The involvement of vitamin D in the pathogenesis of anxiety and depression in benign paroxysmal positional vertigo comorbidities

Benign paroxysmal positional vertigo (BPPV) is a peripheral vestibular disease that can induce transient vertigo and nystagmus when head position changes.¹ BPPV is one of the most common peripheral vestibular nerve diseases, with an annual incidence of 1.6% and a lifetime prevalence of 2.4% in the general population.² The risk factors for the onset of BPPV are related to gender, age, head trauma, high cholesterol, osteoporosis, and vitamin D (VD) deficiency.³ The decrease in bone density and serum 25-hydroxyVD levels promotes frequent otolith detachment and is also associated with the recurrence of BPPV. In recent years, the relationship between VD and BPPV has garnered significant attention, particularly concerning the potential role of VD in preventing the recurrence of BPPV. VD is a type of steroid derivative that mainly exists in the form of 25-hydroxyVD in the bloodstream. It is converted into 1,25-dihydroxyVD by the kidneys and then binds to the vitamin D receptor (VDR) to exert its effects. VDR is a member of the transcription regulatory factor receptor superfamily, involved in gene transcription of VD effects, thereby regulating calcium/phosphorus metabolism, cell proliferation, and immune regulation. While initial studies did not establish a direct link between the occurrence of BPPV and low levels of VD, they have consistently associated the recurrence of BPPV with reduced VD levels. Current research demonstrates that VD supplementation significantly lowers the rate of recurrence and the number of recurrences per patient among those suffering from VD deficiency or insufficiency.⁴

Study on the Pathogenesis of VD Involvement in BPPV

In recent years, multiple studies have shown that the occurrence and recurrence of BPPV are closely related to the lack of VD.^4,5 A systematic review suggests that a supplementation of VD could reduce the BPPV recurrence in patients with subnormal VD levels. Despite the lack of high-quality studies, the current literature highlights the role of VD-level optimization in patients with BPPV.⁶ When VD is severely lacking, the recurrence rate of BPPV significantly increases, and supplementing VD can effectively reduce the recurrence rate of BPPV Disease onset and recurrence.⁷ Sarsitthithum et al. conducted a prospective study and discovered that patients in the BPPV group had significantly lower levels of serum VD, a relationship that exists both among patients with a first-time diagnosis of BPPV and those with recurrent BPPV. Therefore, low serum VD levels may be a risk factor for BPPV.⁸ Similarly, Abdelmaksoud et al. explored the relationship between BPPV recurrence and VD deficiency, and found that the patients of BPPV with a level below 20ng/mL have a higher recurrence rate.⁹ Our previous research team also found that the lack of VD is associated with the recurrence of BPPV. Giving low-dose VD to BPPV patients with low serum 25-hydroxyVD levels can help reduce the recurrence rate of BPPV patients.¹⁰ The potential mechanisms by which VD prevents the recurrence of BPPV may involve its regulatory effects on calcium ion concentration and its influence on ion channels and pumps. Additionally, the role of VD in modulating immune responses and its antioxidant properties might also contribute to its preventative effects against BPPV recurrence.

Deficiency of VD leads to abnormal calcium metabolism leading to BPPV

VD is the most important regulatory factor for calcium metabolism in the body. Related studies have shown that VD is involved in the metabolism of otoliths related to BPPV and plays an important role in maintaining the normal physiological function of otoliths.^7,8 Otoliths are calcareous concretions, predominantly composed of calcium carbonate in the form of aragonite, with a minor component of calcium phosphate. These crystalline structures are affixed to the maculae of the utricle and saccule within the vestibular apparatus of the inner ear.¹¹ 25-hydroxyVD plays a critical role in preserving the functional integrity of otoliths by regulating calcium ion concentrations specifically in the vestibular endolymph.¹² VD can regulate the activity of epithelial ${\text{Ca}}^{2+}$ channels through the VDR receptor, leading to abnormal expression and functional defects of otolith regulatory proteins such as plasma membrane ${\text{Ca}}^{2+}$-ATPase isoform 2 (PMCA2), Pendrin protein, carbonic anhydrase (CA), transient receptor potential V family 5/6 (TRPV5/6), resulting in impaired secretion of ${\text{Ca}}^{2+}$ and ${\text{HCO}}^{3-}$ in the otolith microenvironment.¹³ The decrease in pH value of endolymph and the imbalance of ${\text{Ca}}^{2+}$- ${\text{HCO}}^{3-}$ ratio can lead to a decrease in calcium content, density, and volume of otoliths, making it prone to abnormal degeneration and detachment, leading to vestibular diseases such as BPPV.⁷

