- 1Cognitive Neurology, Dementia and Neuropsychiatry Research Center, Tehran University of Medical Sciences, Tehran, Iran
- 2Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- 3Cell and Molecular Biology Department, Tehran Medical Sciences, Azad University, Tehran, Iran
Background: Dementia, a worldwide health issue characterized by cognitive and functional deterioration, requires effective non-pharmacological interventions. Writing-based therapies, including Handwriting and typing, enhance memory, attention, and executive functions, providing cognitive, emotional, and social advantages. This systematic review examines the changing role of writing in dementia rehabilitation.
Methods: In accordance with PRISMA guidelines, studies from PubMed, Scopus, and Web of Science (1991–2024) were examined. Data were extracted utilizing EndNote 21, concentrating on demographics, and effects of writing. Methodological quality was evaluated employing modified Cochrane and Effective Public Health Practice Project instruments.
Results: The systematic review highlights writing-based interventions, such as journaling, poetry, Chinese calligraphy, and memory notebooks, as effective instruments for cognitive, emotional, and social rehabilitation in mild cognitive impairment (MCI) and dementia. These techniques improve memory, identity, emotional control, and cognitive resilience, while cultural and multimodal approaches provide supplementary advantages.
Conclusion: This review emphasizes writing as an accessible and culturally appropriate therapeutic approach for cognitive rehabilitation in dementia. Calligraphy activities combine memory, motor skills, and concentration, providing cost-effective tools to improve mental and emotional health while fostering cultural connection and engagement.
1 Introduction
Dementia is a progressive neurological disease that affects millions of people worldwide, resulting in considerable cognitive, emotional, and functional loss (1). It is a significant global health challenge, with its prevalence anticipated to rise substantially in the following decades due to the aging population. It is marked by cognitive deterioration, encompassing memory deficits, communication challenges, and diminished quality of life, which profoundly impacts patients and their families. Due to the constraints and side effects of pharmacological therapies, patients become non-compliant with taking their medications, which worsens their clinical symptoms and the response to the medications (2, 3). Therefore non-pharmacological interventions have risen to enhance quality of life, wellbeing and reduce behavioral and psychological symptoms of dementia (4–6).
Artistic interventions have been proven to have great potential for improving cognitive functions and mental health in patients with mild cognitive impairment (MCI) or Dementia (6). Art therapies can stimulate cognition through various pathways, including stimulation of the temporal lobe, affecting recognition and expression using language, and the parietal lobe, improving the spatial position and fine motor functions (7), training the hand-brain interactions and maintaining motor skills and coordination (8), and also providing patients with a non-verbal communication which enables them to overcome disparities of self-expression due to impaired language ability (9). For instance, art appreciation, Sculpture making, painting, and drawing have beneficial effects on overall cognition, including attention, concentration, and memory (6). Moreover, among individuals with dementia, singing is associated with improved verbal fluency, executive function, and episodic memory (10), fostering mood enhancement and social connection.
Artistic interventions also improve behavioral and psychological symptoms of dementia (BPSD), such as motivation, mood, apathy, aggressive behavior, agitation, sadness, self-esteem, communication, and overall self-reported wellbeing in patients with dementia (11–15).
Writing-based therapies are types of non-pharmacological interventions that have garnered attention for their ability to increase cognitive function, enhance memory, recall and emotional expression, and facilitate social engagement (16, 17). Further, Van der Weel and Van der Meer (18) have discovered that writing by hand increases the brain connectivity, which has been shown to facilitate learning and memory (19) on the other hand research indicates that early verbal competence correlates with cognitive resilience in later life (20, 21). Thus, sustaining language involvement through activities like journal writing has been linked to a diminished risk of dementia and enhanced cognitive performance (5, 21). In its diverse manifestations, writing serves as a conduit for self-expression while also stimulating memory, attention, and executive functioning, which are frequently impaired in dementia (22). Writing has emerged as a potential rehabilitation approach for dementia patients, providing a unique combination of cognitive, emotional, and social advantages.
