Month: June 2019

Change the Brain to Improve Resilience with Meditation

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Change the Brain to Improve Resilience with Meditation

 

By John M. de Castro, Ph.D.

 

“Mindful people … can better cope with difficult thoughts and emotions without becoming overwhelmed or shutting down (emotionally). Pausing and observing the mind may (help us) resist getting drawn into wallowing in a setback.” – Badri Bajaj

 

Psychological well-being is sometimes thought of as a lack of mental illness. But it is more than just a lack of something. It is a positive set of characteristics that lead to happy, well-adjusted life. These include the ability to be aware of and accept one’s strengths and weaknesses, to have goals that give meaning to life, to truly believe that your potential capabilities are going to be realized, to have close and valuable relations with others, the ability to effectively manage life issues especially daily issues, and the ability to follow personal principles even when opposed to society. But stress can interfere with the individual’s ability to achieve these goals.  When highly stressed, resilience is required to cope with the stress and continue on the path to psychological well-being.

 

One way that mindfulness practices such as meditation may improve resilience is by altering the brain. The nervous system is a dynamic entity, constantly changing and adapting to the environment. It will change size, activity, and connectivity in response to experience. These changes in the brain are called neuroplasticity. Over the last decade neuroscience has been studying the effects of contemplative practices on the brain and has identified neuroplastic changes in widespread areas. In other words, mindfulness practice appears to mold and change the brain, producing psychological, physical, and spiritual benefits. The changes in the brain, however, that are responsible for increased resilience are unknown.

 

In today’s Research News article “The Immediate and Sustained Positive Effects of Meditation on Resilience Are Mediated by Changes in the Resting Brain.” (See summary below or view the full text of the study at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6448020/), Kwak and colleagues recruited healthy adults to participate in a 4-day retreat. They were randomly assigned to a meditation retreat or a relaxation retreat. They were measured before and after the retreat and 3 months later for mindfulness, resilience, and religious preference. Also, before and after the retreat the participants underwent functional Magnetic Resonance Imaging (f-MRI) of their brains.

 

They found that in comparison to baseline and the relaxation retreat participants, the meditation retreat participants at the 3-month follow-up had significant increases in both mindfulness and resilience. They also found that the meditation group had significantly increased functional connectivity between the left rostral anterior cingulate cortex and the dorsomedial prefrontal cortex, precuneus, and angular gyrus. In addition, the greater the increase in the functional connectivity in the meditation retreat group the greater the increases in resilience and mindfulness. The increase in resilience was associated with the increase in mindfulness and this association was found to be partially mediated by the change in functional connectivity. In other words, increased mindfulness was associated with increased resilience directly and also indirectly by its association with the increased functional connectivity which was in turn associated with greater resilience.

 

The results are interesting and suggest that the effect of meditation on resilience is due to increases in mindfulness that change the brain to produce greater resilience. In particular, meditation appears to increase the functional connectivity between brain regions, the cingulate cortex and the prefrontal cortex and the precuneus, and angular gyrus, and thus is partially responsible for increased resilience.

 

Resilience is very important for the individual to be able to withstand the stress and negative events in life. Meditation appears to change the brain to help people better cope with the stresses of life. This may underlie, at least in part, the psychological and physical benefits of meditation practice.

 

So, change the brain to improve resilience with meditation.

 

“The emotional soup that follows a stressful event can whip up negative stories about yourself or others that goes on and on, beyond being useful. Mindfulness reduces this rumination and, if practiced regularly, changes your brain so that you’re more resilient to future stressful events.” – Shamash Alidina

 

CMCS – Center for Mindfulness and Contemplative Studies

 

This and other Contemplative Studies posts are also available on Google+ https://plus.google.com/106784388191201299496/posts and on Twitter @MindfulResearch

 

Study Summary

 

Kwak, S., Lee, T. Y., Jung, W. H., Hur, J. W., Bae, D., Hwang, W. J., … Kwon, J. S. (2019). The Immediate and Sustained Positive Effects of Meditation on Resilience Are Mediated by Changes in the Resting Brain. Frontiers in human neuroscience, 13, 101. doi:10.3389/fnhum.2019.00101

 