Lack of VD leading to dysfunction of vestibular immune regulation leading to BPPV

In recent years, an increasing number of research results have shown that VD is involved in immune regulation and plays an important role in regulating the activation, proliferation, and differentiation of inflammatory physiological processes.^13,14,15 The excess and deficiency of VD are also related to neurological, endocrine, autoimmune, and other diseases.^13,16 Studies have shown that 1,25-(OH): D3 is an anti-inflammatory helper cell that downregulates expression and produces pro-inflammatory cytokines such as TNF-$\alpha$, IL-1B, IL-6, IL-8¹⁰; upregulation of anti-inflammatory cytokines such as IL-4, IL-5, and IL-10. These functions are mainly mediated by the nuclear vitamin D receptor (nVDR).^10,17 Previous extensive studies have found that nVDR is distributed in the immune system of multiple cells in the human body, such as regulatory T cells (Treg cells), neutrophils, dendritic cells, B lymphocytes, macrophages, as well as the inner ear, ampullary crest epithelium, membranous semi tubules, and peripheral bone cells. Considering the presence of nVDR in the inner ear, the inference that VD may affect vestibular function seems logical.¹³ For example, mice lacking nVDR exhibit reduced expression levels of otolith-associated proteins otoconin-90 and NADPH oxidase 3 significantly. This suggests that VDR may be underexpressed in BPPV patients and is related to the expression level of otolitho-related proteins.¹⁸ When VD levels decrease, the body’s inhibitory adaptive immune system and inflammatory function may weaken. The number of pro-inflammatory mediators may increase, leading to a decrease in microvascular perfusion in the vestibular organs and causing neurological dysfunction.

Mechanisms of VD in Anxiety and Depression

Depression and anxiety significantly impact health and quality of life. Findings have shown that low levels of VD are associated with an increase in symptoms of depression and anxiety.¹⁹ VD, with its antioxidant properties, plays a crucial role in preventing or treating mood disorders. The therapeutic potential of VD for depression and anxiety is due to its multifunctional nature, which extends far beyond its impact on calcium and phosphorus metabolism. Specifically, the antioxidant, anti-inflammatory, neurogenic, and neuromodulatory properties of VD seem to be crucial for its anti-depressive and anti-anxiety effects.²⁰ However, this claim is controversial. One study showed that after a 6-month intervention, VD supplementation improved anxiety symptoms in patients with low levels of VD but did not improve symptoms of depression.²¹

Antioxidant and anti-inflammatory properties

VD can promote redox balance by regulating antioxidant enzymes, thereby mitigating neuroinflammation. Moreover, VD can reduce the expression of IL-1$\beta$, TNF-$\alpha$, and inducible nitric oxide synthase (iNOS) in the prefrontal cortex.

Neurogenic and neuromodulatory properties

VD deficiency has been proven to affect brain development, including processes such as cortical thinning and synaptic plasticity. VD is involved in synthesizing BDNF and the neurotrophic factor NT-3, which are crucial for neuronal survival, growth, and differentiation.

