New Fibromyalgia Treatment: Emotional Awareness and Expression Therapy

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Psychotherapy that encourages addressing emotional experiences related to trauma, conflict, and relationship problems has been found helpful for people with the chronic pain condition fibromyalgia.In the randomized clinical trial at Wayne State University in Detroit, 230 adults with fibromyalgia received one of three treatments. Each was presented for eight weekly sessions to small groups of patients.

The new therapy, called Emotional Awareness and Expression Therapy (EAET), helps patients view their pain and other symptoms as stemming from changeable neural pathways in the brain that are strongly influenced by emotions, the researchers explain.

EAET helps patients process emotional experiences, such as disclosing important struggles, learning how to adaptively express important feelings—especially anger and sadness, but also gratitude, compassion, and forgiveness—and empowering people to be more honest and direct in relationships that have been conflicted or problematic, according to the researchers.

The EAET intervention was compared to both an educational intervention, as well as the gold standard psychological approach in the field, cognitive behavioral therapy. Six months after treatments ended, patients were evaluated for the severity and extent of their pain and other problems that people with fibromyalgia often experience.

Patients who received EAET had better outcomes—reduced widespread pain, physical impairment, attention and concentration problems, anxiety, and depression, and more positive emotions and life satisfaction—than patients who received the education intervention, the researchers report.

More than twice as many people in EAET (34.8 percent) reported that they were “much better” or “very much better” than before treatment, compared to 15.4 percent of education patients.

An important additional finding was that the new emotion therapy also had greater benefits than cognitive behavior therapy in reducing widespread pain and in the number of patients who achieved at least 50 percent pain reduction, the researchers point out.

Mark A. Lumley, Ph.D., a professor of psychology said:

Many people with fibromyalgia have experienced adversity in their lives, including victimization, family problems, and internal conflicts, all of which create important emotions that are often suppressed or avoided. Emerging neuroscience research suggests that this can contribute strongly to pain and other physical symptoms.

We developed and tested an approach that tries to help people overcome these emotional and relationship problems and reduce their symptoms, rather than just help people manage or accept their fibromyalgia. Although this treatment does not help all people with fibromyalgia, many patients found it to be very helpful, and some had dramatic improvements in their lives and their health.

The Wayne State researchers collaborated with a team of researchers from the University of Michigan Medical Center led by David A. Williams, Ph.D., a professor of anesthesiology.

The study was published in the journal PAIN.

This guest article originally appeared on PsychCentral.com: New Therapy Technique Offers Hope to Those with Fibromyalgia by Janice Wood.

References

Lumley, M., Schubiner, H., Lockhart, N., Kidwell, K., Harte, S., Clauw, D., & Williams, D. (2017). Emotional awareness and expression therapy, cognitive behavioral therapy, and education for fibromyalgia. PAIN, 1. DOI: 10.1097/j.pain.0000000000001036.

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How Ketamine Acts on the Brain

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Ketamine is a medication mainly used for starting and maintaining anesthesia although it has also been used to provide rapid relief of treatment resistant depression.

The ability to rapidly stabilize severely depressed patients has been demonstrated in several studies and has led researchers to search for the exact mechanism by which ketamine works.

The effort is important as ketamine is sometimes illicitly used for its psychedelic properties and could also impede memory and other brain functions.

The multiple actions of ketamine has spurred scientists to identify new drugs that would safely replicate its antidepressant response without the unwanted side effects.

Now, emerging research from University of Texas (UT) Southwestern Medical Center scientists has identified a key protein that helps trigger ketamine’s rapid antidepressant effects in the brain. This is a crucial step to developing alternative treatments to the controversial drug being dispensed in a growing number of clinics across the country.

Researchers from the Peter O’Donnell Jr. Brain Institute have now answered a question vital to guiding future research: What proteins in the brain does ketamine target to achieve its effects?

As Dr. Lisa Monteggia, Professor of Neuroscience at UT Southwestern’s O’Donnell Brain Institute states:

Now that we have a target in place, we can study the pathway and develop drugs that safely induce the antidepressant effect.

The study published in Nature shows that ketamine blocks a protein responsible for a range of normal brain functions. The blocking of the N-methyl-D-aspartate (NMDA) receptor creates the initial antidepressant reaction, and a metabolite of ketamine is responsible for extending the duration of the effect.

The blocking of the receptor also induces many of ketamine’s hallucinogenic responses. The drug—used for decades as an anesthetic—can distort the senses and impair coordination.

But if taken with proper medical care, ketamine may help severely depressed or suicidal patients in need of a quick, effective treatment, Dr. Monteggia said.

Studies have shown ketamine can stabilize patients within a couple of hours, compared to other antidepressants that often take a few weeks to produce a response—if a response is induced at all.

As explained by Dr. Monteggia:

Patients are demanding ketamine, and they are willing to take the risk of potential side effects just to feel better. This demand is overriding all the questions we still have about ketamine. How often can you have an infusion? How long can it last? There are a lot of aspects regarding how ketamine acts that are still unclear.

Researchers will work to answer these questions as they plan two clinical trials with ketamine, including an effort to administer the drug through a nasal spray as opposed to intravenous infusions.

The results of these trials will have major implications for the millions of depressed patients seeking help, in particular those who have yet to find a medication that works.

A major national study UT Southwestern led more than a decade ago (STAR*D) yielded insight into the prevalence of the problem: Up to a third of depressed patients don’t improve upon taking their first medication, and about 40% of people who start taking antidepressants stop taking them within three months.

