Exploring communication impairments in children with spastic cerebral palsy through neurovascular coupling: a cross-sectional study

Introduction

Cerebral palsy is a common physical disability among children and adolescents worldwide, referring to a group of persistent central motor and postural developmental disorders characterized by activity limitations. These disorders result from non-progressive brain injuries occurring during fetal or early infant development (1). Motor impairments in individuals with cerebral palsy are often accompanied by communication and behavioral disorders, which significantly affect patients’ daily activities, such as learning, working, and social interactions (2). The global prevalence of cerebral palsy ranges from 1.6 to 3.4 per 1,000 live births, with the overall prevalence in high-income countries currently at 1.6 per 1,000 live births (3). Among the various subtypes of cerebral palsy, spastic cerebral palsy (SCP) is the most prevalent (4). Periventricular white matter injury (PWMI), a primary form of infantile brain white matter injury, is a common cause of SCP (5). However, the complex etiology and neurophysiological alterations associated with SCP remain poorly understood, and effective interventions for associated communication impairments are limited. Early diagnosis and the identification of novel imaging biomarkers associated with brain injury are crucial for improving the prognosis of children with SCP.

Resting-state functional magnetic resonance imaging (rs-fMRI) has been widely used to study the brain’s functional state and spontaneous neural activity in a task-free state, detecting changes in the blood oxygen level-dependent signal, such as fractional amplitude of low-frequency fluctuations (fALFF) and regional homogeneity (ReHo) (6). Prior studies have indicated changes in neural activity in children with SCP (6,7); however, research in this area has been relatively limited. Arterial spin labeling (ASL), a non-invasive technique that measures cerebral blood flow (CBF), is also extensively utilized in neurological research (8-10). For example, diffusion-prepared pseudo-continuous ASL technology reflects blood-brain barrier dysfunction non-invasively by assessing the water exchange rate across the blood-brain barrier, offering insights into both structural and functional alterations (11,12). Studies have demonstrated that there are abnormalities in cerebral blood perfusion in children with cerebral palsy (13), but research in this field is extremely scarce, and both the depth and breadth of the research are far from sufficient. Despite the widespread application of these techniques, studies on SCP often rely on a single imaging modality, which restricts the comprehensive understanding of regional CBF and neuronal activity changes in cerebral palsy.

Neurovascular coupling (NVC) refers to the mechanism that regulates CBF to meet neuronal activity, thereby playing a crucial role in maintaining brain microenvironment homeostasis (14). Disruption of NVC is a major contributor to functional impairments in various pathological conditions. Prior research has documented NVC abnormalities in various conditions affecting children, including developmental disorders, correlating these disruptions with cognitive and motor impairments (15). Evaluating the collaboration of ASL and blood oxygenation level-dependent signals could provide more comprehensive insights into the physiological and pathophysiological mechanisms of the developmental brain (16). For example, Zhang et al. (17) found significant NVC abnormalities in multiple brain regions of amblyopic children based on ReHo and fALFF, and there is a correlation between these abnormalities and neurotransmitters. Baller et al. (16) have demonstrated that NVC evolves during adolescence and is associated with executive functions. Particularly for children with SCP, understanding how NVC is affected and revealing its clinical significance is crucial.

However, the relationship between cerebral perfusion and neuronal activity in SCP remains unclear. This study aimed to utilize ReHo and fALFF (rs-fMRI parameters) to capture regional neuronal activity changes and combine with ASL as a CBF approach to evaluate alterations in NVC in children with SCP. By elucidating these neurophysiological mechanisms, we aimed to offer novel insights into the clinical significance of NVC changes in SCP. We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-19/rc).

