Scientists ‘create’ a tiny brain

For the first time, scientists have grown a brain in a dish.

In a study published in the journal Nature last month, Austrian researchers used human induced pluripotent stem cells or embryonic stem cells and a combination of specialized growth conditions to produce “cerebral organoids.”

Within these organoids, the authors can define many, but not all, of the discrete brain regions found in the human brain. The organization of these regions in relation to one another is not the same as in a human brain, and the connectivity between brain regions is not intact. Nonetheless, some of these regions, including the cerebral cortex, are internally organized exactly as they would be in the human brain. The organoids are developmentally similar to a 9-week old embryo (about the size of a pea), making them a great model for studying early human brain development.

The authors used these miniature brains to make a new discovery about the molecular basis of a disease called microcephaly, where brain size is severely reduced. This disease has been difficult to study using animal models, because the brain regions that malfunction in the human disease don’t exist in many other animals. Importantly, the researchers used induced pluripotent stem cells isolated from the skin of human patients with microcephaly to grow the diseased organoids. Modeling the disease in this way, the researchers come as close as possible to a tailored view of the malfunction that occurred in these same patients during brain development in utero.

The authors do emphasize that it is impossible to grow an entire human brain in a dish — so we are a far cry from Mary Shelley’s Frankenstein. But there is no doubt that cerebral organoids will be a great tool to study many of the complicated pathways that converge for early development of the human brain to proceed properly. By studying these processes in a dish in the lab, scientists have the benefit of examining development in real-time, instead of relying on snap shots from tissue isolated during different developmental time points. Researchers can also manipulate the growth and nutrient environments of the organoids, as well as perform genetic manipulations and drug treatments to tease apart different aspects of brain development. Future studies using these miniature brains may even pave the way for new therapeutic treatments for some developmental diseases.

Kateri Spinelli, Ph.D.
Post doctoral fellow, Dept. of Neurology
OHSU Brain Institute

Should MS drugs cost more than $40,000 a year?

I have been treating people with multiple sclerosis, or MS, for 30 years. While some people with MS have a very mild case — we call that “benign” MS — most do not.  Typically, people develop the illness as young adults and have to contend with the illness for decades. Untreated, over time, most people with MS become permanently disabled. Many lose the ability to walk, become too disabled to work, have thinking problems and a host of other physical, psychological and social problems that result from the illness.

I don’t like MS and am tired of seeing people’s lives limited by the illness.

For the first 10 years of my career, I had no medications that I could prescribe to control MS. But in 1993, the first drug that could alter the course of the disease was approved by the Food and Drug Administration for treating early MS. Now there are 10 FDA-approved drugs for treating MS. None of these drugs cures the illness and none reverses damage that has already happened. They do control the illness and I have no doubt that they help people with MS, particularly if started early. I see far fewer people with MS becoming disabled than I did during the first 10 years of my career when we had no medications. These medications clearly are beneficial to people with MS when used properly.

The MS medications have side effects, and sometimes these are very serious. Some require injecting yourself one or more times a week. Some suppress the immune system, which may cause long-term side effects. However, when used properly, people with MS can take these medications safely and the treatments are definitely better than the illness.

There is a problem, however. These medications are incredibly expensive. The medications all cost more than $40,000 a year! And since the medications are not cures, people take these medications year after year. I am often asked by patients with MS: “Why do these medicines cost so much?” And my answer is: “I don’t know.”

How drug prices for medications are set is a secret. The usual answer from the pharmaceutical companies is that it costs lots of money to develop the drugs and get final FDA approval. But that is only part of the answer. The cost of developing the drugs first released by the FDA for treating MS — Betaseron, Avonex and Copaxone — have long since been recovered, yet the price of these drugs keeps going up. When these drugs were first introduced in the mid-1990s, their cost was about $15,000 a year.  They now cost more than $40,000. Had their cost just kept up with inflation, they should cost half that amount.