In this systematic review, we aimed to gather and highlight the advantages and effects of Handwriting and its therapeutic uses in mild cognitive impairment and dementia rehabilitation. By synthesizing existing evidence, we intend to illustrate how structured writing practices—ranging from reminiscence therapy to creative storytelling—can enhance cognitive and emotional wellbeing in individuals with dementia. This article examines how writing promotes neurocognitive engagement, evaluates the efficacy of writing therapies, and discusses their practical applications in clinical and community contexts.
2 Materials and methods
2.1 Instrument
We adhered to the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) (23, 24) checklist to carry out a systematic review. The databases selected for this research (Figure 1) were PubMed, Scopus, and Web of Science.

Figure 1. Selection of studies. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram. Of the 2,140 identified studies, 21 were included in the synthesis after applying the inclusion and exclusion criteria (24).
2.2 Inclusion and exclusion criteria
The subsequent inclusion and exclusion criteria were defined before the screening. The inclusion criteria were human research only and publications in English. Exclusion criteria included research letters, editorials, reviews, and comments.
2.3 Search strategy
Eligible studies were identified using PubMed, Scopus, and Web of Science searches. They were published between January 1, 1991, and April 1, 2024.
Unique search methodologies were formulated for each database. The search terms employed to retrieve data from each thesaurus commenced with amalgamating general terms from cognitive domains and those based on prior knowledge. A sequence of preliminary scoping searches was performed, leading to the identification of several essential search keywords. An illustration of a conclusive search protocol for the PubMed database is presented below.
1. (dementia*[Title/Abstract]) OR (dementia*[MeSH Terms]) OR (Childhood dementia[Title/Abstract]) OR (Chronic Traumatic Encephalopathy dementia[Title/Abstract]) OR (HIV associated dementia[Title/Abstract]) OR (own syndrome[Title/Abstract] OR Alzheimer's disease[Title/Abstract]) OR (Alcohol related dementia[Title/Abstract]) OR (Frontotemporal dementia[Title/Abstract]) OR (Lewy Body Disease[Title/Abstract]) OR (Vascular dementia[Title/Abstract]) OR (alzheimer*[Title/Abstract]) OR (alzheimer[MeSH Terms])
2. (writing[MeSH Terms]) OR (writing*[Title/Abstract]) OR (handwriting[MeSH Terms]) OR (handwriting*[Title/Abstract]) OR (calligraphy[MeSH Terms]) OR (calligraphy[Title/Abstract])
3. “Review”[Publication Type] OR “Review Literature as Topic”[MeSH] OR “Systematic Review”[Publication Type] OR “Systematic Reviews as Topic”[MeSH] OR “Meta-Analysis”[Publication Type] OR “Meta-Analysis as Topic”[MeSH] OR “Network Meta-Analysis”[MeSH]
4. #1 AND #2 NOT #3 Filters: from 1991 - 2023
The terms placed in brackets indicate whether the phrase is a search keyword or a Medical Subject Heading (MeSH). All search queries were analyzed for registration as MeSH keywords.
A search was conducted to see whether it was necessary to include the search word “dementia” as a MeSH term with explosion and as a search query, as specified.
This was used to simplify the search term while preserving identical search results since specific databases had difficulties processing extensive search phrases. Comparable experiments were conducted across all datasets.
2.4 Data screening
All references were entered into EndNote 21, where duplicates, non-English entries, and irrelevant types not aligned with the article titles were detected and removed.
2.5 Data charting process
A reviewer cooperatively developed a data-charting form to determine the variables to extract. The reviewer independently extracted data and analyzed the results in the case of a disagreement. Demographic data from articles (author, year, nation, journal, and citations) and population characteristics (diagnosis, comorbidities, covariants, and disability) were retrieved, along with sample size (n), mean age, and sex distribution. The conclusion of data extraction was based on the research criteria of intervention, result, and effect. The studies examined the effects of writing in dementia, as well as the positive impact of writing in dementia, the Positive effects of writing in cases other than dementia, and sex differences. The knowledge and information levels of individuals were assessed.
