Abstract
Background: Esketamine is a version of ketamine that has been approved for treatment-resistant depression, but our previous studies showed a link between non-medical use of ketamine and brain structural and functional alterations, including dorsal prefrontal grey matter reduction among chronic ketamine users. In this study, we sought to determine cortical thickness abnormalities following long-term, non-medical use of ketamine.
Methods: We acquired structural brain images for patients with ketamine use disorder and drug-free healthy controls. We used FreeSurfer software to measure cortical thickness for 68 brain regions. We compared cortical thickness between the 2 groups using analysis of covariance with covariates of age, gender, educational level, smoking, drinking, and whole-brain mean cortical thickness.
Results: We included images from 95 patients with ketamine use disorder and 169 controls. Compared with healthy controls, patients with ketamine use disorder had widespread decreased cortical thickness, with the most extensive reductions in the frontal (including the dorsolateral prefrontal cortex) and parietal (including the precuneus) lobes. Increased cortical thickness was not observed among ketamine users relative to comparison participants. Estimated total lifetime ketamine consumption was correlated with reductions in the right inferior parietal and the right rostral middle frontal cortical thickness.
Limitations: We conducted a retrospective cross-sectional study, but longitudinal studies are needed to further validate decreased cortical thickness after nonmedical use of ketamine.
Conclusion: This study provided evidence that, compared with healthy controls, chronic ketamine users have widespread reductions in cortical thickness. Our study underscores the importance of the long-term effects of ketamine on brain structure and serves as a reference for the antidepressant use of ketamine.
Introduction
Although ketamine — a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist — is valued for its clinical applications in anesthesia and pain management, and esketamine (the S-enantiomer of ketamine) has begun to be used for treatment-resistant depression,1 its widespread abuse is a growing problem. Having previously established the effect of long-term, non-medical use of ketamine on grey- and white-matter structure,2,3 understanding these with greater specificity is a pressing challenge.
Ketamine, as an addictive substance, has been used non-medically as a club drug by snorting the powder alone or with other illicit substances.4 The common mental and physical adverse effects of ketamine abuse include psychotic symptoms and cognitive impairment, out-of-body experiences, depressive and anxiety symptoms, sleep disturbances, ulcerative cystitis, and gastrointestinal toxicity.5–10 Controlled, experimental administration of ketamine has been shown to exacerbate psychotic symptoms and cognitive impairment among patients with schizophrenia,11–13 and to induce hallucinations or perceptual distortions among healthy people.13–15 As a consequence, ketamine has proven valuable as an experimental model of both the psychotic experiences and negative symptoms of schizophrenia.16
Our previous studies demonstrated that chronic abuse of ketamine, especially long-term abuse and consumption of large amounts of ketamine, has been associated with reduction in dorsal prefrontal grey matter,3 abnormalities in frontal white matter,2 decreased thalamocortical connectivity,17 and regional homogeneity alterations of resting-state brain activity. 18 However, the previous analysis of grey matter, using voxel-based morphometry (VBM), was necessarily ambiguous and we could not determine whether altered dorsal frontal grey matter reflected a reduction in cortical thickness alterations to the prefrontal area or whether brain structural alteration would be associated with ketamine use variables such as age at ketamine use onset, duration of ketamine use, and quantity of ketamine consumption.
Available evidence indicates the rapid antidepressant effects of ketamine and esketamine.19 However, large-scale controlled trials are needed to test the durability and safety of long-term, low-dose treatment for people with serious depression, and to determine whether treatment can provide long-term benefits to this group of patients. Considering that the dose of ketamine used by those who abuse it as a club drug is much higher than its use as a medication, measuring the consequences of long-term ketamine abuse on brain changes may be irrelevant to its long-term, low-dose use as an antidepressant, but exploring the consequences of ketamine abuse may provide some insight for its use as a medication.
We sought to explore cortical thickness alterations among patients with ketamine use disorder (i.e., ketamine dependence or addiction). Considering that non-medical ketamine use has been associated with poor psychological well-being (e.g., cognitive impairment, depression, anxiety),20–22 that acute23 and chronic24 use of ketamine mimics some aspects of schizophrenia, and that widespread reductions of cortical thickness (especially prefrontal cortical thickness abnormalities linked with negative symptoms) were observed among patients with schizophrenia,25,26 we hypothesized that, compared with healthy controls, ketamine-dependent patients would exhibit widespread reductions in cortical thickness across the brain, with the prefrontal regions being generally more affected than other areas. We also hypothesized that regional cortical thickness alterations would be associated with clinical symptoms (e.g., larger amount of ketamine consumption, longer-term use) among patients with ketamine use disorder.
