Stress Rx: Chant two Ommsss, with food, twice daily

How can and should meditation be used to restore physical and mental health in a clinical setting?  That is the question that Emory University neuroscience graduate student Jordan Kohn posed to begin the latest Neuroethics Journal Club.  The discussion thereafter centered on Black et al.’s 2013 Psychoneuroendocrinology paper entitled “Yogic meditation reverses NF-κB and IRF-related transcriptome dynamics in leukocytes of family dementia caregivers in a randomized controlled trial.”¹ This paper laudably attempts to bridge the mind-body gap and suggests a biological, and perhaps more importantly, a genetic mechanism to explain how yoga can apparently help relieve stress, protect against depression, and restore immune function in caregivers.  The implications of this line of investigation could be widespread as the scientific and medical communities grapple with our fundamental understanding of the mind and body and how to integrate what used to be considered fringe or alternative approaches into the mainstream.



Caregivers for dementia patients have been widely studied because they experience high levels of chronic stress and in turn suffer high rates of depression and other mental and physical health problems.² Both acute and chronic stress can drastically alter immune system function³ and, not surprisingly, dementia patient caregivers show marked impairments in immunological measures.⁴ The connection between the immune system and mental health is increasingly studied for its apparent bi-directionality.  Sickness behavior – characterized by fatigue, poor sleep, irritability, and lack of appetite – closely resembles major depression.  In fact, pro-inflammatory cytokines, which are up-regulated during an infection, can induce depression.⁴





In this study, participants were randomly assigned to practice the Kirtan Kriya Meditation, guided by an audio CD, for only 12 minutes per day, or to listen to a CD of relaxing music for the same amount of time each day.  After 8 weeks, nearly two thirds of the meditators had improved depression scale scores of at least 50% and most of them also scored 50% better than they had at baseline on a cognitive test.  Significantly fewer music listeners improved by 50% in either of these measures. These data had actually been, in part, reported previously⁶ but in this study the authors sought to determine whether meditation modulated gene expression in an attempt to understand how yogic meditation mechanistically elicits these beneficial effects.  Black and colleagues assessed genome-wide expression levels at baseline and post-treatment for both groups and also performed more focused analyses on genes related to immune system function or under the control of the well-known transcription factors NF-κB and IRF-1.⁹  They found that there was a significant reduction in the expression of genes that respond to NF- κB and an increase in those that can be activated by IRF-1 which, together would suggest a decrease in pro-inflammatory cytokines and a better functioning immune system.



This paper, along with a growing literature on the clinical benefits of meditation, raises the question of how ecologically valid such studies are and how one would, on a practical level, implement such interventions.  For one thing there is the issue of standardization.  Several high-profile meta-analyses have been performed to try to answer the question of whether meditative interventions actually improve clinical measures but only a fraction of relevant studies can be included in any one analysis due, at least in part, to the heterogeneity of interventions and study designs.^7,8 This has led to poor power which has made it difficult to determine what effect these interventions actually have.⁹ A second question is in what contexts should meditation be most appropriately prescribed? Our journal club facilitator, Jordan Kohn, noted that meditation has been shown to be useful for people incarcerated in prison and perhaps uniquely beneficial for training the military to cultivate their ‘Warrior Minds’ (though there may be additional ethical concerns for some). However, there may not be a one-size-fits all approach to meditation. While there might be benefit for stress reduction in Alzheimer’s caregivers, or cultivating compassion in those who are incarcerated, or creating sharper minds for our military personnel, Jordan mentioned that there may be some individuals who would not find benefit and might actually be harmed, by certain kinds of meditation. For example, individuals who suffered PTSD might only relive their trauma more vividly during their meditation sessions.



An important issue that this paper speaks to indirectly is the apparent necessity to have biological data to support psychological findings.  This is undoubtedly an important pursuit as it may lead to new therapeutic targets, but it also seems to be missing the point.  Does a psychological or mind-based intervention absolutely need to affect biological measures (in the body) in order to be valid?  In this case, the reported effect is most likely indirect where meditation helps to relieve perceptions of stress which may allow hormone levels to normalize and the immune system to get back to business as usual.  Since the authors do not report effects on any of the biological “levels” between the mind and gene transcripts in immune tissue, their genetics results serve mainly to support the aforementioned psychological data but do not really extend the findings.  However, in the public one can easily find alternative medicine skeptics as well as enthusiasts who are already mesmerized by the exoticism of meditative traditions and alternative medicine. Having a biological marker as compelling as genetic data might convince skeptics that meditation has true validity and is worthy of future funding and integration into clinical care.



Another question along these lines is whether biological measures – which can be altered by meditation – can shift a sense of disease responsibility?  It is well known that not every individual who is exposed to trauma or put under stress will develop a stress-related pathology.  Some people seem to be resilient.  If the remedy for those who are not resilient is a drug that alters neurochemistry, then one would think that the susceptibility must have been due to a pre-existing chemical imbalance – a biological deficit so to speak.  But if the prescribed therapy is to train yourself in mindfulness, then does that mean the disease is the result of a character or personality flaw?  That is, if a patient can just use his/her mind to reduce stress through meditation should the patient just summon the moral fortitude to not be so affected by stress to begin with?  One wonders if prescribing something like a pill versus meditation, indicates that the patient needs “real” medicine for their illness because it is something out of the patient’s control.  These and other issues are likely to be continually discussed as alternative approaches including meditation are increasingly studied and expanded into clinical settings.





References



1.  Black, D. S. et al. Yogic meditation reverses NF-kappa B and IRF-related transcriptome dynamics in leukocytes of family dementia caregivers in a randomized controlled trial. Psychoneuroendocrinology 38, 348-355, doi:DOI 10.1016/j.psyneuen.2012.06.011 (2013).