What about competition? Shouldn’t that be bringing the prices down? Well, just the opposite has occurred. In the past few years, each new drug that has come on the market has had a higher price than already approved drugs and this has resulted in prices for all the drugs going up. In 2010, when the first oral drug for MS — Gilenya  — was released, it cost more than any other MS drug, at $48,000 a year. This led to increases of all of the older drugs by as much as 39 percent.. And the prices have only continued to rise. It seems that the pharmaceutical companies making these drugs are charging more and more because they can get away with it.

All of the pharmaceutical companies have programs to reduce the impact of these costs for patients. For those with private insurance, the companies have co-pay caps. For the uninsured and underinsured, they provide drugs at reduced cost or even free. Unfortunately, people on Medicare are not eligible for these programs, which affects not only older patients but also younger patients who have become disabled and qualify for Social Security Disability and Medicare.

These programs reduce some of the impact of the cost of these medications on the individual patient but they do nothing to reduce the cost to our health care system. There are over 500,000 Americans with MS and over half of them are on these medications. These medications cost our health care system billions of dollars per year.

Is there anything that we can do about these high costs? Patients, doctors and national organizations, like the National MS Society, need to speak out about the cost of these drugs. The NMSS has created a toolkit to help people engage the media or public officials on policies and programs that impact people living with multiple sclerosis. Engaging in these issues has never been easier — all you need is a computer with Internet access. For many with MS who are unable to leave home, such a toolkit can serve as their platform — whether they start a petition, join a patient group, blog about the desire for affordable medication or write their member of Congress.

Physicians need to speak out too. Oncologists at Memorial Sloan-Kettering Cancer  Center recently refused to prescribe a new cancer drug because it was too expensive and not superior to other less expensive drugs. Recently, more than 100 oncologists —  including the OHSU Knight Cancer Institute’s Brian Druker — published a paper in the journal Blood, which is the journal for the American Society for Hematology. They argued that the cost of medications for cancer were often too high and that the high prices may be harming patients. Neurologists need to take a similar position with regard to medications for MS and other expensive medications for neurologic diseases.

We have made significant advances in treating MS over the past 20 years but we need to work together to break down barriers to care, improve access to quality health services and support funding for more MS research.  With your help and voice, we can turn MS issues, like more affordable treatments, into national priorities.

Dennis Bourdette, M.D.
Professor and Chair, Department of Neurology
OHSU Brain Institute

From laboratory to farm: a scientist’s visit to the local herb farm

As a basic scientist, most of my neuroscience training and research has focused on the underlying biological mechanisms of disease. During the past year, I have started working with a natural compound in my research on Parkinson’s disease. Curcumin, the active ingredient in turmeric spice, can act as an anti-oxidant and anti-aggregation agent, and may have a positive effect on the Lewy bodies found in Parkinson’s patients.

At first, I was a bit skeptical about natural compounds and alternative therapies. But as I’ve read more of the literature, attended conferences, and talked with other researchers in the field, I have hope that research on natural compounds could lead to potential therapies. However, for most compounds, many more studies are needed. For a clinician’s perspective on recommending natural compounds to his Alzheimer’s patients, see Dr. Joe Quinn’s post from a few months ago.

I and a few other OHSU scientists recently took an educational trip to the herbal supplement company Oregon’s Wild Harvest farm in Sandy, Ore. Prior to this trip, I had very little knowledge about how herbs were processed into supplements, or into the compounds that I use in the lab. My colleagues and I gave short presentations on our research projects involving natural compounds, and the Oregon’s Wild Harvest staff were engaged with and curious about our experimental findings. We then took a tour of the farm and production facilities. I was impressed with the streamlined process of testing the herbs for quality control, drying and combining particular herbs into supplements, and finally packaging the supplements into capsules for bottling and labeling — all done in a few small buildings on a family-owned farm, practically right in my own back yard.

It just so happened that Oregon’s Wild Harvest, or OWH, was producing its turmeric supplement during my visit, which I was very curious about since it is the natural compound I’m investigating in Parkinson’s. It was interesting and informative to compare notes with the company’s staff about which turmeric forms they put in their supplements and why.

