Effects of high frequency-repetitive transcranial magnetic stimulation on pattern visual evoked potential and vasoactive intestinal peptide expression in visual cortex of rats with amblyopia

Abstract

Aim

To explore the effects of high frequency-repetitive transcranial magnetic stimulation (hf-rTMS) on pattern visual evoked potential (PVEP) and vasoactive intestinal peptide (VIP) expression in visual cortex of rats with amblyopia and to preliminarily discuss the underlying mechanism of action.

Methods

Thirty SD rats aged 3 weeks were randomly selected and equally divided into the normal control group (NC), monocular deprivation group (MD), and monocular deprivation + hf-rTMS group (MD + hf-rTMS). Rats in the NC group were not intervened. Rats in the MD and MD + hf-rTMS groups were used to establish an amblyopia model by suturing the lid in the right eye for 3 weeks, while rats in the MD + hf-rTMS group were further intervened by two weeks of hf-rTMS. PVEP was tested in the right eye of rats at 6 and 8 weeks of age. Rats at 8 weeks of age were sacrificed, and the left visual cortex was extracted for immunohistochemistry (IHC) and in situ hybridization (ISH) examinations.

Results

At 6 weeks of age, there was no significant difference between the MD and MD + hf-rTMS group in terms of the P100 wave (P < 0.05). Besides, in comparison to the NC group, both the two groups had a distinct reduction in P100 amplitude (P < 0.05) and a prolonged latency (P < 0.05). At 8 weeks of age, the P100 amplitude in the MD + hf-rTMS group increased evidently than that in the MD group (P < 0.05). As compared to the NC group, the MD + hf-rTMS group had a remarkably lower P100 amplitude (P < 0.05). No distinct difference was found in the latency between the MD + hf-rTMS group and the MD or NC group (P > 0.05). IHC and ISH analyses demonstrated that VIP was expressed in all groups, and the mean OD value and the number of VIP-positive cells in the MD + hf-rTMS group were significantly higher than those in the MD group (P < 0.05) but distinctly lower than those in the NC group (P < 0.05).

Conclusion

hf-rTMS could increase the VIP expression in visual cortex and improve visual transduction in rats with amblyopia.The mechanism of hf-rTMS may be to participate in the remodeling of the visual system by improving the expression of VIP

Introduction

Amblyopia is a common eye disease in children with a prevalence in Asia of around 1.09% [1]. Treatment for amblyopia is mainly based on the visual cortical plasticity during the critical period for the development of binocular vision, and it will be challenging after the critical period due to the reduced cortical plasticity [2]. In this context, how to increase the visual cortical plasticity and improve the visual function in patients with amblyopia is a new direction in current research. Repetitive transcranial magnetic stimulation (rTMS) is an emerging treatment mode [3] that can induce long-term potentiation (LTP) with a high-frequency (> 5 hz) while long-term depression (LTD) with a low-frequency (< 1 hz). It has significant regulatory effects on cerebral blood flow and synaptic plasticity [4]. Thompson and Hess [5, 6], for the first time, found that application of rTMS to the primary visual cortex could temporarily improve the contrast sensitivity of the amblyopic eye (returned to baseline after 1 week), and it could be more effective in mild cases. It remains poorly understood on the mechanism by which rTMS affects visual function. Vasoactive intestinal peptide (VIP) is a kind of brain-gut peptide widely distributed in cerebral cortex [7]. Previous research reported that VIP played an important role in the occurrence and development of amblyopia [8]. The current study attempted to preliminarily explore the mechanism of high-frequency rTMS (hf-rTMS) for treatment of amblyopia through analyzing the changes of visual transduction and VIP expression in visual cortex in rats with amblyopia.

Materials And Methods

1.2 Establishment Of Animal Model

Rats were equally divided into the normal control group (NC), monocular deprivation group (MD), and monocular deprivation + hf-rTMS group (MD + hf-rTMS) at random. All rats were anesthesized by intraperitoneal injection of 10% chloral hydrate (0.3 ml/100 g). Rats in the MD and MD + hf-rTMS groups were used to establish an amblyopia model by suturing the lids in the right eye. In brief, the hair around the right eyelids was shaved, followed by local application of iodophors for disinfection. Approximately 0.5–1.5 mm margin of the upper and lower eyelids was cut off, and the upper and lower eyelids were closed using 3 − 0 interrupted sutures. Levofloxacin ophthalmic ointment was then applied to the suture. The rats were closely monitored and would be excluded from the experiment if there was corneal damage or palpebral fissure.

