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Lower availability of omega-3 fatty acids in the body associated with bipolar disorder

Omega-3 fatty acid can exist in two forms in the blood, 1) free, 2) bound to protein. It is the free form of omega-3 fatty acids that can cross the blood brain barrier. The ratio of free omega-3 fatty acids to bound fatty acids is lower in people with bipolar disorder (BPD). This means that we, people with BPD, have lower levels of these fatty acids available to be transported to our brains.

Fatty acids are very important as they form the cell membranes of all cells. This is especially important in the brain, as they form cell membranes of neurons as well. And neurons, the cells of the brain, are the ones that have ion channels in their membranes that allow Na+ and K+ to pass through creating ionic gradients across the cell membranes, allowing action potentials, which lead to nerve impulses, which is how information, emotions, sensory information, motor directives, everything is disseminated.

Omega-3 fatty acids also play an important role in the inflammatory response. (Another immune system/brain connection!)

This study is important, and they are going to further study the effect of this lower concentration of fatty acids, and hopefully come up with dietary recommendations for omega-3 fatty acids for people with BPD.

http://www.sciencedaily.com/releases/2015/11/151124082456.htm

People with bipolar disorder have lower levels of certain omega-3 fatty acids that cross the blood-brain barrier compared to those who do not, according to researchers from Penn State College of Medicine and the National Institutes of Health. The finding could have implications for dietary interventions for the disorder.

Fatty acids are a major area of interest in bipolar disorder and depression because of their biological importance in the brain. Studies have shown that fatty acid supplementation may be useful for unipolar depression, but the data has been more mixed for bipolar disorder.

The researchers, led by Dr. Erika Saunders, associate professor and chair of psychiatry at Penn State College of Medicine, compared fatty acids in 27 people with symptomatic bipolar disorder and 31 healthy control subjects. The group measured levels of different forms of the polyunsaturated fatty acids omega-3 and omega-6. They also collected self-reported information on fatty acid consumption and bipolar medication use. Their results were published in the journal Bipolar Disorders.

Free fatty acids are able to cross the blood-brain barrier, while fatty acids bound to proteins are not. In study subjects with bipolar disorder, the ratio of a free-circulating omega-3 fatty acid called EPA to bound EPA was lower than in other people.

“This means that the availability of omega-3 in the body is lower in bipolar subjects,” Saunders said.

Omega-3 fatty acids are a large component of brain-cell membranes and are important for cell-to-cell communication in the brain. In the study, the ratio of free to bound EPA correlated with clinical bipolar symptoms, specifically mania and tendency towards suicide.

Fatty acids also play an important role in the immune system and the inflammatory system.

“Omega-3 and omega-6 fatty acids can shift the balance of inflammation, which we think is important in bipolar disorder,” Saunders said.

However, the researchers did not find altered ratios of omega-3 to omega-6 fatty acids in bipolar subjects.

Although the researchers did find lower levels of omega-3s in patients with bipolar disorder that correlated with symptoms, Saunders said it’s too early to advise dietary changes or omega-3 supplementation.

Omega-3 fatty acids are abundant in fish, vegetable oils, nuts — especially walnuts, flax seeds, flaxseed oil and leafy vegetables.

There was no difference in self-reported fatty acid consumption between bipolar and healthy patients.

“Is that because we only included certain foods in the survey? Or is it because people couldn’t accurately recall what they were eating?” Saunders said.

Another possibility the researchers are considering is that there are differences in how healthy people and people with bipolar disorder convert fatty acids from one form to another. Drugs that treat bipolar disorder are known to affect these conversions, but no association was found between fatty acid levels or ratios and self-reported medication use in the study.

Saunders is currently investigating if modifications in dietary intake of fatty acids could be useful in bipolar disorder.

“We are actively pursuing the next step in this line of inquiry to get to the point where we know what changes in diets are going to help people with bipolar disorder so they can have another option beyond the medications that are currently available,” she said.

A number of trials have turned up no benefit of omega-3 supplementation in bipolar disorder, a brain disorder that causes manic episodes of elevated mood, energy and cognition, and major depressive episodes of lowered mood, energy and cognition. Bipolar disorder affects between 1 and 4.4 percent of the population.

“I think our work, along with the work of others, shows that this is an important area for us to continue to study,” Saunders said. “It’s complicated and hard to study, and there are a lot of factors, but it’s an area we need to keep pursuing.”

Most research on fatty acids in bipolar disorder measures levels of fatty acids in cell membranes. Saunders’s group instead looked at circulating fatty acids in the blood, which is a better indication of dietary intake. Fatty acids in the blood are also the type that crosses the blood-brain barrier to enter the brain.

