Introduction

“I was neither able to sleep, nor was I able to move out. Many don’t take these medications because of this fear only. ” This was from an unnamed 40-year-old rural male patient from Nagpur, India, who reported adverse drug effects as a barrier for treatment adherence.

“I felt like I was going up and down; I could not sleep the whole night. Taking 12-13 pills was impossible for me… I am already weak, even when you utter my name of taking medicine, my head starts cracking. ”

This was from another rural male patient, but this time 28 years of age, who also mentioned that the side effects were exacerbated due to the quantity of pills and consistency of time required to complete treatment, another key factor as to why long treatment fails.

The above quotes represent rural patients’ experiences with multidrug-resistant tuberculosis and its health effects (Deshmukh, Dhande, et. al, 2015). This came from a study between 2012 and 2013, in the Nagpur Drug Resistant TB Centre, a drug resistant tuberculosis center in India, where patients were randomly chosen to describe their feelings after an intensive drug prescription session after they had been diagnosed with multidrug-resistant tuberculosis, one of the most dangerous infectious diseases in India right now, if not the most dangerous, according to the CDC as of 2024. Patients have had difficulty adhering to treatments and consistently upholding their regimens due to many reasons; it could all be too much for them and draining their energy or they could have a mental stigma against these medications. All of these will be discussed later in the paper. But first, we must learn more about the disease of multidrug-resistant tuberculosis, which is lately causing a lot of problems for patients in India across both urban and rural settings in terms of upheavals of social dynamics and biomedical issues.

Multidrug-resistant tuberculosis (MDR-TB), or rifampicin-resistant tuberculosis (RR-TB) is a major, increasingly dangerous, and virulent infectious disease in today ’ s world. Harboring much of the same symptoms of regular tuberculosis, including fever, chest pain, general weakness, cough, and sputum production, MDR-TB is a more dangerous and form of TB, showing large amounts of resistance to major drug classes and products including rifampicin and isoniazid, both commonly used and powerful first-line drugs to treat TB that are now obsolete to treat MDR-TB. This drug resistance is, from the biomedical perspective, caused by increasing numbers of efflux pumps in MDR-TB cells that pump out antibiotic drugs intended to kill the pathogen and more enzymes that inactivate drugs like rifampicin and isoniazid. As a result, the pathogen becomes more potentially fatal considering there are less options for medical professionals to successfully treat the disease as time goes on.

Discovered in 2012 in a Mumbai hospital, the impacts of MDR-TB have gotten worse for a long period of time, mainly explained by the fact that India continues to have 26% of global TB cases as of 2023 (Mandal, Rao, Joshi, et al.). It has become a public health crisis , as this 26% involves 8.2 million people diagnosed with tuberculosis, 1.23 million of those people dying that year.

However, much of the current medical community overlooks the important sociocultural and socioeconomic factors that play a role in exacerbating the MDR-TB situation in India. In culturally-diverse areas with different ways of living and interpreting the world, disparities are bound to occur in terms of medical treatments and how the government and politicians make relevant policies or participate in corruption with regards to MDR-TB regulation and management. These disparities is a main point of focus for medical anthropologists, who use them to explore the historical, sociocultural, socioeconomic, political, economic, and biomedical discrepancies that set the stage for the current crisis of MDR-TB.

The pathogen’ s history of interventions and attempts at treatments, ranging from physical sanatoria to increasing reliance of pharmaceutical drugs after much biomedical research, paints a picture of how global research, beliefs, and actions taken to address tuberculosis has grown over time, especially considering different perspectives and treatment theories that have sprouted throughout history. In addition, socioeconomic disparities, which tend to be highlighted in a densely-populated developing country like India where even an 11.9% poverty rate (as of 2021) is large due to being the most populated nation (as of April 2023), run rampant, consisting of radical differences and discrimination in opportunities for personal and professional development between urban and rural areas (Forbes India, 2024). As will be discussed later, political pressure and corruption is also there to sometimes curb honest data and initiatives being passed, while pharmaceuticalization has grown to be an integral part of India ’ s GDP and overall economic policy.

Integral to the sociological analysis of the TB crisis is the phenomenon of medicalization, a process in which a certain health problem (whether it has to do with psychological, mental, or cultural illnesses) is transformed into a medical problem, where medication and mainstream medicine picks up treatment of this particular illness. In many cases, medicalization can be of benefit to certain sufferers; utilizing prescription drugs and treatments for psychological conditions like schizophrenia and depression has led to success in treating, controlling, and sometimes curing these illnesses. However, most cases of medicalization in other countries (especially developing countries) have actually caused more harm than benefit, often straying the focus away from the ever-important cultural and sociological impacts and influences of disease (Lantz, Goldberg, Gollust, 2023). Therefore, this paper focuses on the classic examples of medicalization in the context of tuberculosis in India, and how that has inadvertently led to its rising drug resistance.

The late sociologist Peter Conrad found that society is now witnessing the “ shifting engines of medicalization, ” explaining how the agents and factors causing medicalization are now shifting away from medical professionals to entities like the pharmaceutical and biotech industries, propelled by consumer demand and commercial influence. The boom in pharmaceutical drugs and treatments via the multiple microbusinesses and private local health practitioners, providing the bulk of Indian healthcare, add further fuel to current medicalization and drug resistance.

This recent emphasis on medicalization also brings forth another aspect into the issue: sociocultural factors. A culturally rich and diverse nation like India harbors multiple cultural beliefs, customs, and practices relating to the health of their various regional populations. Regional cultures, before the arrival of modern medicine and thought, have tended to view disease, especially tuberculosis, in ways that focused more on the social determinants of health rather than the biomedical ones. As we have seen modern medicine and the current global public health system essentially flip the script on this initial approach, community interactions between the old and new will be integral to developing and understanding holistic approaches towards tackling disease.

Historical

Tuberculosis, let alone MDR-TB, has had a long, complex history. Formally discovered in 1882 by Dr. Robert Koch, tuberculosis had been killing “ one in every seven people in the United States and Europe [at the time], ” according to the CDC. However, TB has existed for thousands of years, even showing up in India through ancient medical records and artifacts. During the early 1900s, India largely used sanatoria (isolated medical facilities focusing on good hygiene and care barring antibiotics) to treat tuberculosis, with varying degrees of success. In 1917, the first TB dispensary–a hub for testing and TB treatment–was opened in Bombay, while the first official national study on TB was conducted in 1914 by Arthur Lankester (Central TB Division, 2025 ).

The introduction of allopathic medicine from Europe to colonized nations like India initiated a focus among doctors in India on the biomedical theories and findings of Dr. Koch. Nevertheless, there were a few dissenters who were more keen in delving into alternative theories about the true causes of tuberculosis.

One of these dissenters was David Chowry-Muthu, a T amil Christian doctor specializing in TB. Apart from setting up the first sanatorium hospital in India in 1928, he is also known for challenging the then-largely-accepted bacterial theory of disease causation to instead emphasize the role of environmental factors like poor living conditions and personal well-being in the reduction of illness while avoiding the excessive inclusion of antibiotics. He outlined this stance in his 1921 book Pulmonary Tuberculosis: Its Etiology and Treatment, also proposing reductions in military expenditures to prevent war-related illnesses and investment in urban planning, economic reforms, and improvement in living standards. Even prominent Indian leaders like Jawaharlal Nehru (the first Prime Minister of India) and Mahatma Gandhi (who spearheaded the Indian independence movement), concurred, discussing environmental factors and familial experiences with TB that supported Chowry-Muthu ’ s theory; Nehru used his experience of his wife ’ s struggle with TB to stress the need for more adequate hospital resources while Gandhi emphasized public health and environmental factors like water and air quality, cleanliness, and sanitation as key players in reducing TB’ s spread.

However, Chowry-Muthu ’ s claims could not gain traction mainly due to the Madras Study done in 1950. This study demonstrated that home-based antibiotic treatment was effective in managing TB. It also initiated a rise in randomized controlled trials (RCTs) as a gold standard to determine treatment efficacy, leading to more critical views of prior treatment methods.

This larger emphasis on patient autonomy in health and medication decisions synthesized the foundation for the current state of the Indian pharmaceutical industry, which controls the means of production, ownership, and transfer of drugs and treatments for prominent diseases in India. This also includes tuberculosis, and the increasing emphasis on stronger antibiotic drug regimens. It also led to the emergence of the TB Association of India in 1939, and later the National TB Control Programme in 1962-1963 (now the Revised National TB Control Program to address disparities and deficiencies in the original program).

However, this social and medical shift also spelled problems for the control of TB in India. It opened the possibilities for usual patient non-adherence to treatments (due to indiscipline or insufficient resources and education), drug resistance, and major anxiety about the recency of treatments and their efficacies. The initially popular Bacillus-Calmette-Guerin vaccine for TB became ineffective in 1979, while the spread of human immunodeficiency virus (HIV) in India in 1984 and development of drug resistant strains of TB in 1992 spelled further trouble for those suffering from TB symptoms.These expose the deep sociocultural barriers and disparities present in various Indian communities, which exacerbate the toll TB is taking on the Indian populace with regards to the rampant antimicrobial resistance.

Sociocultural

Arguably the largest factor about the current spread of MDR-TB in India is the influence of sociocultural factors. This is true to a capacity for essentially any disease, but this has been recognized by the current medical community mainly for diseases relating to mental health and wellness, while these same factors that apply to infectious diseases with physical symptoms have been overlooked by much of this mainstream medical community, which tends to focus mostly on the biomedical aspect of these diseases. In the case of tuberculosis, even with all of its physical symptoms like coughing, sputum production, and fatigue, there are extensive cultural habits, beliefs, and practices especially prevalent in India that can be attributed to the exacerbation of certain virulence factors and creating perfect environments for maximum infection and worsening of symptoms.

The rampant medicalization in the modern world, comprised of larger focuses on biomedical aspects without consideration of sociocultural, economic, and other external factors, has led to large cultural shifts in India especially, with more urban participation in biomedical treatment regimens like Direct Observation Therapy, Short-Course (DOTS) being a largely popular treatment option. This treatment option involves regular supervision of TB patients from medical professionals (mainly to ensure treatment adherence) as they take complex doses of specific medications as a multidrug treatment, common among patients whose TB strains have gained resistance. The degree to which these kinds of programs succeed in India vary strongly by unique state funding and political support, but over the years, DOTS has become the main option for a lot of Indian citizens, with over 12 million TB patients using DOTS since the program’ s inception. However, to understand the true sociocultural and anthropological concepts underlying these issues, we need to go over some basic theories.

The concepts of illness and disease, while sounding similar, are defined differently in the medical anthropology field. Illness describes a patient’ s sociocultural experience of disrupted health, characterized by physical symptoms (like a fever or sore throat), or psychological symptoms (like missing out on a vacation with friends), meaning that illnesses are not confined in only the mental, psychological, or physical space. For example, the flu, a disease caused by the influenza virus, portrays these same aspects; an affected individual has physical symptoms like cold and runny nose as well as psychological and mental symptoms like intrinsic feeling of weariness separate from the physical malaise that the flu is known to cause. However, disease is confined to only physical illnesses and biological abnormalities, like a viral infection. It is the illness which can validly have real consequences and effects on both social dynamics and biological health, while the term “disease ” can really only be utilized to describe an ailment with physical symptoms. It is the misuse and misinformation, along with potential for social manipulation, of the definitions of these two terms that set the foundation for the underlying sociological dynamics surrounding India ’ s public health and tuberculosis situation.

Especially in the case of India, social norms and cultural practices often exacerbate and amplify this stigma and these negative social dynamics. In multiple communities, cultural dynamics and disparities continue to alienate TB patients even with current efforts by the government to reduce the incidence of TB. While the government may be dealing with the physical, biological problem of tuberculosis, not much is being done to address its persistent social impacts. Cultural beliefs and practices of citizens

According to a health care providers handbook developed by the Montgomery County Office of Community Partnerships and the Asian Pacific American Advisory Group in Montgomery County, Maryland, multiple considerations into religious, cultural, and ethnic beliefs must be taken in healthcare settings. Some cultural beliefs listed include a steadfast belief in cleanliness and bathing, higher power granted to elders of families for decision-making, occasional reliance on traditional home remedies based in Ayurvedic medicine, and a severe aversion to cow and pig materials due to religious reasons.

Though this pamphlet describes appropriate treatment strategies and ways to approach the health of Hindu patients, this applies fairly well to Indian Hindu citizens due to having the same foundational beliefs, practices, and worldviews (Queensland Health Multicultural Services, 2011). However, whatever is identical in theory may not be identical in social and physical symptoms. Some of these beliefs, including this belief in cleanliness, may not be able to be fully carried out due to inherent vulnerabilities in India surrounding unclean facilities and resources that may make it theoretically impossible to fulfill these things. In many rural communities, taking a bath may constitute bathing and submerging oneself in a holy river or nearby lake, but many of these communities may have unclean water and unsanitary facilities for this activity, resulting in inadvertent bodily contamination in the guise of an important cultural practice and belief in cleanliness.

Ayurvedic medicine, the main native-Indian medical and cultural belief and practice system based on Hindu tenets, is centered around natural materials like herbs, spices, and other plants typically found in South Asian regions, is not a proven legitimate alternative to allopathic medicine, though it shows much promise nonetheless. Due to the uncertainty of value and effectiveness of this medicine, Indian patients, especially older ones, may have a natural preference for Ayurvedic medicine, which could have an impact on the effectiveness of their treatment (if they do ultimately opt for Ayurvedic medicine), or have a psychological impact on the manner in which they utilize allopathic medicine (since they may not fully believe in it).

Most importantly, most Hindu patients view all illnesses as containing a biological, psychological, and spiritual element, often attaching a stigma to mental illness and cognitive dysfunction in particular.

This stigma results in illnesses being considered as karma for misdeeds in a past life, along with the concept of the evil eye (which is usually attributed to being a cause of mental or physical illness). These kinds of stigmas, especially amplified in rural communities, often lead to social ostracization from friend groups and extended families, which can lead to isolation and a real belief of being punished by a religious power.

The nuance doesn’t stop there. While a lack of emphasis on biomedical knowledge could definitely end up badly with social ostracization, medicalization can shake up the entire dynamic. This time, because an illness is related to an actual explainable biological problem, people tend to start avoiding affected individuals and refuse to reach out for social connections or social gathering to help accommodate the individual in the community; essentially, it is an internal exile from society that occurs.

These social conditions and issues are further exacerbated through the specific social dynamics present in care centers and hospitals in both rural and urban India. In fact, doctor-patient dynamics aren’t instrumental to just Indian TB, but to any health condition in any country. And it’ s been mainly due to American medical influence.

For example, Ethan Watters, through his New York Times article The Americanization of Mental Illness, talked about Dr. Sing Lee, a Hong Kong doctor who witnessed the moment when anorexia hit China; before the Western media could describe it, Chinese locals believed that anorexia, like multiple other physical diseases, wasn’t really connected to fat phobia, and not many reports of fat phobia came out initially (Watters, 2010). However, once the local Hong Kong population Western media connected anorexia to fat phobia, the number of reports on fat phobia in Hong Kong skyrocketed (not because there was fat phobia in the first place, but because the perception of individuals ’ health changed due to exertion of social control by the Western media).

This Americanization of illness in general continues to affect Indian tuberculosis, especially through doctor interactions. When an Indian patient visits a doctor from a high-profile medical institute or hospital, the expectation is that prescription medication and biomedical treatments will be given, due to recent Westernization of global medicine. However, the same is not true as to when a patient visits a local clinic or uncertified care provider like a Ayurvedic medicine guru in villages; in this case, patients usually expect local, homely treatments like simple spices, herbs, fruits and vegetables, and more ordinary forms of medicine rather than prescription medication.

The differences don’t stop there. The social dynamics run so deep that even the expectations for quality of care are influenced across backgrounds. Patients may expect allopathic medicine doctors from wealthier, more well-organized areas to be of higher quality, while they may also expect local healers to have less quality health (though they may go to the healer aware of this and ready to take the risk unless they truly believe in alternative forms of medicine). This just goes to show the extent to which the Western world has influenced medicine in India, and it’ s impacting tuberculosis very much.

Often with diseases like tuberculosis, mortality statistics are assumed to be directly related to medical measures and advancements directly taken by national governments to decrease incidence of a particular disease or illness. However, this is not always the case. Around the twentieth century, there was a growing discussion in the scientific community regarding the questionable contribution of medical measures and medical service expansions to a recent decline in mortality rates; this was especially seen with the decline of smallpox in Britain, with people believing that the invention of smallpox inoculation helped eradicate it. While the smallpox inoculation did play a large role in curbing smallpox cases, improvements in environment were also pointed out, mainly by Habakkuk and McKeown, especially focusing on rising standards of living (mainly in diet), hygiene improvements, and a favorable trend in the relationship between microorganisms and their human hosts.

Since 75% of the decline in mortality rates in the 20th century were associated with infectious diseases, there can be three primary influences: medical measures and immunization, reduced exposure, and improved nutrition. In the graph below (citation: McKinlay), this effect has been largely shown between men and women in the US.

Source: Medical Measures and the Decline of Mortality (McKinlay, 2013)

In addition, most of the mortality decline is from a decline in infectious diseases, so medical measures have usually been focused on this instead of other causes of mortality like heart disease, cancer, and other conditions. This further reinforces the fact that medication and biomedical advancements weren’t the chief agents that caused the massive drop in reduction in the 20th century. Especially as can be seen with tuberculosis in the graphs shown below for the nine most common infectious diseases, the first powerful and reliable drug for tuberculosis, isoniazid, came out around 1950, but the mortality rate associated with TB was already decreasing significantly by that time (McKinlay, 2013).

Source: Medical Measures and the Decline of Mortality (McKinlay, 2013)

So because these medical measures contributed little to the overall decline in mortality for the US, this data can be extrapolated and generalized for tuberculosis in India as well. There is, in reality, a much larger emphasis on cultural contexts, practices, and beliefs through this concept than biomedical interventions when it comes to tuberculosis rates in India. Therefore, medicalization, by amplifying the need to focus on the biomedical aspect, is indirectly hurting efforts to control tuberculosis long-term while risking to increase resistance to dangerous levels.

This rampant medicalization in the modern world has led to large cultural shifts in India especially, with more urban participation in biomedical treatment regimens like Direct Observation Therapy, Short-Course (DOTS) being a largely popular treatment option, involving regular supervision of TB patients from medical professionals to ensure treatment adherence. The degree to which these kinds of programs succeed in India vary strongly by unique state funding and political support, but over the years, DOTS has become the main option for a lot of Indian citizens, with over 12 million TB patients using DOTS since the program’ s inception.

DOTS has a lot of social nuances to it. The concept, involving supervision and encouragement from medical professionals to take large, consistent regimens of medication to fight TB (the prescriptions grow larger as TB becomes more resistant), may seem theoretically sound, but practically, it’ s more complicated than that. The main complaint with DOTS has been the social connection between the medical provider and patient. If the medical provider is a distinguished health professional or doctor while the patient is a rural patient, there may not be much trust and connection immediately that may guarantee a consistent adherence to the treatment regimen. However, a local healer facilitating the DOTS process may have much more success due to greater familiarity and connection and trust. This, as will be discussed later, can only be achieved through regulation of the private sector, which has so far been a huge missed opportunity for the Indian government.

Socioeconomic and political economy

Just as there are sociocultural disparities and nuances with the way healthcare resources are utilized for tuberculosis treatment, socioeconomic gaps and political influence reign supreme in determining the way the Indian public health system deals with MDR-TB. However, some major economic drivers and players need to be examined to first get a grasp on the scope of the issue at hand.

As discussed earlier, the newfound citizen medical and health autonomy has come in recent times with a stronger pharmaceutical sector. The Indian pharmaceutical sector is one of the most popular and sought-after markets in the world, and it’ s very easy to see why it’ s called the “Pharmacy of the World” . With over 10,500 manufacturing facilities, this sector, the 3rd largest (by volume) and 14th largest (by value) global provider of generic drugs, is mainly used for aspects of global medicine like affordable vaccines and treatments; this has been so well done that India is known for giving low-cost, high-quality medicines to its citizens and to other countries receiving Indian imports. This cost efficiency and innovation has greatly enhanced India ’ s GDP and improved healthcare outcomes for diseases like tuberculosis.

According to the Indian Brand Equity Foundation (IBEF), as of 2024, the Indian pharmaceutical market was worth 65 billion USD and is expected to reach a valuation of 130 billion USD by 2030 and a valuation of 450 billion USD by 2047. In addition, India has the largest number of USFDA-compliant pharmaceutical plants outside the US, along with over 2,000 World Health Organization Good Manufacturing Practices (WHO-GMP) approved facilities with more than 10,500 facilities in more than 150 countries. These statistics continue to show the sheer dominance, reliability, and influence India holds in the global pharmaceutical market. This ultimately has many effects towards the national economy.

According to the International Monetary Fund (IMF) DataMapper and other recent data from the Indian government, the Drugs and Pharmaceuticals Industry has a large 1.72% contribution to the national GDP (Make in India, 2025). In addition, a trade surplus (meaning more pharmaceutical goods have been exported rather than imported, which increases GDP contribution) has also been maintained since 2010, with an annual trade surplus of about $13.10 billion USD in the 2018-2019 year range. The industry has also received a cumulative FDI (foreign direct investment) of about $16.5 billion USD from April 2000 to March 2020, showing its appeal and potential for further outside investment. Distribution of drugs via the pharmaceutical sector is achieved through multiple health care centers and health-based microbusinesses, mainly prevalent in multiple population-dense areas and making up nearly 30% of India ’ s GDP (Aftab, 2024).

The scope and grandeur of the Indian pharmaceutical industry has so far been conveyed with the above economic statistics and information. However, with a densely populated country like India, problems and socioeconomic disparities are bound to occur with how the pharmaceutical sector transfers and communicates health information and medication to the public, with both urban and rural areas having numerous issues regarding this.

When it comes to the quality of healers, it was already mentioned earlier that perceived higher quality healers, which tend to be more professional healthcare providers from the biomedical sector, are seen more favorably by the expectations of patients than perceived lower quality local healers. In addition to this, as may be obvious, these higher quality healers tend to be more expensive and may be inaccessible to poorer individuals (of which there are many in rural areas), while lower quality healers may be the first choice due to cost efficiency. However, this relationship between quality of care and socioeconomic standing greatly widens the wealth and health gap, as poorer individuals tend to have worse health outcomes with TB than wealthy individuals, all because of class differences between local healers and more high-profile health professionals in relatively large hospitals.

This can also be seen with DOTS, as it was already mentioned earlier that DOTS tends to be more successful if trust and connection is there between patient and health provider; this tends to be truer if a wealthy patient connects with a health professional while a poor patient might connect better with a local healer (again, there will be a difference in quality of care if this occurs, and it may not look good). Therefore, it can be said that higher quality DOTS is more available and viable to individuals in high socioeconomic standing and quality of living, while the opposite is true for lower socioeconomic standing, which may not get proper DOTS treatment from local healers, especially considering the lack of governmental regulation of the private sector of health.

The simple solution to this, one could say, is to meaningfully expand higher quality DOTS care, medication, and health resources to poorer parts of the country. However, an expansion of care, testing units and areas, treatments, and appropriate medical expertise to more rural areas of India while keeping consistency of good quality is incredibly difficult and costly; this is especially true for India, the world’ s most populated nation. Costs for the Central TB Division, the main governmental department dealing with the control and reduction of tuberculosis cases through the National Tuberculosis Elimination Programme (NTEP), have risen from $76 million USD from 2016 to nearly $2.5 billion USD, reflecting India ’ s promise to eradicate tuberculosis by 2025, but this still continues to fall short of their goal of a 2.5% GDP budget allocation, though this may change in the coming years. Additionally, the possibility of false data reporting, internal corruption, and underrepresentation among numerous regions threatens to derail these seemingly promising statistics. Just the baseline upscaling, without even factoring in DOTS and medical private sector regulation, is already costly and not meeting its GDP allocation goals so far, showing that if India wants to upscale its TB testing and treatment centers without sacrificing quality, a shift in the baseline system is necessary.

Biomedical/Biological/Biochemical

Multidrug-resistant tuberculosis (MDR-TB), harboring much of the same symptoms of regular tuberculosis, including fever, chest pain, general weakness, cough, and sputum production, is a more dangerous form of TB, showing large amounts of resistance to major drug classes and products including rifampicin and isoniazid, both commonly used and powerful first-line drugs to treat TB that are now obsolete to treat MDR-TB. This drug resistance, as mentioned earlier in the introduction, is caused by increasing numbers of efflux pumps in MDR-TB cells that pump out antibiotic drugs intended to kill the pathogen and more enzymes that inactivate drugs like rifampicin and isoniazid. As already discussed, patient and sole care-related factors that may exacerbate antimicrobial resistance include inappropriate use of TB drugs and formulations along with premature treatment interruption, causing drug resistance.

Currently, multiple prescription drugs that can treat multidrug-resistant tuberculosis now are in good supply, although the pathogen can threaten these drugs too if resistance goes unchecked into the future. These include second-line drugs like levofloxacin, moxifloxacin (both of which are fluoroquinolones), and combination regimens that include drugs like moxifloxacin, clofazimine, and ethambutol, among others. These combination regimens are commonly used in Direct Observation Therapy Short-Course (earlier described as DOTS), which has had growing global success but still suffers the risk of patient indiscipline and misinformation. This risk, while negligible in the first few decades since antibiotics were introduced to treat tuberculosis due to their great strength, has now become relatively larger, making those same antibiotics powerless against modern infections. Due to this growing resistance, it is imperative for affected nations to focus on widespread access for testing and treatments; in India specifically, as will be discussed in a later section in more detail, the Central TB Division is now hoping to do this.

The actual process of drug resistance is quite complex. Tuberculosis drug resistance occurs when the bacteria that cause TB, Mycobacterium tuberculosis, develop mutations (or are transferred genetic material from other bacteria with resistance genes) that allow them to survive despite the use of anti-TB drugs. These mutations usually become a problem when treatment is not properly followed, as already discussed. For example, mutations in the katG or inhA genes make the bacteria resistant to isoniazid, while mutations in the rpoB gene cause resistance to rifampin, both of which are the top-line drugs to treat tuberculosis. When the bacteria become resistant to both, the condition is called multidrug-resistant TB (MDR-TB). If resistance extends to second-line drugs like fluoroquinolones or injectables, it is called extensively drug-resistant TB (XDR-TB). If the process goes even further and the TB pathogen somehow becomes resistant to all drugs (meaning it is practically impossible to treat with medication), it is called pan-drug-resistant TB (PDR-TB); while there haven’t been much cases of PDR-TB yet, it still remains a looming fear on the horizon should the global public health system continue to neglect drug resistance.

To combat these threats of multidrug-resistance and extensive drug resistance, global public health systems and the modern medical community are focusing a lot on biomedical treatments like novel drug development, new drug therapies, possible applications of immunotherapy, and more. This emphasis on medical conditions, while important, has also come at the expense of neglecting relevant external issues relating to regional cultures, socioeconomic disparities, and other topics that are listed in this paper. While biomedical treatments have been emphasized (especially in India, where , there has been a relatively lack of concern for these conditions, which may include poor living conditions, unsanitary resources (water, food, air), lack of sanitary protocol in everyday life (for example, lack of handwashing), and even certain cultural practices and beliefs that may inadvertently cause this (as was already discussed in a previous section).