Abstract

While recent studies have explored the maintenance of the effect of meditation on stress resilience, the underlying neural mechanisms have not yet been investigated. The present study conducted a highly controlled residential study of a 4-day meditation intervention to investigate the brain functional changes and long-term effects of meditation on mindfulness and resilience. Thirty participants in meditation practice and 17 participants in a relaxation retreat (control group) underwent magnetic resonance imaging scans at baseline and post-intervention and completed the Cognitive and Affective Mindfulness Scale (CAMS) and Resilience Quotient Test (RQT) at baseline, post-intervention, and the 3-month follow-up. All participants showed increased CAMS and RQT scores post-intervention, but only the meditation group sustained the enhancement after 3 months. Resting-state functional connectivity (rsFC) between the left rostral anterior cingulate cortex (rACC) and the dorsomedial prefrontal cortex (dmPFC), precuneus, and angular gyrus was significantly increased post-intervention in the meditation group compared with the relaxation group. The changes in rACC-dmPFC rsFC mediated the relationship between the changes in the CAMS and RQT scores and correlated with the changes in the RQT score both immediately and at 3 months post-intervention. Our findings suggest that increased rACC-dmPFC rsFC via meditation causes an immediate enhancement in resilience that is sustained. Since resilience is known to be associated with the preventative effect of various psychiatric disorders, the improvement in stress-related neural mechanisms may be beneficial to individuals at high clinical risk.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6448020/

 

Improve Obsessive-Compulsive Disorder With Mindfulness

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Improve Obsessive-Compulsive Disorder With Mindfulness

 

By John M. de Castro, Ph.D.

 

“To be able to focus on what is really happening in any given moment, as opposed to dwelling on the past or anticipating the future, takes away the power of OCD.” – Janet Singer

 

Obsessive-Compulsive Disorder (OCD) sufferer have repetitive anxiety producing intrusive thoughts (obsessions) that result in repetitive behaviors to reduce the anxiety (compulsions). In a typical example of OCD, the individual is concerned about germs and is unable to control the anxiety that these thoughts produce. Their solution is to engage in ritualized behaviors, such as repetitive cleaning or hand washing that for a short time relieves the anxiety. The obsessions and compulsions can become so frequent that they become a dominant theme in their lives. Hence OCD drastically reduces the quality of life and happiness of the sufferer and those around them. About 2% of the population, 3.3 million people in the U.S., are affected at some time in their life.

 

Fortunately, OCD can be treated and Mindfulness training has been shown to be effective in treating OCD. In addition, changing the maladaptive thought processes occurring in OCD through Cognitive Restructuring (CR) has also been shown to be effective. In today’s Research News article “A randomized waitlist-controlled trial comparing detached mindfulness and cognitive restructuring in obsessive-compulsive disorder.” (See summary below or view the full text of the study at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6426247/), Rupp and colleagues compare the effectiveness of mindfulness training and cognitive restructuring in treating Obsessive-Compulsive Disorder (OCD).

 

They recruited patients with Obsessive-Compulsive Disorder (OCD) and randomly assigned them to receive either cognitive restructuring or detached mindfulness training or to a wait-list control condition. The treatments were delivered in 100-minute sessions, twice a week for two weeks and contained homework assignments. Cognitive restructuring targets distorted thinking that underlies OCD and teaches the patient to observe the thoughts and question the appraisals produced by the thoughts. Detached mindfulness training also targets the distorted thinking that underlies OCD but teaches the patient to observe the thoughts and detach from them, see them as separate from themselves. They were measured before and after training and 4 weeks later for intelligence, depression, psychological disorders, and Obsessive-Compulsive Disorder (OCD) symptoms.

 

They found that compared to baseline and the wait-list control group both treatments resulted in significant reductions in OCD symptoms that were clinically significant and maintained at the 4-week follow-up. There were also small deceases in depression levels in the patients after both treatments. Hence, both treatments improved the symptoms of patients suffering from Obsessive-Compulsive Disorder (OCD). Hence brief training in cognitive restructuring or detached mindfulness are effective in treating OCD symptoms.