Methods
Study population
The current study included patients with ketamine use disorder from 2 drug rehabilitation centres in China (the Kangda Voluntary Drug Rehabilitation Centre in Hunan Province and the Department of Addiction Medicine, Hunan Brain Hospital). We recruited these patients after the ketamine withdrawal phase. In addition to the data from the previous VBM analysis of grey matter volume (recruited in 2009), we recruited additional participants from 2012 to 2015 to allow a more robust analysis of group differences and to increase power to detect a relationship between any alterations in regional cortical thickness and relevant variables, including duration of use and estimated total ketamine usage. From 2009 to 2015, we recruited age-matched healthy volunteers via a combination of targeted site sampling, social media advertisement, and snowball sampling referrals. Each enrolled healthy control was encouraged to suggest other potential individuals for the study.
For inclusion, we required that patients meet the criteria for ketamine dependence from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, using the Structured Clinical Interview for DSM Disorders.27 We also required that patients had used ketamine for at least 1 year, spoke Chinese, and were aged 18–45 years. Two licensed psychiatrists conducted all clinical interviews. Inclusion for drug-free healthy volunteers were that they never used illicit drugs, spoke Chinese, and were aged 18–45 years. We excluded participants with ketamine use disorder and healthy controls if they had learning disabilities or central nervous system dysfunctions, had any current or previous major medical or psychiatric disorders (excluding ketamine-induced psychiatric symptoms), currently used intravenous drugs, had undergone current or previous electroconvulsive therapy or brain stimulation therapies, had a history of head injury with skull fracture or a loss of consciousness for more than 10 minutes, had a family history of psychotic disorder, met criteria for diagnosis of substance dependence (excluding ketamine and nicotine for patients in the ketamine use group, and nicotine for participants in the control group), were pregnant, or had contraindications for magnetic resonance imaging (MRI).
Clinical measurements
We collected sociodemographic characteristics, including age, gender, educational level, ethnicity, handedness, and marital status. The addictive substance use characteristics collected included ketamine use, cigarette smoking, alcohol drinking, and other variables related to illicit drug use. We applied a structured interview guide for the 30-item Positive and Negative Syndrome Scale (PANSS),28 the 24-item Hamilton Rating Scale for Depression (HAMD),29,30 and the 14-item Hamilton Anxiety Rating Scale (HARS).31–33 All psychiatrists (Y.L., J.T., C.Q., Q.W.) who participated in the evaluation received training in the application of PANSS, HAMD, and HARS before the study.
MRI data acquisition
We obtained 3-dimensional T1-weighted images using a 3.0 T Siemens Magnetom Trio scanner (Allegra, Siemens) at the Magnetic Resonance Center of Hunan Provincial People’s Hospital, China. The magnetization-prepared rapid acquisition with gradient echo (MP-RAGE) sequence parameters of the structured T1-weighted images were 176 sagittal slices of 1 mm thickness without gap, repetition time 2000 ms, echo time 2.26 ms, field of view 256 × 256 mm2, flip angle 8°, and acquisition matrix size 256 × 256.
Image processing and calculation of cortical thickness
We performed cortical reconstruction with the FreeSurfer software package (version 7.1.0) (https://surfer.nmr.mgh.harvard.edu). In brief, preprocessing included motion correction, intensity normalization, removal of non-brain tissue, Talairach transformation, segmentation of the subcortical white-matter and grey-matter volumetric structures, tessellation and smoothing of the white-matter boundary, and automated topology correction and surface deformation following intensity gradients to optimally place the grey–white and grey–cerebrospinal fluid borders, defined at the location with the greatest shift in signal intensity.34–38 We calculated cortical thickness based on the distance between white- and grey-matter boundaries at each vertex. The cortical surface was then parcellated into 68 regions based on the Desikan–Killiany (DK) atlas.39 All results of cortical parcellations were visually inspected and inaccuracies in segmentation were manually edited. We also computed histograms of all regions’ values for each site for visual inspection.
