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Gamma-aminobutyric acid and glutamate/glutamine levels in the dentate nucleus and periaqueductal gray in new daily persistent headache: a magnetic resonance spectroscopy study

The Journal of Headache and Pain volume 25, Article number: 142 (2024) Cite this article

Abstract

Background

Magnetic resonance spectroscopy (MRS) studies have indicated that the imbalance between gamma-aminobutyric acid (GABA) and glutamate/glutamine (Glx) levels was the potential cause of migraine development. However, the changes in the GABA and Glx levels in patients with New daily persistent headache (NDPH) remain unclear. This study aimed to investigate the changes in GABA and Glx levels in the periaqueductal gray (PAG) and dentate nucleus (DN) in patients with NDPH using the MEGA-PRESS sequence.

Methods

Twenty-one NDPH patients and 22 age- and sex-matched healthy controls (HCs) were included and underwent a 3.0T MRI examination, using the MEGA-PRESS sequence to analyze GABA and Glx levels of PAG and DN. The correlations between these neurotransmitter levels and clinical characteristics were also analyzed.

Results

There were no significant differences in the GABA+/Water, GABA+/Cr, Glx/Water, and Glx/Cr levels in both PAG and DN between the two groups (all p > 0.05). Moderate-severe NDPH patients had lower levels of Glx/Water (p = 0.034) and Glx/Cr (p = 0.012) in DN than minimal-mild NDPH patients. In patients with NDPH, higher Glx/Water levels in the PAG (r=-0.471, p = 0.031, n = 21) and DN (r=-0.501, p = 0.021, n = 21) and higher Glx/Cr levels in DN (r=-0.483, p = 0.026, n = 21) were found to be correlated with lower Visual Analogue Scale scores. Additionally, a positive correlation was observed between the GABA+/Cr levels in the DN and the Generalized Anxiety Disorder-7 scores (r = 0.519, p = 0.039, n = 16).

Conclusions

The results of this study indicated that the GABA and Glx levels in the PAG and DN may not be the primary contributor to the development of NDPH. The correlations between certain clinical scales and the neurotransmitter levels may be derived from the NDPH related symptoms.

Peer Review reports

Introduction

New daily persistent headache (NDPH) is a rare primary headache with a prevalence of about 0.03-0.1% in the general population [1]. The primary characteristic of NDPH is the persistent headache that continues in a daily pattern at least three months from its onset and patients can clearly remember the exact time of the onset [2]. The headache phenotype of NDPH may resemble chronic migraine (CM) or chronic tension-type headache [3]. Severe instances may even precipitate psychiatric disorders. However, the pathogenesis of NDPH is still poorly understood [1, 4].

Previous studies have indicated neurotransmitter changes in certain regions of the brain in patients with migraine [5,6,7]. An imbalance between inhibitory and excitatory neurotransmitters may contribute to migraine development [8]. Magnetic resonance spectroscopy (MRS) offers a non-invasive method to quantify metabolites. In particular, the MEGA-PRESS sequence enables quantification of the concentration of gamma-aminobutyric acid (GABA) and glutamate/glutamine (Glx) [9]. The MEGA-PRESS sequence uses J-difference editing to resolve overlapping signals, enabling the accurate quantitative detection of modified GABA and Glx levels [9]. This technology has been widely applied in the study of GABA and Glx in the brain of diverse populations, including healthy people [10], Alzheimer’s disease [11], Parkinson’s disease [12], and migraine [6,7,8]. MEGA-PRESS sequence might be one of the most reliable and commonly used methods for measuring GABA.

Periaqueductal gray (PAG) is one of the most important central hubs for processing ascending and descending pain signals [13]. It has extensive connections with the cortex, various brainstem nuclei, and cerebellum [14,15,16]. Numerous studies have reported abnormalities in PAG and cerebellum in CM and NDPH [17,18,19,20]. A prior study revealed that patients with CM exhibited significantly decreased levels of GABA in the dentate nucleus (DN) and notably elevated levels of Glx in PAG compared to healthy controls (HCs). A strong correlation between these neurochemical levels and migraine characteristics was also identified [6]. It remains unknown whether there are any alterations in GABA and Glx levels of the PAG and DN in patients with NDPH. The investigation in these areas may help to understand the underlying pathological mechanisms of NDPH.