Ketamine, due to the potential side effects, is mainly being explored as a treatment only after other antidepressants have failed. But for patients on the brink of giving up, waiting weeks to months to find the right therapy may not be an option.

Dr. Monteggia touches on expected future developments, where:

Ketamine opens the door to understanding how to achieve rapid action and to stabilize people quickly. Because the (NMDA) receptor that is the target of ketamine is not involved in how other classical serotonin-based antidepressants work, our study opens up a new avenue of drug discovery.

This guest article originally appeared on PsychCentral.com: Researchers Learn How Ketamine Acts on the Brain by Rick Nauert PhD.

References
Suzuki, K., Nosyreva, E., Hunt, K., Kavalali, E., & Monteggia, L. (2017). Effects of a ketamine metabolite on synaptic NMDAR function. Nature, 546(7659), E1-E3. Doi: 10.1038/nature22084

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Ketamine for Rapid Treatment of Depression

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A team of researchers funded by the National Institutes of Health (NIH) recently discovered why the drug ketamine may act as a rapid antidepressant.

Ketamine is best known as an illicit, psychedelic club drug. Often referred to as “Special K” or a “horse tranquilizer” by the media, it has been around since the 1960s and is a staple anesthetic in emergency rooms and burn centers. In the last 10 years, studies have shown that it can reverse — sometimes within hours or even minutes — the kind of severe, suicidal depression that traditional antidepressants can’t treat.

Researchers writing in the August 2010 issue of Archives of General Psychiatry reported that people in a small study who had treatment-resistant bipolar disorder experienced relief from depression symptoms in as little as 40 minutes after getting an intravenous dose of ketamine. Eighteen of these people had previously been unsuccessfully treated with at least one antidepressant medication and a mood stabilizer; the average number of medications they had tried unsuccessfully was seven. Within 40 minutes, 9 of 16 (56 percent) of the participants receiving ketamine had at least a 50 percent reduction in symptoms, and 2 of 16 (13 percent) had full remission and became symptom-free. The response lasted an average of about a week.

In a small 2006 NIMH study, one of the first to look at ketamine for depression, 18 treatment-resistant, depressed (unipolar) patients were randomly selected to receive either a single intravenous dose of ketamine or a placebo. Depression symptoms improved within one day in 71 percent of those who were given ketamine, and 29 percent of the patients became nearly symptom-free in a day. Thirty-five percent of patients who received ketamine still showed benefits seven days later.

In the most recent study published online in the journal Nature in May 2016, researchers discovered that a chemical byproduct, or metabolite, is created as the body breaks down ketamine. The metabolite reversed depression-like behaviors in mice without triggering any of the anesthetic, dissociative, or addictive side effects associated with ketamine.

As put by Carlos Zarate, MD, of the National Institute of Mental Health (NIMH), and a study coauthor and pioneer of research using ketamine to treat depression:

This discovery fundamentally changes our understanding of how this rapid antidepressant mechanism works, and holds promise for development of more robust and safer treatments. By using a team approach, researchers were able to reverse-engineer ketamine’s workings from the clinic to the lab to pinpoint what makes it so unique.”

In response to the Nature report, Sara Solovitch of The Washington Post wrote that:

experts are calling [ketamine] the most significant advance in mental health in more than half a century.

She reported that many academic medical centers, including Yale University, the University of California in San Diego, the Mayo Clinic, and the Cleveland Clinic, have all begun offering ketamine treatments off-label for severe depression.

It all sounds too good to be true, right?

The Drawbacks of Ketamine

The predominant drawback of ketamine is the lack of data.

There haven’t been enough clinical trials on the drug to assure its safety, and there’s a lack of information on the long-term effects of its use.

Ketamine’s effects are also short-lived. To be used as an effective antidepressant, it would need to be administered regularly, which leads to concerns about addiction, tolerance, and, again, long-term effects. The data that we do have on long-term use comes from people who have taken ketamine recreationally, as well as those who have used it to treat chronic pain.

One 2014 study published in the British Journal of Clinical Pharmacology included among possible side effects, psychedelic symptoms (hallucinations and panic attacks), nausea, cardiovascular stimulation, memory defects, and bladder and renal complications.

Still, the drug holds promise for uncovering new ways of treating depression and offers hope for the most severe and complicated mood disorders that baffle psychiatrists today.

Richard J. Hodes, MD, director of the National Institute on Aging, commented on the most recent NIH study and the importance of furthering the research:

Unraveling the mechanism mediating ketamine’s antidepressant activity is an important step in the process of drug development. New approaches are critical for the treatment of depression, especially for older adults and for patients who do not respond to current medications.

Join Project Hope & Beyond, the new depression community.

This guest article appeared on PsychCentral.com: Ketamine: A Miracle Drug for Depression? and was originally posted on Sanity Break at Everyday Health by Therese J. Borchard.

References

Diazgranados, N., Ibrahim, L., Brutsche, N., Newberg, A., Kronstein, P., & Khalife, S. et al. (2010). A Randomized Add-on Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Bipolar Depression. Archives Of General Psychiatry, 67(8), 793. DOI: archgenpsychiatry.2010.90.

Zanos, P., Moaddel, R., Morris, P., Georgiou, P., Fischell, J., & Elmer, G. et al. (2016). NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature, 533(7604), 481-486. DOI: 10.1038/nature17998.