Statistical analysis
We tested for differences in demographics and clinical measurements between chronic ketamine users and controls using Student t tests for continuous variables and χ2 tests of independence for categorical variables. We evaluated group differences in cortical thickness for DK atlas regions between groups using analysis of covariance (ANCOVA), with age, gender, educational level, smoking, drinking, and mean whole-brain cortical thickness as covariates. To test whether cortical thickness differences among chronic ketamine users were potentially related to ketamine use characteristics — including age of ketamine use onset, the duration of ketamine use, and the quantity of ketamine consumption (estimated total lifetime ketamine consumption) — and to severity of psychotic symptoms, we used Pearson correlations to assess associations of thickness of selected cortical regions with ketamine use profiles and PANSS scores. We performed all statistical analyses with R version 4.0.3. We considered results significant if the p value was less 0.01.
Ethics approval
Study data were collected with participants’ written informed consent, approved by the ethics committee of the Second Xiangya Hospital, Central South University (no. S163, 2011). All procedures contributing to this work were carried out in accordance with the Helsinki Declaration of 1975, as revised in 2008.
Results
Table 1 presents demographics and substance use characteristics for the 95 patients with ketamine use disorder (n = 44 from the previous VBM analysis of grey-matter volume, recruited in 2009, and 51 participants recruited from 2012 to 2015) and 169 drug-free healthy controls. We found no significant group differences in age, sex, handedness, or marital status. However, ketamine users received fewer years of education than controls. Smoking and drinking were more prevalent among ketamine users.
Among patients with ketamine use disorder, 68 (71.6%) had psychotic symptoms. For positive symptoms, 34 (35.8%) patients had hallucinations (mostly auditory verbal hallucinations and visual hallucinations) and 18 (18.9%) had delusions (mainly persecutory delusions). Other commonly experienced symptoms included depressive symptoms (n = 61, 64.2%), memory decline (n = 45, 47.4%), and irritability (n = 31, 32.6%).
Cortical thickness
Compared with healthy controls, patients with ketamine use disorder showed significant reduction in cortical thickness in 26 regions (Bonferroni-corrected p < 0.01). Increased cortical thickness was not observed among ketamine-dependent patients. Figure 1 shows significant cortical thinning regions among patients with ketamine use disorder. Regions are listed from the strongest to the weakest effect size in Table 2. Regions with the most extensive reductions in cortical thickness were located in the frontal (including the dorsolateral prefrontal cortex [DLPFC]) and parietal (including the precuneus) lobes.
Correlations between ketamine use variables and reduced cortical thickness
We assessed the correlations between the 26 regions with cortical thickness reductions and age at ketamine use onset, the duration of ketamine use, the estimated total lifetime consumption of ketamine, and severity of positive and negative symptoms by PANSS. Correlation analysis found a negative correlation between estimated total lifetime consumption of ketamine and cortical thickness in the right inferior parietal lobule (r = −0.41, Bonferroni-corrected p < 0.001; Figure 2A) and right rostral middle frontal gyrus (r = −0.38, Bonferroni-corrected p = 0.004; Figure 2B). However, we did not find correlations between age at ketamine use onset or the duration of non-medical ketamine use and regions with significant cortical thinning. Furthermore, we found correlations between negative symptoms and the left inferior temporal gyrus (r = −0.39, Bonferroni-corrected p = 0.003; Figure 3A) and the left superior temporal gyrus (r = −0.36, Bonferroni-corrected p = 0.004; Figure 3B). We further explored the relationships between depression and anxiety and changes in cortical thickness. We found that the cortical thickness in the left precentral gyrus was negatively associated with HAMD scores (r = −0.36, Bonferroni-corrected p < 0.001; Figure 4). However, we did not find any correlations between regional thickness and severity of positive symptoms or anxiety symptoms among patients with ketamine use disorder.
