Review of: Prevention vs. Treatment: Whatâs the Right Balance?

Philosophy

Notre Dame Philosophical Reviews (March 2012) http://ndpr.nd.edu/news/29529-prevention-vs-treatment-what-s-the-right-balance/ 1 Prevention vs. Treatment: What's the Right Balance? Halley S. Faust and Paul T. Menzel (eds.), Prevention vs. Treatment: What's the Right Balance?, Oxford University Press, 2012, 416pp., $49.99 (hbk), ISBN 9780199837373. Reviewed by J. Paul Kelleher, University of Wisconsin-Madison Prevention vs. Treatment: What's the Right Balance? is a collection of 15 essays on various aspects of the perennial tension in health policy between treatment and prevention. There is also a substantial introduction by the two editors, one of whom (Faust) is a preventive medicine physician and President-elect of the American College of Preventive Medicine; the other (Menzel) is a philosopher who has made important and influential contributions to bioethics, health policy, and health economics. The collection is divided into three roughly equal parts: Part One, "Evidence, Policy, and History;" Part Two, "Philosophical and Legal Analysis;" and Part Three, "Religious and Cultural Perspectives." The volume's introduction invites readers to think of the central issue in rather broad terms. Its opening example contrasts the spare-no-expense urgency displayed when a child falls into a well with the lower priority given to preventing such terrible fates in the first place. Some readers may be disappointed, then, to discover that the empirical essays in Part One focus almost exclusively on the evidence, policy, and history of clinical prevention (e.g. vaccinations, screening, counseling about aspirin prophylaxis, cholesterol management, etc.). One of these essays even remarks in passing that "clinical prevention [is] the theme of this volume" (78). By contrast, none of the other essays in Part Two or Part Three share this narrow focus on the clinical. For reasons of space, the remainder of this review focuses on just one of the empirical papers in Part One, and then on the philosophical and legal essays in Part Two. Regrettably, I am unable to discuss the interesting and informative essays in Part Three. The second essay in Part One is by Louise B. Russell and is titled "Prevention vs. Cure: An Economist's Perspective on the Right Balance." Russell is a highly respected economist who has published widely on the costs and effectiveness of preventive medical services and on various methodological issues in health economics. Her essay is exceedingly well written, conveying both authority in her subject matter and pedagogical concern for the reader who comes to health-economics for the first time. I suspect many readers will judge Russell's essay the gem of Part One (and perhaps even of the entire volume). As I will explain, however, I worry that the orthodox economic framework Russell employs is poorly suited to evaluate the balance between prevention and treatment. Russell's boldest and most intriguing thesis is that "[T]he balance between prevention and cure, at least in the medical sector, may not be so far wrong after all" (75). This claim Notre Dame Philosophical Reviews (March 2012) http://ndpr.nd.edu/news/29529-prevention-vs-treatment-what-s-the-right-balance/ 2 stems from studies (some by Russell herself) that show prevention and treatment are by and large equally cost-effective. Cost-effectiveness analysis (CEA) is a health economic framework that compares a given intervention's monetary cost with its expected health benefit. Health benefits are usually measured in quality-adjusted life-years (QALYs), which combine quality-of-life and longevity into one metric by multiplying a given health state's quality score by the time (in years) spent living in that state. Quality scores range from zero ("as bad as death") to 1 ("full health"). So one year lived in full health generates 1 QALY; living in full health for half a year generates 0.5 QALYs; and living for one year in a state one-third as good as full health generates 0.33 QALYs. CEA is thus one measure of efficiency in health: by ranking interventions in terms of their costper-QALY (i.e. their cost-effectiveness ratio), CEA shows how to get the most healthrelated bang for our buck. Interventions with very small ratios (i.e. low costs per QALY) are said to be very cost-effective. Now philosophers have raised lots of worries about CEA, but they have mostly ignored a feature of it that is especially relevant to the prevention vs. treatment debate.1 That feature is this: cost-effectiveness studies virtually never evaluate the overall efficiency of the prevailing mix of covered interventions (e.g. the mix currently covered by Medicare); they instead answer the narrower question of how much more expensive and/or more beneficial a new intervention is when compared to the current standard of care for a specific health problem. Thus, standard CEAs evaluate new interventions in terms of their incremental cost-effectiveness, i.e. the ratio of the new intervention's additional costs to its additional benefits. As Russell explains, "Each cost-effectiveness ratio compares two alternatives that could be applied to the same health problem. Often, the comparison is between a new approach, preventive or therapeutic, and the standard approach to the same problem, which again may be preventive or therapeutic" (59). This method of evaluating an intervention's cost-effectiveness can have problematic implications. To illustrate, consider a very stylized example. Suppose that some current treatment T costs our health plan $200 per year (total, not per person) and generates 1 QALY, and that some new and improved treatment T* would cost $1,000 and generate 81 QALYs. A standard CEA will then report that T*'s incremental cost-effectiveness is $10 per QALY (since T* uses 800 additional dollars and yields 80 additional QALYs, when compared to T). Suppose also that some current preventive service P (which prevents a totally different health problem) costs $200 and generates 20 QALYs, and that a new and improved preventive service P* would cost $1,000 and generate 100 QALYs. Thus P*'s incremental cost-effectiveness is also $10 per QALY. Now here's the problem: if we use the methodology underlying Russell's main thesis, we will conclude that T* and P* are equally cost-effective, despite the fact that $1,000 spent on P* yields 1 An exception, to which I am indebted, is Daniel M. Hausman, "Qualms about Cost-Effectiveness" (unpublished manuscript). Hausman draws attention to the feature of CEA I go on to discuss, but he does not flag or explore its relevance for prevention vs. treatment, as he is focused on other issues. Notre Dame Philosophical Reviews (March 2012) http://ndpr.nd.edu/news/29529-prevention-vs-treatment-what-s-the-right-balance/ 3 100 QALYs while the same $1,000 spent on T* would yield only 81 QALYs. Of course, one could compare T* with P* (and T with P), but this is not done in practice because they address completely different health problems. As this example illustrates, and as economists at the World Health Organization note, the use of incremental CEA "means that major allocative inefficiencies may not be evaluated and thus not identified."2 Incremental CEA therefore seems ill suited to the problem Russell is addressing, which is "to find the most effective mix, the one that makes the best use of our resources to improve health and extend life, whether through prevention or treatment" (74). If one really wishes to reassess the prevailing mix of prevention vs. treatment (as this volume clearly intends), incremental cost-effectiveness ratios are not the right tools to use. Part Two of the Volume, "Philosophical and Legal Analysis," opens with "Our Alleviation Bias: Why Do We Value Alleviating Harm More than Preventing Harm?" by Halley Faust. The essay uses a series of thought experiments to support the "empirical/descriptive claim" that we frequently prioritize treatment over prevention because of the "overwhelming moral emotion" of compassion (141). I fear many readers (especially health policy folks, but even some philosophers) will find Faust's thought experiments far-fetched and of questionable evidential value. Consider: Pond Barrier 2-hour (PB2H): I alone see a pond with an anonymous child playing around it. I know that this child will be drowning in the pond 2 hours from now. If I put $500 into the machine now it will put a barrier between the child and drowning just at the right time, preventing the child from drowning. I have to go to a meeting and can't hang around, so I need to make a decision now. (155, italics added). Nevertheless, Faust claims that "[t]he true test of the priority of preventing or treating harm" comes in the form of a comparison between this and another pond case: I am walking between two ponds. In pond 1 is the Pond Hidden (PH) scenario, in which I will not witness the child's drowning or death, but will be told [and will believe] it is happening in real time [i.e. imminently]. In pond 2 is the Pond Barrier 2-Hour (PB2H) scenario, in which I will prevent [a child] from drowning 2 hours from now. My credit card is limited to $500...Do I put my credit card into the machine at Pond 1 (PH) or Pond 2 (PB2H)? (156) 2 Rob Baltussen, et al., "Methods for Generalized Cost-Effectiveness Analysis" in T. Tan-Torres Edejer, et al. (eds.) WHO Guide to Cost-Effectiveness Analysis (Geneva: World Health Organization, 2003), p. 10. Available online (pdf) at: www.who.int/choice/publications/p_2003_generalised_cea.pdf. One goal of this WHO Guide is to explain and defend an alternative to incremental CEA, which the WHO calls "generalized CEA." Notre Dame Philosophical Reviews (March 2012) http://ndpr.nd.edu/news/29529-prevention-vs-treatment-what-s-the-right-balance/ 4 Faust comments: Empirically most of us likely would put our money into the PH scenario even though PB2H would actually create more net well-being–the child in PB2H would not experience any of the 'process of drowning'...The only conceivable reason to choose PH and not PB2H is because we know harm is happening right now, and this somehow moves us to act right now. (156, italics in original) I agree that many people would choose Pond 1, and that this has to do with the fact that Pond 1 is unfolding now. But I suspect they will choose this option hoping that something else can be done for the child in Pond 2 before danger sets in. So they will not accept that more expected benefit comes from choosing the Pond 2 scenario first. In discussing a related example, Faust concedes that many people will "violate the thought experiment rules" by insisting "that our choices are rarely so limited in time" (167). Is there, then, a better thought experiment to test the hypothesis that compassion drives people to prioritize treatment over prevention? Suppose limited health funds force us to choose between (1) successfully treating an otherwise fatal case of AIDS today or (2) preventing two cases of HIV that will result in death from AIDS in 10 years.3 This strikes me as a more useful example to reflect on (and one that may well be in tension with Faust's empirical hypothesis). It is also tragically realistic.4 The next essay in Part Two is "Treatment and Prevention: What Do We Owe Each Other?" by Norman Daniels. Daniels gives a brief overview of his influential theory of health justice, and then draws some lessons for the topic at hand. He also offers a new positive argument for a very weak form of priority of treatment over prevention. Daniels's account of health justice holds that "we have a robust social obligation to protect and promote health and that this obligation means we owe each other a reasonable array of both preventive and curative interventions" (176). Given limited resources and other pressing social concerns, this is not an obligation to provide all possible healthpromoting assistance. Daniels has long been skeptical that there is one right way to allocate scarce resources, and he encourages citizens to engage one another in respectful deliberation to arrive at publicly legitimate (if not timelessly true) approaches to rationing. This is his general tack toward the prevention/treatment trade-off as well, although he stresses that socially disadvantaged groups should be granted special priority (especially for prevention) in light of the greater social and environmental risks they encounter. Daniels's new positive argument for treatment's limited priority focuses on the fact that those in need of treatment are often "clearly worse off" than those who can benefit from 3 Jotkowitz and Glick pose a similar thought experiment in their contribution to Part Three (at 289). 