2.6 Quality assessment
The bias risk was assessed using methodologies from the Cochrane Collaboration Risk of Bias Tool (CCRBT) and the Effective Public Health Practice Project Quality Assessment Tool to evaluate the methodological quality of primary studies employing various research designs (25). The six assessed components are: (1) selection bias, (2) research design, (3) confounders, (4) blinding, (5) data collection procedures, and (6) withdrawals and dropouts. Each component is classified as strong, moderate, or weak. In the absence of weak ratings, the overall rating is considered strong; one weak rating yields a middling classification, while two or more weak ratings result in a weak overall classification. The tool was modified as the component domain' confounders' is particularly relevant to randomized controlled trials, where controlling group differences is crucial. In the present study, populations served as their controls, diminishing the significance of this element. Two distinct evaluators assessed the research and reconciled any inconsistencies through dialogue.
3 Results
By carefully reviewing the 21 included articles which had been met out a topic, we found physical activities and cognitive activities such as writing, reading books or newspapers, poetry writing, journal writing, Chinese calligraphy writing, drawing, memory notebooks, crossword puzzles, board games or cards, participating in organized group discussions, and playing musical instruments have been mentioned frequently as an empowering tool to reduce the risk of dementia, improve cognitive function and even regulating emotions (26–45) (Table 1).
We have categorized our findings into 6 main classes to provide a better understanding of this topic.
3.1 Cultural and artistic writing practices
Chinese calligraphy therapy (CCT) is a branch of art therapy involving culture, health, behavioral treatment, and rehabilitation for patients with cognitive impairments. CCH performance integrates the mind and body and involves visual perception, spatial structures, and planning (46, 47). The practice of CCH requires relaxing the body and sitting up straight, holding the upper arm at an accurate angle, lightly lifting with an inhalation, and pressing the pen to the paper with an exhalation while moving through the order of brush strokes step by step (48).
Previous studies have suggested that Chinese calligraphy practice can have many advantages on cognitive functions as well as Chan et al. (27) and Kwok et al. (35) found that Chinese calligraphy writing mainly involved visual encoding, memory rehearsal, and attentional control, which significantly improved specific cognitive functions, especially working memory, orientation, attention, and calculation; participants experienced reduced cognitive decline. Therefore, Chinese calligraphy writing was demonstrated to serve as an effective non-pharmacological intervention in participants with Mild Cognitive Impairment (MCI). They also mentioned that CC was recognized as a feasible and culturally relevant cognitive therapy for older Chinese adults, which is crucial for using culturally relevant therapies for older adults.
Moreover, Hsiao et al. (29) conducted a CCH training program, which additionally included oral presentations of the works of each participant. They showed Chinese calligraphy training courses can also help with visuospatial memory, emotion regulation by persistent happiness and looking forward to practicing time, upper limb coordination, language, and deep thinking, improved Speech function through oral presentations, improved writing speed and accuracy, and abstract thinking. Since the training was performed through breathing control, it can also modulate parasympathetic nerves, stabilize mental states, lower respiration and heart rate, and reduce blood pressure.
There are many types of arts, artistic writings, and cognitive activities that were frequently suggested in surveyed studies that can have protective effects against cognitive impairment, reduce the risk of disability onset, and improve executive and memory functions, attention, and cognitive reserve; these activities included reading books or newspapers, writing for pleasure, story-telling, also doing crossword puzzles, playing board games or cards, playing musical instruments and speech therapy (26, 28, 33, 34, 36, 39, 40, 44).
Particularly, Meade et al. (45) discovered that drawing significantly enhanced memory more than writing in healthy individuals with probable dementia. This might result from the weaker memory encoding provided by writing compared to drawing. They also stated that writing engages residual verbal and motor functions, improving some episodic memory in mild cognitive impairments; however, in dementia, due to impaired visual-perceptual brain regions, writing was less effective than drawing.
3.2 Poetry and creative writing as therapeutic tools
Poetry and creative writing have been proven to include significant advantages for cognitive functions. As Petrescu et al. (37) demonstrated, poetry writing workshops improved the conceptions of personhood by motivating the feeling of competence and self-efficacy. This also resulted in overcoming a prevailing stereotype that dementia equates with dependency. Furthermore, their study also showed that poetry writing helps with understanding the experience of dementia, stimulating the participants' creativity, identifying potential talents, and showing a drive for personal growth, which is still present in people with dementia.
