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RESEARCH ARTICLE
Asia Pac J Clin Trials Nerv Syst Dis 2018,  3:1

Abnormal vestibular asymmetries in patients with major depression


1 Vest Brain, Centro de Estudios Neurovestibulares, Santiago, Chile
2 Centro de Medicina Aeroespacial, Santiago, Chile
3 Vest Brain, Centro de Estudios Neurovestibulares; Centro de Medicina Aeroespacial, Santiago, Chile

Date of Web Publication15-May-2018

Correspondence Address:
Ana Maria Soza
Vest Brain, Centro de Estudios Neurovestibulares, Santiago
Chile
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Source of Support: This study was supported by a grant from Centro de Medicina Aeroespacial., Conflict of Interest: None


DOI: 10.4103/2542-3932.232075

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  Abstract 

Background and objectives: The precedents about the existence of bilateral modulatory neuronal pathways between vestibular nuclei and higher brain centers involved in mood regulation, plus previous reports of abnormal vestibular function in major depression, support the relevance of further investigation inquiring the role of the vestibular system in depression's physiopathology and vice versa. The aim of this investigation is to study the vestibular activity in major depression patients using the rotatory test technique.
Methods: Totally 21 major depression subjects (average age 37.9 years) according to Diagnostic and Statistical Manual of Mental Disorders-V criterion, who scored 12 or more in the 21-item Hamilton Rating Scale for Depression (HRS-D21), and 20 control healthy subjects (average age 41.1 years) who scored less than 7 in the HRS-D21, were tested in the rotatory chair. The nystagmus (vestibular-ocular reflex consisting of ocular movements induced by the vestibular system), was registered by electronystagmography. For the quantification of right or left vestibular activity, we measured the nystagmus's slow phase velocity induced by right and leftward rotation of the chair correspondingly.
Results: Depression group showed an asymmetric vestibular pattern of activity (right/left vestibular activity ratio = 0.77 ± 0.2), significantly different (P < 0.01) from healthy who presented symmetric vestibular function (right/left ratio = 1.1 ± 0.3).
Conclusion: Major depressive patients show an abnormal pattern of vestibular activity with lower function at the right side compared to left. We discuss the meaning and the possible underlying physiopathologic mechanisms of this finding. Also, we raise the possibility to consider this particular kind of vestibular asymmetry as a potential biomarker of major depression.
Trial registration: ClinicalTrials.gov identifier: NCT03421847.

Keywords: vestibular system; major depression; insular cortex-asymmetry; biomarker of depression


How to cite this article:
Soza AM, Certanec B, Tapia E. Abnormal vestibular asymmetries in patients with major depression. Asia Pac J Clin Trials Nerv Syst Dis 2018;3:1-7

How to cite this URL:
Soza AM, Certanec B, Tapia E. Abnormal vestibular asymmetries in patients with major depression. Asia Pac J Clin Trials Nerv Syst Dis [serial online] 2018 [cited 2018 May 22];3:1-7. Available from: http://www.actnjournal.com/text.asp?2018/3/2/1/232075


  Introduction Top


Vestibular system's hair cells receptors in the inner ear, detect our motor activity. In the daily life, the capacity to perceive the consecutive changes of position of ourselves in the space, allows us to know (in an unconscious way) that we are alive. Therefore, the perception of the own movement and the correct transmission of this information is probably involved in the neurodevelopment and functioning of self-awareness brain areas. Here, in this article, we wonder, at what point, the abnormal own-feelings found in depressives, are linked to dysfunctions of those self-awareness brain areas and of abnormalities of the vestibular system.