4 Dan W. Brock and Daniel Wikler, "Ethical Challenges in Long-Term Funding for HIV/AIDS: the Moral Imperative for Shifting Priorities from Treatment to Prevention," Health Affairs 28(6) (2009): 1666-76. Notre Dame Philosophical Reviews (March 2012) http://ndpr.nd.edu/news/29529-prevention-vs-treatment-what-s-the-right-balance/ 5 prevention (189). Specifically, they are worse off in having much higher baseline risk. Suppose we have five tablets of medication and face six people. Cory will die if she doesn't receive all five tablets. Each of the other five individuals has a 20% risk of dying of the same disease; one tablet to each prevents the disease by eliminating this 20% risk. Daniels writes, "I believe we have a stronger obligation to treat Cory than to vaccinate the five others," even though "one expected life is saved in either case" (188). (I think Daniels wants us to stipulate for the sake of argument that one of the five others will die from the disease if the group isn't vaccinated.) He suggests that if one does not share his intuition in this case, at some point one will likely agree that the concentration of risk matters (e.g. if Cory needs the available 1,000 pills, which could instead be used to eliminate a 0.1% risk of dying in each of 1,000 others). Daniels isn't sure whether risk concentration is a reason to save one person at 100% risk of dying if we could instead save two lives by reducing already small baseline risks in a large group of people. "Risk concentration may matter in breaking ties but does not do more: this conclusion would need careful examination" (189). I originally shared Daniels's intuition about cases in which only one life can be saved (the Cory vs. Others cases). But this is not my intuition in similar cases. Suppose the enemy has established two firing squads. Firing Squad 1 (FS1) has 1,000 marksmen pointing their guns at one innocent person tied to a post. Only one marksman has live bullets in his gun (the others have blanks). Firing Squad 2 (FS2) has 1 marksman with live bullets standing before 1,000 innocent people tied to numbered posts. If FS1 proceeds, all 1,000 marksmen will pull their triggers, and the innocent person will be killed by the marksman with live bullets. If FS2 proceeds, a random number generator will select a number between 1 and 1,000, and the lone marksman will then shoot and kill the innocent person tied to the post with that number. Suppose you know all this and you can stop one firing squad but not both. Is there a reason to stop one rather than the other? I believe not. But if not, then risk-concentration cannot even break ties in some cases. Is there a relevant difference between "Cory vs. Others" cases and the "FS1 vs. FS2" case? If there is not, then even the weak priority for treatment defended by Daniels is called into question. Depending both on your baseline risk of death and on the size of the reduction you can achieve, you'll be willing to spend more or less money to reduce that risk. If you face near certain death, you might pay whatever you have (and can borrow) to reduce your risk considerably. If you face a 1 in 1,000,000 chance, you'll pay far less to eliminate it. In "The Variable Value of Life and Fairness to the Already Ill: Two Promising but Tenuous Arguments for Treatment's Priority," Paul Menzel notes that economists often work with a notion of "the value of life" that is tied to individuals' willingness to pay for risk reductions. The more individuals are willing to pay to reduce a risk, the more value is accorded to saving a statistical life threatened by that risk. Menzel then asks whether treatment deserves priority over prevention since lives saved by treatment have more value in this economic sense. I agree with his answer: "The value of real life cannot be Notre Dame Philosophical Reviews (March 2012) http://ndpr.nd.edu/news/29529-prevention-vs-treatment-what-s-the-right-balance/ 6 determined simply by values of risk reduction," as expressed by people's willingness to pay for them (208). Instead of concluding, however, that this argument for treatment's priority is weak, Menzel concludes that in fact it supports a "weak form of priority" (211). He bases this surprising conclusion on the fact that individuals' willingness to pay conveys information about their preferences, which ought to be respected "in a society in which noncoerced choices are taken seriously" (209). Nevertheless, Menzel himself seems to believe that each death is equally worth avoiding, and that treatment and prevention should be chosen primarily on the basis of which prevents more deaths. Of course, if we choose prevention because it's more efficient, those who are sick now will neither be treated nor will they benefit much from the new focus on prevention. Menzel concedes that this is prima facie unfair to those who are currently ill, but he believes this unfairness can be morally outweighed by the larger number of lives saved through prevention. Moreover, "the unfairness to the already ill lasts only through the transition generation," after which those who get sick will still have benefited from a preventive reduction in overall population health risks (213). Does this mean we should never offer treatments today if instead we can prevent worse outcomes in the future? Menzel is clearly uncomfortable with that implication, and he later (in a different essay) suggests there are "reasons of fairness" for focusing on the "people all around us whose lives and health are at stake" (264). But he leaves it at that. The next essay in Part Two is Thaddeus Pope's "The Slow Transition of U.S. Law Toward a Greater Emphasis on Prevention." Pope gives an excellent overview of the development of public health law in America, highlighting the transition from a focus on communicable diseases to the current focus on unhealthy lifestyles and personal behaviors. He then explores whether the normative frameworks of communitarianism and liberalism can justify limiting individuals' liberty in order to prevent sickness and death. Pope worries that communitarianism "masks hard paternalism" by "[r]estricting the liberty of a particular individual or group for the good of just that same individual or group" (236, italics added). However, the explicitly stated concern of public health communitarians is the overall "good of the community," not the good of the individuals it contains. Still, I think he is absolutely right that "more justification is needed before the mere invocation of 'community' justifies limiting liberty" (237). I wish only that Pope had ventured to offer a viable alternative to communitarianism. He expresses hope that "a new 'collective harm' liberty-limiting principle" can be added to classical liberalism, but this is not yet much different from the hope that a rights-respecting communitarianism can be salvaged. One theme highlighted by Pope's focus on lifestyle risks (but not explored by him) is that prevention is very often within people's own grasp. So one reason to prioritize treatment might be that prevention often helps those who can easily help themselves but who are too weak-willed or irresponsible to do so. Of course, this reason could only be used to prioritize treatments for individuals who are sick or disabled through no fault of their own. Notre Dame Philosophical Reviews (March 2012) http://ndpr.nd.edu/news/29529-prevention-vs-treatment-what-s-the-right-balance/ 7 An additional concern about standard cost-effectiveness analysis is that it discounts future benefits by 3% to 7% per year. In Part Two's final essay, "Should the Value of Future Health Benefits Be Time-Discounted?", Paul Menzel expertly criticizes this practice, noting at the start that "At a 3.0% discount rate over 20 years...the present value of 10 years of future life drops to less than 6 years" (246). So an intervention that produces 10 QALYs today will be said to produce 4 more QALYs than an alternate intervention that produces 10 QALYs in 20 years. The practice of discounting therefore systematically disadvantages prevention relative to treatment. The debate over discounting usually pits economists (who tend to favor the practice) against philosophers (who tend to reject it). The philosopher's appraisal can seem almost self-evident when one learns that a 5% discount rate will treat one death today as equivalent to 1 billion deaths in 425 years (246n1). It would be a mistake, however, to ignore economists' sometimes quite subtle (if invalid) arguments, especially since they have carried the day in real-world policy analysis. If one reads just one philosophical essay on this topic, it should be Parfit's "The Social Discount Rate" (which Menzel doesn't cite).5 Menzel's should be next. Prevention vs. Treatment is an exceptionally wide-ranging and provocative collection. It is valuable not only for its new contributions but also as an orienting guide to a wider literature. Political philosophy and health policy alike would be well served if there were more volumes like it.6 5 Derek Parfit, Reasons and Persons (New York: Oxford University Press, 1984), Appendix F. 6 I wish to thank Bill Gardner and Brendan Saloner for very helpful comments on a previous draft of this review.


Can the World Learn Wisdom?

Philosophy

The crisis of our times is that we have science without wisdom.  This is the crisis behind all the others.  Population growth, the terrifyingly lethal character of modern war and terrorism, immense differences of wealth across the globe, annihilation of indigenous people, cultures and languages, impending depletion of natural resources, destruction of tropical rain forests and other natural habitats, rapid mass extinction of species, pollution of sea, earth and air, thinning of the ozone layer, above all global warming  -  even the aids epidemic: all these relatively recent crises have been made possible by modern science and technology.  Indeed, in a perfectly reasonable sense of "cause", they have been caused by modern science and technology.  An essential step we need to take, in order to tackle these global problems more effectively, intelligently and humanely than we have done so far, is to create a new kind of academic inquiry which puts problems of living, and the pursuit of wisdom, at the heart of the enterprise.