Zarate, C., Singh, J., Carlson, P., Brutsche, N., Ameli, R., & Luckenbaugh, D. et al. (2006). A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression. Archives Of General Psychiatry, 63(8), 856. DOI: 10.1001/archpsyc.63.8.856.

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Decision-making: the Role of Neuronal Crowdsourcing

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Decision-making, in most cases, is not a straightforward process. Facing contradictory facts and opinions, people often struggle to decide on the best way forward when a complicated problem needs to be solved. In human society, we eventually rely on two methods of decision-making: we can follow the will of the majority, or we can delegate the task of decision-making to a leader thus leaving all deliberations (and responsibilities) to this single person.

Neuroscientists ask: How does this works on the level of brain cells? If your brain has to make a decision, how do your individual neurons come to a unified conclusion? Do they use the “majority mechanism”? Or maybe there are some neurons whose “opinion” dominates the others?

The latter approach is known as a “grandmother theory”. Grandmother analogy was suggested in the 1960s to propagate the idea that the final decision about a single event may be taken by one dominant neuron. However, scientists also suggested that the process might be more “democratic” and involve the contribution of multiple neurons in generating the final outcome. This process is sometimes described as neuronal “crowdsourcing”.  The most recent data points to the possibility that both processes play a role in the human decision-making process.

Coming to any decision is a complex mental process involving the weighing and choosing from a number of options, with each option having various characteristics. Decision-making is not a reflex action. When we make a decision there are some expected or foreseen consequences. And it is also important to note that in making any decision, we use the information that has been accumulated in our brain prior to the time of making that decision. Finally, every decision made involves risk, as there is a degree of uncertainty around making decisions, and we are aware that many of these decisions can have long-term consequences. Although we know that decision-making plays a central part in our mental development, very little is known about how it occurs at the neuronal level.

Decision-making events are far more common than we tend to think. It is not simply deciding the way to take while driving, or what food to have for a lunch. Decision-making is involved even in the easiest of tasks. What seems a simple task at first may have quite a complex mechanism underlying it. Just take any simple conversation as an example. Most words used in a conversation can have multiple meanings, and decisions regarding their appropriate use have to be taken at very high speed. These can be called momentous decisions: they do not require a high level of thinking and are often based on prior experience. At the neuronal level, such decisions are often taken by small groups of neurons or can even be taken by a single dominant neuron.

But not all decisions are momentous. Some decisions require a high level of thinking and calculation, and they require taking the long-term outcome of the decision into consideration. For long-term decision-making, we voluntarily focus on various information sources, and then we decide what is and is not relevant in achieving our long-term goals. Moreover, our decisions continually change according to changes in our environment.

Recent studies on macaque monkeys have shown that a large part of the brain is involved in collecting information in the initial steps of decision-making. After a certain time period, when enough information is processed, the cells reach a threshold where a decision has to be made. It is at this point, it seems, that all cells start to shift in favor of one single criterion and the decision is made. It appears that when the task is complex and there are too many choices, crowdsourcing works best. Lots of information is analyzed before all of the neurons come to a single decision, and this decision is communicated to each other.

I’m not trying to say that quick decision-making cannot be done with crowdsourcing. In fact, many decisions would likely make use of more distant parts of the brain and multiple neurons. We are often faced with decisions that are complex yet have to be taken quickly. Quick decisions have their own benefits and risks. There are higher chances of error, yet, in many cases, making a decision quickly is imperative. It is quite possible that the brain has some kind of mechanism to minimize this rate of error for quick and decentralized decision-making. The process of crowdsourcing and decentralized decision-making has been studied in detail in colonies of ants, where many decisions are taken by the crowd, though it often comes at the cost of time.

Whether decision-making is prompt or delayed, a factor that seems to be of great influence is the expected reward or outcome. It is quite possible that certain areas of the brain may be dedicated to it. Thus playing the role of influencers, be it the decision of some small group of neurons or crowdsourcing.

Whatever way the decision-making is done, what seems to be evident from animal studies is that it has two phases. The first phase is information gathering, and the second phase consists of coming to a consensus and making the final decision. To a degree that depends on the situation, this final step may be influenced by more important neurons. Unsurprising considering the complexity of the mechanisms involved, the ‘details’ of this process are cloudy at best.

References

Binder, M.D., Hirokawa, N., Windhorst, U. (Eds.), 2009. Grandmother Neuron, in: Encyclopedia of Neuroscience. Springer Berlin Heidelberg, pp. 1766–1766. doi: 10.1007/978-3-540-29678-2_2077.

Bowers, J.S., 2011. What is a Grandmother Cell? And How Would You Know if You Found One? Connect Sci 23, 91–95. doi: 10.1080/09540091.2011.568608.

How neurons use crowdsourcing to make decisions [WWW Document], n.d. . ScienceDaily. URL http://ift.tt/2sAGm0U

Huk, A.C., Shadlen, M.N., 2005. Neural activity in macaque parietal cortex reflects temporal integration of visual motion signals during perceptual decision making. J. Neurosci. Off. J. Soc. Neurosci. 25, 10420–10436. doi: 10.1523/JNEUROSCI.4684-04.2005.

Marshall, J.A.R., Dornhaus, A., Franks, N.R., Kovacs, T., 2006. Noise, cost and speed-accuracy trade-offs: decision-making in a decentralized system. J. R. Soc. Interface 3, 243–254. doi: 10.1098/rsif.2005.0075.

