Alterations of brain activity in right brainstem and right entorhinal cortex mediated anti-depressant effects of transcutaneous auricular vagus nerve stimulation in functional dyspepsia rats: a resting-state fMRI study

doi:10.21203/rs.3.rs-5233050/v1

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Alterations of brain activity in right brainstem and right entorhinal cortex mediated anti-depressant effects of transcutaneous auricular vagus nerve stimulation in functional dyspepsia rats: a resting-state fMRI study

https://doi.org/10.21203/rs.3.rs-5233050/v1

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Objective: Functional dyspepsia (FD) is often accompanied by depression. Transcutaneous auricular vagus nerve stimulation (taVNS) has been shown beneficial to FD. However, the effect of taVNS on depression is associated with FD and its central mechanism remains unknown. In this study, we investigated depression-like behavioral changes and cerebral alterations of brain activity of taVNS in a rodent model of FD.

Methods: Neonatal SD rats were gavaged with iodoacetamide (IA) to induce a FD model. Twenty-one SD rats were randomly divided into control, IA, and taVNS groups (each, n=7). taVNS was performed for 30 minutes once daily for 14 days consecutively. The open field test (OFT) and forced swimming test (FST) were conducted to assess depression-like behaviors. The low-frequency fluctuations (ALFF) and regional homogeneity (ReHo) were assessed from resting-state functional magnetic resonance imaging to evaluated the changes of spontaneous neural activity and local neural coordination of FD rats with depression-like behaviors.. Correlations between differential ALFF and ReHo values and depression-like behaviors were analyzed to ascertain taVNS-related central changes.

Results: Compared with the control group, the horizontal and vertical scores of OFT were decreased, and the immobility time of FST was increased in the IA group. The ALFF values of the right brainstem were increased in the IA group. The ALFF values of the left molecular laye of the cerebellum and the ReHo values of the right entorhinal cortex were decreased in the IA group. taVNS increased the horizontal and vertical scores of OFT and reduced the immobility time of FST. After taVNS intervention, the ALFF and ReHo values of the right brainstem decreased. The ALFF values of the left molecular layer of the cerebellum and the ReHo values of the right entorhinal cortex were increased. The horizontal score of OFT was negatively correlated with the ALFF of right brainstem. The vertical score of OFT and immobility time of FST negatively correlated with ReHo values of the entorhinal cortex.

Conclusion: taVNS alleviates depression state in the rodent model of FD possibly mediated by the enhancement of local neural coordination in the right entorhinal cortex and suppression of spontaneous neural activity in right brainstem. taVNS may have a therapeutic potential for depression in FD patients.

Functional dyspepsia

Depression

Transcutaneous auricular electrical vagus nerve stimulation

Brainstem

Entorhinal cortex

Functional dyspepsia (FD) is a multifactorial upper gastrointestinal disease that is usually accompanied with depression or other emotional abnormalities.¹ The severity of the symptoms of FD is related to psychological factors.² Abnormal emotional conditions may be the pathogenic factor of gastrointestinal symptoms³ or the result of gastrointestinal disorders.⁴ Based on the potential role of depression in the pathogenesis of FD, an increased number of studies have included anxiety and depression scores as secondary outcomes in FD studies.⁵ The psychosomatic comorbidities of FD aggravate the economic burden significantly.² First-line medical therapies for functional gastrointestinal disorders have limited efficacy in alleviating anxiety and depression. The second-line drugs as central neuromodulators were reported to improve these symptoms.⁶ However, there are significant side effects, such as drowsiness and dependence.⁷ Accordingly, therapies targeting depression symptoms in FD are urgently needed.

Transcutaneous auricular vagus nerve stimulation (taVNS), as a neuromodulation technique, was recently reported to improve depression and anxiety in patients with FD.⁸ Compared with vagal nerve stimulation, taVNS is more acceptable to patients because it is a non-invasive therapy.⁹ In addition to depression and anxiety, clinical studies have shown that taVNS also relieves gastrointestinal symptoms, visceral pain and improve quality of life in patients with FD and patients with irritable bowel syndrome.^{10, 11} However, the central mechanism of taVNS for depression and anxiety in FD are not yet clear.