Story Source:

The above post is reprinted from materials provided by Penn State Milton S. Hershey Medical Center. Note: Materials may be edited for content and length.

Journal Reference:

  1. Erika FH Saunders, Aubrey Reider, Gagan Singh, Alan J Gelenberg, Stanley I Rapoport. Low unesterified:esterified eicosapentaenoic acid (EPA) plasma concentration ratio is associated with bipolar disorder episodes, and omega-3 plasma concentrations are altered by treatment. Bipolar Disorders, 2015; 17 (7): 729 DOI:10.1111/bdi.12337
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Light Therapy May Work on Chronic Mood Disorders, Too

  http://www.smithsonianmag.com/smart-news/light-therapy-may-work-more-season-affective-disorder-180953431/#uPRmTIuxjzTUis8G.01SMARTNEWS Keeping you current

Light Therapy May Work on Chronic Mood Disorders, Too

Sitting under fake sun could help heal chronic depression, bipolar disorder, and anxiety, too


By Shannon Palus

SMITHSONIAN.COM 

NOVEMBER 21, 2014

Researchers suspect that seasonal affective disorder, first reported in 1984, has something to do with circadian rhythms thrown off by short, dark days. At first, Vox reports, scientists connected SAD to excessive production of melatonin; now they think it has more to do with the mismatch of melatonin production and sleep schedules.

Either way, short periods sitting under a special lamp is recommended as a treatment, and researchers have wondered whether the the effects of phototherapy might be able to treat chronic mood disorders. Now, Nautilus reports, “research into the circadian underpinnings of chronic depression, bipolar disorder, Alzheimer’s disease, and fatigue suggests that light could help these patients readjust too.”
Phototherapy has long been used to treat certain conditions: the power of artificial sunlight for skin disorders was demonstrated over a century ago. The doctor who won the 1903 Nobel Prize in medicine found that an hour a day of light therapy could help cure smallpox, and lupus vulgaris, a form of tuberculosis. But it’s only in the past couple of decades that researchers have looked at light treatment as a possibility for people suffering year-round from depression or other diseases. 
In a 1992 study, two dozen veterans exposed to a bright light treatment saw a decline in depression and bipolar symptoms compared to a control group, exposed to a dim, red, light. A few more recent studies have since shown that there are also positive anti-depressive effects of light therapy for pregnant women and elderly people, Nautilus reports.
This suggests that light therapy could at least augment other forms of treatment for several types of depression. Last year, a study suggested the treatment could work for anxiety, too. These studies are small. But while skin therapies use ultraviolet light, SAD lamps use a smaller, safer spectrum. The side effects of sitting under these sunlamps are almost nonexistent, and even a possibility of a benefit could make the treatment worthwhile.
Read more: http://www.smithsonianmag.com/smart-news/light-therapy-may-work-more-season-affective-disorder-180953431/#HJBMKos2ZvySZUF0.99
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A very happy thanksgiving

Hope all my blogging friends had a wonderful thanksgiving. My family and I had the best thanksgiving since we all used to gather at my mom’s house more than 10 years ago. So thankful for my family, my precious son, my beloved brother and sister and my adored cousins who drove 18 hours to spend thanksgiving with us. This time with my family was so heartening, so happy, so joyful for me. We cooked the thanksgiving meal together. We went for walks in our beautiful park. We went out to dinner. For me, this time with family is so precious. All traces of depression were gone. I sometimes think if I lived in a large compound of homes with my extended family, maybe, just maybe I wouldn’t have bipolar d/o anymore. Perhaps that is some mighty wishful thinking… but sometimes I really do think just that. With all my family around me, I was able to live totally in the moment. No anxiety about the future, no depression about the past. I am grateful we had this time together, to laugh and make memories and to strengthen our relationships. My sister also got me addicted to watching “Jane the Virgin,” a good series. Very well acted, albeit a bit simplistic.

A lovely time. Really a lovely and happy time. Now onto other things. Going to Buffalo for my son’s birthday next week. And going to Pakistan in the end of December. I’m actually traveling on Christmas Day!

A smattering of our thanksgiving pictures.


  
  
  
  

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Choose to Be Grateful. It Will Make You Happier.

There is a gene variant: CD38, (an immune system gene!) that is associated with more grateful people! But don’t worry, even if you aren’t lucky enough to have this gene variant, there are many other things you can do to be grateful and happy!

1) Just pretend you are grateful and your mind will be tricked into it.

2) Just pretend you’re happy, smile for 20 sec, especially while crinkling up your eyes, and your brain will get fooled into thinking you are happy 🙂

3)Keep a list of what you are grateful for, and ten weeks after starting this list. you will feel grateful and happy 🙂

4) Choose to focus on good things 🙂

5) Gratitude is the attitude yo! Interior gratitude, where you feel grateful, and exterior gratitude, where you externally express or show gratitude.