The vestibular input would be essential for the functioning of the neuronal circuits involved in self-recognition at the hippocampus and at the insular cortex. The semicircular canals of the vestibular system have the capacity to detect movements at different axes; yaw, pitch, roll, vertical and horizontal. This tridimensional information provided by the vestibular system, permanently feed the position cells at the hippocampus. The vestibular input is essential for the normal activity of those neurons and prevents the apoptosis of hippocampal cells. Position neurons of the hippocampus contribute directly to the creation of a personal map of the world, a self-referenced representation of the reality, and contribute at the same time, to the production of memories (Moser et al., 2015). We define ourselves as the one that is occupying a particular place inside of the representation of the reality of each; therefore, the vestibular system seems to have a fundamental role in the development of each one's self-idea or concept.

Brain functional images have demonstrated that the vestibular afferents coming from the right or the left inner ear reach the ipsilateral vestibular nuclei, arriving then to the ipsilateral insular cortex. There, the vestibular information merges with the information of other sensorial modalities (Pavuluri and May, 2015). The neuronal integration that happens in the insular cortex allows the construction of the feeling of self-unity, a fundamental condition for mental health sanity. The one who is moving, is me, is the same that perceives a warm sensation in the hands or hear a song. Thus, the traditional understanding of the vestibular system as a detector of our body position has been expanded now towards neuronal networks of self-recognition, influencing on emotional and cognitive functions, in memory and in decision-making processes. For this reason, from now, the vestibular system could be considered a matter that concerns to the mental sphere and vice versa.

The vestibular information is lateralized at the right insular cortex in most of the right-handed people (Dieterich et al., 2003). It means that most of the vestibular information coming from either right or left vestibular receptors arrives at the right hemisphere. Interestingly, the insular cortex of the right hemisphere is also involved in self-perception and self-identification functions (Craig, 2011). These precedents allow considering that, the vestibular system could have a role in the neuro-development and modulation of these higher brain functions. Here, in the present article, we question also, the existence of a modulatory influence coming back from the insular cortex to the vestibular nuclei.

However, despite all the previous conjectures could be very interesting, we still need concrete studies showing the involvement of vestibular system in neuropsychiatric disorders where the self-perception and self-recognition are the main issues. In addition, we need reports about the mechanisms and neuronal pathways possibly involved. The persistent pessimistic self-feeling in depressives, suggests a protagonist role of dysfunctional own-perception neuronal circuits that should be further measured and confirmed.

Two previous studies reveal abnormal vestibular activity in major depression; the first with eight depressed patients and ten healthy controls tested with caloric (water) vestibular stimulation and electronystagmographic registers (Soza Ried and Aviles, 2007), showed that major depression patients had a lower vestibular activity on the right side compared to the left. The other study demonstrates a characteristic pattern of vestibular activity, electrovestibulogram activity (Lithgow et al., 2015), in a group of 43 depressive patients and 31 controls, after vestibular stimulation.

Caloric and rotatory vestibular tests are common exams used to evaluate the vestibular system in people suffering from dizziness, vertigo or imbalance. In caloric tests, the function of each side of the vestibular system is measured by the stimulation of the inner ear receptors induced by hot/cold water or air in the ear canal. This test is not comfortable enough for all patients because of frequent vagal reactions. It also has some disadvantages, the anatomic variabilities of the auricular canal or the presence of tympanic perforations may produce unreliable results (Barber et al., 1978). In the rotatory tests, the participants receives vestibular stimulation consisting in turning while he/she is seated in a computer programmed rotary chair. The acceleration of the head excites the vestibular receptors of one inner ear and inhibits the other simultaneously, (contrary to caloric test that stimulates or inhibits one ear at a time), is a well-tolerated exam with no vagal reactions or minimal ones.

Prior evidence showing the role of the vestibular system in self-awareness, in emotional and memory processes supports to do further investigation on the involvement of the vestibular system in neuropsychiatric disorders. The present study performs objective measurements of the vestibular activity using the rotary test in a well-defined sample of major depression participants and healthy controls using rotatory tests.


  Participants and Methods Top


Participants

The study was conducted in 41 adults, including 21 depressed (depression group) and 20 healthy participants (control group). Both groups included male and females adults (18 years or older) and excluded pregnant woman, and participants with neurologic disorders. All participants provided informed consent.