Resting-state functional magnetic resonance imaging (rs-fMRI), a neuroimaging technique based on blood oxygen level dependence (BOLD), is used to detect resting-state regional brain activities. The rs-fMRI technology has been utilized to explore the central mechanism of taVNS for depression in patients with major depression disorder.¹² Amplitude of low-frequency fluctuations (ALFF) and regional homogeneity (ReHo) reflect the strength of local neural activity, with ALFF reflecting spontaneous brain activity,¹³ and ReHo measuring similarity of time series.¹⁴ The combination of ALFF and ReHo can be used as indicators of neurophysiological changes to explore the central mechanism of taVNS for depression. At present, none rs-fMRI studies were designed to analyze the spontaneous neural activity and local neural coordination in the rodent model of FD with depression state after taVNS intervention. The central mechanism of taVNS for depression state of FD are not yet clear.

The brainstem is believed to play a significant role in the pathophysiology of depression state in FD. A neuroimaging study showed significant structural alterations in the brainstem regions in major depressive disorder patients compared to healthy controls.¹⁵ In addition, lower peristaltic propagation velocity linked to altered brainstem-cortical functional connectivity in FD patients.¹⁶ TaVNS has been proved that may influence afferent vagal networks.¹⁷ The afferent vagal nerves primarily project to the nucleus tractus solitaries (NTS), which in turn transmits the signal to the other brain stem nodes such as the locus coeruleus,¹⁸ spinal trigeminal nucleus,¹⁹ and other subcortical and cortical regions.²⁰ We hypothesized that taVNS would modulate the spontaneous neural activity and local neural coordination in the brainstem, resulting in improvement in depression.

This aims of this study were to investigate the effects of taVNS on depression-like behaviors in a rodent model of FD and to explore the central mechanisms of taVNS by assessing ALFF and ReHo from rs-fMRI.

Animal Model

Five-days-old male Sprague Dawley (SD) rats (Sibeifu, Beijing, China, license NO. SCXK-Beijing-2016-0002) were purchased and housed in animal cages (35 cm x 25 cm x 20 cm; before ablactation: a litter/cage; from ablactation at third week to adult: 3 rats/cages) under the following conditions: room temperature of 23 ± 2℃, relative humidity of 60% ± 5% artificially lighted from 7:00 a.m. to 7:00 p.m. with light intensity similar to daylight. The rats had free access to conventional rodent lab chow and water. The cages and bedding were changed every day. The person in charge of the animal’s welfare carried out the experiments. We used only male rats for the study to avoid possible confounding effects of gender due to differences in hormones. This study was conducted in accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. The experimental protocol was approved by the Animal Care and Use Committee in the Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences (D2019-11-14-1). All efforts were made to minimize suffering.

The modeling, intervention and experimental protocol are shown in Figure 1. Except for the control group, all animals were gavaged with iodoacetamide (IA, 0.2 mL 0.1% IA in 2% sucrose solution) at the age of 10 days daily for 6 days²¹. This process has been utilized in previous studies to bulit the model of FD rats that also induced depression-like behaviors in a rodent model of FD.^{22, 23} Rats in the control group did not received any intervention.

Intervention

Transcutaneous auricular vagus nerve stimulation (taVNS)

The rats in the taVNS group were placed in a fixator, permitting relatively free movement. After 30 min of adaptive fixation, two opposite magnetic electrodes (+/-) were placed on both sides (inside and outside) of bilateral auricula concha so that electrical current could conduct through the tissue. Saline was applied between the electrode and the skin to improve electrical current conduction. At age of 9 weeks, taVNS was performed 30 min once daily for 14 days using the following parameters: 100 Hz, 0.5ms, 0.1s-on, 0.4s-off and an intensity of 0.5 mA via a watch-size electrical stimulator (Transcutaneous Electrical Acustimulation, SNM-FDCM01, Medkinetic, Ningbo, China).

Behavioral Tests

Open field test (OFT)

Rats were acclimatized to the laboratory environment one hour before the test. A black square opaque box (100 cm x 100 cm x 40 cm) was utilized for the OFT test. The box was placed in the center of the room with a camera fixed above the box on the ceiling. Four light sources were used to eliminate shadows. Each rat was placed in the center of the box, and the camera recorded animal movement. The horizontal and vertical scores were recorded for 5 minutes. The horizontal score was the number of horizontal crossing grids of the rat (all four paws enter the square to be counted). The vertical score was the number of vertical standing (the two front paws of the rat were off the cage bottom or against the side wall of the open box). The room was kept quiet during the recording, and the animals had no visual contact with the investigator. The chamber was thoroughly cleaned with 75% ethanol and water to eradicate any remnant animal scent.²⁴

Forced swimming test (FST)

Rats were placed individually in a transparent plexiglass cylinder (60 cm in height, 30 cm in diameter) filled with fresh water (24 -26℃) up to a height of 45 cm from the bottom. The immobility time of each rat, a total of 5 minutes, was individually recorded.²⁵

