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How to Conduct a Literature Review (Health Sciences and Beyond)

What is a literature review, traditional (narrative) literature review, integrative literature review, systematic reviews, meta-analysis, scoping review.

• Developing a Research Question
• Selection Criteria
• Database Search
• Documenting Your Search
• Organize Key Findings
• Reference Management

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Related Guides

• Systematic Reviews by Roy Brown Last Updated Oct 17, 2023 559 views this year
• Write a Literature Review by John Glover Last Updated Oct 16, 2023 2948 views this year

A literature review provides an overview of what's been written about a specific topic. There are many different types of literature reviews. They vary in terms of comprehensiveness, types of study included, and purpose. 

The other pages in this guide will cover some basic steps to consider when conducting a traditional health sciences literature review. See below for a quick look at some of the more popular types of literature reviews.

For additional information on a variety of review methods, the following article provides an excellent overview.

Grant MJ, Booth A. A typology of reviews: an analysis of 14 review types and associated methodologies. Health Info Libr J. 2009 Jun;26(2):91-108. doi: 10.1111/j.1471-1842.2009.00848.x. Review. PubMed PMID: 19490148.

• Next: Developing a Research Question >>
• Last Updated: Mar 15, 2024 12:22 PM
• URL: https://guides.library.vcu.edu/health-sciences-lit-review

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• Citing Sources
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• What are Literature Reviews?
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What are Systematic Reviews? (3 minutes, 24 second YouTube Video)

Systematic Literature Reviews: Steps & Resources

These steps for conducting a systematic literature review are listed below . 

Also see subpages for more information about:

• The different types of literature reviews, including systematic reviews and other evidence synthesis methods
• Tools & Tutorials

Literature Review & Systematic Review Steps

• Develop a Focused Question
• Scope the Literature  (Initial Search)
• Refine & Expand the Search
• Limit the Results
• Download Citations
• Abstract & Analyze
• Create Flow Diagram
• Synthesize & Report Results

1. Develop a Focused   Question 

Consider the PICO Format: Population/Problem, Intervention, Comparison, Outcome

Focus on defining the Population or Problem and Intervention (don't narrow by Comparison or Outcome just yet!)

"What are the effects of the Pilates method for patients with low back pain?"

Tools & Additional Resources:

• PICO Question Help
• Stillwell, Susan B., DNP, RN, CNE; Fineout-Overholt, Ellen, PhD, RN, FNAP, FAAN; Melnyk, Bernadette Mazurek, PhD, RN, CPNP/PMHNP, FNAP, FAAN; Williamson, Kathleen M., PhD, RN Evidence-Based Practice, Step by Step: Asking the Clinical Question, AJN The American Journal of Nursing : March 2010 - Volume 110 - Issue 3 - p 58-61 doi: 10.1097/01.NAJ.0000368959.11129.79

2. Scope the Literature

A "scoping search" investigates the breadth and/or depth of the initial question or may identify a gap in the literature. 

Eligible studies may be located by searching in:

• Background sources (books, point-of-care tools)
• Article databases
• Trial registries
• Grey literature
• Cited references
• Reference lists

When searching, if possible, translate terms to controlled vocabulary of the database. Use text word searching when necessary.

Use Boolean operators to connect search terms:

• Combine separate concepts with AND  (resulting in a narrower search)
• Connecting synonyms with OR  (resulting in an expanded search)

Search:  pilates AND ("low back pain"  OR  backache )

Video Tutorials - Translating PICO Questions into Search Queries

• Translate Your PICO Into a Search in PubMed (YouTube, Carrie Price, 5:11) 
• Translate Your PICO Into a Search in CINAHL (YouTube, Carrie Price, 4:56)

3. Refine & Expand Your Search

Expand your search strategy with synonymous search terms harvested from:

• database thesauri
• reference lists
• relevant studies

Example: 

(pilates OR exercise movement techniques) AND ("low back pain" OR backache* OR sciatica OR lumbago OR spondylosis)

As you develop a final, reproducible strategy for each database, save your strategies in a:

• a personal database account (e.g., MyNCBI for PubMed)
• Log in with your NYU credentials
• Open and "Make a Copy" to create your own tracker for your literature search strategies

4. Limit Your Results

Use database filters to limit your results based on your defined inclusion/exclusion criteria.  In addition to relying on the databases' categorical filters, you may also need to manually screen results.  

• Limit to Article type, e.g.,:  "randomized controlled trial" OR multicenter study
• Limit by publication years, age groups, language, etc.

NOTE: Many databases allow you to filter to "Full Text Only".  This filter is  not recommended . It excludes articles if their full text is not available in that particular database (CINAHL, PubMed, etc), but if the article is relevant, it is important that you are able to read its title and abstract, regardless of 'full text' status. The full text is likely to be accessible through another source (a different database, or Interlibrary Loan).  

• Filters in PubMed
• CINAHL Advanced Searching Tutorial

5. Download Citations

Selected citations and/or entire sets of search results can be downloaded from the database into a citation management tool. If you are conducting a systematic review that will require reporting according to PRISMA standards, a citation manager can help you keep track of the number of articles that came from each database, as well as the number of duplicate records.

In Zotero, you can create a Collection for the combined results set, and sub-collections for the results from each database you search.  You can then use Zotero's 'Duplicate Items" function to find and merge duplicate records.

• Citation Managers - General Guide

6. Abstract and Analyze

• Migrate citations to data collection/extraction tool
• Screen Title/Abstracts for inclusion/exclusion
• Screen and appraise full text for relevance, methods, 
• Resolve disagreements by consensus

Covidence is a web-based tool that enables you to work with a team to screen titles/abstracts and full text for inclusion in your review, as well as extract data from the included studies.

• Covidence Support
• Critical Appraisal Tools
• Data Extraction Tools

7. Create Flow Diagram

The PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) flow diagram is a visual representation of the flow of records through different phases of a systematic review.  It depicts the number of records identified, included and excluded.  It is best used in conjunction with the PRISMA checklist .

Example from: Stotz, S. A., McNealy, K., Begay, R. L., DeSanto, K., Manson, S. M., & Moore, K. R. (2021). Multi-level diabetes prevention and treatment interventions for Native people in the USA and Canada: A scoping review. Current Diabetes Reports, 2 (11), 46. https://doi.org/10.1007/s11892-021-01414-3

• PRISMA Flow Diagram Generator (ShinyApp.io, Haddaway et al. )
• PRISMA Diagram Templates  (Word and PDF)
• Make a copy of the file to fill out the template
• Image can be downloaded as PDF, PNG, JPG, or SVG
• Covidence generates a PRISMA diagram that is automatically updated as records move through the review phases

8. Synthesize & Report Results

There are a number of reporting guideline available to guide the synthesis and reporting of results in systematic literature reviews.

It is common to organize findings in a matrix, also known as a Table of Evidence (ToE).

• Reporting Guidelines for Systematic Reviews
• Download a sample template of a health sciences review matrix  (GoogleSheets)

Steps modified from: 

Cook, D. A., & West, C. P. (2012). Conducting systematic reviews in medical education: a stepwise approach.   Medical Education , 46 (10), 943–952.

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• Next: What are Literature Reviews? >>
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Hanna's Performing a qualitity literature review presentation slides

• Link to the PPT slides via OneDrive anyone can view

Characteristics of a Good Literature Review in Health & Medicine

Clear Objectives and Research Questions : The review should start with clearly defined objectives and research questions that guide the scope and focus of the review.

Comprehensive Coverage : Include a wide range of relevant sources, such as research articles, review papers, clinical guidelines, and books. Aim for a broad understanding of the topic, covering historical developments and current advancements. To do this, an intentional and minimally biased search strategy.

• Link to relevant databases to consider for a comprehensive search (search 2+ databases)
• Link to the video "Searching your Topic: Strategies and Efficiencies" by Hanna Schmillen
• Link to the worksheet "From topic, to PICO, to search strategy" to help researchers work through their topic into an intentional search strategy by Hanna Schmillen

Transparency and Replicability : The review process, search strategy, should be transparent, with detailed documentation of all steps taken. This allows others to replicate the review or update it in the future.

Appraisal of Studies Included : Each included study should be critically appraised for methodological quality and relevance. Use standardized appraisal tools to assess the risk of bias and the quality of evidence.

• Link to the video " Evaluating Health Research" by Hanna Schmillen
• Link to evaluating and appraising studies tab, which includes a rubric and checklists

Clear Synthesis and Discussion of Findings : The review should provide a thorough discussion of the findings, including any patterns, relationships, or trends identified in the literature. Address the strengths and limitations of the reviewed studies and the review itself. Present findings in a balanced and unbiased manner, avoiding over interpretation or selective reporting of results.

Implications for Practice and Research : The review should highlight the practical implications of the findings for medical practice and policy. It should also identify gaps in the current literature and suggest areas for future research.

Referencing and Citation : Use proper citation practices to credit original sources. Provide a comprehensive reference list to guide readers to the original studies.

• Link to Citation Style Guide, includes tab about Zotero

Note: A literature review is not a systematic review. For more information about systematic reviews and different types of evidence synthesis projects, see the Evidence Synthesis guide .

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Ten Simple Rules for Writing a Literature Review

Marco pautasso.

1 Centre for Functional and Evolutionary Ecology (CEFE), CNRS, Montpellier, France

2 Centre for Biodiversity Synthesis and Analysis (CESAB), FRB, Aix-en-Provence, France

Literature reviews are in great demand in most scientific fields. Their need stems from the ever-increasing output of scientific publications [1] . For example, compared to 1991, in 2008 three, eight, and forty times more papers were indexed in Web of Science on malaria, obesity, and biodiversity, respectively [2] . Given such mountains of papers, scientists cannot be expected to examine in detail every single new paper relevant to their interests [3] . Thus, it is both advantageous and necessary to rely on regular summaries of the recent literature. Although recognition for scientists mainly comes from primary research, timely literature reviews can lead to new synthetic insights and are often widely read [4] . For such summaries to be useful, however, they need to be compiled in a professional way [5] .

When starting from scratch, reviewing the literature can require a titanic amount of work. That is why researchers who have spent their career working on a certain research issue are in a perfect position to review that literature. Some graduate schools are now offering courses in reviewing the literature, given that most research students start their project by producing an overview of what has already been done on their research issue [6] . However, it is likely that most scientists have not thought in detail about how to approach and carry out a literature review.

Reviewing the literature requires the ability to juggle multiple tasks, from finding and evaluating relevant material to synthesising information from various sources, from critical thinking to paraphrasing, evaluating, and citation skills [7] . In this contribution, I share ten simple rules I learned working on about 25 literature reviews as a PhD and postdoctoral student. Ideas and insights also come from discussions with coauthors and colleagues, as well as feedback from reviewers and editors.

Rule 1: Define a Topic and Audience

How to choose which topic to review? There are so many issues in contemporary science that you could spend a lifetime of attending conferences and reading the literature just pondering what to review. On the one hand, if you take several years to choose, several other people may have had the same idea in the meantime. On the other hand, only a well-considered topic is likely to lead to a brilliant literature review [8] . The topic must at least be:

• interesting to you (ideally, you should have come across a series of recent papers related to your line of work that call for a critical summary),
• an important aspect of the field (so that many readers will be interested in the review and there will be enough material to write it), and
• a well-defined issue (otherwise you could potentially include thousands of publications, which would make the review unhelpful).

Ideas for potential reviews may come from papers providing lists of key research questions to be answered [9] , but also from serendipitous moments during desultory reading and discussions. In addition to choosing your topic, you should also select a target audience. In many cases, the topic (e.g., web services in computational biology) will automatically define an audience (e.g., computational biologists), but that same topic may also be of interest to neighbouring fields (e.g., computer science, biology, etc.).

Rule 2: Search and Re-search the Literature

After having chosen your topic and audience, start by checking the literature and downloading relevant papers. Five pieces of advice here:

• keep track of the search items you use (so that your search can be replicated [10] ),
• keep a list of papers whose pdfs you cannot access immediately (so as to retrieve them later with alternative strategies),
• use a paper management system (e.g., Mendeley, Papers, Qiqqa, Sente),
• define early in the process some criteria for exclusion of irrelevant papers (these criteria can then be described in the review to help define its scope), and
• do not just look for research papers in the area you wish to review, but also seek previous reviews.

The chances are high that someone will already have published a literature review ( Figure 1 ), if not exactly on the issue you are planning to tackle, at least on a related topic. If there are already a few or several reviews of the literature on your issue, my advice is not to give up, but to carry on with your own literature review,

The bottom-right situation (many literature reviews but few research papers) is not just a theoretical situation; it applies, for example, to the study of the impacts of climate change on plant diseases, where there appear to be more literature reviews than research studies [33] .

• discussing in your review the approaches, limitations, and conclusions of past reviews,
• trying to find a new angle that has not been covered adequately in the previous reviews, and
• incorporating new material that has inevitably accumulated since their appearance.

When searching the literature for pertinent papers and reviews, the usual rules apply:

• be thorough,
• use different keywords and database sources (e.g., DBLP, Google Scholar, ISI Proceedings, JSTOR Search, Medline, Scopus, Web of Science), and
• look at who has cited past relevant papers and book chapters.