Michigan State University, n.d. Is crowdsourcing the future of scientific research? [WWW Document]. MSUToday. URL http://ift.tt/2hdp6dl

Roesch, M.R., Calu, D.J., Schoenbaum, G., 2007. Dopamine neurons encode the better option in rats deciding between differently delayed or sized rewards. Nat. Neurosci. 10, 1615–1624. doi: 10.1038/nn2013.

Wang, X.-J., 2008. Decision Making in Recurrent Neuronal Circuits. Neuron 60, 215–234. doi: 10.1016/j.neuron.2008.09.034.

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Environmental Factors in Development of Alzheimer’s Disease

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Alzheimer’s disease is one of those conditions where genetics is known to play a profound role but is not the sole factor in disease development and progression. The evidence is mounting that the environment has a great deal to do with the development of this neurodegenerative disorder. Moreover, it is now known that the right kind of nutrition and lifestyle may play preventive role in many cases.

Certain environmental factors, like exposure to toxic chemicals and brain injury, have long been known to increase the risk of Alzheimer’s, dementia, and Parkinsonism. However, the intricacies of this interaction between the environment and genetics is poorly understood. What we know for sure is that the environment does play an important role in the diseases’ development and that certain genes can be predisposing factors.

For instance, a gene called APOE4 is considered to be one of the major risk factors in developing familial Alzheimer’s disease. However, studies have shown the much lower prevalence of Alzheimer’s in sub-Saharan Africans as compared to Africans living in Western societies, where pollution, industrial food, stress, and a sedentary lifestyle render people more susceptible to the disease. There have been very few studies comparing the prevalence of Alzheimer’s among genetically similar populations living in completely different environments. One such study compared the residents of a small Nigerian town with African Americans and found the incidence of Alzheimer’s much higher among those living in the USA.

Let us look at the factors that have been strongly linked with neurodegeneration, dementia, and Alzheimer’s disease.

Acute exposure to and poisoning with heavy metals and pesticides has been well studied and documented. However, neurodegeneration occurs due to chronic low-level exposure to these toxic elements. The long term accumulativeexposure to lead has been shown to cause a decrease in memory and progressive decline in mental functions.  In contrast to lead, the role of aluminium has long been overlooked. This metal is present in many medications (like antacid suspensions). Aluminium is an additive in various commercially available food products, food colorants, and is even used to purify water. There is increasing evidence that it may be playing a role in the development of Alzheimer’s disease.

Air pollution is something to that many of us are exposed to from a very young age, and in most cases, we do not have much choice. Polluted air in large cities contains a toxic cocktail of organic and non-organic compounds, metals, and gases. Evidence of a link between neurodegeneration and air pollution is growing.

Unlike in developing nations, non-infectious diseases are the main health threat in Western societies, and an unhealthy lifestyle is the main causative factor in the development of serious chronic conditions. Some estimates suggest that obesity and a sedentary lifestyle are now killing more people than any other disease. Research data show that the risk of developing Alzheimer’s disease increases by as much as 6-fold in obese people with high blood pressure and high cholesterol level.

Physical activity decreases the risk of almost any disease, thus having a direct and indirect effect on the development of Alzheimer’s as well. Apart from physical exercise, it is also important to stay mentally active. Older people who continue to participate in mental activities, such as learning new things, reading, or even listening to music have a lower chance of declines in brain function. Social participation may also help to stay mentally active. Many people tend to become isolated as they grow old. However, maintaining a high level of social activity not only decreases stress and improves mood but may also prevent or delays Alzheimer’s disease and dementia.

Psychological stress results in an increased level of stress hormones that have been shown to be damaging for brain functionality. Emotional distress like depression and anxiety in young people and middle-aged adults is thought to increase the risk of developing dementia and Alzheimer’s later in life. Some researchers think that emotional distress could be considered an early symptom of neurodegeneration. There is now a wide consensus that emotional distress is a risk factor for dementia and mental decline.

Nutrition is perhaps the single most important factor that can either prevent or aggregate mental decline. A balanced diet rich in fruits and vegetables is a preventive factor, due to the high content of vitamins, microelements, and antioxidants. Diets with a high saturated fat and cholesterol content are harmful, as these fats block blood vessels and are the reason for stroke and cardiac diseases. As the brain is mostly made of fats, it is important to have a balanced diet. Omega-3 has been shown to be neuroprotective, and products like fish oil, soya oil, and walnuts, are a rich source of this compound.

The familial genetic history of neurodegenerative diseases does not necessarily mean that a person will develop mental decline. Neurodegenerative diseases are still highly preventable. By avoiding triggers in the environment and living a healthy, active life, one may expect to remain mentally alert until ripe old age.

References

Bazan, N.G., 2007. Omega-3 fatty acids, pro-inflammatory signaling and…?: Current Opinion in Clinical Nutrition & Metabolic Care. Curr. Opin. Clin. Nutr. Metab. Care 10, 136–141. doi: 10.1097/MCO.0b013e32802b7030.

Castillo-Fernandez, J.E., Spector, T.D., Bell, J.T., 2014. Epigenetics of discordant monozygotic twins: implications for disease. Genome Med. 6. doi: 10.1186/s13073-014-0060-z.

Corbo, R.M., Scacchi, R., 1999. Apolipoprotein E (APOE) allele distribution in the world. Is APOE*4 a ‘thrifty’ allele? Ann. Hum. Genet. 63, 301–310. doi: 10.1046/j.1469-1809.1999.6340301.x.