Therefore, the aim of this study was to quantify the GABA and Glx levels in the DN and PAG of NDPH patients using the MEGA-PRESS sequence and to investigate the correlation between GABA and Glx levels and clinical characteristics of patients with NDPH. We hypothesized that GABA-GLX imbalance exists in the PAG and DN of patients with NDPH.

Methods

Participants

Twenty-six patients with NDPH were prospectively recruited from the Headache Centre of the Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, from January 2021 to July 2022. All NDPH patients were diagnosed by two experienced headache physicians according to the diagnostic criteria of the International Classification of Headache Disorders, Third version (ICD-3) [2]; Inclusion criteria: (1) no other neurological or psychiatric disorders; (2) no claustrophobia and other contraindications to MRI examination; (3) no history of cranial and cerebral surgeries or trauma. Exclusion criteria: (1) obvious infarct lesions in the brain; (2) poor cooperation and the quality of MRI images could not satisfy the subsequent analysis; (3) incomplete data.

Thirty-three age- and sex-matched HCs were enrolled in this study. The inclusion criteria for the HC group were as follows: (1) no history of any headache; (2) no history of neurological or psychiatric disorders; (3) no claustrophobia and other contraindications to MRI examination; (4) the quality of the MRI images could satisfy the subsequent analysis. The subjects were excluded if they had obvious infarct lesions, poor MRI image quality, and incomplete data.

Demographic and general clinical information such as age, gender, body mass index (BMI), age of onset of disease, and disease duration were recorded for all participants. Multiple clinical scales have been used to assess the clinical characteristics of NDPH patients. Visual analog scale (VAS) scores were used to assess the headache intensity; the Headache Impact Test-6 (HIT-6) [21] was used to assess the impact of headache in daily life; the Pittsburgh Sleepiness Quality Index (PSQI) [22] was used to assess the quality of sleep; the Generalized Anxiety Disorder-7 (GAD-7) [23] was used to assess anxiety and the Patient Health Questionnaire-9 (PHQ-9) [24] was used to assess depression. We also performed a subgroup analysis of patients with NDPH based on the headache intensity. NDPH patients were divided into minimal-mild group (VAS score 0–3) and moderate-severe group (VAS score 4–10).

This study was a sub-study of the ongoing Chinese Headache Disorders Registry Study (CHAIRS, trial registration: NCT05334927). All participants signed an informed consent form, and the Ethics Committee of Beijing Tiantan Hospital reviewed and approved the study (KY-2022-044).

MRI images acquisition and processing

All participants were examined on a 3.0T MR scanner (Signa Premier, GE Healthcare, USA) equipped to use a 48-channel head coil. All participants had their heads immobilized with foam pads and were asked to keep their heads as still as possible.