Methods

Participants

The diagnosis of SCP was made by experienced pediatric neurologists based on the definition proposed by Rosenbaum et al. (18). The magnetic resonance imaging (MRI) scans of all participants were interpreted by experienced neuroradiologists. In this study, a total of 86 pediatric cases diagnosed with cerebral palsy consecutively at the Affiliated Hospital of Zunyi Medical University from July 2020 to December 2023 were included. The inclusion criteria for the case group were as follows: (I) clinically diagnosed SCP; (II) conventional cranial MRI examination indicating PWMI; and (III) age between 4 and 14 years at the time of MRI scanning. The exclusion criteria were as follows: (I) incomplete clinical information; (II) presence of any other neurological disorders, such as trauma, tumors, or infections; and (III) poor quality MRI images that could impact data analysts. A total of 22 typically developing children, matched for age and gender, were recruited as typically developing controls (TDC). The inclusion criteria for the TDC were as follows: (I) no neurological or mental disorders; and (II) no abnormalities on routine MRI. The exclusion criteria for TDC were as follows: (I) incomplete clinical information; and (II) poor quality MRI images that could impact data analysis.

Language assessment

On the same day as the MRI scans, all children with SCP underwent standardized communication function grading assessment by experienced pediatric neurologists. The Communication Function Classification System (CFCS) (19) evaluates the overall effectiveness of communication based on everyday communication performance in home, school, and community settings and is widely used in China. The CFCS is divided into levels I–V, with higher levels indicating poorer communication and interaction abilities.

MRI data acquisition

MRI data were acquired using a 3 T scanner (Signa HDXT; GE Healthcare, Milwaukee, WI, USA) with eight-channel head coils. All participants were required to wear earplugs to protect their hearing. Each participant’s head was secured with foam padding. During the scanning process, participants were instructed to close their eyes, try not to think of anything, and remain awake. Three-dimensional T1-weighted structural images were acquired using the following parameters: repetition time (TR) =7.8 ms; echo time (TE) =3 ms; slice thickness =1 mm; flip angle =15°; field of view (FOV) =256×256 mm; and matrix size =256×256. The rs-fMRI were acquired with the following parameters: TR =2000 ms; TE =30 ms; FOV =256×256 mm; slice thickness =4 mm; flip angle =90°. Pseudo-continuous ASL images were acquired using the following parameters: TR =4599 ms; TE =9.804 ms; FOV =240×240 mm; flip angle =155°; slice thickness =4 mm.

rs-fMRI data processing

All rs-fMRI data were preprocessed in DPABI V5.0 (http://rfmri.org/DPABI) on the MATLAB R2018b platform (MathWorks, Inc., Natick, MA, USA; https://mathworks.com). The specific data processing steps were as follows: (I) convert data from Digital Imaging and Communications in Medicine (DICOM) format to Neuroimaging Informatics Technology Initiative (NIfTI); (II) remove the data from the first 10 time points; (III) the remaining volumes were corrected for the acquisition time delay between slices; (IV) exclude displacements >3 mm or rotations >3.0° in any direction to achieve head motion correction; (V) segment the image and remove white matter and cerebrospinal fluid signals; (VI) band-pass filter with a frequency range of 0.01–0.1 Hz; (VII) normalize the image to Montreal Neurological Institute (MNI) space; (VIII) resample the functional image to a voxel size of 3-mm isotropic resolution.

The ReHo was computed as follows: first, by calculating the Kendall’s coefficient of concordance of a given voxel’s time series with its nearest 26 voxels, a single ReHo map was generated. This map was then divided by the mean Kendall’s coefficient of concordance value across the whole brain. Finally, spatial smoothing was performed using a 6×6×6 mm full-width at half-maximum kernel (FWHM).

The fALFF were computed as follows: first, the preprocessed rs-fMRI data was transformed into frequency-domain power spectrum using Fourier transform. Next, the square root (amplitude) of the power spectrum at each frequency was calculated. Then, the sum of amplitudes within the low-frequency spectrum (0.01–0.1 Hz) was divided by the sum of amplitudes across the entire frequency range. Subsequently, z-score transformation was applied to individual fALFF maps. Finally, smoothing was performed using a 6×6×6 mm FWHM.

CBF data processing

Based on ASL images, a single CBF image was acquired using FuncTool software (Signa HDXT; GE Healthcare) and preprocessed in the SPM12 toolbox in MATLAB R2018a. First, all individual CBF images of participants were registered and normalized from individual space to the MNI standard space using a one-step registration method. Next, they were resliced to a voxel size of 3 mm isotropic resolution. Then, the resulting images were z-score transformed. Finally, a spatial smoothing process with a Gaussian kernel of 6×6×6 mm was applied to the normalized maps.

