8 Things To Remember When Everything Is Going Wrong. Stopping #3 Changed My Life

Marc and Angel  are two passionate writers, life-hackers, and the authors of 1000 Little Things Happy Successful People Do Differently. Here’s their list of 8 things to remember when everything goes wrong.

“Today, I’m sitting in my hospital bed waiting to have both my breasts removed. But in a strange way I feel like the lucky one. Up until now I have had no health problems. I’m a 69-year-old woman in the last room at the end of the hall before the pediatric division of the hospital begins. Over the past few hours I have watched dozens of cancer patients being wheeled by in wheelchairs and rolling beds. None of these patients could be a day older than 17.”

That’s an entry from my grandmother’s journal, dated 9/16/1977. I photocopied it and pinned it to my bulletin board about a decade ago. It’s still there today, and it continues to remind me that there is always, always, always something to be thankful for. And that no matter how good or bad I have it, I must wake up each day thankful for my life, because someone somewhere else is desperately fighting for theirs.

Truth be told, happiness is not the absence of problems, but the ability to deal with them. Imagine all the wondrous things your mind might embrace if it weren’t wrapped so tightly around your struggles. Always look at what you have, instead of what you have lost. Because it’s not what the world takes away from you that counts; it’s what you do with what you have left.

Here are a few reminders to help motivate you when you need it most:

#1. Pain is part of growing. Sometimes life closes doors because it’s time to move forward. And that’s a good thing because we often won’t move unless circumstances force us to. When times are tough, remind yourself that no pain comes without a purpose. Move on from what hurt you, but never forget what it taught you. Just because you’re struggling doesn’t mean you’re failing. Every great success requires some type of worthy struggle to get there. Good things take time. Stay patient and stay positive. Everything is going to come together; maybe not immediately, but eventually.

Remember that there are two kinds of pain: pain that hurts and pain that changes you. When you roll with life, instead of resisting it, both kinds help you grow.

#2. Everything in life is temporary. Every time it rains, it stops raining. Every time you get hurt, you heal. After darkness there is always light – you are reminded of this every morning, but still you often forget, and instead choose to believe that the night will last forever. It won’t. Nothing lasts forever.

So if things are good right now, enjoy it. It won’t last forever. If things are bad, don’t worry because it won’t last forever either. Just because life isn’t easy at the moment, doesn’t mean you can’t laugh. Just because something is bothering you, doesn’t mean you can’t smile. Every moment gives you a new beginning and a new ending. You get a second chance, every second. You just have to take it and make the best of it. (Read The Last Lecture.)

#3. Worrying and complaining changes nothing. Those who complain the most, accomplish the least. It’s always better to attempt to do something great and fail than to attempt to do nothing and succeed. It’s not over if you’ve lost; it’s over when you do nothing but complain about it. If you believe in something, keep trying. Don’t let the shadows of the past darken the doorstep of your future. Spending today complaining about yesterday won’t make tomorrow any brighter. Take action instead. Let what you’ve learned improve how you live. Make a change and never look back.

And regardless of what happens in the long run, remember that true happiness begins to arrive only when you stop complaining about your problems and you start being grateful for all the problems you don’t have.

#4. Your scars are symbols of your strength. Don’t ever be ashamed of the scars life has left you with. A scar means the hurt is over and the wound is closed. It means you conquered the pain, learned a lesson, grew stronger, and moved forward. A scar is the tattoo of a triumph to be proud of. Don’t allow your scars to hold you hostage. Don’t allow them to make you live your life in fear. You can’t make the scars in your life disappear, but you can change the way you see them. You can start seeing your scars as a sign of strength and not pain.

Rumi once said, “The wound is the place where the Light enters you.” Nothing could be closer to the truth. Out of suffering have emerged the strongest souls; the most powerful characters in this great world are seared with scars. See your scars as a sign of “YES! I MADE IT! I survived and I have my scars to prove it! And now I have a chance to grow even stronger.”

#5. Every little struggle is a step forward.