3D T1 MP-RAGE sequence was performed to obtain structural data using the following parameters: sagittal acquisition, echo time (TE) = 3 ms, repetition time (TR) = 7.2 ms, with 1-mm isotropic resolution, field of view (FOV) = 256 mm; acquisition matrix = 256; slice number = 192; flip angle = 8°; preparation time = 880 ms; recovery time = 400 ms; acceleration factor = 2; (acquisition time = 4 min). The scanning parameters for the MEGA-PRESS sequence were as follows: TE = 68 ms, TR = 2000 ms, number of points = 2048; spectral width = 2000 Hz; and number of averages = 160 (acquisition time = 11 min 28 s). Six very selective saturation (VSS) pulses were used to minimize errors in chemical-shift displacement and to achieve consistent localization volumes across measurements [25]. According to previous literature, two 20 × 20 × 20 mm3 voxels were placed in PAG and DN, respectively (Fig. 1). All images acquired from the MEGA-PRESS sequence were processed using GANNET 3.1 (http://gabamrs.org) [26] (Fig. 2). A Gaussian baseline model was used to fit the edited GABA signal and a Lorentz-Gaussian line shape was employed to fit the unsuppressed water signal. The processing steps included the following: a combination of phased array coil data, time-domain frequency, phase correction using spectral correction, and application of an exponential apodization function for line broadening. Subsequent steps involved fast Fourier transform, time averaging, and frequency and phase correction based on fitting the water and creatine (Cr) signals. Finally, data were pairwise rejected if the fitting parameters deviated by more than three standard deviations from the mean, and subtraction was used to generate the edited difference spectrum and to extract the OFF spectrum. All MRS spectra were reviewed by two experts to exclude data with significant motion artifacts as well as insufficient water suppression.

Fig. 1
figure 1

The examples of voxel placements in the PAG (A) and DN (B). PAG, periaqueductal gray; DN, dentate nucleus; L, Left; R, Right

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Fig. 2
figure 2

MEGA-PRESS data processing. (A) The processed gamma-aminobutyric acid (GABA)-edited difference spectrum before frequency and phase correction (red) and after (blue). (B) The frequency of the maximum point in the residual water signal is plotted against time. (C) The y-axis represents the frequency (in ppm) of the Cr signal, before frequency-and-phase correction and after. (D) The GABA-edited spectrum is shown in blue. The model of best fit is shown in red. The residual between these two is shown in black. GABA, gamma-aminobutyric acid; Glx, glutamate/glutamine; Cr, creatine

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Statistical analysis

The sample size was calculated according to the neurotransmitter levels in the previous study [6]. We set the target power (1-β) at 0.80 and the α-error at 0.05. We calculated that at least 19 participants were needed for each group. All statistical analyses were performed using SPSS software (version 25.0, IBM, Armonk, NY, USA). All data were checked for normality using the Shapiro-Wilk test. Quantitative data that fit the normal distribution were expressed using mean ± standard deviation, and that did not fit the normal distribution were expressed using median and quartiles. Categorical variables were expressed using frequencies and percentages. Differences in sex composition between groups were assessed using the chi-squared test. The independent samples t-test and the Mann-Whitney-U test were applied for comparisons of the two groups, based on whether the quantitative data conformed to a normal distribution. Pearson’s or Spearman’s correlation was used to analyze the correlation between neurotransmitter levels and clinical characteristics. p < 0.05 were considered statistically significant.

Results

Demographics and clinical characteristics

In total, twenty-six NDPH patients and 33 HCs were recruited, five NDPH patients and 9 HCs were excluded due to incomplete images, and two HCs were excluded due to poor image quality. Finally, twenty-one NDPH patients and 22 HCs were included.

There were no significant differences in age, gender, and BMI between the NDPH and HC groups. Sixteen NDPH patients completed the HIT-6, PSQI, GAD-7, and PHQ-9 scale assessments. All demographic and clinical characteristics are presented in Table 1.

Table 1 Demographic and clinical data
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Neurotransmitter levels in NDPH and HC groups

In the PAG, there were no significant differences in GABA+/Water levels, GABA+/Cr levels, Glx/Water, and Glx/Cr between NDPH and HC groups (all p > 0.05).

In the DN, no significant differences were found in GABA+/Water levels, GABA+/Cr levels, Glx/Water, and Glx/Cr between NDPH and HC groups (all p > 0.05). More detailed MRS data were shown in Table 2; Fig. 3.