MRI Experiments

All MRI experiments were conducted using a 7.0 T animal MRI scanner (Bruker ClinScan Germany). During the MRI scans, the animals were anesthetized with isoflurane (1.0–1.5%, 1.0 L/ min). The rodent’s body temperature was maintained using a warm water circulation system. BOLD rs-fMRI images were acquired with the following parameters: field of view (FOV) = 25×20 mm², thickness = 1.0 mm, slice gap=0.2 mm, repetition time (TR)/echo time (TE) = 2691.4 ms/27.6 ms, flip angle = 90°. ²⁶

The fMRI image data pre-processing was performed using Statistical parametric mapping 12 (SPM12) software on the Matlab R2022b. The data were converted to Neuroimaging informatics technology initiative (NIFIT) format for recognition and processing within the software. The image proctor data from the first 10 time points of each subject were removed to exclude the effect of the signal onset instability of the magnetic field and to achieve the adaptation of the experimental animals to the magnetic field. Slice timing: interpolation was used to make the results of each scan converge to the actual results at a certain time. Realign: removing data where the head moved more than 3 mm in each direction (X, Y, Z) or rotated more than 3° in any angle to reduce the effect of head movement on the image. Spatial normalization: the brain images of experimental rats were aligned to the standard brain to exclude the differences in anatomical structures of individual brain tissues and overcome the influence of different brain structures on the data. Smooth: spatial smoothing was performed by using a 6mm half-orbit full-width (FWHM) Gaussian smoothing kernel to blur the differences between the brain structures of different subjects, improve the signal-to-noise ratio of the images, and reduce the remaining inter-individual differences after normalization, to make the images more in line with the assumption of Gaussian distribution. Detrend: used to reduce the effects on the data due to the increased temperature of the MRI machine and the subjects' adaptation to the environment. Low-frequency filtering: extracting their low-frequency signals in the frequency range of 0.01-0.08 Hz to remove the effects of high-frequency respiratory heartbeats and low-frequency noise. The ALFF and ReHo were calculated.²⁷

Statistical Analysis

SPSS 26.0 software was used for statistical analysis. A Shapiro-Wilk test was used to examine the normality of the data. If the data fit a normal distribution, one-way ANOVA was used for comparison among multiple groups. The Fisher's least significant difference (LSD) post hoc test was used for data with a homogeneity of variance. Tamhane's T2 (M) test was used after ANOVA if the data were not by homogeneity of variance. If the data did not conform to normality, the Kruskal-Wallis H test was applied. Analyses and graphing were conducted by GraphPad Prism 8.0. Differences were considered statistically significant at P<0.05.

Differences of ALFF and ReHo among the three groups were used One-way ANOVA with F > 0 representing a significant brain region of difference among the three groups combined with significance criteria of voxel P<0.005 and cluster P<0.05.

To examine the associations between the evaluated behaviors and the cerebral alterations of taVNS for FD, we performed Pearson (data fit a normal distribution) or Spearman (data did not have a normal distribution) correlation analyses between the behavioral test indices and ALLF/ReHo values in the brain regions that exhibited significant differences between the control and IA groups, as well as between the IA and taVNS groups. Differences were considered statistically significant at P<0.05.

taVNS ameliorated depression-like behaviors in the rodent model of FD

To measure the effect of taVNS on depression-like behaviors, we performed OFT and FST in the control, IA and taVNS groups. The IA group showed obvious depression-like behaviors with a decreased horizontal score (P<0.001) and a decreased vertical score (P=0.003) as well as increased immobility time (P<0.001) compared to the control group. In the rats after taVNS, the horizontal score (P<0.001) and vertical scores (P=0.032) of OFT were higher and the immobility time (P<0.001) of FST was lower than those in the IA group (Figure 2a-c). No differences were noted in any of these measures between the taVNS and control groups, suggesting normalization of the behaviors.

taVNS decreased the ALFF values of the right brainstem and increased the ALFF values of the left molecular layer of the cerebellum in the rodent model of FD

As shown in Figure 3a, b and Table 1, the IA group showed higher ALFF values in the right brainstem (P=0.041) and lower ALFF values in the left cerebellar molecular layer (P<0.001) compared to the control group. The ALFF values in the taVNS group was lower in the right brainstem (P<0.001) and higher in the left cerebellar molecular layer (P=0.007) compared to the IA group. (Figure 3c, d)

Table 1 Brain regions with ALFF differences

Brain region	Coordinates			F value	Cluster size
Brain region	X	Y	Z	F value	Cluster size
Brainstem R	1.70	-0.28	-14.90	19.20	125
Molecular Layer of the Cerebellum L	-3.10	0.62	-1.31	18.35	67