6) Apparently gratitude for useless things is key, things like poetry… ummm not useless… neither is a sunset, or birdsong, or a rain shower, nature is surely something to be thankful about.

So, let me say to all my blogger friends, old and new, and my readers, and followers, I am seriously grateful for each and every one of you. Thank you for visiting my blog over 16,700 times in the last 14.5 months.

I hope all of you have a wonderful family holiday.

With love and gratitude,

Samina.

 

http://www.nytimes.com/2015/11/22/opinion/sunday/choose-to-be-grateful-it-will-make-you-happier.html

By Arthur C. Brooks

TWENTY-FOUR years ago this month, my wife and I married in Barcelona, Spain. Two weeks after our wedding, flush with international idealism, I had the bright idea of sharing a bit of American culture with my Spanish in-laws by cooking a full Thanksgiving dinner.

Easier said than done. Turkeys are not common in Barcelona. The local butcher shop had to order the bird from a specialty farm in France, and it came only partially plucked. Our tiny oven was too small for the turkey. No one had ever heard of cranberries.

Over dinner, my new family had many queries. Some were practical, such as, “What does this beast eat to be so filled with bread?” But others were philosophical: “Should you celebrate this holiday even if you don’t feel grateful?”

I stumbled over this last question. At the time, I believed one should feel grateful in order to give thanks. To do anything else seemed somehow dishonest or fake — a kind of bourgeois, saccharine insincerity that one should reject. It’s best to be emotionally authentic, right? Wrong. Building the best life does not require fealty to feelings in the name of authenticity, but rather rebelling against negative impulses and acting right even when we don’t feel like it. In a nutshell, acting grateful can actually make you grateful.

For many people, gratitude is difficult, because life is difficult. Even beyond deprivation and depression, there are many ordinary circumstances in which gratitude doesn’t come easily. This point will elicit a knowing, mirthless chuckle from readers whose Thanksgiving dinners are usually ruined by a drunk uncle who always needs to share his political views. Thanks for nothing.

Beyond rotten circumstances, some people are just naturally more grateful than others. A 2014 article in the journal Social Cognitive and Affective Neuroscience identified a variation in a gene (CD38) associated with gratitude. Some people simply have a heightened genetic tendency to experience, in the researchers’ words, “global relationship satisfaction, perceived partner responsiveness and positive emotions (particularly love).” That is, those relentlessly positive people you know who seem grateful all the time may simply be mutants.

But we are more than slaves to our feelings, circumstances and genes. Evidence suggests that we can actively choose to practice gratitude — and that doing so raises our happiness.

This is not just self-improvement hokum. For example, researchers in one 2003 study randomly assigned one group of study participants to keep a short weekly list of the things they were grateful for, while other groups listed hassles or neutral events. Ten weeks later, the first group enjoyed significantly greater life satisfaction than the others. Other studies have shown the same pattern and lead to the same conclusion. If you want a truly happy holiday, choose to keep the “thanks” in Thanksgiving, whether you feel like it or not.

How does all this work? One explanation is that acting happy, regardless of feelings, coaxes one’s brain into processing positive emotions. In one famous 1993 experiment, researchers asked human subjects to smile forcibly for 20 seconds while tensing facial muscles, notably the muscles around the eyes called the orbicularis oculi (which create “crow’s feet”). They found that this action stimulated brain activity associated with positive emotions.

If grinning for an uncomfortably long time like a scary lunatic isn’t your cup of tea, try expressing gratitude instead. According to research published in the journal Cerebral Cortex, gratitude stimulates the hypothalamus (a key part of the brain that regulates stress) and the ventral tegmental area (part of our “reward circuitry” that produces the sensation of pleasure).

It’s science, but also common sense: Choosing to focus on good things makes you feel better than focusing on bad things. As my teenage kids would say, “Thank you, Captain Obvious.” In the slightly more elegant language of the Stoic philosopher Epictetus, “He is a man of sense who does not grieve for what he has not, but rejoices in what he has.”

In addition to building our own happiness, choosing gratitude can also bring out the best in those around us. Researchers at the University of Southern California showed this in a 2011 study of people with high power but low emotional security (think of the worst boss you’ve ever had). The research demonstrated that when their competence was questioned, the subjects tended to lash out with aggression and personal denigration. When shown gratitude, however, they reduced the bad behavior. That is, the best way to disarm an angry interlocutor is with a warm “thank you.”