Table 2 MRS data in periaqueductal gray and dentate nucleus
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Fig. 3
figure 3

Comparisons of neurotransmitter levels between NDPH and HC groups. (A) GABA+/Water (i.u.) in the PAG and DN of the HC and NDPH groups. (B) GABA+/Cr in the PAG and DN of the HC and NDPH groups. (C) Glx/Water (i.u.) in the PAG and DN of the HC and NDPH groups. (D) Glx/Cr in the PAG and DN of the HC and NDPH groups. PAG, periaqueductal gray; DN, dentate nucleus; HC, healthy control; NDPH, new daily persistent headache; GABA, gamma-aminobutyric acid; Glx, glutamate/glutamine; Cr, creatine; i.u., institutional unit

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Subgroup analysis of neurotransmitter levels in NDPH

Nine patients were divided into the minimal-mild group and 12 patients were divided into the moderate-severe group. In the DN, the Glx/Water (p = 0.034) and Glx/Cr (p = 0.012) levels in the moderate-severe group were significantly lower than the minimal-mild group. However, no significant differences were found in the GABA+/Water (p = 0.650) and GABA+/Cr (p = 0.499) levels. No significant differences were found in the neurotransmitter levels in PAG between the minimal-mild and moderate-severe groups (all p > 0.05). The details were shown in Table 3.

Table 3 Subgroup analysis of neurotransmitter levels in NDPH
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Correlation between neurotransmitter levels and clinical characteristics

The Glx/Water levels in the PAG (r=-0.471, p = 0.031, n = 21) and DN (r=-0.501, p = 0.021, n = 21) and the Glx/Cr levels in DN (r=-0.483, p = 0.026, n = 21) were observed to be negatively correlated with the VAS scores (Fig. 4A-C). The GABA+/Cr levels in the DN were positively correlated with the GAD-7 scores (r = 0.519, p = 0.039, n = 16) (Fig. 4D).

Fig. 4
figure 4

Correlation between clinical characteristics and neurotransmitter levels. (A) Negative correlation between Glx/Water in the PAG and the VAS score (r=-0.471, p = 0.031, n = 21). (B) Negative correlation between Glx/Water in the DN and the VAS score (r=-0.501, p = 0.021, n = 21). (C) Negative correlation between Glx/Cr in the DN and the VAS score (r=-0.483, p = 0.026, n = 21). (D) Positive correlation between GABA+/Water in the DN and the GAD-7 score (r = 0.519, p = 0.039, n = 16). Gray shading represents the 95% confidence intervals of the partial correlations. PAG, periaqueductal gray; DN, dentate nucleus; Cr, creatine; GABA, gamma-aminobutyric acid; Glx, glutamate/glutamine; VAS, Visual analog scale; GAD-7, Generalized Anxiety Disorder-7

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Discussion

In this study, we investigated the GABA and Glx levels within the PAG and DN of NDPH patients using the MEGA-PRESS sequence. We found that there were no significant differences in these neurotransmitter levels between HC and NDPH groups. In the DN, subgroup analysis showed that moderate-severe NDPH patients had lower Glx concentrations than minimal-mild patients. Furthermore, there were significant correlations between neurotransmitter levels and VAS scores, as well as the GAD-7 scores of NDPH patients.

Several MRI studies have revealed abnormal alterations in the structure, functional connectivity, and cerebral blood flow of the cerebellum in patients with migraine [27,28,29]. As the largest nucleus of the cerebellum, DN may play an important role in the pathogenesis of migraine. The role of PAG in migraine has also been emphasized by many studies [29,30,31]. Both DN and PAG have glutamatergic neurons and GABAergic neurons [32,33,34]. Several studies reported abnormal GABA-Glx imbalance in migraine [5, 8]. The previous MEGA-PRESS study in CM patients has demonstrated the GABA-Glx imbalance in PAG and DN [6]. Therefore, these two regions were selected as ROIs in this study. The GABA and Glx levels were measured in DN and PAG in NDPH patients for the first time. Interestingly, we did not observe abnormal alterations in the levels of these neurotransmitters in either the PAG or DN in patients with NDPH compared with HCs.