Over time, Indian biomedical treatments themselves have changed in efficacy towards treating TB (Ministry of Health and Family Welfare; Govt. of India, 2022). Mass Bacillus-Calmette-Guerin (BCG) vaccine campaigns started in India in 1951, but soon proved ineffective in the 1990s, especially against TB strains in India that had grown more resistant and more strongly attacked the lungs of the victim. Shortly after these campaigns, there was a notable shift towards home-based chemotherapy, employing many of the same drugs that are used today to treat tuberculosis; however, access to these drugs varied in the initial days, and access only got strengthened following the rapid growth of India ’ s pharmaceutical market, which was discussed earlier. The treatments and testing methods for TB, while advanced, are relatively costly and hard to implement; a regular DOTS regimen

As mentioned earlier in the introduction, MDR-TB has proven to be a huge problem over the past few years for the country ’ s public health. The impacts have gotten worse since its discovery in 2012 in a Mumbai hospital, explained by the fact that India continues to have 26% of global TB cases as of 2023 according to the National Institutes of Health (NIH). It has become a public health crisis , as this 26% involves 8.2 million people diagnosed with tuberculosis, 1.23 million of those people dying that year (Mandal, Rao, Joshi, 2023).

While this discussion on the biological and social issues and influential factors related to the current case of MDR-TB has been far-reaching, these factors tend to be caused by underlying flaws in global health systems.

Systemic Flaws

A large part of these discrepancies in healthcare, treatment, and true betterment of the afflicted when it comes to MDR-TB in India is due to the underlying public health system of India. There are multiple flaws with the Indian healthcare system when it started to handle the tuberculosis (and later the rising resistance of later strains), and a lot of it has to do with the main government department tasked with controlling the spread of TB: the Central TB Division, carrying out the the National Tuberculosis Elimination Programme (formerly called the Revised National Tuberculosis Control Programme).

The emphasis in this program largely paints MDR-TB as a public problem, which it essentially is. Usually, the government should ideally ensure public action, not necessarily the individuals, but this may need to change in the future, as the public needs help from experts, advocates, pressure groups, and lobbyists to represent their perspectives and interests (which maybe are not being considered by the Central TB Division currently). This conveys that multiple individual actors in Indian society, while having the potential to influence health policies sociopolitically, are usually experiencing a power imbalance, with higher-status actors having more power to influence unlike lower-status actors like the enormous Indian middle class. Systematically speaking, inclusion of all local groups of actors, including public health practitioners, health planners, policy makers, and patients themselves, might seem impractical from a financial and economic standpoint but it is absolutely necessary for this form of equity to show when constructing a public health system.

Additionally, funding tends to gravitate towards the political and medical interests (which tend to be more high-paying and lucrative), which affect the health decisions the Central TB Division takes. This is especially true in defining TB, exerting medical social control over the concept of the disease. This fascinating social dynamic leads to an interesting clash: should we keep the Central TB Division (basically the government) or the vocal actors (that bring in important perspectives, like private practitioners, non-governmental organizations, and researchers) out of the limelight.

Weak data exists for the TB epidemic, as there was a lack of data from the unregulated and diversified private sector (more on this later). When a large TB epidemic sprouted up in 2013, the government took data on a few hospitals in Gujarat and Chennai over the course of a few weeks, hoping to extrapolate and adjust these numbers to represent the whole nation. The data showed 1-3% MDR-TB in Gujarat and Chennai, with 13-17% resistance in previously treated cases. In addition, 3% of TB patients in the Gujarat and Chennai studies are considered to have native MDR-TB (in other words, they had it already when they came into the hospital), while 17% of TB patients were considered to have acquired MDR-TB (meaning they most probably acquired the strain during their hospital stay). This continues to show how drug resistance is especially opportunistic in nosocomial, or hospital-acquired, infections.

Of course, even when assuming that the Central TB Division honestly collected the data as best they could, there are still general epistemological questions to be asked when considering the validity of the data as a whole. For example, mortality statistics may be inadequate; according to sociologist Dr. John B. McKinlay, many conditions may be responsible for deaths (and not just the one that the patient came to the hospital with). In addition, changes in disease classifications and social norms and expectations of health illnesses can also negatively influence these statistics (for example, death by epilepsy might have been perceived as negative spiritual outbursts in an earlier time). However, we should still be able to measure those limitations and hopefully account for them, especially considering these limitations may apply equally to all studies involving mortality stats, especially ones involving TB hospital deaths.

However, critics have a different outlook. Looking at the fishy nature of these numbers and statistics, they feel that the government is not facing up to the problem’ s scope, exaggerating overly optimistic TB data that may give a false sense of security when a 3% nationally-extrapolated rate of MDR-TB, doubting whether the Gujarat and Chennai studies were even representative of the total MDR-TB numbers. In fact, an unnamed microbiologist in these studies mentioned that the government doesn’t like to see high numbers in MDR-TB rates, and therefore the political pressure is on to keep the numbers low (whether it was actually achieved or not). Due to this, most critics are in favor of more rationality and quality of innovations to properly map MDR-TB and bring transparency with the public.

While some of this has already been mentioned in the sociocultural factors section of this paper, multiple drawbacks in the system lead to a lot of discrepancies in the health infrastructure of health facilities like hospitals and clinics. A lot of cases (according to the paper linked at the top of the section) occur due to mismanagement and poor treatment; many times, it ends up being in the hands of the patients, but also can stem from the health professionals in establishments. Central TB Division officers label MDR-TB as a problem created by external factors and the actors themselves (due to lack of regulation and mistreatment at the most direct level, not to mention nonadherent patients). However, critics argue that this is just a narrative pushed by the program to hide its own shortcomings. In reality, this ends up being a little bit of both; while drug pressure does exist with growing strength of TB with each infection and higher malnutrition of a country (making a better “playing ground”).

To add on, DOTS and other standard current TB treatments can also fail if improper direct supervision and little cooperation with the private sector occurs. The private sector, consisting of about 63 million microbusinesses (with over 10,000 of those microbusinesses as recognized health organizations), is probably the most large and far-reaching influential organizational entity in India, across both urban and rural areas (although they do tend to be way more concentrated in urban areas). One issue with the current health system is a noticeable lack of communication and coordination with the private sector, which can lead to many sometimes unscrupulous local healthcare workers deliver improper treatments and drugs to TB patients and may not report proper numbers, distorting the true validity of current data and the effectiveness of the program. If the private sector ends up being regulated by the Central TB Division, multiple local healers and ethnomedical professionals can be held accountable while also having their voices heard on possible holistic treatments, leading to breakthroughs in TB treatment and curbing the rise of resistance.

Conclusion, and Suggestions For the Way Forward

Addressing the growing MDR-TB crisis, in summary, will need a lot more avenues of research and problem-solving than the current steps and solutions being devised to merely keep it at bay. The high emphasis on the biomedical aspects of tuberculosis in India (in general) is unfortunately masking the equally important sociocultural aspects and phenomena that occur with Indian tuberculosis. Therefore, to address these aspects as well, an integrated medical approach is needed; the medical community should not only address the biomedical aspects of tuberculosis, but also take into account the sociocultural and economic aspects which are arguably equally important in vulnerable areas like India.

However, this is easier said than done when trying to scale the full scope of this ambition. However, apart from making necessary changes to the Indian public health system, a great starting point is to build cultural competency and sensitivity with Indian patients, no matter the health professionals ’ qualifications, degree, or amount of knowledge. Respecting the patients ’ perspectives, and smoothly guiding them in the right direction with their cultural beliefs about TB and the appropriate hybrid treatment plans that can combine Ayurvedic medicine and allopathic medicine with alleviations to social conditions, can ultimately result in a more culturally respectful environment in multiple rural and religiously devoted regions that can holistically address TB’ s rising antimicrobial resistance. It can also help break stereotypes commonly associated with the healthcare field, various types of health professionals and treatments, and personal psychological evaluations about one ’ s own health.

In a time when systemic and socioeconomic discrepancies have exacerbated the destructive nature of the recent COVID-19 pandemic in multiple countries, these disparities can serve as a learning moment for India and its Central TB Division to improve their main public health system, mode of testing, cost-effectiveness, reach, and sociocultural sensitivity. Tuberculosis is a curable disease, and yet it is still the most prevalent infectious disease in India to this day; hopefully that changes soon.

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About the author

Akshar Belaguly

Akshar is currently a freshman at Brown University concentrating in Biochemistry and Molecular Biology and wrote the paper while he was a senior at Gretchen Whitney High School in Cerritos, California. Some of his academic interests include biochemistry, genetics, and analytical chemistry, but he also has a deep fascination with medical anthropology that will hopefully give him holistic perspectives in his journey to medical school.

In addition, Akshar has also been part of his school’s Science Olympiad team, loves to watch and play cricket and basketball, and loves to spend time with his family in his free time.

The post The Cultural Influences of Medicalization: How Culture Influences Tuberculosis In India appeared first on Exploratio Journal.

Abstract

Obesity is often misunderstood as a simple matter of overeating or moving too little. In reality, it’s a deeply rooted physiological condition caused by the breakdown of several key systems in the body. This paper examines the development of obesity through five closely interconnected biological mechanisms: fat storage (adiposity), insulin resistance, energy balance, hunger signaling via leptin, and chronic low-grade inflammation. These systems work together to regulate how we store energy, control appetite, burn calories, and respond to stress. When one system begins to fail, like when fat cells grow too large or the brain stops responding to fullness signals, the others often follow, creating a cycle that makes weight gain easier and weight loss harder. The paper also highlights how prevention needs to go far beyond willpower or dieting. Real solutions come from supporting the body’s natural systems through better sleep, balanced eating, physical activity, stress management, and more. Understanding the biology behind obesity helps us replace blame with empathy and find smarter, more lasting ways to support health.

Key terms

Introduction

Obesity is not just a personal struggle; it is a public health crisis that affects over 650 million adults and 124 million children worldwide. Traditional narratives have oversimplified its causes, framing obesity as a result of poor choices, lack of exercise, or overeating. However, such views ignore decades of research that reveal a much deeper truth: obesity is a chronic physiological disorder involving multiple, interdependent systems that govern metabolism, hormonal signaling, energy storage, and immune response.

Rather than a purely behavioral issue, obesity reflects a breakdown in metabolic homeostasis, the body’s ability to maintain internal balance in response to changing environments. At its core, obesity is the result of a persistent imbalance between energy intake and expenditure, complicated by the dysregulation of hormones such as insulin and leptin, altered fat cell function, and chronic low-grade inflammation.

This paper explores the physiological mechanisms that cause obesity and the interventions that can help prevent or reverse it. We focus on five interconnected biological systems:

• Adiposity (fat accumulation and behavior of fat tissue)
• Insulin resistance (metabolic inefficiency and hormonal disruption)
• Energy balance (caloric intake vs. expenditure dynamics)
• Leptin resistance (dysfunctional satiety signaling)
• Inflammation (chronic immune activation affecting metabolism)

By understanding how these systems interact, we can move toward more effective, biologically grounded strategies to prevent obesity not only at the individual level, but across public health, clinical, and policy landscapes.

1. Adiposity: The Biology of Fat Storage

Adiposity is the quantity and distribution of fat, and that fat, as active tissue, is capable of storing excess energy in the form of triglycerides and communicating with the brain and immune system through hormones and messengers such as leptin, adiponectin, and resistin, assists in thermoregulation, and contributes to the body’s response to infections. (Neufingerl and Eilander 2021)

It comes in two primary forms: white adipose tissue (WAT), the primary storage type that also secretes hormones to regulate appetite and guide energy balance, and brown adipose tissue (BAT), rich in mitochondria that burns calories to produce heat through thermogenesis. It is more abundant in infants, and in adults is found in small quantities, which can be activated with safe cold exposure or during some physical activity. Immune cells, such as macrophages, release the inflammatory factors TNF-α and IL-6 while protective adiponectin falls below a certain threshold. This is known as the ‘adipose tissue dysfunction’. This phenomenon lowers the insulin signal and increases the risk for metabolic disease. From a pathobiology perspective, the location of fat tissue is important because subcutaneous fat located just under the skin is usually neutral, sometimes even protective, and visceral fat that envelops the liver, pancreas, and intestines is pathologically active and produces and excretes inflammatory factors and free fatty acids bound for the liver via the portal vein. This visceral fat is associated with type 2 diabetes, heart disease, hypertension, and non-alcoholic fatty liver disease. These behavioral patterns begin at a young age. For example, by performing daily exercise, teens can decrease their fat stores, which improves the functions of the fat cells. These exercise habits, coupled with the intake of healthy unsaturated fatty acids found 5 in nuts, olive oil, and fatty fish, the avoidance of ultra-processed foods, proper hydration that facilitates the lipolytic response, and the application of safe cooling in daily life to invigorate brown fat, shift the ratio of subcutaneous to visceral fat in the desired direction while maintaining the long-term functionality of the adipose tissue. (Guarino et al. 2023)

2. Insulin Resistance: When Cells Stop Listening

Insulin, which is produced in the pancreas, is a hormone that functions as a ‘key’ that enables the cells in the body to absorb blood sugar. Blood sugar (or glucose) comes from the food we eat, and in particular carbohydrates, which serve as energy for anything from the movement of the muscles to activities done in the brain. When blood glucose is well managed in the body, these cells extract the glucose from the blood and either use it for immediate energy or store it for later use. Save this process, other functioning organs in the body would not get energy, and along with that, blood sugar levels would go uncontrolled.

Insulin is like a key that lets sugar from your food into your cells so they can make energy. With insulin resistance, the locks on the cells get sticky. The key still fits, but the door is hard to open. More sugar stays in your blood, so your pancreas sends out extra insulin to try to force it in. Constantly high insulin, called hyperinsulinemia, makes your body store more fat, especially in your belly, and increases the chance of developing type 2 diabetes over time.

When your body stops responding well to insulin, the effects show up everywhere, because your muscles do not pull in sugar for energy and you feel tired or weak after carb-heavy meals, your liver keeps making sugar even when you do not need it and your blood sugar rises, your fat cells get told by high insulin to store more and belly fat often increases, and your brain’s dopamine system can be thrown off so cravings for sweet or fatty foods get stronger and overeating becomes easier. Early signs include feeling wiped out after eating, 6 getting powerful and frequent cravings for sugary or starchy foods, noticing belly fat that does not budge with normal efforts, and sometimes seeing dark, velvety skin patches on the neck or underarms called acanthosis nigricans.

What drives this problem are habits like eating lots of added sugar and refined grains that spike blood sugar and insulin, long periods of sitting that make muscles worse at using sugar, and ongoing stress that raises cortisol and pushes blood sugar up. What helps most are steady changes such as moving every day with walking, biking, swimming, or strength training so muscles listen to insulin better, cutting back on added sugars and refined carbs while eating more fiber from whole grains, vegetables, beans, and lentils to smooth blood sugar, using a consistent daytime eating window of about ten hours if it suits you so insulin can drop between meals, practicing mindfulness, deep breathing, or yoga to lower stress, and protecting sleep so hormones stay in rhythm. The big idea is simple: insulin resistance is usually a response to a long-term mismatch in food, movement, stress, and sleep, so spotting it early in your teens or early twenties and making steady changes can lower your risk of type 2 diabetes later.

Improved lifestyle habits determine levels of insulin resistance. Diets high in added sugars and refined grains cause blood glucose and insulin levels to spike intermittently, leaving your body with no option other than to “tune out” insulin over time. Prolonged periods of physical inactivity result in the muscular system losing the ability to absorb glucose as blood levels of the sugar increase. Chronic stress also adds insult to injury because of the stress hormone, which elevates blood sugar levels and promotes insulin resistance. The positive news here is that gradual changes work. Exercise most days of the week, including low-impact activities: walking, biking, swimming, and weight lifting, to strengthen the ability of muscle tissues to respond to insulin. Avoid added refined sugars and carbs and consume more whole, plant sources of fiber, including whole grains, vegetables, and legumes, to stabilize blood sugar levels. Time-restricted feeding, or an eating schedule with a shorter time of eating around ten 7 hours, works well for some because it promotes a more sustained drop in insulin between meals. Stress is more effectively managed using mindfulness, breathing exercises, and yoga, and sleep quality must be prioritized in order to regulate hormone levels.

By understanding insulin resistance not as a random malfunction but as the body’s response to a sustained imbalance in diet, activity, and stress, we can take proactive steps to restore metabolic health. Early intervention during adolescence or young adulthood can prevent years of progression toward type 2 diabetes and related conditions, making it a vital focus in obesity prevention efforts. (McGlynn et al. 2022)

Figure 1: Insulin resistance is a type of reaction in a person’s body, especially muscle cells, that makes it less responsive to insulin. By having less reactive insulin within the body, normally it would facilitate the amount of glucose consumed to either store it as an energy source, but since it is getting resisted, the cells do not respond correctly to the insulin signal. This leads to a reduced glucose intake and an increased spike in glucose levels.

3. Energy Balance: The Calorie Equation and Beyond

Energy balance is the match between the energy you take in from food and drinks and the energy your body uses for living, moving, and digesting. While it looks like simple math (eat more than you burn to gain, burn more than you eat to lose), your body constantly adapts, so the balance shifts. (Pardo et al. 2021)

Most daily burn comes from basal metabolic rate (BMR), roughly 60–70%, which powers your heart, lungs, brain, and cells even at rest. Physical activity adds a variable share that includes workouts, sports, walking, chores, and small movements like standing and fidgeting (NEAT). Digestion also costs energy via the thermic effect of food (TEF), with protein costing more than carbs or fat. Brown fat can add a small cold-activated boost by turning stored energy into heat. Harsh calorie cuts trigger metabolic adaptation (adaptive thermogenesis) that lowers BMR and, with hormone shifts that raise hunger and reduce fullness, slows loss and promotes regain. Energy imbalance comes in three forms: positive (intake > burn, weight rises), negative (intake < burn, weight falls, but too-large deficits can cause muscle loss, nutrient gaps, and slower metabolism), and neutral (intake ≈ burn, weight holds), and small changes can tip you between them. Long-term balance works best when you support the system rather than obsess over every calorie by building and keeping muscle with resistance training to raise BMR, eating enough protein to protect muscle, increase fullness, and boost TEF, avoiding crash diets that cause large slowdowns, and keeping consistent routines for meals, sleep, and movement. For teens and young adults, habits formed now tend to stick, so favor nutrient-dense foods, daily activity you enjoy, and sustainable patterns, and treat energy balance as a lifelong rhythm rather than a short-term fix to give yourself the best chance at a healthy weight and steady energy. (Kalaitzopoulou et al. 2023)

Figure 2: Energy balance is the amount of calories consumed through food and drink that is equivalent to the amount of calories the body has burned down to equal it out. There are three types of energy balance. A positive energy balance is a state where a person consumes an excessive amount of calories that the body cannot expend. This results in increased adiposity (Obesity) and weight gain. A negative energy balance is the result of taking way too less calories compared to what the body is burning. This will result in weight loss. Lastly, neutral energy balance is the type where the body is equally regulating the amount of calories intake, while the calories are equally burned down. This will lead to weight maintenance.

4. Leptin: The Hunger-Regulating Hormone

Think of leptin as your body’s built-in fuel gauge. It’s a hormone made mostly by your fat cells, and its job is to keep your brain updated on how much energy you have stored. When your body has plenty of fuel, leptin travels through your blood to the hypothalamus, the brain’s control center for hunger, energy, and weight, and delivers a simple message: “We’re good. You can slow down on eating and speed up on burning energy.”

When this system is working as it should, you naturally feel satisfied after eating, your metabolism hums along, and you have the energy and motivation to be active. After a meal, leptin levels rise, telling the brain that your energy needs are met. The brain responds by easing hunger signals and nudging your body to burn a little more. Maybe through movement, maybe through heat production, in a neat feedback loop that helps keep your weight steady without you having to think about it.

When the leptin system breaks, it is called leptin resistance. Leptin levels are high, sometimes very high, but the brain does not “hear” the message. The hunger off-switch feels stuck. Even with plenty of stored energy, the brain acts like fuel is low, so hunger goes up and calorie burn slows down. You can feel hungry soon after eating, and your body holds on to fat. More body fat makes more leptin, which makes the resistance worse, so the cycle repeats. Several forces can throw this system off. Inflammation in the brain, especially in the hypothalamus, can block leptin’s signal. Diets heavy in sugary, ultra-processed, or greasy foods raise oxidative stress, which damages the brain’s appetite pathways. Poor sleep makes it harder too; even one short night can lower leptin, raise ghrelin, and push stronger cravings the next day. Frequent overeating can also numb leptin receptors, the way loud noise can numb hearing.

Leptin affects more than hunger. It interacts with dopamine and serotonin, which shape mood, motivation, and pleasure, so weak leptin signaling can make you feel less driven to move and more likely to eat for comfort. It also affects fertility. If the brain thinks energy is low, it may slow or pause reproductive functions, even when the body has enough fuel. Leptin also links to the thyroid, which sets metabolic speed, so leptin problems often come with a slower metabolism.

The upside is that leptin sensitivity can improve. Getting a solid 8–9 hours of sleep each night helps keep hormone rhythms steady. Regular movement, especially strength training and cardio, reduces brain inflammation and helps leptin signals get through. Omega-3 fats from foods like salmon, walnuts, and flaxseed can also help calm brain inflammation. And avoiding constant snacking, particularly on processed foods, lets leptin rise and fall naturally so your brain has a chance to “hear” it again. (Besci et al. 2023)

Figure 3: Leptin is a peptide hormone made mainly by fat cells, and its blood level reflects total fat stores. Its primary role is to signal the hypothalamus that energy is sufficient, which reduces appetite, adjusts energy expenditure and sympathetic tone, and helps coordinate reproductive, thyroid, and immune functions. In common obesity, leptin levels are high but signaling is blunted (“leptin resistance”), so added leptin seldom causes weight loss, whereas replacement helps in true deficiency and some lipodystrophies. (Kamal-Rahmouni et al. 2002)

5. Inflammation: The Immune System’s Double-Edged Sword

Inflammation is the body’s built-in alarm system. It’s there to protect us when something goes wrong, like when you cut your finger, catch a cold, or sprain your ankle. In those moments, your immune system sends in its “first responders.” The area becomes red, warm, and swollen because immune cells are flooding in to fight off germs, clear away damage, and start the healing process. Once the job is done, the alarm switches off and your body goes back to normal. That’s acute inflammation, and it’s a good thing.

However, sometimes the body’s alarm does not shut off; it stays low and constant for weeks or years, which is called chronic low-grade inflammation, and it quietly damages tissues over time. In obesity, it often starts in fat tissue, where overgrown fat cells get stressed and send out distress signals that call in immune cells called macrophages; these cells release inflammatory chemicals such as TNF-alpha and IL-6 that make cells ignore insulin and handle sugar poorly, and blood tests often show higher C-reactive protein (CRP), a sign that inflammation is active across the body. This slow fire spreads: in the gut it can weaken the lining and let harmful bacteria slip into the bloodstream (leaky gut), in the brain it can disturb the hypothalamus so hunger and fullness signals break down and leptin resistance develops, in the liver it pushes fat buildup that can lead to non-alcoholic fatty liver disease (NAFLD), and in blood vessels it speeds plaque growth, which raises the risk of heart attack and stroke.

What you eat, how much you move, and how you handle stress can all influence inflammation. Diets full of sugary drinks, processed meats, fried foods, and packaged snacks make it worse by increasing oxidative stress, a kind of cellular “rusting” that triggers inflammation. Not moving enough is another problem, because muscles release special anti-inflammatory chemicals when you exercise. High stress levels keep the hormone cortisol elevated, which in turn can push inflammation higher. And when you don’t sleep well, your immune system loses its rhythm, tipping the balance toward more inflammation. (Nagorcka-Smith et al. 2022)

The good news is that you can turn the alarm back down. Eating more anti-inflammatory foods, like berries, leafy greens, olive oil, and fatty fish, gives your body nutrients that help calm the immune system. Fermented foods like yogurt, kefir, or kimchi can feed healthy gut bacteria, which in turn protect against inflammation. Moving your body regularly, even just a brisk 20-minute walk, helps your muscles release anti-inflammatory signals. Learning to manage stress through things like meditation, deep breathing, or simply taking time to relax can lower cortisol levels. And making sleep a priority, aiming for 8 to 9 hours most nights, gives your immune system the time it needs to reset. (Nikooyeh and Neyestani et al. 2021)

Figure 4: In nutrition, inflammation is the body’s immune signaling state as affected by diet and body fat. Acute inflammation helps repair, but chronic low-grade inflammation arises with energy excess and poor food quality, raising markers like hs-CRP, IL-6, and TNF-α and promoting insulin resistance, cardiovascular disease, and fatty liver, while ultra-processed foods, refined carbs, trans fats, and heavy alcohol push inflammation up and whole-food patterns rich in vegetables, fruits, legumes, whole grains, nuts, olive oil, omega-3 fish, and fiber that feeds the gut microbiome tend to bring it down, with weight control, regular activity, sleep, and stress management strengthening the effect.

The Cycle: How All Five Systems Work Together

Obesity isn’t caused by one thing; it’s caused by many things going wrong at once:

These problems feed into each other, making it harder to break the cycle. But the good news is: small changes can help reset the system.

Prevention

You don’t need to be perfect. But supporting your body’s natural systems goes a long way in keeping obesity away.

To support metabolic flexibility, try intermittent fasting to improve insulin and leptin and vary your calorie intake across days through caloric cycling, and if you are under 18 or have a medical condition consult a clinician before fasting; eat anti-inflammatory foods by prioritizing whole, unprocessed meals, colorful fruits and vegetables, and healthy fats such as nuts, seeds, olive oil, and fatty fish instead of fried foods; manage stress with short daily meditation, breathing exercises, or yoga and by journaling or talking with a friend, since chronic stress raises cortisol and can promote belly fat; and align with your body’s clock by eating during daylight hours, sleeping at night, and keeping a consistent bedtime because your hormones follow a daily rhythm that works best on a regular schedule.

Conclusion

Obesity is not a simple choice. It’s not a result of laziness or weakness. It’s a physiological condition caused by complex changes in the body’s systems, especially the way fat is stored, sugar is used, hormones are regulated, and the immune system responds to stress. But that also means obesity can be prevented. Not just with willpower, but with knowledge, consistency, and self-care. When we understand how the body works, we can give it what it needs to function better. Instead of focusing only on weight, we should focus on balance between eating and moving, between sleeping and waking, between stress and rest. That’s the key to helping your body feel strong, energized, and healthy.

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The author utilized an artificial intelligence tool, Google Gemini, and Perplexity to enhance the clarity and readability of the writing. All final content, critical interpretation, and responsibility for accuracy remain solely with the author.

About the author

Ryan Jung

Ryan is currently a junior attending school in Suffield, Connecticut.