I learned this lesson 10 years ago. At the time, I was an academic social scientist toiling in professorial obscurity, writing technical articles and books that would be read by a few dozen people at most. Soon after securing tenure, however, I published a book about charitable giving that, to my utter befuddlement, gained a popular audience. Overnight, I started receiving feedback from total strangers who had seen me on television or heard me on the radio.

One afternoon, I received an unsolicited email. “Dear Professor Brooks,” it began, “You are a fraud.” That seemed pretty unpromising, but I read on anyway. My correspondent made, in brutal detail, a case against every chapter of my book. As I made my way through the long email, however, my dominant thought wasn’t resentment. It was, “He read my book!” And so I wrote him back — rebutting a few of his points, but mostly just expressing gratitude for his time and attention. I felt good writing it, and his near-immediate response came with a warm and friendly tone.

DOES expressing gratitude have any downside? Actually, it might: There is some research suggesting it could make you fat. A new study in the Journal of Consumer Psychology finds evidence that people begin to crave sweets when they are asked to express gratitude. If this finding holds up, we might call it the Pumpkin Pie Paradox.

The costs to your weight notwithstanding, the prescription for all of us is clear: Make gratitude a routine, independent of how you feel — and not just once each November, but all year long.

There are concrete strategies that each of us can adopt. First, start with “interior gratitude,” the practice of giving thanks privately. Having a job that involves giving frequent speeches — not always to friendly audiences — I have tried to adopt the mantra in my own work of being grateful to the people who come to see me.

 

Next, move to “exterior gratitude,” which focuses on public expression. The psychologist Martin Seligman, father of the field known as “positive psychology,” gives some practical suggestions on how to do this. In his best seller “Authentic Happiness,” he recommends that readers systematically express gratitude in letters to loved ones and colleagues. A disciplined way to put this into practice is to make it as routine as morning coffee. Write two short emails each morning to friends, family or colleagues, thanking them for what they do.

Finally, be grateful for useless things. It is relatively easy to be thankful for the most important and obvious parts of life — a happy marriage, healthy kids or living in America. But truly happy people find ways to give thanks for the little, insignificant trifles. Ponder the impractical joy in Gerard Manley Hopkins’s poem “Pied Beauty”:

Glory be to God for dappled things —

For skies of couple-colour as a brinded cow;

For rose-moles all in stipple upon trout that swim;

Fresh-firecoal chestnut-falls; finches’ wings;

Landscape plotted and pieced — fold, fallow, and plough;

And all trades, their gear and tackle and trim.

Be honest: When was the last time you were grateful for the spots on a trout? More seriously, think of the small, useless things you experience — the smell of fall in the air, the fragment of a song that reminds you of when you were a kid. Give thanks.

This Thanksgiving, don’t express gratitude only when you feel it. Give thanks especially when you don’t feel it. Rebel against the emotional “authenticity” that holds you back from your bliss. As for me, I am taking my own advice and updating my gratitude list. It includes my family, faith, friends and work. But also the dappled complexion of my bread-packed bird. And it includes you, for reading this column.

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Another link between inflammation and mental illness! “Could a runny nose make you depressed? Hay fever sufferers may be four times more likely to develop the mental illness.”

I have horrible seasonal allergies, I have food sensitivities, I have manic depression, aka bipolar disorder. My grandmother had rheumatoid arthritis, my mother had RA and elements of lupus. My brother had bad seasonal allergies. A case study in inflammation, immune and autoimmune responses and mental illnesses in the same individuals!  And here is yet another link between inflammation and mental illness! Hay fever sufferers may be much more likely to develop depression. Hay fever peaks during spring, the rates of suicide also peak in Springtime all over the world. There may be a simple cure for allergies, as simple as Ibuprofen, a non steroidal anti inflammatory (NSAID). Hope scientists     figure out the link between inflammation and mental illness, it could save many, many lives.

Could a runny nose make you depressed? Hay fever sufferers may be four times more likely to develop the mental illness.

http://www.dailymail.co.uk/health/article-3321143/Could-runny-nose-make-depressed-Hay-fever-sufferers-four-times-likely-develop-mental-illness.html

Hay fever sufferers may be four times more likely to develop severe depression, according to new research. But it’s not just a runny nose and itchy eyes that triggers mood slumps.

Scientists think inflammation in blood vessels and tissues throughout the body caused by an allergic reaction to pollen has a long-lasting harmful effect on the brain.

This inflammatory response – the cause of typical allergy symptoms, such as sneezing – is the body’s way of trying to get rid of an allergy trigger, such as pollen. But there is a growing body of evidence that sustained exposure to low-level inflammation for several months, such as during the hay fever season, could have serious psychiatric effects later in life. However, treatment such as simple ibuprofen could help.