In life, patience is not about waiting; it’s the ability to keep a good attitude while working hard on your dreams, knowing that the work is worth it. So if you’re going to try, put in the time and go all the way. Otherwise, there’s no point in starting. This could mean losing stability and comfort for a while, and maybe even your mind on occasion. It could mean not eating what, or sleeping where, you’re used to, for weeks on end. It could mean stretching your comfort zone so thin it gives you a nonstop case of the chills. It could mean sacrificing relationships and all that’s familiar. It could mean accepting ridicule from your peers. It could mean lots of time alone in solitude. Solitude, though, is the gift that makes great things possible. It gives you the space you need. Everything else is a test of your determination, of how much you really want it.

And if you want it, you’ll do it, despite failure and rejection and the odds. And every step will feel better than anything else you can imagine. You will realize that the struggle is not found on the path, it is the path. And it’s worth it. So if you’re going to try, go all the way. There’s no better feeling in the world… there’s no better feeling than knowing what it means to be ALIVE. (Angel and I discuss this in more detail in the “Goals and Success” chapter of 1,000 Little Things Happy, Successful People Do Differently.)

#6. Other people’s negativity is not your problem. Be positive when negativity surrounds you. Smile when others try to bring you down. It’s an easy way to maintain your enthusiasm and focus. When other people treat you poorly, keep being you. Don’t ever let someone else’s bitterness change the person you are. You can’t take things too personally, even if it seems personal. Rarely do people do things because of you. They do things because of them.

Above all, don’t ever change just to impress someone who says you’re not good enough. Change because it makes you a better person and leads you to a brighter future. People are going to talk regardless of what you do or how well you do it. So worry about yourself before you worry about what others think. If you believe strongly in something, don’t be afraid to fight for it. Great strength comes from overcoming what others think is impossible.

All jokes aside, your life only comes around once. This is IT. So do what makes you happy and be with whoever makes you smile, often.

7. What’s meant to be will eventually, BE. True strength comes when you have so much to cry and complain about, but you prefer to smile and appreciate your life instead. There are blessings hidden in every struggle you face, but you have to be willing to open your heart and mind to see them. You can’t force things to happen. You can only drive yourself crazy trying. At some point you have to let go and let what’s meant to be, BE.

In the end, loving your life is about trusting your intuition, taking chances, losing and finding happiness, cherishing the memories, and learning through experience. It’s a long-term journey. You have to stop worrying, wondering, and doubting every step of the way. Laugh at the confusion, live consciously in the moment, and enjoy your life as it unfolds. You might not end up exactly where you intended to go, but you will eventually arrive precisely where you need to be. (Read A New Earth.)

#8. The best thing you can do is to keep going. Don’t be afraid to get back up – to try again, to love again, to live again, and to dream again. Don’t let a hard lesson harden your heart. Life’s best lessons are often learned at the worst times and from the worst mistakes. There will be times when it seems like everything that could possibly go wrong is going wrong. And you might feel like you will be stuck in this rut forever, but you won’t. When you feel like quitting, remember that sometimes things have to go very wrong before they can be right. Sometimes you have to go through the worst, to arrive at your best.

Yes, life is tough, but you are tougher. Find the strength to laugh every day. Find the courage to feel different, yet beautiful. Find it in your heart to make others smile too. Don’t stress over things you can’t change. Live simply. Love generously. Speak truthfully. Work diligently. And even if you fall short, keep going. Keep growing.

Awake every morning and do your best to follow this daily TO-DO list:

Think positively. Eat healthy. Exercise today. Worry less. Work hard. Laugh often. Sleep well. Repeat…

Brenda McCarthy

“Everything is temporary, this too shall pass” is a phrase that always comes to my mind whenever things are not going well. All of these are excellent reminders. If you enjoyed this Marc and Angel’s tips, share them with your friends and family.

http://healthist.co/2015/12/23/8-things-to-remember-when-everything-is-going-wrong-stopping-3-changed-my-life-and-difference-between-term-life-and-whole-life/

Slower aging may protect cells in the brain from Parkinson’s disease

Humans have long sought to reduce the effects of aging. Now, there may be another reason to continue searching for ways to slow the clock–preventing Parkinson’s disease.

Parkinson’s disease is the second most common neurodegenerative disorder and affects seven to 10 million people worldwide. Symptoms include slowed movement, resting tremor, postural instability and rigidity, as well as non-motor issues such as dementia, loss of sense of smell, sleep disturbances, constipation and depression.

Scientists at Van Andel Research Institute (VARI) have shown in disease models that slowing aging reduces degeneration related to Parkinson’s. The study was published online Nov. 19 innpj Parkinson’s Disease, a new journal from Nature Publishing Group.