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Abstract

Muscle fatigue is a critical physiological condition that limits physical performance and impacts overall health. While commonly experienced during intense activity, the chemical processes driving fatigue are often overlooked. This paper explores the molecular mechanisms underlying muscular exhaustion, including neurotransmitter imbalances, disruptions in energy metabolism, and calcium regulation failures. By examining the complex processes that result in muscle fatigue, such as glycolysis, byproduct accumulation, and E-C coupling, this paper highlights how biochemical changes affect muscle function. Additionally, strategies such as buffering with sodium bicarbonate to delay fatigue offer insight into potential solutions, thereby enhancing performance. This review first outlines the biological processes that affect muscle fatigue before diving into the deeper chemical aspects of it.

Keywords: fatigue, glycolysis, lactic acid, muscle exhaustion, anaerobic, sodium bicarbonate buffers, E-C coupling, calcium regulation

Introduction

Athletes oftentimes experience severe soreness and slow recovery following a high intensity workout, hindering their ability to perform as usual in the following days. The physiological context of this phenomenon, known as muscle fatigue, was first researched by Angelo Mosso in the late 1800s, who demonstrated how while exercise increases endurance and muscular strength, it simultaneously extends fatigue. He was the first to describe the chemical process behind this fatigue, attributing it to toxic substances and acid. In 1891, he eventually published the paper “La Fatica” (Fatigue), which included a formulation of laws that described the causes of exhaustion. Presently, further research has been established to expand on the cellular and molecular mechanism of muscle fatigue and more specific chemical processes than what Mosso explored over a hundred years ago. Muscle fatigue is now defined as the decline in the body’s ability to produce force, and is known to exist as soreness following physical activity or more critically as a result of a chronic condition.

Fatigue and Hyperthermia

Types of Fatigue Muscle

fatigue results from both central and peripheral mechanisms. Central fatigue originates in the central nervous system (CNS) and occurs when the brain’s ability to send signals to the muscles becomes reduced. Peripheral fatigue, on the other hand, originates within the muscle fibres themselves and reflects impairments within the muscle. Fatigue can also be classified as acute, developing from short term exertion, or chronic, persisting over an extended period due to underlying health conditions. Additionally, hyperthermia, which is a state of increased core body temperature, can worsen both types of fatigue by disrupting homeostatic and neurochemical balances. Key neurotransmitters, including serotonin, dopamine, glutamate, and GABA, play significant roles in the development of fatigue during physical activity.

Hyperthermia and its Impact on Fatigue

Central Fatigue and Key Neurotransmitters

One of the most important neurotransmitters involved in the process of central fatigue is serotonin. Serotonin levels increase during exercise due to a rise in free tryptophan, an amino acid that forms serotonin. As fat stores are broken down during exercise, free fatty acids displace tryptophan from the protein albumin, allowing more tryptophan to enter the brain. There, it is converted into serotonin. High levels of serotonin are linked to sensations of lethargy and reduced motor function. This occurs when serotonin binds to specific receptors (such as 5-HT1A) that inhibit muscle activation once they are overstimulated.

Dopamine, another key neurotransmitter, works in opposition to serotonin in many ways. Dopamine is responsible for maintaining motivation and alertness, both of which are essential for continued physical performance. It is made from the amino acid tyrosine and supports sustained motor output. When dopamine levels are low, central fatigue is more likely to occur. However, regular physical training can increase dopamine synthesis and receptor activity, improving an individual’s resistance to fatigue over time.

Glutamate, the brain’s primary excitatory neurotransmitter, also contributes to central fatigue. Normally glutamate levels are tightly controlled by transporter proteins such as GLT-1. However, intense exercise can impair the function of these transporters, allowing glutamate to build up on the outside of nerve cells. This can disrupt communication between neurons and potentially lead to neurotoxic effects. Additionally, glutamate plays a role in the production of lactate by brain cells, which helps supply energy. If glutamate is not properly regulated, it can affect both brain signaling and energy metabolism, further promoting fatigue.

GABA (gamma-aminobutyric acid) is the main inhibitory neurotransmitter in the CNS. During exercise, GABA levels rise, especially in the sensorimotor cortex. This increase is linked to higher blood lactate levels, suggesting a connection between muscle metabolism and brain chemistry. Elevated GABA activity can reduce the brain’s ability to sustain motor output, leading to the perception of fatigue and a decline in performance.

Peripheral Fatigue

Peripheral fatigue occurs when there are changes inside the muscle that interfere with its ability to contract efficiency. These changes often include the buildup of byproducts like H+ ions, inorganic phosphate, and reactive oxygen species, all of which can reduce the effectiveness of muscle contractions. Metabolic acidosis, caused by a drop in pH, weakens the interactions between actin and myosin, the proteins responsible for muscle contraction. At the same time, depletion of stored energy molecules like ATP and glycogen reduce the muscle’s ability to generate force.

Effect of Hyperthermia on Central and Peripheral Fatigue

Hyperthermia acts as a catalyst that intensifies both central and peripheral fatigue by simultaneously disrupting brain and muscle function. When core body temperature rises above approximately 40°C, brain temperature also increases, which can interfere with the hypothalamus and reduce the brain’s ability to send signals to the muscles. This effect on the CNS becomes especially noticeable during prolonged exercise, leading to a drop in endurance and lower motor unit activation. At the same time, hyperthermia stresses the cardiovascular system, as more blood is sent to the skin to release heat. This reduces the amount of blood and oxygen reaching active muscles, pushing them to rely more on anaerobic metabolism. As a result, lactate and H+ ions build up, resulting in peripheral fatigue. Heat also interferes with energy production in muscle cells, making contractions less effective. Together, these effects cause fatigue to set in faster and more severely, especially in hot environments or during physical exercise.

Energy Depletion: Glycolysis

Muscle fatigue is driven by disruptions in ATP availability, particularly when glycolysis becomes the primary energy source during prolonged physical activity. Glycolysis converts glucose to pyruvate, producing ATP rapidly but in limited amounts. As glycogen, the primary substrate for glycolysis, is depleted, ATP synthesis declines, weakening critical energy-dependent processes within the muscle fiber. This process is shown below by Figure 1:

Figure 1: Blood glucose and muscle glycogen provide glucose for glycolysis, producing ATP . With oxygen, pyruvate enters aerobic respiration. Without the presence of oxygen, pyruvate is converted to lactic acid, which enters the bloodstream (Betts et al., 2013)

One of the most affected systems is excitation-contraction (E-C) coupling, which links electrical signals to mechanical contraction. This process relies on ATP to fuel the sarcoplasmic reticulum (SR) Ca2+-ATPase, which pumps calcium back into the SR, and for cross-bridge cycling between actin and myosin, the proteins responsible for muscle contraction. Glycogen stored near the SR, particularly in intermyofibrillar regions, plays a key role in sustaining ATP levels. Depletion of this glycogen pool has been shown to reduce SR calcium release, disrupting calcium signaling and weakening muscle contraction even when total cellular ATP is maintained.

Consequences of Anaerobic Metabolism in Muscle Fatigue

Intracellular Acidosis and pH Imbalance

Accumulation of Lactic Acid and H+

Intense exercise results in the body having to make energy without oxygen, leading to the accumulation of lactic acid and hydrogen ions in the muscles. During high intensity exercise, the energy consumption of the body’s skeletal muscle cells increases to compensate for what is released. The majority of this Adenosine triphosphate (ATP) comes from anaerobic metabolism, a process which utilizes the breakdown of glycogen into lactic acid to generate ATP at a quicker rate. The anaerobic glycogen breakdown differs from the normal aerobic pathway due to the lack of oxygen available during the process. Initially, the glycogen goes through glycolysis (see section “Energy Depletion: Glycolysis”), which produces pyruvate and a minimal amount of ATP. Aerobic respiration utilizes oxygen to produce substantial amounts of ATP, as the produced pyruvate moves into the mitochondria and produces CO2, H2O, and ATP. In the anaerobic process, the pyruvate is instead converted to lactic acid (C3H6O3) through the lactate dehydrogenase enzyme. Lactic acid is a colorless compound which exists in two active forms, dextro-lactic acid and levo-lactic acid and can occur in the blood, muscles, or organs.

When lactic acid accumulates, it dissociates into lactate and H+ (see Figure 2). The dissociation of lactic acid accumulates H+ , increasing [H+] and therefore reducing pH, as pH is the -log[H+] and is inversely related to the concentration of H+ . The drop in the pH of blood during exercise impairs muscle function and the body’s ability to contract efficiently. In the past, the accumulation of lactic acid was widely considered the main cause of muscle fatigue, but recent studies have attributed the fatigue more to the pH’s effect on the resynthesis of phosphocreatine, rather than a direct effect of the lactic acid.

The Role of Phosphocreatine in Muscle Fatigue

Accumulation of Inorganic Phosphate

Anaerobic metabolism additionally utilizes phosphocreatine as an anaerobic energy system to speed up the process of ATP generation, as it is able to provide a burst of energy by transferring a phosphate group to ADP (stored energy), forming ATP. This reaction is catalyzed by the enzyme creatine kinase (CK), and is demonstrated by the image below:

The equation PCr + ADP → ATP + Cr (see Figure 3) displays how the energy that is liberated from the hydrolysis of the phosphocreatine is used to synthesize ATP when the Pi bonds to the ADP. The breakdown of phosphocreatine to inorganic phosphate and creatine can be displayed by the net ionic equation:

PCr → Pi + Cr

The accumulation of inorganic phosphate can depress contractile function and increase muscle fatigue through the formation of calcium phosphate and its effect on our body’s Ca2+ release.

Formation of Calcium Phosphate and Ca2+ Release

The inorganic phosphate formed by the hydrolyzation of phosphocreatine moves from the myoplasm (the cytoplasm of the muscles) to the sarcoplasmic reticulum (SR), a type of reticulum within muscle cells that is responsible for storing and releasing Ca2+ ions and stabilizing calcium ion concentrations. In normal muscle contractions, when muscle fiber is stimulated, the SR releases calcium ions into the cytosol of the cell, allowing the ions to bind to muscle fibers, and triggering muscle contraction. During muscle fatigue, the Pi ions bind to the Ca2+ ions, resulting in the formation of calcium phosphate (CaPi). Due to this, the number of calcium ions available to release reduces, and therefore, the sarcoplasmic reticulum’s ability to efficiently release and uptake Ca2+ is compromised. With a decline in the amount of Ca2+ available for muscle contraction, the body’s ability to generate force is much lower.

Additionally, the decrease in pH in the blood during high intensity exercise (see section “Accumulation of Lactic Acid and pH”) can disrupt the initial process where Ca2+ binds to muscle fibers and triggers contraction in the SR. The surplus of hydrogen ions caused by the accumulation of lactic acid can displace calcium ions from binding sites, where it would otherwise bind with proteins such as troponin C, and allow for normal muscle contraction. The combination of the effect of low pH on the functions of the SR and the effects of the phosphocreatine from the anaerobic process decrease muscle force and power output, resulting in muscle fatigue.

During recovery from high intensity exercise, the sarcoplasmic reticulum uses its Ca2+-ATPase pumps to reabsorb Ca2+ , and ensure relaxation, as shown in Figure 4. Recovery from endurance training, which requires slow-twitch muscles slightly differs from recovery from rapid muscle contractions that require fast-twitch muscle fibers. Due to their higher affinity for calcium transportation, slow-twitch muscle fibers can more efficiently pump Ca2+ back into the SR, allowing for faster recovery from endurance activities than strength or speed work. The difference between recovery for sprint and endurance athletes can be largely attributed to the variation in how their differing muscle fiber types deal with calcium transportation.

Sodium Bicarbonate as a Buffer and its Effect on Athletic Performance

In recent years, some athletes, primarily semi-endurance bikers and runners, have begun a practice of intaking sodium bicarbonate (also referred to as baking soda) with water about 1.5 to 2 hours before their race or competition, with the goal of enhancing their performance. HCO3 – , which is present in sodium bicarbonate (NaHCO3), is part of the acid-base buffering system present in human bodies that helps regulate blood pH concentrations. The bicarbonate system is the largest buffer system in the blood. When athletes intake sodium bicarbonate, additional reacts with the excess H+ , a process demonstrated by the chemical equation below:

H+ + HCO3 – ⇌ H2CO3 ⇌ H2O + CO2

According to Le Chatelier’s principle and the common ion effect, this shifts the equation to the right and reduces H+ concentration, therefore slightly raising the pH. This further enhances the buffering effect and thus forth delays the decrease in blood pH that occurs as a result of the excess H+ ions. H2CO3 can be defined as a Brønsted-Lowry acid, as it can donate a proton, while HCO3 – , which accepts a proton, can be defined as its conjugate base. A mixture containing an acid and its conjugate base is a buffer and has the ability to resist drastic changes in pH, so by delaying this change, athletes can delay muscle fatigue and slightly improve their performance. As H2CO3 is unstable, it decomposes into H2O and CO2, which is exhaled through the lungs and also helps regulate blood pH. Sodium bicarbonate has also been shown to influence inorganic phosphate creation, again enhancing performance by allowing Ca2+ ions to bind efficiently, even during intense exercise.

Conclusion

Muscle fatigue is not simply the result of overuse, but a result of many chemical processes that often go unnoticed by athletes and many who are struggling from muscular exhaustion. From ATP depletion and lactic acid buildup to pH imbalance, fatigue reflects a breakdown in the body’s ability to maintain muscle contraction at the cellular level. Continued exploration of muscle biochemistry can further practical applications in medicine and sports, and allow for the development of better treatment and training methods for muscle fatigue.

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About the author

Nimeesha Kolari & Radha Panse

Nimeesha Kolari and Radha Panse are currently seniors at Cupertino High School in Cupertino, California. Nimeesha is passionate about chemistry in the context of the human body, and is planning to to study biochemistry in college. In her free time, she enjoys running cross country and track, trying new foods with her friends and family, and walking her dogs.

Radha enjoys biology, chemistry, and mathematics, particularly in areas such as biochemistry and pharmaceutical sciences. Outside of academics, she is a member of the school’s track and field team and enjoys exploring nearby trails, building LEGO creations, and reading in her free time.

The post The Chemistry of Muscle Fatigue: A Review of the Biological and Chemical Processes Behind Muscular Exhaustion appeared first on Exploratio Journal.

Postpartum care in Pakistan is shaped not only by the availability of medical services but by the family power structures that determine whether women are able to use them. Understanding how patriarchal norms and household authority influence access, autonomy, and recovery is essential for addressing persistent gaps between clinical recommendations and women’s lived experiences of postpartum health.

This study asks: How do family dynamics and patriarchal norms in Pakistan shape women’s postpartum care, decision-making power, and recovery experiences? To answer this question, I conducted in-person surveys with 102 postpartum and first-time pregnant women at the Civil Hospital Gynecology Clinic in Sialkot. The survey combined quantitative measures of access, support, and trust with open-ended qualitative responses that captured personal narratives. This mixed-methods design allowed both identification of broad patterns and deeper insight into how women navigate care within their families.

Findings show that education and geography were strong predictors of postpartum autonomy, with women who had higher levels of schooling or who lived in urban or nuclear households reporting more shared decision-making and comfort expressing health needs. Family influence functioned as both support and restriction. Many husbands encouraged clinic visits and helped with household responsibilities, while mothers-in-law in joint families often upheld traditional expectations that delayed or limited care. Although most women trusted medical professionals, many still waited for family approval before acting on advice.

These results suggest that maternal health interventions in Pakistan should involve entire families, especially husbands and elderly women, in order to improve postpartum care and support women’s recovery.

Introduction

Maternal health after childbirth is a critical yet often overlooked aspect of women’s well-being in Pakistan. Postpartum care, which refers to the medical treatment, emotional support, and social conditions that shape a woman’s recovery in the weeks and months after giving birth, goes beyond access to clinics. It is shaped by family power dynamics and cultural norms that determine who controls a woman’s body and recovery. In many households, mothers-in-law or husbands make key decisions about medical treatment, nutrition, and rest, leaving new mothers with limited autonomy. This family-centered control reflects patriarchal norms, meaning the beliefs and expectations that grant men and elder family members authority over women’s bodies, choices, and mobility. These systems of authority influence women’s physical recovery and emotional health in ways that are often invisible in clinical discussions. Understanding postpartum care provides insight into how social structures in Pakistan can both support and restrict a woman’s path to healing. Building on this context, this study is guided by the question: How do family dynamics and patriarchal norms in Pakistan shape women’ s postpartum care, support, and recovery experiences, including access to medical care, emotional support, and decision-making power? This paper first reviews existing research on postpartum care and inequality, then presents survey findings from Sialkot, and concludes with an analysis of how family dynamics shape women’s recovery experiences.

Postpartum health has lasting effects on maternal well-being and child development, which makes this question especially important to investigate. In many parts of Pakistan, women’s health choices are filtered through family authority and cultural traditions, and this can either support or delay recovery. Studying these dynamics allows us to understand why some women are able to access professional medical support while others rely primarily on family guidance or cultural practices. It also highlights the importance of trust, authority, and gender relations in shaping health outcomes.

To address this question, I relied on original survey data that I collected at the Civil Hospital in Sialkot, Pakistan. I selected the Civil Hospital Gynecology Clinic as my primary research site because it allowed me to reach women from diverse social and economic backgrounds living in both urban and rural areas. Through my survey, I gathered information on access to care, the involvement of family members, and the kinds of support women received. Since I administered the survey in person, I was also able to include open-ended questions that encouraged respondents to share their personal stories. Their responses offered valuable insight into how women experienced cultural expectations and family authority in their daily lives. By combining quantitative and qualitative methods, I was able to identify overall trends while also preserving the individual voices of women whose recovery was shaped by their families and communities.

From the data collected, findings reveal a complex picture of postpartum care in Pakistan. Many women described receiving strong support from family members, particularly from husbands who encouraged medical visits, accompanied them to clinics, and sometimes shared childcare or household tasks. This stands in contrast to other accounts in the literature that emphasize restrictive family control, showing that women’s experiences vary widely. The most important contribution here is that support within families can act as a turning point, allowing women to act on medical advice rather than being blocked by household hierarchies. At the same time, women living in conjoint or extended households also reported tension with mothers-in-law, whose hesitation about biomedical care created delays or doubts. Taken together, these findings suggest that postpartum care is shaped less by the availability of services alone and more by how Mother in Laws and paternal family members negotiate authority, trust, and responsibility in everyday life.

These findings point to the need for maternal health programs in Pakistan that address both medical and social factors. Policies that focus only on clinical services risk overlooking the influence of family authority and cultural norms on women’s ability to access care. Interventions that involve husbands, mothers-in-law, and other key family members may be more effective in improving outcomes because they address the reality that health decisions are often made collectively. At the same time, strengthening women’s education and building trust in healthcare providers can help shift reliance away from restrictive practices toward evidence-based care.

More broadly, discussions of maternal health in Pakistan are often shaped by stereotypes that portray women as powerless victims of tradition. While patriarchy and inequality remain pressing barriers, the findings here show that women’s experiences are more complex, shaped by both restriction and support. This variation is not random, it tends to follow predictable special patterns shaped by class and household structure. For instance women in urban and nuclear often exercise more autonomy than women who live in either rural and conjoint family systems. Recognizing this nuance matters because it opens space for imagining new forms of intervention that are grounded in women’s actual realities rather than external assumptions. There is also a clear need for further research that captures these diverse experiences, especially studies that center women’s own voices and explore how family dynamics are changing across different communities. By situating postpartum health within both medical and cultural contexts, this study highlights how improving maternal well-being in Pakistan requires not only better services but also new ways of thinking about women in these settings.

Literature Review

Information Pathways and Trust in Pregnancy Guidance

Understanding how Pakistani women receive and interpret information about pregnancy and postpartum care is central to examining how family dynamics and patriarchal structures shape their health decisions. Habib et al. (2017) found that while nearly 90% of women were aware of at least one contraceptive method, only one-third had ever used them, with unintended pregnancies reported in over one-third of antenatal patients. Health care providers were cited most frequently as the primary source of family planning information, yet the gap between knowledge and practice reflected deeper barriers, including illiteracy, rural residence, and short birth intervals. These structural and educational constraints indicate that medical advice alone does not guarantee adoption of practices, especially when women lack the autonomy or support to act upon it.

Similar evidence from Thatta underscores how trust mediates whether medical guidance is even considered credible. Asim et al. (2021) showed that mistrust of public facilities and fear of biomedical interventions, such as iron/folate tablets or tetanus vaccination, pushed families toward traditional healers, home remedies, or spiritual leaders. Even when women expressed interest in facility births, decisions were often overridden by family members who favored cheaper home-based care. In my survey, 91% of respondents said family members were their main source of pregnancy information, while 78% cited medical professionals, showing that family remains the most influential actor even when clinical advice is available. However there is one limitation in the sample collected, which is the number of women who decided to opt for home care over medical facilities. Omer et al. (2021) also described delays in hospital care due to reliance on spiritual advice, with fatal consequences in some cases. These findings highlight that information is filtered not just through women’s individual understanding but through the social and cultural expectations imposed by family and community.

Past literature shows that women often view family members such as husbands, mothers-in-law, or elders as more credible than doctors. My survey aligns with this pattern: 36% of women reported that their in-laws were “very important” in decision-making, and over 43% of women who sought spiritual advice did so at the request of family members, not by personal choice. At the same time, some studies suggest that increased exposure to clinics or health workers may encourage women to place greater value on medical advice. In my data, 77% of women reported fully trusting medical professionals, showing that trust in doctors is rising but is still expressed within a family-influenced environment. These possibilities create an important motivation to examine how women balance family authority with professional guidance during the postpartum period.

According to Atif et al. (2023), partner support plays a critical role in whether women are able to follow medical advice and access maternal health services. Using national data from the Pakistan Maternal Mortality Survey, the authors found that women whose husbands provided emotional and financial support, helped with pregnancy-related decisions, or accompanied them to health facilities experienced safer childbirth and better maternal outcomes. Their findings show that supportive husbands can help women overcome restrictive family norms and strengthen trust in medical care, illustrating how family roles shape not only who shares health information but also who acts on it. In my survey, 60% of husbands helped with daily household responsibilities, and 40% of couples discussed pregnancy decisions often, suggesting that support from husbands can soften the effects of restrictive household norms. In many households, doubts raised by mothers-in-law could be set aside if husbands pushed for medical treatment. This shows that families with more flexible or shared decision-making are more likely to act on medical guidance, creating pathways that allow women to get care. It also shows that families are not all the same; some continue strict traditions while others move away from them.

In the end, asking who in the family makes the final decision is not just about telling stories. It matters because it shows that trust and care-seeking depend on specific family relationships, not only on general views of medicine. This means that interventions need to look beyond women alone and instead reach the household as a whole. Working with husbands, addressing mothers-in-law, and understanding how authority shifts within families can turn social influence into a tool for improving access to care.

Interpersonal Relationships and Support Systems

Postpartum care in Pakistan is inseparable from household and community relationships, where family structures both provide support and reinforce restriction. In a study of low-income Karachi settlements, Fikree et al. (2004) found that although more than half of women delivered in facilities, postpartum follow-up remained minimal, only one-quarter of those counseled for check-ups actually attended. Symptoms such as high fever (21.1%) and heavy bleeding (13.9%) were common, yet initial responses involved home remedies or traditional healers before seeking professional help. These patterns reflect how postpartum care is first negotiated within the family, often delaying engagement with formal health systems. Family hierarchies exert strong control over such decisions.

Omer et al. (2021) also observed that these delays, rooted in family authority, contributed directly to maternal deaths. Such examples illustrate how family support systems can function as mechanisms of control when patriarchal expectations prioritize household finances, family reputation, or cultural norms over women’s health. Interpersonal dynamics also intersect with violence and neglect. Fikree and Bhatti (1999) found that 34% of women reported physical abuse, with 15% experiencing violence during pregnancy. Abuse was strongly linked to anxiety and depression, underscoring how harmful relationships compromise not only mental health but also women’s willingness and ability to seek care. Mumtaz et al. (2011) expanded this understanding by showing how gender and caste intersect: in the case studies of Shida and Zainab, domestic violence, indebtedness, and social devaluation prevented access to life-saving care, even when facilities were physically available.

Together, these findings emphasize that interpersonal relationships are double-edged Supportive husbands or peers may encourage health-seeking and family planning, as noted by Habib et al. (2017), but patriarchal family structures often silence women’s preferences, limit mobility, and normalize neglect. For this reason, examining postpartum health in Pakistan requires not only mapping medical access but also analyzing how power circulates within the family system, where decisions about women’s care are often made by others, not the women themselves.

Not all family structures operate in ways that restrict women’s health. Atif et al. (2023) found that when husbands provided consistent emotional and financial support during and after pregnancy, women experienced safer childbirth and improved maternal outcomes. These findings suggest that interpersonal networks are not fixed. When families prioritize women’s health, relationships can shift from acting as barriers to enabling access to care. This matters because it shows that interventions should not only treat families as obstacles but also as potential partners in change. By strengthening supportive roles within households, especially those of husbands, health systems can use existing family structures as entry points for improving maternal and postpartum care.

Patriarchal Norms, Family Power Dynamics, and Women’s Health Decision-Making

Patriarchal authority in Pakistan is a defining factor in women’s ability to access postpartum health care. Studies consistently show that men dominate decision-making in reproductive matters, with women’s voices either sidelined or entirely excluded. Ghani and Hassan (2023) found that in households practicing polygyny, women’s autonomy was particularly constrained, with husbands retaining primary control over maternal health decisions. By contrast, nuclear families were more likely to allow women some say in health matters, suggesting that family form plays a role in shaping the balance of authority. Similarly, Rahman (2025) examined joint-family systems in northern Pakistan and reported that while extended families offered social and financial security, they also entrenched patriarchal hierarchies. In these settings, elder males and mothers-in-law dictated women’s health-related movements, reinforcing women’s dependency and limiting their direct decision-making power.

This concentration of authority is not just cultural but institutionalized in Pakistan’s gender system. Ali (2011) argues that gender roles in Pakistan are reinforced through educational, legal, and policy frameworks that privilege male control. The paper emphasizes that discriminatory practices are embedded in social institutions, making autonomy not just a household issue but a national structural one. At the same time, it also highlights women’s education as a key factor that can disrupt patriarchal expectations, opening limited but meaningful pathways for change.

Patriarchal authority in Pakistan shapes women’s health care choices not only through explicit rules but also through everyday expectations about obedience, modesty, and family honor. These unwritten norms create an environment where women learn early that their well-being is often secondary to household reputation or financial priorities. Even when health services are nearby, many women hesitate to seek them if it means challenging the authority of a husband, elder male, or mother-in-law. In rigid households, decisions about rest, travel to a clinic, or the use of contraception are less about medical need and more about maintaining control. Yet in families where authority is more flexible, these same structures can be reinterpreted: a husband who insists on supporting his wife’s care, or an elder who views postpartum recovery as protecting family strength, can transform patriarchal authority into permission rather than denial.

Socioeconomic Inequalities and Access to Care

Economic and social inequalities are equally powerful in shaping postpartum health outcomes. Aftab et al. (2025) conducted a systematic review of maternal health across South Asia and found that economic status, education, women’s occupation, and autonomy were the strongest determinants of access to maternal health services. In Pakistan specifically, women from poorer households and those without formal education were far less likely to receive skilled postnatal care, showing how inequality translates directly into health gaps. Afridi et al. (2025) further demonstrated this by applying an inequality of opportunity framework to Pakistani DHS data, finding that circumstances beyond women’s control, such as family wealth, parental education, and place of birth, accounted for much of the disparity in maternal health use.