2.  Pinquart, M. & Sorensen, S. Differences between caregivers and noncaregivers in psychological health and physical health: A meta-analysis. Psychol Aging 18, 250-267, doi:Doi 10.1037/0882-7974.18.2.250 (2003).

3.  Dhabhar, F. S. & McEwen, B. S. Acute stress enhances while chronic stress suppresses cell-mediated immunity in vivo: A potential role for leukocyte trafficking. Brain Behav Immun 11, 286-306, doi:DOI 10.1006/brbi.1997.0508 (1997).

4.  Lovell, B. & Wetherell, M. A. The cost of caregiving: Endocrine and immune implications in elderly and non elderly caregivers. Neurosci Biobehav Rev 35, 1342-1352, doi:DOI 10.1016/j.neubiorev.2011.02.007 (2011).

5.  Dantzer, R., O'Connor, J. C., Freund, G. G., Johnson, R. W. & Kelley, K. W. From inflammation to sickness and depression: when the immune system subjugates the brain. Nature reviews. Neuroscience 9, 46-56, doi:10.1038/nrn2297 (2008).

6.  Lavretsky, H. et al. A pilot study of yogic meditation for family dementia caregivers with depressive symptoms: effects on mental health, cognition, and telomerase activity. International journal of geriatric psychiatry 28, 57-65, doi:10.1002/gps.3790 (2013).

7.  Goyal, M. et al. Meditation programs for psychological stress and well-being: a systematic review and meta-analysis. JAMA internal medicine 174, 357-368, doi:10.1001/jamainternmed.2013.13018 (2014).

8.  Grossman, P., Niemann, L., Schmidt, S. & Walach, H. Mindfulness-based stress reduction and health benefits. A meta-analysis. Journal of psychosomatic research 57, 35-43, doi:10.1016/S0022-3999(03)00573-7 (2004).

9.  Bartlett, T. "Wait, So Does Meditation Actually Work or Not?" in Percolator  (Chronicle.com, 2014).

10.  NF-κB and IRF-1 are transcription factors which, when activated by an extracellular signal, can induce the expression of a variety proteins in order to mount a cellular response. NF-κB is typically associated with an increase in pro-inflammatory cytokines whereas IRF-1 induces interferon beta, an antiviral cytokine.







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Purcell, R. (2014). Stress Rx: Chant two Ommsss, with food, twice daily. The Neuroethics Blog. Retrieved on , from http://www.theneuroethicsblog.com/2014/04/stress-rx-chant-two-ommsss-with-food.html

Why People's Beliefs about Free Will Matter: Introducing the Free Will Inventory

*Editor's note: Jason Shepard was one of Emory Neuroethics Program's inaugural graduate Neuroethics Scholars. His co-authored manuscript mentioned below is related to his Scholar's project.



Recently, the question of whether our notions of free will, along with whether our responsibility-holding practices that appear to be based on free will, can survive in light of discoveries from the behavioral and brain sciences was named as one of the Top Ten Philosophical Issues of the 21st Century. The interest in free will and how discoveries in neuroscience and psychology affect our beliefs and attitudes about free will extends well beyond the halls of philosophy departments. The topic has also attracted a lot of interest from neuroscientists, biologists, and psychologists [1]. And, of course, these very debates are of central interest to neuroethicists. The wide range of interests in these debates is a symptom of the fact that these debates matter: The debate over what people believe about free will and how discoveries in the behavioral and brain sciences might impact these beliefs matter for a wide range of theoretical, and perhaps more importantly, practical reasons. Much of the empirical research in this area also points to the need for a valid and reliable tool for measuring people’s beliefs about free will. Below, I touch on some of the reasons why people’s belief in free will matters, and I introduce a new tool for measuring beliefs about free will, the Free Will Inventory, which was published in this month’s issue of Consciousness and Cognition [2].

The free will inventory is available in this month's issue of Consciousness and Cognition.

Whether people believe in free will matters. People’s beliefs in free will impact their behaviors. For example, experimental studies have shown that telling people they don’t have free will increases cheating and stealing, decreases prosocial behaviors and increases aggression, increases conformity, reduces self-control, and impairs the detection of errors. Other studies have shown that belief in free will is positively correlated with job performance of day laborers, and belief in free will is positively related to expectations of future occupational success in college students. These findings suggest that believing in free will may be instrumentally valuable from the standpoints of positive psychology and public morality[3].



These recent findings also highlight the importance of having valid and reliable tools for measuring beliefs in free will and related constructs. While the gathering data suggests that diminishing people’s belief in free will leads to all kinds of changes in behavior, the validity of these findings depends in part on the validity and reliability of the scales used to measure people’s beliefs about free will and related constructs. For example, the paradigms used in most of the above-mentioned experimental research involve one group of participants reading an anti-free will passage or reading a series of anti-free will statements. However, the anti-free will primes used in these experiments make claims that go beyond simple claims regarding the existence of free will. For example, some of the anti-free will statements also make claims that support belief in determinism (the view that the state of a system, plus the laws that govern that system, specify all subsequent states of the system) and challenge beliefs in dualism (the view that the mind and body are separate entities). It remains an open question whether these changes in behavior are best explained by changes in beliefs in free will, by changes in beliefs in determinism, by changes in believes in dualism, or some combination of changes in beliefs.