VD and gut microbiome regulation

VD deficiency leads to changes in the gut microbiome, triggering intestinal barrier dysfunction, and gut inflammation. Additionally, VD deficiency or insufficiency may indirectly regulate serotonin production by altering the gut microbiome, where serotonin is a neurotransmitter regulating bodily functions, including digestion, mood, sleep, and social cognition. Whether VD can influence the gut microbiota and regulate serotonin synthesis remains a subject worthy of further research.²²

The Mechanism of VD Involvement in BPPV Comorbidity Anxiety and Depression

In recent years, more and more studies have found that it is common for BPPV patients to have mental and psychological problems.^23,24 Research has found that patients in the BPPV group have more severe psychological problems such as somatized depression and anxiety compared to the normal control group.²⁵ Kozak et al.²⁶ found that the incidence of mental and psychological problems such as depression and generalized anxiety in patients with BPPV is higher than that of the general population; Honaker et al.²⁴ showed that the Beck Anxiety Scale scores of BPPV patients were higher than those of the control group, indicating that BPPV patients had higher levels of anxiety. A prospective cohort study evaluating BPPV patients after 3 months of follow-up found that 12.21% of BPPV patients developed anxiety and depression, and Spearman correlation showed a significant moderate positive association.²⁷ The treatment of patients is often unsatisfactory because of the close interaction among vestibular, psychiatric, and neurological disorders. Therefore, clinicians need to consider psychological issues when facing patients with BPPV.²⁸ A meta-analysis has demonstrated that 27% of patients with BPPV experience anxiety, representing a 3.19-fold increased risk of anxiety in BPPV patients compared to controls. The sudden and unexpected changes in head movement characteristic of BPPV may provoke fear and anxiety among these patients. Furthermore, individuals with anxiety disorders are more likely to develop BPPV.²⁹ The above studies have shown that the incidence of comorbidity between BPPV and anxiety and depression is significantly higher than that of the general population. Although there may be a connection between BPPV and anxiety, the mechanisms linking peripheral vertigo with psychiatric comorbidities are complex and varied. Hypotheses have been proposed to explain the association between vestibular disorders and psychiatric conditions, including the otogenic and psychogenic hypotheses.³⁰ The otogenic hypothesis suggests that vertigo may lead to secondary psychological distress, while the psychogenic hypothesis posits that pre-existing psychological stress may manifest as secondary vertigo or dizziness. There is currently limited research on the mechanism of comorbidity between BPPV and depression.

The VDR receptor family is distributed in multiple human brain regions related to cognitive, language, and other functions, such as the prefrontal lobe, hippocampus, basal forebrain, amygdala, and striatum. The biological effects of 1,25-dihydroxyVD are mediated by VDR, which belongs to the steroid thyroid vitamin A receptor superfamily of ligand-activated transcription factors and controls 3–5% of human genes. The existence of VDR in the central nervous system was first demonstrated in 1982. VDR exists in almost all human tissues and is widely distributed in neurons and glial cells in the adult brain. The highest expression levels in the brain are found in the hippocampus, hypothalamus, thalamus, cortex, and Substantia Nigra. These brain regions are related to the pathophysiology of depression, therefore, VD can exert effects in these regions.

Mechanisms of neuroendocrine immune disorders

VD is closely related to the vestibular nervous system and the neural circuits related to anxiety and depression.³¹ The lack of VD causes vestibular nervous organs directly related to dizziness and balance to obtain information and process it in the amygdala, marginal subcorticus, and hypothalamus, forming higher-level connections with many emotionally related nuclei such as the parabrachial nucleus, dorsal raphe nucleus, and locus coeruleus, participating in the regulation of emotional responses.^6,32

Some literature also points out that VD is associated with vestibular nervous organs, as well as the frontal lobe, dentate gyrus, hippocampus, etc.^33,34 The vestibular nucleus forms neural circuits through neurotransmitters such as serotonin (5-HT), dopamine (DA), and norepinephrine (NE) with the parabrachial nucleus, raphe nucleus, thalamic cortex, and locus coeruleus.³⁵ The deficiency of VD has been associated with an increased risk of developing depression and anxiety, and individuals with these psychiatric conditions have low serum levels of this vitamin. Therefore, dysfunction of related neurotransmitters can have a significant impact on the electrophysiological activity of neurons and dysfunction of vestibular nucleus complexes. Neuroendocrine dysfunction can cause blood flow imbalance in the inner ear, affecting inner ear homeostasis, and is considered a potential risk factor for the occurrence of BPPV.