Can The World Learn Wisdom? (Solidarity, Sustainability, and Non-Violence, vol. 3, no. 4, April 2007) http://www.pelicanweb.org/solisustv03n04maxwell.html Nicholas Maxwell (Emeritus Reader In philosophy of science at University College London https://www.ucl.ac.uk/from-knowledge-to-wisdom The crisis of our times is that we have science without wisdom. This is the crisis behind all the others. Population growth, the terrifyingly lethal character of modern war and terrorism, immense differences of wealth across the globe, annihilation of indigenous people, cultures and languages, impending depletion of natural resources, destruction of tropical rain forests and other natural habitats, rapid mass extinction of species, pollution of sea, earth and air, thinning of the ozone layer, above all global warming even the aids epidemic: all these relatively recent crises have been made possible by modern science and technology. Indeed, in a perfectly reasonable sense of "cause", they have been caused by modern science and technology. It may be objected that it is not science that is the cause of these global problems but rather the things that we do, made possible by science and technology. This is obviously correct. But it is also correct to say that scientific and technological progress is the cause. The meaning of "cause" is ambiguous. By "the cause" of event E we may mean something like "the most obvious observable events preceding E that figure in the common sense explanation for the occurrence of E". In this sense, human actions (made possible by science) are the cause of such things as people being killed in war, destruction of tropical rain forests. On the other hand, by the "cause" of E we may mean "that prior change in the environment of E which led to the occurrence of E, and without which E would not have occurred". If we put the 20th century into the context of human history, then it is entirely correct to say that, in this sense, scientific-andtechnological progress is the cause of our distinctive current global disasters: what has changed, what is new, is scientific knowledge, not human nature. (Give a group of chimpanzees rifles and teach them how to use them and in one sense, of course, the cause of the subsequent demise of the group would be the actions of the chimpanzees. But in another obvious sense, the cause would be the sudden availability and use of rifles – the new, lethal technology.) Yet again, from the standpoint of theoretical physics, "the cause" of E might be interpreted to mean something like "the physical state of affairs prior to E, throughout a sufficiently large spatial region surrounding the place where E occurs". In this third sense, the sun continuing to shine is as much a part of the cause of war and pollution as human action or human science and technology. In short, if by the cause of an event we mean that prior change which led to that event occurring, then it is the advent of modern science and technology that has caused all our current global crises. It is not that people became greedier or more wicked in the 19th and 20th centuries; nor is it that the new economic system of capitalism is responsible, as some historians and economists would have us believe. The crucial factor is the creation and immense success of modern science and technology. This has led to modern medicine and hygiene, to population growth, to modern agriculture and 2 industry, to world wide travel (which spreads diseases such as aids), to global warming, and to the destructive might of the technology of modern war and terrorism, conventional, chemical, biological, nuclear. All this is to be expected. Successful science produces knowledge, which facilitates the development of technology, both of which enormously increase our power to act. It is to be expected that this power will often be used beneficially (as it has been used), to cure disease, feed people, and in general enhance the quality of human life. But it is also to be expected, in the absence of wisdom, that such an abrupt, massive increase in power will be used to cause harm, whether unintentionally, as in the case (initially at least) of environmental damage, or intentionally, as in war and terror. Before the advent of modern science, lack of wisdom did not matter too much; we lacked the means to do too much damage to ourselves and the planet. But now, in possession of unprecedented powers bequeathed to us by science, lack of wisdom has become a menace. The crucial question becomes: How can we learn to become wiser? The answer is staring us in the face. And yet it is one that almost everyone overlooks. Modern science has met with astonishing success in improving our knowledge of the natural world. It is this very success that is the cause of our current problems. But instead of merely blaming science for our troubles, as some are inclined to do, we need, rather, to try to learn from the success of science. We need to learn from the manner in which science makes progress towards greater knowledge how we can make social progress towards greater wisdom. This is not a new idea. It goes back to the Enlightenment of the 18th century, especially the French Enlightenment. Voltaire, Diderot, Condorcet and the other philosophes of the Enlightenment had the profoundly important idea that it might be possible to learn from scientific progress how to achieve social progress towards an enlightened world. They did not just have the idea: they did everything they could to put the idea into practice in their lives. They fought dictatorial power, superstition, and injustice with weapons no more lethal than those of argument and wit. They gave their support to the virtues of tolerance, openness to doubt, readiness to learn from criticism and from experience. Courageously and energetically they laboured to promote reason and enlightenment in personal and social life. And in doing so they created, in a sense, the modern world, with all its glories and disasters. The philosophes of the Enlightenment had their hearts in the right place. But in developing the basic Enlightenment idea intellectually the philosophes, unfortunately, blundered. They botched the job. And it is this that we are suffering from today. The philosophers thought that the proper way to implement the Enlightenment Programme of learning from scientific progress how to achieve social progress towards an enlightened world is to develop the social sciences alongside the natural sciences. If it is important to acquire knowledge of natural phenomena to better the lot of mankind, as Francis Bacon had insisted, then (so, in effect, the philosophes thought) it must be even more important to acquire knowledge of social phenomena. First, knowledge must be acquired; then it can be applied to help solve social problems. They thus set about creating and developing the social sciences: economics, psychology, anthropology, history, sociology, political science. This traditional version of the Enlightenment Programme, despite being damagingly 3 defective, was immensely influential. It was developed throughout the 19th century, by men such as Saint-Simon, Comte, Marx, Mill and many others, and was built into the intellectual-institutional structure of academic inquiry in the first part of the 20th century with the creation of departments of the social sciences in universities all over the world. Academic inquiry today, devoted primarily to the pursuit of knowledge and technological know-how, is the outcome of two past revolutions: the scientific revolution of the 16th and 17th centuries which led to the development of modern natural science, and the later profoundly important but very seriously defective Enlightenment revolution. It is this situation which calls for the urgent need to bring about a third revolution to put right the structural defects we have inherited from the Enlightenment. But what, it may be asked, is wrong with the traditional Enlightenment Programme? Almost everything. In order to implement properly the basic Enlightenment idea of learning from scientific progress how to achieve social progress towards a civilized world, it is essential to get the following three things right. 1. The progress-achieving methods of science need to be correctly identified. 2. These methods need to be correctly generalized so that they become fruitfully applicable to any worthwhile, problematic human endeavour, whatever the aims may be, and not just applicable to the one endeavour of acquiring knowledge. 3. The correctly generalized progress-achieving methods then need to be exploited correctly in the great human endeavour of trying to make social progress towards an enlightened, wise world. Unfortunately, the philosophes of the Enlightenment got all three points wrong. And as a result these blunders, undetected and uncorrected, are built into the intellectualinstitutional structure of academia as it exists today. First, the philosophes failed to capture correctly the progress-achieving methods of natural science. From D'Alembert in the 18th century to Popper in the 20th, the widely held view, amongst both scientists and philosophers, has been (and continues to be) that science proceeds by assessing theories impartially in the light of evidence, no permanent assumption being accepted by science about the universe independently of evidence. But this standard empiricist view is untenable. If taken literally, it would instantly bring science to a standstill. For, given any accepted scientific theory, T, Newtonian theory say, or quantum theory, endlessly many rivals can be concocted which agree with T about observed phenomena but disagree arbitrarily about some unobserved phenomena. Science would be drowned in an ocean of such empirically successful rival theories if empirical considerations alone determined which theories are accepted, which rejected. In practice, these rivals are excluded because they are disastrously disunified. Two considerations govern acceptance of theories in science: empirical success and unity. But in persistently accepting unified theories, to the extent of rejecting disunified rivals that are just as, or even more, empirically successful, science makes a big persistent assumption about the universe. Science assumes that the universe is such that all disunified theories are false. The universe has some kind of unified dynamic structure. It is physically comprehensible in the sense that explanations for phenomena exist to be 4 discovered. But this untestable (and thus metaphysical) assumption that the universe is comprehensible is profoundly problematic. How can we possibly know that the universe is comprehensible? Science is obliged to assume, but does not know, that the universe is comprehensible. Much less does it know that the universe is comprehensible in this or that way. A glance at the history of physics reveals that ideas about how the universe may be comprehensible have changed dramatically over time. In the 17th century there was the idea that the universe consists of corpuscles, minute billiard balls, which interact only by contact. This gave way to the idea that the universe consists of point-particles surrounded by rigid, spherically symmetrical fields of force, which in turn gave way to the idea that there is one unified self-interacting field, varying smoothly throughout space and time. Nowadays we have the idea that everything is made up of minute quantum strings embedded in ten or eleven dimensions of space-time. Some kind of assumption along these lines must be made but, given the historical record, and given that any such assumption concerns the ultimate nature of the universe, that of which we are most ignorant, it is only reasonable to conclude that it is almost bound to be false. The way to overcome this fundamental dilemma, inherent in the scientific enterprise, is to construe science as making a hierarchy of metaphysical assumptions concerning the comprehensibility and knowability of the universe, these assumptions asserting less and less as one goes up the hierarchy, and thus becoming more and more likely to be true. In this way a framework of relatively insubstantial, unproblematic, fixed assumptions and associated methods is created within which much more substantial and problematic assumptions and associated methods can be changed, and indeed improved, as scientific knowledge improves. Put another way, a framework of relatively unspecific, unproblematic, fixed aims and methods is created within which much more specific and problematic aims and methods evolve as scientific knowledge evolves. (A basic aim of science is to discover in what precise way the universe is comprehensible, this aim evolving as assumptions about comprehensibility evolve.) There is positive feedback between improving knowledge, and improving aims-and-methods, improving knowledge-about-how-to-improve-knowledge. This is the nub of scientific rationality, the methodological key to the unprecedented success of science. Science adapts its nature to what it discovers about the nature of the universe. For a detailed exposition and defence of this hierarchical, aim-oriented empiricist conception of science see my The Comprehensibility of the Universe (Oxford University Press, 1998, paperback 2003); see also my The Human World in the Physical Universe (Rowman and Littlefield, 2001) chapter 3 and appendix 3, and Is Science Neurotic? (Imperial College Press, December 2004), chapters 1 and 2. So much for the first blunder of the Enlightenment. Second, having failed to identify the methods of science correctly, the philosophes naturally failed to generalize these methods properly. They failed to appreciate that the idea of representing the problematic aims (and associated methods) of science in the form of a hierarchy can be generalized and applied fruitfully to other worthwhile enterprises