Abbreviation: ALFF, Amplitude of low-frequency fluctuations; R, right; L, left.

taVNS increased the ReHo values in the right entorhinal cortex and decreased the ReHo values in the right brainstem of FD rats

As shown in Figure 4a, b and Table 2, compared to the control group, the IA group showed lower ReHo values in the right entorhinal cortex (P<0.001). The taVNS group showed lower ReHo values in the right brainstem (P<0.001). Compared to the IA group, the taVNS group showed higher ReHo values in the right entorhinal cortex (P<0.001) and lower ReHo values in the right brainstem (P<0.001) (Figure 4c, d).

Table 2 Brain regions with ReHo differences

Brain region	Coordinates			F value	Cluster size
Brain region	X	Y	Z	F value	Cluster size
Entorhinal_Cortex_R	3.40	-1.78	-0.50	29.23	329
Brainstem_R	1.30	-1.48	-14.90	24.89	257

Abbreviation: ReHo, regional homogeneity; R, right; L, left.

Correlation between depression-like behaviors and ALLF value of right brainstem and ReHo of right entorhinal cortex

The horizontal score of OFT was significantly negatively correlated with the ALFF of right brainstem (r=-0.8, P = 0.015). The vertical score of OFT and immobility time of FST was significantly negatively correlated with ReHo values of the entorhinal cortex (r=-0.9, P < 0.01; r=-0.8, P = 0.0467, respectively) (Figure 5a-c).

In this study, taVNS was demonstrated to alleviate the depression-like behaviors in rats with FD, including the elevation of horizontal scores and vertical scores, as well as the reduction of forced swimming immobility time. Concurrently, taVNS improved alterations in ALFF and ReHo in the rodent model of FD, suggesting a central neural mechanism of taVNS for depression.

According to the previous study, visceral motor responsed to gastric distension was remarkably decreased by vagus nerve stimulation at 100Hz.²⁸ Therefore, we chose the 100Hz as the stimulation parameters. In terms of measurement of depression-like behaviors, the OFT can quantitatively evaluate the locomotor activity, exploration behavior, and depression state of animals.²⁹ The FST are commonly employed to assess the extent of behavioral despair in rodents.³⁰ Thus, we evaluated depressive-like behaviors in rodent model of FD by using the two behavioral methods.

FD is considered as the disorder of complex gut-brain interaction.³¹ The vagus nerve is the main neural pathway between the gastrointestinal tract and the brain.³² In the gut, sensory afferent vagus neurons respond to physiological and pathological stimuli and transmit this information to secondary neurons in NTS. NTS neurons further project to almost all other brain regions, including centers involved in emotion regulation.³³ The evidence from animal models,³⁴ as well as human subjects, confirmed that taVNS activates the vagus nerve to exert antidepressant effects.⁹ Aberrant gastric signals transmitted by the vagus nerve may alter key brain regions that regulate emotion. FD patients companying with both postprandial distress syndrome and epigastric pain syndrome display autonomic nerve function damage and depression state.³⁵ A randomized, double-blinded, sham-controlled study showed that taVNS improves FD by enhancing vagal efferent activity.⁸

To the best of our knowledge, this was the first rs-fMRI study designed to explore the spontaneous neural activity and local neural coordination in the rodent model of FD with depression after taVNS intervention. In this study, voxels that overlap in ALFF and ReHo indicated that taVNS decreased the spontaneous neural activity and local neural coordination in right brainstem of FD rats. Meanwhile, taVNS increased the ALFF values of the left cerebellar molecular layer the ReHo values in the entorhinal cortex of FD rats. Further correlation analyses revealed that the horizontal score of OFT was significantly negatively correlated with the ALFF of right brainstem. The vertical score of OFT and immobility time of FST negatively correlated with ReHo values of the entorhinal cortex.

Abnormal brain activities in FD patients during the resting state have been proven by several fMRI studies. A research for FD patients using rs-fMRI showed the significant between-group difference in fALFF in brainstem.³⁶ On the other hand, depressive disorders are associated with a decrease in the volume of the entorhinal cortex.³⁷ Multi-modal MRI measures reveal that major depressive disorder patients showed decreased surface area in the entorhinal cortex than the controls.³⁸ According to a neuropathology study, the entorhinal cortex may be impacted by brainstem pathology and implicated in affective changes.³⁹ Cerebellum is related to motor learning⁴⁰ and emotional process.⁴¹ Previous rs-fMRI study found that, compared with healthy control, FD patients displayed spontaneous brain activity abnormalities in cerebellum.³⁶ The current study is in parallel with previous rs-MRI research findings that showed abnormal activity in the brain in FD patients, including the enhancement of spontaneous neural activity and local neural coordination in right brainstem, the decline of spontaneous neural activity in left cerebellar molecular layer,⁴² and the decline of local neural coordination in right entorhinal cortex and brainstem.