Observing the front end of herbal supplement production gave me a new perspective on how my research is connected to the bigger picture. As a neuroscientist, I always strive to see the “connections” between my research in the lab and other sectors of society. I now have a better understanding of how curcumin is transformed from the root of a plant to the compound I use in the laboratory. It was refreshing to interact with the founders and staff of OWH, who approach natural compounds from the farmer’s and manufacturer’s point of view — a perspective that is good to keep in mind as my research progresses forward.

While natural supplements and alternative therapies are becoming more main stream, clinical trials using natural compounds, including curcumin, to treat neurological diseases have been disappointing thus far. However, a few of the scientific studies currently underway at OHSU are giving some exciting positive results. As the scientific community continues to investigate potential therapeutic applications for natural compounds, I believe it’s important for us to also stay connected to where and how these compounds are derived.

Kateri Spinelli, Ph.D.
Post doctoral fellow, Dept. of Neurology
OHSU Brain Institute

What causes a migraine?

“I have a pounding headache!”

We’ve all heard that lament – from a friend or family member, and very likely felt one ourselves. That throbbing, pounding head pain that makes it hard to think, much less do everything we need to do.

According to surveys, more than 10 percent of the U.S. population suffers from migraine headaches. Women are more frequent sufferers than men, with up to 25 percent of women experiencing migraines, but less than 10 percent of men. Migraines often have a range of symptoms, including nausea, light sensitivity, and a visual disturbance called an “aura.” But the predominant and common symptom among almost all migraine sufferers is headache pain. Available treatments for migraine pain leave much to be desired. Relief is rarely complete, and most patients have to try several drugs before finding one that is at least partially effective.

Plus, the treatments themselves can cause headaches! This phenomenon, referred to as “medication overuse headache” or MOH, is very common. As the individual takes his or her headache medicine more and more frequently, the medicine itself causes more and more headaches, a painful vicious cycle that can be broken only by stopping all drug treatment. MOH can be triggered even by over-the-counter agents like aspirin.

So what causes headaches? Migraines have long been referred to by doctors as “neurovascular” headaches, because the pain had been thought to arise from distension of the blood vessels in the head. This theory was based in part on the pulsing character of the pain, which was attributed to stretching of the vessels as the heart beats. In addition, although the brain itself lacks pain sensors, patients undergoing brain surgery reported pain when vessels inside the head were stimulated. Further bolstering this idea, many of the drugs that have been used for migraine treatment can constrict blood vessels, and some drugs that dilate blood vessels can cause headaches, at least in some people.

However, this idea of blood vessels as the source of headache has recently been viewed with increasing skepticism by headache researchers. Not all effective anti-migraine agents constrict blood vessels in the head, and evidence that blood vessels were dilated during migraine was weak at best. On top of this, a couple of recent studies have found that the throbbing pain of the migraine is not in synch with the heartbeat.

With the demise of the blood vessel theory, we are now starting to recognize that migraine is a disorder of the brain itself. The throbbing character of migraine pain was recently found to be correlated with certain brain waves, the so-called “alpha” waves, although this has so far been studied only in one patient. There are also a whole host of migraine triggers, ranging from foods to hormones, to light and stress. The tremendous variety of stimuli that can trigger a migraine implies that there are many brain systems that feed into the pathways that ultimately give rise to headache. We also know that people with migraine can be more sensitive to many sensations, even between migraine attacks.  This implies that the “migraine brain” is more alert and poised to respond to any input. We also know from animal studies that the pain-facilitating system in the brain contributes to headache-related pain. (See my earlier blog post about how your brain controls pain.)

What does all of this mean for migraine sufferers? The demise of the blood vessel theory is important, because it tells us that we should focus our attention on the brain itself when trying to help migraine patients. The fact that the source of the pain is the brain also means patients and their doctors should consider the full range of factors that can trigger pain in a “migraine brain” — things like diet, stress, exercise, hormones, or even just bright light.

Finally, without adequate treatment, occasional migraines can become more and more frequent, due to changes in the brain itself. This makes it important to seek treatment — if necessary from a headache specialist — to control migraines before they become a chronic daily event.