besides science. Many other enterprises have problematic aims; these would benefit from employing a hierarchical methodology, generalized from that of science, 5 thus making it possible to improve aims and methods as the enterprise proceeds. There is the hope that, in this way, some of the astonishing success of science might be exported into other worthwhile human endeavours, with aims quite different from those of science. Third, and most disastrously of all, the philosophes failed completely to try to apply such generalized progress-achieving methods to the immense, and profoundly problematic enterprise of making social progress towards an enlightened, wise world. The aim of such an enterprise is notoriously problematic. For all sorts of reasons, what constitutes a good world, an enlightened, wise or civilized world, attainable and genuinely desirable, must be inherently and permanently problematic. Here, above all, it is essential to employ the generalized version of the hierarchical, progress-achieving methods of science, designed specifically to facilitate progress when basic aims are problematic. Properly implemented, in short, the Enlightenment idea of learning from scientific progress how to achieve social progress towards an enlightened world would involve developing social inquiry as social methodology, or social philosophy, not primarily as social science. A basic task would be to get into personal and social life, and into other institutions besides that of science – into government, industry, agriculture, commerce, the media, law, education, international relations – hierarchical, progress-achieving methods (designed to improve problematic aims) arrived at by generalizing the methods of science. A basic task for academic inquiry as a whole would be to help humanity learn how to resolve its conflicts and problems of living in more just, cooperatively rational ways than at present. This task would be intellectually more fundamental than the scientific task of acquiring knowledge. Social inquiry would be intellectually more fundamental than physics. Academia would be a kind of people's civil service, doing openly for the public what actual civil services are supposed to do in secret for governments. Academia would have just sufficient power (but no more) to retain its independence from government, industry, the press, public opinion, and other centres of power and influence in the social world. It would seek to learn from, educate, and argue with the great social world beyond, but would not dictate. Academic thought would be pursued as a specialized, subordinate part of what is really important and fundamental: the thinking that goes on, individually, socially and institutionally, in the social world, guiding individual, social and institutional actions and life. The fundamental intellectual and humanitarian aim of inquiry would be to help humanity acquire wisdom – wisdom being the capacity to realize (apprehend and create) what is of value in life, for oneself and others, wisdom thus including knowledge and technological know-how but much else besides. One important consequence flows from the point that the basic aim of inquiry would be to help us discover what is of value, namely that our feelings and desires would have a vital rational role to play within the intellectual domain of inquiry. If we are to discover for ourselves what is of value, then we must attend to our feelings and desires. But not everything that feels good is good, and not everything that we desire is desirable. Rationality requires that feelings and desires take fact, knowledge and logic into account, just as it requires that priorities for scientific research take feelings and desires into account. In insisting on this kind of interplay between feelings and desires 6 on the one hand, knowledge and understanding on the other, the conception of inquiry that we are considering resolves the conflict between Rationalism and Romanticism, and helps us to acquire what we need if we are to contribute to building civilization: mindful hearts and heartfelt minds. Another outcome of getting into social and institutional life the kind of aimevolving, hierarchical methodology indicated above, generalized from science, is that it becomes possible for us to develop and assess rival philosophies of life as a part of social life, somewhat as theories are developed and assessed within science. Such a hierarchical methodology "provides a framework within which diverse philosophies of value – diverse religions, political and moral views – may be cooperatively assessed and tested against the experience of personal and social life. There is the possibility of cooperatively and progressively improving such philosophies of life (views about what is of value in life and how it is to be achieved) much as theories are cooperatively and progressively improved in science. In science diverse universal theories are critically assessed with respect to each other, and with respect to experience (observational and experimental results). In a somewhat analogous way, diverse philosophies of life may be critically assessed with respect to each other, and with respect to experience – what we do, achieve, fail to achieve, enjoy and suffer – the aim being so to improve philosophies of life (and more specific philosophies of more specific enterprises within life such as government, education or art) that they offer greater help with the realization of value in life" (See my From Knowledge to Wisdom, Blackwell, 1984, p. 254). All in all, if the Enlightenment revolution had been carried through properly, the three steps indicated above being correctly implemented, the outcome would have been a kind of academic inquiry very different from what we have at present. We would possess what we so urgently need, and at present so dangerously and destructively lack, institutions of learning well-designed from the standpoint of helping us create a better, a wiser world. Here, to conclude, is a summary of the changes that need to be made to science, and to academic inquiry more generally, to put right the blunders we have inherited from the Enlightenment, thus creating a kind of inquiry rationally designed to help humanity realize what is genuinely of value, actually and potentially, in existence. 1. There needs to be a change in the basic intellectual aim of inquiry, from the growth of knowledge to the growth of wisdom - wisdom being taken to be the capacity to realize what is of value in life, for oneself and others, and thus including knowledge, understanding and technological know-how. 2. There needs to be a change in the nature of academic problems, so that problems of living are included, as well as problems of knowledge. Furthermore, problems of living need to be treated as intellectually more fundamental than problems of knowledge. 3. There needs to be a change in the nature of academic ideas, so that proposals for action are included as well as claims to knowledge. Furthermore, proposals for action need to be treated as intellectually more fundamental than claims to knowledge. 7 4. There needs to be a change in what constitutes intellectual progress, so that progress-in-ideas-relevant-to-achieving-a-more-civilized-world is included as well as progress in knowledge, the former being indeed intellectually fundamental. 5. There needs to be a change in the idea as to where inquiry, at its most fundamental, is located. It is not esoteric theoretical physics, but rather the thinking we engage in as we seek to achieve what is of value in life. 6. There needs to be a dramatic change in the nature of social inquiry (reflecting points 1 to 5). Economics, politics, sociology, and so on, are not, fundamentally, sciences, and do not, fundamentally, have the task of improving knowledge about social phenomena. Instead, their task is threefold. First, it is to articulate problems of living, and propose and critically assess possible solutions, possible actions or policies, from the standpoint of their capacity, if implemented, to promote wiser ways of living. Second, it is to promote such cooperatively rational tackling of problems of living throughout the social world. And third, at a more basic and long-term level, it is to help build the hierarchical structure of aims and methods of aim-oriented rationality into personal, institutional and global life, thus creating frameworks within which progressive improvement of personal and social life aims-and-methods becomes possible. These three tasks are undertaken in order to promote cooperative tackling of problems of living - but also in order to enhance empathic or "personalistic" understanding between people as something of value in its own right. Acquiring knowledge of social phenomena is a subordinate activity, engaged in to facilitate the above three fundamental pursuits. 7. Natural science needs to change, so that it includes at least three levels of discussion: evidence, theory, and research aims. Discussion of aims needs to bring together scientific, metaphysical and evaluative consideration in an attempt to discover the most desirable and realizable research aims. 8. There needs to be a dramatic change in the relationship between social inquiry and natural science, so that social inquiry becomes intellectually more fundamental from the standpoint of tackling problems of living, promoting wisdom. 9. The way in which academic inquiry as a whole is related to the rest of the human world needs to change dramatically. Instead of being intellectually dissociated from the rest of society, academic inquiry needs to be communicating with, learning from, teaching and arguing with the rest of society - in such a way as to promote cooperative rationality and social wisdom. Academia needs to have just sufficient power to retain its independence from the pressures of government, industry, the military, and public opinion, but no more. Academia becomes a kind of civil service for the public, doing openly and independently what actual civil services are supposed to do in secret for governments. 10. There needs to be a change in the role that political and religious ideas, works of art, expressions of feelings, desires and values have within rational inquiry. Instead of being excluded, they need to be explicitly included and critically assessed, as possible indications and revelations of what is of value, and as unmasking of fraudulent values in satire and parody, vital ingredients of wisdom. 11. There need to be changes in education so that, for example, seminars devoted to the cooperative, imaginative and critical discussion of problems of living are at the 8 heart of all education from five-year-olds onwards. Politics, which cannot be taught by knowledge-inquiry, becomes central to wisdom-inquiry, political creeds and actions being subjected to imaginative and critical scrutiny. 12. There need to be changes in the aims, priorities and character of pure science and scholarship, so that it is the curiosity, the seeing and searching, the knowing and understanding of individual persons that ultimately matters, the more impersonal, esoteric, purely intellectual aspects of science and scholarship being means to this end. Social inquiry needs to give intellectual priority to helping empathic understanding between people to flourish (as indicated in 6 above). 13. There need to be changes in the way mathematics is understood, pursued and taught. Mathematics is not a branch of knowledge at all. Rather, it is concerned to explore problematic possibilities, and to develop, systematize and unify problemsolving methods. 14. Literature needs to be put close to the heart of rational inquiry, in that it explores imaginatively our most profound problems of living and aids personalistic understanding in life by enhancing our ability to enter imaginatively into the problems and lives of others. 15. Philosophy needs to change so that it ceases to be just another specialized discipline and becomes instead that aspect of inquiry as a whole that is concerned with our most general and fundamental problems - those problems that cut across all disciplinary boundaries. Philosophy needs to become again what it was for Socrates: the attempt to devote reason to the growth of wisdom in life. This is the revolution we need to bring about in our traditions and institutions of learning, if they are to be properly and rationally designed to help us learn how to make progress towards a wiser world. Nicholas Maxwell is Emeritus Reader in Philosophy of Science at University College London. He has devoted much of his working life to trying to get across the message of this essay in numerous articles and five books: What's Wrong With Science? (1976), From Knowledge to Wisdom (Blackwell, 1984; second edition, enlarged, Pentire Press, 2007), The Comprehensibility of the Universe (OUP, 1998, paperback 2003), The Human World in the Physical Universe (Rowman and Littlefield, 2001), and Is Science Neurotic? (Imperial College Press, 2004). NICHOLAS MAXWELL, 13 TAVISTOCK TERRACE, LONDON N19 4BZ firstname.lastname@example.com


Philosophy

Ontologies, as the term is used in informatics, are structured vocabularies comprised of human- and
          computer-interpretable terms and relations that represent entities and relationships. Within informatics
          fields, ontologies play an important role in knowledge and data standardization, representation, integra-
          tion, sharing and analysis. They have also become a foundation of artificial intelligence (AI) research. In what follows, we outline the Coronavirus Infectious Disease Ontology (CIDO), which covers multiple areas in the domain of coronavirus diseases, including etiology, transmission, epidemiology, pathogenesis, diagnosis, prevention, and treatment. We emphasize CIDO development relevant to COVID-19.