Recent national-level data highlight the persistence of these divides. A study by Maleki et al. (2024) found that illiteracy, unemployment, and rural residence were consistently associated with lower postnatal care use, even when services were theoretically available. They argue that trust in healthcare facilities erodes further among poorer women, who often experience low-quality treatment or unaffordable fees. Similarly, Misu et al. (2023) compared Pakistan with Bangladesh and found that Pakistan’s PNC coverage had the widest inequality gaps by education and wealth. In particular, the richest, most educated women were many times more likely to access postnatal care than the poorest, least educated, suggesting that class-based disparities are entrenched within Pakistan’s health system.

Economic inequality does not only determine whether services are available, but also how women experience them. For many, the decision to seek care is filtered through the reality of daily survival. A woman from a low-income household may know that postnatal check-ups are important, yet the cost of transport, the need to return quickly to wage labor, or the fear of being treated poorly in a public facility can make professional care feel out of reach. By contrast, women in wealthier families often have both the means and the social confidence to demand better treatment, which widens the divide further. These patterns show that access is not just about the existence of clinics but about whether women can realistically use them with dignity and trust. Without addressing these underlying inequalities, expanding services risks reinforcing the very divides it is meant to reduce.

The literature reviewed above highlights major structural inequalities in postpartum care, but it also reveals a gap that my research is designed to address. While existing studies document which groups of women face the greatest barriers, far fewer examine how women themselves interpret postpartum advice, negotiate family expectations, or build trust in medical care after giving birth. Much of the current evidence comes from national surveys or quantitative analyses, which identify patterns but cannot fully capture women’s lived experiences of navigating these inequalities. My study addresses this gap by focusing on women’s postpartum decision making and their perceptions of care quality in everyday life. Based on the literature, I expect to find that socioeconomic constraints interact with family dynamics, cultural norms, and experiences inside healthcare facilities to shape whether women feel able and willing to seek postnatal care. This approach allows my study to contribute a more detailed and grounded understanding of how inequality affects postpartum health access in daily life.

Data and Methods

I chose this research site and population because the Civil Hospital serves a wide range of women from diverse socioeconomic backgrounds, making it an ideal setting for examining how income, education, family roles, and trust in medical care shape postpartum decisions. Surveying 102 women at this location allowed me to reach participants from both urban and peri-urban areas who rely on affordable public healthcare rather than private clinics, which typically serve higher-income families. This site also provided access to both postpartum mothers and first-time pregnant women, making it possible to understand not only women’s reflections after childbirth but also the expectations and concerns that shape care-seeking earlier in pregnancy. Focusing on this diverse population helps address the gap in the literature by providing detailed insight into how women navigate postpartum care in everyday life. Participants ranged in age from late teens to early forties, reflecting the wide reproductive age span served by the clinic. Most respondents were married and living in extended family systems, where mothers-in-law and husbands often influenced decisions about medical treatment and rest. Educational backgrounds varied: while some women had completed secondary or higher education, others had limited formal schooling, particularly those from rural villages surrounding Sialkot. This variation in age, education, and living arrangements made it possible to observe how family authority and socioeconomic conditions differently shaped women’s postpartum experiences and access to care.

The survey instrument was designed to capture both quantitative and qualitative data. Closed-ended questions measured factors such as frequency of clinic visits, type of medical care accessed, involvement of husbands and mothers-in-law in health decisions, and sources of postpartum support. These items provided a systematic picture of women’s access to care and the distribution of decision-making authority within households. To complement this, the survey also included some open-ended questions that encouraged women to share their personal experiences in their own words. These narratives revealed the cultural meanings and emotional aspects of postpartum recovery that numbers alone cannot capture.

Data collection took place through in-person administration to over 100 postpartum and first time pregnant women attending the clinic. In-person surveys reduced literacy barriers and made it possible to build trust with respondents. When appropriate, questions were translated into local dialects to ensure clarity and accessibility. Respondents were assured of confidentiality, and participation was voluntary.

Results

When the data are examined across education, location, trust, and family structure, clear relationships emerge in how social and structural factors shape women’s postpartum experiences. Education level appears to be one of the most influential variables. Among respondents, 18 % had no formal education, another 18 % had completed only primary school, and 35 % had finished secondary school, while 25 % held a college or university degree and 4% had graduate or professional qualifications. Women with higher education were more likely to describe shared or cooperative decision making with their husbands and greater comfort expressing their health needs. For example, many of the women who rated themselves as very comfortable talking to their husbands when they felt unwell were also those with secondary or higher education, contributing to the 70 % who chose the highest comfort rating. Their responses suggested that education provides both knowledge and confidence, allowing them to navigate healthcare systems and negotiate with family authority. In contrast, women with limited or no schooling often relied more heavily on in-laws and deferred to others in medical and household decisions. A 24 year old participant with limited schooling explained, “I wanted to tell the doctor about my pain, but I felt shy. My mother-in-law spoke instead, and she said everything was fine.” This pattern indicates that education not only expands access to information but also influences power dynamics within families, shaping whether a woman’s voice is heard in her recovery process.

Economic inequality also emerged as an underlying factor, reflected indirectly through patterns of residence. None of the 102 respondents lived in major cities such as Karachi or Lahore. Instead, 59 women, or about 58 %, lived in small cities or towns such as Sialkot, and 43 women, about 42 %, lived in rural villages. These distributions suggest that most of the surveyed women live in lower to middle income settings with limited healthcare infrastructure. Regional location also shaped access to education and services. Women in rural or semi rural households often described financial barriers such as the cost of transportation, clinic fees, or medication, which discouraged them from seeking professional care. A 32 year old mother from a rural village said, “The clinic is far and we cannot pay for a rickshaw every time. Sometimes I just stay home and take the advice of my sister-in-law.” In contrast, women from more urbanized or economically stable families, often those with higher education levels, reported greater mobility, better nutrition, and more frequent engagement with healthcare providers. This indicates that geography in Pakistan not only represents physical distance from hospitals but also mirrors economic divisions that influence health outcomes. Economic constraints therefore reinforce social hierarchies, limiting autonomy for poorer women while amplifying dependence on family authority to make healthcare decisions.

Patterns of information sources also reflect underlying social divides. Overall, 91 % of respondents identified family members as a main source of information about pregnancy, while 78 % cited medical professionals. Only small minorities reported relying on social media, 8 %, or journalists, 2 %. Women in rural or small town households, who are more likely to experience economic hardship, appear to depend primarily on informal, family based knowledge networks rather than institutional or technological ones. In contrast, participants with higher education levels and more urban residence more frequently mentioned doctors or online platforms, indicating greater exposure to formal healthcare systems. Despite these differences, trust levels revealed a striking contradiction. Although medical professionals were widely trusted, with 77 % of respondents giving doctors the highest trust rating, many women still deferred to family approval before acting on medical advice. A 29 year old woman living in a joint family shared, “I trust the doctor, but if my husband’s mother says wait, then we wait. It is not my decision alone.” This pattern suggests that economic and cultural hierarchies intersect, where lower income families place collective authority above individual medical autonomy. Women from wealthier or more educated households, by contrast, demonstrated greater confidence in navigating between traditional and professional advice. These findings illustrate how economic inequality influences not only access to information but also the ability to act on trusted knowledge, reinforcing the idea that empowerment depends as much on social permission as it does on awareness.

The survey also highlights how husbands and in-laws shape everyday postpartum support. Most respondents lived with their husbands, 89 %, and a majority also lived with their children, 80 %. Just over half, 51 %, lived with their husband’s parents or other in-laws, reflecting the prevalence of joint or extended household arrangements. During pregnancy and the postpartum period, 60 % of women reported that their husbands helped with household responsibilities daily, while another 25 % received help a few times a week or occasionally. At the same time, 46 % of respondents described their in-laws as “very important” in pregnancy related decisions, and another 18 % said they were “somewhat important,” meaning almost two thirds saw in-laws as significant decision makers. Many women also reported having to compromise their own preferences, with about 67 % agreeing or strongly agreeing that they had to set aside their own wants and feelings to please a husband or another family member. These numbers show that even in households where husbands are supportive, authority is often shared or negotiated with elders.

Satisfaction levels further support these relationships. Nearly three quarters of respondents, 74.5 % , described themselves as very satisfied with their most recent pregnancy experience, and another 16.7% were somewhat satisfied. Many of the women who expressed high satisfaction also reported active spousal involvement and shared household responsibilities. One 26 year old first time mother reflected, “I felt happiest when my husband helped. Even small things made a big difference. When he listened, I felt safe.” This connection suggests that emotional support and cooperative family dynamics can have as much impact on well being as medical treatment itself. On the other hand, women who faced stronger in-law authority or limited say in their own care tended to describe neutral or lower satisfaction levels, indicating that social restrictions can directly affect perceptions of recovery. An older mother of three from a small town commented, “We trust the doctors, but still ask elders before doing anything. It feels wrong to go against them.” Her statement reflects the emotional weight of respect and obedience in shaping decisions.

Spiritual and religious guidance also played a role in women’s experiences. Thirty eight % of respondents reported visiting a religious leader during their most recent pregnancy. Among those who did, 43 % said they went because it provided personal comfort, and another 43 % said they went because in-laws expected or required it. Some also described visits as a result of pressure from husbands or other family members. These patterns show that religious consultations are not only a matter of individual belief but are intertwined with family expectations and authority. For some women, religious leaders provided reassurance alongside medical care. For others, spiritual advice contributed to delays or doubts about biomedical treatment, especially when elders prioritized ritual or tradition over clinical recommendations.

In addition to survey responses, interviews with several women provided deeper insight into how these dynamics unfold in daily life. A 27 year old mother from rural Sialkot explained, “The doctor told me to rest after my delivery, but my mother-in-law said too much lying down makes a woman weak. So, I got up to cook again after two days.” Her statement reflects the tension between professional medical guidance and traditional family expectations. Another participant, a university educated woman living in an urban neighborhood, described a contrasting experience: “My husband and I decide things together. If the doctor says I need medicine, we buy it the same day. He even comes with me to appointments.” These accounts illustrate how education and family structure intersect to shape women’s autonomy.

Taken together, these patterns reveal that postpartum health in Pakistan is shaped by overlapping systems of influence, including education, geography, trust, religion, and family structure, that together determine whether women experience empowerment or constraint. Families remain central to recovery, but their influence can either reinforce patriarchal control or evolve into a source of shared support. As women gain education or move closer to urban environments, they are increasingly able to advocate for themselves, transforming traditional hierarchies from within. These findings highlight that improving maternal well being requires not only access to healthcare but also the reshaping of the social and cultural environments that define how women heal.

Discussion/Conclusion

The results of this study show that postpartum care in Pakistan is shaped not only by access to healthcare but by the social relationships that determine who supports or restricts a woman after childbirth. Education, geography, and trust emerged as the strongest predictors of autonomy and satisfaction. Women with higher education and those living in urban settings described greater independence, stronger partnerships with husbands, and more comfort communicating their needs. In contrast, rural and less-educated women were more likely to depend on in-laws and family approval before acting on medical advice. Yet across these differences, a common thread appeared: families remain the center of care. When relationships were cooperative and emotionally supportive, women were more likely to trust doctors, attend clinics, and report high satisfaction with their recovery. This demonstrates that postpartum health is both a medical and relational outcome, built through dialogue, understanding, and shared responsibility within households.

These findings help answer the core research question by revealing how patriarchal norms and family dynamics interact to shape postpartum recovery. The study challenges the idea that patriarchal families are entirely restrictive and instead shows that change is emerging from within them. Education, communication, and exposure to urban environments are gradually transforming rigid hierarchies into systems of shared authority. This perspective fills a major gap in current literature, which often depicts Pakistani women as passive or powerless. Instead, this research shows that women are active participants who use negotiation, trust, and relational understanding to advocate for their health. The implications are clear: improving maternal well-being requires engaging with the family structure itself, transforming it from a site of control into a network of care.

Theoretically, this study reframes how gender and authority are understood in patriarchal societies. It supports the idea that patriarchy is not a fixed system but a social process that can evolve through education and everyday interaction. Women’s agency operates within these systems, not outside them. By voicing needs, seeking medical help, or involving husbands in decision-making, women subtly reshape cultural norms that once silenced them. This research therefore deepens our understanding of family systems theory and feminist health perspectives by showing that social change often begins at the household level, where shared understanding replaces hierarchy.

From a policy perspective, the results suggest that health interventions should not isolate women from their families but include those families as allies. Programs that encourage spousal communication, provide couple-based counseling, and train community health workers to engage in-laws can bridge the gap between trust in medicine and the freedom to act on it. Expanding education for both men and women remains essential, as knowledge empowers families to move away from harmful customs toward evidence-based care. By focusing on collective education and trust, policymakers can promote care environments that support rather than limit women’s recovery.

Culturally, the findings highlight an ongoing transformation in how families perceive care and authority. Younger, more educated couples often practice forms of partnership that were rare in earlier generations. These evolving relationships reveal that traditional values and modern health practices do not have to conflict; they can coexist when grounded in empathy and communication. This gradual shift from control to cooperation represents a quiet cultural revolution within Pakistani households, one that holds the potential to improve maternal outcomes across communities.

At the emotional and familial level, the research reveals that support functions as a form of healing. When husbands share household work, when mothers-in-law encourage rest rather than judgment, and when women feel safe expressing discomfort, recovery becomes both physical and emotional. Better support creates better pregnancies, not only because it improves access to care but because it restores dignity and peace of mind. Families that nurture women during the postpartum period create cycles of trust that benefit future generations.

Although this study offers important insight into how family structures influence. Because the research was conducted exclusively at the Civil Hospital Gynecology Clinic in Sialkot, the findings likely reflect the experiences of women who have at least some level of access to biomedical care. This means the results may be skewed toward women who are more open to seeking medical help, more trusting of healthcare providers, or more financially and socially able to visit a public hospital. Women who cannot reach facilities at all, or who rely on home births, traditional healers, or private clinics, may face different barriers that are not captured in this sample. If the study had taken place in a rural village, the results might have shown stronger effects of geographic isolation, poverty, or elder family control on postpartum care-seeking. Similarly, a study in a private hospital might have highlighted how wealth shapes access to higher quality services and stronger trust in providers. Using a different research design, such as in-depth interviews or home observations, might also have revealed more detailed information about women who avoid or delay postpartum care entirely. These possibilities show that the sample likely leans toward women who are able to access public healthcare, and future work in alternative settings would provide a fuller picture of postpartum experiences across Pakistan. Additionally, while in-person oral surveys minimized literacy barriers and allowed clarification of questions, they sometimes limited depth, as responses were brief and constrained by time and setting. The modest sample size further restricts generalization to the national level.

Nonetheless, these constraints do not diminish the study’s significance. By centering women’s firsthand narratives within existing family power hierarchies, this research highlights how maternal recovery is shaped less by medical access alone and more by cultural authority within households. Even within a localized setting, these findings illuminate broader social patterns, offering a foundation for future studies and policy efforts aimed at balancing familial influence with maternal autonomy in postpartum care.

In conclusion, this study shows that family authority in Pakistan can either suppress or sustain maternal health, depending on how it is practiced. Education, trust, and shared responsibility act as turning points that redefine what care looks like within patriarchal systems. The research reminds us that true progress in maternal health will not come only from new hospitals or doctors but from reshaping the relationships at home. When families become partners in healing, postpartum care transforms from a private struggle into a collective act of compassion and empowerment.

References

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About the author

Eshal Afzal

Eshal Afzal is a senior at West Windsor–Plainsboro High School South whose academic work focuses on maternal health, gender equity, and the sociocultural dynamics of postpartum care. She conducted survey-based field research with postpartum women at the Civil Hospital Gynecology Clinic in Sialkot, Pakistan, under the guidance of Dr. Bart Bonikowski.

She is also the founder of Nisa Maternal Care, an initiative providing postpartum health kits and educational support to underserved women. Her broader interests include medical anthropology, global health, and women’s health in low-resource settings.

The post Beyond Access: How Family Power Dynamics Shape Postpartum Care in Pakistan appeared first on Exploratio Journal.

Abstract 

Recent breakthroughs in AI and neural interfacing devices are transforming the landscape of prosthetic capabilities, bringing us closer to creating bionic solutions that we can embody as natural limbs. This review paper looks at how that is possible by surveying cutting-edge advancements in surgical techniques, control strategies, and neural interfaces aimed at restoring human functions. The scope encompasses innovations in materials such as biocompatible polymers and titanium rods, as well as implantable systems like osseointegrated prostheses. Methodologically, the paper synthesizes findings from studies published in the last decade, highlighting state-of-the art bionic devices. Key findings demonstrate that recent technologies significantly enhance prosthetic functionality, user comfort, and sensory perception, which are important factors for improving the quality of life for amputees. Despite these technological leaps, challenges related to device durability, bio compatibility, data privacy and accessibility remain. Overall, this review underscores the importance of creating life-like, adaptive devices that seamlessly blend with our biological systems, ultimately creating a better life for individuals who suffer from limb loss.  

Keywords:deep learning, reinforcement learning, artificial intelligence, bionic, prostheses, bi-directional, adaptive, osseointegration, neural interfaces, electromyography (EMG), electroencephalogram (EEG), electronystagmography (ENG)

1. Introduction

Bionic devices are advanced prostheses, implants, and neural interfaces designed to augment or restore natural human functions (Figure 1). The field holds major significance for society as millions of people globally suffer from major physical limitations that reduce their quality of life. As shown in table 1, more than 500,000 Americans have suffered from limb loss (Rivera et al., 2024). Moreover, from 2020, the annual rate of limb amputations is over 430,000 for people from all of Europe (Bumbaširević et al., 2020). Hence, many people await functional solutions that integrate technology with the human body. Despite the progress, challenges remain in restoring and nurturing natural human mechanisms, highlighting the need for more innovation. 

The selection of papers for this literature review was driven by a focus on the latest advancements in novel surgical techniques, integration of sensory components, adaptive control strategies, and machine learning algorithms. For novel surgical techniques, osseointegration is primarily discussed to highlight how setting up the residual area for a prosthetic is just as important as the prosthetic itself. For sensory components, their implementation brings the prosthetic limb closer to its biological counterpart by incorporating sensory information such as temperature perception or physical embodiment of the prosthesis. For adaptive control strategies, studies compare control schemes such as biomimetic and arbitrary controls with one another to identify ways in which one might be better than the other. Last but not least, papers that involve machine learning applications highlight how these advanced predictive models can be used to facilitate the learning process from internal signals to external movements. 

The selected papers do not put much emphasis on logistical matters such as complete clinical trials, cost-effectiveness, or accessibility of these bionic solutions. The experiments that were conducted in these papers were to showcase a proof of concept, which means that the sample size collected was not sufficient in either volume or variation to pass as clinical trial data. Moreover, while the papers do highlight the significance of such advancements to the millions of people who suffer from physical disabilities, it does not discuss in great detail how such sophisticated technology can be made accessible to those who are constrained by their physical location or financial capacity. Nevertheless, this review attempts to discuss some of these challenges and limitations in greater detail to give a more holistic idea of the reality of the bionic solutions industry. 

Overall, this paper aims to summarize recent advancements, identify existing limitations, and delineate future trajectories in bionic research and application. 

Table 1: Number of amputation procedures in the US from 2016-2019. Note that diabetes is nested within vascular diseases, so the diabetes row should not be included in the sum (Rivera et al., 2024).

2. Overview of Bionic Devices

Bionic devices include prosthetic limbs, visual and sensory augmentation systems, and neural interfaces that mimic or restore physiological connections. Historically, early prostheses relied on passive mechanical structures that felt like a separate entity from the human body. Earliest prostheses could be found as early as the Middle Ages, starting with hooks and continuing to Ambroise Paré’s mechanical hand to modern robotic, osteointegrated and bionic limbs, which are the results of both medical and technological progress. Modern-age prosthesis development was prompted as a consequence of the World Wars primarily due to the limb loss suffered in battles – first in Germany and then in the former USSR. However, recent decades have seen the integration of sensors, actuators, machine learning, neural interfaces, etc., that leverage the body’s electrical activity to build sophisticated bi-directional bionic solutions (Bumbaširević et al., 2020).

3. Current Types of Bionic Devices

In this review, bionic devices will be broken down into 3 basic structures: bionic limbs, bionic eyes, and interface devices (Figure 3-5).

3.1 Bionic Limbs: 

Recent research demonstrates sophisticated control systems for lower-limb and upper-limb prostheses primarily due to the implementation of electrodes that pick up electrical signals – using EMG, ENG, and EEG – from the muscles, nerves or brain, and classify them typically into biomimetic movements typically through machine learning algorithms that are trained on these signal patterns. The movements are later translated into commands for the hardware motor to execute as actual gestures. Moreover surgical techniques like osseointegration have been applied to not only augment the performance of these devices but reduce physical discomfort for the amputee. 

For instance, in the sub-field of upper-limb prostheses, Ortiz-Catalan et al. describes a highly integrated bionic hand that uses neural control and sensory feedback via an osseointegrated implant, allowing the prosthesis to communicate directly with residual nerves and bones (2023). Titanium rods were implanted into the bones and electrodes into the muscles and nerves to create natural control and sensory feedback. The neuromusculoskeletal interface, using an osseointegrated implant engineered to enable bidirectional communication between electrodes and the prosthesis, mitigates common issues such as discomfort and/or unreliable prosthetic control. 

In the sub-field of lower-limb prostheses, researchers Azocar et al. were able to build an open source bionic limb. In terms of hardware, the prosthesis combines knee and ankle joints using high-toque and low-cost motors from drones. They produce 2-10 more torque than the average prosthetic leg which allows for more natural movement. The series-elastic actuator, which uses springs, helps with force control which makes movements smoother and more adaptive. The hardware design is highly customizable in general and relatively economical which makes it convenient for outside researchers. In terms of software, it has a hierarchical control system: low-level control (precise joint movements), mid-level control (translate user intent into a sequence of joint movements), high-level control (recognition of user intent and adjust the ambulation mode). While their product does not use electrical signals from the residual limb for more refined movement, they use sophisticated software and hardware designs to build a robust prosthetic (2020).

3.2 Bionic Eyes: 

The replication of complex sensory organs such as the bionic eye exemplifies the expanding scope of bionic devices. Vision is a multi-step process: environmental light is focused onto the retina, converted into neural signals, transmitted via the optic nerve, and processed through layered brain regions that analyze features, interpret the scene, and generate responses. The machine vision process involves capturing optical images and then converting them into digital signals. These are then processed through the image processor (most commonly GPU) where they integrate machine vision perceptions and recognition algorithms (CNN, RNN, YOLO). The outputs are then used for something actionable. The primary missing ingredient in these neural network algorithms that are found in our brain neurons are the complex temporal integration capabilities (Zhang & Lee, 2022). Hence, researchers in this study have looked to develop not only how well the visuals can be captured, but how they are processed and stored for higher level brain functions. 

For example, Zhang et al. introduce a neuromorphic broadband vision device that mimics biological photoreceptors using a TIPS-pentacene-based phototransistor array retina (2023). The device tries to mimic how neurons may react to light, in order to handle visual sensing and memory tasks efficiently.

3.3 Interface Devices:

Development in neural interfaces underpin some of the most advanced bionic solutions available in present time. They are what are developed to control the bidirectional prostheses by decoding motor commands from the signals or stimulating afferent pathways to restore sensation. From the hardware end, optimal access to the nervous system requires invasive procedures interfacing the nerve pathways. From the software end, mathematical modelling is required to decode neural information to produce motor outputs that reliably predict the intention of the user (Pasluosta et al., 2022). 

As mentioned previously, Ortiz-Catalan et al used a neuromusculoskeletal interface, via an osseointegration, which allowed for seamless bi-directional communication between the electrodes and prosthesis, which in turn facilitated precise bionic movement (2023).

4. Technological Advancements and State-of-the-Art

This section consists of the state-of-the-art research in materials (Section 4.1), Sensors and Actuators (Section 4.2), Neural Interfaces (Section 4.3), and Machine Learning Classification (Section 4.4), which are summarized in Figure 6. 

4.1 Materials:

4.1.1 Osseointegrated Implants:

The use of titanium rods embedded into bones offers a durable and biocompatible platform to facilitate direct skeletal attachment. The efficacy hinges on the osseointegration, addressing prior issues of discomfort and instability with socket-based mechanics (Ortiz-Catalan et al., 2023).

4.1.2 Neuromorphic Device Materials:

These devices utilize organic materials such as TIPS-pentacene to develop flexible, broadband phototransistors capable of mimicking biological visual sensors.It responds to a broad range of light wavelengths, similar to the human eye. The device also tries to mimic how neurons may react to light, in order to handle visual sensing and memory tasks efficiently (Zhang et al., 2023).

Other materials such as perovskite nanowire arrays have been used to build a retina that can perform filter-free color detection. The nanowire array also produces photocurrent without external bias which enables self-powered operations (Long et al., 2023). 

4.2 Sensors and actuators:

4.2.1 Bidirectional Control Systems:

These use advanced sensor arrays and actuators that decode neural signals (EMG, nerve signals) and provide sensory feedback. This addresses the limitation of unidirectional control of passive prostheses that fail to create embodiment with the human body (Pasluosta et al., 2022). 

4.2.2 Sensory Devices:

Incorporation of sensory devices such as thermal sensors linked neural feedback pathways, allow for temperature perception, which help humans embody their prosthetic limb more readily due to increased alignment with an intact biological limb (Ortiz-Catalan, 2024). 

4.3 Neural interfaces:

4.3.1 Invasive Neural Interfaces:

These deploy direct nerve muscle interfacing with surgically implanted electrodes to collect stronger ENG Signals which allows for greater selectivity. These methods provide precise control and sensory feedback but face challenges such as the increased risk of damaging the nerve due to its invasive nature (Ortiz-Catalan, 2024).

4.3.2 Hybrid Interfaces

Surface EMG (electrical signals from the muscles) electrodes remains the primary non-invasive approach. While it is safer, it struggles to achieve as powerful signals as more invasive electrodes. Recent innovations such as the regenerative peripheral nerve interface (RPNI) with a peripheral neural interface records signals from both the nerve and muscle graft and controls a robotic leg. The results suggest that it enhanced prosthetic control compared to singular approaches (Cho et al., 2023). 

4.3.3 Osseointegrated Neural Interfaces

The use of titanium implants have created a bridge between the skeletal system, and nerves and muscles which has enabled robust, bidirectional communication that imitates natural proprioception. It effectively combines control and sensation within a single interface (Ortiz-Catalan et al., 2023).