Mechanism of gene polymorphism

The VDR gene is located on chromosome 22, 12q13, consisting of nine exons and eight introns, with a length of approximately 75 kb.³⁶ It is a ligand-induced transcription factor that encodes a protein belonging to the nuclear receptor superfamily. Under the activation of VD, VDR binds to hormone-responsive elements in DNA, regulating the expression of target genes. Currently, there are five loci have been extensively studied for VDR gene polymorphism, all named after endonuclease sites, namely ApaI, BsmI, TapI, FokI, and Cdx-2.³⁶ There is evidence to suggest that there are four single nucleotide polymorphisms (SNPs) in VDR that may be associated with diseases; three at the 3’ end (TaqI, BsmI, ApaI) of the VDR gene and one at the 5’ end (FokI). Cdx-2 is located in the promoter region and regulates transcriptional activity.³⁷ Our research group conducted a comparative analysis of clinical data, biochemical indicators, and the distribution of VD gene restriction endonuclease ApaI and BsmI genes in 98 patients with BPPV and 100 healthy patients in the early stage. The results showed that the VDR ApaiI gene rs7975232 and BsmI gene rs1544410 have a certain correlation with the onset of BPPV, which is consistent with the conclusions obtained from other studies.³⁸

Oxidative stress and neuroinflammatory mechanisms

The pathophysiological mechanism underlying the increased risk of developing BPPV in patients with anxiety and depression may begin with the inflammatory process. Neuroinflammation is considered to play a crucial role in the pathophysiology of BPPV, and studies have shown that patients with BPPV have lower total antioxidant levels, with IL-1 being a key factor $\beta$ and oxidative stress is involved in the pathogenesis of BPPV.³⁹ Depression, on the other hand, occurs through similar inflammatory reactions, such as pro-inflammatory cytokines inducing endothelial cell oxidative stress leading to recurrent vasospasm, and otolith translocation from the macular epithelium leading to the occurrence of BPPV.⁴⁰ One of the important pathophysiological factors of BPPV is that its otolith dysfunction may be related to the degradation process related to oxidative stress and pro-inflammatory response.⁴¹ Some studies have evaluated the total antioxidant status and inflammatory mediator levels of the BPPV case group and control group by collecting peripheral blood. The results indicate that IL-1 $\beta$ and oxidative stress are involved in the pathogenesis of BPPV. Therefore, it is also necessary to pay attention to the inflammatory response and oxidative stress levels of patients, which can help clarify the specific pathogenesis of BPPV.⁵

Outlook

In recent years, an increasing number of BPPV patients with anxiety and depression have gradually attracted widespread attention from researchers both domestically and internationally, but there are still many controversial issues. The pathogenesis of this disease is not yet very clear, there are still many uncertainties, and there are many related susceptibility factors. Some of these susceptibility factors are not directly related to this disease, and further exploration is needed through multicenter, large sample, and prospective randomized controlled studies to draw accurate conclusions.

Acknowledgment

Jinmei Ren and Yuzhu Jiang contributed equally to the development and writing of this paper. Both authors participated significantly in the research design and manuscript preparation.

ORCID

Jinmei Ren  https://orcid.org/0000-0002-5700-0832

Yuzhu Jiang  https://orcid.org/0009-0003-7317-0254

Qinghong Zeng  https://orcid.org/0000-0003-2861-8139

Yang Wang  https://orcid.org/0000-0002-1081-8899

Qianhong Yang  https://orcid.org/0009-0005-8415-6516

Yulong Jiang  https://orcid.org/0009-0005-9840-3469