 

It has previously been demonstrated that Mindfulness training is effective in treating OCD. The current study suggests that an unusual mindfulness technique, detached mindfulness, may also be effective. It appears that very different types of treatments, cognitive restructuring and detached mindfulness are effective in treating the symptoms of Obsessive-Compulsive Disorder (OCD). The control condition, however, received no treatment. So, it is possible that the improvements observed may have been due to subject expectancy effects (placebo effects) and not to the treatments. Future research should include placebo control conditions.

 

So, improve obsessive-compulsive disorder with mindfulness.

 

“a person trapped by an endless cycle of washing, checking, or cleaning is experiencing exactly the same struggle with accepting thoughts, feelings, and sensations as people with intrusive thoughts.  So, mindfulness is really for anyone who wants to stop feeling like what is going on inside their mind is a burden.  It’s hard to imagine anyone with OCD who would wish to continue feeling that way.” – John Hershfield

 

CMCS – Center for Mindfulness and Contemplative Studies

 

This and other Contemplative Studies posts are also available on Google+ https://plus.google.com/106784388191201299496/posts and on Twitter @MindfulResearch

 

Study Summary

 

Rupp, C., Jürgens, C., Doebler, P., Andor, F., & Buhlmann, U. (2019). A randomized waitlist-controlled trial comparing detached mindfulness and cognitive restructuring in obsessive-compulsive disorder. PloS one, 14(3), e0213895. doi:10.1371/journal.pone.0213895

 

Abstract

Objective

Whereas research has demonstrated the efficacy of cognitive restructuring (CR) for obsessive-compulsive disorder (OCD), little is known about the efficacy of specific metacognitive interventions such as detached mindfulness (DM). Therefore, this study compared the efficacy of CR and DM as stand-alone interventions.

Design

We conducted a randomized waitlist-controlled trial. n = 43 participants were randomly assigned to either DM or CR. Out of those participants, n = 21 participants had been previously assigned to a two-week waitlist condition.

Materials and methods

In both conditions, treatment comprised four double sessions within two weeks. Assessment took place at baseline (Pre1), after treatment (Post) and four weeks after the end of treatment (FU). There was a second baseline assessment (Pre2) in the waitlist group. Independent evaluators were blinded concerning the active condition. Adherence and competence ratings for the two therapists were obtained from an independent rater.

Results

40 patients completed the treatment. Two patients dropped out because of exacerbated depression. There were no further adverse events. Both CR and DM were shown to be superior to waitlist and equally effective at reducing OCD symptoms from pre to post assessment as measured with the Y-BOCS (CR: d = 1.67, DM: d = 1.55). In each of the two treatment conditions, eight patients (40%) exhibited a clinical significant change at post assessment.

Conclusions

The results of this clinical trial suggest the potential efficacy of DM as a stand-alone intervention for OCD, however, our findings need to be interpreted with caution. Results indicate that both CR and DM should be considered as possible alternative treatments for OCD, whereas the working mechanisms of DM have yet to be elucidated.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6426247/

 

Reduce Eating Disorders with Effective Coping and Mindfulness

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Reduce Eating Disorders with Effective Coping and Mindfulness

 

By John M. de Castro, Ph.D.

 

“For individuals suffering from an eating disorder, becoming mindful, or aware of the present moment, can help save individuals from the critical voices inside of their heads.”

 

Around 30 million people in the United States of all ages and genders suffer from an eating disorder; either anorexia nervosa, bulimia, or binge eating disorder. 95% of those who have eating disorders are between the ages of 12 and 26. Eating disorders are not just troubling psychological problems, they can be deadly, having the highest mortality rate of any mental illness. Eating disorders can be difficult to treat because eating is necessary and cannot be simply stopped as in smoking cessation or abstaining from drugs or alcohol. One must learn to eat appropriately not stop. So, it is important to find methods that can help prevent and treat eating disorders. Contemplative practices, mindfulness, and mindful eating have shown promise for treating eating disorders.

 

In today’s Research News article Mindfulness, rumination, and coping skills in young women with Eating Disorders: A comparative study with healthy controls.” (See summary below or view the full text of the study at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6420013/), Hernando and colleagues explored the relationship between eating disorders and mindfulness. They recruited female patients diagnosed with an eating disorder and a matched healthy female control group. The participants completed measures of mindfulness, rumination, effective coping, and coping styles.