Fleminger, S., Oliver, D.L., Lovestone, S., Rabe-Hesketh, S., Giora, A., 2003. Head injury as a risk factor for Alzheimer’s disease: the evidence 10 years on; a partial replication. J. Neurol. Neurosurg. Psychiatry 74, 857–862. doi: 10.1136/jnnp.74.7.857.

Fratiglioni, L., Paillard-Borg, S., Winblad, B., 2004. An active and socially integrated lifestyle in late life might protect against dementia. Lancet Neurol. 3, 343–353. doi: 10.1016/S1474-4422(04)00767-7.

González-Maciel, A., Reynoso-Robles, R., Torres-Jardón, R., Mukherjee, P.S., Calderón-Garcidueñas, L., 2017. Combustion-Derived Nanoparticles in Key Brain Target Cells and Organelles in Young Urbanites: Culprit Hidden in Plain Sight in Alzheimer’s Disease Development. J. Alzheimers Dis. 59, 189–208. doi: 10.3233/JAD-170012.

Grant, W.B., Campbell, A., Itzhaki, R.F., Savory, J., 2002. The significance of environmental factors in the etiology of Alzheimer’s disease. J. Alzheimers Dis. 4, 179–189. doi: 10.3233/JAD-2002-4308.

Hendrie, H.C., Ogunniyi, A., Hall, K.S., Baiyewu, O., Unverzagt, F.W., Gureje, O., Gao, S., Evans, R.M., Ogunseyinde, A.O., Adeyinka, A.O., Musick, B., Hui, S.L., 2001. Incidence of Dementia and Alzheimer Disease in 2 Communities: Yoruba Residing in Ibadan, Nigeria, and African Americans Residing in Indianapolis, Indiana. JAMA 285, 739–747. doi: 10.1001/jama.285.6.739.

Jorm, A.F., 2000. Is Depression a Risk Factor for Dementia or Cognitive Decline? Gerontology 46, 219–227. doi: 10.1159/000022163.

Kivipelto, M., Ngandu, T., Fratiglioni, L., Viitanen, M., Kåreholt, I., Winblad, B., Helkala, E.-L., Tuomilehto, J., Soininen, H., Nissinen, A., 2005. Obesity and Vascular Risk Factors at Midlife and the Risk of Dementia and Alzheimer Disease. Arch. Neurol. 62, 1556–1560. doi: 10.1001/archneur.62.10.1556.

Liu, C.-C., Kanekiyo, T., Xu, H., Bu, G., 2013. Apolipoprotein E and Alzheimer disease: risk, mechanisms, and therapy. Nat. Rev. Neurol. 9, 106–118. doi: 10.1038/nrneurol.2012.263.

Stewart, W.F., Schwartz, B.S., Davatzikos, C., Shen, D., Liu, D., Wu, X., Todd, A.C., Shi, W., Bassett, S., Youssem, D., 2006. Past adult lead exposure is linked to neurodegeneration measured by brain MRI. Neurology 66, 1476–1484. doi: 10.1212/01.wnl.0000216138.69777.15.

Thompson, N.P., Driscoll, R., Pounder, R.E., Wakefield, A.J., 1996. Genetics versus environment in inflammatory bowel disease: results of a British twin study. BMJ 312, 95–96. doi: 10.1136/bmj.312.7023.95.

Wilson, R.S., Leon, C.F.M. de, Barnes, L.L., Schneider, J.A., Bienias, J.L., Evans, D.A., Bennett, D.A., 2002. Participation in Cognitively Stimulating Activities and Risk of Incident Alzheimer Disease. JAMA 287, 742–748. doi: 10.1001/jama.287.6.742.

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The Mystery of Amyotrophic Lateral Sclerosis

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Almost 150 years have passed since Jean-Martin Charcot first described amyotrophic lateral sclerosis (ALS), also known as motor neuron disease, an ailment that leads to the destruction of motor neurons. Medical sciences have progressed tremendously in the last century, resulting in serious improvements in health care and our ability to manage even the most serious of conditions. However, this is not the case for ALS. The progress in understanding this disease has been slow. Even today, there is no clear diagnostic criteria, no single confirmatory diagnostic test, not to mention a cure. But that does not mean that nothing has changed. The first effective drug to slow down the progress of the disease was approved in the 1990s. This article will briefly review the progress that has been made towards combating this disease.

Our muscles are made in such a way that if the neurons that supply them fail, the muscles also start to degrade. ALS is a disease characterized by progressive weakening of muscles due to the failure of neurons until the muscles are no longer able to support the body’s vital activities. For the majority of patients, the lifespan after disease onset is only two to five years, but there are long-term survivors too. The famous physicist Stephen Hawking was diagnosed with ASL in 1963 and has lived with the condition for over 40 years already.