The ability to tease apart these explanations depends, in large part, on having psychometric tools that have the precision and specificity necessary to accurately measure beliefs in free will and related constructs such as determinism and dualism. While psychometric tools for measuring beliefs in free will and determinism exist, these tools are not without their problems. For example, many of the existing tools simply assume that free will and determinism are incompatible with each other, and, worse yet, often define free will and determinism as polar opposites of each other. Such an assumption rules out by fiat the ability of people to express a pattern of beliefs that is compatible with the philosophically rich tradition known as compatibilism, or the view that free will and determinism are compatible. As it turns out, this is an important mistake. There is accumulating evidence that compatibilist intuitions are more widespread than philosophers and psychologists have traditionally assumed [4]. In other words, many of the previous psychometric tools for measuring beliefs about free will not only rule out the ability for people to express agreement with a theoretically rich philosophical position but also rule out the ability to express patterns of beliefs that may actually be common among non-philosophers (i.e. most of society)! Though some more recent psychometric tools for measuring beliefs in free will avoid this mistake, these more recent tools still fail to measure these constructs in a way that is useful for all stakeholders in these debates. For example, the ways these constructs are defined and measured often appear theoretically uninteresting (if not theoretically confused) from the philosopher’s point of view. Furthermore, these tools often have just-barely acceptable psychometric properties from the psychologist’s point of view, which again points to the possibility of problems of definition and measurement. Furthermore, none of the existing measures measure people’s beliefs in dualism, which is itself an important construct that is often claimed to be relevant for how people think about free will [e.g., 5].

The Chronicle of Higher Education (top) recently featured a multi-disciplinary discussion on how the brain and behavioral sciences might inform the free will debate. Walter Sinnott-Armstrong's recently released Moral Psychology, Vol. 4 provides a thorough sampling of some of the best thinking on the topic of how the brain and behavioral science might inform the free will debate.

What people believe about free will matters. Whether discoveries in science challenge the existence of free will depends a great deal on what we believe about free will. For example, if we believe that free will requires human behavior to be unpredictable in principle, and if discoveries in science provide evidence that all behavior is in principle fully predictable, then these discoveries would challenge the existence of free will … or would at least challenge the existence of the sort of free will that we believe in. However, if we didn’t believe that free will requires unpredictability in principle, then these sorts of discoveries would be irrelevant to the free will debate … or would at least be irrelevant to our beliefs about free will. In other words, determining what sorts of discoveries are relevant to free will depends a lot on what people believe about free will.



Unfortunately, the existing psychometric tools for free will beliefs primarily measure the extent to which people believe in free will. These tools provide very little insight into what people believe about free will. In other words, these tools can tell you whether someone believes in free will a little, a lot, or not at all; but these tools cannot tell you whether free will requires unpredictability or dualism or the ability to act outside the laws of nature. And this is an important oversight. We need tools that not only measure how much people believe in free will, but we also need tools that measure what people believe about free will.



Given the importance of having a good measurement tool that is useful to a wide range of stakeholders in the debate, a diverse research team that was comprised of philosophers and psychologists, compatibilists and incompatibilists recently set out to develop a new psychometric tool for measuring beliefs in free will and related constructs. This team was led by the philosopher Thomas Nadelhoffer and included myself, Eddy Nahmias, Chandra Sripada, and Lisa Ross. The new tool, The Free Will Inventory (FWI), was published in this month’s issue of Consciousness and Cognition. The FWI consists of two parts. The first part consists of three subscales: one that measures belief in free will, one that measures belief in determinism, and one that measures beliefs in dualism. While part 1 of the FWI measures people’s beliefs in free will, determinism, and dualism, part 2 measures people’s beliefs about free will and these related concepts (e.g., does free will depend on being unpredictable, on having an immaterial soul, on being able to act at least partially independent of the laws of nature).



While no psychometric tool is perfect, we hope we have developed a tool that avoids some of the problems that plagued the earlier tools and that is of interest to a wider range of stakeholders in the debate, from the psychologist to the philosopher, from the neuroscientist to the neuroethicist, and to anyone else who is interested in rigorously exploring people’s beliefs in and about free will.





References:



[1] For recent, accessible multi-disciplinary discussion of how the brain and behavior sciences might inform the free will debate, see the Chronicle of Higher Education special series on "Is Free Will an illusion". For a thorough introduction to some of the best thinking on the topic, see: Sinnott-Armstrong, W. (2014). Moral Psychology, Vol. 4: Free Will and Moral Responsibility. Cambridge, MA: MIT Press.



[2] Nadelhoffer, T., Shepard, J., Nahmias, E., Sripada, C., & Ross, L.T. (2014). The free will inventory: Measuring beliefs about agency and responsibility. Consciousness and Cognition, 25, 27-41.



[3] For recent reviews, see: Baumeister, R.F., & Brewer, L.E. (2012). Believing versus disbelieving in free will: Correlated and consequences. Social and Personality Psychology Compass, 6, 736-745. and Rigoni, D. & Brass, M. (2014). From intentions to neurons: Social and neural consequences of disbelieving in free will. Topoi, 33, 5-12.



[4] A review of much of this research is discussed in the introduction of the paper on the FWI. See: Nadelhoffer, T., Shepard, J., Nahmias, E., Sripada, C., & Ross, L.T. (2014). The free will inventory: Measuring beliefs about agency and responsibility. Consciousness and Cognition, 25, 27-41.



[5] Montague, P.R. (2008). Free will. Current Biology, 18, 584-585.





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Shepard, J. (2014). Why people's beliefs in free will matter: Introducing the Free Will Inventory. The Neuroethics Blog. Retrieved on , from http://www.theneuroethicsblog.com/2014/04/why-peoples-beliefs-about-free-will.html

Ethics, Genetics, and Autism: A Conversation with Dr. Joseph Cubells

Dr. Joseph Cubells

Dr. Joseph Cubells is an Emory psychiatrist who focuses on working with adults with developmental and behavioral disorders, especially Autism Spectrum Disorders (ASD). He is on the cutting edge of using molecular genetics to identify genetic anomalies in his patients with the aim of improving and refining treatment packages. I spoke with Dr. Cubells about his work and the ethical implications of the use of genetic microarray tests with patients. After providing more details about how he uses molecular genetics in his practice, I will focus on our discussion of two primary issues related to his work: (1) the communication of genetic testing procedures and results to families and, (2) the role of health care systems in the widespread use of these tests. 