Although several factors have been proposed associated with NDPH, such as infections (e.g., viral or bacterial infections) and cervical spine joint hyperactivity [35,36,37], the underlying mechanism of NDPH remains unclear. So far, MRI studies on NDPH were not common and the results vary widely. Negative results were reported in white matter abnormalities [38], voxel-based morphometry (VBM) structural brain alterations [39], as well as glymphatic dysfunction [40]; while some studies have identified abnormalities in structure, cerebral perfusion, white matter micro-structural changes, and functional connectivity in patients with NDPH [20, 41,42,43,44,45]. The findings of our study provide the first group of data in neurotransmitter levels changes in NDPH cases, which indicated that the pathogenesis of NDPH might differ from that of CM, and it is not primarily caused by an imbalance of GABA-GLX in PAG and DN.

The factors that affect the GABA and Glx levels were complex. The findings of MRS studies on migraine have also been heterogeneous in recent years. The location of ROI placement [46], the stimulation [47], the presence or absence of an aura [48], and the severity of migraine [49, 50] may all have an impact on the results. The headache intensity in NDPH patients was comparatively milder than that in the previous study [39]. Whether it is one of the reasons for the negative results in the current study may need further validation. NDPH patients were categorized into a self-limiting form and a persistent refractory form [2]. In another recent study, NDPH patients were classified into three subtypes using cluster analysis [39]. The heterogeneity of patients with NDPH may also be an important reason for the negative results.

In addition to GABA and Glx, other neurotransmitters such as serotonin may also contribute to the development of migraine [51, 52]. It has been suggested that there may be interactions between serotonin, GABA, and Glx [53,54,55]. Taking selective serotonin reuptake inhibitors has been linked to increased GABA levels in the occipital lobe [53, 54]. Animal studies have demonstrated that sumatriptan also inhibits GABAergic and glutamatergic synaptic transmission within the PAG [56]. PAG also has somatostatin, dopamine, and other neurotransmitters [57, 58]. The role of these neurotransmitters in the pathogenesis of NDPH was not verified in this current study. It is plausible that other mechanisms beyond the known neurotransmitter interactions exist in NDPH patients.

Depression, anxiety, and sleep disturbance were prevalent comorbidities in patients with NDPH [4]. Previous studies have shown that the majority of NDPH patients exhibit high scores on both GAD-7 and PHQ-9 assessments [59]. In patients with migraine, Wang et al. [6] reported that the neurotransmitter levels may be correlated with depression, sleep, and disability severity. It has been proposed that lower GABA levels may be associated with more severe migraine [49]. In the present study, moderate-severe patients also had significantly lower Glx levels than the minimal-mild patients. In addition, our results showed that the Glx levels in DN and PAG were negatively correlated with VAS scores. The GABA level in DN was found to be positively correlated with the GAD-7 score. This phenomenon may be associated with neurotransmitter adaptation to clinical characteristics. In the previous study, Peek et al. [60] also found that the increased GABA levels in the anterior cingulate cortex may be a protective factor to suppress further migraine attacks. Alterations in GABA and Glx levels may be adaptive responses to disease states. The relationship between neurotransmitters and migraine characteristics is complex and not yet fully understood. Further research is needed to investigate the mechanisms associated with migraine characteristics and neurotransmitter levels.

There were some limitations in our study. First, this study was a single-center cross-sectional study with a relatively small sample size. Considering the incidence of NDPH, the results of our study might provide data to help with the understanding of this rare disease. Another limitation of our study was that the clinical scales of the NDPH patients were not complete, which might affect the correlation results. There are still some difficulties in achieving high-quality MRS acquisition in the PAG due to its small size. In this study, we used an ROI size of 20 × 20 × 20mm3 to achieve this purpose, which was larger than PAG. Our previous study on patients with migraine found abnormalities in neurotransmitter levels in PAG using the same protocol, which may indicate the feasibility and reliability of the MEGA-PRESS protocol in this area [6]. This approach improved the signal-to-noise ratio, but sacrificed the regional specificity in a certain degree. Recently, Sirucek L et al. [25] proposed a new approach to achieve higher-quality MRS acquisition in PAG. The new imaging method would help to obtain high-quality MRS data with better regional specificity to investigate the neurotransmitter levels in the PAG in future studies. Furthermore, due to the relatively long acquisition time, only DN and PAG were chosen and included in the analysis. Whether there are any changes in the neurotransmitter levels of other regions of the brain still needs further investigation. A longitudinal study with larger sample size and complete clinical scale data will be needed for validation of the findings in the current study.