Mary Heinricher, Ph.D.
Professor, departments of Neurological Surgery and Behavioral Neuroscience
OHSU Brain Institute

‘Neuroprotection’: an elusive goal in fighting brain diseases

About 15 years ago, I wrote an article about treating Alzheimer’s disease that divided treatments into two categories: “symptomatic” and “neuroprotectant.”

There were real options in the former category. But the “neuroprotectant” idea was more theoretical — more of a “coming attractions” approach — citing the studies that were underway to identify treatments that would actually save brain cells, protecting those neurons from further harm, and actually slowing or arresting the disease process.

Sadly, despite 15 years of research since, neuroprotection has not come to pass for Alzheimer’s disease, nor for the next most common neurodegenerative diseases — Parkinson’s disease and Lou Gehrig’s disease, also known as ALS. In fact, despite the fact that arresting disease progression is the most important goal for any neurodegenerative disease, we do not have a single proven neuroprotectant strategy.

A story in Neurology Today last month describes the latest failed attempts in ALS: a clinical trial testing a drug named “ceftriaxone” in 500 patients and a second trial testing “dexpramipexole”  in 1,000 patients. The second one was the largest clinical trial so far in ALS. Both studies found that the drugs failed to make any difference in patient outcomes, despite very strong “preclinical” and early clinical evidence justifying these multi-million-dollar studies.

Commentators pointed to two key factors:

1)   The disease being studied is a heterogeneous disease, so expecting to find a “one size fits all” treatment strategy may be fundamentally flawed.

2)   The trials did not incorporate measurements to show whether the drugs were “hitting the target.” So it is impossible to be sure whether these results mean that the overall strategies should be abandoned, or just this particular drug and dose.

The story struck a chord because these are the same issues that plague Alzheimer’s and Parkinson’s disease research, and the stories leave us with the same uncomfortable feeling that we need to do better than this.

We need to be more precise in defining our study population, and more aggressive about incorporating measures to show that we “hit the target” with our treatments.

Neuroprotection is absolutely the right goal, but we need to work harder and smarter to ensure that our clinical trials are robustly informative, even when they fail to show a treatment benefit.

Joseph Quinn, M.D.
Professor of Neurology
Layton Aging & Alzheimer’s Disease Center
OHSU Brain Institute

They’re not just in your head — functional neurological disorders

Functional or psychogenic neurological disorders are conditions with neurological symptoms that are thought to be due to psychological dysfunction rather than an underlying neurological disorder.

They can be classified as malingering if the person is intentionally having the symptoms. Perhaps someone is pretending an arm or leg is weak after a car accident in hopes of getting compensation from the other driver. However, in most cases, the symptoms are not conscious or voluntary. Common symptoms include blackout spells, the inability to move a limb or abnormal movements. We now know that although there is not a neurological condition like a stroke or a seizure in these cases, people who have functional disorders have brains that function a bit differently.

These disorders have been given many names —  including psychogenic, functional, non-organic, and dissociative. It is common for persons with these disorders to struggle to find care. Neurologists often feel that since there is not a clear neurological condition such as a seizure disorder, a stroke or Parkinson’s, they do not need to treat these disorders. Psychiatrists and psychologists often feel uncomfortable because of the appearance of neurological symptoms. Persons with these disorders often feel they are not being taken seriously, feel they are being told they are faking it or are “crazy.” Some estimates indicate that up to one-third of patients seeking new consultation by a neurologist have functional symptoms.

It is important that persons with these disorders are diagnosed correctly so that they are not exposed to unnecessary tests and inappropriate treatments. Many tests have risks and almost all medications have potential side effects.

It also is important that persons with these disorders are open to the correct diagnosis so that they can pursue proper treatment. With treatment, the symptoms can often improve and even go away entirely. A website produced by a Scottish neurologist who specializes in these disorders explains things in much more detail and can help a person understand his or her symptoms and the disorder better.

Treatment is often multidisciplinary, involving a neurologist, physical therapist and psychiatrist or psychologist. Not all persons need all of these groups involved. But a group approach where everyone is aware and comfortable with the diagnosis is often the best hope for a successful outcome.