 

They found that in comparison to the matched healthy controls, the women with eating disorders had significantly lower levels of mindfulness and effective coping and higher levels of rumination. They also found that the higher the levels of mindfulness or the higher the levels of effective coping, the lower the likelihood of an eating disorder. In addition, they found that the higher the levels of rumination, the greater the likelihood of an eating disorder.

 

It should be kept in mind that the study was cross-sectional in nature and thus caution must be exercised in reaching conclusions especially regarding causation. Nevertheless, the results suggest that mindfulness is associated with less likelihood of an eating disorder and the higher the levels of rumination the greater the likelihood of and eating disorder. This makes sense as being able to be focused in the present moment is the antithesis of rumination which is being focused in the past (worry) or the future (anxiety). The results also suggest that being able to effectively cope with negative feeling is also associated with less likelihood of and eating disorder. This suggests that disordered eating may be a means that the patient uses to cope with negative feelings. If the patient has other more effective means of coping, disordered eating is less likely.

 

Reduce eating disorders with effective coping and mindfulness.

 

“It is common for individuals with eating disorders to numb emotions through restricting, binging or choosing foods that are not pleasurable while eating. Mindful eating can help a person reconnect to the joy and experience of eating by creating an awareness of thoughts, emotions, feeling, and behaviors associated with the eating experience.” – Julia Cassidy

 

CMCS – Center for Mindfulness and Contemplative Studies

 

This and other Contemplative Studies posts are also available on Google+ https://plus.google.com/106784388191201299496/posts and on Twitter @MindfulResearch

 

Study Summary

 

Hernando, A., Pallás, R., Cebolla, A., García-Campayo, J., Hoogendoorn, C. J., & Roy, J. F. (2019). Mindfulness, rumination, and coping skills in young women with Eating Disorders: A comparative study with healthy controls. PloS one, 14(3), e0213985. doi:10.1371/journal.pone.0213985

 

Abstract

Eating Disorders (ED) have been associated with dysfunctional coping strategies, such as rumination. Promoting alternative ways of experiencing mental events, based on a mindfulness approach, might be the clue for learning more effective coping and regulatory strategies among young women with ED. This study examined the comparison between patients with ED diagnosis and healthy subjects in mindfulness, rumination and effective coping. In addition, we analyzed the independent association of those with the presence of ED. The study sample was formed by two groups of young women ranged 13–21 years: Twenty-five with an ED diagnosis and 25 healthy subjects. They were assessed by using the Freiburg Mindfulness Inventory (FMI) and the Responses Styles Questionnaire (RSQ). Our findings show that ED patients have significantly lesser average scores in mindfulness and effective coping than the healthy sample (p < .05). Also, our data concludes that mindfulness and effective coping independently predict the presence or absence of ED in young women. The study results suggest that training mindfulness abilities may contribute to making effective coping strategies more likely to occur in ED patients, which is incompatible with some eating-related symptoms. Further studies are needed, trough prospective and experimental designs, to evaluate clinical outcomes of mindfulness training among young women with ED.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6420013/

 

Improve Attention and Hyperactivity in Kindergarten Children with Yoga

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Improve Attention and Hyperactivity in Kindergarten Children with Yoga

 

By John M. de Castro, Ph.D.

 

“Yoga is a systematic workout regimen that has rejuvenating and calming effects on our body and mind. Young kids go through conflicting emotions, and yoga helps calm them down. They are also extremely flexible and therefore, a practice like yoga will help them contort their bodies in different ways.” – Shirin Mehdi

 

Yoga practice has been shown to have a large number of beneficial effects on the psychological, emotional, and physical health of the individual and is helpful in the treatment of mental and physical illness. The acceptance of yoga practice has spread from the home and yoga studios to its application with children in schools. Studies of these school programs have found that yoga practice produces a wide variety of positive psychosocial and physical benefits.

 

Teachers also note improvements in their students following yoga practice. These include improved classroom behavior and social–emotional skills, concentration, mood, ability to function under pressure, social skills, and attention and lower levels of hyperactivity. In addition, school records, academic tests have shown that yoga practice produces improvements in student grades and academic performance. This, in turn, improves the classroom experience for the teachers. Hence there are very good reasons to further study the effects of yoga practice early in children’s schooling; kindergarten.