Scientific Data | (2020) 7:181 | https://doi.org/10.1038/s41597-020-0523-6 www.nature.com/scientificdata CIDO, a community-based ontology for coronavirus disease knowledge and data integration, sharing, and analysis Yongqun He 1 ✉, Hong Yu2,3, Edison Ong1, Yang Wang1,2,3, Yingtong Liu1, anthony Huffman1, Hsin-hui Huang1,4, John Beverley 5, Junguk Hur 6, Xiaolin Yang7, Luonan Chen8,9, Gilbert S. Omenn1, Brian athey1 & Barry Smith10 the Coronavirus Infectious Disease Ontology (CIDO) is a community-based ontology that supports coronavirus disease knowledge and data standardization, integration, sharing, and analysis. Ontologies, as the term is used in informatics, are structured vocabularies comprised of humanand computer-interpretable terms and relations that represent entities and relationships. Within informatics fields, ontologies play an important role in knowledge and data standardization, representation, integration, sharing and analysis. They have also become a foundation of artificial intelligence (AI) research. In what follows, we outline the Coronavirus Infectious Disease Ontology (CIDO), which covers multiple areas in the domain of coronavirus diseases, including etiology, transmission, epidemiology, pathogenesis, diagnosis, prevention, and treatment. We emphasize CIDO development relevant to COVID-19. Human coronaviruses have given rise to a series of major crises in global public health. Severe acute respiratory syndrome (SARS) emerged in China in November 2002, lasted for eight months and resulted in 8,098 confirmed human cases in 29 countries with 774 deaths (case-fatality rate: 9.6%)1. Approximately ten years later in June 2012, the Middle East Respiratory Syndrome (MERS), another highly pathogenic coronavirus disease, was identified in Saudi Arabia. The MERS outbreak has caused 2,260 cases in 27 countries and 803 deaths (35.5%)2. More recently, the World Health Organization (WHO) declared the Coronavirus Disease 2019 (COVID-19) outbreak as a pandemic on March 11, 2020, when there were 118,326 confirmed cases and 4,292 deaths. As of May 13, there have been over 4.4 million confirmed cases and over 295,000 deaths globally. Unfortunately, we still do not have available effective drugs and vaccines against these highly pathological coronaviruses. Extensive studies have been conducted on coronaviruses, the results of many of which exist in publicly available data repositories such as GEO3. Publications concerning COVID-19 have exploded in recent months, and new clinical trials have been and are being conducted to develop drugs and vaccines against COVID-19, 1,430 of which have been registered in ClinicalTrials.gov as of May 13, 2020. As of May 13, 2020, a PubMed search of "SARS", "MERS", and "SARS-CoV-2 OR COVID-19" resulted in 12,993, 4,493 and 11,813 publications, respectively. A coordinated study of all such results would likely help with understanding and developing treatments for COVID-19. This coordinated study requires the integration of the large and exponentially growing data and research concerning COVID-19 to better understand its etiology, transmission, and pathogenesis mechanism. Moreover, we must be able to translate that understanding into rapid development of patient stratification 1University of Michigan Medical School, Ann Arbor, MI, 48109, USA. 2People's Hospital of Guizhou Province, Guiyang, Guizhou, 550002, China. 3Guizhou University Medical College, Guiyang, Guizhou, 550025, China. 4National YangMing University, Taipei, 112-21, Taiwan. 5Northwestern University, Evanston, IL, 60208, USA. 6University of north Dakota School of Medicine and Health Sciences, Grand Forks, ND, 58203, USA. 7institute of Basic Medical Sciences, chinese Academy of Medical Sciences (cAMS) & School of Basic Medicine, Peking Union Medical college (PUMc), Beijing, china. 8Key Laboratory of Systems Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, 200031, China. 9center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, 650223, China. 10University at Buffalo, Buffalo, NY, 14260, USA. ✉e-mail: firstname.lastname@example.com COmmEnt OPEn 2Scientific Data | (2020) 7:181 | https://doi.org/10.1038/s41597-020-0523-6 www.nature.com/scientificdatawww.nature.com/scientificdata/ methods leveraging precision medicine, therapeutic drugs, and preventive vaccines. However, there are two bottlenecks to achieving these tasks: First, the characteristic five V's of our Big Data4 era lead to disintegrated and non-interoperable data and knowledge. The amount of data (volume), speed at which it is produced (velocity), range of its sources (variety), quality and accuracy (veracity), and assessment of utility (value), result in large, complex, multidimensional, and diverse datasets. Disintegrated and non-interoperable data cannot be interpreted by computers and this inhibits computer-assisted reasoning, which is the essence of artificial intelligence. Consequently, our knowledge – data and information that embodies awareness and understanding – of domains represented by various datasets is seriously hindered. This is a familiar problem for biomedical research in general, which relies heavily on data acquisition, and for coronavirus research in particular, given the global challenge we currently face. The second bottleneck is the lack of bioinformatics tools that can efficiently and robustly integrate and analyze heterogeneous data and knowledge. This is likely a major stumbling block that is slowing the discovery of effective measures against coronaviruses even despite extensive effort across the globe. A critical key to data/information/knowledge disintegration and big data analysis is ontologies. Ontologies are widely used in biomedical data and metadata standardization, and robustly support data integration, sharing, reproducibility, and computer-assisted data analysis. Ontologies are also regarded as the foundation of knowledge representation and reasoning (KR2, KR&R), a major field of artificial intelligence. An important biomedical example is the Gene Ontology (GO)5, which was originally developed in the late 1990s by researchers studying the genomes of three model organisms: fruit fly, mouse, and yeast (Saccharomyces cerevisiae), but later extended to provide terms and relations used to annotate genes from humans, plants, animals, and microbes. GO includes three branches, for cellular components, molecular functions, and biological processes, forming a controlled vocabulary that can be used to represent attributes of gene products in a species-neutral way. Many GO-based tools and algorithms have been developed6. Since publication in 2000, the original GO paper5 has been cited some 25,000 times. GO makes possible consistent and reproducible annotations and analyses of genes and genomes from and across different organisms. The success of GO inspired the development of hundreds of biomedical ontologies over the past two decades7. Included among those ontologies are many relevant to COVID-19: the Disease Ontology (DOID)8 classifies 18,000 human diseases now including COVID-19; the Human Phenotype Ontology (HPO)9 defines 26,000 human phenotypes; the Chemical Entities of Biological Interest ontology (ChEBI)10 includes 135,000 chemical entities; the Ontology for General Medical Sciences (OGMS) includes 200 terms for general medical classification; and the Ontology for Biomedical Investigations (OBI)11 includes nearly 4,000 terms related to all aspects of biomedical investigations. All these ontologies can be applied to the study of coronavirus diseases. Of most relevance to us here is the Infectious Disease Ontology (IDO)12, which defines 550 terms relating to infectious diseases in general and provides a basis for more specific IDO ontologies, for flu, malaria, brucellosis, and other diseases. Ontology openness and interoperability are critical for data sharing and integration. The FAIR Guiding Principles propose that all research data should be Findable, Accessible, Interoperable and Reusable (FAIR) for both machine and human users13. "Interoperability" is the basis of the four FAIRness principles, which see ontology interoperability as the foundation of data/information/knowledge interoperability. With hundreds of ontologies developed, many ontologies overlap each other but, unfortunately, are not interoperable. Many ontologies, through lack of interoperability with other, more widely used ontologies, form silos and thereby fail to support integrative research. To foster interoperability, the Open Biomedical and Biological Ontologies (OBO) Foundry was initiated in 2007 by ontology developers who agreed to adopt a set of principles – including the commitment to collaboration and openness, use of definitions in both humanand computer-readable formats – specifying best practices in ontology development14. The OBO ontology library includes approximately 200 ontologies (including GO). To meet the challenge of COVID-19, we recently initiated the development of CIDO, a community-driven open-source biomedical ontology in the area of coronavirus infectious disease (https://github.com/ CIDO-ontology/cido). CIDO provides standardized humanand computer-interpretable annotation and representation of various coronavirus infectious diseases, including their etiology, transmission, epidemiology, pathogenesis, host-coronavirus interactions, diagnosis, prevention, and treatment. CIDO will be used as a state-of-the-art knowledge base for standard and logical representation of heterogeneous coronavirus knowledge. Having been accepted as an OBO library ontology, CIDO follows the OBO Foundry principles14, and uses an OBO-compatible extensible ontology development strategy15. To support data interoperability, CIDO reuses relevant coronavirus terms from existing reliable reference ontologies themselves aligning with OBO Foundry principles, and aligns these terms under the Basic Formal Ontology (BFO)16, an ISO/IEC standard 21838-2 (https://www.iso.org/standard/74572.html) top-level ontology. BFO is a realism-based ontology that covers all domains by providing highly general ontology classes such as material entity, process, role, site, and so forth. By using BFO as its upper-level architecture, CIDO is automatically interoperable and integrated with >300 other ontologies that also align with BFO. Currently, CIDO contains over 4,000 terms, imported from some 20 further ontologies such as ChEBI, Human Phenotype Ontology, Disease Ontology8, and the NCBI taxonomy ontology (NCBITaxon). Additionally, new CIDO-specific terms have been developed to meet the special needs arising in the research of COVID-19 and other coronavirus diseases. Developing robust ontologies adequate for representing complex domains requires more than the simple construction of taxonomies. Taxonomies reflect important hierarchical relationships among class and subclass terms, represented using is_a relations. For example, instances of coronavirus are instances of viruses, which is to say coronavirus is_a virus. Extending beyond taxonomies, ontologies provide additional relations among entities within and across domains. Figure 1 illustrates a general design of how we can logically link ontology terms that may come from different branches of CIDO. The relations along the arrows in Fig. 1 are computer-understandable 3Scientific Data | (2020) 7:181 | https://doi.org/10.1038/s41597-020-0523-6 www.nature.com/scientificdatawww.nature.com/scientificdata/ links between ontology classes. For example, we can define a logical axiom using the 'caused by' relation to link the COVID-19 disease process and SARS-CoV-2 virus: COVID-19 disease process: 'caused by infection with' some SARS-CoV-2 Such an axiom defines the causal relation between the COVID-19 disease process and the virus strain SARS-COV-2. More specifically, the development of the COVID-19 disease process (or realization of the COVID-19 disease disposition) in a patient is causally induced by an infection of the SARS-CoV-2 virus in the patient, involving viral invasion of and replication in host cells. In CIDO, diseases such as COVID-19 and pathogens such as SARS-CoV-2 have distinct hierarchies, with relations linking terms in these hierarchies. The inclusion of the relations (e.g., 'caused by infection with') in