Another study figured out that even poetry writing in caregivers of patients with dementia can have many positive impacts, such as psychological benefits, Self-Affirmation, improved sense of achievement, greater acceptance, empathy, self-awareness, reflection, positive challenge, and helping others, all of them can result in enhancing understanding of their roles and the challenges they face (31).
Journaling and storytelling are other therapeutic tools that can help with different aspects of dementia. Journal writing was suggested by Tsuda et al. (43) to Improve self-awareness, promote emotional recovery, aid memory, and help maintain a sense of identity; however, it intensified regrets and pessimistic emotions due to reviewing past independence or losses. Moreover, they discovered that journal writing enhanced caregivers' insights into participants' challenges and achievements. Another study by Ryan et al. (39) also stated that writing and story-telling foster emotional clarity and stress reduction, which were provided by expressing their experiences. Despite this, the study showed writing may reinforce feelings of frustration when cognitive impairments negatively affect the ability to express thoughts effectively; also, writing about traumatic events can initially cause emotional distress and rumination in some individuals.
Memory notebook training has also been mentioned as having potential benefits for cognitive impairments and Alzheimer's disease. Johnson (30) studied the effectiveness of Memory Notebooks in patients with Alzheimer's Disease; they concluded Memory notebooks reduced anger, agitation, and confusion and encouraged participation in activities; they also found Caregivers and families gained insights into residents' needs through these memory notebooks. Another study about assessing memory notebook intervention for Memory-impaired individuals without major functional decline was conducted by Schmitter-Edgecombe et al. (41) and resulted in enhanced memory strategy use, improved memory task performance, and emotional and confidence in obtaining social support; additionally, caregivers gained better coping strategies.
Writing letters is another type of writing that links to lower dementia conversion rates and improved cognitive function (26).
3.3 Writing to reaffirm identity and social roles
Selfhood is equated with memory and language (49), autobiographical memories (50), and through the accounts of caregivers (51); therefore, selfhood gets lost in dementia. Therefore, there is a significant need to reconstruct and reaffirm identity and social roles in dementia since Cohen-Mansfield et al. (52) also provided clear evidence that treatment aimed at strengthening the residual self-identities, favored roles, and personal attributes of elderly persons with dementia can improve their wellbeing.
Journal writing is one of the activities that appeared to support self-reflection, identity reaffirmation, recovery, and mental organization (43). Storytelling writing can also empower social identity reclamation and create a sense of purpose in individuals (39).
As Petrescu et al. (37) found that poetry writing can also be used as a tool to maintain and reinforce a sense of self-identity.
3.4 Impacts of structured writing interventions
In the study conducted by Krajenbrink et al. (32), they surveyed treatments for spoken and written word recall in primary progressive aphasia, in which they evaluated the efficacy of two treatments of Repetition and Reading in the Presence of a Picture (RRIPP) with and without required written responses, and procedures of Conceptual Enrichment (COEN). COEN treatment did not result in significant gains in word retrieval or comprehension; however, RRIPP led to considerable improvement of treated items on a comprehension task, improvements in spoken and written word retrieval, improvement in naming, and improved lexical retrieval, although more significant improvement got demonstrated when written production was required.
Thiel and Conroy (42) conducted a study on patients with acquired written and sometimes verbal communication impairments from strokes. They performed errorful and errorless therapies that focused on spelling and writing accuracy as part of their rehabilitation. The study demonstrated that writing therapy (errorless or errorful) enhanced spelling accuracy and speed. Writing, especially errorless methods, improved retention by reinforcing correct orthographic representations without confusion from errors; however, errorful therapy showed negative influences on spelling. They also concluded that awareness of mistakes and self-monitoring influenced therapy success.
On the other hand, despite previous studies, Crane et al. (53) found Proficiency in written Japanese had no protective effects against dementia, and literacy and language usage were associated with cultural and educational background, not dementia prevention.