Region-wise calculation of NVC metrics

In order to assess the metabolic consumption of each unit of neural activity, we used the raw values of CBF, fALFF, and ReHo to calculate the CBF/fALFF and CBF/ReHo ratios to represent regional NVC. For each participant, the CBF/fALFF and CBF/ReHo ratios were standardized into z-scores and smoothed using a 6-mm FWHM. Voxel-wise comparisons were performed to determine significant differences in CBF/fALFF and CBF/ReHo ratios between groups.

Ethical considerations

This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Each participant’s parents or legal guardians provided written informed consent. This study was approved by the Medicine Ethics Committee of the Affiliated Hospital of Zunyi Medical University (No. KLL-2024-065) and registered with the Chinese Clinical Trial Registry (Clinical trial registration number: ChiCTR2400090575).

Statistical analysis

Statistical analysis of demographic data and clinical information between the two groups was conducted using the software SPSS 29.0 (IBM Corp., Armonk, NY, USA). Quantitative information that conformed to a normal distribution was expressed in the form of mean ± standard deviation. Quantitative information that did not conform to a normal distribution was expressed as median (interquartile range). Qualitative information was expressed as a percentage. Parametric data conforming to a normal distribution were analyzed using the two-sample t-test, whereas non-parametric data were analyzed using the Mann-Whitney U test. Categorical variables, including gender, gestational age, and CFCS, were analyzed using a χ² test. A significance level of P<0.05 was considered statistically significant.

In the DPABI software V5.0 (http://rfmri.org/DPABI) on the MATLAB R2018b platform, a two-sample t-test was conducted to analyze fALFF, ReHo, CBF, CBF/fALFF, and CBF/ReHo. Age and gender were used as covariates, and multiple comparison correction was performed using Gaussian random field (GRF) correction, with a significance level set at P<0.001 at the voxel level and P<0.05 at the cluster level.

After correcting for age and gender, Spearman rank correlation was used to assess the correlation between the average values of fALFF, ReHo, CBF, CBF/fALFF, and CBF/ReHo in brain regions showing significant between-group differences and the CFCS level.

Results

Demographics and clinical assessments

The study ultimately included 20 children with SCP and 22 TDC (Figure 1). There was a statistically significant difference in gestational age (χ²=19.549, P<0.001) between the groups. However, there were no statistically significant differences in age (P=0.095) and gender (P=0.474) between the SCP and TDC groups. Demographic and clinical data are presented in Table 1.

Figure 1 Flowchart of patient inclusion process. MRI, magnetic resonance imaging; PWMI, periventricular white matter injury; SCP, spastic cerebral palsy.

Changes of NVC at regional levels

Compared to the TDC group, children with SCP showed increased CBF/ReHo ratios in the left fusiform gyrus, right lingual gyrus, bilateral thalamus, left calcarine fissure and surrounding cortex, and left caudate nucleus (Figure 2, Table 2). The SCP group exhibited a higher CBF/fALFF in the left lingual gyrus, left middle temporal gyrus, right middle occipital gyrus, bilateral caudate nucleus, left angular gyrus, and left median cingulate and paracingulate gyri (Figure 3, Table 2).

Figure 2 Comparison of the alterations in CBF/ReHo ratio between the SCP and TDC groups. The cold and warm colors represent the areas with significantly decreased and increased CBF/ReHo ratio in SCP children, respectively. CBF, cerebral blood flow; L, left; R, right; ReHo, regional homogeneity; SCP, spastic cerebral palsy; TDC, typically developing controls.

Figure 3 Comparison of the alterations in CBF/fALFF ratio between the SCP and TDC groups. The cold and warm colors represent the areas with significantly decreased and increased CBF/fALFF ratio in SCP children, respectively. CBF, cerebral blood flow; fALFF, fractional amplitude of low-frequency fluctuation; L, left; R, right; SCP, spastic cerebral palsy; TDC, typically developing controls.