Conclusion

In conclusion, the results of this study indicated that the neurotransmitter levels changes in the periaqueductal gray and dentate nucleus may not be the primary contributor to the development of NDPH, which may be taken as supportive data for the different underlying mechanisms between NDPH and primary migraine diseases. Further studies using multimodal MRI are necessary and may provide more valuable information for the exploration of underlying pathological mechanisms in patients with NDPH.

Data availability

Data can be made available upon request.

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Acknowledgements

We would like to express our gratitude to all participants and physicians at the Headache Center, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University in this study. We appreciate the support of the General Electric Company.

Funding

This work was supported by the National Natural Science Foundation of China (Grant No. 62271061, 32170752, 91849104, and 31770800), Beijing Municipal Natural Science Foundation (L232130), and the National Natural Science Foundation of Beijing (Z200024).

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Authors and Affiliations

  1. Tiantan Neuroimaging Center of Excellence, China National Clinical Research Center for Neurological Diseases, No.119 South Fourth Ring West Road, Fengtai District, Beijing, 100070, China

    Tong Chen, Xiaoyan Bai, Xue Zhang, Xun Pei, Yuanbin Zhao & Binbin Sui

  2. Department of Radiology, Beijing Tiantan Hospital, Capital Medical University, No.119 South Fourth Ring West Road, Fengtai District, Beijing, 100070, China

    Tong Chen, Xiaoyan Bai, Xue Zhang, Xun Pei & Yuanbin Zhao

  3. Department of Neuroradiology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China

    Tong Chen, Xiaoyan Bai, Xue Zhang, Xun Pei, Yuanbin Zhao & Binbin Sui

  4. Headache Center, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, No.119 South Fourth Ring West Road, Fengtai District, Beijing, 100070, China

    Wei Wang, Ziyu Yuan & Yonggang Wang

  5. Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

    Xueyan Zhang

  6. Department of Radiology, Beijing Chaoyang Hospital, Key Lab of Medical Engineering for Cardiovascular Disease, Capital Medical University, Ministry of Education, Beijing, China

    Qi Yang

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  1. Tong Chen
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  2. Xiaoyan Bai
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  3. Wei Wang
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  10. Yonggang Wang
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  11. Binbin Sui
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Contributions

TC, YGW, and BBS supported the conception and design of this project. WW, XYB, XZ, XYZ, ZYY, XP, QY, and YBZ acquired data. TC and XYB analyzed the data. XYB and WW contributed to data quality control. TC produced the first draft. All authors contributed intellectual content to the revised manuscript and have read and approved the final manuscript.

Corresponding authors

Correspondence to Yonggang Wang or Binbin Sui.

Ethics declarations

Ethics approval and consent to participate

This study had been registry on Clinical Trial (NCT05334927). All participants signed an informed consent form, and the Ethics Committee of Beijing Tiantan Hospital reviewed and approved the study (KY-2022-044).

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All authors have agreed to the current submission.

Competing interests

The authors declare no competing interests.

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Chen, T., Bai, X., Wang, W. et al. Gamma-aminobutyric acid and glutamate/glutamine levels in the dentate nucleus and periaqueductal gray in new daily persistent headache: a magnetic resonance spectroscopy study. J Headache Pain 25, 142 (2024). https://doi.org/10.1186/s10194-024-01845-9

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Keywords

The Journal of Headache and Pain

ISSN: 1129-2377

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