TaVNS activates the afferent vagal nerves that may boosts stomach-brain coupling in the brainstem, midbrain, and transmodal cortex.⁴³ A rs-fMRI research⁴⁴ found a significant response to acute taVNS stimulation in downstream targets of vagal afferents, including the NTS, the substantia nigra, and the subthalamic nucleus. Entorhinal cortex mediates the formation of spatial memory.⁴⁵ Rats with depression state displayed impairment of spatial memory retrieval.⁴⁶ The results of rs-fMRI indicated that the central changes in FD rats were normalized by taVNS, including decline of spontaneous neural activity and local neural coordination of right brainstem, enhancement of spontaneous neural activity of the left molecular layer of the cerebellum and enhancement of right entorhinal cortex. A series of experiments shows that the cerebellum receives afferents from the autonomic nervous system.⁴⁷ fMRI studies show activation of cerebellum during taVNS.⁴⁸ However, correlation analysis did not reveal correlations between ALFF values and the depression symptoms in patients with gastrointestinal disease.⁴⁹ In this study, the results of correlated analyses indicated that taVNS might decrease the spontaneous neural activity of the right brainstem and increase the local neural coordination in the right entorhinal cortex to improve the depression behaviors of FD rats.

TaVNS has the advantage of being non-invasive in clinical application, and this safe and effective method provides another treatment option for functional gastrointestinal diseases and can be used as a non-drug treatment option for this disease. TaVNS is a promissing therapy with relatively few side effects.⁵⁰ Self-medication and non-invasive treatment were able to be achieved at home or work. Treatment was automatically stopped after completion and at any time if necessary. Compared with repeated visits, the time and economic costs are reduced. Therefore, FD patients have greater benefits in terms of medical expenditure.

There were several limitations in the current study. We could not have a pre-intervention and post-intervention brain comparison due to laboratory regulations limiting the physical movement of the animals after r-fMRI. On the other hand, the molecular biological mechanism focusing on the brainstem and entorhinal cortex should be conducted in the future.

In conclusion, taVNS alleviates depression state in the rodent model of FD possibly mediated by the enhancement of local neural coordination in the right entorhinal cortex and suppression of spontaneous neural activity in right brainstem. taVNS may have a therapeutic potential for depression in FD patients.

FD	Functional dyspepsia
taVNS	Transcutaneous auricular vagus nerve stimulation
OFT	Open field test
FST	Forced swimming test
rs-fMRI	Resting-state functional magnetic resonance imaging
BOLD	Blood oxygen level dependence
ALFF	Low-frequency fluctuations
ReHo	Regional homogeneity
IA	Iodoacetamide
SPM12	Statistical parametric mapping 12
NIFIT	Neuroimaging informatics technology initiative
FWHM	Half-orbit full-width
LSD	Least significant difference
NTS	Nucleus of the solitary tract

Ethics approval and consent to participate

The experimental protocol was approved by the Animal Care and Use Committee in the Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences (D2019-11-14-1).

Clinical trial number

Not applicable

Consent for publication

Not applicable. The study-protocol does not contain any individual person’s data.

Availability of data and materials

The data sets used in the current study are applicable from the corresponding author on reasonable requests.

Competing interests

The authors declare that they have no competing interests.

Acknowledgements

Not applicable.

Funding

This work was supported by the Qihuang Scholar Support Project of National Administration of Traditional Chinese Medicine (2022-6, Peijing Rong) and National Natural Science Foundation of China (81820108033, Wei Wei).

Author contributions

Bowen Feng and Shaoyuan Li wrote the manuscript. Bowen Feng, Ningyi Zou and Shaoyuan Li analyzed the data. Juan Han performed the experiments. Jiande D. Z. Chen provided technical support for the animal behavioral experiments and revised the manuscript. Yu Wang revised the manuscript. Peijing Rong and Wei Wei supervised the research and have full access to all the data in this study and take responsibility for data accuracy and integrity. All authors read and approved the final manuscript.

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Alterations of brain activity in right brainstem and right entorhinal cortex mediated anti-depressant effects of transcutaneous auricular vagus nerve stimulation in functional dyspepsia rats: a resting-state fMRI study

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