Introduction

Stroke is a common and serious neurologicaldisorder that has a profound impact on both the physical and mental health of patients1. Post-stroke depression is a prevalent psychological disorder, particularly among stroke survivors2,3. The presence of depressive symptoms not only exacerbates the physical discomfort experienced by patients but also hinders the rehabilitation process4. Therefore, it is vital to explore effective treatment approaches for alleviatingpost-stroke depression symptoms. Phototherapy, as a non-pharmacological treatment modality, has garnered significant attention and research interest in recent years. It involves the use of light with specific wavelengths and intensities to stimulate the human body and improve overall physical and mental well-being5,6,7. Studies have demonstrated the efficacy of phototherapy in various mental disorders, such as seasonal affective disorder and depression. However, there is a paucity of research on the application and effectiveness of phototherapy in patients with post-stroke depression. Biopterin (BH4), neopterin (BH2), and tryptophan (Trp) are important chemical compounds closely associated with mood regulation and neurotransmitter synthesis8,9. BH4 and BH2 are essential components of the vitamin B family and play a pivotal role in neurotransmitters synthesis10. Trp is an essential substance for the synthesis of serotonin, a crucial neurotransmitter and highly associated with mood regulation and depressive symptoms11. Therefore, investigating the effects of phototherapy on the levels of BH4, BH2 and Trp holds great significance in elucidating the mechanism by which phototherapy treats post-stroke depression. Furthermore, behavioral neuroinflammatory response, characterized by immune system activation and release of inflammatory factors, is an important feature of post-stroke depression12. Increasing evidence are available to show that behavioral neuroinflammatory reaction plays a pivotal role in the development of depression13. Therefore, exploring the impact of phototherapy on behavioral neuroinflammatory response can enhance our understanding of the mechanism by which phototherapy ameliorates post-stroke depression symptoms. Based on the above-mentioned background, this study aimed to explore the effects of phototherapy on the levels of BH4, BH2, and Trp, as well as behavioral neuroinflammatory response in patients with post-stroke depression. Through our investigation, we sought to uncover the efficacy and underlying mechanism of phototherapy as a potential non-pharmacological treatment for post-stroke depression, with a particular focus onproviding novel treatment options for this condition, ultimately enhancing patients’ rehabilitation and quality of life.

Materials and methods

General information

A total of 100 hospitalized patients with post-stroke depression at our hospital from February 2021 to December 2022 were recruited for the present study. The age of the participants ranged from 36 to 68 years, with an average age of 48.62 ± 6.74 years. Among them, 47 were male and 53 were female. The participants were randomly assigned to either the control group or the experimental group, with 50 individuals in each group. Patients in the control group received routine treatment, including medication and psychological support, while patients in the experimental group underwent 30 min of daily phototherapy for 8 weeks. All patients voluntarily participated in the study and provided informed consent. The stroke duration of the selected stroke patients in this study was 1 week.

Inclusion criteria

In order to be included in this study, the following inclusion criteria should be met: age between 18 to 70 years old, regardless of gender; diagnosisof post-stroke depression (mild to severe) with a BDI score ≥ 14 and a HAM-D score ≥ 8; history of ischemic stroke or hemorrhagic stroke; ability to undergo phototherapy without light sensitivity or any other conditions or treatments that may interfere with phototherapy; Willingness to comply with the research protocol and complete the required evaluations and interventions; signed informed consent form.

Exclusion criteria

The exclusion criteria were serious heart disease, kidney disease, or other major health problems that may affect exercise capacity or intervention outcomes; severe cognitive dysfunction or intellectual disability; patients currently receiving other interventions or medications; pregnant or lactating individuals; coexistence of other severe mental illnesses, such as severe anxiety disorder or bipolar disorder; refusal to sign the informed consent form for the study protocol. Both the experimental group and the control group received placebo treatment and implemented a double-blind design.

Medical ethical issues

This study was conducted in accordance with the principles in the Helsinki Declaration and was approved by the Hospital Ethics Committee of our hospital. Prior to any research-related procedures, all patients provided written informed consent.

Methods

Patient treatment plan

All patients first undergo routine stroke treatment. Provide routine symptomatic plans for lowering blood pressure, maintaining water and electrolyte balance, protecting brain cells, administering oxygen, and antiplatelet therapy. Subsequently, the patient was given intravenous thrombolytic therapy with 0.9 mg/kg alteplase (specification: 50 mg/vial; approval number: S20110052; manufacturer: Boehringer Ingelheim Pharma GmbH & Co. KG). The initial dose was 10.00% of the total dose, which was administered intravenously within 10 min, and the remaining 90.00% was injected via intravenous pump. The treatment was completed within one hour.