addition to is_a greatly expands expressiveness, reasoning capabilities, and expected inferences. Figure 1 illustrates many other key relations. Particularly, COVID-19 occurs in the lung, and some genes in the cells of the lung would have the disposition of being susceptibly upor down-regulated in the cells of SARS-CoV2-infected lung. Such genes may function as gene markers and play important roles in pathogenesis. In addition, the infected patient will display different phenotypes after manifesting the disease, and such phenotypes may be associated with other patient attributes (e.g., biological sex, age) and the patient's gene profile. CIDO thus provides semantically interoperable representations of host-coronavirus interaction mechanisms. Although Fig. 1 provides only a high-level overview of some CIDO resources, more details, such as specific signature genes in some cells of the lung that are susceptible to be upor down-regulated in patients with COVID-19 will be added to the CIDO as new knowledge is acquired. Such systematic modeling and representation of the host-coronavirus interaction mechanisms would facilitate rational design of anti-coronavirus drugs and vaccines17,18. In pursuit of that aim, CIDO can logically define relations between drugs and roles or mechanisms of action – distinct hierarchies in CIDO – and so support advanced analysis of potential drugs used to treat COVID-19, as well as the quick query of drugs having specific roles or mechanisms of action potentially useful as treatments. Such application of CIDO for ontology-based integration and analysis of anti-coronavirus drugs is shown in our recent preprint paper17. Using literature mining we identified 72 chemical drugs and 27 monoclonal or polyclonal antibodies that have anti-coronavirus effects in experimental studies in vivo or in vitro. Many of these drugs were mapped to three ontologies: Chemical Entities of Biological Interest ontology (ChEBI)10, National Drug File – Reference Terminology (NDF-RT)19, and the Drug Ontology (DrON)20. The subbranches of these ontologies that contain the mapped drugs and their related characteristics were extracted using the Ontofox tool21. Key information was identified by examining these subbranches. For example, based on their ChEBI annotations, many drug active ingredients are classified under the same chemical group: for example, chlorpromazine, dasatinib, terconazole, and chloroquine, all organochlorine compounds. Meanwhile, ChEBI classifies many drug chemicals having the same roles: chloroquine, conessine, lycorine, and mefloquine, all exhibit antimalarial activity. A ChEBI-based semantic similarity calculation method clustered 60 drugs into five major categories. The chemical information in ChEBI has also been imported to DrON. Developed by the U.S. Department of Veterans Affairs, Veterans Health Administration (VHA), NDF-RT organizes drugs by means of a formal representation of various drug characteristics such as mechanism of action (MoA), physiologic effect, and related diseases19. Using NDF-RT, we found that, of 35 drugs that have MoA annotations, 34 have MoAs of various inhibitors and antagonists. One shortcoming is that none of these ontologies covers all the needed information pertaining to our identified drugs. To study the anti-coronavirus drugs in a thorough manner we will need to identify and ontologically represent missing information of the sort that falls under the domain of the CIDO ontology. Thus, we plan to build logical relations linking drugs, coronaviruses, and the conditions under which the drugs work against the coronaviruses. Another example of our ongoing work is the use of CIDO for the representation of vaccines against coronaviruses. We recently released another preprint paper on COVID-19 vaccine design using reverse vaccinology and machine learning18. Data pertaining to experimentally verified vaccine candidates in laboratory animal models Fig. 1 The design pattern of CIDO for logically representing and linking different components related to a coronavirus disease, e.g., COVID-19. The terms presented in the figure are generated in CIDO or imported by CIDO from other ontologies. To reduce complexity, the ontology sources of the terms are not labeled. 4Scientific Data | (2020) 7:181 | https://doi.org/10.1038/s41597-020-0523-6 www.nature.com/scientificdatawww.nature.com/scientificdata/ have also been collected and annotated18. We will systematically annotate these vaccine candidates, including their formulations and host responses, and work with the Vaccine Ontology (VO) development team to model, represent, and analyze these vaccines (http://www.violinet.org/vaccineontology/). Moreover, CIDO can be used alongside VO to support literature mining of vaccine-associated gene-gene interactions22. In future research, we will use ontology-based approaches to investigate relevant host-coronavirus interactions to support the fundamental understanding of the disease and protective immune system mechanisms, precision medicine research, and rational vaccine design23,24. More broadly, CIDO will provide community-based metadata standardization for interoperable and reproducible clinical and experimental studies, insofar as the coronavirus metadata ontology will be extracted from CIDO as a lightweight and relatively independent ontology to support data integration and knowledge discovery. We will use the standard to analyze clinical and basic research data and align the identified disease phenotype and transmission data with the underlying mechanisms introduced in other aims. The extensive study of COVID-19 is generating new knowledge quickly. Given that our understanding of COVID-19 is changing rapidly, we need not only an ontology as wide in purview as CIDO, but also to be readily updated in a timely matter as more knowledge is generated about the disease, the virus, and the host response. To that end, we follow OBO Foundry guidelines for term requests and updating via issue tracking on the CIDO GitHub site (https://github.com/CIDO-ontology/cido). We welcome wide community participation in CIDO development and applications. CIDO is an open community; everyone is welcome. We are already collaborating with many groups and look forward to more collaborations with colleagues and people around the world. Starting with CIDO and its supported data integration, we expect that innovative computational and statistical algorithms and tools will be developed and applied to support basic studies of mechanisms, and translational applications such as predicting drugs and vaccines that hold promise for treating and preventing COVID-19. Received: 15 April 2020; Accepted: 19 May 2020; Published: xx xx xxxx References 1. Xu, R. Chance missed, but still there! Memoirs at the 10(th) anniversary of 2003 SARS outbreak. J. Thorac. Dis. 5(Suppl 2), S90–93 (2013). 2. Bernard-Stoecklin, S. et al. Comparative Analysis of Eleven Healthcare-Associated Outbreaks of Middle East Respiratory Syndrome Coronavirus (Mers-Cov) from 2015 to 2017. Sci. Rep. 9, 7385 (2019). 3. Barrett, T. et al. NCBI GEO: archive for functional genomics data sets–update. Nucleic Acids Res. 41, D991–995 (2013). 4. Higdon, R. et al. Unraveling the Complexities of Life Sciences Data. Big Data 1, 42–50 (2013). 5. Ashburner, M. et al. Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat. Genet. 25, 25–29 (2000). 6. du Plessis, L., Skunca, N. & Dessimoz, C. The what, where, how and why of gene ontology–a primer for bioinformaticians. Brief. Bioinform. 12, 723–735 (2011). 7. Whetzel, P. L. et al. BioPortal: enhanced functionality via new Web services from the National Center for Biomedical Ontology to access and use ontologies in software applications. Nucleic Acids Res. 39, W541–545 (2011). 8. Kibbe, W. A. et al. Disease Ontology 2015 update: an expanded and updated database of human diseases for linking biomedical knowledge through disease data. Nucleic Acids Res. 43, D1071–1078 (2015). 9. Groza, T. et al. The Human Phenotype Ontology: Semantic Unification of Common and Rare Disease. Am. J. Hum. Genet. 97, 111–124 (2015). 10. Hastings, J. et al. ChEBI in 2016: Improved services and an expanding collection of metabolites. Nucleic Acids Res. 44, D1214–1219 (2016). 11. Bandrowski, A. et al. The Ontology for Biomedical Investigations. PloS One 11, e0154556 (2016). 12. Babcock, S., Beverley, J., Cowell, L. G. & Smith, B. The Infectious Disease Ontology in the Age of COVID-19. Preprint at, https://doi. org/10.31219/osf.io/az6u5 (2020). 13. Wilkinson, M. D. et al. The FAIR Guiding Principles for scientific data management and stewardship. Sci. Data 3, 160018 (2016). 14. Smith, B. et al. The OBO Foundry: coordinated evolution of ontologies to support biomedical data integration. Nat. Biotechnol. 25, 1251–1255 (2007). 15. He, Y. et al. The eXtensible ontology development (XOD) principles and tool implementation to support ontology interoperability. J. Biomed. Semant. 9, 3 (2018). 16. Arp, R., Smith, B. & Spear, A. D. Building Ontologies with Basic Formal Ontology. (Cambridge, MA, USA, 2015). 17. Liu, Y. et al. Ontological and bioinformatic analysis of anti-coronavirus drugs and their Implication for drug repurposing against COVID-19. Preprint at, https://doi.org/10.20944/preprints202003.0413.v1 (2020). 18. Ong, E., Wong, M. U., Huffman, A. & He, Y. COVID-19 coronavirus vaccine design using reverse vaccinology and machine learning. Preprint at, https://doi.org/10.1101/2020.03.20.000141 (2020). 19. Carter, J. S. et al. Categorical information in pharmaceutical terminologies. In AMIA Annu. Symp. Proc. 116–120 (2006). 20. Hogan, W. R. et al. Therapeutic indications and other use-case-driven updates in the drug ontology: anti-malarials, antihypertensives, opioid analgesics, and a large term request. J. Biomed. Semant. 8, 10 (2017). 21. Xiang, Z., Courtot, M., Brinkman, R. R., Ruttenberg, A. & He, Y. OntoFox: web-based support for ontology reuse. BMC Res. Notes 3, 175 (2010). 22. Ozgur, A., Xiang, Z., Radev, D. R. & He, Y. Mining of vaccine-associated IFN-gamma gene interaction networks using the Vaccine Ontology. J. Biomed. Semant. 2(Suppl 2), S8 (2011). 23. Hoehndorf, R., Dumontier, M. & Gkoutos, G. V. Evaluation of research in biomedical ontologies. Brief. Bioinform. 14, 696–712 (2013). 24. Haendel, M. A., Chute, C. G. & Robinson, P. N. Classification, Ontology, and Precision. Medicine. N. Engl. J. Med. 379, 1452–1462 (2018). acknowledgements This project is supported by NIH grants U24CA210967 and P30ES017885 (to GSO); R01GM080646, 1UL1TR001412, 1U24CA199374, and 1T15LM012495 (to B.S.); 1UH2AI132931 (to Y.H.); the non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences 2019PT320003 (to H.Y.); and University of Michigan Medical School Global Reach award (to Y.H.). 5Scientific Data | (2020) 7:181 | https://doi.org/10.1038/s41597-020-0523-6 www.nature.com/scientificdatawww.nature.com/scientificdata/ Competing interests The authors declare no competing interests. additional information Correspondence and requests for materials should be addressed to Y.H. Reprints and permissions information is available at www.nature.com/reprints. Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. © The Author(s)


Philosophy

Recent fndings illustrate how changes in consciousness accommodated by neural correlates and plasticity of the brain advance a model of perceptual change as a function of meditative practice. During the mindbody response neural correlates of changing awareness illustrate how the autonomic nervous system shifts from a sympathetic dominant to a parasympathetic dominant state. Expansion of awareness during the practice of meditation techniques can be linked to the Default Mode Network (DMN), a network of brain regions that is active when the one is not focused on
          the outside world and the brain is restful yet awake (Chen et al., 2008). A model is presented illustrating the dynamic mindbody response before and after mindfulness meditation, and connections are made with prefrontal cortex activity, the cardiac and respiratory center, the thalamus and amygdala, the DMN and cortical function connectivity. The default status of the DMN changes corresponding to autonomic modulation resulting from meditation practice.