The worldwide incidence of ALS is not known exactly, but in Europe 2.6 cases of disease per 100,000 people are diagnosed each year. The highest onset is in the age group of 58–63 years. Not all causes of the disease are understood, but familial (~10%) and genetic (~65%) factors are usually considered to be the main causes. Old age, male gender, and genetics remain the only recognized risk factors. The risk for the disease also appears to be increased by a number of environmental and lifestyle factors. Below is the summary of all the risk factors known to date:

  • Familial aggregation – persons with a family history of ALS are at increased risk.
  • Genetics – several genes have been identified, although their role is not fully understood. The most common genes accepted to play a role in ALS include SOD1, TARDBP, FUS, OPTN, VCP, UBQLN2, C9ORF72, and PFN1.
  • Chromosomes – the expanded GGGGCC repeat is associated with ALS.
  • Lifestyle risk factors: Most of them are preventable.Smoking is known to be neurotoxic and increase the risk of ALS; dietary factors such as antioxidants like vitamin E may have a preventive role in ALS. Consequently, diet may have something to do with ALS; low body weight may increase risk and worsen outcomes; athleticism and chronic traumatic encephalopathy should not be misinterpreted, physical exercise decreases the risk of ALS, but the risk is higher among professional athletes who tend to be at higher risk of trauma.
  • Occupations with high trauma rates – ALS prevalence has been shown to be higher in US war veterans and people working with low magnetic fields like welders and electricians.
  • Pesticides – are widely used and have been suggested as a risk factor in various neurodegenerative disorders for some time.
  • Some medical conditions – include head trauma, cancer, chronic inflammatory diseases, certain viral infections, and neuroinflammation.

The existence of so many factors influencing the development of the disease underlines the complex nature of ALS.

The presentation of ALS varies greatly from person to person, so does the survival rate. However, the vast majority (almost half) of patients do not live for more than 30 months after disease onset. Despite this, ~20% can survive for five to ten years, while others can expect to live even longer.

There is little clarity when it comes to predicting the chance of survival for a person with ALS. However, the odds are better when the disease starts at a younger age. Also, life expectancy depends on where in the body the disease first started. The three major early stage presentations include:

  1. Limb-onset ALS with the involvement of both the upper and lower motor neurons (UMNs and LMNs).
  2. Bulbar-onset ALS that often starts with speech and swallowing difficulties, and with limb features developing later.
  3. Less common is pure UMN involvement and muscular atrophy with LMN involvement.

The bulbar-onset ALS has the worst prognosis since the vital functioning of organs is affected at an early stage. This often leads to early respiratory failure.

There is also lots of controversy in the scientific literature when it comes to the question of where the disease begins. Some researchers believe that it starts in the brain and then migrates to the peripheral nerves and muscles (hence this theory is called “Dying-forward”). Other scientists believe that it all starts at the periphery at the neuromuscular junction and later affects the neurons in the brain (hence this theory is called “Dying-backward”).

Due to the lack of diagnostic tests in early disease, clinicians have to depend on clinical symptoms, identifying combinations of UMN and LMN signs. There is usually further delay with definite diagnostics, as the typical ALS symptoms can be part of many other rare neurodegenerative disorders. Thus, an elaborate clinical and laboratory analysis is required for differential diagnosis, where tests involving brain imaging are often helpful for early diagnosis.

As there is no complete understanding of why, where, and how the disease starts, finding treatment remains challenging. Further, the lack of proper early stage diagnostic techniques means that precious time is lost when the probability of effective treatment is at its highest.

To date, there is only one drug, Riluzole, that has been shown to change the course of the disease, and it only helps for a few months. But this does not mean that there is no progress. Lots of promising research has been achieved in other animals, and there is need to translate this research to humans.

At present, most of the treatment for ALS is symptomatic and supportive. They include physiotherapy, orthotics, and treatment of pain, dysphagia (difficulty in swallowing), dyspnea (difficulty in breathing), pain, constipation, loss of voice, and mental and emotional problems.

References

Armon, C., 2009. Smoking may be considered an established risk factor for sporadic ALS. Neurology 73, 1693–1698. doi: 10.1212/WNL.0b013e3181c1df48.

Ascherio, A., Weisskopf, M.G., O’Reilly, E.J., Jacobs, E.J., McCullough, M.L., Calle, E.E., Cudkowicz, M., Thun, M.J., 2005. Vitamin E intake and risk of amyotrophic lateral sclerosis. Ann. Neurol. 57, 104–110. doi: 10.1002/ana.20316.

Beard, J.D., Kamel, F., 2015. Military Service, Deployments, and Exposures in Relation to Amyotrophic Lateral Sclerosis Etiology and Survival. Epidemiol. Rev. 37, 55–70. doi: 10.1093/epirev/mxu001.

Das, K., Nag, C., Ghosh, M., 2012. Familial, environmental, and occupational risk factors in development of amyotrophic lateral sclerosis. North Am. J. Med. Sci. 4, 350–355. doi: 10.4103/1947-2714.99517.

Gallo, V., Wark, P.A., Jenab, M., Pearce, N., Brayne, C., Vermeulen, R., Andersen, P.M., Hallmans, G., Kyrozis, A., Vanacore, N., Vahdaninia, M., Grote, V., Kaaks, R., Mattiello, A., Bueno-de-Mesquita, H.B., Peeters, P.H., Travis, R.C., Petersson, J., Hansson, O., Arriola, L., Jimenez-Martin, J.-M., Tjønneland, A., Halkjær, J., Agnoli, C., Sacerdote, C., Bonet, C., Trichopoulou, A., Gavrila, D., Overvad, K., Weiderpass, E., Palli, D., Quirós, J.R., Tumino, R., Khaw, K.-T., Wareham, N., Barricante-Gurrea, A., Fedirko, V., Ferrari, P., Clavel-Chapelon, F., Boutron-Ruault, M.-C., Boeing, H., Vigl, M., Middleton, L., Riboli, E., Vineis, P., 2013. Prediagnostic body fat and risk of death from amyotrophic lateral sclerosis: the EPIC cohort. Neurology 80, 829–838. doi: 10.1212/WNL.0b013e3182840689.