Rule 3: Take Notes While Reading

If you read the papers first, and only afterwards start writing the review, you will need a very good memory to remember who wrote what, and what your impressions and associations were while reading each single paper. My advice is, while reading, to start writing down interesting pieces of information, insights about how to organize the review, and thoughts on what to write. This way, by the time you have read the literature you selected, you will already have a rough draft of the review.

Of course, this draft will still need much rewriting, restructuring, and rethinking to obtain a text with a coherent argument [11] , but you will have avoided the danger posed by staring at a blank document. Be careful when taking notes to use quotation marks if you are provisionally copying verbatim from the literature. It is advisable then to reformulate such quotes with your own words in the final draft. It is important to be careful in noting the references already at this stage, so as to avoid misattributions. Using referencing software from the very beginning of your endeavour will save you time.

Rule 4: Choose the Type of Review You Wish to Write

After having taken notes while reading the literature, you will have a rough idea of the amount of material available for the review. This is probably a good time to decide whether to go for a mini- or a full review. Some journals are now favouring the publication of rather short reviews focusing on the last few years, with a limit on the number of words and citations. A mini-review is not necessarily a minor review: it may well attract more attention from busy readers, although it will inevitably simplify some issues and leave out some relevant material due to space limitations. A full review will have the advantage of more freedom to cover in detail the complexities of a particular scientific development, but may then be left in the pile of the very important papers “to be read” by readers with little time to spare for major monographs.

There is probably a continuum between mini- and full reviews. The same point applies to the dichotomy of descriptive vs. integrative reviews. While descriptive reviews focus on the methodology, findings, and interpretation of each reviewed study, integrative reviews attempt to find common ideas and concepts from the reviewed material [12] . A similar distinction exists between narrative and systematic reviews: while narrative reviews are qualitative, systematic reviews attempt to test a hypothesis based on the published evidence, which is gathered using a predefined protocol to reduce bias [13] , [14] . When systematic reviews analyse quantitative results in a quantitative way, they become meta-analyses. The choice between different review types will have to be made on a case-by-case basis, depending not just on the nature of the material found and the preferences of the target journal(s), but also on the time available to write the review and the number of coauthors [15] .

Rule 5: Keep the Review Focused, but Make It of Broad Interest

Whether your plan is to write a mini- or a full review, it is good advice to keep it focused 16 , 17 . Including material just for the sake of it can easily lead to reviews that are trying to do too many things at once. The need to keep a review focused can be problematic for interdisciplinary reviews, where the aim is to bridge the gap between fields [18] . If you are writing a review on, for example, how epidemiological approaches are used in modelling the spread of ideas, you may be inclined to include material from both parent fields, epidemiology and the study of cultural diffusion. This may be necessary to some extent, but in this case a focused review would only deal in detail with those studies at the interface between epidemiology and the spread of ideas.

While focus is an important feature of a successful review, this requirement has to be balanced with the need to make the review relevant to a broad audience. This square may be circled by discussing the wider implications of the reviewed topic for other disciplines.

Rule 6: Be Critical and Consistent

Reviewing the literature is not stamp collecting. A good review does not just summarize the literature, but discusses it critically, identifies methodological problems, and points out research gaps [19] . After having read a review of the literature, a reader should have a rough idea of:

• the major achievements in the reviewed field,
• the main areas of debate, and
• the outstanding research questions.

It is challenging to achieve a successful review on all these fronts. A solution can be to involve a set of complementary coauthors: some people are excellent at mapping what has been achieved, some others are very good at identifying dark clouds on the horizon, and some have instead a knack at predicting where solutions are going to come from. If your journal club has exactly this sort of team, then you should definitely write a review of the literature! In addition to critical thinking, a literature review needs consistency, for example in the choice of passive vs. active voice and present vs. past tense.

Rule 7: Find a Logical Structure

Like a well-baked cake, a good review has a number of telling features: it is worth the reader's time, timely, systematic, well written, focused, and critical. It also needs a good structure. With reviews, the usual subdivision of research papers into introduction, methods, results, and discussion does not work or is rarely used. However, a general introduction of the context and, toward the end, a recapitulation of the main points covered and take-home messages make sense also in the case of reviews. For systematic reviews, there is a trend towards including information about how the literature was searched (database, keywords, time limits) [20] .

How can you organize the flow of the main body of the review so that the reader will be drawn into and guided through it? It is generally helpful to draw a conceptual scheme of the review, e.g., with mind-mapping techniques. Such diagrams can help recognize a logical way to order and link the various sections of a review [21] . This is the case not just at the writing stage, but also for readers if the diagram is included in the review as a figure. A careful selection of diagrams and figures relevant to the reviewed topic can be very helpful to structure the text too [22] .

Rule 8: Make Use of Feedback

Reviews of the literature are normally peer-reviewed in the same way as research papers, and rightly so [23] . As a rule, incorporating feedback from reviewers greatly helps improve a review draft. Having read the review with a fresh mind, reviewers may spot inaccuracies, inconsistencies, and ambiguities that had not been noticed by the writers due to rereading the typescript too many times. It is however advisable to reread the draft one more time before submission, as a last-minute correction of typos, leaps, and muddled sentences may enable the reviewers to focus on providing advice on the content rather than the form.

Feedback is vital to writing a good review, and should be sought from a variety of colleagues, so as to obtain a diversity of views on the draft. This may lead in some cases to conflicting views on the merits of the paper, and on how to improve it, but such a situation is better than the absence of feedback. A diversity of feedback perspectives on a literature review can help identify where the consensus view stands in the landscape of the current scientific understanding of an issue [24] .

Rule 9: Include Your Own Relevant Research, but Be Objective

In many cases, reviewers of the literature will have published studies relevant to the review they are writing. This could create a conflict of interest: how can reviewers report objectively on their own work [25] ? Some scientists may be overly enthusiastic about what they have published, and thus risk giving too much importance to their own findings in the review. However, bias could also occur in the other direction: some scientists may be unduly dismissive of their own achievements, so that they will tend to downplay their contribution (if any) to a field when reviewing it.

In general, a review of the literature should neither be a public relations brochure nor an exercise in competitive self-denial. If a reviewer is up to the job of producing a well-organized and methodical review, which flows well and provides a service to the readership, then it should be possible to be objective in reviewing one's own relevant findings. In reviews written by multiple authors, this may be achieved by assigning the review of the results of a coauthor to different coauthors.

Rule 10: Be Up-to-Date, but Do Not Forget Older Studies

Given the progressive acceleration in the publication of scientific papers, today's reviews of the literature need awareness not just of the overall direction and achievements of a field of inquiry, but also of the latest studies, so as not to become out-of-date before they have been published. Ideally, a literature review should not identify as a major research gap an issue that has just been addressed in a series of papers in press (the same applies, of course, to older, overlooked studies (“sleeping beauties” [26] )). This implies that literature reviewers would do well to keep an eye on electronic lists of papers in press, given that it can take months before these appear in scientific databases. Some reviews declare that they have scanned the literature up to a certain point in time, but given that peer review can be a rather lengthy process, a full search for newly appeared literature at the revision stage may be worthwhile. Assessing the contribution of papers that have just appeared is particularly challenging, because there is little perspective with which to gauge their significance and impact on further research and society.

Inevitably, new papers on the reviewed topic (including independently written literature reviews) will appear from all quarters after the review has been published, so that there may soon be the need for an updated review. But this is the nature of science [27] – [32] . I wish everybody good luck with writing a review of the literature.

Acknowledgments

Many thanks to M. Barbosa, K. Dehnen-Schmutz, T. Döring, D. Fontaneto, M. Garbelotto, O. Holdenrieder, M. Jeger, D. Lonsdale, A. MacLeod, P. Mills, M. Moslonka-Lefebvre, G. Stancanelli, P. Weisberg, and X. Xu for insights and discussions, and to P. Bourne, T. Matoni, and D. Smith for helpful comments on a previous draft.

Funding Statement

This work was funded by the French Foundation for Research on Biodiversity (FRB) through its Centre for Synthesis and Analysis of Biodiversity data (CESAB), as part of the NETSEED research project. The funders had no role in the preparation of the manuscript.

Nursing: How to Write a Literature Review

• Traditional or Narrative Literature Review

Literature Review Overview

What is a Literature Review? Why Are They Important?

A literature review is important because it presents the "state of the science" or accumulated knowledge on a specific topic. It summarizes, analyzes, and compares the available research, reporting study strengths and weaknesses, results, gaps in the research, conclusions, and authors’ interpretations.

Tips and techniques for conducting a literature review are described more fully in the subsequent boxes:

• Literature review steps
• Strategies for organizing the information for your review
• Literature reviews sections
• In-depth resources to assist in writing a literature review
• Templates to start your review
• Literature review examples

Literature Review Steps

Graphic used with permission: Torres, E. Librarian, Hawai'i Pacific University

1. Choose a topic and define your research question

• Try to choose a topic of interest. You will be working with this subject for several weeks to months.
• Ideas for topics can be found by scanning medical news sources (e.g MedPage Today), journals / magazines, work experiences, interesting patient cases, or family or personal health issues.
• Do a bit of background reading on topic ideas to familiarize yourself with terminology and issues. Note the words and terms that are used.
• Develop a focused research question using PICO(T) or other framework (FINER, SPICE, etc - there are many options) to help guide you.
• Run a few sample database searches to make sure your research question is not too broad or too narrow.
• If possible, discuss your topic with your professor. 

2. Determine the scope of your review

The scope of your review will be determined by your professor during your program. Check your assignment requirements for parameters for the Literature Review.

• How many studies will you need to include?
• How many years should it cover? (usually 5-7 depending on the professor)
• For the nurses, are you required to limit to nursing literature?

3. Develop a search plan

• Determine which databases to search. This will depend on your topic. If you are not sure, check your program specific library website (Physician Asst / Nursing / Health Services Admin) for recommendations.
• Create an initial search string using the main concepts from your research (PICO, etc) question. Include synonyms and related words connected by Boolean operators
• Contact your librarian for assistance, if needed.

4. Conduct searches and find relevant literature

• Keep notes as you search - tracking keywords and search strings used in each database in order to avoid wasting time duplicating a search that has already been tried
• Read abstracts and write down new terms to search as you find them
• Check MeSH or other subject headings listed in relevant articles for additional search terms
• Scan author provided keywords if available
• Check the references of relevant articles looking for other useful articles (ancestry searching)
• Check articles that have cited your relevant article for more useful articles (descendancy searching). Both PubMed and CINAHL offer Cited By links
• Revise the search to broaden or narrow your topic focus as you peruse the available literature
• Conducting a literature search is a repetitive process. Searches can be revised and re-run multiple times during the process.
• Track the citations for your relevant articles in a software citation manager such as RefWorks, Zotero, or Mendeley

5. Review the literature

• Read the full articles. Do not rely solely on the abstracts. Authors frequently cannot include all results within the confines of an abstract. Exclude articles that do not address your research question.
• While reading, note research findings relevant to your project and summarize. Are the findings conflicting? There are matrices available than can help with organization. See the Organizing Information box below.
• Critique / evaluate the quality of the articles, and record your findings in your matrix or summary table. Tools are available to prompt you what to look for. (See Resources for Appraising a Research Study box on the HSA, Nursing , and PA guides )
• You may need to revise your search and re-run it based on your findings.

6. Organize and synthesize

• Compile the findings and analysis from each resource into a single narrative.
• Using an outline can be helpful. Start broad, addressing the overall findings and then narrow, discussing each resource and how it relates to your question and to the other resources.
• Cite as you write to keep sources organized.
• Write in structured paragraphs using topic sentences and transition words to draw connections, comparisons, and contrasts.
• Don't present one study after another, but rather relate one study's findings to another. Speak to how the studies are connected and how they relate to your work.

Organizing Information

Options to assist in organizing sources and information :

1. Synthesis Matrix

• helps provide overview of the literature
• information from individual sources is entered into a grid to enable writers to discern patterns and themes
• article summary, analysis, or results
• thoughts, reflections, or issues
• each reference gets its own row
• mind maps, concept maps, flowcharts
• at top of page record PICO or research question
• record major concepts / themes from literature
• list concepts that branch out from major concepts underneath - keep going downward hierarchically, until most specific ideas are recorded
• enclose concepts in circles and connect the concept with lines - add brief explanation as needed

3. Summary Table

• information is recorded in a grid to help with recall and sorting information when writing
• allows comparing and contrasting individual studies easily
• purpose of study
• methodology (study population, data collection tool)

Efron, S. E., & Ravid, R. (2019). Writing the literature review : A practical guide . Guilford Press.