Changes of fALFF, ReHo, and CBF

Compared to TDC, the SCP group showed decreased fALFF in the right fusiform gyrus, left precuneus, right medial superior frontal gyrus, right dorsolateral superior frontal gyrus, bilateral middle frontal gyrus, left middle occipital gyrus, right angular gyrus, and left superior parietal gyrus (Figure 4A). There were no apparent differences in ReHo between SCP and TDC. The SCP group showed a significantly lower CBF than the TDC group in the right inferior temporal gyrus, right superior temporal gyrus, and right dorsolateral superior frontal gyrus, and a higher CBF in the right parahippocampal gyrus and left lingual gyrus (Figure 4B).

Figure 4 Comparison of the alterations in fALFF and CBF between the SCP and TDC groups. (A) Comparison of the alterations in fALFF between the SCP and TDC groups. (B) Comparison of the alterations in CBF between the SCP and TDC groups. The cold and warm colors represent the areas with significantly decreased and increased fALFF and CBF in SCP children, respectively. CBF, cerebral blood flow; fALFF, fractional amplitude of low-frequency fluctuation; L, left; R, right; SCP, spastic cerebral palsy; TDC, typically developing controls.

Relationships between clinical variables and NVC

In SCP with PWMI, increased CBF in the right dorsolateral superior frontal gyrus was negatively correlated with communication function level (r=−0.563, P=0.010) (Figure 5A); increased CBF/fALFF in the left middle temporal gyrus (r=−0.560, P=0.010) and left angular gyrus (r=−0.541, P=0.014) were negatively correlated with communication function level (Figure 5B).

Figure 5 Relationship between the significant group difference regions and CFCS in SCP patients. (A) Spearman’s correlation between CBF/fALFF ratios in the left middle temporal and CFCS. (B) Spearman’s correlation between CBF/fALFF ratios in the left angular and CFCS. CBF, cerebral blood flow; CFCS, communication function classification system; fALFF, fractional amplitude of low-frequency fluctuation; SCP, spastic cerebral palsy.

Discussion

This study integrated ASL and rs-fMRI techniques to investigate the alterations in NVC in children with SCP by examining the coupling parameters between CBF and neural activity. We found that NVC significantly increased in multiple brain regions of SCP children and was related to the level of communication function. These findings enhance the understanding of the pathophysiological mechanisms of SCP from the perspective of NVC.

The structural basis of NVC is the neurovascular unit, which is primarily composed of neurons, astrocytes, and blood vessels (20). The NVC mechanism ensures that after local neural activation, regional blood flow increases to rapidly supply more nutrients and remove metabolic waste (21). Damage to any component of the neurovascular unit can lead to abnormal NVC (22). Astrocytes serve as crucial intermediary cells between neurons and blood vessels within the neurovascular unit (23). Damage to astrocytes in cerebral palsy may lead to impaired coordination between neural activity and blood supply, which could be one of the reasons for the decoupling of NVC in SCP (24,25). Neurons are also a critical component of the neurovascular unit, regulating CBF through signal generation, and are considered the driving force behind NVC (21). Prior research suggests that neurons may sustain a certain degree of damage within the pathological mechanisms of SCP (26), which could also be a potential cause of abnormal NVC in SCP. Endothelial cells, as integral components of blood vessels, possess potent vasoactive factors, and their alterations also affect the integrity of the neurovascular unit (21). Endothelial cell dysfunction has been found in cerebral palsy (27), which may lead to impairment in cerebral perfusion regulation, ultimately resulting in abnormal NVC.