3.5 Evolution of writing skills in dementia
Platel et al. (38) studied the evolution of writing impairment in Alzheimer's disease; they found agraphia in Alzheimer's disease follows a logical development including three phases: moderate impairment, prolonged impairment characterized by non-phonological spelling mistakes, and severe impairment accompanied by considerable concerns in graphic motor function. Moreover, patients with Alzheimer's disease have shown a restricted level of awareness of their mistakes.
3.6 Writing as a multimodal rehabilitation component
Multidisciplinary rehabilitation, including reading, writing letters, memory training, speech therapy, logic games, art therapy, and physical therapy, were proven to have positive influences on cognition, quality of life, and reduced depression in Mild/Moderate Alzheimer's Disease (AD) and Cognitive Impairment Without Dementia (CIND) (26, 40, 44).
Writing tasks enhanced cognitive stimulation in mild AD participants as a part of the rehabilitation (40).
Kurita et al. (33, 34) suggested that engaging in both physical activities (PA) and cognitive activities (CA) is more effective in reducing the risk of disability onset than engaging in either PA or CA alone and demonstrated High physical and cognitive activity showed additive protective effects against cognitive impairment and synergistic benefits of combining physical and cognitive activities.
Therefore, Raising awareness about the importance of maintaining an active and engaged physical and cognitive lifestyle is crucial to reducing the risk of cognitive decline and dementia (28).
3.7 Sex differences
The impact of cognitive and physical activities might vary between sexes in terms of cognitive health (28), and it has also been suggested that males engaged more in physical activities; females participated more in cognitive activities (26).
3.8 Educations
Higher education has been found to help with increased leisure activity engagement and improved cognitive resilience (26). Malcorra et al. (36) indicated that higher education and frequent reading and writing habits (RWH) in individuals with normal cognitive function could improve macro- and micro-structural aspects of oral discourse linguistic coherence, build cognitive reserve, and delay potential cognitive decline.
4 Discussion
After carefully reviewing 12 studies on this subject, we determined that the most mentioned benefits of writing in people with dementia were significant improvements in working memory, attentional control, visuospatial memory, word retrieval, and overall cognitive resilience.
Writing by hand has been found to cause a wide variety of beneficial effects on brain functioning, for instance, improvement of memory, recall of words, and connectivity within the dorsal attentional network (54–56). Writing can cause significant improvements in the rehabilitation of people with cognitive impairment and dementia (35). Additionally, the remarkable advantages of calligraphy in dementia have been proven, and calligraphy therapy has been considered the most effective art therapy for improving cognitive function (4). This outcome may be because calligraphy integrates visual performance with spatial abilities and cognitive planning, which helps with a better cognitive function, and it also can improve concentration, orientation, calculation, controlling the body, emotional stability, and eventually quality of life (35, 57, 58). Japanese calligraphy has positively affected relaxation, mindfulness, depression, emotional regulation, and mental health in older adults (59) which can be concluded to have indirect impacts on cognitive improvements.
In Iran, Persian calligraphy is being taught in early elementary school. This activity demands coordination of the upper limb, visuospatial domains, working memory, and concentration to perform the curves, edges, strokes, and correct spelling. Thus, for Persian-speaking elderly with or without cognitive impairments, Persian calligraphy could be considered a magnificent therapy for their rehabilitation.
No studies have evaluated the impact of writing in a specific language as cognitive rehabilitation and have compared it with other languages. However, due to the various cognition levels involved in different languages (60), further evaluation is suggested around this subject in the future.
We also noted that Handwriting as a rehabilitation tool, particularly the types of writing through which individuals could express their emotions, thoughts, and experiences, such as journaling, storytelling, and creative writing, will significantly improve the emotional wellbeing through reducing anxiety, depression and self-awareness of patients with MCI or dementia which help maintain a sense of social identity and communication with others. As Social isolation and lack of social activity have been highly identified with an increased risk of dementia (61–63), and social interactions that provide feelings of satisfaction and perceived reciprocity have demonstrated preventive effects toward dementia (64).