Gordon, P.H., 2013. Amyotrophic Lateral Sclerosis: An update for 2013 Clinical Features, Pathophysiology, Management and Therapeutic Trials. Aging Dis. 4, 295–310. doi: 10.14336/AD.2013.0400295.

Gordon, P.H., Cheng, B., Katz, I.B., Pinto, M., Hays, A.P., Mitsumoto, H., Rowland, L.P., 2006. The natural history of primary lateral sclerosis. Neurology 66, 647–653. doi: 10.1212/01.wnl.0000200962.94777.71.

Hardiman, O., Kiernan, M.C., Berg, L.H. van den, 2016. Amyotrophic Lateral Sclerosis, in: Neurodegenerative Disorders. Springer, Cham, pp. 145–165. doi: 10.1007/978-3-319-23309-3_8.

Ingre, C., Roos, P.M., Piehl, F., Kamel, F., Fang, F., 2015. Risk factors for amyotrophic lateral sclerosis. Clin. Epidemiol. 7, 181–193. doi: 10.2147/CLEP.S37505.

Kiernan, M.C., Vucic, S., Cheah, B.C., Turner, M.R., Eisen, A., Hardiman, O., Burrell, J.R., Zoing, M.C., 2011. Amyotrophic lateral sclerosis. The Lancet 377, 942–955. doi: 10.1016/S0140-6736(10)61156-7.

Logroscino, G., Traynor, B.J., Hardiman, O., Chiò, A., Mitchell, D., Swingler, R.J., Millul, A., Benn, E., Beghi, E., Eurals, F., 2010. Incidence of amyotrophic lateral sclerosis in Europe. J. Neurol. Neurosurg. Psychiatry 81, 385–390. doi: 10.1136/jnnp.2009.183525.

Marangi, G., Traynor, B.J., 2015. Genetic causes of amyotrophic lateral sclerosis: New genetic analysis methodologies entailing new opportunities and challenges. Brain Res., The multifaceted nature of ALS. Discoveries and Challenges of the last 5 years 1607, 75–93. doi: 10.1016/j.brainres.2014.10.009.

Poppe, L., Rué, L., Robberecht, W., Van Den Bosch, L., 2014. Translating biological findings into new treatment strategies for amyotrophic lateral sclerosis (ALS). Exp. Neurol., Special Issue: ALS genetics and pathogenesis 262, 138–151. doi: 10.1016/j.expneurol.2014.07.001.

Renton, A.E., Chiò, A., Traynor, B.J., 2014. State of play in amyotrophic lateral sclerosis genetics. Nat. Neurosci. 17, 17–23. doi: 10.1038/nn.3584.

Talbot, K., 2009. Motor neuron disease: THE BARE ESSENTIALS. Pract. Neurol. 9, 303–309. doi: 10.1136/jnnp.2009.188151.

Vergara, X., Kheifets, L., Greenland, S., Oksuzyan, S., Cho, Y.-S., Mezei, G., 2013. Occupational exposure to extremely low-frequency magnetic fields and neurodegenerative disease: a meta-analysis. J. Occup. Environ. Med. 55, 135–146. doi: 10.1097/JOM.0b013e31827f37f8.

Xu, Z., Poidevin, M., Li, X., Li, Y., Shu, L., Nelson, D.L., Li, H., Hales, C.M., Gearing, M., Wingo, T.S., Jin, P., 2013. Expanded GGGGCC repeat RNA associated with amyotrophic lateral sclerosis and frontotemporal dementia causes neurodegeneration. Proc. Natl. Acad. Sci. 110, 7778–7783. doi: 10.1073/pnas.1219643110.

Image via simonwijers/Pixabay.

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Trans — From the Moment of Birth

The latest from http://brainblogger.com!

The moment I was born, the doctor looked at my nether regions, saw a penis, and announced to my parents, “It’s a boy”. Along with that announcement came a long list of expectations about how a boy’s life should unfold in rural Nebraska in the 1940s and ’50s. No ambiguity. No nuance. Boys will be boys—or else!

Gender reveal parties are a hot trend among today’s expectant parents.1 At about twenty weeks of gestation, an ultrasound is completed, and family and friends are called together for “the reveal,” a celebration of the newly identified biologic sex of the child. Sometimes a baby-carriage-piñata filled with candy is struck until the candy, wrapped in either pink or blue, comes rolling out—along with all the expectations about gender roles that will be established even prior to birth.

Although it could be confusing to guests, I think those parties might better be called “sex reveal parties,” but I understand that guests might come with a different set of expectations. You see, what is being revealed isn’t gender at all but the biological sex of the child. Sex and gender are not the same, although they are often confused and the terms used interchangeably.

Humans have a natural tendency to categorize, sometimes out of respect, sometimes based on stereotypes. At birth, infants are assigned a sex by a third party. It’s a binary choice based on their external genitalia or, in some cases, by chromosomes. Sex is binary: boy or girl. Gender is more of a psychological and societal concept. Gender is not binary; it may not even be linear. Enter the world of the transgender. (A discussion of intersex children who may have incomplete physical characteristics is beyond the scope of this article.)