Literature Review Sections

• Lit reviews can be part of a larger paper / research study or they can be the focus of the paper
• Lit reviews focus on research studies to provide evidence
• New topics may not have much that has been published

* The sections included may depend on the purpose of the literature review (standalone paper or section within a research paper)

Standalone Literature Review (aka Narrative Review):

• presents your topic or PICO question
• includes the why of the literature review and your goals for the review.
• provides background for your the topic and previews the key points
• Narrative Reviews: tmay not have an explanation of methods.
• include where the search was conducted (which databases) what subject terms or keywords were used, and any limits or filters that were applied and why - this will help others re-create the search
• describe how studies were analyzed for inclusion or exclusion
• review the purpose and answer the research question
• thematically - using recurring themes in the literature
• chronologically - present the development of the topic over time
• methodological - compare and contrast findings based on various methodologies used to research the topic (e.g. qualitative vs quantitative, etc.)
• theoretical - organized content based on various theories
• provide an overview of the main points of each source then synthesize the findings into a coherent summary of the whole
• present common themes among the studies
• compare and contrast the various study results
• interpret the results and address the implications of the findings
• do the results support the original hypothesis or conflict with it
• provide your own analysis and interpretation (eg. discuss the significance of findings; evaluate the strengths and weaknesses of the studies, noting any problems)
• discuss common and unusual patterns and offer explanations
•  stay away from opinions, personal biases and unsupported recommendations
• summarize the key findings and relate them back to your PICO/research question
• note gaps in the research and suggest areas for further research
• this section should not contain "new" information that had not been previously discussed in one of the sections above
• provide a list of all the studies and other sources used in proper APA 7

Literature Review as Part of a Research Study Manuscript:

• Compares the study with other research and includes how a study fills a gap in the research.
• Focus on the body of the review which includes the synthesized Findings and Discussion

Literature Reviews vs Systematic Reviews

Systematic Reviews are NOT the same as a Literature Review:

Literature Reviews:

• Literature reviews may or may not follow strict systematic methods to find, select, and analyze articles, but rather they selectively and broadly review the literature on a topic
• Research included in a Literature Review can be "cherry-picked" and therefore, can be very subjective

Systematic Reviews:

• Systemic reviews are designed to provide a comprehensive summary of the evidence for a focused research question
• rigorous and strictly structured, using standardized reporting guidelines (e.g. PRISMA, see link below)
• uses exhaustive, systematic searches of all relevant databases
• best practice dictates search strategies are peer reviewed
• uses predetermined study inclusion and exclusion criteria in order to minimize bias
• aims to capture and synthesize all literature (including unpublished research - grey literature) that meet the predefined criteria on a focused topic resulting in high quality evidence

Literature Review Examples

• Breastfeeding initiation and support: A literature review of what women value and the impact of early discharge (2017). Women and Birth : Journal of the Australian College of Midwives
• Community-based participatory research to promote healthy diet and nutrition and prevent and control obesity among African-Americans: A literature review (2017). Journal of Racial and Ethnic Health Disparities

• Vitamin D deficiency in individuals with a spinal cord injury: A literature review (2017). Spinal Cord

Resources for Writing a Literature Review

These sources have been used in developing this guide.

Resources Used on This Page

Aveyard, H. (2010). Doing a literature review in health and social care : A practical guide . McGraw-Hill Education.

Purdue Online Writing Lab. (n.d.). Writing a literature review . Purdue University. https://owl.purdue.edu/owl/research_and_citation/conducting_research/writing_a_literature_review.html

Torres, E. (2021, October 21). Nursing - graduate studies research guide: Literature review. Hawai'i Pacific University Libraries. Retrieved January 27, 2022, from https://hpu.libguides.com/c.php?g=543891&p=3727230

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What is a literature review?

A literature review is an integrated analysis -- not just a summary-- of scholarly writings and other relevant evidence related directly to your research question.  That is, it represents a synthesis of the evidence that provides background information on your topic and shows a association between the evidence and your research question.

A literature review may be a stand alone work or the introduction to a larger research paper, depending on the assignment.  Rely heavily on the guidelines your instructor has given you.

Why is it important?

A literature review is important because it:

• Explains the background of research on a topic.
• Demonstrates why a topic is significant to a subject area.
• Discovers relationships between research studies/ideas.
• Identifies major themes, concepts, and researchers on a topic.
• Identifies critical gaps and points of disagreement.
• Discusses further research questions that logically come out of the previous studies.

APA7 Style resources

APA Style Blog - for those harder to find answers

1. Choose a topic. Define your research question.

Your literature review should be guided by your central research question.  The literature represents background and research developments related to a specific research question, interpreted and analyzed by you in a synthesized way.

• Make sure your research question is not too broad or too narrow.  Is it manageable?
• Begin writing down terms that are related to your question. These will be useful for searches later.
• If you have the opportunity, discuss your topic with your professor and your class mates.

2. Decide on the scope of your review

How many studies do you need to look at? How comprehensive should it be? How many years should it cover? 

• This may depend on your assignment.  How many sources does the assignment require?

3. Select the databases you will use to conduct your searches.

Make a list of the databases you will search. 

Where to find databases:

• use the tabs on this guide
• Find other databases in the Nursing Information Resources web page
• More on the Medical Library web page
• ... and more on the Yale University Library web page

4. Conduct your searches to find the evidence. Keep track of your searches.

• Use the key words in your question, as well as synonyms for those words, as terms in your search. Use the database tutorials for help.
• Save the searches in the databases. This saves time when you want to redo, or modify, the searches. It is also helpful to use as a guide is the searches are not finding any useful results.
• Review the abstracts of research studies carefully. This will save you time.
• Use the bibliographies and references of research studies you find to locate others.
• Check with your professor, or a subject expert in the field, if you are missing any key works in the field.
• Ask your librarian for help at any time.
• Use a citation manager, such as EndNote as the repository for your citations. See the EndNote tutorials for help.

Review the literature

Some questions to help you analyze the research:

• What was the research question of the study you are reviewing? What were the authors trying to discover?
• Was the research funded by a source that could influence the findings?
• What were the research methodologies? Analyze its literature review, the samples and variables used, the results, and the conclusions.
• Does the research seem to be complete? Could it have been conducted more soundly? What further questions does it raise?
• If there are conflicting studies, why do you think that is?
• How are the authors viewed in the field? Has this study been cited? If so, how has it been analyzed?

Tips: 

• Review the abstracts carefully.  
• Keep careful notes so that you may track your thought processes during the research process.
• Create a matrix of the studies for easy analysis, and synthesis, across all of the studies.
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Literature Reviews

• Organizing/Synthesizing
• Peer Review
• Ulrich's -- One More Way To Find Peer-reviewed Papers

"Literature review," "systematic literature review," "integrative literature review" -- these are terms used in different disciplines for basically the same thing -- a rigorous examination of the scholarly literature about a topic (at different levels of rigor, and with some different emphases).  

1. Our library's guide to Writing a Literature Review

2. Other helpful sites

• Writing Center at UNC (Chapel Hill) -- A very good guide about lit reviews and how to write them
• Literature Review: Synthesizing Multiple Sources (LSU, June 2011 but good; PDF) -- Planning, writing, and tips for revising your paper

3. Welch Library's list of the types of expert reviews

Doing a good job of organizing your information makes writing about it a lot easier.

You can organize your sources using a citation manager, such as refworks , or use a matrix (if you only have a few references):.

• Use Google Sheets, Word, Excel, or whatever you prefer to create a table
• The column headings should include the citation information, and the main points that you want to track, as shown

Synthesizing your information is not just summarizing it. Here are processes and examples about how to combine your sources into a good piece of writing:

• Purdue OWL's Synthesizing Sources
• Synthesizing Sources (California State University, Northridge)

Annotated Bibliography  

An "annotation" is a note or comment. An "annotated bibliography" is a "list of citations to books, articles, and [other items]. Each citation is followed by a brief...descriptive and evaluative paragraph, [whose purpose is] to inform the reader of the relevance, accuracy, and quality of the sources cited."*

• Sage Research Methods (database) --> Empirical Research and Writing (ebook) -- Chapter 3: Doing Pre-research  
• Purdue's OWL (Online Writing Lab) includes definitions and samples of annotations  
• Cornell's guide * to writing annotated bibliographies  

* Thank you to Olin Library Reference, Research & Learning Services, Cornell University Library, Ithaca, NY, USA https://guides.library.cornell.edu/annotatedbibliography

What does "peer-reviewed" mean?

• If an article has been peer-reviewed before being published, it means that the article has been read by other people in the same field of study ("peers").
• The author's reviewers have commented on the article, not only noting typos and possible errors, but also giving a judgment about whether or not the article should be published by the journal to which it was submitted.

How do I find "peer-reviewed" materials?

• Most of the the research articles in scholarly journals are peer-reviewed.
• Many databases allow you to check a box that says "peer-reviewed," or to see which results in your list of results are from peer-reviewed sources. Some of the databases that provide this are Academic Search Ultimate, CINAHL, PsycINFO, and Sociological Abstracts.

What kinds of materials are *not* peer-reviewed?

• open web pages
• most newspapers, newsletters, and news items in journals
• letters to the editor
• press releases
• columns and blogs
• book reviews
• anything in a popular magazine (e.g., Time, Newsweek, Glamour, Men's Health)

If a piece of information wasn't peer-reviewed, does that mean that I can't trust it at all?

No; sometimes you can. For example, the preprints submitted to well-known sites such as  arXiv  (mainly covering physics) and  CiteSeerX (mainly covering computer science) are probably trustworthy, as are the databases and web pages produced by entities such as the National Library of Medicine, the Smithsonian Institution, and the American Cancer Society.

Is this paper peer-reviewed? Ulrichsweb will tell you.

1) On the library home page , choose "Articles and Databases" --> "Databases" --> Ulrichsweb

2) Put in the title of the JOURNAL (not the article), in quotation marks so all the words are next to each other

3) Mouse over the black icon, and you'll see that it means "refereed" (which means peer-reviewed, because it's been looked at by referees or reviewers). This journal is not peer-reviewed, because none of the formats have a black icon next to it:

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Doing a literature review in nursing, health and social care (second edition), claire lee paediatric research nurse, department of paediatric gastroenterology, addenbrooke’s hospital, cambridge.

This book provides a concise and informative guide to the process of literature review in nursing, health and social care, and is applicable to students and professionals.

Nurse Researcher . 24, 4, 8-8. doi: 10.7748/nr.24.4.8.s3

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The effectiveness of digital twins in promoting precision health across the entire population: a systematic review

• Mei-di Shen 1 ,
• Si-bing Chen 2 &
• Xiang-dong Ding   ORCID: orcid.org/0009-0001-1925-0654 2  

npj Digital Medicine volume  7 , Article number:  145 ( 2024 ) Cite this article

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Digital twins represent a promising technology within the domain of precision healthcare, offering significant prospects for individualized medical interventions. Existing systematic reviews, however, mainly focus on the technological dimensions of digital twins, with a limited exploration of their impact on health-related outcomes. Therefore, this systematic review aims to explore the efficacy of digital twins in improving precision healthcare at the population level. The literature search for this study encompassed PubMed, Embase, Web of Science, Cochrane Library, CINAHL, SinoMed, CNKI, and Wanfang Database to retrieve potentially relevant records. Patient health-related outcomes were synthesized employing quantitative content analysis, whereas the Joanna Briggs Institute (JBI) scales were used to evaluate the quality and potential bias inherent in each selected study. Following established inclusion and exclusion criteria, 12 studies were screened from an initial 1321 records for further analysis. These studies included patients with various conditions, including cancers, type 2 diabetes, multiple sclerosis, heart failure, qi deficiency, post-hepatectomy liver failure, and dental issues. The review coded three types of interventions: personalized health management, precision individual therapy effects, and predicting individual risk, leading to a total of 45 outcomes being measured. The collective effectiveness of these outcomes at the population level was calculated at 80% (36 out of 45). No studies exhibited unacceptable differences in quality. Overall, employing digital twins in precision health demonstrates practical advantages, warranting its expanded use to facilitate the transition from the development phase to broad application.

PROSPERO registry: CRD42024507256.

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Digital twins for health: a scoping review

Digital twins in medicine

The health digital twin to tackle cardiovascular disease—a review of an emerging interdisciplinary field

Introduction.

Precision health represents a paradigm shift from the conventional “one size fits all” medical approach, focusing on specific diagnosis, treatment, and health management by incorporating individualized factors such as omics data, clinical information, and health outcomes 1 , 2 . This approach significantly impacts various diseases, potentially improving overall health while reducing healthcare costs 3 , 4 . Within this context, digital twins emerged as a promising technology 5 , creating digital replicas of the human body through two key steps: building mappings and enabling dynamic evolution 6 . Unlike traditional data mining methods, digital twins consider individual variability, providing continuous, dynamic recommendations for clinical practice 7 . This approach has gained significant attention among researchers, highlighting its potential applications in advancing precision health.

Several systematic reviews have explored the advancement of digital twins within the healthcare sector. One rapid review 8 identified four core functionalities of digital twins in healthcare management: safety management, information management, health management/well-being promotion, and operational control. Another systematic review 9 , through an analysis of 22 selected publications, summarized the diverse application scenarios of digital twins in healthcare, confirming their potential in continuous monitoring, personalized therapy, and hospital management. Furthermore, a quantitative review 10 assessed 94 high-quality articles published from 2018 to 2022, revealing a primary focus on technological advancements (such as artificial intelligence and the Internet of Things) and application scenarios (including personalized, precise, and real-time healthcare solutions), thus highlighting the pivotal role of digital twins technology in the field of precision health. Another systematic review 11 , incorporating 18 framework papers or reviews, underscored the need for ongoing research into digital twins’ healthcare applications, especially during the COVID-19 pandemic. Moreover, a systematic review 12 on the application of digital twins in cardiovascular diseases presented proof-of-concept and data-driven approaches, offering valuable insights for implementing digital twins in this specific medical area.