See	discussions,	stats,	and	author	profiles	for	this	publication	at:	http://www.researchgate.net/publication/232236929 Dynamic	Change	of	Awareness	during Meditation	Techniques:	Neural	and Physiological	Correlates ARTICLE in FRONTIERS	IN	HUMAN	NEUROSCIENCE	*	SEPTEMBER	2012 Impact	Factor:	2.99	*	DOI:	10.3389/fnhum.2012.00131	*	Source:	PubMed CITATIONS 9 READS 83 5	AUTHORS,	INCLUDING: Ravinder	Jerath Augusta	Women's	Center 16	PUBLICATIONS 130	CITATIONS SEE	PROFILE Vernon	A	Barnes Georgia	Regents	University 53	PUBLICATIONS 1,009	CITATIONS SEE	PROFILE David	Dillard-Wright University	of	South	Carolina	Aiken 7	PUBLICATIONS 10	CITATIONS SEE	PROFILE Available	from:	Vernon	A	Barnes Retrieved	on:	01	October	2015 HUMAN NEUROSCIENCE IntroductIon Recent findings illustrate how changes in consciousness accommodated by neural correlates and plasticity of the brain advance a model of perceptual change as a function of meditative practice. During the mindbody response neural correlates of changing awareness illustrate how the autonomic nervous system shifts from a sympathetic dominant to a parasympathetic dominant state. Expansion of awareness during the practice of meditation techniques can be linked to the Default Mode Network (DMN), a network of brain regions that is active when the one is not focused on the outside world and the brain is restful yet awake (Chen et al., 2008). A model is presented illustrating the dynamic mindbody response before and after mindfulness meditation, and connections are made with prefrontal cortex activity, the cardiac and respiratory center, the thalamus and amygdala, the DMN and cortical function connectivity. The default status of the DMN changes corresponding to autonomic modulation resulting from meditation practice. ModelIng spatIal awareness durIng the MInd-body response The dynamic mind-body response supports the interrelationship between one's physical health and the state of one's mind. The mind-body response may be illustrated by a hypothetical psychophysiological condition before meditation, with decreased prefrontal cortex activity, with increased mind wandering (Hasenkamp et al., 2012) leading to an unsynchronized cardiac and respiratory center (elevated sympathetic nervous system activity) and increased activity of the thalamus and amygdala (see Figure 1). Increased thalamo-cortical activity is associated with baseline or increased DMN activity and decreased cortical function connectivity. During and after meditation, DMN activity is decreased and there is increased prefrontal cortex activity, leading to a more synchronized cardiac and respiratory center (elevated parasympathetic nervous system activity) and decreased activity of the thalamus and amygdala. This decreased thalamo-cortical activity is associated with decreased DMN activity and increased cortical function connectivity. This model is supported by a number of recent fMRI and other imaging studies. fMrI and other IMagIng fIndIngs In MInd-body practIces Studies using fMRI suggest that, due to the plasticity of brain, there are dynamic changes in activation of the bilateral temporoparietal junction and the temporal gyri frontal eye field when an individual closes and opens his eyes (Mayer et al., 2004). Endogenous (internal) vs. exogenous (external) facilitation (referring to speed of orienting response) results in widespread cortical activation including the bilateral temporoparietal junction, bilateral superior temporal gyrus, right middle temporal gyrus, right frontal eye field, and left intraparietal sulcus (Mayer et al., 2004). Conversely, exogenous visual space orientation compared to endogenous facilitation results in only a single focus of activation in the left superior temporal gyrus. In our model, the normal activation resulting from endogenous orientation at the start of meditation with eyes closed shifts from the temporal (somatosensory) gyri to the parietal and visual cortex. fMRI evidence suggests increased blood flow in frontal and parietal lobes after focused meditation (Newberg et al., 2010). A study conducted with mindfulness-based stress reduction on patients with social anxiety disorder reported that during a breath-focused attention task, subjects showed (a) decreased negative emotional experiences, (b) reduced amygdala activity, and (c) increased activity in brain regions implicated in attentional deployment (Goldin and Gross, 2010). Mindfulness meditation has been shown to: (1) decrease pain-related activity of the primary somatosensory cortex, (2) increase activity of the anterior cingulate cortex and anterior insula, and (3) reduce activity of the limbic gating mechanism with the thalamus (amygdala). The findings suggest that mindfulness meditation improves visuospatial processing, working memory, and executive functioning (Zeidan et al., 2010). Mindfulness practitioners exhibit lower trait frontal gamma activity, as well as state and trait increases in posterior gamma power, irrespective of practice proficiency suggesting that mindfulness induces neuroplasticity in self-referential and attentional networks (Berkovich-Ohana et al., 2012). In meditation, cardio-respiratory synchronization leads to a long-lasting neural response as indicated by EEG, fMRI, and other imaging techniques. In an fMRI study where the effects of respiration variations on independent component analysis of DMN were analyzed, it was shown that functional connectivity can be greatly Dynamic change of awareness during meditation techniques: neural and physiological correlates Ravinder Jerath1,2*, Vernon A. Barnes2, David Dillard-Wright 3, Shivani Jerath4 and Brittany Hamilton1 1 Department of Obstetrics and Gynecology, Augusta Women's Center, Augusta, GA, USA 2 Georgia Prevention Center, Institute of Public and Preventive Health, Georgia Health Sciences University, Augusta, GA, USA 3 University of South Carolina, Aiken, SC, USA 4 College of Medicine, American University of Antigua, New York, NY, USA *Correspondence: firstname.lastname@example.com Edited by: Hauke R. Heekeren, Freie Universität Berlin, Germany Reviewed by: Bruce Friedman, Virginia Tech, USA Frontiers in Human Neuroscience www.frontiersin.org September 2012 | Volume 6 | Article 131 | 1 OpiniOn Article published: 17 September 2012 doi: 10.3389/fnhum.2012.00131 affected by cardiac and respiratory activity (Birn et al., 2008). Regarding coupling between the hemodynamic response and neuronal activity (neurovascular coupling), findings suggest that the hemodynamic response is significantly correlated with neuronal activity. This concept is further illustrated by recent findings of effects of meditation on the DMN. the default Mode network In MedItatIon practIce The DMN is a specific, anatomically defined network of brain regions preferentially active when one is wakeful but resting and not focused on the external environment (Buckner et al., 2008). The DMN is characterized by low frequency 0.1 Hz bloodoxygen-level dependent (BOLD) fMRI signal fluctuations within brain regions (Chen et al., 2008). These fluctuations are hypothesized to result from neuronal activity synchronized within and across brain regions (Birn et al., 2006). Independent component analysis has distinguished waveform activity within the DMN and respiratory induced changes (Birn et al., 2008). It is our hypothesis that respiratory impulses synchronize with the DMN via activity of slowly adapting stretch receptors (SARs) in the lungs. These receptors are activated during inspiration and expiration (Schelegle, 2003). Animal-based studies have shown the origin of rhythmically generated inhibitory impulses by inflation of respiratory alveoli in the lungs, that are detected in the brainstem and other areas of the brain. These neuronal impulses inhibit over-inflation and are involved with the Hering–Breuer reflex (Hering and Breuer, 1868). The DMN average frequency of 0.1 Hz synchronizes activity in widespread regions of the brain and is highly correlated with respiration. Our model suggests that decreased DMN activity during and after mindfulness meditation may lead to increased cortical function connectivity (Figure 1). After meditation, there is a decreased rate of breathing, and decreased activity of the DMN leads to selective inhibition of thalamus and amygdala (sensory relay center and emotional centers respectively) and activation of cortical function connectivity. Different mind-body techniques may be expected to produce differences in physiological changes as well as different experiences and brain states (OrmeJohnson and Walton, 1998) and these may also be attributed to variations in methodology (Travis et al., 2009). One factor that seems to be common among different types of meditation is respiratory and cardiac synchronization, a feature that underlies increased heart rate variability that is indicative of autonomic modulation. Cardio-respiratory phase synchronization has been shown to be enhanced during meditation, compared with normal relaxation (Wu and Lo, 2010). In Zen and Kinhin meditation, the breathing frequency decreases spontaneously even in novices leading to the cardio-respiratory synchronization (Cysarz and Büssing, 2005). The activity of pulmonary SARs is also known to be transmitted to the heart where respiratory sinus arrhythmia is observed during lung inflation. Central and autonomic nervous system interaction has been shown to be impacted by only 5 days of meditation, including lower heart rate and increased heart rate variability (Tang et al., 2009). Cardiorespiratory modulation synchronizes with the DMN and causes increased cortical function connectivity. The physiological response from the Yogic breathing technique of pranayama leads to an autonomic shift from sympathetic to parasympathetic dominance (Jerath et al., 2006), e.g., slower breathing rate (<10 breaths per min) reduces sympathetic and increases parasympathetic activity (Pramanik et al., 2009). The change to a calmer state of mind can be induced by synchronization of hemodynamic changes to slower heart and breathing rates – a higher degree of cardiorespiratory synchronization during meditation (Cysarz and Büssing, 2005). Awareness of the mental transformation leads to a state of increasing calm Figure 1 | The dynamic mind-body response is illustrated by a hypothetical psychophysiological condition before mindfulness meditation, with mind wandering and decreased prefrontal cortex activity, leading to unsynchronized cardiac and respiratory centers (elevated sympathetic nervous system activity) and increased activity of the thalamus and amygdala associated with baseline or increased activity of the Default Mode Network (DMN) and decreased cortical function connectivity. In the final stage and after meditation, there is decreased mind wandering and increased prefrontal cortex activity, leading to synchronized cardiac and respiratory centers (elevated parasympathetic nervous system activity) and decreased activity of the thalamus and amygdala associated with decreased DMN activity and increased cortical function connectivity. Jerath et al. Psychophysiological changes during meditation Frontiers in Human Neuroscience www.frontiersin.org September 2012 | Volume 6 | Article 131 | 2 Baron Short, E., Kose, S., Mu, Q., Borckardt, J., Newberg, A., George, M. S., and Kozel, F. A. (2010). Regional brain activation during meditation shows time and practice effects: an exploratory FMRI study. Evid. Based Complement. Alternat. Med. 7, 121–127. Berkovich-Ohana, A., Glicksohn, J., and Goldstein, A. (2012). Mindfulness-induced changes in gamma band activity – implications for the default mode network, self-reference and attention. Clin. Neurophysiol. 