4.4 Machine Learning Classification:

4.4.1 Reinforcement Learning:

Reinforcement Learning is one of the optimization techniques deployed by researchers to improve the robustness and accuracy of bionic limb controllers that decode motor intent into actual movements. Researchers Freitag et al. test out this method by essentially fine-tuning a pretrained control policy with dynamic EMG data from a Guitar Hero-type game environment (2023). Initial results indicate that it is a promising path to explore for more refined control, particularly for prosthetic hands since human hands require greater number of degrees of freedom than its lower-limb counterparts.
4.4.2 Arbitrary Control: 

Arbitrary control refers to a control strategy where gesture-to-movement mappings are not based on natural or biological mimicry. Unlike the more traditional biomimetic control, this approach emphasizes functionality and flexibility over biological similarity. The training emphasized developing control schemes from scratch, without relying on natural movement patterns. Schone et al. found out that not only does it perform almost as well as biomimetic control in terms of speed, dexterity, and gesture switching, but it has better increased generalization to control mapping (2024). However, it would be more cognitively demanding to learn these new unintuitive associations between muscle activation and bionic movement

5. Patient Adaptation

5.1 Performance Metrics:

The review shows that most of the work documented in research papers for bionic solutions represent early experimental or POC stage rather than widespread clinical application. For instance, the aforementioned integrated neuromusculoskeletal prosthesis trial was conducted on a single participant with below-elbow amputation. While the performance metric showcased promising results – task score improved from 65 to 80 – these still come from a limited sample size with numerous variables, and cannot be indicative of broad clinical adoption (Ortiz-Catalan et al., 2023). 

Widespread adoption requires large-scale validation – thousands of participants, regulatory approvals and integration into standard prosthetic care pathways. 

5.2 Motor Function Improvements:

Advancements in neural interfaces, surgical techniques and biomechanical analysis have already begun to produce tangible improvements in motor control, functionality, and rehabilitation outcomes. For example, De Marchis et al performed a multimodal prosthetic gait assessment using datasets collected on individuals with different amputations and prosthetics. This study is for analyzing movement neural control and mechanical actuation of prosthetic limb as a whole that can facilitate better prosthetic design and therapies for patients (Frossard et al., 2022). 

5.3 Qualitative Studies: 

The incorporation of qualitative studies across several research papers highlight the importance of user satisfaction when it comes to receiving bionic augmentations. Generally, amputees face issues with their residuum health such as physical discomfort or mental distress. Hence, for the success of bionic solutions, it is important to listen to the users and acknowledge their impression of the device. In Ortiz-Catalan’s paper, the received experiential questionnaires suggest that quality of life improved as a result of using the neuromusculoskeletal prosthesis, with scores suggesting lower perceived disability, and reduced intensity of stump and phantom limb pain (2023).

6. Technical and Ethical Obstacles

The challenges and limitations from developing advanced bionic solutions can be found across several domains which include technical, biological and ethical issues. 

6.1 Technical Challenges:

6.1.1 Durability:

Prosthetic systems face issues with long-term durability. Physical components such as electrodes and neural implants are liable to mechanical wear, electrode degradation, and scar tissue formation, none of which are easily repairable or maintainable (Amin, 2022). 

6.1.2 Power Supply:

Bionic devices, particularly neural prostheses with sensory feedback and control algorithms require efficient and long-lasting power sources. The need for miniaturized, reliable batteries can limit device operation time and increase the need for recharging or replacement. This is especially true for bionic eye devices that are trying to create the sensing, processing and memory capabilities of a biological eye (Zhang et al., 2023). 

6.1.3 Signal Reliability

Electrical signals collected from the brain, nerves or muscles are susceptible to noise which complicates decoding the signals into proper movement classifications. For example, EMG can be affected by muscle fatigue or neighboring electrical activity, which reduces control reliability (Freitag et al., 2023). 

6.2 Surgical Risks

6.2.1 Encapsulation:

Invasive neural interfaces or osseointegration can elicit negative immune responses from the body. Without more tissue engineered neural interfaces that integrate encapsulated neural cells within the electrodes, scar tissue formation is an issue which can lead to decreased biocompatibility (Amin, 2022). 

6.2.2 Infection Risks

While osseointegrated bionic limbs substantially improve mobility and general quality of life, it can cause issues such as bone fracture, infections, and breakage of the implant part. In other words, it’s not likely to work out well in a prolonged period without regular monitoring and cautiousness from the healthcare clinic and user respectively. 

6.3 Patient Concerns 

6.3.1 Patient Privacy:

Prosthetic devices collect biological data such as neural signals and motor intentions in order to analyze and perform the required bionic movements as discussed in great length in previous sections. Ensuring secure data transmission and storage is critical to protect users, not only from potential privacy breaches but unauthorized access to data that could be tampered with and lead to harmful effects for the prosthetic device user. For example, Prochor and Frossard’s diagnostic device collects information from the sensors implanted in the bionic limb to monitor performance and make suggestions accordingly (Prochor et al., 2021). If one were to trifle with the sensory data – which would lead to misdiagnosis – it could put the user in severe harm’s way. 

6.3.2 Cost Effectiveness 

Advanced bionic technologies are often costly and require specialised surgical and rehabilitation procedures. Ensuring equitable access, particularly in underdeveloped regions or in struggling socioeconomic groups, presents a challenging situation pertaining to resource allocation, fairness and affordability. 

There is a clear disparity in prosthetic access between high-income and low-income regions. Prosthetic manufacturing is typically concentrated in developed countries. Hence, there is a major reliance on imports of these devices which presents logistical challenges such as long waiting times, high shipping costs, and high consumer costs. Moreover, there is a scarcity in prosthetic clinics and specialists who would be able to guide the user through their prosthetic device integration which can pose higher failure rates.

7.Emerging Fields

Given the latest innovations in bionic devices, the future will see bionic limbs into highly integrated, intelligent, and fully embodied systems capable of restoring function and sensation in  a manner that resembles human biology (Figure 8). 

7.1 Integration of Human Physiology, Prosthetics, and AI: 

Emerging research is increasingly focussing on integrated closed-loop systems that combine sensory feedback with motor control to create more natural and intuitive prosthetic functions. For instance, Pasluosta emphasizes the importance of bidirectional interfaces that can stimulate afferent pathways, improving one’s proprioception and enabling an increased sense of embodiment (2022). 

Future developments are likely to explore incorporation of physiological signals like temperature, pressure, and moisture too, which would enhance the user’s experience with their prosthetic limb. As Ortiz-Catalan showed, phantom maps and compact thermal stimulation devices that can be leveraged to provide thermal sensations for the user’s prosthetic limb (2024). Given the physical disadvantages – discomfort, heaviness, reduced mobility – that come with these early prototypes of these sensory components, it may not be practical to incorporate such devices in the short term. However, it provides the user an array of options that would allow them to customize their bionic device as they would desire.

7.2 AI in Decoding

AI, especially machine learning algorithms and techniques like reinforcement learning, is poised to exponentially improve prosthetic control systems. Freitag et al. illustrate how RL can optimize control policies for their recognition system pattern by training bionic hands in dynamic, game-like environments, making the decoding of signals more accurate (2023). Similarly, Schone et al. show how arbitrary control systems provide increased generalizations to new mappings after several rounds of training (2024). 

In the future, AI can be expected to enable prostheses to learn and adapt to individual users’ movement patterns relatively quickly and with accuracy, which not only personalizes the control but allows for a reduced adaptation period. 

7.3 Fully Implantable Systems

Powering advanced implanted neural interfaces and feedback mechanisms is a promising field for creating more self-sufficient and pain-free devices. Implantable systems like osseointegrated implants have been able to minimize experience of discomfort and enable bi-directional communication which allows for seamless limb operations. 

Such innovations make prostheses more autonomous and comfortable for users. As these become more refined, user intervention and device maintenance – in case of any movement malfunction or extreme discomfort –  will be minimized

8. Conclusion

Innovations such as bidirectional neural interfaces, sensory feedback mechanisms, reinforcement learning for control, and fully implantable energy solutions are demonstrating promising potential to enhance prosthetic functionality, comfort, and user experience. These developments could significantly improve the quality of life for amputees by providing prostheses that can restore biological limb functionalities in both movement and sensation.

The significance of these findings lies in their capacity to revolutionize prosthetic rehabilitation—transforming devices from merely functional tools into seamless extensions of the body, capable of restoring complex motor and sensory functions. The potential impact includes increased independence, reduced phantom limb pain, broader range of high-performance prosthetics, and a better overall quality of life for the amputee.

Looking ahead, there is a critical need for further research to integrate these emerging technologies into affordable, reliable, and user-friendly solutions. Future opportunities encompass developing fully autonomous, adaptive systems powered by AI, and expanding upon sensory feedback system designs to encompass as many environmental cues as possible. Beyond just technical work, ethical concerns need to be considered too so that the technology can reach substantially more people who are in need. Addressing these needs will be essential to realize fully functional, life-like prosthetic limbs that improve rehabilitation outcomes and profoundly enhance human mobility and perception.

About the Author

Tauhid Shifat A Noor received his B.Sc Degree in Mathematics-Computer Science from University of California, San Diego in 2024. His current research interests include retrieval-augmented generation, integration of large language models into applied domains, machine learning techniques in bionic solutions, and computer vision applications. 

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Bumbaširević, M., Lesic, A., Palibrk, T., Milovanovic, D., Zoka, M., Kravić-Stevović, T., & Raspopovic, S. (2020). The current state of bionic limbs from the surgeon’s viewpoint. EFORT Open Reviews, 5(2), 65–72. https://doi.org/10.1302/2058-5241.5.180038

Cho, Y., Jeong, H. H., Shin, H., Pak, C. J., Cho, J., Kim, Y., Kim, D., Kim, T., Kim, H., Kim, S., Kwon, S., Hong, J. P., Suh, H. P., & Lee, S. (2023). Hybrid bionic nerve interface for application in bionic limbs. Advanced Science, 10(35). https://doi.org/10.1002/advs.202303728

Dosen, S. (2023). Toward self-contained bidirectional bionic limbs with high information throughput. SCIENCE ROBOTICS.

Freitag, K., Laezza, R., Zbinden, J., & Ortiz-Catalan, M. (2023). Improving bionic limb control through reinforcement learning in an interactive game environment. ICML.

Frossard, L., Conforto, S., & Aszmann, O. C. (2022). Editorial: Bionics limb prostheses: Advances in clinical and prosthetic care. Frontiers in Rehabilitation Sciences, 3. https://doi.org/10.3389/fresc.2022.950481

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Ortiz-Catalan, M., Zbinden, J., Millenaar, J., D’Accolti, D., Controzzi, M., Clemente, F., Cappello, L., Earley, E. J., Mastinu, E., Kolankowska, J., Munoz-Novoa, M., Jönsson, S., Cipriani, C., Sassu, P., & Brånemark, R. (2023). A highly integrated bionic hand with neural control and feedback for use in daily life. Science Robotics, 8(83). https://doi.org/10.1126/scirobotics.adf7360

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About the author

Tauhid Noor

Tauhid Shifat A Noor received his B.Sc Degree in Mathematics-Computer Science from University of California, San Diego in 2024. His current research interests include retrieval-augmented generation, integration of large language models into applied domains, machine learning techniques in bionic solutions, and computer vision applications.

The post Toward Embodiment of Intelligent Prosthetics: Bidirectional Neural Interfaces and Adaptive Control Systems appeared first on Exploratio Journal.

‭Abstract‬

‭Elastin, a protein responsible for skin elasticity, undergoes damage during its lifespan‬ from several environmental and internal factors. This causes elastolytic activity and produces‬ elastokines, otherwise known as elastin derived peptides (EDPs), which are responsible for the‬ degradation of elastin. T helper cells, crucial in the adaptive immune response, are impacted by‬ the degradation of elastin. EDPs promote T cell differentiation in favor of Th-1 cytokines, IFN-y,‬ IL-2, and IL-12, by binding to the‬‭ 67-kDa spliced-galactosidase‬‭ (S-gal)–elastin receptors‬‭ (ERC)‬‭ .‬ The production of Th-2 cytokines counteracts Th-1 cytokines, and vice versa. Therefore,‬‭ EDPs‬ promotion of Th-1 subsequently suppresses the expression of Th-2 cytokines, IL-4, IL-5, IL-10,‬ and IL-13.‬‭ Optimal immune scenarios aim to have a‬‭ balance between Th-1 and Th-2, therefore‬ there is an imbalance favoring Th-1.‬‭ Elastokines support‬‭ the development of pathological‬ conditions, which includes but is not limited to, atherosclerosis, emphysema, and chronic‬ obstructive pulmonary disease. In addition, T helper cells are crucial for the immune system by‬ amplifying the immune response, regenerating tissue, and clearing infections. Thus, we‬ investigated the role of elastokines in wound healing and its effects on T-helper cells, specifically‬ Th-1 and Th-2, and hypothesized that EDPs would promote cytokine production and enhance‬ the Th-1 response to release pro-inflammatory signals. Our findings indicated that EDPs result‬ in the polarization of T helper cells in favor of Th-1 cytokine expression, subsequently‬ suppressing Th-2 cytokines.‬‭ Research indicates EDPs‬‭ upregulation of Th-1 can contribute to‬ cancer therapeutics.‬‭ However, excessive upregulation‬‭ of Th-1 phenotype can cause‬ autoimmune diseases in the central nervous system. Therefore, it is crucial to find a balanced‬ medium between Th-1 and Th-2 expressions.‬

‭ Keywords: elastin-derived peptides, TH-1, TH-2, adaptive immune system‬

‭Introduction‬

‭Elastin is a protein consisting of crosslinked tropoelastin polymer molecules bound‬ together in the extracellular matrix of tissue. It is responsible for the elasticity and the resilience‬ of tissues and organs. Elastin is durable and resistant, with a half life of approximately seventy‬ years during which it undergoes little turnover. Throughout this lifespan, it endures damage from‬ the aging process, UV radiation, environmental stressors, enzymic functions, and more. Loss of‬ elastic fiber functions can be caused by enzymic degradation, oxidative stress, binding to‬ proteins or lipids, calcium build up,‬‭ amino acid racemization,‬‭ protein modification, and‬ mechanism fatigue.‬‭ Degradation of elastin also occurs‬‭ when an organism acquires a wound,‬ which catalyzes the release of proteases. Elastin undergoes further enzymatic degradation‬ when exposed to proteases, particularly elastases, which has the ability to break down elastic‬ fibers. This elastolytic activity causes peptides with biological activity, elastokines, to be‬ released. The effects of elastases and elastokines on elastin cause damage to elastin‬ structures. Elastokines accelerate angiogenesis, upregulate cell activity including cell adhesion,‬ chemotaxis, migration, proliferation, proteases activation, and apoptosis. Elastases combined‬‭ with elastokines supports the development of pathological conditions, which includes but is not‬ limited to, atherosclerosis, emphysema, and chronic obstructive pulmonary disease (Heinz et‬ al., 2020). Inflammation is the body’s initial, essential response to injury, which is regulated‬ through T helper cells. It has been shown that EDPs activate the‬‭ 67-kDa spliced-galactosidase‬ (S-gal)–elastin receptors (ERC)‬‭ , which is associated‬‭ with cytokine production (Debret et al,.‬ 2005). Thus, we investigated the role of elastokines in wound healing and its effects on T-helper‬ cells, specifically Th-1 and Th-2, and hypothesized that EDPs would promote cytokine‬ production and enhance the Th-1 response to release pro-inflammatory signals. The role of‬ EDPs regulation of Th-2 cells remains unclear. Some evidence indicated it enhances the Th-2‬ response to combat infectious cells while others have seen a restriction in Th-2 activity.‬

‭The Immune System: T Helper Cells‬

‭ The immune system can be characterized into the innate and adaptive system, which‬ work together during wound healing. The innate system is a non-specific, rapid reaction and the‬ body’s first line of defense against foreign bacteria and viruses. The adaptive immune system is‬ a specialized, delayed wound healing reaction that targets specific pathogens not captured by‬ the innate system (NIH, 2006) (Figure 1). One cell type strongly affected by the degradation of‬ elastin is CD4+ T helper cells. T helper cells have five subtypes that each play distinct roles in‬ the immune response, Th-1, Th-2, Th-17, Tfh, and Treg cells. Th-1, which targets cell mediated‬ immunity and protective responses against pathogens, and Th-2, which promotes humoral‬ immunity and released anti inflammatory cytokines, are both part of the immune response that‬ trigger cell remodeling (Romagnani, 2007). Th-1 and Th-2 are produced during cellular immune‬ responses that play a pivotal role in the adaptive immune response. Cytokines are released by‬ the immune system to protect against inflammation when injury occurs, which include Th-1 and‬ Th-2 cells. EDPs cause the activation of cytokine production which subsequently increases‬ T-helper cell subpopulations (Debret et al., 2005). EDPs are a stimulus for Th-1 differentiation,‬ which is crucial for combating pathogens (Figure 2). It also induces a change in the Th-1‬ phenotype, which causes the secretion of MMP-9, thus promoting tissue remodeling (Maurice et‬ al., 2013). EDPs have been shown to downregulate pro-inflammatory cytokines, such as IL-1,‬ IL-6, IL-8, and TNF-a, in human monocytes, white blood cells crucial for innate immune‬ responses (Maurice et al,. 2013). Although EDPs enhance Th-1 cell response, on stimulation‬ Th-2 cells were reduced (Debret et al,. 2005). Taken together, these signals suggest that EDPs‬ are an important trigger for resolving inflammation and moving into a remodeling phase.‬

T helper cells are crucial components of the healing process by amplifying the immune‬ response, regenerating tissue, and clearing infections. Without T-helper cells, a host organism‬ would be unable to fight against microbes and the immune system would be severely‬ compromised (Alberts et al., 2002). Elastokines are typically considered detrimental because‬ they occur during the degradation of elastin. Less is known about their beneficial effects, such‬ as their signalling ability in immune cell migration. Little research has been conducted on the‬ interplay and communication between elastokines and other elastin receptors (Heinz et al.,‬ 2020).‬

‭EDPs effect on Th-1‬‭

EDPs are a crucial regulator for Th-1 activation. When testing the effects of EDPs on‬ human peripheral blood lymphocytes (PBLs), researchers exposed T cells to EDPs under‬ different conditions. This included activated, non activated, and cytokine induced T cells. Th-1‬ and Th-2 cytokine production was quantified to demonstrate which T helper cell was more‬ prevalent. They concluded that EDPs shifted T helper cells to Th-1 cytokine production (IL-2,‬ IFN-y, IL-12), therefore enhancing the Th-1 phenotype (Debret et al., 2005) (Figure 2). Th-1‬ cytokines are responsible for the proinflammatory responses to eliminate intracellular parasites‬ and enhance autoimmune responses (Berger, 2000). Therefore, EDP triggered upregulation of‬ Th-1 cells is likely an adaptive immune response indicating cellular immunity against pathogens‬ and other viruses.‬

‭EDPs effect on Th-2‬

‭ Although EDPs do not directly suppress Th-2, it occurs consequently through the‬ enhancement of Th-1. A surplus amount of proinflammatory cells can cause tissue damage,‬ thus revealing the necessity to mediate Th-1 overproduction. Th-2 cytokines, IL-4, IL-5, and‬ IL-13, produce IgE, a type of antibody. IgE has been shown to counteract IL-12, which is‬ produced by Th-1 cytokines, and skews T cell differentiation in favor of Th-2 production. Th-2‬ cytokines also cause the activation of eosinophilic which inhibits Th-1 activation. Th-2 cytokines‬ also include IL-10, which has an anti-inflammatory response. The production of Th-2 cytokines‬ therefore counteracts Th-1 cytokines, and vice versa. Therefore, since EDPs enhance Th-1,‬ they subsequently inhibit Th-2. Optimal immune scenarios aim to have a balance between Th-1‬ and Th-2. Previous studies indicate Th-2 can be reduced through increased allergen dosage,‬ mycobacterial vaccines, and pregnancy or early postnatal life (Berger, 2000).‬

Medical Use of T helper Cell Regulation‬

‭ EDPs upregulation of Th-1 could be beneficial in combating cancer. Upregulation of Th-1‬ response has demonstrated beneficial in curing tumors. In experimental mice with cancer, those‬ with recurring tumors experienced decreased levels‬‭ of CD44+3CD621- effector memory T cells‬‭.‬ Therefore, tumor relapse was associated with a return to Th-2 microenvironment‬‭. Mice who‬ remained regressed were observed to have increased Th-1 genes (Tbx21, IL12, IFNγ, and‬ TNFα) and low Th-2 genes (Gata3, IL4, TIM3) (Dai et al., 2018).‬

‭Excessive upregulation of Th-1, known as Th-1 dominance, can worsen organ specific‬ autoimmunity. Overexpression of the Th-1 phenotype can cause autoimmune diseases in the‬ central nervous system. Excess production of IFN-y has the potential to produce inflammatory‬ lesions and excess IL-12 can accelerate collagen induced arthritis. Current therapeutics to‬ mediate Th-1 dominance include‬‭ TNF-α inhibitors‬‭ ,‬‭ corticosteroids,‬‭ and immunosuppressants.‬‭ In‬ a study conducted on mice, a lack of Th-1 and upregulation of Th-2 protected the development‬ of T-bet diseases, a transcription factor crucial for immune responses (Dardalhon et al., 2008).‬ Th-2 dominance can be caused by allergic and autoimmune diseases. Therapeutics to combat‬ overexpression of Th-2 include Th-2 cytokine antibodies and mast cell stabilizers.‬

Conclusion‬

T helper cells’ response is crucial for understanding the immune system. Elastokines, a‬ typically negative bodily response to the degradation of elastin, have exhibited beneficial effects‬‭ in enhancing Th-1 cytokines and restricting Th-2 cytokines to produce a balanced immune‬ response. This is achieved by binding to the ERC which triggers an inflammatory response and‬ differentiation of T cells to the Th-1 phenotype. Th-1 cytokines then suppress the‬ over-expression of Th-2 cytokines, which fight against larger pathogens, but over-expression‬ can cause allergic diseases. EDPs interact with T helper cells to promote Th-1 differentiation.‬ The enhancement of Th-1 and cytokines it produces directly counteracts the expression of Th-2‬ cytokines. While elastokines have been suggested as an approach for treating osteoarthritis,‬ excessive upregulation of Th-1 can cause detrimental long term effects, causing the necessity to‬ find a mediated amount of Th-1 regulation. Since elastokines’ role is to upregulate tissue‬ damage and inflammation, using them to treat T helper cells is typically not a favorable‬ approach (Debret et al., 2005). Therefore, more research is necessary to not only focus on‬ upregulation of Th-1, but to find a balanced medium. Overall, less is known about the adaptive immune system. This research provides insight into the proinflammatory responses which occur‬ in the system and can be beneficial for improving or dictating new wound healing therapeutics.‬‭

Figure 1. Wound environment with upregulation Th-1. Th-1 comes first in the healing process‬ and releases cytokines (IFN-y, IL-2, and IL-12) responsible for inflammation. Then Th-2 releases‬ cytokines (IL-4, IL-5, IL-10, and IL-13) necessary for remodeling and tissue construction.‬

‭Figure 2: Elastin fragments attach to the ERC located on the native CD4+ T helper cell. This‬ interaction promotes Th-1 cell differentiation, causing more Th-1 to be produced than Th-2. The‬ cytokines from Th-1 are IFN-y, IL-2, and IL-12 The cytokines produced from Th-2 are IL-4, IL-5,‬ IL-10, and IL-13.‬

‭References‬‭

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About the author

Rose Filippazzo

Rose is a junior currently living in Brooklyn, New York. She enjoys taking Science Research classes through her school and is interested in pursuing a career in medicine. Outside of academics, Rose enjoys playing volleyball and helps lead several service endeavors, which include refurbishing and donating assistive technology to public schools and fundraising through the Anthony Filippazzo Grant for Williams Syndrome Research.

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Abstract

Parkinson’s disease is a progressive neurodegenerative disorder marked by motor and non-motor symptoms, primarily due to loss of dopaminergic neurons. Gene therapy presents a promising approach to address the molecular mechanisms of this disorder. This paper explores the genetic basis of PD, including monogenic forms involving mutations in the SNCA, LRRK2, VPS35, PINK1, PRKN and GBA genes that contribute to PD pathogenesis. Current gene therapy strategies involve gene delivery to control hyperexcitability of the subthalamic nucleus, restore dopamine biosynthesis, promote neuronal survival via neurotrophic factors and suppress α-synuclein aggregation. The progress of gene therapy procedures in both pre-clinical and clinical settings have been evaluated, demonstrating safety and efficacy in humans and highlighting their potential as gene-modifying targets. However, some challenges such as therapy delivery methods, vector cargo capacity, immune responses and transgene expression longevity still remain. Innovations in regulatory elements, vector design and surgical interventions offer hope for future breakthroughs.     

Introduction

Parkinson’s disease (PD) is a chronic, advanced neurodegenerative disorder characterized by a broad spectrum of symptoms. PD affects around 10 million people worldwide, and the prevalence is increasing. It has been nearly 200 years since PD was described and yet the initiating mechanism for this sporadic disease has not been fully elucidated. PD diagnosed by rigidity, bradykinesia, dystonia, postural instability, tremors and gait changes (motor symptoms). Non-motor symptoms include cognitive problems, anxiety, hallucinations and dysphagia. There is an amalgamation of genetic2 and environmental risks3. One of the major environmental risks is aging4. Other risks include familial inheritance, exposure to toxins such as pesticides5, industrial solvents and air pollution, and sex (males are more likely to develop PD)6. The pathophysiology of PD includes aggregation of α-synuclein (for PD with lewy bodies), loss of dopaminergic neurons and hyperexcitable neurons due to various gene changes. Monogenic PD exhibits mendelian inheritance through autosomal dominant mutations in SNCA and VPS35 genes, or recessive mutations in DJ1 and PINK1 genes7.

Many therapeutic interventions have been investigated to treat PD. These include the drug Levodopa8, a precursor to dopamine, which is one of the most effective treatments for managing motor symptoms, anticholinergics, deep brain stimulation9 and various physical therapies. 

Here, we will specifically discuss modern gene therapy technologies and their applications for treating PD. Gene therapy is an umbrella term that involves gene editing (modification of an existing gene), gene silencing (suppressing gene expression), gene supplementation (introducing a functional gene) and gene complementation (dysfunctional gene is complemented with a functional copy). While a small percentage of PD cases are directly attributed to specific genetic mutation, gene therapies that target an underlying molecular pathway associated with PD offer the possibility for a wide range of therapeutic strategies 10

Gene therapies under current clinical development for this disorder aim to restore dopamine production, survival of dopaminergic neurons, restore neural excitability, support lysosomal function, deliver growth factors and reduce α-synuclein expression 11.

Genetic Basis of PD

A significant amount of data has shown that risk for PD has a strong genetic basis 12. There are 3 main forms of Parkinson’s: Idiopathic PD is the most common type of the disease. The cause for this type is unknown, but is believed to be both genetic and environmental.

Juvenile PD is a rare form of the disease and refers to parkinsonian symptoms prior to the age of 21, usually due to mutations in parkin, PINK1 and DJ1 genes

Familial PD is inherited due to specific gene mutations. The pattern of inheritance differs based on the gene altered. Different mutations in different genes are linked to development of PD. A lot of them are missense mutations (codon changes by a single nucleotide resulting in a different amino acid at a single position). Other types include nonsense (premature stop codon due to single nucleotide change), frameshift mutations (deletion/insertion of one or multiple nucleotides) and deletions (segment of DNA is missing).  

Chromosomal mutations are observed as well. These include duplications (segments of DNA or even an entire chromosome has one or more extra copies) and triplications (a region of chromosome has 3 copies)13.                      