Around ten million people a year in Britain suffer during the hay fever season, which peaks during the late spring and summer. Researchers are investigating whether inflammation can trigger depression, bipolar disorder and schizophrenia.

In the latest study, scientists at the National Yang-Ming University of Taiwan looked at nearly 10,000 teenagers with hay fever and 30,000 without it.

They monitored both groups for almost a decade and recorded how many went on to be diagnosed with bipolar disorder – a condition characterised by periods of mania (when people appear over-excited and have an inability to concentrate or sleep) followed by deep depression. The results, in the Journal of Psychosomatic Research, showed that adolescents with hay fever were four times more likely to be diagnosed as bipolar as adults.

An earlier Danish study, in 2010, discovered people with allergies such as hay fever had a 30 per cent higher risk of suicide than those who were allergy-free.

Researchers from Aarhus University came up with the findings after comparing allergy rates among suicide victims with those of a group of healthy people.

But how could something as innocuous as a runny nose be linked to mental illness?

Scientists are not completely sure, but it’s already known that during any allergic reaction, the brain churns out substances called pro-inflammatory cytokines.

These are proteins that then trigger inflammation and the release of chemicals in the blood in a bid to flush out foreign ‘invaders’, such as pollen. Inflammation develops in order to alert the immune system that the body is under attack. Normally, it subsides once the threat has been eliminated and the inflamed tissue heals. But problems develop when the inflammation does not dampen down.

More recent research also suggests cytokines can cause a dip in the brain’s levels of serotonin, the so-called happiness chemical, low levels of which can lead to depression.

This could be a vital clue to why allergy-induced inflammation leads to psychiatric illness.

Now, researchers are investigating whether anti-inflammatory drugs, such as ibuprofen, could treat depression.

Earlier this year, King’s College London began the largest ever investigation into inflammation in depressed patients by scanning their brains.

In the past, inflammatory markers have been found in the blood of depressed patients, but this does not prove that inflammation is also present in the brain, which is what is thought could cause depressive symptoms.

The scientists will now test if anti-inflammatory drugs can help patients who have not responded to antidepressants by improving levels of serotonin.

Dr Valeria Mondelli, one of the researchers, said that because inflammation is a natural response, up to a certain level it can protect the brain against infection. ‘But if it is chronic, then it appears to start to damage brain cells,’ she says.

Here’s a link to a video that talks about Immunotherapy to treat allergies: http://www.dailymail.co.uk/health/article-3321143/Could-runny-nose-make-depressed-Hay-fever-sufferers-four-times-likely-develop-mental-illness.html#v-3789507278001

Read more: http://www.dailymail.co.uk/health/article-3321143/Could-runny-nose-make-depressed-Hay-fever-sufferers-four-times-likely-develop-mental-illness.html#ixzz3sHb4yitQ
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My friend and I were talking

Recently, my friend “A” and I met for coffee. She is a part of a book club that decided to go to a movie without taking her schedule into account. Consequently, she couldn’t go. So she was feeling bad about being left out. I had gone through something like this many months ago, some people I know had decided to make a group video. Although I was part of this group, they did not ask me to be in the video. I was feeling left out because of this. I had spoken to my brother about my situation months earlier, and he had said not to wallow in self pity. He recommended that I simply get in touch with these people about including me for the video and tell them the reasons why I really belonged in it. I was going to do that, but the video project fell through. So I decided if there was ever a situation like this again, instead of feeling sorry for myself and feeling justifiably outraged and pitiful at the same time, I would contact people and let them know my feelings.

So when my friend “A” told me about her situation, I was sort of ready. I listened to her and told her exactly what my brother had told me, i.e. to not wallow in self pity because someone didn’t include her, but to contact people and let them know that you would like to be a part of this little soiree. Basically, speak up instead of feeling sorry for yourself.

It is so much better to take control and advocate for your self than to sit and do the “Poor me” thing! It is empowering and strengthening rather than feeling bad and weak and unwanted.

And one more thing, I love this! My sister sent me this video of Oprah, so, so, so empowering. I must share it with my blogger friends and readers!

OPRAH

http://www.supersoul.tv/supersoul-sessions/your-own-truth/

 

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Bacterial protein can help convert stem cells into neurons

Korean scientists have found a way to make stem cells differentiate into neurons by using a two step method. Stem cells are cells that are capable of becoming or differentiating into any cell type in the body. They are the progenitor cells. This Korean group serendipitously discovered that a protein from the bacterium E. coli, called Skp, upon bonding to a stem cell protein called Sox2, suppresses their “sremness” as they call it. Then when these suppressed stem cells are exposed to two small molecules called Neurodazine and Neurodazole, they differentiate into neurons! This is a good way to get neurons in large quantities. Then these neurons can be used for various therapies. For example, stem cells (without prior differentiation) have been used as a treatment for Parkinson’s disease with good results.