Dr. Cubells is primarily engaged in clinic work. He has over 200 cases and works exclusively with adults (he does not see patients under the age of 16). Molecular genetics is one technique used in his patient management strategies: “I am very interested in the role of molecular genetic testing in the care of people with neurodevelopmental disabilities. Not so much establishing a diagnosis of autism though because autism is a behavioral diagnosis.” In other words, because there is no genetic or otherwise biologically based test currently available for autism, Dr. Cubells and his team are interested in diagnosing other genetic differences, such as Phelan McDermid Syndrome which occurs when a chromosome is deleted after conception (de novo) and can lead to a variety of physical and developmental disabilities. This condition, and many other genetic anomalies, may contribute or directly lead to the development of autistic characteristics. Most professionals, including myself and Dr. Cubells, now agree that there is not a single ‘autism’ but, rather, many different ‘autisms’ with many different causal pathways, both genetic and environmental.

Last November, Dr. Cubells and his team presented a paper on their use of molecular genetics in direct patient care at the American Society for Human Genetics. They sent chromosomal microarray tests¹ to be analyzed for 44 of their patients. Seven of these tests “came back with definitely clinically relevant differences that had not been previously diagnosed.” This is a rate of 16%, which, for Dr. Cubells, is “a substantial and important rate.” This rate may seem small but the impact of these findings are critical. For example, among those seven, one adult male’s test showed a deletion of the monoamine oxidase (MAO) A and B gene. This effects of this deletion are similar to the effects of taking a MAO inhibitor (MAOI), a type of pharmacological treatment for depression. Both this medication and this genetic deletion can lead to a fatal hypertensive crises if a person consumes tyramine (found in many aged or fermented foods, foods high in protein, and some alcoholic beverages) or in the presence of sympathomimetic drugs, which mimic transmitters such as catecholamines (i.e., epinephrine, norepinephrine, and dopamine). Because this genetic deletion was identified, the patient now wears a medic alert bracelet stating that he must be treated as a patient on a MAOI to avoid unexpected drug reactions. This knowledge is potentially life-saving.

These microarray genetic analyses can help refine patient management; however, the actual purpose and results of tests are difficult to accurately communicate to families. Dr. Cubells related another story of an adult who has significant autistic characteristics for whom his team identified another type of anomaly: a 15q13.3 deletion for which a small part chromosome 15 is deleted in each cell. They discovered that this participant’s mother has the same deletion, however, unlike her son, does not show any of the developmental delays. The man’s grandmother, however, also has the deletion and exhibits some developmental delays. This patient’s cousin is recently married and is wondering if he should be tested for this deletion. I asked Dr. Cubells what, in cases like this, a genetic counselor or clinician is ethically responsible to communicate to families regarding the implications of obtaining the tests and the implications of the results. This issue is an important concern for eventual pre-natal diagnoses of autism as well as for the project I am working on as the current Neuroethics Program Scholar, which involves considering the implications of using eye-tracking technologies for early, presymptomatic screening of ASD.

The gene copy number (also "copy number variants" or CNVs) is the number of copies of a particular gene in the genotype of an individual.

Dr. Cubells responded that “the first thing you have to make clear is there is a lot of uncertainty.” For cases like the one described above, he would start by explaining that the test will only tell him whether he carries the deletion. If he does not, then there is an “infinitesimally small” likelihood that his future children would have that deletion. However, if he does carry the deletion, things are a much more complicated. There is a big chance that this gentleman’s children would have learning or developmental difficulties, however, as the patient’s mom exemplified, there could also be no discernible influence. “And so the range of possibilities ranges from very challenging to fine.” Regardless, at this stage, Dr. Cubells believe that with this particular chromosomal variation, or copy-number variant (CNV), there are “reasonable odds” that there will be challenges but the field is not ready to be quantitative about it. This is the kind of information, he says, of which genetic counselors must be aware.

There are significant differences in the understanding of risk between the lay public and professionals.² Explaining probabilities to patients or families is difficult, but Dr. Cubells urges that the physician’s role is “to be helpful when he can and to give them [the family and patient] as much information as he can to explain things.” This information should include an explanation of the meaning and difference of variable penetrance and variable expressivity. The former is the proportion of people who carry a particular gene that also expresses and particular trait, or phenotype. The latter describes the differences within this expression, or the ranges of phenotypes linked to a particular gene or genetic anomaly. This information is often confusing for patients and families to understand. It is critical that patients understand these terms in order to  consent to taking part in a microarray test and for comprehending the consequences of test results. Given that the responsibility of making decisions lies with the patient and family, this information needs to be communicated clearly and reliably.