This study found that in SCP, decreased fALFF values were concentrated in the right fusiform gyrus, left precuneus, right medial superior frontal gyrus, right dorsolateral superior frontal gyrus, bilateral middle frontal gyrus, left middle occipital gyrus, right angular gyrus, and left superior parietal gyrus. The aforementioned brain regions are primarily associated with motor, visual, cognitive, and language functions, which corresponds to the clinical manifestations observed in SCP children. The core clinical manifestation of SCP is motor dysfunction (1). The superior frontal gyrus is associated with motor control, particularly playing a key role in the coordination and execution of complex movements (28). Therefore, abnormal brain activity in this region may be one of the neuro-pathological bases for motor disorders in SCP children. A previous study on children with SCP has reported reduced cortical volume, supporting damage to the motor pathways (29). Beyond morphological abnormalities, there is a decrease in motor cortical connectivity within the prefrontal cortex (7), which further reinforces the likelihood that the superior frontal gyrus plays a crucial role in the motor dysfunction observed in SCP children. Visual impairments are relatively common in individuals with cerebral palsy, particularly cerebral visual impairment (30). The right fusiform gyrus is implicated in the secondary classification and recognition of objects, playing a role in information processing (31), and the abnormal brain activity in this area may be one of the reasons for the visual impairments in children with SCP. Children with SCP exhibit impairments in language functions, which may be associated with cognitive dysfunction (2). The medial superior frontal gyrus is a key brain area closely related to higher cognitive functions, especially playing an important role in decision-making, planning, and specific language tasks (32). Therefore, damage to this area may impact the development of language functions through the impairment of cognitive functions. The SCP group showed a significantly lower CBF than the TDC group in the right inferior temporal gyrus, right superior temporal gyrus, and right dorsolateral superior frontal gyrus, and a higher CBF in the right parahippocampal gyrus and left lingual gyrus. This can be attributed to the chronic exposure of children with SCP to pathological conditions such as inflammation, infection, and hypoxia (33). Severe perfusion deficits or hypoxia led to a decrease in their CBF values (34). Prolonged hypoxia can affect the diameter and/or number of blood vessels to compensate for the low blood supply, ultimately resulting in an increase in brain blood flow and an elevation of CBF value (35). Unlike in one previous study (7), there were no significant differences in ReHo between the two groups in this study, which may be related to the small sample size. Alternatively, this discrepancy could be attributed to differences in the specific brain regions analyzed or the varying severity of SCP among the study participants. Future studies with larger sample sizes and more homogeneous SCP populations are needed to further investigate these findings.

In a healthy brain, NVC ratios are balanced (16). This study found that in some brain regions, individual metrics did not exhibit significant differences between groups, whereas NVC ratios increased noticeably. This may be due to a slight increase in CBF or a slight decrease in neural activity (ReHo, fALFF). When single indicators change slightly, they do not show significant differences in group comparisons. Therefore, NVC ratios can detect changes in brain regions of SCP children earlier and more sensitively than single indicators. The right fusiform gyrus displays normal CBF but reduced neural activity, indicating that the regional NVC abnormality is mainly due to decreased neural activity. Significant differences in NVC ratios were observed in the thalamus and caudate nucleus between groups, whereas no significant differences in CBF and neural activity were detected. A previous study based on multimodal MRI of children with SCP has reported changes in gray matter volume in the thalamus and caudate nucleus (36). Therefore, we speculate that these changes in NVC ratios may be due to changes in grey matter volume. Previous perspectives held that SCP primarily impairs the motor network centered on the sensorimotor circuit (37). However, some studies have indicated that SCP is not confined to impairments within the sensorimotor network; it also encompasses more extensive brain network damage, including abnormalities in the frontoparietal network, the default mode network, and cerebellum networks (38,39). In this study, changes in the NVC indices also involve multiple brain networks, such as the sensorimotor network, language network, visual network, and default mode network. This finding further corroborates and supports the notion that the clinical dysfunctions in SCP may be the result of the combined effects of damage to multiple brain networks.