SNCA mutations

The first discovered genetic cause of PD was a mutation in the SNCA gene, which encodes a neuronal protein called α-synuclein. Pathogenic variants misfold, promoting a structural conversion to crossed β-sheet monomers and leading them to aggregate into structures called Lewy bodies (the pathological trademark of PD)14. Mutations in this gene are rare, with a frequency of 0.045% to 1.1%. They cause autosomal dominant PD. The mutations that cause PD can be missense, duplications or triplications. Individuals with triplications present a rapidly progressive PD with early onset and widespread Lewy body pathology. On the other hand, individuals with duplications resemble the phenotype of idiopathic PD.

The aggregation of α-synuclein is neurotoxic and is accelerated by SNCA pathogenic variants. Impaired mitochondrial respiration, energy deficits and altered lipid metabolism in dopaminergic neurons is also seen.

LRRK2 mutations

LRRK2 encodes the leucine-rich repeat kinase 2 protein which has both kinase and GTPase domains. Pathogenic variants lead to hyperactivation of the kinase domain15. 

Missense mutations in this gene were identified as an additional cause of autosomal dominant PD. On an individual level, LRRK2-PD is indistinguishable from idiopathic PD. However, it may display a milder phenotype, such as decreased likelihood of non-motor symptoms. The most common mutation is the p.G2019S mutation, with a prevalence of 1% of PD patients. Different mutations pose different risks of PD and have variable prevalence in different ethnic/regional groups of people, e.g. in Chinese populations the p.G2019S mutation is very rare, however the p.G2385R and p.R1628P variants are common 16.

VPS35 mutations

VPS35 (vacuolar protein sorting 35) encodes a component of the multimeric retromer complex, which mediates trafficking of endosomes. Pathogenic variants cause disruptions in endosomal transport and an unusual aggregation of α-synuclein. There may also be a defect in autophagy and membrane receptor cycling17.

VPS35 mutations are implicated in autosomal dominant PD. The overall prevalence of the only mutation (missense) confirmed, p.D620N, is 0.115% of PD patients. The median onset age is 49 years but the disease progression may be slower than other forms, with less cognitive impairment even after a decade of onset. 18

PINK1 and PRKN mutations

These two genes are considered together because mutations in both cause autosomal recessive PD, and both protein products impact mitochondrial function. 19

PRKN encodes parkin, an E3 ubiquitin ligase involved in the proteasomal degradation system. It also has a role in maintaining DNA integrity.  Mutations in PRKN are the most common cause of early onset PD. Slow disease progression and frequent dystonia are characteristic features. A variety of mutations including exonic deletions, duplications, missense and frameshift mutations are described, all of which cause a loss in the function of the PRKN gene20. 

PINK1 encodes PTEN-induced kinase 1, a serine/threonine kinase that has a mitochondrial translocation sequence 21. Although relatively rare, PINK1 mutations  are the second most common cause of

Table-1: Commonly mutated genes in PD

autosomal recessive PD. With a median onset age of 32, the disease is characterized by typical phenotypic features such as bradykinesia, but there is a higher rate of psychiatric manifestations than PRKN mutations. The major type of mutations are missense and nonsense which cause loss of function. These two genes interact within the ubiquitin-proteasome system and maintain mitochondrial quality. Parkin ubiquinates the outer mitochondrial membrane proteins while PINK1 phosphorylates parkin, which helps regulate parkin’s role in mitochondrial stabilization. Pathogenic variants likely disturb the PRKN/PINK1-mediated mitophagy22. Furthermore, mutations in LRRK2 also interfere in this process. 23

GBA mutations

Pathogenic GBA variants, found in 5-15% of PD patients, are the most common genetic risk factor for the disease. This gene encodes glucocerebrosidase (GCase)24. Biallelic variants can cause Gaucher disease (GD), a lysosomal storage disorder. The interest of these mutations as a risk for PD arose when clinicians noticed GD patients develop parkinsonism. Both pathogenic and non-pathogenic variants of GBA are common in PD, with a more aggressive course in terms of dementia and motor development. A recent genetic study about the pathogenic variants of genes that cause lysosomal storage disorders (LSDs) found that more than 50% of the individuals with PD carried variants linked to those genes and there was evidence for burden of damaging alleles associated with risk of PD25. Mutations in the GBA1 gene have attracted the most attention because they are extremely prevalent and increase the risk of PD by 5-30 fold 26.

In contrast to many other genes implicated in monogenic PD, the biological role of GBA is well understood. GCase is a lysosomal hydrolase that breaks down glucosylceramide (GluCer) to ceramide and glucose in the lysosomes. GBA mutants have differential effects on the enzyme’s activity and its trafficking within cells: there is a reciprocal relationship between GCase activity and α-synuclein  aggregation, endoplasmic reticulum stress, defective autophagic-lysosomal pathway, dysfunction of lipid homeostasis and neuroinflammation27.  

Modern Gene Therapies and their Applications to Parkinson’s

In preclinical studies, researchers have sought to select the best animal model to evaluate PD. Most PD gene therapy studies use 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 6-hydroxydopamine (6-OHDA) or synucleinopathy, commonly induced in rodents to develop parkinsonian symptoms 28.           

Enzyme replacement therapy (ERT) is a widely used gene therapy for PD, in which inactive/absent enzymes are replaced with functional enzyme molecules by injecting the genes that encode them. Substrate reduction therapy (SRT) aims to restore metabolic homeostasis by limiting the amount of substrate synthesized, to a level that can be effectively cleared by the impaired enzyme . 

The first step towards an effective gene therapy is engineering a suitable vector. Viruses such as adenovirus and lentivirus are popular as a vector because of their capability of carrying transgenes and delivering them efficiently to target cells29. Each viral vector system comes with its challenges for consideration, which include size of transgene cassette, immunogenicity, cytotoxicity and insertional mutagenesis. In this paper we will discuss about some developing gene therapies targeting various molecular symptoms of PD.

Controlling hyperexcitability

A significant consequence of dopamine loss in basal ganglia, specifically the striatum, is an increase in the excitatory neuronal activity in the subthalamic nucleus. The depolarization pattern of the STN is affected in the form of increased firing frequency (∼30 Hz) along with spike bursts of activity with subsequent hyperpolarization. The excitatory signal affects the internal globus pallidus (GPi) and substantia nigra pars reticulata (SNr). Increased activation of GPi and SNr exerts inhibitory effect on the thalamocortical circuits resulting in the classic parkinsonian motor symptoms 30. A gene therapy that uses a recombinant AAV vector system to deliver glutamic acid decarboxylase (GAD) is being explored as an attractive potential therapy31. GAD catalyzes the conversion of glutamate to gamma aminobutyric acid (GABA), an inhibitory neurotransmitter that controls neuronal firing. The therapy consists of a 1:1 ratio of recombinant AAV (rAAV) encoding the two isoforms of GAD cDNA, GAD65 and GAD67. Transgene expression was driven by CMV/CBA promoter and WPRE viral enhancer.                       

An early study investigating this gene therapy in 6-OHDA parkinsonian rats found it to be both well tolerated and able to diminish parkinsonian motor symptoms. The authors even found the therapy to exert neuroprotective effect on nigral neurons32.                                                

A phase 1 human trial conducted between 2005 and 2007 also demonstrated effectiveness. 12 patients with PD were recruited and divided into 3 groups. They were treated with either a low (10¹¹ vg/ml), medium (3 × 10¹¹ vg/ml) or high dose (10¹² vg/ml) of rAAV-GAD via a cannula into the subthalamic nucleus for 1 hour 40 minutes. Significant improvements in motor UPDRS (unified Parkinson’s disease rating scale) scores were observed at 3 months post-surgery and remained evident until 12 months. This led to a phase 2 placebo-controlled trial, with 44 patients having advanced PD. They received bilateral injections of rAAV-GAD in the STN at a vector concentration of 10¹² vg/ml via a cannula for 2.5 hours. Six months after delivery motor UPDRS scores improved by 23.1% as compared to patients with sham surgery, which persisted for an year after the surgery 33.

Restoring dopamine production

In PD, the loss of dopaminergic neurons in the substantia nigra is a key characteristic which cause reduced dopamine levels. Dopamine replacement therapy, which uses drugs (e.g. Levodopa) to replenish dopamine levels, is the primary treatment for PD. Levodopa is a precursor to dopamine and can cross the blood brain barrier where it is converted to dopamine by dopa decarboxylase. To prevent peripheral conversion, a dopa decarboxylase inhibitor is typically administered alongside. This inhibitor is unable to cross the BBB, which results in levodopa being converted to dopamine inside the midbrain.                                                             

An enticing gene therapy approach to treat dopamine loss is to entirely reconstruct the dopamine synthesis machinery at a specific tissue in the midbrain. In this approach, a lentiviral vector is used to deliver 3 transgenes: tyrosine hydroxylase (TH), GTP cyclohydrolase I (GCH1) and aromatic L-amino acid decarboxylase (AADC). TH converts tyrosine to  l-3,4-dihydroxyphenylalanine (l-DOPA), which then gets converted by AADC to dopamine. GCH1 is the rate limiting enzyme in the production of tetrahydrobiopterin, a cofactor of TH 34. ProSavin is a tricistronic lentiviral vector coding TH1, AADC, and GTPCH and was the first lentiviral-based gene therapy vector for a chronic neurodegenerative disorder of the CNS to be tested in humans35.                                                                                        

In another study, the vesicular monoamine transporter (VMAT2) gene was added to TH, GTPCH and AADC to form a four-gene vector in a helper virus-free HSV type 1 vector. This controlled not only dopamine production, but also dopamine release. VMAT2 transports dopamine into synaptic vesicles supporting regulated vesicular release of dopamine, thereby relieving TH from dopamine feedback inhibition 36.                                                                                            

In patients with PD, AADC activity is decreased due to autosomal recessive pathogenic mutants of dopa decarboxylase (DDC) gene, causing defective dopamine synthesis. This depletion of AADC activity could be an important etiology of movement disorders. The overexpression of AADC in rodent37 and non-human primate38 model studies showed therapeutic potential for PD.                                                                                                                         

A phase 1 human trial in 2019 was conducted to check the safety and tolerability of the AAV-AADC therapy. The study was run by  Michael J. Fox Foundation, Voyager Therapeutics, Inc., and Neurocrine Biosciences, Inc. VY-AADC01 consists of recombinant AAV2 capsids carrying the cDNA of the human AADC gene under the control of the cytomegalovirus immediate early promoter. 15 subjects were divided into 3 cohorts and received different concentrations of the treatment: Cohort 1 received 8.3 × 10¹¹vg/ml and up to 450 μl per putamen for a total dose of up to 7.5 × 10¹¹vg; cohort 2 received the same concentration of 8.3 × 10¹¹vg/mL and up to 900 μl per putamen for a total dose of up to 1.5 × 10¹²vg; and cohort 3 received a higher concentration of 2.6 × 10¹²vg/ml with the same volume as cohort 2 of up to UPDRS s UPDRS scores were recorded. AADC enzyme activity correlated with treatment dosage increase, improving UPDRS III scores, motor fluctuations and overall quality of life. In general, participants reported improvement in motor functions at 6 months, which increased at later timepoints. Cohorts 2 and 3 showed good improvement in responses at 12 months. 

Table-2: Clinical trials for PD gene therapy

Delivering neurotrophic factors

Naturally occurring proteins that support the growth, differentiation, functioning, survival and synaptic plasticity of neurons are called trophic factors. Some trophic factors have the potential to protect or regenerate progressively damaged dopaminergic neurons in PD patients. Particular focus has been placed on the glial cell-line derived neurotrophic factor family of ligands (GFL) that encompass glial cell-line derived neurotrophic factor (GDNF), neurturin (NRTN), artemin (ARTN) and persephin (PSPN). The GFL signals by activating the RET receptor complex with the GDNF family receptor α (GFRα), initiating the MAP kinase and PI3-kinase pathways that promote neuronal survival and neuritogenesis. Activation of GFRα also activates transcription factors Nurr1 and Pitx3 which are crucial for the activation of the gene which induces expression of AADC.

GDNF is a potent factor associated with survival and regeneration, along with maintenance of dopaminergic neurons. Several clinical trials have assessed the intraputaminal infusion of GDNF 40. One was a phase 1 safety study of AAV2-GDNF infused via CED into bilateral putamina of adult patients with PD. Four escalating dose levels were administered to 6 patients per cohort: 9 × 10¹⁰vg, 3 × 10¹¹vg, 9 × 10¹¹vg and 3 x 10¹² vg. For each outcome measure, a repeated-measures analysis of variance (RM-ANOVA) examined the effect of time on [¹⁸F]FDOPA (fluorinated L-dopa) values, UPDRS score, and TLED (total levodopa equivalent doses). Increased FDOPA uptake was recorded with increase in concentration, indicating GDNF expression. However, no statistically significant changes in UPDRS scores were observed between dose cohorts 41. A phase 2 study began in mid-2024 where moderately affected PD patients received the same gene therapy, the results of which are yet to be published.

NRTN is another important trophic factor known to exert protective effect on dopaminergic midbrain neurons. It uses roughly the same molecular pathway as GDNF. A phase 1 trial of PD patients receiving bilateral intraputaminal injections of AAV2–NTRN (CERE-120) was conducted. Individuals received dosage in two groups: 1.3 × 10¹¹ and 5.4 × 10¹¹ vg, and it was found to be safe and well tolerated. However, it did not change UPDRS scores after 12 months 42. A subsequent phase 2 study to evaluate the safety and efficacy of AAV2–NRTN in a double-blind randomized trial with 34 patients were enrolled who received 40 μL per hemisphere of AAV2-NTRN (5.4 × 10¹¹ vg/mL). This cohort, however, did not experience clinically significant improvements compared to a placebo group, at 12 months following the infusion43. A long-term and postmortem analysis of patients who received the therapy for 10 years revealed that although transgene expression could persist long term, it did not produce clinical improvements. Investigators hypothesized the lack of efficiency to be a result of failure of retrograde transport of the vector from putamen to substantia nigra. Another phase-1 study was conducted, where CERE-120 was bilaterally delivered to 6 subjects in two dosage groups, to both the substantia nigra (SN) and the putamen. The procedure was well-tolerated, with no adverse effects over the two year follow up44.

GBA1 Delivery

Substantial evidence highlights the importance of lysosomal mechanisms in PD pathogenesis and susceptibility. The GBA gene encodes for GCase, deficiency of which causes accumulation of GluCer and other glycolipids, leading to neuroinflammation and toxicity. GCase has also been hypothesized to impact α-synuclein aggregation. Therefore, a viable gene therapy strategy would be to increase GCase activity to enhance the functioning of lysosomes and limit the aggregation of α-synuclein. This is supported by several studies utilizing experimental mouse models of PD. They have demonstrated that restoring GCase activity through viral-mediated delivery of GBA1 is sufficient to rescue α-synuclein pathology, reduce neuroinflammation and gliosis, and prevent cognitive and motor deficits. The delivery of GBA1 cDNA in the AAV9-PHP.B vector (GBA1-P2A-GFP) was sufficient to prevent the formation of insoluble α-synuclein deposits across multiple brain regions in a A53T-SNCA transgenic mouse model of PD45.

Patients with GBA1-PD often exhibit a more aggressive disease phenotype, requiring more intensive treatment strategies to counteract poor prognosis. ERT and SRT are being studied as effective approaches. The major roadblock with them is that the recombinant forms of GCase cannot penetrate through the BBB. AAV-GBA1 delivery directly into the midbrain circumvents the problems with the BBB and the short half-life of recombinant enzymes.

Based on these promising preclinical studies, 3 clinical trials, sponsored by Prevail Therapeutics, were conducted. Although all 3 use the same gene therapy, only one of these involves patients with PD. First is the PROPEL study, a phase 1/2a trial of PR001(aav9 recombinant vector) on individuals who carried at least one GBA mutation. It began in 2020 with 20 individuals split into high and low dose groups (dosage not disclosed), and PR001 was administered by intracisternal injection. During the first year, patients will be evaluated for the effect of PR001 on safety, tolerability, immunogenicity, biomarkers, and clinical efficacy measures. Patients will continue to be followed for an additional 4 years to continue to monitor safety as well as selected biomarker and efficacy measures. PROVIDE is a phase 1/2 study to evaluate a single intravenous dose of PR001 in infants with type-2 GD that started in 2021. PROCEED is a phase 1/2 study to evaluate a single intravenous dose of PR001 in patients with peripheral manifestations of GD that started in 2022. All three studies are currently ongoing, with results expected to be released by 2028 for PROVIDE, 2029 for PROPEL and 2030 for PROCEED trial.                        

Considerations for Future Research and Treatment

Despite decades of research, two main problems persist in this field. The first is the difficulty in delivering the vector system to the target tissue, and the second is inadequate expression of the transgene and small size of the transgene cassette.

Promoters in the transgene cassettes should be optimized for specific needs such as tissue type and level of expression. The specificity of transgene expression within the targeted tissues is crucial in order to achieve sufficient transduction efficiency with low dosing and to minimize off-target effects. Additional regulatory elements such as enhancers can be engineered to improve expression activity and specificity46.

Riboswitches are non-coding RNAs that can bind specific metabolites and control gene expression47. Using them over other regulatory systems has the advantages of being compatible with FDA-approved drugs, negligible immunogenicity and short length of the sequences, which is particularly useful when combined with the limited packaging capacity of rAAVs, making it a powerful system for regulating rAAV-based gene therapy48.

Although AAV has a lower immunogenicity than other viruses, it has been reported that it can trigger pre-existing immunity, innate immunity, and adaptive immune responses against the vector49. These reactions can hinder therapeutic effectiveness in clinical applications. A potential solution to suppress AAV-neutralizing antibodies is to introduce bacterial endopeptidases such as imlifidase (IdeS) concurrent with drug administration that degrade circulating immunoglobin G (IgG) molecules, and thus allow better vector transduction50. Another strategy to counter AAV antibody response is to block toll-like receptor 9 (TLR9), an immune sensor of DNA, through the administration of specific single stranded DNA oligonucleotides (termed “TLR9i”). TLR9i sequences can be directly incorporated into the vector genome to dampen immune responses51. Furthermore, many gene therapy trials use a triple immune suppression regimen that includes steroids, rituximab, and rapamycin.                                                           

The cargo capacity of the virus is another topic of consideration, as many strains demonstrate very limited transgene capacity. The small size of AAV for example, allows only about 4.7 kilobases of foreign DNA to be packaged, which is a major drawback52. The HSV-1 amplicon system provides an opportunity to address this, with the potential to deliver transgenes of up to 150 kb. This uniquely large cargo capacity has been shown to support the delivery of large genomic DNA sequences expressing neurological disease genes53. HSV-amplicon-based delivery of a Parkinson’s gene into the nigrostriatal system has shown to work effectively in mice, suggesting that such an approach could be used for delivering an entire locus to correct a mutation of PD genes 54.

Treatment administration still remains one of the greatest challenges to effectively deliver a gene therapy. Most clinical trials use a cannula to directly deliver the viral vector to the targeted brain tissue, however the technology and rates of infusion vary across studies. Intraparenchymal, intravenous, intracerebroventricular and intrathecal delivery are some approaches for transducing the CNS55. Direct intraparenchymal delivery into the brain is an effective way to reduce the dose/volume of AAV required and thereby alleviates concerns regarding off-target delivery and extra-cranial side effects56. A pre-clinical approach to improve this method is to utilise focused ultrasound to increase the permeability of the BBB within the target tissue, in company with peripheral vascular delivery of the rAAV within microbubbles57. Rodent studies with this technique have shown good biodistribution within targeted brain regions.     

Gene therapy with optogenetics58 or chemogenetics59 could also prove to be a viable alternative to treating PD because they provide a more specific intervention than deep brain stimulation (DBS) or ablation. Editing the genome with CRISPR-CAS9 technology60 61might be another successful upcoming form of personalized gene therapy.

As the field of gene therapy progresses, new genetic targets and gene editing technology would evolve. More therapies for neurodegenerative diseases would emerge, which target successful delivery and sustained gene expression. Furthermore, the role of neurosurgeons may be key in developing surgeries to this complex problem. In conclusion, while challenges remain prevalent in this field, encouraging studies, pre-clinical and clinical trials suggest that we can remain optimistic about the future of gene therapy for PD. 

Abbreviations

PD                 Parkinson’s disease
LRRK2           Leucine-rich repeat kinase
VPS35           Vacuolar protein sorting
PRKN             Parkin
PINK1            PTEN-induced kinase
LB                   Lewy Body
EOPD             Early onset PD
ER                   Endoplasmic reticulum
GCase            Glucocerebrosidase
GD                  Gaucher disease
GluCer           Glucosylceramide
MPTP             1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
6-OHDA         6-hydroxydopamine
ERT                 Enzyme replacement therapy
SRT                 Substrate reduction therapy                                                                                    
STN                Subthalamic nucleus
SNr                 Substantia nigra pars reticulata
SN                   Substantia nigra
GPi                 Internal globus pallidus
GAD                Glutamic acid decarboxylase 
GABA              Gamma aminobutyric acid
rAAV               Recombinant adeno associated virus
CMV/CBA       Cytomegalovirus/Chicken β-actin
WPRE              Woodchuck hepatitis virus post-transcriptional regulatory element
UPDRS             Unified parkinson’s disease rating scale
BBB                  Blood brain barrier
TH                    Tyrosine hydroxylase
AADC               Aromatic L-amino acid decarboxylase
GTPCH              GTP cyclohydroxylase I
CNS                   Central nervous system                                                                                             
l-DOPA              l-3,4-dihydroxyphenylalanine                                                                                  
VMAT2              Vesicular monoamine transporter                                                                             
DDC                   Dopa decarboxylase
MRI                    Magnetic resonance imaging                                                                                      
CED                    Convection enhanced delivery                                                                                 
GFL                    Glial cell-line derived neurotrophic factor family of ligands
GDNF                 Glial cell-line derived neurotrophic factor
NRTN                  Neurturin
ARTN                  Artemin
PSPN                   Persephin
GFRα                  GDNF family receptor α
RM-ANOVA        Repeated measures.analysis of varianc
FDOPA                 Fluorinated L-dopa 
TLED                    Total levodopa equivalent doses
IdeS                      Imlifidase 
IgG                       Immunoglobin G
TLR9i                   Toll-like receptor 9 inhibitory
HSV-1                   Herpes simplex virus 1
vg                          Vector genome
kb                          Kilobase                

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About the author

Aneesh Rajput

Aneesh is currently studying in grade 12 at Lotus Valley Noida. In the past two years he has developed a strong passion for molecular biology and has decided to pursue it as a career. Although Aneesh has worked on projects related to the field before, this is his very first research paper. He is also a core member of a band, Music Factory, and actively participates in a plethora of social service events. Apart from this, he likes to write and sketch during his leisure time.

The post Targeting the genetic basis of Parkinson’s disease: A review of gene therapy approaches appeared first on Exploratio Journal.

Abstract

Artificial intelligence (AI) has rapidly advanced into domains once considered uniquely human, raising urgent questions about the nature and limits of machine creativity. This paper reviews current evidence by analyzing AI performance on established creativity measures such as the Alternative Uses Task (AUT) and the Torrance Tests of Creative Thinking (TTCT). Results show that models like GPT-4 rival or even surpass average human scores in fluency and originality, suggesting strong competence in combinational and exploratory creativity. However, AI still falls short in transformational creativity—the radical, paradigm-shifting insights that redefine domains—due to its lack of curiosity, anomaly detection, emotional grounding, and embodied experience. While AI can expand the idea space and act as a powerful creative collaborator, concerns remain about algorithmic homogenization and the potential downgrading of human creative confidence. Drawing on perspectives from psychology, philosophy, law, and human–AI collaboration research, this paper argues that AI’s role is best understood as that of an amplifier and assistant rather than an autonomous inventor. Ultimately, the boundary between remix and revelation highlights both the impressive potential and the enduring limitations of artificial creativity, with implications for intellectual property law, cultural production, and the future of human imagination.

Key Terms Table

• Novelty: Degree to which an idea or output differs from known examples or reference sets; can be measured statistically (semantic/image distance) or subjectively
• Transformational Creativity: Creativity that alters the defining rules, constraints, or conceptual spaces of a domain
• Combinational Creativity: Creativity achieved by combining previouslyunrelated ideas or concepts
• Algorithmic flattening: Hypothesized narrowing of creative diversity due to model training biases and averaging tendencies, reducing variance in outputs
• Torrance Tests of Creative Thinking (TTCT): Standardized test assessing divergent thinking and other creative abilities through structured tasks, scored for fluency, originality, elaboration, and flexibility.

Introduction

Throughout the entire history of the human race, creativity has been considered an exclusively human trait — a blend of imagination, intuition, and lived experience that machines cannot replicate. Now with recent advances like GPT-5, AI is expanding into domains once thought to be uniquely human, prompting renewed urgency in asking what creativity truly means. From generating images to crafting poems to producing research papers, today’s AI capabilities are raising the question of whether these AI models represent true creativity or are just recombining old human work.

First, this review clarifies and defines creativity using frameworks before jumping in and testing AI against such definitions. Tests such as the Alternative Uses Task (AUT) and Torrance Tests of Creative Thinking (TTCT) are used to examine where AI’s abilities align with human creativity and where they diverge. Finally, this review considers what the future implications are for law, collaboration, and authorship, including its impact on human creative practice.

Defining Creativity

Figure 1: Frameworks of Creativity

(a) Three Components of Creativity. Creativity has external, subjective, and social dimensions: the external focus on whether an output is novel and useful, the subjective on the mental processes of insight and refinement, and the social on how communities judge value. Together, these show that creativity is not just a product but also a process shaped by context (Mammen et al., 2024). (b) The Four C’s Model. Creativity ranges in scale: mini-c (personal learning), little-c (everyday expression), Pro-c (professional innovation), and Big-C (paradigm-shifting breakthroughs). Most human and AI creativity falls in the first two levels, while Big-C remains rare (Kaufman & Beghetto, 2009). (c) Boden’s Three Types. Creativity can be combinational (rearranging ideas), exploratory (pushing within existing rules), or transformational (changing the rules entirely). AI excels at the first two, but transformational creativity is still largely human-driven (Boden, 2014). Together, these frameworks map the landscape of creativity across processes, products, and scales, providing a foundation for evaluating AI alongside humans.

Creativity as Product

At the simplest level, creativity shows up in the things people make, like a new TikTok trend or clever science project. For something to count as creative, it usually needs two components: it should be novel (new) and it should be valuable in some way (Zhou & Lee, 2024). As psychologist Anna Abraham explains, it’s not enough to just be different. A creative combination like matcha and rice might be “new,” but unless it works — tastes good, solves a problem, or moves people — it doesn’t feel creative. Margaret Boden, one of the most influential philosophers of creativity, breaks novelty into two types: P-creativity, new just to you, like inventing a new way to decorate your room, and H-creativity, new to human history, like when Einstein introduced relativity (Boden, 2014). Both matter, and both give us a way to ask: when AI generates an artwork or idea, is it doing something new just for us, or something genuinely groundbreaking?