However, nowadays, digitalization has affected every aspect of our lives, such as banking, purchasing, learning, and significant communications that have become mostly through social networks; digital writing by computers, tablets, or mobile phones is increasingly replacing writing by hand (65, 66). Adults mostly use typing to produce written texts such as messages, letters, or notes in everyday or professional life instead of Handwriting. Writing on paper with a pen or pencil has become old-fashioned and uncommon. Unfortunately, due to these changes, people cannot benefit from writing on paper Traditional Handwriting by pen and paper significantly impacts cognitive rehabilitation and has been demonstrated to have many advantages over typing on cognition and memory (18, 67). Since typing and Handwriting activate the brain with different patterns, typing contributes to less activation (68), functional magnetic resonance imaging also demonstrated that Handwriting activates a broader network of brain regions involved in motor, sensory, and cognitive processing compared to typing, which engages fewer neural circuits and lowers cognitive engagement (69). Moreover, many studies have suggested Handwriting over typing, for example, typing has been associated with impaired learning in students due to the shallower processing (17), Handwriting showed enhancements in brain connectivity, not typing (18).
Some evidences support the benefits of computer-based interventions as a rehabilitation in patients with dementia and cognitive impairments (70), such as significant improvements in delayed, working, and short-term memory and in language abilities (71), But not particularly mentioned typing.
There was a crucial need to reflect on the benefits of writing on paper as a potential rehabilitation therapy for dementia to encourage and motivate patients and their caregivers to pay more attention to this area and to get healthcare systems to consider writing therapy as a part of routine rehabilitation therapies. Therefore, in this study, we assessed the potency of writing as a part of rehabilitation in people with cognitive impairments by reviewing previous studies.
We aim to raise awareness about the importance of physically and cognitively maintaining an active life in people with dementia by providing an accessible and affordable solution. Writing as a rehabilitation therapy has these characteristics and can be done quickly by anyone, even with physical or mental limitations. Also, using culturally relevant cognitive activities is noticeable for older adults to get better results, as calligraphy therapy in Taiwanese individuals, which caused a sense of nostalgia and wealth of sensory stimulation since they had been taught Chinese calligraphy during early school life in Taiwan (29).
5 Conclusion
We found that writing has benefits other than cognitive improvements, such as positive effects on mental health, increased coordination of upper limbs, and higher self-confidence.
Eventually, by gathering all this information and proving results, we suggest writing on paper with a pen or pencil as an old-fashioned way to be a part of rehabilitation therapy for people with dementia and even healthy older adults, as it has preventive effects toward cognitive impairments. If writing therapy is done, creative writing can have more privileges, such as enabling self-expression and communication, and promoting positive self-worth.
Data availability statement
The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding author.
Author contributions
AH-H: Conceptualization, Data curation, Formal analysis, Visualization, Writing – original draft, Writing – review & editing. SR: Conceptualization, Data curation, Writing – original draft, Writing – review & editing. MN: Project administration, Resources, Supervision, Writing – review & editing. DJ: Funding acquisition, Resources, Writing – review & editing.
Funding
The author(s) declare that no financial support was received for the research and/or publication of this article.
Acknowledgments
We really appreciate the participation of all participants in this research.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement
The author(s) declare that no Gen AI was used in the creation of this manuscript.
Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
Supplementary material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fneur.2025.1568336/full#supplementary-material
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Keywords: writing-based therapies, cognitive rehabilitation, mild cognitive impairment (MCI), Handwriting, dementia
Citation: Hajikarim-Hamedani A, Rassa S, Noroozian M and Jafari D (2025) Writing as cognitive rehabilitation in MCI and dementia: a systematic review of therapeutic benefits and applications. Front. Neurol. 16:1568336. doi: 10.3389/fneur.2025.1568336
Received: 10 May 2025; Accepted: 28 July 2025;
Published: 02 September 2025.
Edited by:
Paolo Taurisano, University of Bari Aldo Moro, ItalyReviewed by:
Tamer Abou-Elsaad, Mansoura University, EgyptVaitsa Giannouli, Aristotle University of Thessaloniki, Greece
Copyright © 2025 Hajikarim-Hamedani, Rassa, Noroozian and Jafari. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Maryam Noroozian, bWFyeWFtLm5vcm9vemlhbi5tbkBnbWFpbC5jb20=
†These authors have contributed equally to this work