While the existing literature offers valuable insights into the technological aspects of digital twins in healthcare, these systematic reviews failed to thoroughly examine the actual impacts on population health. Despite the increasing interest and expanding body of research on digital twins in healthcare, the direct effects on patient health-related outcomes remain unclear. This knowledge gap highlights the need to investigate how digital twins promote and restore patient health, which is vital for advancing precision health technologies. Therefore, the objective of our systematic review is to assess the effectiveness of digital twins in improving health-related outcomes at the population level, providing a clearer understanding of their practical benefits in the context of precision health.

Search results

The selection process for the systematic review is outlined in the PRISMA flow chart (Fig. 1 ). Initially, 1321 records were identified. Of these, 446 duplicates (446/1321, 33.76%) were removed, leaving 875 records (875/1321, 66.24%) for title and abstract screening. Applying the pre-defined inclusion and exclusion criteria led to the exclusion of 858 records (858/875, 98.06%), leaving 17 records (17/875, 1.94%) for full-text review. Further scrutiny resulted in the exclusion of one study (1/17, 5.88%) lacking health-related outcomes and four studies (4/17, 23.53%) with overlapping data. Ultimately, 12 (12/17, 70.59%) original studies 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 were included in the systematic review. Supplementary Table 1 provides a summary of the reasons for exclusion at the full-text reading phase.

Flow chart of included studies in the systematic review.

Study characteristics

The studies included in this systematic review were published between 2021 (2/12, 16.67%) 23 , 24 and 2023 (8/12, 66.67%) 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 . Originating from diverse regions, 4/12 studies (33.33%) were from Asia 13 , 14 , 21 , 24 , 5/12 (41.67%) from America 15 , 17 , 19 , 20 , 22 , and 3/12 (25.00%) from Europe 16 , 18 , 23 . The review encompassed various study designs, including randomized controlled trials (1/12, 8.33%) 14 , quasi-experiments (6/12, 50.00%) 13 , 15 , 16 , 18 , 19 , 21 , and cohort studies (5/12, 41.67%) 17 , 20 , 22 , 23 , 24 . The sample sizes ranged from 15 13 to 3500 patients 19 . Five studies assessed the impact of digital twins on virtual patients 15 , 16 , 18 , 19 , 20 , while seven examined their effect on real-world patients 13 , 14 , 17 , 21 , 22 , 23 , 24 . These patients included had various diseases, including cancer (4/12, 33.33%) 15 , 16 , 19 , 22 , type 2 diabetes (2/12, 16.66%) 13 , 14 , multiple sclerosis (2/12, 16.66%) 17 , 18 , qi deficiency (1/12, 8.33%) 21 , heart failure (1/12, 8.33%) 20 , post-hepatectomy liver failure (1/12, 8.33%) 23 , and dental issues (1/12, 8.33%) 24 . This review coded interventions into three types: personalized health management (3/12, 25.00%) 13 , 14 , 21 , precision individual therapy effects (3/12, 25.00%) 15 , 16 , 18 , 19 , 20 , 22 , and predicting individual risk (3/12, 25.00%) 17 , 23 , 24 , with a total of 45 measured outcomes. Characteristics of the included studies are detailed in Table 1 .

Risk of bias assessment

The risk of bias for the studies included in this review is summarized in Fig. 2 . In the single RCT 14 assessed, 10 out of 13 items received positive responses. Limitations were observed due to incomplete reporting of baseline characteristics and issues with blinding. Among the six quasi-experimental studies evaluated, five (83.33%) 13 , 15 , 16 , 18 , 21 achieved at least six positive responses, indicating an acceptable quality, while one study (16.67%) 19 fell slightly below this threshold with five positive responses. The primary challenges in these quasi-experimental studies were due to the lack of control groups, inadequate baseline comparisons, and limited follow-up reporting. Four out of five (80.00%) 17 , 20 , 22 , 23 of the cohort studies met or exceeded the criterion with at least eight positive responses, demonstrating their acceptable quality. However, one study (20.00%) 24 had a lower score due to incomplete data regarding loss to follow-up and the specifics of the interventions applied. Table 1 elaborates on the specific reasons for these assessments. Despite these concerns, the overall quality of the included studies is considered a generally acceptable risk of bias.

The summary of bias risk via the Joanna Briggs Institute assessment tools.

The impact of digital twins on health-related outcomes among patients

This review includes 12 studies that collectively assessed 45 outcomes, achieving an overall effectiveness rate of 80% (36 out of 45 outcomes), as depicted in Fig. 3a . The digital twins analyzed were coded into three functional categories: personalized health management, precision individual therapy effects, and predicting individual risks. A comprehensive analysis of the effectiveness of digital twins across these categories is provided, detailing the impact and outcomes associated with each function.

a The overall effectiveness of digital twins; b The effectiveness of personalized health management driven by digital twins; c The effectiveness of precision individualized therapy effects driven by digital twins; d The effectiveness of prediction of individual risk driven by digital twins.

The effectiveness of digital twins in personalized health management

In this review, three studies 13 , 14 , 21 employing digital twins for personalized health management reported an effectiveness of 80% (24 out of 30 outcomes), as shown in Fig. 3b . A self-control study 13 involving 15 elderly patients with diabetes, used virtual patient representations based on health information to guide individualized insulin infusion. Over 14 days, this approach improved the time in range (TIR) from 3–75% to 86–97%, decreased hypoglycemia duration from 0–22% to 0–9%, and reduced hyperglycemia time from 0–98% to 0–12%. A 1-year randomized controlled trial 14 with 319 type 2 diabetes patients, implemented personalized digital twins interventions based on nutrition, activity, and sleep. This trial demonstrated significant improvements in Hemoglobin A1c (HbA1C), Homeostatic Model Assessment 2 of Insulin Resistance (HOMA2-IR), Nonalcoholic Fatty Liver Disease Liver Fat Score (NAFLD-LFS), and Nonalcoholic Fatty Liver Disease Fibrosis Score (NAFLD-NFS), and other primary outcomes (all, P  < 0.001; Table 2 ). However, no significant changes were observed in weight, Alanine Aminotransferase (ALT), Fibrosis-4 Score (FIB4), and AST to Platelet Ratio Index (APRI) (all, P  > 0.05). A non-randomized controlled trial 21 introduced a digital twin-based Traditional Chinese Medicine (TCM) health management platform for patients with qi deficiency. It was found to significantly improve blood pressure, main and secondary TCM symptoms, total TCM symptom scores, and quality of life (all, P  < 0.05). Nonetheless, no significant improvements were observed in heart rate and BMI (all, P  > 0.05; Table 2 ).

The effectiveness of digital twins in precision individual therapy effects

Six studies 15 , 16 , 18 , 19 , 20 , 22 focused on the precision of individual therapy effects using digital twins, demonstrating a 70% effectiveness rate (7 out of 10 outcomes), as detailed in Fig. 3c . In a self-control study 15 , a data-driven approach was employed to create digital twins, generating 100 virtual patients to predict the potential tumor biology outcomes of radiotherapy regimens with varying contents and doses. This study showed that personalized radiotherapy plans derived from digital twins could extend the median tumor progression time by approximately six days and reduce radiation doses by 16.7%. Bahrami et al. 16 created 3000 virtual patients experiencing cancer pain to administer precision dosing of fentanyl transdermal patch therapy. The intervention led to a 16% decrease in average pain intensity and an additional median pain-free duration of 23 hours, extending from 72 hours in cancer patients. Another quasi-experimental study 18 created 3000 virtual patients with multiple sclerosis to assess the impact of Ocrelizumab. Findings indicated Ocrelizumab can resulted in a reduction in relapses (0.191 [0.143, 0.239]) and lymphopenic adverse events (83.73% vs . 19.9%) compared to a placebo. American researchers 19 developed a quantitative systems pharmacology model using digital twins to identify the optimal dosing for aggressive non-Hodgkin lymphoma patients. This approach resulted in at least a 50% tumor size reduction by day 42 among 3500 virtual patients. A cohort study 20 assessed the 5-year composite cardiovascular outcomes in 2173 virtual patients who were treated with spironolactone or left untreated and indicated no statistically significant inter-group differences (0.85, [0.69–1.04]). Tardini et al. 22 employed digital twins to optimize multi-step treatment for oropharyngeal squamous cell carcinoma in 134 patients. The optimized treatment selection through digital twins predicted increased survival rates by 3.73 (−0.75, 8.96) and dysphagia rates by 0.75 (−4.48, 6.72) compared to clinician decisions, with no statistical significance.

The effectiveness of digital twins in predicting individual risk

Three studies 17 , 23 , 24 employing digital twins to predict individual patient risks demonstrated a 100% effectiveness rate (5 out of 5 outcomes), as shown in Fig. 3d . A cohort study 17 used digital twins to forecast the onset age for disease-specific brain atrophy in patients with multiple sclerosis. Findings indicated that the onset of progressive brain tissue loss, on average, preceded clinical symptoms by 5-6 years among the 519 patients ( P  < 0.01). Another study 23 focused on predicting postoperative liver failure in 47 patients undergoing major hepatectomy through mathematical models of blood circulation. The study highlighted that elevated Postoperative Portal Vein pressure (PPV) and Portocaval Gradient (PCG) values above 17.5 mmHg and 13.5 mmHg, respectively, correlated with the measured values (all, P  < 0.0001; Table 2 ). These indicators were effective in predicting post-hepatectomy liver failure, accurately identifying three out of four patients who experienced this complication. Cho et al. 24 created digital twins for 50 adult female patients using facial scans and cone-beam computed tomography images to evaluate the anteroposterior position of the maxillary central incisors and forehead inclination. The analysis demonstrated significant differences in the position of the maxillary central incisors ( P  = 0.04) and forehead inclination ( P  = 0.02) between the two groups.

This systematic review outlines the effectiveness of digital twins in improving health-related outcomes across various diseases, including cancers, type 2 diabetes, multiple sclerosis, qi deficiency, heart failure, post-hepatectomy liver failure, and dental issues, at the population level. Distinct from prior reviews that focused on the technological dimensions of digital twins, our analysis shows the practical applications of digital twins in healthcare. The applications have been categorized into three main areas: personalized health management, precision individual therapy effects, and predicting individual risks, encompassing a total of 45 outcomes. An overall effectiveness of 80% was observed across these outcomes. This review offers valuable insights into the application of digital twins in precision health and supports the transition of digital twins from construction to population-wide implementation.

Digital twins play a crucial role in achieving precision health 25 . They serve as virtual models of human organs, tissues, cells, or microenvironments, dynamically updating based on real-time data to offer feedback for interventions on their real counterparts 26 , 27 . Digital twins can solve complex problems in personalized health management 28 , 29 and enable comprehensive, proactive, and precise healthcare 30 . In the studies reviewed, researchers implemented digital twins by creating virtual patients based on personal health data and using simulations to generate personalized recommendations and predictions. It is worth noting that while certain indicators have not experienced significant improvement in personalized health management for patients with type 2 diabetes and Qi deficiency, it does not undermine the effectiveness of digital twins. Firstly, these studies have demonstrated significant improvements in primary outcome measures. Secondly, improving health-related outcomes in chronic diseases is an ongoing, complex process heavily influenced by changes in health behaviors 31 , 32 . While digital twins can provide personalized health guidance based on individual health data, their impact on actual behaviors warrants further investigation.

The dual nature of medications, providing benefits yet potentially leading to severe clinical outcomes like morbidity or mortality, must be carefully considered. The impact of therapy is subject to various factors, including the drug attributes and the specific disease characteristics 33 . Achieving accurate medication administration remains a significant challenge for healthcare providers 34 , underscoring the need for innovative methodologies like computational precise drug delivery 35 , 36 , a example highlighted in our review of digital twins. Regarding the prediction of individual therapy effects for conditions such as cancer, multiple sclerosis, and heart failure, six studies within this review have reported partly significant improvements in patient health-related outcomes. These advancements facilitate the tailored selection and dosing of therapy, underscoring the ability of digital twins to optimize patient-specific treatment plans effectively.

Furthermore, digital twins can enhance clinical understanding and personalize disease risk prediction 37 . It enables a quantitative understanding and prediction of individuals by continuously predicting and evaluating patient data in a virtual environment 38 . In patients with multiple sclerosis, digital twins have facilitated predictions regarding the onset of disease-specific brain atrophy, allowing for early intervention strategies. Similarly, digital twins assessed the risk of liver failure after liver resection, aiding healthcare professionals in making timely decisions. Moreover, the application of digital twins in the three-dimensional analysis of patients with dental problems has demonstrated highly effective clinical significance, underscoring its potential across various medical specialties. In summary, the adoption of digital twins has significantly contributed to advancing precision health and restoring patient well-being by creating virtual patients based on personal health data and using simulations to generate personalized recommendations and predictions.

Recent studies have introduced various digital twin systems, covering areas such as hospital management 8 , remote monitoring 9 , and diagnosing and treating various conditions 39 , 40 . Nevertheless, these systems were not included in this review due to the lack of detailed descriptions at the population health level, which constrains the broader application of this emerging technology. Our analysis underscores the reported effectiveness of digital twins, providing unique opportunities for dynamic prevention and precise intervention across different diseases. Multiple research methodologies and outcome measures poses a challenge for quantitative publication detection. This systematic review employed a comprehensive retrieval strategy across various databases for screening articles on the effectiveness of digital twins, to reduce the omission of negative results. And four repeated publications were excluded based on authors, affiliation, population, and other criteria to mitigate the bias of overestimating the digital twins effect due to repeated publication.