We also discussed issues related to the cost of these genetic arrays and resource allocation. Dr. Cubells explained that genomic micro-arrays cost, at a minimum, around $800. If the company wants to stay in business and possibly make a profit, then they need to charge around $1400. He admits that this amount of money can be also used towards valuable and efficacious behavioral or psychological treatment. And so where should we put our resources? He admits that, despite the obvious benefits of the work he is doing, he is “ambivalent about pushing the importance of genetics in autism because [he] spends a lot of time explaining what ought to happen but the resources aren’t there.” This is a large debate in the field. Many self-advocates and family members struggle, knowing that there is a lack of funding for research on quality of life issues and services, especially for adults who lose a host of services, such as instruction on daily living skills as well as occupational and speech therapies, once they age out of the public school system at the age of 21.³

“But on the other hand,” Dr. Cubells explains, “we do need to understand things at the level of etiology. We need to know if a person has Phelan McDermott versus 15q versus 22q11⁴ because even now there are clinical implications for that.” Dr. Cubells sees a problem in the lack of reimbursement for genetic counselors who see patients with psychiatric problems; insurance companies do not have to pay for this kind of consultation. He says this situation needs to change, but the only way this change will happen is for politicians and professionals to work towards changing the minds of insurance and health care administrators. 

Cost is a real barrier to access to emerging medical technologies like this for many families. This means that critical information will potentially not be available to many patients unless these tests become a mandated part of health care coverage. It is also possible that tests like these will become part of standard pre-natal check-ups, in which case a host of other ethical concerns arise. Disability activists, especially those adherent to neurodiversity, see pre-natal diagnostics of disabilities as an attempt to eradicate disability and difference from the human population—a eugenic enterprise. Additionally, as was discussed in my last post, cultural and faith-based backgrounds of families may mean less acceptance of the use of these technologies. Families may rely on more spiritually-based explanations of disabilities and so may not be open to discussions of genetic causes, which can be seen as more chronic and stigmatizing. Finally, for many of the genetic anomalies identifiable by these tests, no reliable treatments are available. There are educational and behavioral therapies for autism and related disorders; however, there is no guarantee that any intervention will dramatically change behavior or if, given the variability of autistic manifestation, any intervention will even be necessary! These issues will be discussed more fully in my next blog post, where I describe the impact of the use of eye tracking technologies to identify autistic markers in infancy. 

This discussion reminded me of a recent op-ed in the New York Times in which the columnist, Nicholas Kristof, called for more attention in the media and government on mental health. We may be working in the right direction as the Affordable Care Act does include mental health care, but costs remain high and the consequences of these costs are having real effects on real lives. Bringing the impact of psychiatric, intellectual, and developmental disorders has on the quality of life of diagnosed individuals and their families into the public realm is imperative to obtaining more funding for services and more research on how to develop, implement, and distribute these services most effectively. As genetic testing and prescreening for psychiatric conditions continues to become more advanced, I agree with Mr. Kristof and Dr. Cubells. Improving coverage for psychiatric services should be a high priority issue for politicians, health care administrators, scientists, physicians, and, most importantly, families.

Dr. Joseph Cubells is a psychiatrist whose clinical and research interests lay in molecular genetic factors of developmental and behavior disorders, such as autism, schizophrenia, and major depression. He is the Medical Director and Attending Psychiatrist at the Emory Autism Center where he work with adults on the autism spectrum and with genetic and chromosomal disorders that lead to various psychiatric disorders.

References

1. A chromosomal microarray test is a new method of detecting alterations in a person’s DNA. Specifically, these tests look for areas on the DNA with too many or too few copies of genetic material. This method is more specific than earlier genetic tests, thereby allow for more exact maps of the DNA and, ostensibly, the ability to identify more anomalies. For more information, see The American College of Obstetricians and Gynecologists’ Committee Opinion on the use of this test in prenatal diagnosis here: http://www.acog.org/Resources_And_Publications/Committee_Opinions/Committee_on_Genetics/The_Use_of_Chromosomal_Microarray_Analysis_in_Prenatal_Diagnosis.


2. For example, see: Hamepl, J. (2006). Different concepts of risk - A challenge for risk communication. International Journal of Medical Microbiology, 296(S1): 5-10; Miller, A.M, Hayeems, R.Z, & Bytautas, J.P. (2010). What is a meaningful result? Disclosing the results of genomic research in autism to research participants. European Journal of Human Genetics, 18: 867-871; McMahon, W.M., Baty, B.J., & Botkin, J. (2006). Genetic counseling and ethical issues for autism.  American Journal of Medical Genetics Part C (Semin. Med. Genet.), 142C: 52-57; Slovic, R. (1987). Perception of Risk. Scienze, 236(4799): 280-285.


3. For more explanation of this perspective, see this report by the Autistic Self Advocacy Network (ASAN), “ASAN expresses concern regarding new HHS report on autism research” at http://autisticadvocacy.org/2012/07/asan-expresses-concern-regarding-new-hhs-report-on-autism-research/.


4. These are all genetic disorders associated with autistic phenotypes. Phelan-McDermid is “the result of a disruption of the SHANK3/ProSAP2 gene on the terminal end of chromosomee 22,” according to the website for the Phelan-McDermid Syndrome Foundation (www.22q13.org). 15q  and 22q11 refers to partial deletions of chromosomes 12 and 22 that leads to a variety of developmental disorders.

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Sarrett, J. (2014). Ethics, Genetics, and Autism: A Conversation with Dr. Joseph Cubells. The Neuroethics Blog. Retrieved on , from http://www.theneuroethicsblog.com/2014/04/ethics-genetics-and-autism-conversation.html

Can free will be modulated through electrical stimulation?

The will to persevere when many of life’s challenges are thrown at us is an ability that comes more naturally for some than for others. Additionally, even the most determined among us have days and times when moving forward through a challenging task just proves too difficult. The subjective nature of this experience can make it difficult to study, but recently researchers from Stanford University published a case study where electrical brain stimulation (EBS) to the anterior midcingulate cortex (aMCC) left two patients with the feeling that a challenge was approaching, but also that they could overcome it [1]. For the most recent journal club of the semester, Neuroscience graduate student and AJOB Neuroscience editorial intern Ryan Purcell led a discussion on the experimental procedure to stimulate what is referred to as the “the will to persevere” and the effect this technology may have if it were to become more mainstream in society.