The treatment plan for the patients in the experimental group was determined aftera comprehensive evaluation by the physician to ensure the suitability of phototherapy for each patient. Phototherapy was conducted using a blue light with a specific wavelength, and the patients were placed in a quiet and comfortable environment withmoderate indoor lighting and no strong stimulation. The patientswere instructed to lie down and position themselves so that their eyes were facing the light source without direct exposure. During the session, patients were allowed to relax their eyes moderately, either by closingtheir eyes or looking indoors. The duration of each phototherapy session was 30 to 40 min, and the treatment was administered daily for 8 weeks. The physician made adjustments and monitoredthe treatment according to the individual needs and progress of each patient. Patients in the control group received standard treatment for post-stroke depression, including medication therapy and psychotherapy.

Depression scale and quality of life assessment

The hamilton depression scale, Beck depression inventory, and short form 36 are tested after completing treatment. The severity of depressive symptoms was evaluated using the hamilton depression scale (HAMD) and the beck depression inventory (BDI).The HAMD consists of 17 items. Each item is scored by doctors or trained professionals based on patients’ responses and observations. The items cover various aspects of depression symptoms, including depression, insomnia, anxiety, and suicidal ideation. A higher total score indicates the more severe depressive symptoms. The BDI consists of 21 items, and patients are required to choose the statement that best describes situation for each item according to their own feelings. The items assess cognitive, emotional, and physiological aspects of depressive symptoms, such as pessimism, fatigue, and self-blame. Each item is assigned a specific score, and a higher total score indicates more severe depressive symptoms. The Short Form 36 (SF-36) questionnaire was used to assess the health-related quality of life. It is awidely used tool that evaluates patients’ physical functioning and mental health. Each dimension of the SF-36 questionnaire is scoredby adding up the scores from the corresponding question chosen by the patient. The score range for each dimension is generally from 0 to 100, with higher scores indicating better health status in that dimension.

Detection of plasma neuroinflammatory factors

The detection time for plasma neuroinflammatory factors is after completion of treatment. Venous blood samples from patients were collected and allowed to stand for 2 h. Subsequently, the sampleswere centrifuged and the resulting serum was scored at −80 °C for analysis. The levels of TNF-α, IL-6, and IL-1β in the serum were measured using a commercial ELISA kit (R&D Systems, USA).

Analysis of plasma levels of BH4, BH2, and Trp

The detection time for plasma levels of BH4, BH2, and Trp is after completion of treatment. 10 mL venous blood sample was collected from each patient and transferred to centrifugal tubes. The tubes were centrifuged to separate the plasma. To the plasma sample, 20 μL of internal standard (chlorinated p-aminophenol) was added, followed by the addition of 400 μL of protein precipitant (such as glacial acetic acid) for proteinprecipitation. The sample was then centrifuged to separate the supernatant. A methanol/acetate buffer (with a ratio of 95:5) was prepared as the elution solvent. The elution solvent was connected to the mobile phase system of the HPLC equipment. A reversed-phase chromatographic column, such as C18 column,was used as the chromatographic column. A 200 μL plasma supernatant was injected into the HPLC system through an automatic sampler. The chromatographic operation was initiated, and the chromatogram and peak area data were recorded. The concentrations of BH4, BH2, and Trp were determined based on the peak area of the internal standard using specialized data processing software.

Analysis of oxidative stress level

The detection time for oxidative stress level is after completion of treatment. Venous blood samples were collected from the patients and subjected to centrifugation to obtain plasma. For the measurement of SOD, GPx, CAT, and MDA, an appropriate amount of plasma sample was taken and added to the reaction solution provided by the kit. The mixture was then incubated in a water bath for a specific duration to allow the reaction to proceed. The colorimetric reagent included in the kit was used, and the colorimetric reaction was performed following the instructions provided in the manual. The absorbance was measured using a spectrophotometer,and the results were recorded.

Statistical analysis

The data were presented as mean ± S.E.M.Statistical analysis involved the use of unpaired t-teststo compare between groups, as well as one-way analysis of variance for comparisons among multiple groups. Analysis using the Student–Newman–Keuls test was conducted tocomparespecific groups. A significance level of P < 0.05 was considered statistically significant in all analyses.

Ethics approval and consent to participate

This study protocol was in accordance with the Declaration of Helsinki of the World Medical Association. This study was approved by the Ethics Committee of The First Hospital of Hebei Medical University. Prior to participation in the study, patients and their guardians provided informed consent, demonstrating their willingness to be included in the research.

