The results indicate that the dorsal and subgenual anterior cingulate, as well as the left and right insula are important in the central control of heart rate variability in tinnitus patients. Whereas the sympathovagal balance is controlled by the subgenual and pregenual anterior cingulate cortex, the right insula controls sympathetic activity and the left insula the parasympathetic activity. The perceived distress in tinnitus patients seems to be sympathetically mediated.

The aim of the present study is to investigate the relationship between tinnitus distress and the autonomic nervous system and find out which cortical areas are involved in the autonomic nervous system influences in tinnitus distress by the use of source localized resting state electroencephalogram (EEG) recordings and electrocardiogram (ECG). Twenty-one tinnitus patients were included in this study.

Tinnitus is defined as an intrinsic sound perception that cannot be attributed to an external sound source. Distress in tinnitus patients is related to increased beta activity in the dorsal part of the anterior cingulate and the amount of distress correlates with network activity consisting of the amygdala-anterior cingulate cortex-insula-parahippocampus. Previous research also revealed that distress is associated to a higher sympathetic (OS) tone in tinnitus patients and tinnitus suppression to increased parasympathetic (PS) tone.

Copyright: © 2013 Vanneste, De Ridder. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Introduction

Tinnitus is defined as an intrinsic sound perception that cannot be attributed to an external sound source. This phantom perception is a common disorder. The American Tinnitus Association estimates that 50 million Americans are affected by it, and that 12 million of these people seek medical attention because of their tinnitus [1]. In about 6 to 25% of the affected people tinnitus causes a considerable amount of distress [2]–[4], resulting in about 2–4% of the population who are severely impaired in their quality of life [5]. Tinnitus can interfere with sleep and concentration, social interaction and work [6]. Increased prevalence rates of anxiety and depression are reported among tinnitus patients [7], [8].

Distress in tinnitus patients is related to increased beta activity in the dorsal part of the anterior cingulate and the amount of distress correlates with an EEG alpha network activity consisting of the amygdala-anterior cingulate cortex-insula-parahippocampus as demonstrated both by source analysis of Fourier based data [9] and independent component analysis [10]. Using MEG, long-range coupling between frontal, parietal and cingulate brain areas in alpha and gamma phase synchronization has been shown to be related to tinnitus distress [11]. The distress in tinnitus patients also correlates with an increase in incoming and outgoing connections in the gamma band in the prefrontal cortex and the parieto-occipital region [12].

Adaptation under conditions of stress is a priority for all organisms. Stress can be broadly defined as an actual or anticipated disruption of homeostasis or an anticipated threat to well-being [13]. Stressor-related information from all major sensory systems is conveyed to the brain, which recruits neural and neuroendocrine systems (effectors) to minimize the net cost to the animal. The physiological response to stress involves an efficient and highly conserved set of interlocking systems and aims to maintain physiological integrity even in the most demanding of circumstances [13].

The autonomic nervous system provides the most immediate response to stressor exposure - through its sympathetic and parasympathetic arms, which provoke rapid alterations in physiological states through neural innervation of end organs. The autonomic nervous system is a collection of afferent and efferent neurons that link the central nervous system with visceral effectors. The two efferent arms of the autonomic nervous system - the sympathetic and parasympathetic arms - consist of parallel and differentially regulated pathways made up of cholinergic neurons (preganglionic neurons) located within the central nervous system that innervate ganglia (for example, para- or pre-vertebral sympathetic ganglia), glands (adrenal glands) or neural networks of varying complexity (enteric or cardiac ganglionic networks). These peripheral ganglia and networks contain the motor neurons (ganglionic neurons) that control smooth muscles and other visceral targets. The sympathetic ganglionic neurons that control cardiovascular targets are primarily noradrenergic [14]. The sympatho-adrenomedullary arm can rapidly (in seconds) increase heart rate and blood pressure by exciting the cardiovascular system. Importantly, excitation of the autonomic nervous system wanes quickly - owing to reflex parasympathetic activation - resulting in short-lived responses [13]. Previous research also revealed that distress is associated to a higher sympathetic (OS) tone in tinnitus patients [15] and tinnitus suppression to increased parasympathetic (PS) tone [16]. The heart is dually innervated by the autonomic nervous system such that relative increases in sympathetic activity are associated with heart rate increases and relative increases in parasympathetic activity are associated with heart rate decreases. In addition, human lesion and electrical stimulation studies have revealed that the right insula controls cardiac sympathetic activity whereas the left insula is predominantly associated to parasympathetic activity [17]–[19].

Heart rate variability (HRV) is a physiological phenomenon where the time interval between heart beats varies. It is measured by the variation in the beat-to-beat interval. HRV is a simple and non-invasive quantitative marker of autonomic function. As a result of continuous variations of the balance between OS and PS neural activity influencing heart rate, intervals between consecutive heartbeats (RR intervals) show spontaneously occurring oscillations. For HRV analysis, a Fourier-based spectral analysis is performed of the beat to beat intervals, yielding two main frequencies: a low frequency range (LF: 0.05–0.15 Hz) and a high frequency range (HF 0.15–0.4 Hz) [20]. The high frequency component of HRV is believed to be influenced by vagal activity and is also related to the frequency of respiration [21]. Low-frequency (LF) power is modulated by baroreceptor activities and fluctuations in heart rate in the LF range reflect OS as well as PS influences. Low-frequency power, therefore, cannot be considered to reflect selective OS activity. However if normalized units of LF and HF are considered, the OS and PS influences respectively are emphasized [20]. In HRV frequency domain, normalized units of LF and HF components therefore reflect OS and PS influences respectively.

In two recent PET studies it was demonstrated that inducing a certain amount of stress, HRV correlates positively with activity in the anterior cingulate cortex, caudate nucleus, insula, medial prefrontal cortex extending into the dorsal prefrontal cortex [22], [23]. These areas are also involved in tinnitus related distress [9]. Using similar PET studies, the neural correlates of the HF component (PS) have been delineated as the caudate nucleus, periaqueductal gray and left mid-insula [23], while in fMRI the HF component correlates positively with activity in the hypothalamus, amygdala and anterior hippocampal area, dorsomedial/dorsolateral prefrontal cortex and negatively with the cerebellum, parabrachial nucleus/locus coeruleus, periaqueductal gray, posterior parahippocampal area, thalamus, posterior insular and middle temporal cortices [24]. The left inferior part of the pregenual anterior cingulate cortex also correlates with the HF component of the HRV [25]. The increased LF/HF-ratio (in rectal distension) is correlated with activity in the bilateral insula, putamen, thalamus, midbrain, pons, and cerebellum [26].

The aim of the present study is to investigate the relationship between tinnitus distress and the autonomic nervous system and find out which cortical areas are involved in the autonomic nervous system influences in tinnitus distress by the use of source localized resting state electroencephalogram (EEG) recordings and electrocardiogram (ECG).

Quantitative analysis of EEG is a low-cost and useful neurophysiological approach to study the brain physiology and pathology [27]. Cortical sources of the EEG rhythms were estimated by standardized low-resolution brain electromagnetic tomography (sLORETA) [28]. sLORETA is a functional imaging technique estimating maximally smoothed linear inverse solutions accounting for distributed EEG sources within Montreal Neurological Institute (MNI) space [28]. This feature is of special importance for the comparison of EEG results with those of most structural and functional neuroimaging studies. sLORETA has been successfully used in recent EEG studies on tinnitus [29]. In this study we investigate which brain areas are involved in tinnitus distress and in the autonomic nervous system control of the distress.