Discussion
We sought to identify regions with cortical thickness alterations among patients with ketamine use disorder and to establish whether cortical thickness reductions were related to ketamine use characteristics. We found that patients with ketamine use disorder, compared with drug-free healthy volunteers, showed impairments of mental well-being (including psychotic symptoms and symptoms of depression) and widespread reductions in cortex thickness, with the most extensive thickness reductions in the frontal (including the DLPFC) and parietal (including the precuneus) lobes. We also found that estimated total lifetime consumption of ketamine (but not age at ketamine use onset or the duration of non-medical ketamine use) was correlated with 2 specific cortical regions of cortical thickness reductions, namely the right inferior parietal lobule and the right rostral middle frontal gyrus. The observation of these cortical thickness deficits among patients reflects an important extension of the previous demonstration of less specific abnormalities, as shown by VBM of grey-matter volume.3
In the current study, we found that more than 70% of patients with ketamine use disorder had psychotic symptoms, including auditory verbal hallucinations, visual hallucinations, and persecutory delusions. More than 60% of patients with ketamine use disorder had depressive symptoms. Data from the Canadian Community Health Survey reported that people with substance use disorders are more likely to have major depression.40 Furthermore, stressful life experiences may contribute to the comorbidity of substance use disorders and depression or other mental problems.41 However, all the patients in this study were from rehabilitation centres; psychosis induced by chronic use of ketamine with comorbid depression is more prevalent among treatment-seeking people with ketamine dependence.42 Mental health problems related to ketamine use — such as hallucinations, agitation, and anxiety — were also reported among recreational ketamine users from the general population or subpopulation (clubbers). 43 Furthermore, several clinical studies have found that long-term, non-medical ketamine use was associated with poor psychological well-being, including psychotic symptoms and cognitive impairment, out-of-body experiences, symptoms of depression and anxiety, sleeping problems.5–8,44 Preclinical studies found that repeated exposure to ketamine for a period of 14 days45 or 28 days46 led to cognitive impairments. The current study further indicates a link between long-term ketamine abuse and impaired mental well-being.
We found significant and consistent ketamine-associated cortical thinning in a wide range of regions, with the most extensive thickness reductions in the frontal (including the DLPFC) and the parietal (including the precuneus) lobes. A similar study involving 28 chronic ketamine users and 30 healthy controls also reported reduction of cortical thickness in the prefrontal cortex and many other brain regions among ketamine users.47 Frontal cortical thinning has also been observed among people with other drug dependencies, such as cocaine,48 heroin,49 and alcohol dependence.50 One interesting aspect of the present findings is that patients with ketamine use disorder exhibited only significantly decreased cortical thickness, with no areas showing an increase relative to healthy controls. This is in contrast to people with heroin dependence who showed both increases and decreases in cortical thickness.49 Thus, the consistent findings of thinning with long-term ketamine use may suggest a unique pathophysiology and, interestingly, are more akin to findings from patients with schizophrenia, who exhibit excessive cortical thinning in widespread areas of the brain, particularly in the frontal and temporal areas.51,52 Chronic ketamine use may not only cause grey-matter volume reduction, but also induce subthreshold psychotic symptoms, and these likely arise through distinct mechanisms.3,53
We found correlations between estimated total lifetime consumption of ketamine and cortical thickness in the right inferior parietal lobule and the right rostral middle frontal gyrus. However, this study failed to find correlations between age at ketamine use onset or the duration of non-medical ketamine use and regions of any significant cortical thinning. Our previous studies also showed correlations between estimated total lifetime consumption of ketamine and alterations of grey matter, 3 as well as white matter,2 among chronic ketamine users. Another study reported that dose, frequency, and duration of ketamine use were negatively correlated with cortical thickness of some specific brain regions.47 These findings suggest that heavier ketamine users may display stronger cortical thickness reductions in specific regions, which may serve as neuroimaging-based biomarkers for stratifying severity of ketamine use. However, there is a need to further explore why only specific brain regions’ cortical thickness reductions were linked to ketamine consumption.