Results

Baseline characteristics

According to the baseline characteristics of the patients, the control group consisted of 22 males and 28 females, with an average age of 46.24 ± 6.35 years and an average BMI of 23.16 ± 2.05 kg/m2. Among them, 3 patients had a family history of stroke, 8 patients had a history of smoking within the past 5 years, and 9 patients had a history of alcohol consumption within the past 3 years. Additionally, 17 cases had hypertension or hyperlipidemia, and 5 cases had basic diabetes. The experimental group consisted of 25 males and 25 females, with an average age of 49.33 ± 7.48 years and an average BMI of 23.66 ± 1.99 kg/m2. Among them, 5 patients had a family history of stroke, 6 had a history of smoking within the past 5 years, and 11 had a history of alcohol consumption within the past 3 years. Additionally, 18 cases had hypertension or hyperlipidemia, and 6 cases had basic diabetes. There were no significant differences in baseline characteristics between the two groups (P > 0.05). (Table 1, Fig. 1).

Table 1 Baseline characteristic statistics (x̅ ± s).
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Figure 1
figure 1

Baseline characteristic of patients.

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Comparison of the severity of depression in patients

By using the HAMD and BDI to evaluate the severity of depressive symptoms, it was observed that the scores of HAMD and BDI in the experimental group were lower than those in the control group (P < 0.05). These findings indicated that phototherapy could effectively reduce the severity of post-stroke depression. (Fig. 2, Table 2).

Figure 2
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HAMD and BDI scores.

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Table 2 HAMD and BDI scores (x̅ ± s).
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Amino acid neurotransmitter indexes before and after treatment in the two groups

The levels of amino acid neurotransmitters including GABA, Asp, and Glu were detected by radioimmunoassay. After treatment, the levels of GABA in the experimental group were remarkably higher than those in the control group (P < 0.01), while the levels of Glu and Asp were lower than those in the control group (P < 0.01). Moreover, the levels of GABA, Glu, and Asp in both groups significantly increased after treatment compared to their respective levels before treatment (P < 0.01). Conversely, the levels of these indexes were initially lower before treatment (P < 0.01). (Fig. 3, Table 3).

Figure 3
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Amino acid neurotransmitter indexes before and after treatment in the two groups.

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Table 3 Amino acid neurotransmitter indexes before and after treatment in the two groups (x̅ ± s).
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ELISA analysis

The levels of plasma neuroinflammatory factors TNF-α, IL-6, and IL-1β were measured using ELISA. It was found that the levels of plasma TNF-α, IL-6, and IL-1β in the experimental group were significantly lower than those in the control group (P < 0.05). This indicated that phototherapy could greatly improve the levels of plasma inflammatory factors in patients with post-stroke depression. (Fig. 4, Table 4).

Figure 4
figure 4

Detection of plasma inflammatory factors by ELISA.

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Table 4 Detection of plasma inflammatory factors by ELISA (x̅ ± s).
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Analysis of bh4, BH2 and Trp levels

The levels of plasma BH4, BH2, and Trp were detected using HPLC. The levels of BH4 and Trp in the experimental group were higher than those in the control group (P < 0.05), whereas the levels of BH2 in the experimental group was lower than those in the control group (P < 0.05). (Fig. 5, Table 5).

Figure 5
figure 5

Analysis of plasma BH4, BH2 and Trp.

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Table 5 Analysis of plasma BH4, BH2 and Trp (x̅ ± s).
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Comparison of oxidative stress levels

The levels of SOD, GPx, CAT, and MDA in the plasma of patients were measured with the use of corresponding kits and colorimetry. The experimental group showed elevated levels of SOD, GPx, and CAT and reducedlevels of MDA compared to the control group (P < 0.05) (Fig. 6, Table 6).

Figure 6
figure 6

Comparison of oxidative stress level.

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Table 6 Comparison of oxidative stress level (x̅ ± s).
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Evaluation of quality of lifeusing the SF-36 scale

The scores of physical function, mental health, social function, and overall health were significantly higher in the experimental group compared to the control group (P < 0.05), suggesting thatphototherapy could enhance the overall quality of life in patients with post-stroke depression. (Fig. 7, Table 7).

Figure 7
figure 7

Evaluation of quality of life using the SF-36 scale.

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Table 7 Evaluation of quality of life using the SF-36 scale (x̅ ± s).
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Discussion

The overall purpose of this study was to investigate the effects of phototherapy on the levels of BH4, BH2, and Trp, as well as the behavioral neuroinflammatory response in patients with post-stroke depression. The study compared the differences in the severity of depressive symptoms, levels of neuroinflammatory factors, levels of BH4, BH2, and Trp, behavioral neuroinflammatory reaction, and improvement in quality of life.