“It is unknown why symptoms take many decades to develop when inherited mutations that cause the disease are present from birth,” said Jeremy Van Raamsdonk, a VARI assistant professor and the study’s senior author. “Aging is the greatest risk factor for developing Parkinson’s–we believe changes that occur during the aging process make brain cells more susceptible to disease-causing mutations that don’t cause issues in younger people.”In the brain, Parkinson’s is marked by the dysfunction and death of the nerve cells that produce dopamine–a chemical that plays a key role in many important functions, including motor control. Clumps of a protein called alpha-synuclein also are found in brain cells of most people with Parkinson’s, although scientists are still trying to pin down their exact role.

As part of their search for ways to prevent the disease, Van Raamsdonk’s team delayed the aging process in genetic models of Parkinson’s disease. They demonstrated that slower aging imparts protection against the loss of dopamine-producing cells in the brain and decreases the formation of alpha-synuclein clumps–¬both hallmark features of Parkinson’s.

“This work suggests that slowing aging can have protective effects on the brain cells that otherwise may become damaged in Parkinson’s,” Van Raamsdonk said. “Our goal is to translate this knowledge into therapies that slow, stop or reverse disease progression.”

Slowing aging, preserving brain cell function the study, Van Raamsdonk and his team used the worm Caenorhabditis elegans as a genetic model for Parkinson’s. Thanks to its simple and well-mapped nervous system, and the ease of genetic manipulation and maintenance of the worm, C. elegans is well-suited for the identification of novel treatment strategies for neurodegenerative diseases.

Worm models of Parkinson’s disease that expressed either a mutated LRRK2 gene or a mutated alpha-synuclein gene–both of which cause Parkinson’s–were crossed with a long-lived strain of the worm to create two new strains with longer lifespans.

Van Raamsdonk’s team then compared the two original LRRK2 and alpha-synuclein models with normal lifespans to the resulting two long-lived Parkinson’s models, and found that long-lived LRRK2 and alpha-synuclein worms lost dopamine neurons at a much slower rate than their counterparts with normal lifespans. In fact, the long-lived LRRK2 worms had more dopamine neurons left on day 30 of the study than the LRRK2 worms with a normal lifespan of three weeks had on day eight of adulthood. Slowing aging also effectively reduced motor deficits related to the loss of dopamine-producing cells and eliminated the increased sensitivity to stress shown by worms with a normal lifespan.

From worms to people

The long-lived strain of C. elegans Van Raamsdonk used for the crosses has a mutation in daf-2, a gene that encodes for a member of the insulin and IGF1 signaling pathways. Genes in these pathways are also associated with longevity in humans; however, therapies that affect the pathways may need to be carefully controlled to mitigate potential side effects. As such, Van Raamsdonk plans to investigate this link in other Parkinson’s disease models and to search for additional pathways involved in longevity that have a lower risk of side effects, while still effectively slowing or preventing disease onset.

ABOUT VAN ANDEL RESEARCH INSTITUTE

Van Andel Institute (VAI) is an independent nonprofit biomedical research and science education organization committed to improving the health and enhancing the lives of current and future generations. Established by Jay and Betty Van Andel in 1996 in Grand Rapids, Michigan, VAI has grown into a premier research and educational institution that supports the work of more than 330 scientists, educators and staff. Van Andel Research Institute (VARI), VAI’s research division, is dedicated to determining the epigenetic, genetic, molecular and cellular origins of cancer, Parkinson’s and other diseases and translating those findings into effective therapies. The Institute’s scientists work in onsite laboratories and participate in collaborative partnerships that span the globe.

source

http://mymedclinic.info/?p=3231

Brain propagation of transduced α-synuclein involves non-fibrillar protein species and is enhanced in α-synuclein null mice.

Dec. 30, 2015

Aggregation and neuron-to-neuron transmission are attributes of α-synuclein relevant to its pathogenetic role in human synucleinopathies such as Parkinson's disease. Intraparenchymal injections of fibrillar α-synuclein trigger widespread propagation of amyloidogenic protein species via mechanisms that require expression of endogenous α-synuclein and, possibly, its structural corruption by misfolded conformers acting as pathological seeds.