Depression group included patients who met the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV, American Psychiatric Association, 2000) criterion. They had a score of 12 or more in the Hamilton Rating Scale, 21 items for Depression. The patients were with or without actual pharmacological treatment, except benzodiazepines that were suspended 24 hours before the rotary test when corresponding.



Control group consisted of healthy participants without psychiatric, vestibular symptoms, epilepsy, mood or depression history, who scored ≤ 7 on the Hamilton Rating Scale, 21 items for Depression.

No retribution was given to participants.

The study was developed under the principles of the Declaration of Helsinki and approved by Comité de Ética Científica Hospital Clínico Gral. Raul Yazigi. Res#110.

Depression group was civil people selected by psychiatrists from the ambulatory mental health consultation of the hospital; the control group included 20 healthy volunteers, composed by desk workers from the center.

Methods

All participants sat in the rotatory chair (Tonnies, Erben KG model), and prepared for the exam. After cleaning the skin, the registration electrodes adhered in each external angle of the eyes and the forehead, then the calibration was assessed. Once we obtained a good register, we instructed the participants to close the eyes and to incline the head around 30º forward. Further that, the chair began to move at two different accelerations consisting on per and post rotatory stimulation.

Per rotatory

Per rotatory acceleration is 25°/s2 for 4 seconds, final velocity 100°/s (rightward rotation stimulates the right ear's vestibular system, and vice versa for leftward rotations).

Per rotatory measurements fundaments: The rotation of the head towards the right side excites the right ear horizontal channel's receptors. The vestibular information is transmitted through the right VIII pair nerve to the right vestibular nuclei in the brain stem, which in turn, originates the slow movement (slow phase of nystagmus) of both eyes towards the contrary side of the head movement. Namely, the slow phase velocity (SPV) depends on the activity of the right vestibular nuclei. The rapid compensatory eye movement (fast phase) towards the same side of the head rotation depends on the Pontine Paramedian Reticular Formation, a neuronal center of the brain stem.

In sum, the SPV during the right-sided rotation (Right Per) depends on the activity of the right vestibular nuclei and vice versa; during left-sided rotation (Left Per) the SPV depends on the left vestibular nuclei.

Post rotatory

Once reached 100°/s the chair stops eliciting a rapid deceleration (100º/s2) (Right Post rotatory stimulates the left vestibular receptors meanwhile Left Post rotatory stimulates the vestibular system of the right ear) [Figure 1].
Figure 1: Vestibular nystagmus of a subject in a rotary chair.
Note: Rightward rotation stimulates right ear's vestibular receptors (red ear in the figure) and elicits a leftward slow phase of nystagmus (red colored lines in the oculomotor register). Leftward rotation is shown in blue. The slope of the slow phase corresponds to the slow phase velocity (SPV) and represents the vestibular activity. In A, the depression patient shows lower SPV (red lines) during the rightward compared to leftward rotation (blue lines). Healthy control shows similar SPV in both directions of rotation (B).


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Post rotatory measurements fundaments: This measurement corresponds to the vestibular activity that is elicited by the abrupt detention of the chair. The detention of the chair after right per sided rotation generates the right post rotatory vestibular activity that consists of stimulation of the left vestibular receptors and the inhibition of the right ear horizontal semicircular canal's vestibular receptors. In sum, right post rotatory SPV depends mainly on the activation of the left side of the vestibular system, and left post rotatory SPV, on the right vestibular activity.

Vestibular asymmetry

A simple form to appreciate the symmetry of the vestibular activity is calculating a ratio between right and left SPV. Thus, we calculated the Per ratio (right/left per rotatory SPV), which corresponds to right/left ratio at low accelerations, and Post ratio (left/right post rotatory SPV), which corresponds to right/left ratio at high accelerations.