Creativity as Process

However, creativity is more than just the final product; it’s also about the process of getting there. Psychologists J.P. Guilford and later E. Paul Torrance described this process as a balance between divergent thinking — brainstorming wild, out-of-the-box ideas, like all the weird uses you could imagine for a paperclip, and convergent thinking — narrowing them down to the ones that actually make sense (Ding & Li, 2025). Humans also bring in qualities AI lacks: things like curiosity, emotion, and those sudden “aha!” moments when a solution clicks. For visualization, picture the process of planning a vacation. Divergent thinking is brainstorming destinations, throwing out all the different, wide-ranging, and free-flowing ideas. On the other hand, convergent thinking is choosing the destination. The group considers practical constraints like budget, time off, and personal preferences to narrow the list down to the single best option.

Creativity as Scale

Finally, creativity comes in different sizes and levels. James Kaufman and Ronald Beghetto’s Four Cs model lays this out nicely. There’s mini-c, which are personal insights; little-c, which is everyday social creativity, like making up a joke in a conversation; pro-c, expert-level creativity in a career, like a coder designing a new algorithm; and finally big-c, the kind of genius that changes history like Steve Jobs or Picasso. This framework will be key later on once as we start to see where AI’s creative limits fall on this spectrum through various tests. Boden adds another helpful layer to this idea of creativity on a scale. She adds that some creativity is combinational (remixing old ideas), some is exploratory (pushing boundaries within a system), and some is transformational (changing the rules altogether) (Boden, 2014). For humans, creativity can stretch across all these levels. For AI, the story is more complicated. It’s already powerful at combinational and sometimes pro-c creativity, but whether it will ever touch big-c, transformational breakthroughs is still very much an open question.

Where and How AI’s Creativity Excels

Figure 2: Standardized Tests of Creativity

(a) The Alternative Uses Task (AUT) measures divergent thinking by asking participants to propose as many uses as possible for a common object (e.g., a brick or a paperclip). Scoring emphasizes fluency, originality, flexibility, and elaboration. (b) The Torrance Tests of Creative Thinking (TTCT) use both verbal and visual prompts to assess originality, elaboration, abstractness, and resistance to premature closure. These tools remain the most widely used benchmarks for comparing human and AI creativity (Haase & Hanel, 2023).

Alternative Uses Task (AUT):

One of the simplest and most famous creativity tests is the Alternative Uses Task (AUT), first popularized by J.P. Guilford in the 1960s. The challenge is straightforward: take an everyday object, like a brick or a paperclip, and come up with as many unusual uses for it as possible. Humans usually shine here because our brains make odd connections: a brick can be a paperweight, a stepstool, or even a doorstop. What’s shocking is that today’s AI models are catching up. Where older AIs struggled to go beyond direct and obvious uses like “a knife for cutting food”, newer systems like GPT-4 produce long, creative lists that rival the best human responses. This is a significant leap from GPT-3, a model almost any human can beat. In fact, GPT-4’s top outputs in the AUT are now better than about 90% of human participants. To illustrate its significance, GPT-4 was only released a few years after GPT-3, and AI’s advancement and evolution potential does not seem to slow down anytime soon (Haase & Hanel, 2023).

Torrance Tests of Creative Thinking (TTCT):

Another more comprehensive test called the Torrance Tests of Creative Thinking (TTCT) was used to measure AI’s creativity. Designed by psychologist E. Paul Torrance, the TTCT measures different aspects of divergent thinking, like fluency (how many ideas you generate), flexibility (how different the ideas are), originality (how rare they are), and elaboration (how detailed they get). These tests have been used for decades to spot gifted kids and track creative growth over time. What’s surprising is that GPT-4 doesn’t just keep up. In some cases, it actually outperforms the human average (Haase & Hanel, 2023). For example, when scored on fluency and originality, its responses are judged as more creative than many human test-takers. We can take from these findings that AI is, without a doubt, at least starting to “look” creative, whether or not it truly is or isn’t. It’s important to note that tests like AUT and TTCT are designed only to test mini-c and little-c levels of creativity, as formulating tests for pro-c and big-c require years of domain experience. In other words, you can’t measure pro- or big-c-level creativity with a quick brainstorming task; it emerges only after long and specific training in a certain field.

What These Results Really Mean: Remix Masters, Not Rule-Breakers

So, does passing these tests mean AI is truly creative? Here’s where it gets tricky. Under Boden’s framework for the three kinds of creativity (combinational, exploratory, and transformational), we can conclude that AI is undeniably strong in the first two. It can remix patterns from its training data into fresh combinations faster than any human, which explains why it shines on tests like the AUT and TTCT (Boden, 2014). One study even shows that AI tends to expand the overall “idea space”: while its average novelty may be lower than a human’s, the maximum novelty, those rare outlier ideas, often rise when AI is in the mix (Zhou & Lee, 2024). In other words, AI sometimes surprises us with ideas no individual human would have considered, simply because it can churn through countless recombinations. Overall, these strengths are real and impressive, but they also hint at the limits we’ll uncover in the next section.

It’s also important to note that these tests were done on AI models that were accessible to the general public, like ChatGPT. Models like these are censored, limited, and hindered for obvious security reasons, meaning the clarification must be made that it’s not that Artificial Intelligence in general can’t achieve such creative thresholds, just that the restricted models that were tested were. There may be secret, unhinged AI models that reveal such capabilities.

Where AI Creativity Falls Short

No Curiosity, No “Aha” Moments

One of the clearest limits of AI creativity is that it has no genuine curiosity or capacity for sudden epiphany. Humans often spark new ideas by noticing anomalies, that weird result in an experiment, the unexpected twist in a conversation, and asking, what if? Psychologists call this the “aha moment,” when something clicks in a way that reshapes your thinking. AI doesn’t do this. Studies show it tends to treat every output as expected and rarely adjusts when evidence contradicts its assumptions (Ding & Li, 2025). Simply, it’s stubborn. Humans notice when the math doesn’t add up or when an experiment produces something strange, and that sparks new theories. AI, by contrast, often doubles down on its first guess; confident, but wrong. If Einstein had been like today’s AI, he would have ignored the oddities in Newton’s physics and kept grinding out the same equations. Without curiosity or the instinct to pivot from anomalies, AI struggles to produce the kind of breakthroughs that drive transformational creativity.

Take a look at how AI is actually being used in climate science for example. Google’s NeuralGCM can process 40 years of weather data and match existing climate models for accuracy, but it still struggles with the extremely unexpected. As one NASA climate scientist notes, climate models face the challenge of “simulating conditions more extreme than any previously observed” (The Economist, 2024). This is exactly the kind of anomaly detection that drives scientific breakthroughs. It’s bounded by its known parameters, and while it may excel within that system, it means that it will struggle when reality doesn’t match its training data or the expected.

Figure 3: This flow chart contrasts AI’s process (pretrained knowledge → pattern matching → limited hypothesis set → no anomaly detection) with human scientific reasoning (observation → anomaly detection → hypothesis → experiment/revision). It illustrates why AI lacks “aha moments” and curiosity.

No Emotional Evaluation or Embodied Knowledge

Creativity is also tied to our emotions and our bodies. A painting feels powerful not just because of how it looks, but because it stirs something in us, emotions like awe, joy, or even discomfort. Humor works the same way: a joke lands because it makes your chest tighten with laughter. As scholars point out, AI lacks both emotional evaluation and embodied knowledge (Slack, 2023). It can generate jokes or images that look like art or humor, but it doesn’t know why they matter, why they’re moving, or why they’re funny. Why does this matter, and how does it connect to its creative abilities? Without a body to experience the world, the shiver of cold water, the ache of heartbreak, the thrill of scoring a goal, it misses a core ingredient of human creativity. This absence makes AI outputs impressive on the surface but hollow underneath. It lacks a soul, a voice, that is vital for the human creativity experience. This is more a philosophical argument rather than a technical one, as it pushes the idea of an entity lacking creative abilities because it lacks the emotional capabilities to create.

Homogenization and the Downgrading of Human Creativity

Finally, there are real concerns about how AI affects our creativity. With overusage and overreliance of AI, research suggests that people are beginning to lose their curiosity and confidence in their own ideas. Teenagers, for instance, have reported that their writing feels less original after leaning heavily on AI prompts. We can attribute this to a concept known as algorithmic flattening. This is the process by which algorithms reduce a complex, multidimensional entity or concept into a single, simplistic metric or ranking, often losing critical context and nuance in the process. As a result, creative outputs start to look and sound the same, narrowing our imaginative and creative angles (Mammen et al., 2024; Haase & Hanel, 2023). Instead of opening up new directions for possibility, overreliance on AI risks nudging both individuals and society toward sameness and conformity. This tendency makes sense for AI models. They are trained to spit out the most probable or most likely answer from their training data. What computer wouldn’t go against the odds? In contrast, humans often make decisions that defy probability or logic, and it is precisely these imperfect, unexpected leaps that ironically give humans that true sense of individuality and creativity.

Future Implications and Conclusion

Figure 4: The Evolution of AI Regulations & Frameworks

This timeline illustrates key legal landmarks shaping AI and creative ownership. From early privacy laws like GDPR, it progresses through the U.S. Copyright Office’s formal reaffirmation that only “human-authored” works qualify for copyright, exemplified by rulings such as Thaler v. Vidal and the rejection of AI-generated entries. It also notes the emerging framework of the EU’s Artificial Intelligence Act, which extends obligations—such as respecting opt-out provisions under the EU Copyright Directive—to AI providers globally, affecting how GPT-style systems train their models. These milestones highlight how lawmakers are actively defining what counts as creative ownership in the age of AI (Vartabedian, 2025).

Creativity and the Law: Who Owns AI Art?

The law is still playing catch-up with AI’s creative boom. In the U.S., U.K., and E.U., copyright and patent systems are still firmly confined to human authorship. For example, The U.S. Copyright Office, states plainly: “an original work of authorship must be created by a human author”, which is why attempts to register AI-only works have all been denied. Patent rulings, like Thaler v. Vidal, reinforce this idea. The inventor must be human. This is as much a philosophical tension as a legal one. Policymakers will have to decide whether we should protect creativity because of the process (the human imagination, emotional meaning, and social context) or the product (the output itself, no matter how it was made) (Mammen et al., 2024; Haase & Hanel, 2023). The stakes of these decisions are enormous. The New York Times is currently suing Microsoft and OpenAI for billions of dollars,” claiming ChatGPT can reproduce their journalism “word for word.” OpenAI counters that this “regurgitation” is just a rare bug, but the case reveals a fundamental tension: if AI can perfectly reproduce copyrighted work, is it truly creating something new, or just performing sophisticated plagiarism? How lawmakers answer this will shape the creative economy for decades to come (The Economist, 2024).

Human-AI Collaboration: Designing for Co-Creation, Not Replacement

Right now, most human-AI teamwork is surprisingly shallow. Studies find that the dominant patterns are things like “AI-first”, which is where the AI makes a prediction and the human supervises; or “AI-follow”, where the human leads and the AI supports. True collaboration is rare. But more dynamic possibilities exist: “request-driven” help (asking AI-specific questions), “AI-guided dialogue” (AI keeps a creative back-and-forth alive), and “user-guided adjustments” (the human actively reshapes AI outputs). What about the risks? They’re real, as people can fall into cognitive biases like anchoring and confirmation biases. The true danger is a loss of agency where humans give up control of the creative process. The challenge for future AI developers and users is to design and use AI in a way that empowers humans rather than numbing them (Gomez et al., 2025). Some collaborations already show this potential. Board game designer Alan Wallat used AI to play his game ‘Sirius Smugglers’ thousands of times, discovering a rule flaw that could make games run indefinitely—something human playtesters might have missed or taken much longer to find (The Economist, 2025). Here, AI served as a powerful testing tool while Wallat retained creative control over the design and final decisions. Scientific Discovery: Incremental vs. Transformational Innovation Science gives us another lens on AI’s limits. We’ve covered how current generative models are excellent at incremental discoveries: recombining existing knowledge and running through known hypothesis spaces, but stumbling on the kind of transformational breakthroughs that come from curiosity and anomaly detection (Ding & Li, 2025). What does this mean? AI makes for a great lab assistant, it’s fast, tireless, and precise, but not yet a scientific revolutionary. It can help us test thousands of variations of a drug molecule, but it won’t suddenly “guess” DNA’s double helix or imagine relativity out of the blue. For now, only humans are capable of those flashes of genius.

Acknowledgments

The author would like to acknowledge Dr. Pan for his support and guidance during the research and publishing of this paper.

References

Boden, M. A. (2014). Creativity and Artificial Intelligence: A Contradiction in Terms? In The Philosophy of Creativity: New Essays. Oxford Academic. https://academic.oup.com/book/6463/chapter/150310938

Ding, A. W., & Li, S. (2025). Generative AI lacks the human creativity to achieve scientific discovery from scratch. Scientific Reports, 15(1), 9587. https://doi.org/10.1038/s41598-025-93794-9

Kaufman, J. C., & Beghetto, R. A. (2009). Beyond Big and Little: The Four C Model of Creativity. Review of General Psychology, 13(1), 1–12. https://doi.org/10.1037/a0013688

Mammen, C., Collyer, M., Dolin, R. A., Gangjee, D. S., Melham, T., Mustaklem, M., Sundaralingam, P., & Wang, V. (2024). Creativity, Artificial Intelligence, and the Requirement of Human Authors and Inventors in Copyright and Patent Law. SSRN Electronic Journal. https://doi.org/10.2139/ssrn.4892973

Slack, G. (2023). What DALL-E Reveals About Human Creativity | Stanford HAI. https://hai.stanford.edu/news/what-dall-e-reveals-about-human-creativity The Economist. (2024). Artificial intelligence is helping improve climate models.

The Economist. https://www.economist.com/science-and-technology/2024/11/13/artificial-intelligence-is-h elping-improve-climate-models

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The Economist. https://www.economist.com/the-economist-explains/2024/03/02/does-generative-artificial -intelligence-infringe-copyright The Economist. (2025). How artificial intelligence can make board games better.

The Economist. https://www.economist.com/science-and-technology/2025/02/26/how-artificial-intelligenc e-can-make-board-games-better

Vartabedian, M. (2025). AI Governance: When In Doubt, Ask. Then Ask Again. No Jitter. https://www.nojitter.com/ai-automation/ai-governance-when-in-doubt-ask-then-ask-again-

Zhou, E., & Lee, D. (2024). Generative artificial intelligence, human creativity, and art. PNAS Nexus, 3(3), pgae052. https://doi.org/10.1093/pnasnexus/pgae0

About the author

Connor Luke Kao

Connor is a high school senior interested in cognitive science and exploring how AI can help future sports and business applications. He’s a competitive soccer player and enjoys creating spray paint murals in his free time. Through various business programs, he’s gained entrepreneurial experience reselling clothes on Depop and founding The Harvesting Sustainability Project, a community initiative that harvests overgrown produce from local neighborhoods and repurposes and redistributes it to those in need.

The post Imitation or Innovation? Measuring AI’s Creative Limits & Implications in the 21st Century appeared first on Exploratio Journal.

Abstract

Chronic pain is a multifaceted condition characterized by persistent sensory, cognitive, and emotional distress that extends beyond normal healing time. Affecting nearly one in five individuals globally, chronic pain represents one of the leading causes of disability and reduced quality of life. Opioid analgesics, historically the cornerstone of moderate-to-severe pain treatment, are increasingly recognized as problematic in long-term use due to tolerance, dependence, hyperalgesia, and addiction risk. Consequently, there is an urgent need to identify alternative approaches that are both effective and sustainable. Recent scientific interest has turned to classic serotonergic psychedelics such as psilocybin, lysergic acid diethylamide (LSD), and N,N-dimethyltryptamine (DMT), which may exert analgesic effects through modulation of serotonin receptors, enhancement of neuroplasticity, and reorganization of large-scale brain networks involved in pain perception and emotional distress. This review synthesizes current knowledge of chronic pain neurobiology, evaluates the mechanisms and limitations of opioids, and examines emerging evidence for psychedelics in pain management. Particular focus is placed on receptor-level pharmacology, network-level brain circuit changes, and clinical evidence across pain disorders. While preliminary data suggest that psychedelics may offer durable relief and address both sensory and affective dimensions of pain, challenges remain regarding safety, variability of response, and regulatory hurdles. Psychedelics represent a promising, though experimental, paradigm shift in chronic pain management that warrants rigorous investigation.

Introduction

Chronic pain is not merely a prolonged form of acute pain but rather a distinct pathological state involving maladaptive changes in peripheral and central nervous system function [1,2]. Unlike acute pain, which serves an adaptive role by signaling tissue injury, chronic pain often persists independent of nociceptive stimuli and is increasingly understood as a disorder of central processing and neural plasticity [3]. The personal, societal, and economic impact of chronic pain is profound, with high prevalence, reduced productivity, psychiatric comorbidities such as depression and anxiety, and substantial health care utilization [4,5].

Traditional treatments for chronic pain include nonsteroidal anti-inflammatory drugs (NSAIDs), anticonvulsants, antidepressants, and opioids [6]. Of these, opioids remain the most potent pharmacological tools available, particularly for acute and cancer-related pain [7]. However, in the context of chronic non-cancer pain, long-term opioid therapy has proven controversial due to limited functional benefit and high risks of tolerance, dependence, and addiction [8,9]. The ongoing opioid crisis underscores the dangers of widespread opioid prescribing and highlights the necessity of alternative strategies [10].

Parallel to the opioid story, psychedelics have re-emerged in biomedical research after decades of prohibition. Early investigations in the mid-20th century explored their potential in psychiatry and pain management before regulatory restrictions halted progress [11]. In recent years, renewed interest has focused on the ability of psychedelics to modulate brain networks, enhance neuroplasticity, and produce long-lasting therapeutic effects across psychiatric conditions [12-14]. These properties raise the possibility that psychedelics could also play a role in addressing chronic pain syndromes.

This review aims to provide a comprehensive synthesis of chronic pain neurobiology, the pharmacological basis and limitations of opioids, and the mechanistic and clinical rationale for psychedelic-assisted approaches to pain.

Chronic Pain and Its Neurobiology

Chronic pain is typically defined as pain that persists for longer than three months and extends beyond the expected period of tissue healing [15,16]. In contrast to acute pain—which is transient, protective, and usually linked to a discrete injury or illness—chronic pain represents a maladaptive condition characterized by persistent activation of pain pathways within both the peripheral and central nervous systems [3,4]. Rather than serving as a biological warning signal, chronic pain often becomes a disease state in itself, marked by complex neurobiological, psychological, and social dimensions [5].

The clinical manifestations of chronic pain are heterogeneous and can be categorized according to their underlying mechanisms and anatomical origins. Neuropathic pain arises from injury or dysfunction of the somatosensory nervous system and includes conditions such as peripheral neuropathy, sciatica, trigeminal neuralgia, and phantom limb pain, in which pain is perceived in an amputated limb [17]. Musculoskeletal pain involves bones, joints, and muscles, and is common in disorders such as osteoarthritis, rheumatoid arthritis, fibromyalgia, and myofascial pain syndrome [18]. Inflammatory pain develops in the context of immune dysregulation or persistent inflammation, as seen in autoimmune diseases such as systemic lupus erythematosus or localized conditions including tendinitis and bursitis [19]. Visceral pain, originating from internal organs, is often diffuse, difficult to localize, and exemplified by conditions such as irritable bowel syndrome, endometriosis, and chronic pelvic pain [20]. Finally, centralized pain is increasingly recognized as a distinct category, characterized by hypersensitivity of central nervous system processing mechanisms and evident in conditions such as fibromyalgia and chronic migraine. In these cases, pain persists without any ongoing peripheral injury and is frequently amplified by dysregulated central neural networks [4].

A key feature of chronic pain is its impact on brain circuitry. Neural processing of persistent pain involves the so-called “pain matrix, ” a distributed network of cortical and subcortical regions that underlies the sensory, affective, and cognitive dimensions of pain [21]. Within this matrix, the primary and secondary somatosensory cortices encode the intensity and spatial localization of painful stimuli, while the anterior cingulate cortex integrates the emotional salience of pain. The insula plays a central role in interoception and the integration of sensory information with autonomic and affective states, and the prefrontal cortex contributes to higher-order modulation, decision-making, and appraisal of pain experiences [22]. Neuroimaging studies have demonstrated that chronic pain is associated with structural and functional remodeling of these regions, including altered gray matter density, aberrant connectivity, and maladaptive patterns of activation [23].

These changes are underpinned by neuroplasticity, the brain’s capacity to reorganize and form new synaptic pathways in response to persistent stimuli. While neuroplasticity normally supports adaptation and learning, in the context of chronic pain it becomes maladaptive, leading to hyperexcitability of nociceptive pathways, enhanced pain perception, and decreased efficacy of endogenous pain inhibition [3]. Such changes can also contribute to psychological comorbidities, including depression, anxiety, and cognitive impairment, further compounding the burden of chronic pain. Thus, rather than being a passive symptom, chronic pain represents a dynamic driver of neurobiological remodeling that perpetuates its own persistence and complexity [5].

Opioid Treatment for Pain Management

Opioids have long been employed as a primary pharmacological intervention for a range of chronic pain conditions, yet their clinical efficacy and appropriateness depend critically on the underlying etiology and severity of pain [24]. Mild to moderate pain, such as early-stage musculoskeletal disorders or postoperative discomfort, is often managed with lower-potency opioids, including codeine or tramadol. While these agents are comparatively less potent than full agonists, they nonetheless carry notable risks of dependence and addiction. For moderate to severe pain, particularly neuropathic conditions such as diabetic neuropathy or sciatica, stronger opioids—such as morphine, oxycodone, or hydrocodone—are typically prescribed. In instances of severe, refractory pain, including advanced cancer or complex regional pain syndrome, high-potency opioids such as hydromorphone or fentanyl may be indicated. Fentanyl, in particular, exhibits up to 100-fold greater potency than morphine and is generally reserved for patients with significant opioid tolerance [24]. Notably, opioids demonstrate limited efficacy in certain centralized pain syndromes, including fibromyalgia, where non-opioid interventions are often preferred.

The analgesic effects of opioids are primarily mediated through the activation of mu-opioid receptors (μORs), a class of G-protein-coupled receptors distributed throughout both the central and peripheral nervous systems [25]. Within the brain, MORs are densely expressed in key regions associated with pain processing, modulation, and affective response, including the periaqueductal gray (PAG), thalamus, anterior cingulate cortex (ACC), amygdala, and nucleus accumbens (NAc). MOR activation inhibits adenylate cyclase activity, reduces cyclic AMP production, decreases calcium influx, and increases potassium efflux across neuronal membranes, leading to hyperpolarization and attenuated excitability of nociceptive neurons. In the PAG and rostral ventromedial medulla (RVM), opioids engage descending inhibitory pathways, while in the thalamus and somatosensory cortices, they modulate sensory-discriminative aspects of pain. Simultaneously, opioid effects in the amygdala and prefrontal cortex influence the emotional and cognitive dimensions of pain perception. Importantly, the NAc and ventral tegmental area (VTA) mediate opioid-induced reward and reinforcement, contributing to the high addictive potential of these drugs [25].

Chronic opioid exposure frequently results in tolerance, necessitating escalating doses to maintain analgesia, and can precipitate physical dependence and addiction. The activation of reward circuits further reinforces compulsive drug-seeking behaviors. Adverse effects such as respiratory depression, constipation, sedation, and endocrine dysregulation complicate long-term therapy and can significantly impair quality of life. Moreover, opioids often fail to adequately address the affective and psychological components of chronic pain, which are central to its persistence and functional impact. Collectively, these limitations underscore the pressing need for alternative pain management strategies that target both the sensory and affective dimensions of pain while minimizing the risks associated with chronic opioid therapy.

Psychedelics: An Emerging Alternative

Classic serotonergic psychedelics, including psilocybin, lysergic acid diethylamide (LSD), and N,N-dimethyltryptamine (DMT), have garnered increasing attention for their potential role in the management of chronic pain [26]. Both preclinical and clinical investigations suggest that these compounds may exert analgesic effects through mechanisms involving agonism of the serotonin 5-HT2A receptor and modulation of functional connectivity across key brain regions implicated in pain processing, including the thalamus, anterior cingulate cortex (ACC), and prefrontal cortex (PFC) [27]. Importantly, psychedelics appear to disrupt rigid neural patterns and entrenched circuit dynamics, a property that may be particularly relevant for chronic pain conditions in which affective, cognitive, and perceptual factors contribute substantially to symptom persistence [27].

Pain is inherently a subjective experience, shaped not only by peripheral nociceptive input but also by higher-order emotional, cognitive, and contextual influences. This complexity is exemplified by disorders such as fibromyalgia, which often lack identifiable tissue pathology and are considered central sensitization syndromes. In these conditions, patients frequently perceive pain as an emergent property of altered central processing rather than a direct reflection of peripheral injury [28]. Therapeutic interventions such as hypnosis and mindfulness-based practices have demonstrated that pain perception can be modulated by top-down processes, highlighting the brain’s capacity to suppress or reframe nociceptive experiences. Psychedelics may act through analogous mechanisms, promoting neuroplasticity and facilitating the decoupling of maladaptive neural circuits from conscious pain perception, thereby enabling patients to reinterpret or disengage from their pain experience [28].

Emerging evidence suggests that the analgesic effects of psychedelics can be durable. Clinical studies have reported that single or limited psychedelic-assisted sessions may produce sustained reductions in pain intensity lasting several weeks or months, in contrast to opioids, which require repeated administration and are associated with tolerance, dependence, and opioid-induced hyperalgesia [29]. These enduring effects are thought to arise from profound modulation of brain network dynamics, particularly within the default mode network (DMN), and enhanced integration of sensory, limbic, and prefrontal circuits, which collectively alter both the perception and the affective salience of pain [29].

Despite their promise, psychedelic therapies are not without limitations. Individual responses are highly variable, and while many patients report significant improvements in pain and quality of life, adverse psychological reactions—such as anxiety, paranoia, or perceptual disturbances—can occur [30]. Psychedelics are contraindicated in individuals with a history of psychosis or certain mood disorders, necessitating careful screening and administration within controlled therapeutic settings [30]. Furthermore, legal and regulatory barriers pose substantial challenges, as most classic psychedelics are classified as Schedule I substances under federal law, restricting clinical access and research opportunities [30].

In summary, serotonergic psychedelics represent a compelling, mechanistically distinct alternative to conventional pharmacologic therapies for chronic pain, particularly in conditions that are refractory to standard interventions. Their capacity to modulate both neurobiological circuits and cognitive-affective frameworks of pain positions them as a promising, though complex, frontier in pain medicine [26, 27,30]. Ongoing research is required to elucidate their precise mechanisms of action, optimize dosing protocols, and establish robust safety and efficacy profiles to support their responsible integration into clinical practice.

Serotonin Receptors and Psychedelic Action

The analgesic and therapeutic potential of classic psychedelics in chronic pain management is closely linked to their modulation of serotonin receptors, with the 5-HT2A receptor playing a central role, as seen in figure 2 [31]. These receptors are densely expressed in cortical regions critical for pain processing, including the prefrontal cortex (PFC), anterior cingulate cortex (ACC), and insula, which collectively govern sensory perception, cognitive evaluation, and affective integration of pain. 5-HT2A receptors are also present in subcortical structures such as the thalamus and amygdala, which mediate the relay of nociceptive signals and the emotional appraisal of painful stimuli [31].