As ketamine induces psychosis, it has been used as a model for schizophrenia for decades.54 The current study found that cortical thickness in the left inferior temporal gyrus and the left superior temporal gyrus was negatively correlated with PANSS negative symptom severity. We speculated that non-medical use of ketamine would lead to higher risk for psychotic disorders. A previous study compared ketamine users with polydrug-using controls and found significantly higher subthreshold psychotic symptoms among ketamine users.53 The presence of psychotic symptoms among chronic ketamine users reflects a further noteworthy overlap between this condition and schizophrenia. Previous studies found abnormal brain structural and functional properties of the temporal gyrus among patients with schizophrenia, correlating with clinical symptoms. For example, a morphological MRI study found that patients with first-episode schizophrenia exhibited smaller grey-matter volumes in the middle and inferior temporal gyrus relative to healthy controls.55 A resting-state functional MRI study demonstrated that patients with schizophrenia showed reduced spontaneous activity in the lingual gyrus, left cuneus, left superior temporal gyrus, and right caudate by the fractional amplitude of low-frequency fluctuations, an index of resting-state functional MRI, and these brain regions showed a trend for correlations with PANSS negative and total scores.56 However, we did not find any correlations between reduced cortical thickness among ketamine users with positive symptoms. Reduced cortical thickness in the superior temporal region among people at high clinical risk of psychosis is a potential biomarker to predict conversion to schizophrenia or other psychotic disorders.57 Furthermore, a systematic review and meta-analysis reported accelerated age-related reductions in cortical thickness among patients with schizophrenia.58
Ketamine has a long history of medical use for starting and maintaining anesthesia with safety and effectiveness. As a novel antidepressant, however, ketamine has some safety concerns. A small but growing body of highly consistent studies have demonstrated unique, rapid, and robust antidepressant properties with short-term ketamine use,59 even for older adults (aged ≥ 60 yr) with treatment-resistant depression.60 Single and repeated ketamine infusions also decreased suicidal ideation among patients with treatment-resistant depression.61,62 To date, only a few studies have examined the safety of long-term, low-dose use of ketamine in a clinical setting. An open-label study demonstrated the long-term (up to 1 yr) safety and manageable tolerability of weekly or biweekly dosing of esketamine nasal spray (28 mg, 56 mg, or 84 mg) plus a new oral antidepressant for people with treatment-resistant depression.63 Furthermore, psychiatric, psychotomimetic, and other effects were reported after single and repeated doses of esketamine in the treatment of depression.64 Although preclinical evidence demonstrated the sustained antidepressant effects of ketamine, 65 whether long-term administration of low-dose ketamine would increase propensity for ketamine addiction following antidepressant treatment is still unclear. Numerous problems and controversies remain unsolved in terms of its addictive properties and its role as an antidepressant. Considering that long-term, low-dose safety remains largely unknown, intranasal esketamine for treatment-resistant depression is still controversial. For example, esketamine for treatment-resistant depression is not recommended by the National Institute for Health and Care Excellence (NICE) in the United Kingdom.66 From a neuroimaging perspective, however, a review indicated that ketamine perturbs components of depression-relevant neural circuits, including brain regions related to inhibition, reward processing, and anhedonia.67
The abused dose of ketamine (500–1000 mg per use by snorting ketamine powder; on average 800 mg per use among patients in the current study) is often much higher than the low dose of esketamine or ketamine for treatment of depression or other purposes (about 50 mg per use or 0.5 mg/kg).1,68 In comparisons of ketamine and esketamine, research found no significant differences in the trajectory of depression severity, including response rates and remission.1 The current findings of cortical thickness reductions among patients with ketamine use disorder suggest the need for caution and careful monitoring with long term, low-dose, medical use of ketamine. It is important to balance the promise and risks of ketamine treatment for treatment-resistant depression in the clinical setting.69 Further work is warranted to explore the exact mechanism behind ketamine’s ability to treat treatment-resistant depression, which may provide more valuable strategies to prevent ketamine’s potential addiction or abuse. Future neurobiological studies of regions with thickness reduction and their functions may help clarify the pathological mechanism for ketamine addiction and its medical properties.
Despite the harmful effects of ketamine abuse, medical use of ketamine should never be discouraged or devalued. Compared with other antidepressants, ketamine is unique in its ability to rapidly help people with severe treatment-resistant depression, especially with suicidal ideation.70,71 Evidence indicates that short-term medical use of ketamine is safe for treatment-resistant depression.72 Furthermore, a wealth of evidence has indicated the value of ketamine as an accessible and affordable medication for anesthesia (especially in less privileged medical facilities), and use of ketamine is also well established for pain management and critical care.73–75 Nevertheless, the findings of this study provide an important insight into the safety precautions of medical use of ketamine, especially when it is used in the long term or in large amounts. Many ketamine use–related issues need more investigation, especially matters related to addictive potential and strategies to mitigate illicit use, and adverse effects of long-term, low-dose administration of ketamine or esketamine on the brain.