This is a great discovery as one can have the cells one needs beforehand and can lead to treatments for many diseases. 

http://www.neuroscientistnews.com/research-news/bacterial-protein-can-help-convert-stem-cells-neuronsAs the recipe book for turning stem cells into other types of cells keeps growing larger, the search for the perfect, therapeutically relevant blend of differentiation factors is revealing some interesting biology. A study published in Chemistry & Biology, for example, found that a protein in E. coli bacteria combined with small molecules can act synergistically to push pluripotent cells into functional neurons.

The research began when Sungkyunkwan University scientists in Korea made a serendipitous discovery that Sox2–one of the four Yamanaka factors that affect a stem cell’s ability to remain a stem cell or differentiate–can bind to a bacterial chaperone protein, Skp. They then tested what would happen if Skp was introduced into stem cells and found that it could initiate differentiation. This led to the hypothesis that Skp could be combined with other techniques to make differentiation more efficient.

“Although there has been considerable research in this field, there is still a bottleneck in being able to produce a high number of stem cells efficiently,” says study co-author Kyeong Kyu Kim, of the Sungkyunkwan University School of Medicine. “This problem can be solved, but we need to look for new ways to guide stem cell differentiation and then understand the molecular mechanisms underlying improved protocols.”
Injae Shin of Yonsei University and Kim say that the differentiation of pluripotent stem cells can be conceived as two simple steps: first, a stem cell decides to no longer be a stem cell and begins to differentiate; second, the cell decides what kind of cell it wants to be. In their protocol to induce neuron differentiation, the bacterial protein Skp acts in the first step by binding to Sox2 and inhibiting its function. The small chemicals neurodazine (Nz) and neurodazole (Nzl) then act in the second step by telling the stem cell to become a neuron.
By influencing both steps, more functional neurons can be produced per batch of stem cells and at a faster rate if using either protein or small molecules alone. “The synergy thus mainly arises from combining suppression of stemness by protein and directing lineage-specific commitment by chemical inducers,” Shin says. “Hence this process stands as an example of rationally designed cell differentiation to achieve a high level of lineage commitment efficiency.”

One weakness of the protocol is that there are safety concerns around using bacterial proteins such as Skp in a therapeutic setting. However, using this protein is advantageous compared to introducing genetic elements because protein cannot cause any genetic alteration or instability, which are the major concerns of using virus-mediated gene delivery to the stem cells. The authors hope that this study can encourage others to develop similar approaches based on small molecule mimics of the first stage of stemness suppression.
They are now working on using similar combinatorial approaches to explore how to make differentiation more efficient in other cell types, particularly those in the heart.

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Yin and yang of serotonin neurons in mood regulation

IMG_9892

http://www.sciencedaily.com/releases/2015/11/151119134012.htm

More nuanced view of brainstem neurons could lead to better drugs for depression, anxiety

Low levels of serotonin in the brain are known to play a role in depression and anxiety, and it is customary to treat these disorders with medications that increase the amount of this neurotransmitter. However, a new study carried out by researchers at Columbia University Medical Center (CUMC) suggests that this approach may be too simple. It appears that neighboring serotonin-producing brainstem regions exert different and sometimes opposing effects on behavior.

The findings, published in the online edition of Cell Reports, provide new insights into the development of mood disorders and may aid in designing improved therapies.

“Our study breaks with the simplistic view that ‘more is good and less is bad,’ when it comes to serotonin for mood regulation,” said study leader Mark S. Ansorge, Ph.D., assistant professor of psychiatry at CUMC and research scientist at New York State Psychiatric Institute. “Rather, it tells us that a more nuanced view is necessary.”

From anatomical studies, researchers knew that the brainstem contains two distinct clusters of serotonergic neurons: one in dorsal raphe nucleus (DRN) and another in the median raphe nucleus (MRN). Together both regions harbor the vast majority of neurons that supply serotonin to the rest of the brain, but it was unclear how neuronal activity within these clusters controls behavior.

To learn more, the CUMC team used a technique called pharmacogenetics to control the activity of serotonergic neurons in the DRN and MRN in both normal mice and in a mouse model of depression- and anxiety-like behavior. (The model was created by giving mice the drug fluoxetine shortly after birth, which produces long-lasting behavioral changes.)

The experiments revealed that alterations in serotonergic neuronal activity in the DRN and MRN produce markedly different behavioral consequences.