Amie Peterson, M.D.
Assistant Professor of Neurology
OHSU Parkinson Center of Oregon
OHSU Brain Institute

Brain News Roundup: ‘Seeing’ emotions, concussions and ‘multi-tasking’

Scientists can now see “sad” and “happy” in our brains. More news on the impact of concussions, including long-term impacts. And a roundup of more brain news, including fatherhood and our (mistaken) belief about how well we multi-task.

Scientists have discovered a way to “see” emotions with brain imaging technology, according to a recent study. Beyond being just plain fascinating, scientists hope the findings could bring a new way to analyze emotions beyond people’s self-reporting.

• People are becoming increasingly aware how often athletes are suffering concussions. Now scientists have measured the long-term effects of a basic soccer move — heading the ball — on  the brain. And the news is not good.

• Also, scientists have discovered how brain abnormalities linked to concussions are similar to abnormalities related to Alzheimer’s.

• Meanwhile, brain researchers are finding that it’s not just females hormones that change with motherhood; there are also very specific hormonal brain changes associated with fatherhood.

• And finally … multi-tasking? Talking on your cell phone while you’re driving your car? Or doing your real work while you’re reading this (for instance)?  You’re not as good at it as you think you are.

 

Todd Murphy
Senior Communications Specialist
OHSU Brain Institute

The continuing search for the answer to Alzheimer’s disease

Alois Alzheimer, a German physician in 1906, was studying a woman who came to his clinic complaining about memory loss, language problems, and behavioral changes. She ultimately died of complications from her illness. After her death, Dr. Alzheimer examined her brain and found abnormal protein clumps, now referred to as amyloid deposits, and bundles of fibers, now called neurofibrillary tangles. The dementia exhibited by this patient acquired the name Alzheimer’s dementia because of its discovery by Dr. Alzheimer.

In current studies of post mortem brains from patients who have died from Alzheimer’s disease, the research also revealed amyloid deposits and neurofibrillary tangles in almost all cases.  These two protein accumulations are considered the major hallmarks of Alzheimer’s disease.

At the beginning of the disease process, these protein accumulations appear mainly in the hippocampus, a brain region that is critical in learning and the formation of memories. As the disease spreads, so do these protein deposits to other brain regions. Other studies have revealed multiple cellular changes – including synapses that lose their ability to connect with synapses from other brain cells — in the brains of patients with early-onset familial Alzheimer’s and late-onset sporadic Alzheimer’s. Synaptic loss has been found to be the best correlate of cognitive decline in patients with Alzheimer’s.

During the last three decades, Alzheimer’s researchers have worked to better understand how both amyloid beta and another protein called tau are associated with cognitive decline in Alzheimer’s disease.

Some researchers believe amyloid beta plays the more important role; other researchers believe tau also plays a very important role.

Recent clinical trials that focused on using drug inhibitors to limit amyloid beta levels in the brain were disappointing; the drugs did not improve patients’ cognitive function.

But those trials raised important questions in Alzheimer’s research:

  • Are the drugs targeting the right kind of amyloid beta?
  • Might the drugs help if patients were given them earlier, before the disease had advanced so far?
  • What might be the long-term consequences of these drugs, and
  • Do we need to better understand how tau might be affecting brain synapses, before we see clinical symptoms of Alzheimer’s?

I also believe that to better understand synaptic loss in Alzheimer’s, the interaction of amyloid beta and tau with each other needs to be better researched. My colleague and I recently published an article in the Journal of Alzheimer’s Disease that explored that question. My laboratory looked for evidence of amyloid beta and tau interactions. And we found that the Alzheimer’s disease process was strongest where those interactions happened.

More research needs to focus on molecules that might prevent or affect that amyloid beta/tau interaction. Those molecules might end up being an important treatment for Alzheimer’s, as they could significantly improve cognitive and memory functions for people who have this debilitating disease.

Hemachandra Reddy, Ph.D.
Associate Scientist, Division of Neuroscience
Oregon National Primate Research Center, OHSU

Recovering from stroke — through music

In the early 2000s, as part of the OHSU Stroke Center, I saw disabled stroke patients make remarkable progress in their recoveries — simply by exerting a large amount of extra effort and determination in their rehab exercises.