Registration and analysis technique

Eye movements (nystagmus) were registered by three electrodes: one in each external angle of eyes and the third in the forehead. Displacements of the eyes were plotted on millimetric paper running at 25 mm/s. Electronystagmography registers of slow phase of the nystagmus were compared between control and depression groups. We analyzed the slopes of the slow phase corresponding to the velocity of eye movements (SPV). For each variable (Right Per, Left Per, Right Post, Left Post), we measured the average SPV of six different nystagmus.

Bias

To avoid bias, two researchers made blind analysis of the vestibular exams.

Study size

According to the differences of vestibular asymmetry between groups (healthy/depression) that we found in a previous pilot study, we calculate (STATA 12.0 software, Stata Corp., Texas, USA) that to have a 90% power and alpha 5%, we need 19 participants per group. We estimate that 30 participants per group would allow a security margin of 30% of missing data or abandon after the recruitment. For the depression group, 28 patients match the inclusion criteria, 7 declined to participate. For the control group, 32 matches the inclusion criteria and 12 of them declined to participate. We had no missing data in this study.

Statistical analysis

For the group's comparison, we used the Student's t-test with STATA 12.0 software (Stata Corp., College Station, TX, USA).


  Results Top


General characteristics of participants

The average age was similar between depression group (37.9 ± 13.7) and control group (41.1 ± 14.1) (P = 0.45). The distribution by sex showed significant differences; 60% of the control participants were females vs. 38% in the depression group. In the depression group, 3 patients were left-handed out of a total of 21 (14%), whereas in the control group, all (20 participants) were right-handed. We did not find ambidextrous. The main characteristics of age, gender, Hamilton Rating Scale for Depression score and the mean between Per and Post vestibular asymmetry ratios are shown separately in the depression and control groups in [Table 1].
Table 1: Characteristics and vestibular activity in the depression and control groups

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Rotatory chair testing results

Right Per rotatory SPV of the nystagmus was significantly lower in the depression group than that of control group, 30.1 ± 11.9º/s vs. 37.5 ± 7.0º/s (P = 0.02). Left Per rotatory SPV was not significantly different between the depression group (38.6 ± 10.6º/s) and the control group (33.26 ± 7.3º/s) (P = 0.06). Right Post rotatory SPV in the depression group (38.9 ± 11.4º/s) was statistically similar to that of control group (35.22 ± 12.5º/s) (P = 0.33). Left Post rotatory SPV (27.5 ± 7.1º/s) (which corresponds to the vestibular activity on the right side) in the depression group was significantly lower than that of control group (34.89 ± 10.2º/s) (P = 0.01).

Per ratio was substantially lower in depressives (0.77 ± 0.2) compared with controls (1.16 ± 0.3) (P < 0.01). Post ratio was also significantly lower in the depression group (0.73 ± 0.2) compared with control group (1.02 ± 0.2) (P < 0.001). The mean between Per and Post ratio was 0.75 ± 0.09 in depression group, significantly lower than that of control group (1.1 ± 0.18) (P < 0.001; [Figure 2]).
Figure 2: Distribution of vestibular asymmetry in depressive and control participants.
Note: Per ratio: DG vs. CG, P < 0.00001; post ratio: DG vs. CG, P < 0.0001. DG: Depression group (n = 21); CG: control group (n = 20).


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  Discussion Top


The present study demonstrates that major depression presents abnormal vestibular asymmetries consisting in lower vestibular activity at the right side compared to the left.

Here we confirm the previous findings assessed with caloric exams, now using a different technique consisting of the rotary test in a larger group of depressed patients. Having such confirmation allows us to question about the origin of this particular pattern of vestibular asymmetry in major depression. It also allows inquiring into the pathophysiologic meaning of it and wondering about the role of the vestibular system in neuropsychiatry.