"The location of the electrodes in P1 and P2 overlaid onto the standard emotional salience network derived from a group of normal human subjects." Parvizi et al.

It has long been known that the anterior cingulate cortex (ACC) and its midcingulate region (aMCC) are involved in emotions that rely on cognitive control, and recent research has shown that this brain network is possibly involved in complex emotions such as motivation and endurance [2,3]. In the case study discussed during journal club though, researchers went beyond an animal study and recorded a first-hand account of two patients becoming determined and motivated to overcome what they perceived as an oncoming challenge during EBS to the aMCC. The aMCC, located deep within the brain, is not typically implanted with electrodes for clinical reasons, but researchers were attempting to discover the origin of seizure activity in two patients with epilepsy by implanting intracranial electrodes in four different deep brain regions. Electrical currents at each of these regions were delivered and then based on patient feedback and physiological reports, researchers could localize the epileptic activity. It was determined that the patients were suffering from medial temporal epilepsy, but when electrical stimulation occurred at the aMCC, while no signs of seizures were observed, both patients did report similar and unique emotional states, along with specific physical symptoms. Patients physically experienced what was described as “shakiness,” hot flashes, and an increase in heart rate, but interestingly also psychologically felt a sense of foreboding regarding a challenge and the confidence that the challenge could be overcome. As seen in this supplemental video, patient 1 describes the experience as driving “towards a storm that’s on the other side, maybe a couple of miles away, and you've got to get across that hill.” Although this seems like a situation that would cause worry and anxiety, the same patient reported that the feeling was not really negative, but instead “it was more of a positive thing like…push harder, push harder, push harder to try and get through this.” These patient accounts suggest that researchers had tapped into the part of the brain responsible for motivation, endurance, and the will to persevere, and in doing so were able to elicit these feelings on command - far removed from any situation similar to stressful driving.



Researchers also realized that by stimulating the aMCC, the behavioral and emotional changes caused by EBS could potentially be due to functional changes that take place within a vast neuronal network connected to the aMCC. Using fMRI and functional connectivity analysis, researchers observed that EBS in the aMCC region of interest led to the activation of a network previously characterized as the emotional salience or cingulo-opercular network [4]. This suggests that the motivation, endurance, or the lack of these two emotions are most likely not alone regulated by a single brain region, the aMCC, but instead a complex, distributed network.



This paper presents the exciting and interesting idea that we could regulate motivation with stimulation to the brain, but really this is just a small case study with two patients. These findings may have been an unexpected result from trying to find the source of epilepsy, and may only occur in this experimental setting, perhaps even only in patients who have a history of epilepsy. The paper reads as if the researcher asking the questions of the patients was the same researcher conducting the stimulation trials, and as a result many of the questions are very biased and leading. After patient 1 has vividly compared his experience to driving in a storm, the researcher attempts to ask patient 2 about driving as well. To which patient 2 responds with laughter “I don’t get to drive.”



This is an interesting observation, but would need to be replicated on a larger scale with blind research practices put into place. However, since the aMCC is located deep within the brain and typically electrodes are not inserted for clinical reasons, it may prove difficult to conduct invasive procedures without a clinical agenda. In this case study, these patients were already unique in that they may have been very determined individuals even without external stimulation since they were undergoing invasive brain surgery for epilepsy most likely as a last resort. Having the power to increase motivation and/or determination could be used in a clinical setting for depression or chronic pain, and while it is only speculation regarding the personality traits of these two patients, a study that is open to participants without any diagnosed neurological disorders could provide more baseline activity for modulating the aMCC and its neuronal network. For this large study to take place though and to find interested participants, most likely the technology would need to advance with a noninvasive procedure.



While this type of technology would have obvious clinical benefits for treating depression and perhaps one day the ability to self-regulate our motivations at home, having the power to externally regulate free will begs certain questions. Should anyone be denied the chance to become a more productive, motivated version of themselves? Or, if this type of technology were considered acceptable, should anyone be forced to become a more determined, motivated citizen who does not experience weakness of will? If advances in neuroscience continue to address the questions of whether free will even exists at all, and then if we ever have the power to impose a standard of willpower that everyone should meet, this would have important implications for our legal and justice system. Two common theories for justifying punishment include the utilitarianism and the retributivism theory [5]. Simply put, utilitarianism is based on the idea that punishment is justified because it produces a situation in which the balance of good and evil (or happiness and unhappiness) is maximized [6]. Punishment helps to reduce crimes, which promotes a society where good prevails over evil. For example, punishment in the form of imprisonment can lead to the reduction of crime because the idea of prison can deter criminals and criminals are removed from society. The retributivism theory relies more on the idea of a social consensus on what is deemed a moral wrongdoing and criminals who commit crimes deserve to be punished [7]. If we had the power to control weakness of will and modulate willpower, this could be very powerful when applied to crimes that are associated with a weakness of will, perhaps those that involve illicit drugs, alcohol, or even the more heinous pedophilia, as specifically discussed in this previous blog post. However, then the justification of additional punishment according to the utilitarian viewpoint would be less valid, since the stimulation alone would potentially reduce crime. In this situation, a criminal would be giving up some level of free will in the name of societal benefits, so one could argue that electrical stimulation could be considered similar to jail time, a punishment that removes freedom and the ability to make many choices from perpetrators’ lifestyles. In this sense, additional punishment according to the retributivism theory would also be less valid since the electrical stimulation would be punishment enough. Finally, there is an additional possibility that is being explored by neuroscientists like David Eagleman who believe that our retributivist justice system (resulting in an overcrowded prison system) should be revised to one focused on rehabilitation, or rather neuro-rehabilitation [8, 9, 10]. Even in the name of rehabilitation though, does such a crime exist that justifies the punishment of nonconsensual direct manipulation of neuronal networks? Having the strength and the will to persevere is most likely a characteristic that we all want all the time, but is choosing not to persevere still a choice that we are always entitled to make, regardless of the context of the choice?