Activation of 5-HT2A receptors by serotonergic psychedelics, including psilocybin and LSD, enhances excitatory glutamatergic signaling within cortical pyramidal neurons [32]. This increase in cortical excitability facilitates greater inter-regional connectivity and disrupts rigid neural network dynamics, mechanisms thought to underpin both the altered states of consciousness characteristic of the psychedelic experience and the observed analgesic effects [32]. Functional neuroimaging in humans has demonstrated that psychedelic-induced 5-HT2A activation reduces coherence within the default mode network (DMN) while simultaneously enhancing connectivity between sensory, limbic, and associative cortical regions. These network-level changes correlate with reductions in perceived pain intensity and improvements in cognitive and emotional coping with pain [32].

Preclinical studies further support the mechanistic role of 5-HT2A signaling in pain modulation. Animal models reveal that 5-HT2A agonists reduce nocifensive behaviors, whereas pharmacological blockade of these receptors abolishes the analgesic effects, underscoring a causal link between serotonergic modulation and pain attenuation [33]. Additional serotonin receptor subtypes, including 5-HT1A and 5-HT2C, may also contribute to anxiolytic effects and affective regulation, complementing the analgesic properties of 5-HT2A activation [33]. As seen in figure 3, these findings suggest that modulation of serotonin receptors—particularly 5-HT2A agonism—constitutes a key mechanistic bridge connecting psychedelic neuropharmacology to durable reductions in chronic pain [31-33].

Brain Circuits Linking Pain and Psychedelic Experience

Pain perception is mediated by a distributed neural network that integrates both sensory-discriminative and affective-motivational dimensions. The thalamus serves as a critical relay, transmitting nociceptive signals to the primary and secondary somatosensory cortices, which encode the location, intensity, and quality of painful stimuli. Concurrently, the anterior cingulate cortex (ACC) and insula process the emotional and motivational aspects of pain, linking the sensory experience to affective and autonomic responses. These regions form a tightly interconnected system: thalamic projections reach both the somatosensory cortices and the ACC, while the ACC and insula communicate with the amygdala and prefrontal cortex (PFC) to regulate the emotional salience and cognitive appraisal of nociceptive input. The medial PFC, in particular, plays a pivotal role in self-referential processing, evaluating pain in the context of one’s personal identity, and often amplifying distress when pain is perceived as a threat to the self [27].

Classic serotonergic psychedelics, including psilocybin, LSD, and DMT, modulate these pain-related circuits by altering functional connectivity within and between the default mode network (DMN), limbic structures, and sensory pathways. As seen in table 1, their primary mechanism involves agonism at the 5-HT2A receptor, with additional contributions from 5-HT2C and 5-HT1A receptors [27]. Activation of 5-HT2A receptors enhances excitatory glutamatergic signaling in layer V cortical pyramidal neurons, promoting cross-talk between sensory and associative cortical regions while concurrently reducing top-down inhibitory control exerted by the DMN [27]. This disruption of rigid network dynamics leads to a disintegration of entrenched self-referential processing in the medial PFC and posterior cingulate cortex, effectively reshaping the emotional interpretation of pain. By weakening hyperconnected pain-related circuits—such as thalamus-ACC-PFC loops—and strengthening communication between limbic and sensory regions, psychedelics may attenuate the negative affective weight of nociceptive input and enhance cognitive flexibility in pain reappraisal [27].

Functional neuroimaging studies further demonstrate that psychedelics reduce DMN coherence and alter connectivity within the limbic system, including the amygdala and hippocampus, regions critically involved in the emotional amplification of pain [34]. Altered ACC and PFC activity under psychedelic influence has been associated with decreased affective suffering and improved adaptive coping strategies, while reductions in amygdala reactivity may diminish the emotional salience of pain. One emerging hypothesis posits that psychedelics “reset” maladaptive neural circuitry by promoting neuroplasticity and disrupting entrenched pain pathways, thereby enabling the reorganization of networks implicated in pain chronification [35]. This network “reset” may reduce hyperconnectivity within pain circuits and restore more adaptive patterns of brain activity, offering a novel neurobiologically informed avenue for chronic pain therapy [27,34].

Clinical Evidence and Trials

Recent studies provide preliminary evidence that classic psychedelics may modulate both the sensory-discriminative and affective-motivational dimensions of pain [36]. Early human research, including small pilot trials, has demonstrated reductions in headache burden and migraine frequency following psilocybin administration [33]. Complementary studies in healthy volunteers using crossover designs have reported increased tolerance to noxious stimuli, such as cold-pressor tasks, alongside reductions in the perceived unpleasantness of pain [36]. These effects are hypothesized to arise from 5-HT2A receptor-mediated reorganization of neural networks and top-down recalibration of salience and affective appraisal mechanisms [36].

Preclinical rodent models support these findings, showing that serotonergic psychedelics reduce inflammatory hyperalgesia and neuropathic allodynia while promoting cortical plasticity within thalamo-cortico-limbic circuits implicated in the chronification of pain [36]. Despite these encouraging results, current evidence is limited by several methodological constraints, including small sample sizes, open-label designs susceptible to expectancy effects, heterogeneous pain phenotypes, variable dosing regimens, limited active-placebo controls, short follow-up periods, and the frequent exclusion of individuals on long-term opioid therapy [36]. These factors constrain both generalizability and mechanistic inference [36].

Future research directions aim to overcome these limitations through rigorous, translationally oriented studies. Promising strategies include adequately powered randomized controlled trials with active placebo comparators, integration of quantitative sensory testing and neuroimaging (including resting-state and pain-evoked fMRI/EEG) to assess circuit-level changes, and the incorporation of inflammatory and neurotrophic biomarkers as potential mediators [33]. Comparative studies evaluating macrodosing versus low-dose protocols, the development of non-hallucinogenic 5-HT2A-biased analogs, and protocols that combine psychedelic administration with behavioral pain-rehabilitation or affect regulation training may further leverage experience-dependent neuroplasticity to optimize therapeutic outcomes [36].

Ethical, Regulatory, and Translational Challenges

The reintroduction of psychedelics into medicine raises ethical and regulatory challenges. Despite growing evidence, psychedelics remain Schedule I substances under international law, classified as having high abuse potential and no accepted medical use [37]. This status imposes significant barriers to research, including restricted funding and complex regulatory approvals [37].

Ethical concerns include the intensity and unpredictability of psychedelic experiences, the necessity of careful screening and psychotherapeutic support, and the potential for adverse psychological reactions [36]. Unlike opioids, psychedelics are not drugs of daily administration but are instead delivered in structured, supervised sessions. This model requires new infrastructure, trained facilitators, and integration with psychological care [35].

There are also questions of accessibility, cultural sensitivity, and equitable distribution. Without careful regulation, there is risk that psychedelic therapies could become commodified and inaccessible to those most in need [37].

Discussion

The emerging evidence comparing classic psychedelics to traditional opioid analgesics highlights fundamentally distinct mechanisms of action and clinical profiles. Opioids exert analgesia primarily through activation of G-protein-coupled mu-opioid receptors, leading to neuronal hyperpolarization and reduced nociceptive transmission [38]. While opioids are highly effective for acute pain, their long-term use is limited by tolerance, physical dependence, risk of misuse, and numerous adverse effects [39]. By contrast, classic serotonergic psychedelics act primarily as 5-HT2A receptor agonists and modulate pain indirectly by altering cortical network dynamics, affective processing, and cognitive appraisal rather than directly blocking nociceptive input [40]. This mechanistic distinction suggests that psychedelics may be particularly well-suited to chronic pain states with pronounced affective-cognitive components, such as neuropathic pain, headache disorders, and centralized pain syndromes [40].

Clinical evidence for psychedelic-assisted pain therapy is promising but remains preliminary. Systematic reviews, small controlled trials, and case series indicate that psychedelic interventions can reduce pain intensity, improve mood, and enhance functional outcomes [41]. However, sample sizes are small, study designs are heterogeneous, and large-scale randomized trials are largely lacking [41]. By comparison, opioids have robust evidence for short-term analgesia but demonstrate limited efficacy for many chronic pain conditions in the long term and carry well-documented risks [42].

Mechanistically, psychedelics appear to “reset” maladaptive neural circuits involved in pain chronification, promoting neuroplasticity and network reorganization that may reduce hyperconnectivity in pain-related pathways while enhancing adaptive processing of sensory and affective input [44]. This contrasts with opioids, which primarily suppress nociceptive signaling without addressing the cognitive and emotional dimensions of chronic pain [42]. Such network-level effects may allow psychedelics to provide sustained analgesia and improvements in quality of life following a limited number of treatment sessions, unlike opioids, which require ongoing administration and are associated with tolerance and dependence [41,42].

It is important to note that this review does not include non-classical psychoactive compounds such as ketamine, Salvia divinorum, or MDMA, each of which has distinct pharmacological and clinical profiles. Ketamine acts primarily as an NMDA receptor antagonist with rapid antidepressant and analgesic effects and interacts with the endogenous opioid system [40], whereas Salvinorin A, the active component of Salvia divinorum, is a potent kappa-opioid receptor agonist with dysphoric subjective effects [42]. MDMA is an entactogen whose primary actions involve robust monoaminergic release [41]. Furthermore, MDMA, Salvia divinorum, and ketamine are highly addictive drugs. Since these drugs do not overcome the risk of addiction, they are not a viable substitute for opioid in treating pain. These differences underscore that the current focus on classic serotonergic psychedelics provides a coherent mechanistic framework distinct from other psychoactive therapies [42].

Conclusion

In conclusion, classic psychedelics offer a mechanistically unique, non-opioid approach to chronic pain management, targeting both neurobiological and psychological dimensions. While preliminary findings suggest potential for durable analgesia, affective modulation, and network-level neuroplasticity, robust, adequately powered clinical trials and mechanistic studies are required. Careful attention to safety, therapeutic context, and regulatory constraints will be essential for translating these promising compounds into responsible clinical interventions that may complement or, in selected cases, provide alternatives to conventional opioid therapy.

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About the author

Emerson G. Brown

Emerson Brown is a student researcher with strong interests in psychology, chemistry, and neurobiology. She has conducted independent research under the mentorship of Dr. Adam Behensky, focusing on the intersection of neuroscience and medicine. Beyond her academic studies, she is an active competitor in Science Olympiad, where she explores scientific inquiry in a team-based setting. Emerson is passionate about medicine and aspires to contribute to advancements in patient care and biomedical research.

The post Exploring Psychedelics as Alternatives to Opioids for Chronic Pain Management: A Neurobiological Perspective appeared first on Exploratio Journal.

Abstract

Interferons (IFNs) are a group of proteins produced by cells in response to viral infections, making them a crucial aspect of the immune system. They essentially regulate the immune system and how it responds to threats by signaling when a pathogen is present, interfering with viral replication and triggering various defense mechanisms. While IFNs are often protective, their effects are not universally beneficial. In certain contexts, particularly chronic infections, prolonged IFN signaling can suppress immunity, cause tissue damage, and contribute to disease severity. This paper explores the dual role of IFN responses in both acute and chronic infections, specifically focusing on influenza A, HCV , HIV , and SARS-CoV-2. By examining both the protective and pathological impacts of IFN activity, this review highlights IFN signaling as a double edged sword and underscores the need for more targeted strategies in the future.

Between Shield and Sword: How Interferons Protect and Harm the Host Immune System

Interferons are vitally important for defending the body against viruses, yet in some infections, they can become problematic. IFNs are a type of cytokine, which are signaling proteins that aid communication between cells during immune responses (Isaacs et al., 1957). IFNs are critical in the innate immune system, which is the first line of non-specific defense against pathogens. The IFN pathway is indispensable for the innate immune system response because IFNs antagonize pathogens, which limits infection and its spread. IFNs essentially are messengers in the immune system, as they alert cells to the presence of a virus and allow them to trigger antiviral defenses (Katze et al., 2002). They are particularly helpful because many IFNs can be found at mucosal surfaces, where disease prevention is key. They help detect viral threats and facilitate the activation and production of antiviral defenses and immune pathways, therefore proving themselves critical in the recovery from viral infections.

Most cells in the body may produce IFNs in response to a viral infection, including lymphocytes (Fenner et al., 1987). Lymphocytes produce many IFNs and are the main source of their circulation when a virus is present and replicating in the bloodstream. IFNs are formed when they bind viral molecules to cell surface or intracellular pattern recognition receptors and they are released by the host cell in response to the presence of viruses. This binding signals the transcription and secretion of IFNs (Katze et al., 2002). They can be made in a laboratory to be used as treatment as well (Gibbert et al., 2012). There are three main types of IFNs—type I, II, and III—that aid the immune system in different functions.

Type I IFNs include IFN-α, IFN-β, IFN-ε, IFN-κ, IFN-ω, IFN-δ, IFN-ζ, and IFN-τ and they bind to specific surface cell receptors, IFN-α/β (Murira et al., 2016). They are produced after pattern-recognition receptor (PRR) stimulation as part of the innate immune response 4 (Walker et al., 2021). The IFN wave produced by this receptor induces IRF7 phosphorylation and causes a positive feedback loop. This wave releases type I IFNs that signal through the IFN-α/β receptors which then signal in the janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway (Lee et al., 2018). These IFNs inactivate eukaryotic translation initiation factor 2a (elF-2α), which inhibits viral protein synthesis. They also activate RNase L using the interferon stimulated gene (ISG) oligoadenylate synthetase (OAS), which splits any ssRNA in the cytoplasm of the infected cell, also inhibiting viral replication (Cusic et al., 2024). They are released early on in viral infection and provide direct antiviral effects and innate immune activation. They induce more than 300 ISGs which block viral replication and stimulate NK cells (Lee et al., 2018).

Type II IFNs are much different than other IFNs, which is why types I and III are at the center of this review. Type II IFNs include IFN-γ and they signal through a different receptor than other IFN types, known as the IFN-γ receptor complex, which is why only some cells respond to these IFNs (Lee et al., 2018). They are mainly produced by NK cells or innate lymphoid type 1 cells, but not directly by virus infected cells, which is another reason why they are not further discussed in this review (Kim et al., 2021). Their main function is to regulate innate immunity and activate other immune cells, such as macrophages. They enhance the body’s adaptive immune response, whereas other IFNs elicit a generalized response to pathogens (Platanias, 2005).

Type III IFNs include IFN-λ1, IFN-λ2, IFN-λ3, and IFN-λ4 and they are similar to type I IFNs in the way they inhibit viral infections. They are produced mainly by plasmacytoid dendritic cells. They bind to the receptors IFRL1 and IL-10R2 and they are synthesized when the host cell detects pathogen-associated molecular patterns and also signals through the JAK/STAT 5 pathway, similar to type I IFNs (Chyuan et al., 2019). Unlike type I IFNs, type III IFNs mainly help maintain healthy mucosal surfaces and control viral infections there. They also target the human liver, induce antiviral state in hepatocytes, and can impair the clearance of HCV . Only some cells respond to type III IFNs, unlike how most respond to type I (Odendall et al., 2015).

As mentioned earlier, JAK/STAT pathway is an IFN signaling pathway shared by both type I and III IFNs. 50+ cytokines and growth factors are found in the JAK/STAT pathway, including IFNs. JAK/STAT mediates events including apoptosis, inflammation, tissue repair, hematopoiesis, immune fitness, and adipogenesis (Hu et al., 2021). Upon ligand binding, JAK trans-phosphorylation is triggered by receptor dimerization. This leads to phosphorylation of receptor tyrosines and then to recruitment of STAT proteins (STAT1–6). Phosphorylated STATs then form homo/heterodimers and they then enter the nucleus and regulate target gene transcription.

Figure 1 The signaling pathways of type I and III IFNs

Innate Immune Sensing

The innate immune system is characterized by its production of inflammatory cytokines that lead to inflammatory cell activation/recruitment. Innate immune cells have pattern recognition receptors (PRRs) which sense pathogens (Uehata et al., 2020). The best characterized PRRs are toll-like receptors (TLRs) which recognize many pathogens. As seen in figure 2, different types of TLRs have different specialties. TLR 3 recognizes double stranded (ds) RNA and viral replication intermediates localized in endosomes. TLR 7/8 recognizes single stranded (ss) RNA and viral genomes localized in endosomes. TLR 9 recognizes CpG DNA and DNA viruses localized in endosomes. TLR 2/4 recognizes viral glycoproteins and some enveloped viruses localized at the cell surface (Kawai et al., 2010). Essentially, Viral nucleic acids are taken up into endosomes, where TLRs detect them.

Figure 2: TLR overview

Retinoic acid-inducible gene I (RIG-I) receptors are another type of PRR that contribute to inflammatory responses by activating downstream signaling pathways. RIG-I recognizes short dsDNA with 5’ triphosphate ends and ssRNA from negative sense RNA viruses (Yoneyama et al., 2004). TLRs and RIG-I like receptors (RLRs) activate signal pathways and downstream signaling modules that then activate NF-κB, AP-1, and IRF3/7 that induce inflammatory cytokines (Uehata et al., 2020). ISGs also play a role in innate immune sensing. PRRs, JAKs, and STATs are ISGs. ISGs control infections by directly targeting functions and pathways that are required during pathogen life cycles (Schneider et al., 2015). They enhance the detection of pathogens using PRRs and refine the signaling machinery of IFN pathways, allowing for effective and regulated immune responses.

While IFNs are generally protective, their impact can vary dramatically based on timing, context, and infection type. In some situations, particularly in chronic or severe infections, IFN responses can become dysregulated, leading to excess inflammation and immune suppression, along with other damages. This dual role of interferons, as both defenders and potential damagers, forms the focus of this paper.

Type I IFNs in Acute Infections

Influenza A

Type I IFNs are known to be critical in acute infections, such as influenza or SARS-CoV-2, but they also are attributed to various negative side effects. Specifically in influenza A, early type I IFN response demonstrates how type I IFNs can have protective antiviral effects but can also contribute to immunopathology (Wu et al., 2020). Immunopathology is adverse effects generated by the immune response (Marshall et al., 2018). It is known that type I IFNs are only effective against influenza in mice if Myxovirus-resistance protein (Mx1), an IFN-induced resistance factor, is present (Abebaw et al., 2024). In a 2007 study conducted by Koerner et al., they generated mutated mice, two of the types being Mx-wild type (wt) and Mx-BKO. Mx-wt mice had both functional IFN-β and Mx1 capabilities, while Mx-BKO mice had functional Mx1 but no IFN-β. Both types of mice were infected with influenza A via injection, as shown in figure 3. Through their studies, they found that IFN-β has a relevant role in early antiviral defense. Mx-BKO mice were significantly more susceptible to influenza A infection compared to Mx-wt mice. These mice allowed lots more viral growth in lab tests, especially when infected through the nose. This was because the 50% lethal dose was 20x lower in Mx-BKO mice compared to Mx-wt mice. In comparison, the Mx-wt mice were highly resistant to the virus and survived high doses of the virus that killed Mx-BKO mice. Their immune system was able to stop the virus from replicating efficiently because they produced IFN-I that induces ISGs that suppress replication in lung epithelial cells. This study illustrated how IFN-β is key in suppressing acute viral replication and without it, the body’s defenses are compromised.

Figure 3: IFN-I in Influenza A Note: Based on a 2007 study by Koerner et al. Syringe and lab mouse graphic taken from NIAID Visual & Medical Arts.

While this study showed the beneficial effects of type I IFNs in influenza A infection, they also hold a negative role. In a 2012 study conducted by Li et al., it was discovered that IFN-I induction during influenza A infection increases susceptibility to Secondary Streptococcus pneumoniae. The majority of deaths after influenza A infection in influenza pandemics are caused by secondary bacterial pneumonia superinfection, illustrating the importance of the role IFN-I plays (McCullers, 2006). In this study, wild type (WT) mice and mice lacking IFNAR (IFNAR KO) were infected with S. pneumoniae following influenza A infection. The WT faced 10 a deadly secondary Streptococcus pneumoniae infection and IFNAR KO mice successfully cleared the infection, proving how IFN-I induction leads to susceptibility.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)

SARS-CoV-2 is the virus that causes coronavirus disease 2019 (COVID-19). Late type I IFN response in SARS-CoV-2 also highlights how improper timing can turn IFNs into contributors of immunopathology. While mutations in the type I IFN pathway have been linked to life threatening symptoms in SARS-CoV-2 infection, they have also been linked to cytokine storms (Kim et al., 2021). A cytokine storm is a hyperinflammatory reaction where the body releases too many cytokines into the blood too quickly (Zanza et al., 2022). It manifests similarly to influenza and can lead to organ failure, coagulopathy and death (Fajgenbaum et al., 2020). Cytokine storms have been determined to be a key pathogenic factor in SARS-CoV-2 infection (King et al., 2021). Various studies have discovered the increased presence of inflammatory cytokines such as IL-1β, IL-2, IL-6, IL-10, and IFN-γ in SARS-CoV-2 patients (Zanza et al., 2022). These increased levels of cytokines are associated with disease severity (Brunet-Ratnasingham et al., 2024). Severely ill COVID-19 patients showed an impaired early IFN response which was followed by a sustained type I IFN storm. This was linked to hyperinflammation and acute respiratory distress syndrome (ARDS) (Hadjadj et al., 2020).

Figure 4 Type I IFN Dysregulation and Cytokine Storm in SARS-CoV-2 11

Type I IFNs in Chronic Infections

The presence of type I IFNs in chronic infections, such as HCV or HIV , is notable as well.

Human Immunodeficiency Virus (HIV)

The dual role of IFN-I is also highlighted during HIV infection. Although HIV activates host immune defenses, IFN-I and ISGs are ultimately insufficient to eradicate the virus. In the acute phase of infection, IFN-I hinders HIV-1 spread by stimulating key immune defenses, including ISGs that help contain the virus (Cheng et al., 2017). Despite this though, during chronic HIV infection, prolonged type I IFN exposure has been linked detrimental effects such as desensitization, detrimental hyperimmune activation leading to disease progression, impaired viral control, and upregulation of exhaustion markers on T cells (Scagnolari et al., 2018 and Le Saout et al., 2014). HIV also evades IFN-I’s defense using multiple tactics such as downregulating key signaling factors IRF3, RIG-I, PKR, and MHC-I via viral proteins like Vpr, protease, Tat, and Nef, therefore disrupting IFN-I pathways (Ranganath et al., 2016). In addition, 12 IFN-I can inadvertently induce apoptosis of uninfected CD4⁺ T cells via TRAIL-DR5 signaling, further accelerating immune depletion (Herbeuval et al., 2007). From a therapeutic standpoint, some experimental models suggest that blocking IFN-I signaling during chronic HIV infection in combination with antiretroviral therapy (ART) can diminish immune activation, revitalize CD8⁺ T cell responses, reduce viral reservoirs, and improve viral suppression (Zhen et al., 2016). This highlights the potential benefits of modulating IFN-I dynamics in treated HIV patients. Overall, the role of IFN-I in HIV infection highlights chronic exposure and how timing and duration of IFN responses shape outcome.

Figure 5: Type I IFNs in HIV Infection

Hepatitis C

Virus (HCV) Pegylated interferon and ribavirin treatment has become standard for treating HCV , mainly due to its pharmacokinetic properties which allow for less frequent dosing compared to conventional IFN-α (Aghemo et al., 2010). This treatment is made by chemically attaching polyethylene glycol (PEG) chains to interferon molecules (Friedman et al., 2010). Pegylated IFN-α treatment exerts direct antiviral effects by inducing ISGs that block viral replication and 13 also enhances adaptive and innate immunity, including the upregulation of major histocompatibility complex (MHC) class I and II molecules, encoding cell surface proteins crucial for the immune system, antigen presentation and increased T cell activation (Dill et al., 2014). Combining IFN-α with ribavirin, an antiviral nucleoside analog, has been found to enhance treatment effectiveness (Friedman et al., 2010). This treatment supports the idea that IFNs can be successful protectors against viruses.

Type III IFNs in Infections

IFN λ-3 and λ-4 in HCV are great examples of the effects of type III IFNs in infections. In HCV infection, IFN-λ3 is linked with clearance of HCV infection as well as a protective antiviral role in the liver (Liu et al., 2015). It is inducible during viral infection and enhances innate antiviral defense without triggering widespread inflammation. IFN λ-4 is linked with impaired clearance of HCV infection (Boisvert et al., 2016). It is known to attenuate HCV-specific T cell responses that leads to a negative impact on cellular immunity (Chen et al., 2021). Production of IFN-λ4 triggers chronic inflammation and persistent ISG expression which can inhibit an effective immune response. It can also lead to a pre-exhausted immune state which can limit the effectiveness of other IFN therapies (Prokunina-Olsson et al., 2013). IFN-λ4 is also only found in ΔG carriers (O’Brien et al., 2014). Some people clear HCV faster than others and this is mostly due to genetic variation. The IFN-λ3 and IFN-λ4 location on chromosome 19 shows single nucleotide polymorphisms (SMPs) linked to HCV outcomes (Ge et al., 2009). One of these SNPs is at Rs12979860 in IFN-λ3. This SNP is highly linked to the spontaneous clearance of HCV without treatment and improved response to therapy. There are three different genotypes individuals may possess that are relevant to this SNP: CC, TT, or CT. Individuals with the CC genotype have higher IFN-λ3 expression which leads to stronger ISG activation and 14 better viral clearance. Those with the CT or TT genotype are less likely to clear the virus naturally or respond well to older treatments (Wu et al., 2015). Rs368234815 in IFN-λ4 is another SNP linked to HCV outcomes. Those with the TT genotype do not produce IFN-λ4 and typically clear the virus more efficiently. Those with the other genotype, ΔG, produce IFN-λ4 which makes it harder to clear the virus. These SNPs illustrate how some IFNs, such as IFN-λ4, can be inherently maladaptive.

Figure 6: IFN-λ3 and λ4 in HCV infection

Conclusion

Interferon signaling is regarded as one of the immune system’s most powerful antiviral tools, yet its strength makes it a double edged sword. On one side, rapid IFN responses promote viral clearance, activate innate and adaptive immunity, and protect mucosal surfaces. On the other, sustained or dysregulated IFN signaling can promote chronic inflammation, tissue damage, and 15 immune exhaustion, as seen in infections like HCV or SARS-CoV-2. Recognizing the duality of IFN signaling underscores the importance of context, timing, and regulation in immune responses and defense. As research advances, the challenge will be to maintain IFN’s protective qualities in therapies while minimizing their pathological consequences.

Figure 7: Summary of the role of IFNs in viral infections

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About the author

Madeline Wiley

Madeline is a senior at Westtown School in Pennsylvania with a strong interest in biology and chemistry, particularly their intersection in the field of pharmacology. Her fascination with how these disciplines explain disease and drive medical innovation led her to explore topics such as molecular biology, pharmacokinetics, and the pharmaceutical industry. Over time, this curiosity grew into a deep desire to contribute original research and become part of the discovery process for new therapies.

Madeline is passionate about addressing real-world challenges in public health, illness, and medicine. Outside of her scientific interests, she enjoys playing guitar and piano, singing, and performing at local venues.

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