Right and left vestibular functions depend directly on the vestibular nuclei's activity on respective sides in the brain stem. Vestibular nuclei receive excitatory and inhibitory modulation. Vestibular nerves come from each inner ear to the correspondent ipsilateral vestibular nuclei in the brain stem; they are essential afferents to vestibular nuclei. We look for previous reports of abnormalities at the right ear's vestibular receptors or the vestibular nerve in depression, but, as we expected, we did not find precedents of it. It led us to suggest that the hypo activity on the right side would depend on a lateralized modulation of the vestibular nuclei coming from “other” neuronal centers different to the vestibular nerve. Those centers would include the “inner cortical vestibular circuit” defined by Guldin et al. (1992), corresponding to descending modulation of vestibular activity coming from higher brain centers (Brandt et al., 2014).

The first evidence of the existence of this descendant modulation came from Carmichael, who described functional vestibular changes in brain lesioned patients (Carmichael et al., 1954). However, the description of the specific descending neuronal pathways to the vestibular nuclei was not done until 1988 (Ventre and Faugier-Grimaud, 1988; Faugier-Grimaud and Ventre, 1989) in macaque monkeys. The existence of those neuronal pathways was further reconfirmed by Akbarian et al. (1993, 1994) using retrograde tracer techniques also in monkeys. After that, Ventre-Dominey et al. (2003) demonstrated that the vestibular response to rotatory tests in brain lesioned patients was asymmetric, mainly when the lesion was on the right side. According to the previously mentioned works, the central neuronal afferents to the vestibular nucleus complex in the brain stem come from the parieto-insular vestibular cortex, areas 2a and 3a.

The insular cortex (the equivalent to the parieto-insular vestibular cortex in macaque monkeys) has been implicated in self-recognition. As the own identification and self-feelings are crucial for the maintenance of mental health, the insular cortex has been one of the leading targets in the study of mood and other psychiatric disorders during the last years.

Some prior investigations allowed suggest that the neuronal functions regarding own perception would be lateralized at the right frontoinsular cortex (Sridharan et al., 2008; Butti et al., 2009; Menon and Uddin, 2010; Allman et al., 2011). Interestingly, other studies have shown the involvement of the insular cortex in depression (Cohen et al., 2013; Liu et al., 2014; Stratmann et al., 2014). Unfortunately, there are still no definite conclusions regarding which side would be dysfunctional in depression. Abnormal self-feelings and impairment of decision-making in depression, suggest the involvement of right insular cortex (Allman et al., 2010; Preuss et al., 2014). All previous precedents support the existence of a modulatory role coming from the right insular cortex to the ipsilateral vestibular nuclei resulting in the correspondent vestibular hypoactivity found in this paper [Figure 3].
Figure 3: Proposed model of asymmetric neuromodulation of the vestibular activity in depression.
Note: Right and left vestibular nuclei in the brain stem governs each side of the vestibular activity correspondingly. The insular cortex of each hemisphere sends ipsilateral descending modulation to vestibular nuclei. The right insular cortex, involved in self-awareness, would be dysfunctional in depression. We propose that the abnormal functioning of the right insular cortex, which is involved in own-recognition and self-awareness, contributes to the vestibular asymmetry found in depressive patients.


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The studies in major depression patients show abnormal asymmetries of the hippocampus consisting in the diminished volume on the right or left side, depending on the publication (Savitz and Drevets, 2009). One study with a hundred and thirty-two depressives showed that the grey matter of the hippocampus and insular cortex on the right side was less than the average (Stratmann et al., 2014). The hippocampus receives important input from the vestibular nuclei (Stackman et al., 2002), we suggest that the vestibular asymmetry found here could contribute to the hippocampal asymmetry described previously. On the other side, since there are no precedents of afferents coming from the hippocampus to the vestibular nuclei, we think that the vestibular asymmetry probably does not depend on hippocampal asymmetry.

Other afferents, coming from the hypothalamus to the vestibular nuclei, could also explain the right-sided vestibular hypoactivity. Halberstadt and Balaban (2003, 2006) showed the existence of vestibular nuclei modulation coming from the hypothalamus through serotoninergic raphe nuclei neurons. Despite anatomic and functional abnormalities of raphe nuclei in depression has been widely described (Becker et al., 1994, 1995; Baumann et al., 2002), there is no evidence of abnormal lateralization. We think that directed studies in this respect must be done before discarding a possible contribution to the vestibular asymmetry found in depression.

