increases with age (reviewed in91). Older age is associated with higher mean cortisol levels, a disruption of the negative feedback loop and a flatter diurnal pattern, in particular an attenuated awakening response and a less steep decline in the evening.113 Since the brain is responsive to stress hormones, the age-related changes in SAM and HPA reactivity by themselves may produce increased excitability of brain systems. This assumption is supported by the observation of age-related elevations in EEG-betaactivity which is thought to be associated with increased arousal.93 Additionally a reduction of inhibition, which is well documented for the ageing auditory system114 and has been associated with tinnitus in animals115 may be a cause of elevated excitation with advancing age. Taken together, these findings provide evidence that ageing is related to increasing arousal which may further the development of tinnitus and insomnia. Comordidity of tinnitus and sleep disturbances, results from a survey with 4705 respondents We performed a cross-sectional survey in a population of 4705 persons with tinnitus who were all members of the German Tinnitus Association (Deutsche Tinnitus-Liga (DTL)116). Information about age and gender as well as measures of subjective tinnitus loudness and chronic somatic conditions was gathered. Tinnitusrelated distress, depressive and anxious mood and somatic symptom severity were addressed with validated questionnaires,14,117,118 and clinically-relevant hyperacusis, i.e., the pathological sensitivity to sound which is rather common in tinnitus patients was determined as described by Hiller and Goebel.14 Two questions with the option to answer “yes” or “no” addressed difficulties initiating and/or maintaining sleep. In addition, it was asked whether the tinnitus was held responsible for the experienced sleep disturbances. The subjectively perceived sleep quality was measured on a Likert rating scale ranging from 0 (sleep not restorative at all) to 10 (very restorative sleep). A detailed description of the questionnaire is found in.116 Almost 77% of the responders reported some difficulty associated with sleep (see Table 1). Problems with sleep maintenance were more frequent than problems with prolonged sleep latency. The average rating of sleep quality of the whole sample was 5.53[2.27] (mean [standard deviation]) and 46.4% regarded the tinnitus as cause for their sleep disturbances. Ninety-five percent of the participants with high scores in tinnitus-related distress, depressivity (depressive disorders screener: PHQ-9118), anxiety (generalized anxiety disorders screener: GAD-7117,118), and somatic symptom severity (somatic symptom scale: PHQ-15118) reported sleep problems and low sleep quality (Table 1). Age above 50 doubled the likelihood for problems

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Table 1 Sleep onset and sleep maintenance in tinnitus patients.

Total population (n ¼ 4670) Tinnitus-related distress Mild distress (n ¼ 1734) Severe distress (n ¼ 612) OR severe/mild (95% CI) Tinnitus loudness T-NRS  2 (n ¼ 377) T-NRS  8 (n ¼ 1323) OR high/low (95% CI) Age 50y (n ¼ 1112) >50y (n ¼ 3321) OR > 50/50 (95% CI) Gender Female (n ¼ 1865) Male (n ¼ 2693) OR female/male (95% CI) Permanent awareness of the tinnitus (n ¼ 3694) OR permanent/intermittent (95% CI) Hyperacusis (n ¼ 404) OR yes/no (95% CI) Chronic pain (n ¼ 2898) OR yes/no (95% CI) Somatic comorbidities (n ¼ 4179) OR yes/no (95% CI) Psychopathologies PHQ-9  15 (n ¼ 461) OR  15  5 (95% CI) GAD-7  15 (n ¼ 329) OR  15  5 (95% CI) PHQ-15  5 (n ¼ 529) OR  15  5 (95% CI)

Problems with sleep onset %

Problems with sleep maintenance %

Problems with sleep onset and maintenance %

Sleep disturbance total %

Sleep-NRS mean [SD]

47.2

71.4

41.8

76.5

5.53 [2.27]

24.6 83.0 14.93 (11.78e18.91)

56.3 89.8 6.82 (5.17e9.00)

19.8 77.8 14.14 (11.30e17.70)

60.9 94.8 11.63 (8.05e16.82)

6.69 [1.94] 3.61 [2.15]

27.6 59.9 3.92 (3.05e5.03)

55.2 71.3 3.07 (2.41e3.92)

21.9 41.4 4.34 (3.32e5.67)

60.4 76.4 3.42 (2.65e4.41)

6.61 [2.19] 4.47 [2.38]

40.6 49.3 1.42 (1.24e1.63)

59.8 75.2 2.04 (1.77e2.35)

44.6 33.0 1.63 (1.42e1.89)

79.6 66.9 1.93 (1.66e2.25)

5.51 [2.28] 5.63 [2.29]

54.5 42.3 1.63 (1.45e1.84)

74.2 69.4 1.27 (1.11e1.44)