 

In today’s Research News article “12 Weeks of Kindergarten-Based Yoga Practice Increases Visual Attention, Visual-Motor Precision and Decreases Behavior of Inattention and Hyperactivity in 5-Year-Old Children.” (See summary below or view the full text of the study at: https://www.frontiersin.org/articles/10.3389/fpsyg.2019.00796/full?utm_source=F-AAE&utm_medium=EMLF&utm_campaign=MRK_963174_69_Psycho_20190416_arts_A), Jarraya and colleagues recruited kindergarten students and randomly assigned them to either practice yoga, normal physical education, or no treatment control. Yoga and Physical Education occurred twice per week for 30 minutes for 12 weeks. The Hatha yoga practice included postures and breathing exercises. The children were measured by their kindergarten teacher before and after the treatments for visual attention, visuomotor precision, inattention, and hyperactivity/impulsivity.

 

They found that in comparison to PE and control children, the children who practiced yoga had significantly improved visual attention and visuomotor precision, and significantly lower inattention, and hyperactivity/impulsivity. Visuomotor precision is a measure of cognitive function and includes measures of language, memory and learning, sensorimotor, social perception, and visuospatial processing. Hence, yoga practice improved attention, behavioral control, and higher-level thinking in the kindergarten children.

 

These are exciting results that are similar to those observed with older children. The abilities observed to have improved in the kindergarten children who practiced yoga are abilities that are essential for school performance. Attention is a key ability and that along with an additional reduction in hyperactivity sets the stage for learning. Then improved cognitive ability further heightens learning ability. This suggests that yoga practice has large benefits and should be recommended for young children to promote their ability to learn and perform in school.

 

So, improve attention and hyperactivity in kindergarten children with yoga.

 

“It sounds kind of goofy to people who don’t work with little kids, but kids that have a weak core have a hard time sitting still, and that can look like they’re not paying attention. Those are the kinds of mind-body connections you don’t think about until you start looking into it.” – Chas Zelinsky

 

CMCS – Center for Mindfulness and Contemplative Studies

 

This and other Contemplative Studies posts are also available on Google+ https://plus.google.com/106784388191201299496/posts and on Twitter @MindfulResearch

 

Study Summary

 

Jarraya S, Wagner M, Jarraya M and Engel FA (2019) 12 Weeks of Kindergarten-Based Yoga Practice Increases Visual Attention, Visual-Motor Precision and Decreases Behavior of Inattention and Hyperactivity in 5-Year-Old Children. Front. Psychol. 10:796. doi: 10.3389/fpsyg.2019.00796

 

The present study assesses the impact of Kindergarten-based yoga on cognitive performance, visual-motor coordination, and behavior of inattention and hyperactivity in 5-year-old children. In this randomized controlled trial, 45 children (28 female; 17 male; 5.2 ± 0.4 years) participated. Over 12 weeks, 15 children performed Hatha-yoga twice a week for 30 min, another 15 children performed generic physical education (PE) twice a week for 30 min, and 15 children performed no kind of physical activities, serving as control group (CG). Prior to (T0) and after 12 weeks (T1), all participants completed Visual Attention and Visuomotor Precision subtests of Neuropsychological Evaluation Battery and teachers evaluated children’s behavior of inattention and hyperactivity with the Attention-Deficit/Hyperactivity Disorder (ADHD) Rating Scale-IV. At T0, no significant differences between groups appeared. Repeated measures analysis of variance revealed that following Bonferroni–Holm corrections yoga, in comparison to PE and CG, had a significant positive impact on the development on behavior of inattention and hyperactivity. Further, yoga has a significant positive impact on completion times in two visumotor precision tasks in comparison to PE. Finally, results indicate a significant positive effect of yoga on visual attention scores in comparison to CG. 12 weeks of Kindergarten-based yoga improves selected visual attention and visual-motor precision parameters and decreases behavior of inattention and hyperactivity in 5-year-old children. Consequently, yoga represents a sufficient and cost-benefit effective exercise which could enhance cognitive and behavioral factors relevant for learning and academic achievement among young children.

https://www.frontiersin.org/articles/10.3389/fpsyg.2019.00796/full?utm_source=F-AAE&utm_medium=EMLF&utm_campaign=MRK_963174_69_Psycho_20190416_arts_A

 

Affect the Brain with Religious Chanting

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Affect the Brain with Religious Chanting

 

By John M. de Castro, Ph.D.