 Here we describe another paradigm of long-distance brain diffusion of α-synuclein that involves inter-neuronal transfer of monomeric and/or oligomeric species and is independent of recruitment of the endogenous protein. Targeted expression of human α-synuclein was induced in the mouse medulla oblongata through an injection of viral vectors into the vagus nerve. Enhanced levels of intra-neuronal α-synuclein were sufficient to initiate its caudo-rostral diffusion that likely involved at least one synaptic transfer and progressively reached specific brain regions such as the locus coeruleus, dorsal raphae and amygdala in the pons, midbrain and forebrain. Transfer of human α-synuclein was compared in two separate lines of α-synuclein-deficient mice versus their respective wild-type controls and, interestingly, lack of endogenous α-synuclein expression did not counteract diffusion but actually resulted in a more pronounced and advanced propagation of exogenous α-synuclein. Self-interaction of adjacent molecules of human α-synuclein was detected in both wild-type and mutant mice. In the former, interaction of human α-synuclein with mouse α-synuclein was also observed and might have contributed to differences in protein transmission. In wild-type and α-synuclein-deficient mice, accumulation of human α-synuclein within recipient axons in the pons, midbrain and forebrain caused morphological evidence of neuritic pathology. Tissue sections from the medulla oblongata and pons were stained with different antibodies recognizing oligomeric, fibrillar and/or total (monomeric and aggregated) α-synuclein. 

Following viral vector transduction, monomeric, oligomeric and fibrillar protein was detected within donor neurons in the medulla oblongata. In contrast, recipient axons in the pons were devoid of immunoreactivity for fibrillar α-synuclein, indicating that non-fibrillar forms of α-synuclein were primarily transferred from one neuron to the other, diffused within the brain and led to initial neuronal injury. This study elucidates a paradigm of α-synuclein propagation that may play a particularly important role under pathophysiological conditions associated with enhanced α-synuclein expression. Rapid long-distance diffusion and accumulation of monomeric and oligomeric α-synuclein does not necessarily involve pathological seeding but could still result in a significant neuronal burden during the pathogenesis of neurodegenerative diseases.

by: Michael Helwig, Michael Klinkenberg, Raffaella Rusconi, Ruth E. Musgrove, Nour K. Majbour, Omar M. El-Agnaf, Ayse Ulusoy, Donato A. Di Monte © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. 

Fast Cycling Benefits Parkinson's Patients

Jan. 1, 2016

Cycling on stationary bikes may benefit people with Parkinson's disease, especially if they cycle hard and fast. This was the finding of a new study presented this week at a scientific meeting in the US, that describes how researchers found cycling, especially at rates above what patients would choose for themselves, appeared to make regions of the brain that deal with movement connect to each other more effectively.

Results of the study were revealed on Monday at the Radiological Society of North America 2012 Scientific Assembly and Annual Meeting in Chicago.

Parkinson's Disease

Approximately 7 to 10 million people worldwide live with Parkinson's disease, a chronic, progressive neurological disorder where part of the brain gradually becomes more damaged as the years go by. The main symptoms of the disease are movement related, and include shaking or tremor, muscle stiffness and rigidity, and slowness of physical movements (bradykinesia).  

Most cases occur after the age of 50, and as the disease progresses, cognitive and behavioral problems such as dementia, may also develop.

Idea for the Study Started on a Charity Ride

Study investigator Jay L. Alberts, a neuroscientist at the Cleveland Clinic Lerner Research Institute, first got the notion that exercise might be beneficial for Parkinson's patients during a 2003 charity cycle ride across Iowa, to raise awareness of Parkinson's disease. During that event he rode a tandem with a female Parkinson's patient, whose symptoms improved after the ride.

In a statement, in which he describes the finding as "serendipitous", Alberts recalls:

"I was pedaling faster than her, which forced her to pedal faster. She had improvements in her upper extremity function, so we started to look at the possible mechanism behind this improved function." 

What the Researchers Did

For their study, Alberts, co-researcher Chintan Shah, and other colleagues from the Cleveland Clinic, used functional connectivity magnetic resonance imaging (fcMRI) to investigate the effect of exercise on 26 patients aged from 30 to 75 with mild to moderate Parkinson's disease.

fcMRI measures changes in blood oxygen in the brain, which enables researchers to look at how active different brain regions are and how well they connect with each other, explains Shah.