However, there are still limitations. Firstly, the limited published research on digital twins’ application at the population level hinders the ability to perform a quantitative meta-analysis, possibly limiting our findings’ interpretability. We encourage reporting additional high-quality randomized controlled trials on the applicability of digital twins to facilitate quantitative analysis of their effectiveness in precision health at the population level. Secondly, this review assessed the effectiveness of digital twins primarily through statistical significance ( P -value or 95% confidence interval). However, there are four quasi-experimental studies did not report statistical significance. One of the limitations of this study is the use of significant changes in author self-reports as a criterion in these four quasi-experimental studies for identifying effectiveness. In clinical practice, the author’s self-reported clinical significance can also provide the effectiveness of digital twins. Thirdly, by focusing solely on studies published in Chinese and English, this review may have omitted relevant research available in other languages, potentially limiting the scope of the analyzed literature. Lastly, our review primarily emphasized reporting statistical differences between groups. Future work should incorporate more application feedback from real patients to expose digital twins to the nuances of actual patient populations.

The application of digital twins is currently limited and primarily focused on precision health for individual patients. Expanding digital twins’ application from individual to group precision health is recommended to signify a more extensive integration in healthcare settings. This expansion involves sharing real-time data and integrating medical information across diverse medical institutions within a region, signifying the development of group precision health. Investigating both personalized medical care and collective health management has significant implications for improving medical diagnosis and treatment approaches, predicting disease risks, optimizing health management strategies, and reducing societal healthcare costs 41 .

Digital twins intervention encompasses various aspects such as health management, decision-making, and prediction, among others 9 . It represents a technological and conceptual innovation in traditional population health intervention. However, the current content design of the digital twins intervention is insufficient and suggests that it should be improved by incorporating more effective content strategies tailored to the characteristics of the target population. Findings from this study indicate that interventions did not differ significantly in our study is from digital twins driven by personalized health management, which means that compared with the other two function-driven digital twins, personalized health management needs to receive more attention to enhance its effect in population-level. For example, within the sphere of chronic disease management, integrating effective behavioral change strategies into digital twins is advisable to positively influence health-related indicators, such as weight and BMI. The effectiveness of such digital behavior change strategies has been reported in previous studies 42 , 43 . The consensus among researchers on the importance of combining effective content strategies with digital intervention technologies underscores the potential for this approach to improve patient health-related outcomes significantly.

The applications of digital twins in precision health are mainly focused on model establishment and prediction description, with limited implementation in multi-center settings. A more robust and detailed data foundation is recommended to improve clinical decision-making and reduce the likelihood of imprecise treatments. This requires continuous updating and capturing of dynamic information by digital twins in the future, as well as the improvement of the data platform that facilitates mapping, interaction, and iterative optimization. Integrating digital twins effectively into clinical workflows can support clinical interventions, assist physicians in making informed decisions, and increase the standard of patient care 6 .

The accessibility of health data is a significant challenge for the clinical implementation of digital twins. Although the internet and information technology have significantly enhanced health data availability, health data, including information systems and electronic health records, remain heterogeneous and are difficult to share 44 . Health data often contains confidential patient information, as well as unreliable information, posing challenges for implementing digital twins in healthcare settings. The primary technology utilized in digital twins, artificial intelligence algorithms, demands high-performance hardware devices and software platforms for data analysis 45 , necessitating healthcare organizations to allocate increased investment and budget for computing infrastructure supporting digital twins’ application. Therefore, future research should be focused on the technical aspects of digital twins to resolve these challenges. The automated processing of health data using a large language model and the rapid conversion of complex natural language texts into comprehensive knowledge texts are encouraged. The development of high-performance computing technology is essential for cost-effective computing requirements, which can facilitate the application of digital twins in clinical practice 46 .

Overall, this systematic review offers a comprehensive overview of digital twins in precision health, examining their impact at the population level. The findings indicate a significant overall effectiveness rate of 80% for the measured outcomes, highlighting digital twins’ pivotal role in advancing precision health. Future research should broaden the application of digital twins across various populations, integrate proven content strategies, and implement these approaches in various healthcare settings. Such efforts will maximize the benefits of digital technologies in healthcare, promoting more precise and efficacious strategies, thereby elevating patient outcomes and improving overall healthcare experiences. While digital twins offer great promise for precision health, their broad adoption and practical implementation are still in the early stages. Development, and application are essential to unlock the full potential of digital twins in revolutionizing healthcare delivery.

This systematic review was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines 47 . The protocol for this systematic review was prospectively registered on PROSPERO, which can be accessed via the following link: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024507256 . The registered protocol underwent an update, which included polishing the title of the article, modifying the limitation of the control group and language in the inclusion/exclusion criteria, and refining the process of data synthesis and analysis to enhance that clarity and readability of this systematic review. These modifications were updated in the revision notes section of the PROSPERO.

Literature search strategy

Literature searches were conducted in PubMed, Embase, Web of Science, Cochrane Library, CINAHL, SinoMed, CNKI, and Wanfang Database, covering publications up to December 24, 2023. A comprehensive search strategy was developed using a combination of Medical Subject Headings terms and free-text terms, as detailed in Supplementary Table 2 . Furthermore, reference lists of articles and reviews meeting the inclusion criteria were reviewed for additional relevant studies.

Inclusion and exclusion criteria

The inclusion criteria for this systematic review included: 1) Population: Patients diagnosed with any diseases or symptoms; 2) Intervention: Any interventions involving digital twins; 3) Controls: Non-digital twin groups, such as standard care or conventional therapy, as well as no control group; 4) Outcomes: Health-related outcomes as the primary outcomes of interest; 5) Study design: All study designs that measured patient health-related outcomes after digital twins were included, including intervention studies and predictive cohort studies.

Initially, duplicates were removed. Exclusion criteria included: 1) Papers lacking original data, such as reviews, protocols, and conference abstracts; 2) Studies not in English or Chinese; 3) Surveys focusing on implementation and qualitative studies related to requirements. In cases of data duplication, the most comprehensive data report was included.

Study selection and Data extraction

Following the automatic removal of duplicates, two independent reviewers (MD.SHEN and SB.CHEN) conducted initial screenings of titles and abstracts against the predefined inclusion and exclusion criteria to identify potentially relevant studies. Afterward, the same reviewers examined the full texts of these shortlisted articles to confirm their suitability for inclusion. This process also involved checking the reference lists of these articles for any additional studies that might meet the criteria. Data from the included studies were systematically extracted using a pre-designed extraction form. Recorded information included the first author’s name, publication year, country of origin, type of study, sample size, study population, intervention, controls, measurements, and an appraisal of each study. Disagreements between the reviewers were resolved by consultation with a third senior reviewer (XD.DING), ensuring consensus.

Quality appraisal

The Joanna Briggs Institute (JBI) scales 48 were used to assess the quality and potential bias of each study included in the review, employing specific tools tailored to the type of study under evaluation. These tools feature response options of “yes,” “no,” “unclear,” or “not applicable” for each assessment item. For randomized controlled trials (RCTs), the JBI scale includes 13 items, with answering “yes” to at least six items indicating a high-quality study. Quasi-experimental studies were evaluated using a nine-item checklist, where five or more positive responses qualify the research as high quality. Cohort studies underwent evaluation through an 11-item checklist, with six or more affirmative responses indicating high quality. The assessment was independently carried out by two reviewers (MD.SHEN and SB.CHEN), and any disagreements were resolved through consultation with a third senior reviewer (XD.DING), ensuring the integrity and accuracy of the quality assessment.

Data synthesis and analysis

Given the heterogeneity in type of study and outcome measures, a meta-analysis was deemed unfeasible. Instead, a quantitative content analysis was employed to analyze all the selected studies 49 , 50 . Key information was extracted using a pre-designed standardized form, including the first author’s name, patient characteristics, intervention functional characteristics, measurements, results, effectiveness, and adverse events. Two reviewers (MD.SHEN and SB.CHEN) independently coded digital twin technology into three categories for descriptive analysis: personalized health management, precision individual therapy effects, and predicting individual risk, based on its functional characteristics. The Kappa statistic was applied to evaluate the inter-rater reliability during the coding process, yielding a value of 0.871, which signifies good agreement between the researchers 51 , 52 . The assessment of digital twins effectiveness was based on statistical significance ( P -value or 95% confidence interval). Outcomes with statistical significance were labeled as “resultful,” whereas those lacking statistical significance were deemed “resultless.” For quasi-experimental studies, significant changes in the authors’ self-reports were used to determine the effectiveness in the absence of reporting of statistical significance. The proportion of effectiveness was calculated as the number of “resultful” indicators divided by the total number of outcomes within each category.

Data availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Code availability

Code sharing is not applicable to this article as no codes were generated or analyzed during the current study.

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Shen, Md., Chen, Sb. & Ding, Xd. The effectiveness of digital twins in promoting precision health across the entire population: a systematic review. npj Digit. Med. 7 , 145 (2024). https://doi.org/10.1038/s41746-024-01146-0

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Research Article

Functional connectivity changes in the brain of adolescents with internet addiction: A systematic literature review of imaging studies

Roles Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Software, Validation, Visualization, Writing – original draft, Writing – review & editing

Affiliation Child and Adolescent Mental Health, Department of Brain Sciences, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom

Roles Conceptualization, Supervision, Validation, Writing – review & editing

* E-mail: [email protected]

Affiliation Behavioural Brain Sciences Unit, Population Policy Practice Programme, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom

• Max L. Y. Chang, 
• Irene O. Lee

• Published: June 4, 2024
• https://doi.org/10.1371/journal.pmen.0000022
• Peer Review
• Reader Comments

Internet usage has seen a stark global rise over the last few decades, particularly among adolescents and young people, who have also been diagnosed increasingly with internet addiction (IA). IA impacts several neural networks that influence an adolescent’s behaviour and development. This article issued a literature review on the resting-state and task-based functional magnetic resonance imaging (fMRI) studies to inspect the consequences of IA on the functional connectivity (FC) in the adolescent brain and its subsequent effects on their behaviour and development. A systematic search was conducted from two databases, PubMed and PsycINFO, to select eligible articles according to the inclusion and exclusion criteria. Eligibility criteria was especially stringent regarding the adolescent age range (10–19) and formal diagnosis of IA. Bias and quality of individual studies were evaluated. The fMRI results from 12 articles demonstrated that the effects of IA were seen throughout multiple neural networks: a mix of increases/decreases in FC in the default mode network; an overall decrease in FC in the executive control network; and no clear increase or decrease in FC within the salience network and reward pathway. The FC changes led to addictive behaviour and tendencies in adolescents. The subsequent behavioural changes are associated with the mechanisms relating to the areas of cognitive control, reward valuation, motor coordination, and the developing adolescent brain. Our results presented the FC alterations in numerous brain regions of adolescents with IA leading to the behavioural and developmental changes. Research on this topic had a low frequency with adolescent samples and were primarily produced in Asian countries. Future research studies of comparing results from Western adolescent samples provide more insight on therapeutic intervention.

Citation: Chang MLY, Lee IO (2024) Functional connectivity changes in the brain of adolescents with internet addiction: A systematic literature review of imaging studies. PLOS Ment Health 1(1): e0000022. https://doi.org/10.1371/journal.pmen.0000022

Editor: Kizito Omona, Uganda Martyrs University, UGANDA

Received: December 29, 2023; Accepted: March 18, 2024; Published: June 4, 2024

Copyright: © 2024 Chang, Lee. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the paper and its Supporting information files.

Funding: The authors received no specific funding for this work.

Competing interests: The authors have declared that no competing interests exist.

Introduction

The behavioural addiction brought on by excessive internet use has become a rising source of concern [ 1 ] since the last decade. According to clinical studies, individuals with Internet Addiction (IA) or Internet Gaming Disorder (IGD) may have a range of biopsychosocial effects and is classified as an impulse-control disorder owing to its resemblance to pathological gambling and substance addiction [ 2 , 3 ]. IA has been defined by researchers as a person’s inability to resist the urge to use the internet, which has negative effects on their psychological well-being as well as their social, academic, and professional lives [ 4 ]. The symptoms can have serious physical and interpersonal repercussions and are linked to mood modification, salience, tolerance, impulsivity, and conflict [ 5 ]. In severe circumstances, people may experience severe pain in their bodies or health issues like carpal tunnel syndrome, dry eyes, irregular eating and disrupted sleep [ 6 ]. Additionally, IA is significantly linked to comorbidities with other psychiatric disorders [ 7 ].

Stevens et al (2021) reviewed 53 studies including 17 countries and reported the global prevalence of IA was 3.05% [ 8 ]. Asian countries had a higher prevalence (5.1%) than European countries (2.7%) [ 8 ]. Strikingly, adolescents and young adults had a global IGD prevalence rate of 9.9% which matches previous literature that reported historically higher prevalence among adolescent populations compared to adults [ 8 , 9 ]. Over 80% of adolescent population in the UK, the USA, and Asia have direct access to the internet [ 10 ]. Children and adolescents frequently spend more time on media (possibly 7 hours and 22 minutes per day) than at school or sleeping [ 11 ]. Developing nations have also shown a sharp rise in teenage internet usage despite having lower internet penetration rates [ 10 ]. Concerns regarding the possible harms that overt internet use could do to adolescents and their development have arisen because of this surge, especially the significant impacts by the COVID-19 pandemic [ 12 ]. The growing prevalence and neurocognitive consequences of IA among adolescents makes this population a vital area of study [ 13 ].