References:



1) Parvizi, J. et al. (2013). The Will to Persevere Induced by Electrical Stimulation of the Human Cingulate Gyrus. Neuron 80, 1359.

2) Rudebeck, P.E. et al. (2006). Separate neural pathways process different decision costs. Nat. Neurosci. 9, 1161.

3) Shackman, A.J. et al. (2011). The integration of negative affect, pain and cognitive control in the cingulate cortex. Nat. Rev. Neurosci. 12, 154.

4) Seeley, W.W. et al. (2007). Dissociable intrinsic connectivity networks for salience processing and executive control. J Neurosci. 27, 2349.

5) Greene, J.; Cohen, J. (2004). For the law, neuroscience changes nothing and everything. Phil. Trans. R. Soc. Lond. B 359, 1775.

6) Bernstein, R.F. (1979). Legal Utilitarianism. Ethics 89, 127.

7) Scheid, D.E. (1983). Kant's Retributivism. Ethics 93, 262.

8) Eagleman, D.The Brain on Trial. (2011). The Atlantic. Retrieved on April 7, 2014 from http://www.theatlantic.com/magazine/archive/2011/07/the-brain-on-trial/308520/.

9) A novel addiction therapy: The real-time fMRI. Initiative on Neuroscience and Law. Retrieved on April 7, 2014 from http://www.neulaw.org/research/real-time-fmri. 

10) Rommelfanger, K. (2011). Neuro-rehabilitation: A vision for a new justice system. The Neuroethics Blog. Retrieved on April 7, 2014, fromhttp://www.theneuroethicsblog.com/2011/10/neuro-rehabilitation-vision-for-new.html



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Strong, K. (2014). Can free will be modulated through electrical stimulation? The Neuroethics Blog. Retrieved on , from http://www.theneuroethicsblog.com/2014/04/can-free-will-be-modulated-through_8.html

Lamarckian sh*t? Why epigenetics is not eugenics

An argument could be made that communicating scientific advances to the public has never been more important. As the NIH budget stagnated, and then was cut by Sequestration, many of us have realized what a poor job we have been doing convincing the public of the importance of basic science research. Neuroscience itself has been under more scrutiny recently. As Adam Gopnik of The New Yorker wrote in a review of three new books bashing brain research, “Neuroscience can often answer the obvious questions but rarely the interesting ones.” If that is the way that the public sees it, then clearly we are losing something in translation. Recently there has been a push to reverse this trend and reaffirm biomedical research as a source of inspiration and hope for the public. The actor and author Alan Alda, who has long held a passion for science, has made it a personal mission to improve communication about science because “How are scientists going to get money from policy makers, if our leaders and legislators can’t understand what they do?”¹

Late last year, Brian Dias, a postdoctoral fellow in Kerry Ressler’s laboratory at Emory, found out just how difficult communicating his work to the public can be. Dias and Ressler had been working on testing whether olfactory fear conditioning would transmit a sensitivity to the conditioned odor across generations. That is, using a mouse model they were exploring whether an experience in your lifetime could affect your children or grandchildren’s response to their environment. They studied the olfactory system because it is extraordinarily well-mapped (thanks in large part to work that Dr. Ressler did in Nobel Laureate Linda Buck’s lab as a graduate student) and shows gross structural changes in mice when they learn to associate an odor with an unpleasant experience¹. Recently, there has been a great deal of interest in understanding how an organism’s environment can affect the way in which genes are expressed via a phenomenon call epigenetics.



Epigenetics refers to chemical modifications to the genome that do not affect the DNA sequence itself. Normally, the DNA molecule of each chromosome is tightly packed in a highly complex yet orderly fashion so that it can fit inside the nucleus of the cell. Several types of chemical modifications can be made to DNA that affect how tightly it packs and in turn, the ability of enzymes to transcribe the sequence and initiate the production of the proteins that it codes for. Epigenetic marks do not affect the letters in the code, just how often it is read. Genes can effectively be silenced or activated by these mechanisms, which are still not completely understood.



Researchers have found that the early life environment can have long term effects on individuals and even their offspring² – so called inter-generational epigenetics³. Lately, interest has even shifted to assessing trans-generational epigenetic effects. In 2010, an Australian group reported that in rodents, paternal high-fat diet can lead to dysfunction in pancreatic insulin-producing β-cells in female offspring⁴. More recently, a study of pre-diabetic mice found that epigenetic marks in the pancreas and, importantly, in sperm persisted for multiple generations as did a pre-disposition to impaired glucose metabolism⁵. Trans-generational epigenetic inheritance has been reported to affect lifespan in the nematode C. elegans⁶, and now some studies suggest that the effects of stress or abuse can be passed to the next generation in mice⁷ and humans⁸.



In this special Neuroethics Journal Club focused on “Neuroscience in the News”, the group was fortunate to get to hear the story of publishing this exciting paper⁹ first hand from Dr. Dias. One of the most interesting aspects of the discussion was the timing of the initial presentation of the results and publication of the paper. Dias gave a presentation at Neuroscience 2013 on November 12^th that created a great deal of buzz, so much so that Virginia Hughes of National Geographic’s “Only Human” blog reported on the presentation and also on the Twitter activity itself. Reponses ranged from “Astonishing if true” to “Crazy Lamarkian [sic] shit”.