47.6 37.9 1.49 (1.32e1.68)

80.7 73.6 1.50 (1.30e1.73)

5.38 [2.24] 5.63 [2.30]

49.3 1.56 (1.34e1.82)

73.0 1.42 (1.21e1.67)

44.1 1.64 (1.40e1.92)

77.8 1.43 (1.21e1.70)

5.42 [2.28]

74.3 3.62 (2.88e4.57)

85 2.41 (1.82e3.19)

66.7 3.12 (2.51e3.87)

92.3 3.98 (2.74e5.78)

4.01 [2.21]

53.6 2.12 (1.87e2.40)

76.8 2.12 (1.86e2.42)

48.2 2.21 (1.94e2.52)

81.9 2.31 (2.01e2.66)

5.14 [2.24]

48.8 1.47 (1.29e1.67)

58 1.61 (1.40e1.85)

43.5 1.59 (1.39e1.81)

78.1 1.59 (1.37e1.85)

5.44 [2.27]

76.4 4.27 (3.41e5.34) 78.1 7.52 (5.70e9.93) 76.7 13.54 (10.51e17.43)

89.8 4.03 (2.96e5.49) 91.6 7.21 (4.85e10.73) 93.2 18.11(12.63e25.95)

71.0 4.05 (3.28e5.01) 74.2 7.90 (6.06e10.30) 73.2 16.79(12.95e21.79)

95.0 6.72 (4.39e10.29) 95.5 11.15 (6.56e18.87) 96.8 32.12 (19.51e52.87)

3.18 [1.96] 2.99 [1.95] 3.50 [1.88]

In this table, population percentages (%) and odds ratios (OR) with 95% confidence intervals (CI) regarding difficulties to initiate and to maintain sleep are shown. Tinnitusrelated distress was recorded by the short version of the tinnitus questionnaire (MTQ14) whereas the subjectively perceived loudness of the tinnitus (T-NRS) was rated on a Likert scale ranging from 0 (tinnitus audible only during silence) to 10 (tinnitus louder than all other sounds). Modules of the patient health questionnaire (PHQ118) indicate levels of depressivity (depressive disorders screener: PHQ-9118), anxiety (generalized anxiety disorder screener: GAD-7117,118) and somatic symptom severity (somatic symptom scale: PHQ-15118), and severe levels are defined by sum scores of 15 and above in a module. Subjective rating of sleep quality on a Likert rating scale (sleep-NRS) ranged from 0 (sleep not restorative at all) to 10 (very restorative sleep). Clusters within the population were composed with respect to mild (MTQ score 7) and most severe (MTQ score 19) tinnitus-related distress, low (T-NRS 2) and high (T-NRS 8) subjective tinnitus loudness, age of 50 years and below versus above 50 years, gender, permanent awareness of the tinnitus, hyperacusis, chronic pain, chronic somatic comorbidities as well as severe depressivity, anxiety and somatic symptom severity. OR were calculated for the different expressions of a variable as indicated and between severe (15) and no (<5) psychopathologies. OR of two and above respectively of 0.5 and below, indicate a 2 (or more)-fold likelihood respectively a 0.5 (or less)-fold likelihood of a characteristic in one condition compared to the other. Because of missing values on single items, 4670 completed questionnaires contributed to this data.

with sleep maintenance, while chronic pain doubled the likelihood for problems with either sleep onset or maintenance. By contrast somatic comorbidities, gender or permanent awareness of the tinnitus had minor influence on sleep quality (Table 1). These findings suggest that severe tinnitus-related distress as well as severe depressive and anxious mood, somatic symptom severity and hyperacusis are often associated with sleep disturbances, whereas factors related to tinnitus perception play a minor role. Although some limitations apply to this analysis since the members of DTL may not be entirely representative for the general tinnitus population, and because the evidence relies on self-report questionnaires, findings of the present study are in line with previous research. They demonstrate that sleep problems augment tinnitus-related distress, that they enhance the tinnitus perception and vice versa, a consequence that aggravates with the passage of time.119 Although many tinnitus patients think that they wake up because they hear their tinnitus during sleep, it has been hypothesized that the tinnitus perception vanishes during sleep.39 Alternatively, reduced masking by environmental sound because of low

external noise levels may increase awareness of the tinnitus sensation after waking up during the night. The time needed to go back to sleep might then be prolonged by anxious focussing and worries about the tinnitus.13 In this case not tinnitus but a mechanism commonly found in tinnitus patients and insomniacs is responsible for nightly awakenings and non-restorative sleep. Central arousal constitutes such a mechanism. Of further support for this assumption is the observation that central arousal is associated with elevated anxiety and depressivity (e.g.,120) which are frequent comorbidities of distressing tinnitus and of insomnia. Similarities of brain activation patterns between animal models of tinnitus and insomnia and implications for a neurocircuitry of hyperarousal Animal models of tinnitus mostly concentrate on the auditory system, while only few studies suggest mechanisms beyond it.121e123 In gerbils, brain activation patterns were investigated after systemic application of a large dose of salicylate or exposure to loud