Adolescence is a crucial developmental stage during which people go through significant changes in their biology, cognition, and personalities [ 14 ]. Adolescents’ emotional-behavioural functioning is hyperactivated, which creates risk of psychopathological vulnerability [ 15 ]. In accordance with clinical study results [ 16 ], this emotional hyperactivity is supported by a high level of neuronal plasticity. This plasticity enables teenagers to adapt to the numerous physical and emotional changes that occur during puberty as well as develop communication techniques and gain independence [ 16 ]. However, the strong neuronal plasticity is also associated with risk-taking and sensation seeking [ 17 ] which may lead to IA.

Despite the fact that the precise neuronal mechanisms underlying IA are still largely unclear, functional magnetic resonance imaging (fMRI) method has been used by scientists as an important framework to examine the neuropathological changes occurring in IA, particularly in the form of functional connectivity (FC) [ 18 ]. fMRI research study has shown that IA alters both the functional and structural makeup of the brain [ 3 ].

We hypothesise that IA has widespread neurological alteration effects rather than being limited to a few specific brain regions. Further hypothesis holds that according to these alterations of FC between the brain regions or certain neural networks, adolescents with IA would experience behavioural changes. An investigation of these domains could be useful for creating better procedures and standards as well as minimising the negative effects of overt internet use. This literature review aims to summarise and analyse the evidence of various imaging studies that have investigated the effects of IA on the FC in adolescents. This will be addressed through two research questions:

• How does internet addiction affect the functional connectivity in the adolescent brain?
• How is adolescent behaviour and development impacted by functional connectivity changes due to internet addiction?

The review protocol was conducted in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (see S1 Checklist ).

Search strategy and selection process

A systematic search was conducted up until April 2023 from two sources of database, PubMed and PsycINFO, using a range of terms relevant to the title and research questions (see full list of search terms in S1 Appendix ). All the searched articles can be accessed in the S1 Data . The eligible articles were selected according to the inclusion and exclusion criteria. Inclusion criteria used for the present review were: (i) participants in the studies with clinical diagnosis of IA; (ii) participants between the ages of 10 and 19; (iii) imaging research investigations; (iv) works published between January 2013 and April 2023; (v) written in English language; (vi) peer-reviewed papers and (vii) full text. The numbers of articles excluded due to not meeting the inclusion criteria are shown in Fig 1 . Each study’s title and abstract were screened for eligibility.

• PPT PowerPoint slide
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https://doi.org/10.1371/journal.pmen.0000022.g001

Quality appraisal

Full texts of all potentially relevant studies were then retrieved and further appraised for eligibility. Furthermore, articles were critically appraised based on the GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) framework to evaluate the individual study for both quality and bias. The subsequent quality levels were then appraised to each article and listed as either low, moderate, or high.

Data collection process

Data that satisfied the inclusion requirements was entered into an excel sheet for data extraction and further selection. An article’s author, publication year, country, age range, participant sample size, sex, area of interest, measures, outcome and article quality were all included in the data extraction spreadsheet. Studies looking at FC, for instance, were grouped, while studies looking at FC in specific area were further divided into sub-groups.

Data synthesis and analysis

Articles were classified according to their location in the brain as well as the network or pathway they were a part of to create a coherent narrative between the selected studies. Conclusions concerning various research trends relevant to particular groupings were drawn from these groupings and subgroupings. To maintain the offered information in a prominent manner, these assertions were entered into the data extraction excel spreadsheet.

With the search performed on the selected databases, 238 articles in total were identified (see Fig 1 ). 15 duplicated articles were eliminated, and another 6 items were removed for various other reasons. Title and abstract screening eliminated 184 articles because they were not in English (number of article, n, = 7), did not include imaging components (n = 47), had adult participants (n = 53), did not have a clinical diagnosis of IA (n = 19), did not address FC in the brain (n = 20), and were published outside the desired timeframe (n = 38). A further 21 papers were eliminated for failing to meet inclusion requirements after the remaining 33 articles underwent full-text eligibility screening. A total of 12 papers were deemed eligible for this review analysis.

Characteristics of the included studies, as depicted in the data extraction sheet in Table 1 provide information of the author(s), publication year, sample size, study location, age range, gender, area of interest, outcome, measures used and quality appraisal. Most of the studies in this review utilised resting state functional magnetic resonance imaging techniques (n = 7), with several studies demonstrating task-based fMRI procedures (n = 3), and the remaining studies utilising whole-brain imaging measures (n = 2). The studies were all conducted in Asiatic countries, specifically coming from China (8), Korea (3), and Indonesia (1). Sample sizes ranged from 12 to 31 participants with most of the imaging studies having comparable sample sizes. Majority of the studies included a mix of male and female participants (n = 8) with several studies having a male only participant pool (n = 3). All except one of the mixed gender studies had a majority male participant pool. One study did not disclose their data on the gender demographics of their experiment. Study years ranged from 2013–2022, with 2 studies in 2013, 3 studies in 2014, 3 studies in 2015, 1 study in 2017, 1 study in 2020, 1 study in 2021, and 1 study in 2022.

https://doi.org/10.1371/journal.pmen.0000022.t001

(1) How does internet addiction affect the functional connectivity in the adolescent brain?

The included studies were organised according to the brain region or network that they were observing. The specific networks affected by IA were the default mode network, executive control system, salience network and reward pathway. These networks are vital components of adolescent behaviour and development [ 31 ]. The studies in each section were then grouped into subsections according to their specific brain regions within their network.

Default mode network (DMN)/reward network.

Out of the 12 studies, 3 have specifically studied the default mode network (DMN), and 3 observed whole-brain FC that partially included components of the DMN. The effect of IA on the various centres of the DMN was not unilaterally the same. The findings illustrate a complex mix of increases and decreases in FC depending on the specific region in the DMN (see Table 2 and Fig 2 ). The alteration of FC in posterior cingulate cortex (PCC) in the DMN was the most frequently reported area in adolescents with IA, which involved in attentional processes [ 32 ], but Lee et al. (2020) additionally found alterations of FC in other brain regions, such as anterior insula cortex, a node in the DMN that controls the integration of motivational and cognitive processes [ 20 ].

https://doi.org/10.1371/journal.pmen.0000022.g002

The overall changes of functional connectivity in the brain network including default mode network (DMN), executive control network (ECN), salience network (SN) and reward network. IA = Internet Addiction, FC = Functional Connectivity.

https://doi.org/10.1371/journal.pmen.0000022.t002

Ding et al. (2013) revealed altered FC in the cerebellum, the middle temporal gyrus, and the medial prefrontal cortex (mPFC) [ 22 ]. They found that the bilateral inferior parietal lobule, left superior parietal lobule, and right inferior temporal gyrus had decreased FC, while the bilateral posterior lobe of the cerebellum and the medial temporal gyrus had increased FC [ 22 ]. The right middle temporal gyrus was found to have 111 cluster voxels (t = 3.52, p<0.05) and the right inferior parietal lobule was found to have 324 cluster voxels (t = -4.07, p<0.05) with an extent threshold of 54 voxels (figures above this threshold are deemed significant) [ 22 ]. Additionally, there was a negative correlation, with 95 cluster voxels (p<0.05) between the FC of the left superior parietal lobule and the PCC with the Chen Internet Addiction Scores (CIAS) which are used to determine the severity of IA [ 22 ]. On the other hand, in regions of the reward system, connection with the PCC was positively connected with CIAS scores [ 22 ]. The most significant was the right praecuneus with 219 cluster voxels (p<0.05) [ 22 ]. Wang et al. (2017) also discovered that adolescents with IA had 33% less FC in the left inferior parietal lobule and 20% less FC in the dorsal mPFC [ 24 ]. A potential connection between the effects of substance use and overt internet use is revealed by the generally decreased FC in these areas of the DMN of teenagers with drug addiction and IA [ 35 ].

The putamen was one of the main regions of reduced FC in adolescents with IA [ 19 ]. The putamen and the insula-operculum demonstrated significant group differences regarding functional connectivity with a cluster size of 251 and an extent threshold of 250 (Z = 3.40, p<0.05) [ 19 ]. The molecular mechanisms behind addiction disorders have been intimately connected to decreased striatal dopaminergic function [ 19 ], making this function crucial.

Executive Control Network (ECN).

5 studies out of 12 have specifically viewed parts of the executive control network (ECN) and 3 studies observed whole-brain FC. The effects of IA on the ECN’s constituent parts were consistent across all the studies examined for this analysis (see Table 2 and Fig 3 ). The results showed a notable decline in all the ECN’s major centres. Li et al. (2014) used fMRI imaging and a behavioural task to study response inhibition in adolescents with IA [ 25 ] and found decreased activation at the striatum and frontal gyrus, particularly a reduction in FC at inferior frontal gyrus, in the IA group compared to controls [ 25 ]. The inferior frontal gyrus showed a reduction in FC in comparison to the controls with a cluster size of 71 (t = 4.18, p<0.05) [ 25 ]. In addition, the frontal-basal ganglia pathways in the adolescents with IA showed little effective connection between areas and increased degrees of response inhibition [ 25 ].

https://doi.org/10.1371/journal.pmen.0000022.g003

Lin et al. (2015) found that adolescents with IA demonstrated disrupted corticostriatal FC compared to controls [ 33 ]. The corticostriatal circuitry experienced decreased connectivity with the caudate, bilateral anterior cingulate cortex (ACC), as well as the striatum and frontal gyrus [ 33 ]. The inferior ventral striatum showed significantly reduced FC with the subcallosal ACC and caudate head with cluster size of 101 (t = -4.64, p<0.05) [ 33 ]. Decreased FC in the caudate implies dysfunction of the corticostriatal-limbic circuitry involved in cognitive and emotional control [ 36 ]. The decrease in FC in both the striatum and frontal gyrus is related to inhibitory control, a common deficit seen with disruptions with the ECN [ 33 ].

The dorsolateral prefrontal cortex (DLPFC), ACC, and right supplementary motor area (SMA) of the prefrontal cortex were all found to have significantly decreased grey matter volume [ 29 ]. In addition, the DLPFC, insula, temporal cortices, as well as significant subcortical regions like the striatum and thalamus, showed decreased FC [ 29 ]. According to Tremblay (2009), the striatum plays a significant role in the processing of rewards, decision-making, and motivation [ 37 ]. Chen et al. (2020) reported that the IA group demonstrated increased impulsivity as well as decreased reaction inhibition using a Stroop colour-word task [ 26 ]. Furthermore, Chen et al. (2020) observed that the left DLPFC and dorsal striatum experienced a negative connection efficiency value, specifically demonstrating that the dorsal striatum activity suppressed the left DLPFC [ 27 ].

Salience network (SN).

Out of the 12 chosen studies, 3 studies specifically looked at the salience network (SN) and 3 studies have observed whole-brain FC. Relative to the DMN and ECN, the findings on the SN were slightly sparser. Despite this, adolescents with IA demonstrated a moderate decrease in FC, as well as other measures like fibre connectivity and cognitive control, when compared to healthy control (see Table 2 and Fig 4 ).

https://doi.org/10.1371/journal.pmen.0000022.g004

Xing et al. (2014) used both dorsal anterior cingulate cortex (dACC) and insula to test FC changes in the SN of adolescents with IA and found decreased structural connectivity in the SN as well as decreased fractional anisotropy (FA) that correlated to behaviour performance in the Stroop colour word-task [ 21 ]. They examined the dACC and insula to determine whether the SN’s disrupted connectivity may be linked to the SN’s disruption of regulation, which would explain the impaired cognitive control seen in adolescents with IA. However, researchers did not find significant FC differences in the SN when compared to the controls [ 21 ]. These results provided evidence for the structural changes in the interconnectivity within SN in adolescents with IA.

Wang et al. (2017) investigated network interactions between the DMN, ECN, SN and reward pathway in IA subjects [ 24 ] (see Fig 5 ), and found 40% reduction of FC between the DMN and specific regions of the SN, such as the insula, in comparison to the controls (p = 0.008) [ 24 ]. The anterior insula and dACC are two areas that are impacted by this altered FC [ 24 ]. This finding supports the idea that IA has similar neurobiological abnormalities with other addictive illnesses, which is in line with a study that discovered disruptive changes in the SN and DMN’s interaction in cocaine addiction [ 38 ]. The insula has also been linked to the intensity of symptoms and has been implicated in the development of IA [ 39 ].

“+” indicates an increase in behaivour; “-”indicates a decrease in behaviour; solid arrows indicate a direct network interaction; and the dotted arrows indicates a reduction in network interaction. This diagram depicts network interactions juxtaposed with engaging in internet related behaviours. Through the neural interactions, the diagram illustrates how the networks inhibit or amplify internet usage and vice versa. Furthermore, it demonstrates how the SN mediates both the DMN and ECN.

https://doi.org/10.1371/journal.pmen.0000022.g005

(2) How is adolescent behaviour and development impacted by functional connectivity changes due to internet addiction?