The researchers randomly assigned the patients to one of two groups. One group (13 patients) cycled at their own voluntary pace, while the other group cycled at a forced rate.

The groups completed exercise sessions on stationary bikes three times a week for 8 weeks. Both groups underwent MRI scans at the start and the end of the period, and also after four weeks of follow up.

The forced rate group had bikes fitted with specially controlled motors to make them cycle faster than their voluntary rate, as Alberts explains:

"We developed an algorithm to control a motor on the bike and used a controller to sense the patient's rate of exertion and adjust the motor based on their input."

What they Found

Using the fcMRI data, the team then calculated brain activation and connectivity levels, and correlated them to average pedalling rates.

They found increases in task-related connectivity between the primary motor cortex and the posterior region of the brain's thalamus, and conclude that faster pedaling rate was the key factor in these improvements, which were still present at follow-up.

Some of the results were similar to patterns of activation during deep brain stimulation of Parkinson's patients, which is a costly and invasive treatment for late stage disease.

Effective, Low-Cost Therapy

Shah says their study suggests "forced-rate bicycle exercise is an effective, low-cost therapy for Parkinson's disease".

However, Alberts says while forced-rate pedalling appears to give better results, not all Parkinson's patients would need to do exercise so fast to see improvement:

"We're now looking at this phenomenon in patients with exercise bikes in their home; and other exercises like swimming and rowing on tandem machines may provide similar benefits," he adds.

Written by Catharine Paddock PhD

http://health.einnews.com/article_detail/304315636/04yyuo3mb6pplT0d?n=2&code=lAb0qDE0aV13cmUw

Parkinsonian Patients Show Different Brain Activity Tied to Balance

Front of man’s brain photo by shutterstock.

By Traci Pedersen
Dec. 31, 2015

Patients with Parkinsonian syndromes have different brain activity patterns in regard to balance control compared to healthy people, according to a new study by researchers from Albert Einstein College of Medicine who used a new portable measuring device developed at Drexel University.

The findings highlight the critical role of the prefrontal cortex in balance control and may eventually lead to better detection and treatment of Parkinsonian symptoms in older patients.

Parkinson’s disease is a neurological disorder that arises when brain cells that control movement die, leaving many patients in the late stages of the disease unable to walk at all. Parkinsonian syndromes, which are common in the elderly, are conditions that do not result in a Parkinson’s diagnosis but include many symptoms of the disease, such as rigidity, tremor and walking difficulties.

Previous attempts to analyze brain activity and stability in people with Parkinsonian syndromes have been limited, because neuroimaging tools could only be used when a study participant was lying flat, rather than walking or standing. In these cases, the patient receiving the brain scan could only imagine that he or she was performing the tasks.

A portable system created by researchers in Drexel’s School of Biomedical Engineering and Health Systems has fixed this problem. It has allowed scientists, for the first time, to better understand the role of the brain’s prefrontal cortex during standing and walking.

The prefrontal cortex is an area of the brain linked to higher-level processing, such as memory, attention, problem solving and decision-making. When a person is learning a new skill, for example, neural activity is greater in this region.

Unlike fMRI (functional magnetic resonance imaging), the new fNIR system (functional near-infrared spectroscopy) is fully portable: Participants wear a headband, allowing them to talk and move around while a computer collects data in real time.

“This initial study allowed us to measure brain activity in real-time, in a realistic setting. It shows that there are indeed differences in the prefrontal cortex of healthy and Parkinsonian syndrome patients, and those differences relate to their performance in maintaining stability while standing,” said co-author Meltem Izzetoglu, Ph.D., an assistant research professor of biomedical engineering at Drexel. “It opens up new fields of research.”

For the study, researchers compared 126 healthy adults to 117 individuals with mild Parkinson’s symptoms and 26 with more severe symptoms. While wearing a headband device, the participants were asked to stand and look straight ahead while counting for 10 seconds. 

They then walked on a mat that captured their gait speed, pace and stride length. The system recorded their brain oxygen levels during the entire testing period.

The findings show that those with Parkinsonian symptoms had significantly higher prefrontal oxygenation levels to maintain stability when standing than participants with mild and no symptoms.

“In fact, brain activity in the frontal brain region was nearly twice as large,” said lead author Jeannette R. Mahoney, Ph.D., assistant professor of neurology at Einstein.