E. Wallhäusser-Franke et al. / Sleep Medicine Reviews 17 (2013) 65e74

noise, manipulations that reliably evoke tinnitus in animals and humans. Brains were screened for neurons containing the c-fos protein, a transcription factor widely used as a marker of neuronal activity. After salicylate injections, auditory cortex was the only auditory area with consistently increased numbers of immunoreactive neurons compared to controls, whereas exposure to impulse noise led to prolonged c-fos expression in auditory cortex and dorsal cochlear nucleus. Most important in the present context, however, was that both manipulations lead to increased c-fos expression in frontal cortex, specifically in cingulate gyrus, and in the amygdala, in particular in CeA and BNST. The latter is part of the extended amygdala.97 C-fos expression increased also in thalamic midline and intralaminar areas as well as in regions involved in behavioural and physiological stress reactions such as vPAG, the noradrenergic LC in the brainstem, and the hypothalamic paraventricular nucleus (PVN). Furthermore brain regions controlling autonomic functions such as the lateral parabrachial nucleus in the brainstem were activated.33,122,124 These areas are related to the central autonomic network,125 and they are reciprocally interconnected so that information flows in top-down as well as in bottom-up direction. Activation of brain nuclei belonging to the autonomic network was attributed to acute stress, to aversiveaffective components and to autonomous reactions associated with the treatments and the resulting tinnitus. In particular CeA/ BNST is regarded as a key structure for the generation of tinnitus since it is in the position to modulate a variety of cognitive as well as emotional, endocrine and autonomous functions (Fig. 1; discussed in33,126), and it is involved in aversive conditioning.43 Insomnia can be induced by social stress in rodents97 resulting in sleep patterns that resemble those of humans with primary insomnia. Rats were exposed to an unfamiliar rat odour through

Activity patterns in animal models of tinnitus and stress-induced insomnia

Sensory input Auditory system (tinnitus) Olfactory system (stress-induced insomnia)

PFC

Attention to salient stimuli

CeA/BNST

HPA-axis SAM-axis

Stress hormones

71

cage exchange, i.e., they were inescapably exposed in a territory that had been marked by another male. Several hours after the initial stress response this stressor lead to increased sleep latency, decreased NREM and rapid eye movement (REM) sleep, increased sleep fragmentation, and high frequency EEG activity during NREM sleep. To identify the brain circuitry activated, c-fos expression was studied in these rats. The pattern of activated areas was remarkably similar to that found after tinnitus induction. Elevated numbers of c-fos immunoreactive neurons were observed in cortex, in the limbic system, in particular in CeA/BNST. Furthermore several areas of the arousal system like LC and the autonomic system showed increased c-fos expression in the stressed animals.78 In further experiments Cano et al.78 selectively lesioned some of the activated areas and found that difficulties falling asleep were mainly mediated by CeA/BNST, and to a lesser extent by the arousal system (LC, TMN), whereas sleep fragmentation in the stressed animals reverted to the normal pattern after lesioning infralimbic cortex, or the LC and several hypothalamic areas. Therefore all of these areas seem to contribute to the NREM and wake perturbations induced by stress. By contrast REM sleep disruption depended mainly upon the activity of CeA/BNST. The activation pattern in sleep-disturbed rats parallels that found in an imaging study comparing insomnia patients and good sleepers,80 and it resembles the activation pattern of non-auditory areas found after experimental tinnitus induction.33,121,122 For the cortex, comparison to humans is limited because the rodent cortex is less developed, but organization and connectivity of the amygdala appears to be similar in animal and human brains.127 As outlined in Fig. 1 the amygdala plays a key role in the connection between sensory areas, the frontal cortex and autonomous hypothalamic and brainstem regions. An extensive body of research in animals126 has established a model wherein sensory information enters the amygdala through the lateral (auditory, visual) and medial parts (olfactory). Auditory information reaches the lateral amygdala by two different paths, via a projection from the auditory cortex and via a projection from the medial, non-lemniscal part of the thalamic auditory relay nucleus, the medial geniculate body. It was assumed that information transfer by the thalamic-amygdalar route might be enhanced in individuals with tinnitus.128 The lateral and medial areas then activate the central nucleus depending on the emotional significance of the stimuli, which is essential for the defensive responses associated with fear.43 The central nucleus achieves these functions through projections to brainstem and hypothalamic targets that control autonomous physiological parameters.126

Sympathetic system

Peripheral adjustments Modulation of amygdala tone

metabolic rate, heart rate, blood pressure, muscle tone, ….