1.3 Pattern Visual Evoked Potential (Pvep) Test

During PVEP test, three animal electrodes were inserted successively: the recording electrode was inserted subcutaneously to the mid-occipital site of the binaural line; the reference electrode was inserted subcutaneously to the nasal bone; and the ground electrode was inserted subcutaneously into the tail. The resistance between the three electrodes was measured and required to be less than 10 kΩ. PVEP was tested by stimulation with the checkerboard reversal mode. The left eye was occluded, and the right eye was stimulated at a distance of 15 cm, a spatial frequency of 0.04 cycles/degree, a temporal frequency of 1 Hz, a contrast of 97%, and a duration of 300 ms, with a total of 100 superpositions. The whole testing process was completed in a dark chamber, and the rats were allowed to acclimate for 1 h before the beginning of the test. The modeling was considered successful in case that the P100 wave amplitude of the right eye in MD and MD + hf-rTMS groups was statistically different with that in NC group [9].

1.4 Hf-rtms Scheme

hf-rTMS was performed in awake rats. Briefly, the midpoint of a figure-of-eight stimulation coil was aligned with the occipital vertex of rats, tangential to the scalp. hf-rTMS was accomplished at a frequency of 20 Hz for 10 s, with 60 s interval, and an intensity of 30% of the maximum output for a total of 5 sequences. Rats were stimulated at the same time every day for consecutive 14 days. [10]

1.5 Experimental Methods

Immunohistochemistry (IHC): Tissues were prepared as paraffin sections followed by dewaxing to water. 3%H₂O₂ was added to eliminate endogenous peroxidase activity, and heat-induced antigen retrieval was achieved using a microwave. Following blocking with 5% BSA blocking solution, primary antibodies and biotin-labelled secondary goat anti-rabbit IgG were added in succession. Subsequently, DAB chromogen was used to develop color, and hematoxylin was applied for nuclear counterstaining. Slides were sealed after dehydration. Images were captured with a MicroImaging System and used to calculate the number and mean optical density (OD) of positive cells.

In situ hybridization (ISH): Tissues were prepared as paraffin sections followed by dewaxing to water. Then, they were exposed to pepsin to obtain nucleic acid fragments and 3%H₂O₂ to eliminate endogenous peroxidase activity. The tissue sections were then processed for pre-hybridization, hybridization, washing, blocking with blocking solution, and incubation with rabbit anti-digoxigenin antibody. Subsequently, DAB chromogen was used to develop color, and hematoxylin was applied for nuclear counterstaining. Slides were sealed after dehydration. Images were captured with a MicroImaging System and used to calculate the number and mean OD of positive cells.

1.6 Statistical Analysis

Statistical software SPSS 22.0 was used. data are expressed as mean ± standard deviation (X±s). The results of P100 wave, immunohistochemistry and in situ hybridization were compared using analyzed by one-way ANOVA. Paired sample t-test was used to compare the differences between different ages in the same group.

Results

2.1 Pattern visual evoked potential (PVEP) results

At 6 weeks of age, there was no statistically significant difference between the P100 wave amplitude and latency of rats in the MD and MD + hf-rTMS groups (P > 0.05); the P100 wave latency was prolonged (P < 0.05) and the amplitude decreased (P < 0.05) in the MD and MD + hf-rTMS groups compared with the NC group, indicating the formation of monocular amblyopia in the MD and MD + hf-rTMS group.See Tables1and 2, Fig. 2.

At 8 weeks of age, the P100 wave amplitude was increased in the MD + hf-rTMS group compared with the MD group (P < 0.05), and the difference in latency was not statistically significant (P > 0.05), while the amplitude was lower in the MD + hf-rTMS group compared with the NC group (P < 0.05), and the difference in latency was not statistically significant (P > 0.05). See Tables1and 2, Figs. 1 and 2.

Comparing the PVEP of 8-week-old rats with that of 6-week-old rats, it was found that the P100 wave amplitude was increased in the 8-week-old MD group (P < 0.05) with no significant change in latency (P > 0.05); the P100 wave amplitude was increased in the 8-week-old MD + hf-rTMS group (P < 0.05) with an advanced latency (P < 0.05); the P100 wave amplitude was increased in the 8-week-old NC group (P < 0.05), no significant change in latency (P > 0.05). See Tables1and 2, Figs. 1 and 2.