123, 700–710. Birn, R. M., Diamond, J. B., Smith, M. A., and Bandettini, P. A. (2006). Separating respiratory-variation-related fluctuations from neuronal-activity-related fluctuations in fMRI. Neuroimage 31, 1536–1548. Birn, R. M., Murphy, K., and Bandettini, P. A. (2008). The effect of respiration variations on independent component analysis results of resting state functional connectivity. Hum. Brain Mapp. 29, 740–750. Brown, R. P., and Gerbarg, P. L. (2005). Sudarshan Kriya Yogic breathing in the treatment of stress, anxiety, and depression. Part II – clinical applications and guidelines. J. Altern. Complement. Med. 11, 711–717. Buckner, R. L., Andrews-Hanna, J. R., and Schacter, D. L. (2008). The brain's default network: anatomy, function, and relevance to disease. Ann. N. Y. Acad. Sci. 1124, 1–38. Chen, A. C., Feng, W., Zhao, H., Yin, Y., and Wang, P. (2008). EEG default mode network in the human brain: spectral regional field powers. Neuroimage 41, 561–574. Cysarz, D., and Büssing, A. (2005). Cardiorespiratory synchronization during Zen meditation. Eur. J. Appl. Physiol. 95, 88–95. Goldin, P. R., and Gross, J. J. (2010). Effects of mindfulness-based stress reduction (MBSR) on emotion regulation in social anxiety disorder. Emotion 10, 83–91. Hasenkamp, W., Wilson-Mendenhall, C. D., Duncan, E., and Barsalou, L. W. (2012). Mind wandering and attention during focused meditation: a fine-grained temporal analysis of fluctuating cognitive states. Neuroimage 59, 750–760. Hering, E., and Breuer, J. (1868). Die selbststeuerung der atmung durch den nervus vagus. Sitzung Akad Wiss Wien 57, 672–677. Jerath, R., Edry, J. W., Barnes, V. A., and Jerath, V. (2006). Physiology of long pranayamic breathing: neural respiratory elements may provide a mechanism that explains how slow deep breathing shifts the autonomic nervous system. Med. Hypotheses 67, 566–571. Mayer, A. R., Dorflinger, J. M., Rao, S. M., and Seidenberg, M. (2004). Neural networks underlying endogenous and exogenous visual-spatial orienting. Neuroimage 23, 534–541. Newberg, A. B., Wintering, N., Waldman, M. R., Amen, D., Khalsa, D. S., and Alavi, A. (2010). Cerebral blood flow differences between long-term meditators and non-meditators. Conscious. Cogn. 19, 899–905. Newberg, A., Travis, F., Wintering, N., Nidich, S., Alavi, A., and Schneider, R. (2006). "Cerebral 416 glucose metabolic changes associated with Transcendental Meditation practice," Paper Presented at Neural Imaging, Miami, FL. Orme-Johnson, D. W., and Walton, K. G. (1998). All approaches of preventing or reversing effects of stress are not the same. Am. J. Health Promot. 12, 297–299. Pramanik, T., Sharma, H. O., Mishra, S., Mishra, A., Prajapati, R., and Singh, S. (2009). Immediate effect of slow pace bhastrika pranayama on blood pressure and heart rate. J. Altern. Complement. Med. 15, 293–295. of DMN and to activate DMN compared to simple eyes closed rest (Travis et al., 2010). A positron emission tomography study reported that TM practice increases blood flow in the prefrontal cortex, reduces activity in the thalamus and the medial occipital lobe, and reduces hippocampal activity (Newberg et al., 2006). Increased brain wave coherence, commonly seen during TM (Travis et al., 2002), has been reported to "stabilize" in activity outside of meditation. Regular practice engaging DMN over time may induce neuroplastic changes that improve health for the mind and body. conclusIon Recent research illustrates how the neural correlates and plasticity of the brain accommodate changes in consciousness. Neural correlates of expanding awareness during the mind-body response illustrate how the autonomic nervous system shifts from a sympathetic dominant to a parasympathetic dominant state. We have attempted to synthesize the literature in order to advance a model illustrating meditation's dynamic mind-body response, and associations are made with the cardiac and respiratory center, the thalamus and amygdala, the DMN and cortical function connectivity. Synchronization of the hemodynamic response during meditation was shown to lead to inhibition of the limbic system, and deactivation of DMN leads to an increase in cortical functional connectivity. This article provides evidence to support the mechanism of neurophysiological changes during meditation at the cellular level based on neurovascular coupling, and at the global brain activity level from the autonomic response generated by cardiorespiratory synchronization. Future research will benefit from use of a standardized set of psychophysiological variables and imaging protocols, for comparison of studies different kinds of meditation, that would foster clearer understanding of the relationship between the DMN and experiences during meditation (Travis et al., 2009). references Alexander, C. N., Cranson, R. W., Boyer, R. W., and OrmeJohnson, D. (1987). "Transcendental consciousness: a fourth state of consciousness beyond sleep, dreaming, and waking," in Sleep and Dreams: A Sourcebook, ed. J. Gackenbach (New York: Garland Publishing), 282–315. and outer focus via increased self-awareness through pranayama practice (Brown and Gerbarg, 2005). Variations in brain wave patterns have been observed in different meditation techniques, for example, increased alpha coherence in Transcendental Meditation®, higher theta wave activity in Zen meditation and increased gamma activity in mindfulness meditation (Travis and Shear, 2010). Alpha and theta power increase with eyes closed compared to eyes open in normal subjects tested via fMRI scans to monitor the DMN, suggesting a network of spectral EEG activities simultaneously operative at well defined regional fields in the eyes closed state, varying specifically between eyes closed and eyes open states (Chen et al., 2008). The amount of deactivation within the DMN is modulated by the effort required to perform the task. This feature may help explain why effort in meditation (e.g., concentration) has been shown to decrease activation of the DMN as compared to DMN activation in techniques requiring no effort. The TM technique utilizes automatic self-transcending to allow the mind to settle to a state of quiescence (Alexander et al., 1987). This experience is associated with significantly increased EEG coherence and physiological rest (Travis et al., 2001). Alpha EEG coherence and synchrony, as seen during the TM technique, is associated with neural communication and integration which may be the neurophysiological basis of beneficial physiological and clinical effects of TM (Travis and Shear, 2010). TM produces higher alpha power in the frontal cortex and lower beta and gamma waves in the same frontal areas during practice, and creates greater alpha coherence between the left and right hemispheres of the brain. Activation of the DMN has been found to be increased during periods of low cognitive load and decreased under greater executive control. Findings reflect differences in specific meditation practices employed, which may also be attributed to methodological differences in measurement of fluctuating cognitive states (Hasenkamp et al., 2012), and meditation studies including TM have shown increased DMN activity during meditation practice (Baron Short et al., 2010; Travis et al., 2010). The practice of TM has been shown to increase functional connectivity Jerath et al. Psychophysiological changes during meditation Frontiers in Human Neuroscience www.frontiersin.org September 2012 | Volume 6 | Article 131 | 3 Schelegle, E. S. (2003). Functional morphology and physiology of slowly adapting pulmonary stretch receptors. Anat. Rec. A Discov. Mol. Cell. Evol. Biol. 270, 11–16. Tang, Y. Y., Ma, Y., Fan, Y., Feng, H., Wang, J., Feng, S., Lu, Q., Hu, B., Lin, Y., Li, J., Zhang, Y., Wang, Y., Zhou, L., and Fan, M. (2009). Central and autonomic nervous system interaction is altered by short-term meditation. Proc. Natl. Acad. Sci. U.S.A. 106, 8865–8870. Travis, F., Haaga, D. A., Hagelin, J., Tanner, M., Arenander, A., Nidich, S., Gaylord-King, C., Grosswald, S., Rainforth, M., and Schneider, R. H. (2009). A selfreferential default brain state: patterns of coherence, power, and eLORETA sources during eyes-closed rest and Transcendental Meditation practice. Cogn. Process. 11, 21–30. Travis, F., Haaga, D. A., Hagelin, J., Tanner, M., Arenander, A., Nidich, S., Gaylord-King, C., Grosswald, S., Rainforth, M., and Schneider, R. H. (2010). A selfreferential default brain state: patterns of coherence, power, and eLORETA sources during eyes-closed rest and transcendental meditation practice. Cogn. Process. 11, 21–30. Travis, F., Olson, T., Egenes, T., and Gupta, H. K. (2001). Physiological patterns during practice of the transcendental meditation technique compared with patterns while reading Sanskrit and a modern language. Int. J. Neurosci. 109, 71–80. Travis, F., and Shear, J. (2010). Focused attention, open monitoring and automatic self-transcending: categories to organize meditations from Vedic, Buddhist, and Chinese traditions. Conscious. Cogn. 19, 1110–1118. Travis, F., Tecce, J., Arenander, A., and Wallace, R. K. (2002). Patterns of EEG coherence, power, and contingent negative variation characterize the integration of transcendental and waking states. Biol. Psychol. 61, 293–319. Wu, S. D., and Lo, P. C. (2010). Cardiorespiratory phase synchronization during normal rest and inwardattention meditation. Int. J. Cardiol. 141, 325–328. Zeidan, F., Johnson, S. K., Diamond, B. J., David, Z., and Goolkasian, P. (2010). Mindfulness meditation improves cognition: evidence of brief mental training. Conscious. Cogn. 19, 597–605. Received: 15 September 2011; accepted: 22 August 2012; published online: 17 September 2012. Citation: Jerath R, Barnes VA, Dillard-Wright D, Jerath S and Hamilton B (2012) Dynamic change of awareness during meditation techniques: neural and physiological correlates. Front. Hum. Neurosci. 6:131. doi: 10.3389/ fnhum.2012.00131 Copyright © 2012 Jerath, Barnes, Dillard-Wright, Jerath and Hamilton. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc. Jerath et al. Psychophysiological changes during meditation Frontiers in Human Neuroscience www.frontiersin.org September 2012 | Volume 6 | Article 131 |