Fig. 1. In rodents tinnitus was induced pharmacologically by a high dose of sodium salicylate or noise, and insomnia was induced by olfactory cues generated by an unknown conspecific. Brain activation was evidenced through immunocytochemical detection of the c-fos protein which is the product of the immediate early c-fos gene that is expressed in neurons following continued activation. As shown in the diagram, similar brain areas show activation in either condition. The amygdala represents a crucial link between alterations in sensory input (experimental tinnitus: auditory; experimental insomnia: olfactory) and reactions on the respective sensory signal. The amygdala receives auditory input via its lateral nucleus and olfactory input via its medial nucleus (not shown). All partitions of the amygdala project to the central nucleus (CeA) which is continuous with the bed nucleus of the stria terminalis (BNST). CeA/BNST represents the exclusive output structure of the amygdala with projections to prefrontal cortex (PFC), to hypothalamic nuclei that belong to the hypothalamuspituitary-adrenal (HPA) axis and to autonomic brain stem centres that are part of the sympathetic-adrenal-medullary (SAM) axis. Through stress hormones and the sympathetic nervous system these areas control peripheral variables such as heart and respiration rate, blood pressure and metabolic rate. Alterations in the peripheral variables may constitute stressors on their own. By proprio-receptors these peripheral adjustments are fed back to central structures including the amygdala.

Conclusions In our view, there exists strong evidence for characterizing distressing tinnitus and primary insomnia as expressions of physiological hyperarousal. Even though there are differences between the two conditions, the major one obviously being the presence of the phantom auditory percept tinnitus in the tinnitus condition, there are striking similarities in which hyperarousal appears to play a major role. Distressing tinnitus is often accompanied by insomnia, and even when occurring in separation, both conditions are associated with similar comorbidities such as depressivity and anxiety. Consequently those affected tend to be worried about their tinnitus or sleep problems. There exists some evidence for hyperactivation of the autonomous nervous system during insomnia (e.g.,76,83,85) and preliminary evidence indicates that autonomous hyperactivation may be associated with tinnitus.129 Likewise, the neurophysiological tinnitus model41 proposes that the tinnitusrelated distress is caused by undue activation of the limbic and autonomous nervous systems. In addition, the brain circuits delineated in basic research on tinnitus and insomnia78,122 provide

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evidence that brain areas regulating emotions and the activity of the autonomous nervous system including the HPA and SAM axes are activated in the conditions of distressing tinnitus and insomnia. There are theoretical as well as therapeutic implications of this hypothesis: if hyperarousal is specific to distressing tinnitus, patients with distressing tinnitus should differ from those with non-distressing tinnitus in several cardiovascular and endocrine parameters that relate to these systems. Moreover, therapeutic interventions that specifically aim to reduce hyperarousal should ameliorate a distressing tinnitus, even more so if the tinnitus is accompanied by insomnia. For example, neurofeedback which has been applied successfully to treat tinnitus130 and insomnia99 might be modified to decrease arousal more specifically resulting in therapies that demand less effort than the existing behavioural approaches.

Practice points 1) Insomnia is a relevant comorbidity in many tinnitus patients that augments tinnitus-related distress. Treatments of tinnitus patients should therefore aim to reduce insomnia as well. 2) Tinnitus is a potential problem in insomnia patients and has to be taken into account for diagnosis and choice of treatment. 3) Given that hyperarousal is the common denominator of distressing tinnitus and insomnia, provisions to reduce hyperarousal should attain higher significance for future therapies.

Research agenda In the future we need 1) Systematic investigations of hyperarousal-related parameters in tinnitus patients in relation to tinnitusrelated distress. 2) Systematic investigations of the interaction between insomnia and tinnitus. 3) To delinate the role of excessive activation of the sympathetic nervous system (hyperarousal) for the generation and maintenance of distressing tinnitus. 4) To find treatment strategies specific to tinnitus patients with relevant insomnia.

Acknowledgements The authors thank Dr. J. Brade from the Unit of Medical Statistics and Biomathematics of the Medical Faculty Mannheim for statistical advice, and wish to acknowledge the help of the medical students Alexander Eiffler, Tobias Hofbauer and Herve Nguewoun who inscribed the data into the database. Special thanks to the past president of the DTL, Elke Knör, for enabling this study, and to the members of the DTL who contributed their data. Conflict of interest This work was partly supported by the German Tinnitus Association (Deutsche Tinnitus-Liga DTL); auric Hörsysteme, Rheine, Germany; and Schaaf and Maier Hörgeräte, Mannheim, Germany. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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