2.2 Ihc Results

IHC was performed to explore the VIP protein expression in the left visual cortex of rats. Positive VIP protein expression was found in the visual cortex of all groups, and the expression was mainly localized to the cytoplasm colored brown-yellow or light-yellow, with the nuclei presenting as blue. VIP protein expression was positive or weakly positive in a few cells in the MD group, positive in more cells in the MD + hf-rTMS group, and intensively positive in a large number of cells in the NC group (Fig. 3). Two fields of view were randomly selected from each section, and significant difference was demonstrated as analyzed by one-way ANOVA (P < 0.05). Pairwise comparisons showed that the mean OD value and the number of VIP protein-positive cells were the highest in the NC group, followed by the MD + hf-rTMS group and the MD group (P < 0.05, Table 3.)

2.3 Ish Results

ISH results indicated that VIP mRNA expression was present in the visual cortex of rats in all groups. The expression was distributed to the cytoplasm colored brown-yellow or light-yellow and overlapped with the blue-stained nuclei. VIP mRNA expression was positive or weakly positive in a few cells in the MD group, positive or weakly positive in more cells in the MD + hf-rTMS group, and intensively positive in a large number of cells in the NC group (Fig. 4). Two fields of view were randomly selected from each section, one-way ANOVA demonstrated a significant difference (P < 0.05). Pairwise comparisons showed that the mean OD value and the number of VIP mRNA-positive cells were the highest in the NC group, followed by the MD + hf-rTMS group and the MD group (P < 0.05, Table 4).

Discussion

The current study constructed an amblyopia model by suturing the lid in the right eye of rat and performed hf-rTMS for 2 weeks. We found that the VIP expression in the visual cortex and the P100 amplitude significantly increased in amblyopic rats after intervention with hf-rTMS. The finding suggested that hf-rTMS could elevate the VIP expression in the visual cortex and improve the visual transduction function of rats with amblyopia.

Previous morphological and anatomic studies on amblyopia revealed that amblyopia was mainly attributed to a lesion in the visual cortex presenting with decline in synaptic plasticity and disorder of connectivity between neurons [11]. VEP provides an objective test of visual function [12] to reflect the connectivity between neurons. The occurrence of amblyopia is always accompanied by a significant decrease in VEP amplitude with or without extension of the latency period [13]. It has been proved that the absolute value of VEP amplitude is a frequently used criterion to quantify the severity of amblyopia and assess the therapeutic efficacy [14, 15]. The critical period for the development of binocular vision in rats usually is around 2–6 weeks of age [16]. In the present study, we selected rats at 3 weeks of age for MD by suturing the lid in the right eye. The P100 amplitude of the amblyopic eye was reduced while the latency was prolonged, suggesting successful modeling of amblyopia by form deprivation. Further analysis found that NC rats at 8 weeks of age had a significantly higher P100 amplitude than rats at 6 weeks of age, indicating age-related P100 amplitude, consistent with the previous study [17]. In addition, the P100 amplitude in MD rats also showed a similar changing trend. We speculated that single removal of deprivation has certain effects to improve amblyopia in rats, but further research is needed to confirm whether the rat age makes an effect.

rTMS is a neuromodulatory technique that can act on cerebral cortex to regulate neural excitability via generating a magnetic field. It is easy to operate, safe, and has few side effects, and thus it has been widely applied in clinical treatment of nervous system diseases, such as depression, seizure, and Parkinson’s disease (PD). It was first found as effective to temporarily improve the contrast sensitivity of the amblyopic eye of adult patients (returned to baseline after 1 week) by Thompson and Hess [5, 6], and it could be more effective in mild cases. To extend the effect, Clavagnie et al. [18] applied continuous theta burst stimulation (cTBS) for consecutive 5 days. They found that cTBS could long-term improve the contrast sensitivity of patients with amblyopia and stabilized it for up to 78 days, suggesting the long-term effect of cTBS on functional recovery from amblyopia. However, whether cTBS has promoting effect to other visual functions in patients with amblyopia was not explored in their study. Tuna et al. [19] examined the visual acuity, suppressive imbalance, and stereoacuity of amblyopic eye before and after cTBS and found significant improvement after cTBS. This result implied that TMS could change the visual cortical plasticity and concurrently strengthen the neural function of patients with amblyopia. Nevertheless, the majority of the current studies are limited to the subjective visual function associated with amblyopia without further exploring the potential molecular mechanism.