The severity of depressive symptoms was assessed usingthe HAMD and BDI. The results demonstrated that the HAMD and BDI scores in the experimental group were significantly lower than those in the control group after phototherapy. This indicated that phototherapy effectively alleviated depressive symptoms in individuals harboring post-stroke depression and improved their psychological well-being. In terms of neuroinflammatory factors, the levels of TNF-α, IL-6, and IL-1β in the plasma of the patients were measured. It was observed that the levels of these neuroinflammatory factors in the experimental group were significantly lower than the control group after phototherapy. This suggested that phototherapy may regulate the neuroinflammatory response, leading to a reduction in the release of inflammatory factors and improvement in the neuroinflammatory status of depressed patients. In the investigation of BH4, BH2, and Trp levels, it was found that phototherapy resulted in anincrease inplasma levels of BH4 and Trp, and reduced levels of BH2, suggesting that phototherapy may have a positive effect on regulating BH4 metabolism and Trp metabolism in patients with post-stroke depression. The elevation of BH4 levels could enhance the activity of Trp hydroxylase and promote the metabolism of Trp into 5-hydroxytryptamine, while the reduction in BH2 levels may decrease peroxidase production, thereby enhancing antioxidant and anti-inflammatory effects.

Neurotransmitters are chemical substances released by nerve endings in the human body,exhibiting effects in the communication between neurons. Amino acid transmitters and monoamine transmitters, as well as neuropeptides, choline transmitters, and other types of transmitters, play important roles as central neurotransmitters closely related to neuropsychiatric activities. Among these, amino acid transmitters and monoamine transmitters are particularly relevant to depression. Amino acid transmitters primarily contribute to maintaining and regulating the balance between neural inhibition and excitability. Notably, GABA acts as an inhibitory neurotransmitter, while Glu and Asp function as excitatory neurotransmitters. In this study, the levels of GABA, Glu, and Asp in both groups increased following treatment, with higher levels observed in the experimental group compared to the control group. It was suggested that phototherapy could enhance the levels of neurotransmitters in individuals with post-stroke depression. Moreover, phototherapy may exert an antidepressant effect by regulating the synthesis of monoamine neurotransmitters and hormones associated with the endocrine system.

Patients with post-stroke depression often exhibit alterations in the levels of BH4, BH2, and Trp14,15,16. Decreased levels of these substancescan disrupt neurotransmitter synthesis and metabolism, potentially contributing to mood dysregulation and the onset of depressive symptoms17,18. The results of this study demonstrated that phototherapyled to an increase in the levels of BH4, BH2, and Trp in the experimental group. This indicated that phototherapy positivelyaffects the levels of BH4, BH2, and Trp. By elevating their levels, phototherapy may help restore normal neurotransmitters synthesis and metabolism, thereby improving depressionsymptoms. The increase of BH4 and BH2 levels may reflect the regulation of phototherapy on coenzyme metabolism in patients with post-stroke depression19,20. Phototherapy may enhance BH2 production by promoting BH4 synthesis and reducing its metabolism, thus improving the levels of these two substances21,22. In addition, phototherapy may increase the availability of Trp by stimulating its synthesis, leading to an improvement in its levels23,24,25. These findings further supported for the important role of BH4, BH2, and Trp in post-stroke depression. By modulating the levels of these substances, phototherapy may contribute to restoringthe balance of the neurotransmitter system and improving the severity of depressive symptoms. Furthermore, the levels of antioxidant enzymes such as SOD, GPx, and CAT increased in the experimental group, while the level of MDA decreased. These results indicated that phototherapy could enhance the antioxidant capacity in patients with post-stroke depression, thereby reducing oxidative stress reactions and mitigating the production and damage caused by free radicals. These findings were consistent with the regulation effects of phototherapy on neuroinflammatory factors and demonstrated an improvement in the biochemical indexes of individuals with depression.

The findings of this study revealed that the physical functioning, mental health, social functioning, and overall well-being in the experimental group were significantly higher than those in the control group. It was suggested that phototherapy not only alleviated depressive symptoms but also had a positive impact on the overall quality of life of patients with depression. However, it is important to acknowledge the limitations of this study, such as the small sample size and short duration of the research. Therefore, further clinical research with larger sample sizes and long-term follow-up is needed to verify the efficacy and safety of phototherapy.

The very small sample size of this study is one restriction that may affect the generalizability of the results. Furthermore, the brief follow-up period might not have captured phototherapy’s long-term effects. Longer follow-up periods and broader sample sizes should be taken into account in future research.

To sum up, this study offered preliminary evidence for the application of phototherapy in the treatment of post-stroke depression and held important implications for clinical practice. Phototherapy may attenuate neuroinflammatory reactions and enhance antioxidant capacity by regulating the metabolism of BH4, BH2, and Trp, thereby improving depressive symptoms and quality of life in affected patients. Future research should delve into the underlying mechanisms of phototherapy, optimize treatment protocols, and conduct multi-center, long-term randomized controlled trials in combination with other therapeutic approaches to comprehensively and accuratelyevaluate the efficacy and safety of phototherapy in the treatment of post-stroke depression more.