The new portable technology could aid in diagnosing Parkinsonian syndromes or developing new treatments.

“Our goal is to be able to intervene with Parkinsonian symptoms and develop novel remediation in the not-so-distant future to improve elders’ quality of life,” Mahoney said.

The findings are published in the journal Brain Research.

Source: Drexel University

http://www.topix.com/health/parkinsons-disease/2016/01/parkinsonian-patients-show-different-brain-activity-tied-to-balance

PRE-MOTOR SYMPTOMS OF PARKINSON'S DISEASE

31st December 2015 

Parkinson's disease is characterised by motor and non-motor clinical features. The latter may present as pre-motor symptoms several years before the onset of motor symptoms. Pre-motor symptoms have been found to be associated to a later motor onset of Parkinson's Disease.

The overall frequency of pre-motor symptoms was 76%. Among the most prevalent symptoms were depression (38%), sleep disorders (37%) and anxiety (36%). The time prior to motor onset was greatest for constipation (9 years) and pain (8 years). 

People with more than two pre-motor symptoms had a later age at motor onset when compared to people without pre-motor symptoms (56 v 52). Late onset patients had a higher frequency of pre-motor symptoms (79% v 65% in early onset) and worse symptoms than early onset. Females reported a higher number of pre-motor symptoms (1.9 v 1.4). Anxiety lead-time was greater in tremor-dominant compared to bradykinetic-rigid patients (3 years). 

Pre-motor symptoms load is associated to a later motor onset of PD. Pre-motor symptoms are more frequent in subjects with late onset Parkinson's disease. Female subjects report a higher number of pre-motor symptoms, depression and anxiety being the most common.

Reference : Journal of Parkinson's Disease [2015] Dec 10 [Epub ahead of print] (M. Rodríguez-Violante, A.J.de Saráchaga, A.Cervantes-Arriaga, R.Millán-Cepeda, R.Leal- Ortega, I.Estrada-Bellmann, C.Zuñiga-Ramírez)

Complete abstract : http://www.ncbi.nlm.nih.gov/pubmed/26683422
http://www.viartis.net/parkinsons.disease/news/151231.pdf mail@viartis.net
©2015 Viartis 

Healthy Living: Preventing Parkinson's

Healthy Living: Preventing Parkinson's

Please click on Healthy Living: Preventing to see video

Posted: Dec 30, 2015 11:59 AM EST

As many as one-million Americans are living with Parkinson’s disease, a progressive movement disorder with no cure. 

Medications may help control the symptoms for a period of time, but eventually, they lose their punch.

Researchers now say they've found a way to prevent Parkinson’s from developing in animals, a huge step toward eliminating the disease in people.

Dr. Burton says a clinical trial of gene therapy in humans is only two to three years away.

He says the therapy needs to be tested in other animals and researchers need to assess the long-term effects before it could move to human trial.

http://www.9and10news.com/story/30853901/healthy-living-preventing-parkinsons#.VoVKPLs7IrE.blogger

Vanishing Parkinson’s Disease.

How ‘sham’ brain surgery could be killing off valuable therapies for Parkinson’s disease.

Alla Katsnelson

DECEMBER 30, 2015 BY ADMIN

Peggy Willocks was 44 when she was diagnosed with Parkinson’s disease. It progressed quickly, forcing her to retire four years later from her job as a primary-school principal in Elizabethton, Tennessee. Soon, her condition had deteriorated so much that she was often unable to dress and feed herself, take care of basic hygiene or walk unaided across a room.

Willocks enrolled in a trial for an experimental therapy called Spheramine, developed by Titan Pharmaceuticals, a biotechnology company in South San Francisco, California. Spheramine consists of cultured human retinal epithelial cells bound to specialized man-made carrier molecules. The cells are implanted into the brain, where it is hoped that they will produce the dopamine precursor levodopa, which can reduce the symptoms of Parkinson’s disease. In August 2000, Willocks became the second person ever to receive the treatment. After having a steel halo — a stereotactic frame — bolted to her skull, she was put under general anaesthesia. Surgeons then used the frame and coordinates obtained from numerous magnetic resonance imaging (MRI) scans to pinpoint the location at which to drill. They then snaked a catheter through her brain’s white matter to deliver the cells into the striatum.