Limitations
A notable limitation of this study was its retrospective cross-sectional design. It does not directly and unequivocally establish a causal relationship between ketamine use and alterations of cortical thickness. Whether cortical thickness abnormalities in ketamine addiction are only a reflection of chronic ketamine use, or also a pre-existing disposition to ketamine addiction remains unclear, as is whether other potential confounding influences — such as duration of abstinence and developmental time courses from recreational use to dependence of ketamine — are associated with cortical thickness reductions. Whether these deficits are reversible and to what extent therapy or abstinence might reverse them is also unknown. Studies with a more comprehensive longitudinal design are needed to explore these confounding factors. The 2 groups we studied were not matched for cigarette smoking, with a higher rate of cigarette smoking among ketamine-dependent participants (although there were no significant group differences in years of smoking and smoked cigarettes per day among smokers). Some studies have reported reduced cortical thickness among cigarette smokers.76,77 Thus, the analysis included smoking as a covariate. We did not find significant association between years of smoking and cortical thickness reduction, and we found no correlation between any significant regions and estimated total smoked cigarettes (p > 0.1). The prevalence of alcohol drinking was also not well matched between the 2 groups. Compared with healthy controls, both males and females with alcohol dependence show reduced cortical thickness,50 especially in the prefrontal cortical region.78 However, we excluded participants with alcohol dependence and included drinking as a covariate in the analysis. Education levels were not well matched between the 2 groups. However, when we explicitly explored the impact of education level on cortical thickness reduction among ketamine users, we found no statistically significant correlation (p > 0.1). Furthermore, we included it as a covariate in the analysis. Although none of the ketamine users in our sample had current clinical presentations or history of bipolar disorder, schizophrenia, or any other psychotic disorders, many had ketamine use–induced psychosis and symptoms of depression and anxiety. Although there was a time link between ketamine use and the development of psychotic or depressive symptoms, we could not fully ascertain that these symptoms were caused by using ketamine and we could not ensure that the change of cortical thickness was not related to depression. Confounding by other substances (especially stimulants) cannot be totally excluded, although we did excluded participants with other drug dependencies, except for nicotine. As some patients with ketamine use disorder had psychotic or depressive symptoms, history of medications (e.g., antipsychotic or antidepressant medications) could not be totally excluded, which may be associated with alterations in cortical thickness. However, to minimize medication effects, few ketamine users who had administration of medication within 2 weeks of scanning were included in this study, and none of them reported the use of any antipsychotic and antidepressant medications within these 2 weeks. Furthermore, we excluded patients who reported any psychotic or depressive symptoms before using ketamine from this study.
Conclusion
The findings from this study provide evidence that long-term ketamine abuse was linked to widespread reductions in cortical thickness, especially among patients with ketamine use disorder with high total lifetime consumption. This study advances understanding of the effects of ketamine addiction and provides insights in the safety of repeated ketamine infusions for the treatment of depression. A greater understanding of the underlying mechanism of cortical thickness reductions among patients with ketamine use disorder could lead to the marked improvement of risk–benefit ratios of esketamine use for people with treatment-resistant depression.
Acknowledgement
The authors thank Paul Fletcher for his assistance in the study.
Footnotes
Competing interests: None declared.
Contributors: Jinsong Tang and Yanhui Liao contributed to the conception and design of the work. Qiuxia Wu, Chang Qi, An Xie, Jianbin Liu, Xu Shao, Yunkai Sun, Tifei Yuan, and Tieqiao Liu contributed to data acquisition, analysis, and interpretation. Jinsong Tang, Wei Chen, Wei Hao, and Yanhui Liao drafted the manuscript. All of the authors revised it critically for important intellectual content, gave final approval of the version to be published, and agreed to be accountable for all aspects of the work.
Funding: This study was supported by the National Natural Science Foundation of China (no. U22A20302 to Y.L.), and by the STI 2030 — Major projects (no. 2022ZD0211200 to Y.L.). The funders had no role in study design, data collection and analysis, or decision to write the report or to submit the paper for publication.
- Received August 1, 2023.
- Revision received November 12, 2023.
- Revision received February 17, 2024.
- Accepted February 17, 2024.
This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY-NC-ND 4.0) licence, which permits use, distribution and reproduction in any medium, provided that the original publication is properly cited, the use is noncommercial (i.e., research or educational use), and no modifications or adaptations are made. See: https://creativecommons.org/licenses/by-nc-nd/4.0/