The findings that IA individuals demonstrate an overall decrease in FC in the DMN is supported by numerous research [ 24 ]. Drug addict populations also exhibited similar decline in FC in the DMN [ 40 ]. The disruption of attentional orientation and self-referential processing for both substance and behavioural addiction was then hypothesised to be caused by DMN anomalies in FC [ 41 ].

In adolescents with IA, decline of FC in the parietal lobule affects visuospatial task-related behaviour [ 22 ], short-term memory [ 42 ], and the ability of controlling attention or restraining motor responses during response inhibition tests [ 42 ]. Cue-induced gaming cravings are influenced by the DMN [ 43 ]. A visual processing area called the praecuneus links gaming cues to internal information [ 22 ]. A meta-analysis found that the posterior cingulate cortex activity of individuals with IA during cue-reactivity tasks was connected with their gaming time [ 44 ], suggesting that excessive gaming may impair DMN function and that individuals with IA exert more cognitive effort to control it. Findings for the behavioural consequences of FC changes in the DMN illustrate its underlying role in regulating impulsivity, self-monitoring, and cognitive control.

Furthermore, Ding et al. (2013) reported an activation of components of the reward pathway, including areas like the nucleus accumbens, praecuneus, SMA, caudate, and thalamus, in connection to the DMN [ 22 ]. The increased FC of the limbic and reward networks have been confirmed to be a major biomarker for IA [ 45 , 46 ]. The increased reinforcement in these networks increases the strength of reward stimuli and makes it more difficult for other networks, namely the ECN, to down-regulate the increased attention [ 29 ] (See Fig 5 ).

Executive control network (ECN).

The numerous IA-affected components in the ECN have a role in a variety of behaviours that are connected to both response inhibition and emotional regulation [ 47 ]. For instance, brain regions like the striatum, which are linked to impulsivity and the reward system, are heavily involved in the act of playing online games [ 47 ]. Online game play activates the striatum, which suppresses the left DLPFC in ECN [ 48 ]. As a result, people with IA may find it difficult to control their want to play online games [ 48 ]. This system thus causes impulsive and protracted gaming conduct, lack of inhibitory control leading to the continued use of internet in an overt manner despite a variety of negative effects, personal distress, and signs of psychological dependence [ 33 ] (See Fig 5 ).

Wang et al. (2017) report that disruptions in cognitive control networks within the ECN are frequently linked to characteristics of substance addiction [ 24 ]. With samples that were addicted to heroin and cocaine, previous studies discovered abnormal FC in the ECN and the PFC [ 49 ]. Electronic gaming is known to promote striatal dopamine release, similar to drug addiction [ 50 ]. According to Drgonova and Walther (2016), it is hypothesised that dopamine could stimulate the reward system of the striatum in the brain, leading to a loss of impulse control and a failure of prefrontal lobe executive inhibitory control [ 51 ]. In the end, IA’s resemblance to drug use disorders may point to vital biomarkers or underlying mechanisms that explain how cognitive control and impulsive behaviour are related.

A task-related fMRI study found that the decrease in FC between the left DLPFC and dorsal striatum was congruent with an increase in impulsivity in adolescents with IA [ 26 ]. The lack of response inhibition from the ECN results in a loss of control over internet usage and a reduced capacity to display goal-directed behaviour [ 33 ]. Previous studies have linked the alteration of the ECN in IA with higher cue reactivity and impaired ability to self-regulate internet specific stimuli [ 52 ].

Salience network (SN)/ other networks.

Xing et al. (2014) investigated the significance of the SN regarding cognitive control in teenagers with IA [ 21 ]. The SN, which is composed of the ACC and insula, has been demonstrated to control dynamic changes in other networks to modify cognitive performance [ 21 ]. The ACC is engaged in conflict monitoring and cognitive control, according to previous neuroimaging research [ 53 ]. The insula is a region that integrates interoceptive states into conscious feelings [ 54 ]. The results from Xing et al. (2014) showed declines in the SN regarding its structural connectivity and fractional anisotropy, even though they did not observe any appreciable change in FC in the IA participants [ 21 ]. Due to the small sample size, the results may have indicated that FC methods are not sensitive enough to detect the significant functional changes [ 21 ]. However, task performance behaviours associated with impaired cognitive control in adolescents with IA were correlated with these findings [ 21 ]. Our comprehension of the SN’s broader function in IA can be enhanced by this relationship.

Research study supports the idea that different psychological issues are caused by the functional reorganisation of expansive brain networks, such that strong association between SN and DMN may provide neurological underpinnings at the system level for the uncontrollable character of internet-using behaviours [ 24 ]. In the study by Wang et al. (2017), the decreased interconnectivity between the SN and DMN, comprising regions such the DLPFC and the insula, suggests that adolescents with IA may struggle to effectively inhibit DMN activity during internally focused processing, leading to poorly managed desires or preoccupations to use the internet [ 24 ] (See Fig 5 ). Subsequently, this may cause a failure to inhibit DMN activity as well as a restriction of ECN functionality [ 55 ]. As a result, the adolescent experiences an increased salience and sensitivity towards internet addicting cues making it difficult to avoid these triggers [ 56 ].

The primary aim of this review was to present a summary of how internet addiction impacts on the functional connectivity of adolescent brain. Subsequently, the influence of IA on the adolescent brain was compartmentalised into three sections: alterations of FC at various brain regions, specific FC relationships, and behavioural/developmental changes. Overall, the specific effects of IA on the adolescent brain were not completely clear, given the variety of FC changes. However, there were overarching behavioural, network and developmental trends that were supported that provided insight on adolescent development.

The first hypothesis that was held about this question was that IA was widespread and would be regionally similar to substance-use and gambling addiction. After conducting a review of the information in the chosen articles, the hypothesis was predictably supported. The regions of the brain affected by IA are widespread and influence multiple networks, mainly DMN, ECN, SN and reward pathway. In the DMN, there was a complex mix of increases and decreases within the network. However, in the ECN, the alterations of FC were more unilaterally decreased, but the findings of SN and reward pathway were not quite clear. Overall, the FC changes within adolescents with IA are very much network specific and lay a solid foundation from which to understand the subsequent behaviour changes that arise from the disorder.

The second hypothesis placed emphasis on the importance of between network interactions and within network interactions in the continuation of IA and the development of its behavioural symptoms. The results from the findings involving the networks, DMN, SN, ECN and reward system, support this hypothesis (see Fig 5 ). Studies confirm the influence of all these neural networks on reward valuation, impulsivity, salience to stimuli, cue reactivity and other changes that alter behaviour towards the internet use. Many of these changes are connected to the inherent nature of the adolescent brain.

There are multiple explanations that underlie the vulnerability of the adolescent brain towards IA related urges. Several of them have to do with the inherent nature and underlying mechanisms of the adolescent brain. Children’s emotional, social, and cognitive capacities grow exponentially during childhood and adolescence [ 57 ]. Early teenagers go through a process called “social reorientation” that is characterised by heightened sensitivity to social cues and peer connections [ 58 ]. Adolescents’ improvements in their social skills coincide with changes in their brains’ anatomical and functional organisation [ 59 ]. Functional hubs exhibit growing connectivity strength [ 60 ], suggesting increased functional integration during development. During this time, the brain’s functional networks change from an anatomically dominant structure to a scattered architecture [ 60 ].

The adolescent brain is very responsive to synaptic reorganisation and experience cues [ 61 ]. As a result, one of the distinguishing traits of the maturation of adolescent brains is the variation in neural network trajectory [ 62 ]. Important weaknesses of the adolescent brain that may explain the neurobiological change brought on by external stimuli are illustrated by features like the functional gaps between networks and the inadequate segregation of networks [ 62 ].

The implications of these findings towards adolescent behaviour are significant. Although the exact changes and mechanisms are not fully clear, the observed changes in functional connectivity have the capacity of influencing several aspects of adolescent development. For example, functional connectivity has been utilised to investigate attachment styles in adolescents [ 63 ]. It was observed that adolescent attachment styles were negatively associated with caudate-prefrontal connectivity, but positively with the putamen-visual area connectivity [ 63 ]. Both named areas were also influenced by the onset of internet addiction, possibly providing a connection between the two. Another study associated neighbourhood/socioeconomic disadvantage with functional connectivity alterations in the DMN and dorsal attention network [ 64 ]. The study also found multivariate brain behaviour relationships between the altered/disadvantaged functional connectivity and mental health and cognition [ 64 ]. This conclusion supports the notion that the functional connectivity alterations observed in IA are associated with specific adolescent behaviours as well as the fact that functional connectivity can be utilised as a platform onto which to compare various neurologic conditions.

Limitations/strengths

There were several limitations that were related to the conduction of the review as well as the data extracted from the articles. Firstly, the study followed a systematic literature review design when analysing the fMRI studies. The data pulled from these imaging studies were namely qualitative and were subject to bias contrasting the quantitative nature of statistical analysis. Components of the study, such as sample sizes, effect sizes, and demographics were not weighted or controlled. The second limitation brought up by a similar review was the lack of a universal consensus of terminology given IA [ 47 ]. Globally, authors writing about this topic use an array of terminology including online gaming addiction, internet addiction, internet gaming disorder, and problematic internet use. Often, authors use multiple terms interchangeably which makes it difficult to depict the subtle similarities and differences between the terms.

Reviewing the explicit limitations in each of the included studies, two major limitations were brought up in many of the articles. One was relating to the cross-sectional nature of the included studies. Due to the inherent qualities of a cross-sectional study, the studies did not provide clear evidence that IA played a causal role towards the development of the adolescent brain. While several biopsychosocial factors mediate these interactions, task-based measures that combine executive functions with imaging results reinforce the assumed connection between the two that is utilised by the papers studying IA. Another limitation regarded the small sample size of the included studies, which averaged to around 20 participants. The small sample size can influence the generalisation of the results as well as the effectiveness of statistical analyses. Ultimately, both included study specific limitations illustrate the need for future studies to clarify the causal relationship between the alterations of FC and the development of IA.

Another vital limitation was the limited number of studies applying imaging techniques for investigations on IA in adolescents were a uniformly Far East collection of studies. The reason for this was because the studies included in this review were the only fMRI studies that were found that adhered to the strict adolescent age restriction. The adolescent age range given by the WHO (10–19 years old) [ 65 ] was strictly followed. It is important to note that a multitude of studies found in the initial search utilised an older adolescent demographic that was slightly higher than the WHO age range and had a mean age that was outside of the limitations. As a result, the results of this review are biased and based on the 12 studies that met the inclusion and exclusion criteria.

Regarding the global nature of the research, although the journals that the studies were published in were all established western journals, the collection of studies were found to all originate from Asian countries, namely China and Korea. Subsequently, it pulls into question if the results and measures from these studies are generalisable towards a western population. As stated previously, Asian countries have a higher prevalence of IA, which may be the reasoning to why the majority of studies are from there [ 8 ]. However, in an additional search including other age groups, it was found that a high majority of all FC studies on IA were done in Asian countries. Interestingly, western papers studying fMRI FC were primarily focused on gambling and substance-use addiction disorders. The western papers on IA were less focused on fMRI FC but more on other components of IA such as sleep, game-genre, and other non-imaging related factors. This demonstrated an overall lack of western fMRI studies on IA. It is important to note that both western and eastern fMRI studies on IA presented an overall lack on children and adolescents in general.

Despite the several limitations, this review provided a clear reflection on the state of the data. The strengths of the review include the strict inclusion/exclusion criteria that filtered through studies and only included ones that contained a purely adolescent sample. As a result, the information presented in this review was specific to the review’s aims. Given the sparse nature of adolescent specific fMRI studies on the FC changes in IA, this review successfully provided a much-needed niche representation of adolescent specific results. Furthermore, the review provided a thorough functional explanation of the DMN, ECN, SN and reward pathway making it accessible to readers new to the topic.

Future directions and implications

Through the search process of the review, there were more imaging studies focused on older adolescence and adulthood. Furthermore, finding a review that covered a strictly adolescent population, focused on FC changes, and was specifically depicting IA, was proven difficult. Many related reviews, such as Tereshchenko and Kasparov (2019), looked at risk factors related to the biopsychosocial model, but did not tackle specific alterations in specific structural or functional changes in the brain [ 66 ]. Weinstein (2017) found similar structural and functional results as well as the role IA has in altering response inhibition and reward valuation in adolescents with IA [ 47 ]. Overall, the accumulated findings only paint an emerging pattern which aligns with similar substance-use and gambling disorders. Future studies require more specificity in depicting the interactions between neural networks, as well as more literature on adolescent and comorbid populations. One future field of interest is the incorporation of more task-based fMRI data. Advances in resting-state fMRI methods have yet to be reflected or confirmed in task-based fMRI methods [ 62 ]. Due to the fact that network connectivity is shaped by different tasks, it is critical to confirm that the findings of the resting state fMRI studies also apply to the task based ones [ 62 ]. Subsequently, work in this area will confirm if intrinsic connectivity networks function in resting state will function similarly during goal directed behaviour [ 62 ]. An elevated focus on adolescent populations as well as task-based fMRI methodology will help uncover to what extent adolescent network connectivity maturation facilitates behavioural and cognitive development [ 62 ].