The Nature Neuroscience editors themselves may have been thinking something along the same lines as the latter commenter as they made a portrait of Jean-Baptiste Lamarck – the champion of the contentious evolutionary theory that acquired adaptations during life shape subsequent generations – the cover image for the issue with Dias and Ressler’s article. The trouble with associating Lamarck and trans-generational epigenetics is that it could lead to the same type of reasoning that gave rise to eugenics in the early to mid-20^th century. Disadvantaged individuals who have lived with hunger and been exposed to violence or other trauma could be seen as permanently damaged and may be dissuaded from having children to avoid perpetuating some sort of “bad epigenetics”. The fact is, genes simply code for proteins and the jump from the molecular level to behavior is complex to say the least. Dias and Ressler were careful to describe the behavioral phenomenon in the offspring of the fear-conditioned mice as an increased sensitivity, not specifically a fear of the odor. At this point, they were not able to determine a molecular mechanism or specific cause of the behavioral change.



The paper appeared online December 1^st, almost three weeks after Dias’ SfN talk and the ensuing controversy and armchair critiquing. However, during most of that time the authors were essentially handcuffed by the journal’s press embargo policy until the paper was published online on December 1^st. Granted, it is rare that a presentation at a conference would generate this much excitement before the paper was published, but it seems that even with early online publication of articles, peer-reviewed journals have trouble keeping up with 21^st century, 140-character communication. The rapid, yet accurate dissemination of results will likely be an issue that journals continue to struggle with, while occasionally leaving authors in limbo.



In addition to the discussion surrounding publication of a controversial paper, the journal club also delved into some of the ethical issues that may arise from studies such as this one. For example, should the children of veterans who have suffered from PTSD be treated as an “at-risk” group, and what would that entail? Or, should members of the military be screened for a family history of trauma based on the idea that those individuals whose parents experienced traumatic events may be more vulnerable to adverse outcomes during or after their tour of duty? It seemed that there was agreement that when a plausible mechanism for how a fear memory – and particularly one associated with a certain smell – could impact the epigenetic marks in sperm cells in order to be passed on to subsequent generations, and then tested, the field would be better able to understand intervention opportunities. Trauma and stress are major public health issues just based on what we know about how they can shape an individual’s behavioral and physiological responses to later challenges in life^10,11. If in fact trauma and adversity can also shape our children’s sensory experience of the world through heritable, epigenetic changes, then it will be even more important to understand how the effects can be mitigated.



Additionally, accurate and clear communication of results to the public remains as important as ever. While the avenues for communication have changed drastically in recent years, and in many ways have made communicating easier, publishers and authors will likely continue to grapple with the new speed and power of social media. What role, if any, should these platforms play in the communication of science? If one of the goals is to engage the public’s interest then it seems that social media presents a great opportunity to do that but there are obvious concerns. While it may not be possible to fit detailed methods and results into 140 characters, new initiatives such as PubMed Commons may help reduce the formality and finality associated with published papers and increase discussion among scientists. Still, it will be interesting to see how social media is adopted by scientists and whether it helps at all in bridging our current communication gap with the public.





References



1. Jones, S. V., Choi, D. C., Davis, M. & Ressler, K. J. Learning-dependent structural plasticity in the adult olfactory pathway. The Journal of neuroscience : the official journal of the Society for Neuroscience 28, 13106-13111, doi:10.1523/JNEUROSCI.4465-08.2008 (2008).

2. Jirtle, R. L. & Skinner, M. K. Environmental epigenomics and disease susceptibility. Nature reviews. Genetics 8, 253-262, doi:10.1038/nrg2045 (2007).

3. Heard, E., Martienssen, R.A. Transgenerational Epigenetic Inheritance: Myths and Mechanisms. Cell 157, 95-109 (2014).

4. Ng, S. F. et al. Chronic high-fat diet in fathers programs beta-cell dysfunction in female rat offspring. Nature 467, 963-966, doi:10.1038/nature09491 (2010).

5. Wei, Y. et al. Paternally induced transgenerational inheritance of susceptibility to diabetes in mammals. Proceedings of the National Academy of Sciences of the United States of America 111, 1873-1878, doi:10.1073/pnas.1321195111 (2014).

6. Greer, E. L. et al. Transgenerational epigenetic inheritance of longevity in Caenorhabditis elegans. Nature 479, 365-371, doi:10.1038/nature10572 (2011).

7. Dietz, D. M. et al. Paternal transmission of stress-induced pathologies. Biological psychiatry 70, 408-414, doi:10.1016/j.biopsych.2011.05.005 (2011).

8. Jovanovic, T. et al. Physiological markers of anxiety are increased in children of abused mothers. Journal of child psychology and psychiatry, and allied disciplines 52, 844-852, doi:10.1111/j.1469-7610.2011.02410.x (2011).

9. Dias, B. G. & Ressler, K. J. Parental olfactory experience influences behavior and neural structure in subsequent generations. Nature neuroscience 17, 89-96, doi:10.1038/nn.3594 (2014).

10. Gluckman, P. D., Hanson, M. A., Cooper, C. & Thornburg, K. L. Effect of in utero and early-life conditions on adult health and disease. The New England journal of medicine 359, 61-73, doi:10.1056/NEJMra0708473 (2008).

11. Murgatroyd, C. et al. Dynamic DNA methylation programs persistent adverse effects of early-life stress. Nature neuroscience 12, 1559-1566, doi:10.1038/nn.2436 (2009).





Want to cite this post?



Purcell, R. (2014). Lamarckian sh*t? Why epigenetics is not eugenics. The Neuroethics Blog. Retrieved on , from http://www.theneuroethicsblog.com/2014/03/lamarckian-sht-why-epigenetics-is-not.html