Brain pathophysiology concepts

Intrinsic connectivity networks describe a set of large-scale functionally connected brain networks that can be captured in either resting state or task-based neuroimaging data.^{Reference Seeley, Menon, Schatzberg, Keller, Glover and Kenna30} Intrinsic connectivity network dysfunction forms the neural basis of functional disorders. Three important intrinsic connectivity networks are the default mode network, salience network and the central executive network, which are shown in Figure 4. The default mode network is involved in information monitoring, social cognition and initiating prediction signals. It is active in a range of internally directed cognitive processes including autobiographical memory and thinking of the future.^{Reference Buckner, Andrews-Hanna and Schacter31} The central executive network has a role in cognitive control. The salience network is important in processing sensory, emotional and cognitive information along with identifying relevant events. The triple network model of psychopathology proposes the salience network acts as a ‘switch’ that engages the default mode network and disengages the central executive network, leading to symptoms.^{Reference Seeley, Menon, Schatzberg, Keller, Glover and Kenna30,Reference Menon and Uddin32}

Aberrant salience is the assignment of significance to innocuous stimuli^{Reference Kapur33} and has an adverse effect on how external and internal signals are processed. The salience network plays a crucial role in switching between brain networks involved in externally oriented attention and internally oriented mental processes.^{Reference Sridharan, Levitin and Menon34} The central experience that defines aberrant salience is when stimuli that ordinarily would not seem important become more significant.^{Reference Bowers35} Aberrant salience has been implicated in the pathophysiology of functional neurological disorders,^{Reference Perez, Williams, Matin, LaFrance, Costumero-Ramos and Fricchione36} anxiety and mood disorders.^{Reference Salviati, Bersani, Valeriani, Minichino, Panico and Romano37}

Distress in response to tinnitus has been localised to salience network nodes such as the anterior cingulate cortex, insula and amygdala.^{Reference Vanneste, Plazier, der Loo, de Heyning, Congedo and De Ridder38} Paralimbic involvement in tinnitus patients has been suggested to indicate tinnitus distress as a state of aberrant salience, similar to other brain disorders.^{Reference Salviati, Bersani, Valeriani, Minichino, Panico and Romano37} Furthermore, attenuated activation of the central executive network and downregulated baseline connectivity between the central executive network with salience network and autobiographical memory networks has been suggested to maintain chronic tinnitus awareness.^{Reference Trevis, Tailby, Grayden, McLachlan, Jackson and Wilson39}

The intrinsic dynamics of thalamocortical network oscillations are crucial for early sensory processing.^{Reference Hodkinson, Wilcox, Veggeberg, Noseda, Burstein and Borsook40} Electrophysiological studies have shown altered thalamocortical rhythm, termed thalamocortical dysrhythmia, in a range of disorders including tinnitus, migraine, fibromyalgia and visual snow syndrome.^{Reference Llinas, Ribary, Jeanmonod, Kronberg and Mitra3,Reference De Ridder, Vanneste, Langguth and Llinas41,Reference Schulman, Cancro, Lowe, Lu, Walton and Llinas42} These disorders share a common temporal pattern of beta-theta and theta-gamma coupling. Self-sustaining generation of low-frequency oscillations can result in long-term cortical dysfunction.^{Reference Walton, Llinás, Kruger and Light43} The enhancement of low-frequency theta oscillations may be linked to the emergence of negative functional symptoms, while gamma upregulation could serve to induce more positive or excitatory functional symptoms.^{Reference Llinas and Steriade44}

Neurology relationship

Compared with neurology clinics, our study suggests functional disorders are twice as prevalent in otology (34.6 per cent vs 16 per cent).^{Reference Stone, Carson, Duncan, Roberts, Warlow and Hibberd2} However, functional disorders commonly overlap. In visual snow syndrome, 52–63 per cent of patients experience tinnitus,^{Reference van Dongen, Waaijer, Onderwater, Ferrari and Terwindt45,Reference Renze46} and the effectiveness of cognitive behavioural therapy in tinnitus has led to its utilisation for visual snow syndrome.^{Reference van Dongen, Waaijer, Onderwater, Ferrari and Terwindt45} The currently accepted view is that primary headache is a result of abnormal brain function with normal brain structure.^{Reference May, Ashburner, Büchel, McGonigle, Friston and Frackowiak47} There is a significant relationship between tinnitus and headache laterality and symptom interaction over time, and both disorders may be linked by common pathophysiological mechanisms.^{Reference Langguth, Hund, Busch, Jürgens, Lainez and Landgrebe48} It has been suggested that clocking tinnitus may be an audiological manifestation of a migraine disorder.^{Reference Chen, Hsu, Chen and Yin49} In a population-based study, the prevalence of tinnitus has been found to be significantly higher in migraine patients.^{Reference Hwang, Tsai, Liu, Chen and Lai50} Similarly, isolated prolonged aural fullness has been found to improve with migraine-related lifestyle changes and prophylactic treatment.^{Reference Moshtaghi, Ghavami, Mahboubi, Sahyouni, Haidar and Ziai13}