Vestibular nuclei receive afferent modulation not only from the insular cortex and the raphe nuclei, but also from the somatosensory cortex (Akbarian et al., 1994), the cerebellum and the nucleus of the optic tract (Watanabe et al., 2003). Strictly talking any of those neuronal structures could be the potential origin of the right-sided vestibular dysfunction. Since, now, no publications suggest it, probably those brain areas are not seriously involved in the vestibular asymmetry described in this paper. However, we should do specific studies looking for abnormal lateralization of those neuronal centers in depression.

In sum, given the fact that the vestibular nuclei receive afferents from a multiplicity of neural structures, dysfunctions of any of them could theoretically originate the asymmetric vestibular hypofunction found in the present investigation. Of all those neuronal centers, only the insular cortex shows evidence of asymmetric activity in depression.

It is interesting to highlight that we observed right-sided vestibular hypoactivity in depressed patients even using different kinds of stimulation; caloric (Soza Ried and Aviles, 2007), Per rotatory and Post rotatory stimulation, each of them corresponding to varying accelerations of movement. Since we found that Per rotatory (low acceleration) was more asymmetric than Post rotatory (higher acceleration), we propose that in major depression, the type I hair cells (which have more sensibility for low accelerations) are more disabled than type II hair cells (involved in higher accelerations). Else, we wonder if there exists a differential modulation of different kinds of vestibular hair cell receptors. The physiologic and physiopathological significance of this finding has to be in mind for future investigations.

The vestibular asymmetry found here opens a different form to understand the vestibular system in the light of neuropsychiatric disorders. This finding introduces different physiopathological meanings of “abnormal brain asymmetry” and of “the vestibular system” renewing the traditional approach to depression. It also constructs a new framework to the whole functioning of the “human” nervous system that includes the role of brain centers involved in self-recognition, and the participation of the vestibular system as a fundamental input and output of them.

The absence of matching of sex and hand preference between both groups may limit the scope of this study. In the depression group, we found a significantly higher proportion of males and of left-handers than in the control group. Gender and manual preference may influence brain asymmetries, possibly affecting the vestibular asymmetry found here. Another weakness of this study is the inability to know the real proportion of controls without depression or mental disorders. As the control group was composed of desk workers of the hospital, some of them could have some apprehensions about telling their real symptoms or could have a poor insight.

 
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Acknowledgments
Thanks to J.F. Arrau S. for the artwork, and to Centro de Medicina Aeroespacial, Fuerza Aérea de Chile for local facilities.
Author contributions
AMS designed the experiment and wrote the paper. BC and ET conducted the vestibular exams and performed their subsequent analysis. All authors approved the final version of the paper.
Conflicts of interest
The authors report no conflicts of interest.
Financial support
This study was supported by a grant from Centro de Medicina Aeroespacial. The funder did not participate in data collection and analysis, article writing or submission.
Institutional review board statement
The study was developed under the principles of Declaration of Helsinki and approved by the BRI.
Declaration of participant consent
The authors certify that they have obtained all appropriate participant consent forms. In the form, the participants have given their consent for their images and other clinical information to be reported in the journal. The participants understand that their names and initials will not be published and due efforts will be made to conceal their identify, but anonymity cannot be guaranteed.
Reporting statement
This study follows the Recommendations for the Conduct, Reporting, Editing and Publication of Scholarly Work in Medical Journals developed by the International Committee of Medical Journal Editors.
Biostatistics statement
The statistical methods of this study were reviewed by the biostatistician of the University of Chile in Santiago.
Copyright license agreement
The Copyright License Agreement has been signed by all authors before publication.
Data sharing statement
Data will be available in Mendeley dataset.
Plagiarism check
Checked twice by iThenticate.
Peer review
Externally peer reviewed.


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Abstract
Introduction
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