Previous research revealed that rTMS has certain effect to improve the function and structural plasticity of impaired synapse, such as increasing the synaptic curvature, the thickening of postsynaptic compact zone, the length of synaptic active zone [20, 21], the number of dendrites in neurons, the axon length, and the intercellular neural connections [22, 23]. The present study found that at 8 weeks of age, the P100 wave amplitude in the MD + hf-rTMS group was higher than that in the MD group but remained lower than that in the NC group. This result suggested that hf-rTMS affected the visual transduction function of rats with amblyopia via increasing neural excitability and improving synaptic connections between neurons.

It has been proven that amblyopia can lead to reductions of cerebral blood flow and metabolic function [24]. VIP was first found within the pig small intestine [25] and then proven with a wide distribution in cerebral cortex and lateral geniculate body [26]. It mainly acts as a neurotransmitter and neuromodulator [27] to help for vasodilation, increasing cerebral blood flow, and promoting cell proliferation and differentiation. In addition, it can also modulate the plasm level of hormones and affect the metabolic function of neurons [28]. Existing studies have also shown that activation of VIP-positive neurons can lead to gain of visual responses. For instance, amblyopia can induce paraptosis in visual cortical neurons [29], while VIP positive expression can inhibit the occurrence and development of amblyopia with antioxidant and anti-apoptotic activities [30, 31]. Consistently, our previous studies found that amblyopia resulted in down-regulated VIP expression in the visual cortex of kittens with amblyopia [8], and that exogenous introduction of VIP increased the VIP expression in the visual cortex and elevated the PVEP amplitude [32]. Combining the findings, VIP is critical to visual development.

hf-rTMS can elevate neuronal excitability and cerebral blood flow through inducing depolarization on the membrane potential of visual cortical neurons. Long-term hf-rTMS can trigger a series of physiological changes of neurons in turn to modulate synaptic plasticity, such as the release of excitatory and inhibitory neurotransmitters [33, 34] and increased expression of related proteins [35]. In rats, ~ 95% of the optic nerve axons cross in the optic chiasm to the contralateral side [36], which is different with the human. Therefore, the monocular amblyopia induced by form deprivation only involves the contralateral visual cortex. In the current study, the left visual cortex was selected for IHC and ISH analyses. We found that both the mRNA and protein expression of VIP in the visual cortex of rats were down-regulated after form deprivation, in agreement with the research mentioned above. Additionally, the mRNA and protein expression of VIP in the visual cortex were reversely increased following 2 weeks of hf-rTMS application, while it has been proven that elevation of VIP expression can physiologically improve visual functions. Research also reported that positive VIP expression can increase cerebral blood flow and nutritional support for neurons, and inhibit the paraptosis in neurons, thereby playing a neuroprotective role. Collectively, it could be inferred that hf-rTMS participates in the remodeling of the visual system via up-regulating VIP expression in the visual cortex.

One of the limitations of the present study is that this is a preliminary study on the mechanism of action of hf-rTMS with a single stimulation intensity, and its effect on neural transduction and VIP expression did not reach the levels found in healthy controls. We speculated that the full effects of hf-rTMS were not seen under such stimulation intensity. Further studies will be carried out to explore the effects of different stimulation intensities in rats with amblyopia.

To conclude, hf-rTMS can increase the VIP expression in the visual cortex and improve the neural transduction in rats with amblyopia, providing certain theoretical basis for amblyopia treatment with hf-rTMS. However, the specific pathways involved in visual cortical plasticity requires to be further clarified.

A participated in the design of the experiment, analyzed the data, and revised the manuscript. B participated in the establishment of animal models, specimen collection, experimental operations, data collection and analysis, and manuscript writing. C, D, and E participated in the creation of animal models, PVEP testing, specimen collection, and experimental operations. All authors read and approved the final manuscript.

Declarations

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. 

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article Natural Science Foundation of Sichuan (No.2022NSFSC0754). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. 

Ethical approval

The study that has been performed according to the ARRIVE guidelines was approved by the Medical Ethics Committee of North Sichuan Medical College and supervised throughout the process. (NSMC Appl. No. 2021 [66])

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