In the present study, we observed that the brain regions exhibiting altered NVC were predominantly located in the left cerebral hemisphere. We speculate that this finding may reflect subtle differences or asymmetry in the development of the left and right hemispheres in children with SCP. This observation is consistent with the study by Mailleux et al., who investigated the corticospinal tract connectivity patterns (including contralateral, bilateral, and ipsilateral) in SCP children with PWMI (40). Their findings revealed that SCP patients with ipsilateral corticospinal tracts exhibited more severe corticospinal tract injuries compared to those with contralateral corticospinal tracts. Additionally, the study found increased asymmetry in the fractional anisotropy of the corticospinal tracts between the cerebral hemispheres in SCP patients, with 74% of patients showing significant differences in manual motor abilities between their two hands. These findings suggest that the degree of functional impairment in the upper limbs may be closely associated with the asymmetrical injuries in the bilateral brain tissues. Meanwhile, animal models of cerebral palsy induced by hypoxia-ischemia have played an irreplaceable role in relevant research. Ambwani et al. (41) employed three-dimensional rendering techniques to measure dynamic apparent diffusion coefficient and found that brain injuries caused by hypoxia-ischemia exhibited significant lateralized characteristics in cerebral palsy rabbits. Future studies should consider expanding the sample size and conducting more in-depth lateralization analyses to further investigate the asymmetrical developmental features of the left and right hemispheres in SCP children and their underlying mechanisms.

The results of this study demonstrate that the changes in the NVC ratios in the left middle temporal gyrus and the left angular gyrus are associated with the grading of communication function, specifically manifesting as an improvement in communication dysfunction in SCP children as the NVC ratio increases. The left middle temporal gyrus (42) and left angular gyrus (43) play important roles in language comprehension, word memory, and semantic processing. Therefore, alterations in NVC in these regions may be one of the reasons for the communication dysfunction in SCP children. This study is consistent with previous research. For example, Timofeeva et al. (44) found that the posterior middle temporal gyrus and the left angular gyrus make significant contributions to lexical-semantic processing across languages. Morese et al. (45), based on functional MRI research, have demonstrated that the left middle temporal gyrus plays a crucial role in understanding more complex communicative behaviors, particularly in terms of the inferential workload required to correctly comprehend the speaker’s communicative intentions. In addition, according to our findings, gestational age may influence NVC outcomes to some extent. However, the effect of gestational age on NVC needs further study.

Limitations

This study has the following limitations. Firstly, the sample size was relatively small, limiting the generalizability of the results; further studies with larger sample sizes are needed to validate these findings. Secondly, this study was cross-sectional in design, and future longitudinal analyses should be conducted to verify the relationship between CBF and neural activity in children with SCP. Thirdly, NVC is an indirect measure of NVC and may not accurately elucidate the specific neurobiological mechanisms underlying NVC changes in children with SCP. Furthermore, although astrocytic and endothelial dysfunctions may contribute to the altered NVC observed in children with SCP, it is important to note that our study lacks direct neurobiological validation of these mechanisms. Future studies incorporating blood biomarkers, cerebrospinal fluid analysis, or histological techniques (e.g., in animal models) are warranted to validate these neurovascular mechanisms. Subsequently, we recognize that gestational age could potentially influence the outcomes of our study. Regrettably, the limited sample size precluded us from performing subgroup analyses for term and preterm births. Moving forward, we intend to investigate the effects of gestational age more thoroughly in larger cohort studies. Lastly, this study investigated changes in CBF and NVC at the group level but did not account for the potential impact of individual differences in baseline CBF on the results. Future research should not only include larger samples but also consider individual baseline perfusion normalization to better validate the NVC metrics.

Conclusions

In summary, this study, by combining ASL and rs-fMRI techniques, found that the NVC in SCP children is increased and is related to the degree of communication function impairment. It provides evidence for the dysfunction of the coupling between perfusion and neural activity in SCP, elucidates new neuropathological foundations for SCP, and offers potential imaging biomarkers for assessing communication function impairment in SCP.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-19/rc

Data Sharing Statement: Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-19/dss

Funding: This work was supported by the Young Outstanding Scientific and Technological Talent of Guizhou Province (grant No. Qiankehepingtairencai[2021]5620) and Key Basic Research Program of Guizhou Province (grant No. Qiankehejichu-ZK[2022]zhongdian051). The authors express heartfelt gratitude for the support from these projects.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-19/coif). L.N. is currently employed by GE Healthcare. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Each participant’s parents or legal guardians have signed the written informed consent. This study was approved by the Medicine Ethics Committee of the Affiliated Hospital of Zunyi Medical University (No. KLL-2024-065) and registered with the Chinese Clinical Trial Registry (Clinical trial registration number: ChiCTR2400090575).

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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