“Going into the study, our hypothesis was that reduced activity of serotonergic neurons is what drives these mood behaviors,” said Dr. Ansorge. “But what we found was more complicated. First, it appears that hyperactivity of the MRN drives anxiety-like behavior. We also observed that decreased DRN activity increases depression-like behavior, while decreased MRN activity reduces it. This led us to conclude that an imbalance between DRN and MRN activity is what leads to depression-like behavior.”

“This new understanding of the raphe nuclei should help us better understand why certain medications are effective in treating depression and anxiety, and aid in designing new drugs,” Dr. Ansorge added. “In the future, it may be possible to find treatments that selectively target the DRN or the MRN, or that correct any imbalance between the two.”

Jeffrey Lieberman, M.D., chair of the department of psychiatry at CUMC, observed that “Neurobiological studies such as this are essential to elucidate the molecular mechanisms of antidepressant treatments and to develop more effective therapies.”

The study also demonstrated, in experiments using the fluoxetine-treated mice, that inhibition of serotonin reuptake early in life leads to long-lasting imbalances between the DRN and MRN. “This raises possible concerns about exposure to serotonin-specific reuptake inhibitors during gestation,” said Dr. Ansorge. “SSRIs cross the blood-brain barrier as well as the placenta, and bind maternal and fetal serotonin transporters alike. It’s too early to say whether this has any effect on behavior in humans, but it’s certainly something worth looking into.”

Story Source:

The above post is reprinted from materials provided byColumbia University Medical Center. Note: Materials may be edited for content and length.

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New Nerve Drugs May Finally Prevent Migraine Headaches

migraine

http://www.scientificamerican.com/article/new-nerve-drugs-may-finally-prevent-migraine-headaches/

The 63-year-old chief executive couldn’t do his job. He had been crippled by migraine headaches throughout his adult life and was in the middle of a new string of attacks. “I have but a little moment in the morning in which I can either read, write or think,” he wrote to a friend. After that, he had to shut himself up in a dark room until night. So President Thomas Jefferson, in the early spring of 1807, during his second term in office, was incapacitated every afternoon by the most common neurological disability in the world.

The co-author of the Declaration of Independence never vanquished what he called his “periodical head-ach,” although his attacks appear to have lessened after 1808. Two centuries later 36 million American migraine sufferers grapple with the pain the president felt. Like Jefferson, who often treated himself with a concoction brewed from tree bark that contained quinine, they try different therapies, ranging from heart drugs to yoga to herbal remedies. Their quest goes on because modern medicine, repeatedly baffled in attempts to find the cause of migraine, has struggled to provide reliable relief.

Now a new chapter in the long and often curious history of migraine is being written. Neurologists believe they have identified a hypersensitive nerve system that triggers the pain and are in the final stages of testing medicines that soothe its overly active cells. These are the first ever drugs specifically designed to prevent the crippling headaches before they start, and they could be approved by the U.S. Food and Drug Administration next year. If they deliver on the promise they have shown in studies conducted so far, which have involved around 1,300 patients, millions of headaches may never happen.

“It completely changes the paradigm of how we treat migraine,” says David Dodick, a neurologist at the Mayo Clinic’s campus in Arizona and president of the International Headache Society. Whereas there are migraine-specific drugs that do a good job stopping attacks after they start, the holy grail for both patients and doctors has been prevention.

Migraine attacks, which affect almost 730 million people worldwide, typically last from four to 72 hours. Most sufferers have sporadic migraines and are laid low during 14 or fewer days a month. Those with a chronic form—almost 8 percent of the migraine population—suffer 15 or more monthly “headache days.” Attacks are often preceded by fatigue, mood changes, nausea and other symptoms. About 30 percent of migraine patients experience visual disturbances, called auras, before headaches hit. The total economic burden of migraine in the U.S., including direct medical costs and indirect costs such as lost workdays, is estimated at $17 billion annually.

In the 5,000 years since migraine symptoms were first described in Babylonian documents, treatments have reflected both our evolving grasp and our almost comical ignorance of the condition. Bloodletting, trepanation and cauterization of the shaved scalp with a red-hot iron bar were common treatments during the Greco-Roman period. The nadir of misguided remedies was probably reached in the 10th century a.d., when the otherwise discerning ophthalmologist Ali ibn Isa recommended binding a dead mole to the head. In the 19th century medical electricity had become all the rage, and migraine patients were routinely jolted with a variety of inventions, including the hydroelectric bath, which was basically an electrified tub of water.

By the early 20th century clinicians turned their attention to the role of the blood vessels, inspired in part by observations of strong pulsing of the temporal arteries in migraine patients, as well as patients’ descriptions of throbbing pain and the relief they got from compression of the carotid arteries. For decades to come, migraine pain would be blamed primarily on the dilation of blood vessels (vasodilation) in the brain.