 

“According to a recent medical report, chanting Om has been associated with reducing stress. One of the biggest health benefits of Om chanting is that it brings down stress levels. It provides relief from anxiety and tension. Regular chanting ensures that you feel peaceful from within and are less distracted while doing any form of work.” – Pavankumar elkoochi

 

Contemplative practices have been shown to improve health and well-being. One ancient practice that is again receiving acceptance and use is chanting. It is a very common component of many contemplative practices. Chanting is claimed to be helpful in contemplative practice and to help improve physical and mental well-being. But there is very little empirical research on chanting or its effectiveness.

 

The nervous system is a dynamic entity, constantly changing and adapting to the environment. It will change size, activity, and connectivity in response to experience. These changes in the brain are called neuroplasticity.  Over the last decade neuroscience has been studying the effects of contemplative practices on the brain and has identified neuroplastic changes in widespread area. and have found that meditation practice appears to mold and change the brain, producing psychological, physical, and spiritual benefits. What changes in the brain that may occur with chanting are not known.

 

In today’s Research News article “The neurophysiological correlates of religious chanting.” (See summary below or view the full text of the study at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6414545/), Gao and colleagues recruited participants who practiced Buddhist chanting for at least one year for 15 minutes per day. The participants were measured for brain electrical activity with the electroencephalogram (EEG) and for cardiac activity with an electrocardiogram (ECG) under 3 conditions, rest, silent Buddhist chanting (religious chanting), and silent chanting Santa Claus (non-religious chanting). One Buddhist monk who had spent years chanting underwent a function Magnetic Resonance Imaging (fMRI) brain scan under similar conditions.

 

They found that the fMRI revealed altered activity in the posterior cingulate cortex during religious vs. non-religious chanting. In the experienced chanters the EEG activity was found to have significantly higher power in the Delta low frequency region (1-4 Hertz) from the posterior cingulate cortex region during religious, but not non-religious chanting. In addition, the ECG had significantly lower power during religious, but not non-religious chanting.

 

These findings are very interesting and suggest that religious chanting has specific effects upon the brain and peripheral nervous system that might explain some of the benefits of this chanting. The lowered cardiac power suggests relaxation and a predominance of the parasympathetic division of the autonomic nervous system. This could in part be responsible for anti-stress effects of meditation practice.

 

The posterior cingulate cortex has been shown through multiple lines of evidence to be involved in self-referential thinking. Delta frequency waves are associated with reduced actual activity as they are increased during light sleep. Hence the results suggest that religious chanting suppresses thinking about the self. This is exactly what most meditation practices attempt to do. The results, then suggest that religious chanting is an effective contemplative practice in altering the brain activity to reduce self-referential thinking and peripheral nervous system activity to increase relaxation.

 

So, affect the brain with religious chanting.

 

“Mantras give the wandering mind a focal point. They produce a beat and a flow that is easy for the mind and body’s energy system to grasp a hold of. When the mind wants to wander out of the meditative state, the mantra helps bring it back.” – EOC

 

CMCS – Center for Mindfulness and Contemplative Studies

 

This and other Contemplative Studies posts are also available on Google+ https://plus.google.com/106784388191201299496/posts and on Twitter @MindfulResearch

 

Study Summary

 

Gao, J., Leung, H. K., Wu, B., Skouras, S., & Sik, H. H. (2019). The neurophysiological correlates of religious chanting. Scientific reports, 9(1), 4262. doi:10.1038/s41598-019-40200-w

 

Abstract

Despite extensive research on various types of meditation, research on the neural correlates of religious chanting is in a nascent stage. Using multi-modal electrophysiological and neuroimaging methods, we illustrate that during religious chanting, the posterior cingulate cortex shows the largest decrease in eigenvector centrality, potentially due to regional endogenous generation of delta oscillations. Our data show that these functional effects are not due to peripheral cardiac or respiratory activity, nor due to implicit language processing. Finally, we suggest that the neurophysiological correlates of religious chanting are likely different from those of meditation and prayer, and would possibly induce distinctive psychotherapeutic effects.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6414545/