Stress relationship

Neuroimaging studies suggest amygdala prefrontal circuitry dysfunction in anxiety, creating a bias towards threat-related responses.^{Reference Bishop51} Stress and anxiety shift the balance of attention away from a task-directed mode, governed by the prefrontal cortex, to a sensory-vigilance mode, governed by the amygdala and other threat-sensitive regions.^{Reference Arnsten52} In our study, 30 per cent of patients with functional ear symptoms reported increased levels of stress. Stress symptoms have been reported in 65 per cent of tinnitus patients using Lipp's inventory symptoms of stress and are related to increased tinnitus perception.^{Reference Ciminelli, Machado, Palmeira, Carta, Beirith and Nigri53} Other studies have shown a direct correlation between duration of tinnitus and stress severity.^{Reference Gomaa, Elmagd, Elbadry and Kader54} Studies provide evidence that stressful life experiences are accompanied by autonomic and neuroendocrine changes capable of influencing immune function, thereby influencing susceptibility to infectious, autoimmune and chronic illness.^{Reference Ader and Kelley55} Childhood adversity and cumulative adverse life events can prime the stress system into a state of readiness, and even minor subsequent stressors trigger a stress response.^{Reference Kozlowska56}

Mental health relationship

A high incidence of anxiety and depression in primary tinnitus is described in the literature, and co-morbid psychiatric illness increases severity.^{Reference Pinto, Marcelos, Mezzasalma, Osterne, de Melo Tavares de Lima and Nardi57,Reference Reynolds, Gardner and Lee58} Indeed, the incidence rate of depression in people with tinnitus has been cited as being more than twice that of the national average in the US population (approximately 35 per cent vs approximately 15 per cent, respectively).^{Reference Folmer, Griest, Meikle and Martin59} Depressive symptoms play a role in triggering and maintaining chronic tinnitus.^{Reference Trevis, McLachlan and Wilson60} Post-traumatic stress disorder is associated with functional symptoms. A study of 468 Iraq War veterans with post-traumatic stress disorder showed higher levels of dizziness compared with veterans without post-traumatic stress disorder.^{Reference Hoge, Terhakopian, Castro, Messer and Engel61} Vulnerability to fear and threat is evidenced by increased functional disorders with childhood adversity.^{Reference Roelofs and Pasman62,Reference Roelofs, Keijsers, Hoogduin, Naring and Moene63} Interestingly, three patients in our study with post-traumatic stress disorder had a clear history of developing a functional disorder after a traumatic event.

Somatosensory amplification

One of the functions of fear is to enhance sensory perception for survival.^{Reference Susskind, Lee, Cusi, Feiman, Grabski and Anderson64} Somatosensory amplification describes body hypervigilance and the tendency to focus on mild body sensations, which is a key step in leading to functional symptoms (Figure 4). It relates to modern health worries, expectations of symptoms or medication side effects.^{Reference Koteles and Witthoft65} Somatosensory amplification has been suggested in functional pulsatile tinnitus, where there is no underlying pathology but there is deficient noise-cancelling mechanism^{Reference Song, Vanneste and De Ridder66} and impaired sensory gating.^{Reference Campbell, Bean and LaBrec67} Somatosensory catastrophising involves false attribution of bodily sensations to serious illness.^{Reference Seto and Nakao68} In our study, several patients reported increasing anxiety and severity of symptoms after internet searching. The term ‘cyberchondria’ has been coined to describe the unfounded escalation of concerns about common symptomology based on the review of search results and literature online.^{Reference White and Horvitz69}

Functional otalgia and aural fullness

In our study, the symptoms of otalgia and aural fullness were reported in 22.8 per cent and 19.1 per cent of patients, respectively, who exhibited a functional disorder. Tinnitus and chronic pain have been demonstrated to share an overlapping brain network with common activation and connectivity patterns.^{Reference Vanneste, To and De Ridder70} Vagal nerve stimulation has been employed to neuromodulate brain circuits in a variety of functional disorders, including depression, chronic pain and migraine.^{Reference Howland71} The role of dysregulation of the autonomic nervous system and central pain pathways in the emergence of temporomandibular disorders has a growing evidence base.^{Reference Monaco, Cattaneo, Marci, Pietropaoli and Ortu27} The external ear canal has afferent vagal supply, via the auricular branch of the vagus nerve, to brain regions mediating multisensory integration. Autonomic nervous system dysfunction could have mechanistic overlap in aural fullness and otalgia because these symptoms are also associated with temporomandibular disorders.

Patient history

Functional symptoms can arise within the context of stress, pain, fatigue, injury, psychological trauma and sudden intense and overwhelming emotions.^{Reference Kozlowska56} In our study, 103 patients reported functional symptoms coinciding with increased stress, 14 patients during a bereavement and 23 patients during a period of significant sleep deprivation. Otological negative experience included prolonged or distressing loud noise, painful microsuction or ear syringing, ear trauma, ear surgery, childhood ear problems, and otalgia during flights or diving. Other experiences included physical illnesses, surgery and symptoms coinciding with a negative emotional reaction to starting medication because somatosensory amplification can arise from patient fear of drug side effects.^{Reference Koteles and Witthoft65}

Management of functional ear symptoms

Functional disorders are at the intersection of many disciplines, and treatment options are listed in Table 1. Neurologists, neuro-vestibular physiotherapists and clinical psychologists have substantial experience in managing functional disorders, and working with multidisciplinary teams of otologists and audiologists is warranted for more challenging cases. Sound therapy has been shown to alter limbic and auditory networks,^{Reference Han, Pengfei, Chunli, Zhaodi, Xindi and Qian72} and neurostimulation has been increasingly explored for neuromodulating brain networks in refractory primary headache.^{Reference Vukovic Cvetkovic and Jensen73}

Table 1. Treatment options for functional ear symptoms

Limitations of our study include single-centre data collection and retrospective review. Future work utilising validated questionnaires could formally assess risk factors including childhood adversity, stress and co-morbid conditions.