A treatment implication is the potential usage of bupropion for the treatment of IA. Bupropion has been previously used to treat patients with gambling disorder and has been effective in decreasing overall gambling behaviour as well as money spent while gambling [ 67 ]. Bae et al. (2018) found a decrease in clinical symptoms of IA in line with a 12-week bupropion treatment [ 31 ]. The study found that bupropion altered the FC of both the DMN and ECN which in turn decreased impulsivity and attentional deficits for the individuals with IA [ 31 ]. Interventions like bupropion illustrate the importance of understanding the fundamental mechanisms that underlie disorders like IA.

The goal for this review was to summarise the current literature on functional connectivity changes in adolescents with internet addiction. The findings answered the primary research questions that were directed at FC alterations within several networks of the adolescent brain and how that influenced their behaviour and development. Overall, the research demonstrated several wide-ranging effects that influenced the DMN, SN, ECN, and reward centres. Additionally, the findings gave ground to important details such as the maturation of the adolescent brain, the high prevalence of Asian originated studies, and the importance of task-based studies in this field. The process of making this review allowed for a thorough understanding IA and adolescent brain interactions.

Given the influx of technology and media in the lives and education of children and adolescents, an increase in prevalence and focus on internet related behavioural changes is imperative towards future children/adolescent mental health. Events such as COVID-19 act to expose the consequences of extended internet usage on the development and lifestyle of specifically young people. While it is important for parents and older generations to be wary of these changes, it is important for them to develop a base understanding of the issue and not dismiss it as an all-bad or all-good scenario. Future research on IA will aim to better understand the causal relationship between IA and psychological symptoms that coincide with it. The current literature regarding functional connectivity changes in adolescents is limited and requires future studies to test with larger sample sizes, comorbid populations, and populations outside Far East Asia.

This review aimed to demonstrate the inner workings of how IA alters the connection between the primary behavioural networks in the adolescent brain. Predictably, the present answers merely paint an unfinished picture that does not necessarily depict internet usage as overwhelmingly positive or negative. Alternatively, the research points towards emerging patterns that can direct individuals on the consequences of certain variables or risk factors. A clearer depiction of the mechanisms of IA would allow physicians to screen and treat the onset of IA more effectively. Clinically, this could be in the form of more streamlined and accurate sessions of CBT or family therapy, targeting key symptoms of IA. Alternatively clinicians could potentially prescribe treatment such as bupropion to target FC in certain regions of the brain. Furthermore, parental education on IA is another possible avenue of prevention from a public health standpoint. Parents who are aware of the early signs and onset of IA will more effectively handle screen time, impulsivity, and minimize the risk factors surrounding IA.

Additionally, an increased attention towards internet related fMRI research is needed in the West, as mentioned previously. Despite cultural differences, Western countries may hold similarities to the eastern countries with a high prevalence of IA, like China and Korea, regarding the implications of the internet and IA. The increasing influence of the internet on the world may contribute to an overall increase in the global prevalence of IA. Nonetheless, the high saturation of eastern studies in this field should be replicated with a Western sample to determine if the same FC alterations occur. A growing interest in internet related research and education within the West will hopefully lead to the knowledge of healthier internet habits and coping strategies among parents with children and adolescents. Furthermore, IA research has the potential to become a crucial proxy for which to study adolescent brain maturation and development.

Supporting information

S1 checklist. prisma checklist..

https://doi.org/10.1371/journal.pmen.0000022.s001

S1 Appendix. Search strategies with all the terms.

https://doi.org/10.1371/journal.pmen.0000022.s002

S1 Data. Article screening records with details of categorized content.

https://doi.org/10.1371/journal.pmen.0000022.s003

Acknowledgments

The authors thank https://www.stockio.com/free-clipart/brain-01 (with attribution to Stockio.com); and https://www.rawpixel.com/image/6442258/png-sticker-vintage for the free images used to create Figs 2 – 4 .

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Millions of Americans need drugs like Ozempic. Will it bankrupt the healthcare system?

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An April 24 letter from Vermont Sen. Bernie Sanders to the CEO of Novo Nordisk began with heartfelt thanks to the Danish drugmaker for inventing Ozempic and Wegovy, two medications poised to improve the health of tens of millions of Americans with obesity and related diseases.

But the senator’s grateful tone faded rapidly.

“As important as these drugs are, they will not do any good for the millions of patients who cannot afford them,” Sanders wrote . “Further, if the prices for these products are not substantially reduced they also have the potential to bankrupt Medicare, Medicaid, and our entire health care system.”

It’s a sentiment that comes up regularly among people who are huge fans of the medications and their close relatives, Eli Lilly’s Mounjaro and Zepbound. All of them work by masquerading as a natural hormone called GLP-1 and tricking the body into slowing digestion and reducing blood sugar.

The medications help patients lose double-digit percentages of their body weight and keep it off — an average of 12.4% in the clinical trial for Wegovy, and an average of 18% at the highest dose in the trial for Zepound. It’s rare for insurance companies to cover GLP-1 drugs for weight loss alone, and Medicare is forbidden by law from doing so. But as the pounds fall, so do the risks of serious problems like type 2 diabetes , hypertension , heart attacks and strokes , and the medications can be covered to prevent these conditions.

“Obesity is a huge public health crisis, and for so long we had no treatments that really made a difference,” said Dr. Lauren Eberly , a cardiologist and health services researcher at the University of Pennsylvania. “These medicines could change the trajectory of your disease and save your life.”

That makes these drugs extremely valuable. Unfortunately, they’re also extremely expensive.

The sticker price for Ozempic , which the Food and Drug Administration approved to treat type 2 diabetes, is more than $12,600 per year. Wegovy , a higher-dose version approved for weight loss in people with obesity and as a way for overweight patients with cardiovascular disease to reduce their risk of heart attack and stroke, retails for nearly $17,600 a year.

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Ozempic and other drugs raised the possibility of reversing the country’s obesity crisis. Doctors are frustrated that they’ve made health disparities worse.

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Mounjaro and Zepbound mimic GLP-1 as well as a related hormone called glucose-dependent insulinotropic peptide, or GIP . Their list prices add up to roughly $13,900 per year for Mounjaro, which is approved as a diabetes treatment, and about $13,800 per year for Zepbound, the weight-loss version .

Eberly said those prices are simply too high.

“We as a public health medical community — and the community at large — really need to advocate for increased affordability,” she said. “I think we’re overdue for a real reckoning on this.”

In the United States, the tab for these GLP-1 drugs is exorbitant almost any way you look at it.

In 2022, the prescription drug that accounted for the biggest share of Medicare Part D spending was the blood thinner Eliquis . More than 3.5 million beneficiaries used it that year, at a cost of $15.2 billion , the U.S. Department of Health and Human Services says.

That total was more than double the amount spent on the next-costliest drug, the type 2 diabetes medication Trulicity , according to the Centers for Medicare and Medicaid Services, or CMS.

But $15.2 billion is practically a rounding error compared to the $268-billion price tag if Wegovy were to be provided to all 19.7 million Medicare beneficiaries with obesity, researchers estimated in the New England Journal of Medicine.

Even if the drug were prescribed only to Medicare patients with a clinical diagnosis of obesity, the cost would exceed $135 billion. That’s more than the $130 billion Medicare spent on all retail prescription drugs in 2022, according to CMS.

“This is a real budgetary situation for CMS,” said Melissa Barber , a public health economist who studies pharmaceutical policy at Yale School of Medicine. “They’re going to have to deal with this.”

No matter how expensive a drug, it’s “extremely unlikely” that Medicare would actually go bankrupt, a CMS spokesperson said. Spending for the Medicare Part B and Part D programs is reset every year, and if it goes up, beneficiaries and the government share the burden of covering the difference, the spokesperson said.

Sanders offered another perspective. A report released this month by the Senate Health, Education, Labor, and Pensions Committee, which he chairs, noted that Americans get charged $1,349 for a 28-day supply of Wegovy, while the same amount of the medication goes for $186 in Denmark, $137 in Germany and $92 in the United Kingdom.

“The prices for these drugs are so high in the United States that everyone — regardless of whether they use the products or not — will likely be forced to bear the burden of Novo Nordisk’s profit maximizing strategy through higher insurance premiums and taxes,” Sanders wrote in his letter to the company.

The financial impact on Medicare is tempered by a 2003 federal law that prevents the government health insurance program from covering weight-loss medications.The drugs can be added to formularies if prescribed for another “medically accepted indication,” such as to treat type 2 diabetes or reduce heart risk, but patients can’t get it if their only medical issue is obesity .

Rep. Brad Wenstrup (R-Ohio) has introduced a bill that would reverse that 2003 ban. Though the Treat and Reduce Obesity Act has 97 co-sponsors from both sides of the aisle, its financial implications have made it difficult to muster the votes needed for the legislation to advance, he said.

Indeed, Phillip Swagel , director of the Congressional Budget Office, said last month that if the goal was to provide weight-loss drugs without increasing the deficit, their net cost would need to fall by a factor of 10 just to “get in the ballpark.”

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Dr. Caroline Apovian , co-director of the Center for Weight Management and Wellness at Brigham and Women’s Hospital in Boston, is concerned that the budget-busting potential of Wegovy and Zepbound has made private health insurers too scared to cover them.

“No insurance company is going to be able to afford to give these lifesaving drugs to the 42% of Americans with obesity,” she said. “So we have to do something.”

Exactly what that something should be is not clear.

One possibility is for the federal government to ask Novo Nordisk and Eli Lilly to discount their GLP-1 drugs. The Inflation Reduction Act empowers Medicare to negotiate lower prices for 10 medicines each year, and researchers in the Congressional Budget Office expect at least some GLP-1s to make the list “within the next few years.”

Private insurers are free to seek deals of their own, and the similarities between the Novo Nordisk and Eli Lilly drugs give insurers quite a lot of bargaining power, said John Cawley , a health economist at Cornell.

“They should be more effective at playing them off each other,” Cawley said. “They can say, ‘We’re only going to cover one of these. Which do you want to be, the one we cover or the one we don’t?’”

There’s reason to think the drugmakers could afford to offer significant discounts if they were so inclined.

Novo Nordisk charges Americans $968.52 for a 28-day supply of Ozempic, regardless of whether the dose of the active ingredient semaglutide is 0.5, 1 or 2 milligrams per injectable pen. Likewise, Wegovy is priced at $1,349.02 every 28 days, no matter whether the weekly injections contain 0.25, 0.5, 1, 1.7 or 2.4 mg of semaglutide.

Yet a 2022 report in the journal Obesity estimated that a 2.4-mg weekly dose of semaglutide could be made for “about $40” a month.

Barber is part of a team that also examined what it would cost to produce various diabetes drugs using methods designed to keep prices low. Her group calculated that a 30-day supply of an injectable medicine with 0.77 milligrams of semaglutide could be manufactured for as little as 89 cents, a total that includes a 10% profit. Even with higher costs and a 50% profit, the drug could be made for $4.73 a month, the team reported in March in JAMA Network Open.

“They could be very affordable,” Barber said.

A spokeswoman for Novo Nordisk said the company was “unaware of the analysis” used in the study, but it recognizes the need to find ways to make its products more affordable. She also said the company is reviewing the report from Sanders’ Senate committee and noted that “75% of our gross US sales goes to rebates and discounts reimbursed to insurance companies and other payers.”

Representatives from Eli Lilly did not comment on the cost of its drugs.

If manufacturers don’t agree to reduce prices voluntarily, the federal government could take more forceful steps. The Inflation Reduction Act put a $35-a-month limit on what seniors with Medicare Part D plans need to pay for insulin. Congress could set a limit on GLP-1 drug prices too, though that would be “a last resort,” said Lawrence Gostin , an authority on public health law at Georgetown University.

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Rationing the drugs is another way to keep spending in check, health economists say. High sticker prices have limited access to the drugs, often making income a determining factor in deciding who can take them and who must go without. But there are other ways to prioritize patients.

A person with a “healthy weight” — defined as a body mass index between 18.5 and 24.9 — incurs about $2,780 a year in healthcare costs, on average. That figure rises by $2,781 for a person with a BMI of 30 or above , according to the 2024 edition of “The Handbook of Obesity.”

Most of those added costs are concentrated among people at the higher end of the BMI curve. Someone with a BMI between 35 and 39.9 requires $3,336 in additional health spending per year, on average, while a person with a BMI of 40 or above needs an extra $6,493 in medical care.

“If your goal is to target interventions in order to reduce healthcare spending, you’d want to target it to people with more extreme or morbid obesity,” said Cawley, who co-wrote the handbook’s chapter on obesity’s economic toll.

Even if all else fails, prices are bound to fall over a period of years as new drugs win FDA approval and make the market more competitive, economists said. And once generic versions become available, prices will plummet. That’s what happened with pricey medications for hepatitis C and HIV .

“Eventually things become generic,” Wenstrup said. “They still do the same thing but it costs less.”

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Karen Kaplan covers science and medical research for the Los Angeles Times. She has been a member of the science team since 2005, including 13 years as an editor. Her first decade at The Times was spent covering technology in the Business section as both a reporter and editor. She grew up in San Diego and is a graduate of MIT and Columbia University.

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