The patients were part of a program led by an innovative OHSU physical therapist named Andrea Serdar. The program was within what is now known as the OHSU Outpatient Neurological Rehabilitation Department within the OHSU Brain Institute.

I loved to talk to Andrea about what might encourage more patients to put this kind of serious effort into their rehab.

And I thought about this later, when — of all things — I started to play ukulele and sing with friends on a weekly basis. Through trial and error, I started to learn what makes a recreational music group super successful, rewarding and long-lived. And it was not long before Andrea and I colluded to start a music group of our own — for stroke survivors.

We started the group in October 2011. And it did not take long to gain a regular group of about eight stroke survivors, and an amazing blues guitarist named Trace Wiren. The group, called Backstrokes, was just featured in a KOIN TV story.

About a year in, we realized that the speech of some of our members with expressive aphasia — the significantly decreased ability to use language, often because of a stroke — had noticeably improved, both in clarity of words and also the increased ability to get the words out. More recently, I have noticed that members with cognitive disabilities have noticeably improved in their ability to answer a question without wandering into another subject. When asked, members report an increased sense of independence, as well as the improvement with speech.

Because a large portion of the brain is used to experience music, scientists think that music is able to bypass the damaged area of the brain, and form new neural pathways.

On occasion, the beauty of our singing harmonies catches me by surprise. My favorite thing, by far, is when we finish a song, and we look around and we all know that we totally nailed it!

I look forward to the coming year, as we are determined to figure out how to find the financial and other support to reach more and more stroke survivors. We hope to accomplish this by taking our music group to stroke support groups and medical center inpatient units and skilled nursing facilities. Although people initially come to our group because they need help with their own recovery, it does not take long at all before they are able to help others in this way. This is an amazing transformation to witness, and is clearly empowering for the individuals in the group.

Anne Tillinghast
Administrative Coordinator, OHSU Stroke Center
OHSU Brain Institute

Stroke basics: Understand the symptoms, and call 911

“Dial 911 for emergencies.”

You think this is simple and obvious, right? It turns out that a recent study found that one-third of patients with stroke symptoms did not call 911 when they were having a stroke. Often, patients show up in the emergency room by having their families drive them or, even worse, by driving themselves.  Also, there are many instances that I know of personally where patients wait until the next day to call their primary care physician, especially if their symptoms have resolved.

It is important to seek emergent medical care quickly when it comes to stroke. As you have seen on this blog before, as well as on other stroke websites, the mantra of all stroke physicians is “Time is Brain.” The sooner one is assessed by medical professionals, the higher the chance that a stroke victim can get intravenous tPA, which is a clot-busting medication that can substantially improve one’s outcome after a stroke.

Calling 911 ensures that one gets the best stroke care possible. Emergency medical services knows to take patients to certified stroke centers — like OHSU’s — that have the proper tools necessary to treat stroke. In addition, having medical personnel assessing and starting treatment on a patient before he or she gets to the hospital can potentially save more brain cells. Lastly, families and patients can potentially drive dangerously when rushing to the hospital, which is an added risk.

It is also important to recognize stroke symptoms, as often they can be overlooked in family members, which can lead to delays in care. The American Stroke Association has been promoting stroke awareness during American Stroke Month in May. It promotes a F.A.S.T. checklist to recognize common symptoms:

Face Drooping — Does one side of the face droop, or is it numb?

Arm Weakness — If a person tries to raise both arms, does one drift downward?

Speech Difficulty — Is speech slurred, or hard to understand?

Time to call 911.

Other stroke symptoms: sudden numbness or weakness in a leg, sudden trouble seeing out of one or both eyes, dizziness, confused behavior and sudden severe headache with no apparent cause.

If you see anyone having a few of these symptoms at the same time — or if you are experiencing them yourself — immediately call 911 and get medical treatment. The time — and brain — you save could change the rest of your life.

Hormozd Bozorgchami, M.D.
Instructor, Oregon Stroke Center
OHSU Brain Institute

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