That idea was reinforced in the late 1930s with the publication of a paper on the use of ergotamine tartrate, an alkaloid that was known to constrict blood vessels. Despite an array of side effects, among them vomiting and drug dependence, it did stop attacks in a number of patients.

But if vasodilation was part of the puzzle, it was not the only thing going on in the brains of migraine sufferers, as the next wave of treatments suggested. In the 1970s cardiac patients who also had migraines started telling their doctors that the beta blockers they were taking to slow rapid heartbeats also reduced the frequency of their attacks. Migraine sufferers taking medicines for epilepsy and depression, and others receiving cosmetic Botox injections, also reported relief. So headache specialists began prescribing these “borrowed” drugs for migraines. Five of the medications eventually were approved by the FDA for the condition. Unfortunately, it is still not known exactly how the adopted drugs (which are effective in only about 45 percent of cases and come with an array of side effects) help migraines. Dodick says they may act at various levels of the brain and brain stem to reduce excitability of the cortex and pain-transmission pathways.

The first migraine-specific drugs, the triptans, were introduced in the 1990s. Richard Lipton, director of the Montefiore Headache Center in New York City, says triptans were developed in response to the older idea that the dilation of blood vessels is the primary cause of migraine; triptans were supposed to inhibit it. Ironically, subsequent drug studies show that they actually disrupt the transmission of pain signals in the brain and that constricting blood vessels is not essential. “But they work anyway,” Lipton says. A survey of 133 detailed triptan studies found that they relieved headache within two hours in 42 to 76 percent of patients. People take them to stop attacks after they start, and they have become a reliable frontline treatment for millions.

What triptans cannot do—and what Peter Goadsby, director of the Headache Center at the University of California, San Francisco, has dreamed about doing for more than 30 years—is prevent migraine attacks from happening in the first place. In the 1980s, in pursuit of this goal, Goadsby focused on the trigeminal nerve system, long known to be the brain’s primary pain pathway. It was there, he suspected, that migraine did its dirty work. Studies in animals indicated that in branches of the nerve that exit from the back of the brain and wrap around various parts of the face and head, overactive cells would respond to typically benign lights, sounds and smells by releasing chemicals that transmit pain signals and cause migraine. The heightened sensitivity of these cells may be inherited; 80 percent of migraine sufferers have a family history of the disorder.

Goadsby co-authored his first paper on the subject in 1988, and other researchers, including Dodick, joined the effort. Their goal was to find a way to block the pain signals. One of the chemicals found in high levels in the blood of people experiencing migraine is calcitonin gene-related peptide (CGRP), a neurotransmitter that is released from one nerve cell and activates the next one in a nerve tract during an attack. Zeroing in on CGRP and interfering with it was hard. It was difficult to find a molecule that worked on that neurotransmitter and left other essential chemicals alone.

As biotech engineers’ ability to control and design proteins improved, several pharmaceutical companies developed migraine-fighting monoclonal antibodies. These designer proteins bind tightly to CGRP molecules or their receptors on trigeminal nerve cells, preventing cell activation. The new drugs are “like precision-guided missiles,” Dodick says. “They go straight to their targets.”

It is that specificity, and the fact that scientists actually know how the drugs work, that has Dodick, Goadsby and others excited. In two placebo-controlled trials with a total of 380 people who had severe migraines up to 14 days per month, a single dose of a CGRP drug decreased headache days by more than 60 percent (63 percent in one study and 66 percent in the other). In addition, in the first study, 16 percent of the patients remained totally migraine-free 12 weeks into the 24-week trial. Larger clinical trials to confirm those findings are currently under way. So far the CGRP drugs work better at prevention than any of the borrowed heart or epilepsy drugs and have far fewer side effects. They are given to patients in a single monthly injection.

Migraine specialists are also exploring other treatments, including forehead and eyelid surgery to decompress branches of the trigeminal nerve, as well as transcranial magnetic stimulation (TMS), a noninvasive way of altering nerve cell activity.

Lipton says he has had some good results with TMS. He has also referred patients for surgical interventions but says the experience “has been disappointing,” and he is not recommending it. For his part, Goadsby views surgeries and high-tech efforts as a kind of desperation: “They strike me as a cry for help. If we better understood migraine, we’d know better what to do.”

Even though the cause now appears rooted in the trigeminal nerve system, the origin of its overactive cells is still a mystery, Goadsby says. “What’s the nature of what you inherit when you inherit migraine?” he asks. “Why you, and why not me?” If researchers untangle the genetics of migraine, Jefferson’s “periodical head-ach” may loosen its painful modern grip.