Transgender individuals are those who identify with a gender that differs from the biological sex they were assigned at birth. They are born biologically male or female but express their gender in ways more consistent with the opposite sex.

Although it may seem like we have a wave of newly identified transgender people, the percent of trans people remains consistent at about 0.3%, and rather than a change in incidence, we are likely experiencing more visibility. While interviewing me, MJ Schwader said that he first came out as a lesbian at age nineteen and only many years later came out as a transgender man. He said:

Something wasn’t right; even without language around it, I knew from a very early age that I wasn’t going to be able to stay there. When I came to a realization that I was trans, there was this complete peace inside.2

Whether speaking of sexual orientation or gender orientation, many people live in a kind of purgatory of sexual confusion until they acquire the words to describe their individual identity.

Another layer of confusion is added when considering “drag,” that is practiced by people of all sexual orientations and gender identities. The term “drag” is used when someone wears clothing that is more conventionally worn by a person of the opposite sex, especially when a man wears women’s clothes. Drag is a performance; it does not refer to people who wish to assume a gender different from their assigned sex. Transgender women want to dress as women because they are women, transgender men are men.

One morning I heard a television pundit who opposes transgender rights say that if men can gain an advantage by saying they are women, many will do so. He was wrong on so many levels. In our patriarchal society, most would agree that not many advantages accrue to women over men. He also implied that all a man had to do was put on a dress and a wig and suddenly he is transformed into a woman. His statement ignores the complexities and pain of a trans person’s decision to transition to a different gender. Some trans people work hard to leave no doubt as to the gender they believe they are.

When a conflict exists between one’s biological sex and the gender with which one identifies, it creates gender dysphoria, a clinically significant form of distress. A report titled “Suicide Attempts among Transgender and Gender Non-Conforming Adults” states that over 40% of trans men and women have attempted suicide, with the prevalence being highest among the young, economically disadvantaged, less educated, and ethnic minorities.3

Until a recent change in the Diagnostic and Statistical Manual of the American Psychiatric Association, this condition was labeled “gender dysphoria disorder.” Although trans men and women experience dysphoria (anxiety, depression, and suicidal thoughts) at a higher rate than the general population, it is no longer considered a “disorder.” For many, their psychiatric symptoms disappear or markedly diminish once they have decided to transition to the gender with which they identify.

Why would anyone, then, choose to assume a gender different from the biological sex with which they were born? Many studies on the causes of transsexuality have been widely discredited, particularly psychological studies. A recent review of literature on the causes of gender identity concluded that a fixed, biologic basis exists for gender identity and that the best clinical outcomes are associated with hormone therapy and surgical sexual transition.4

One classic way for scientists to test whether a trait is influenced by genetics is twin studies. Identical twins have the same chromosomes; fraternal twins are raised in the same environment but share only half their genes. Several studies have shown that among twins, both identical twins are transgender more often than both fraternal twins. Studies of the brain structure have also shown that the brains of transgender males or females are more similar to the brains of the sex with which these people identify than the brains of the sex they were assigned at birth.5

Transgender identity is complex. It is not binary; it may not be linear. It is also most certainly not a capricious choice made to seek a particular advantage. It may also be more fluid than once thought. Sex and gender are most likely a matrix of identities without one precise set of causes. The most promising choices for understanding transsexualism is in epigenomics, a study that combines the effects of the environment on genetic expression.

More than one in four trans people has faced a bias-driven assault, and rates are higher for trans women and trans people of color.6 Although more than half of Americans oppose laws requiring transgender people to use bathrooms that correspond to their birth sex, the current political environment is a very difficult one for transgender men and women. “Bathroom bills” have become the focal point of anti-LGBT measures across the country. In most cases, bathroom bills have been proposed by politicians up for re-election. The bills are being used to energize these politicians’ conservative base now that the issue of same-sex marriage has been resolved, and the arguments that they are using are the same that were used against same-sex marriage—for example, to protect children.

President Trump, indebted to conservative Christians, has reversed his pre-election position and has rescinded President Obama’s rule that trans people must be allowed to use the bathroom consistent with the sex with which they identify. In an administration that so easily dismisses science, the evidence that transsexualism is biologically determined will have little impact.

We have a great deal to learn about transsexualism. For example, we know that the earlier hormonal treatment is given, the more apparent the physical transformation will be, but what are the long-term consequences of putting children on hormones with irreversible effects?

One thing we can be certain of is this: issues of sexual orientation and gender identification are complex and will not be resolved at a gender reveal party during the twentieth week of gestation.

1. Sirois M. (2017) A Word of Caution on Gender Reveal Parties. HuffPost. Available here.

2. Olson L. (2017) Finally Out: Letting Go of Living Straight with Loren Olson, MD. OMTimes Radio. Available here.

3. Haas A, Rodgers P, Herman J. (2017) Suicide Attempts Among Transgender and Gender Non-Conforming Adults – Williams Institute. Williams Institute. Available here.

4. Saraswat A, Weinland J, Shafer J. (2015) Evidence Supporting the Biologic Nature of Gender Identity, Endocrine Practice, 21(2), 199-204. doi: 10.4158/EP14351.RA.

5. Wu K. Between the (Gender) Lines: the Science of Transgender Identity – Science in the News. Harvard University – The Graduate School of Arts and Sciences. 2017. Available here.

6. (2017) Anti-Violence. National Center for Transgender Equality. Available here.

Image via congerdesign/Pixabay.

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