At first there was no effect, but Willocks says that after 6–8 months she began to feel better. The changes were always moderate and gradual, except for once, about nine months after her surgery, when she showed what her doctor called a “radical” improvement in balance. By a year after the treatment, she and the five other patients in the phase I trial showed an improvement in motor ability of 48%, and those gains largely held 4 years later1.

Ten years on, she says she notices her condition worsening, but is still doing much better than she was before her operation. She has no doubt that the treatment works. Investigators disagree: Spheramine was shelved in 2008 after a follow-up phase II, double-blind study found that it was no more effective than placebo2. This time, the researchers compared the treatment with a ‘sham’ brain surgery that copied almost every aspect of the procedure Willocks received, short of injecting cells into the brain.

For many investigators aiming to treat Parkinson’s and other neurological diseases invasively, using sham brain surgery as a control is, well, a no-brainer. And the practice is likely to expand in coming years, as researchers continue to develop experimental tissue transplants, gene therapies and stem-cell treatments. Small safety trials such as the one in which Willocks was enrolled may hint at the efficacy of a treatment, but they are not designed to prove it. And because they are ‘open label’ — both the investigators and the participants know that the drug is being administered — they are riddled with biases that can skew results. “It is so clear that open-label studies provide information that is not reliable,” says Warren Olanow, a neurologist at New York’s Mount Sinai Medical Center who has worked on cell-based neurosurgical therapies in Parkinson’s for more than two decades. “It’s almost impossible for me to imagine how a serious scientist can not desire their data or hypothesis to be tested in double-blind studies.”

Other scientists, however, say that sham brain surgery is an expensive, potentially dangerous and possibly unethical bit of biomedical theatrics. It may also be unnecessary. Clinical neuroscientist Roger Barker at the University of Cambridge, UK, contends that because there is huge variation in how these therapies are administered and in how patients respond, the protocols need to be refined in an open-label setting before going on to the next stage of development. And because cost, complexity and the small number of people eligible for such invasive therapies limit the size of the studies, a sham control provides results of limited statistical utility. Barker and his colleagues across Europe are currently enrolling patients in a €12-million (US$17-million) multicentre trial of a fetal dopaminergic nerve-cell treatment for Parkinson’s disease. The treatment may never be tested against a sham-surgery control. “There’s a sort of historical precedent” for using placebo controls, but it may not apply to neurosurgical trials, he says. Willocks and other patients go further. Placebo-controlled studies aren’t just unnecessary, they say, they are actually causing the downfall of potentially valuable treatments.

A complicating control

During the past 25 years, surgical therapies for Parkinson’s disease have travelled a rocky road. In 1987, a report by Mexican surgeons3 described seemingly miraculous effects in two patients with severe Parkinson’s who received transplants of tissue from the adrenal gland, which produces dopamine. In the next several years, hundreds of patients received the treatment, but some autopsies later showed that the cells didn’t in fact survive4. Around the same time, researchers started to test fetal nerve-cell transplants (similar to those in Barker’s trial) in small-scale studies, finding mixed but promising results. Two studies5,6 comparing the treatment to sham surgery concluded, however, that the transplants were not only ineffective, but also often caused dyskinesia — the movement disorder that plagues people with Parkinson’s disease. In the past seven years, three experimental treatments (including Spheramine) that showed promise in small, open-label studies1,7,8 failed in phase II trials2,4,9 comparing them with a sham control (see ‘The sham wall’).

Sham brain surgery is no sugar pill. After the stereotactic frame is affixed to the skull, the patient is usually anaesthetized and surgeons drill into the skull. In most cases, the burr holes stop at the dura mater, a protective membrane covering the brain, but they sometimes go deeper: in a phase II trial testing the nerve growth factor GDNF, investigators catheterized the brain in all participants but infused saline, rather than GDNF, into the controls9.

“We have to stage the whole thing such that from the outside it’s completely indistinguishable” from the real thing, says Joao Siffert, chief medical officer of Ceregene, a company in San Diego, California, that is working on a therapy that delivers a gene for another nerve growth factor, called neurturin, using a viral vector. For many sham treatments, everyone in the operating room, from surgeons to nurses’ assistants, must pretend that they are busily performing the complete operation — in some cases, turning on machines to elicit appropriate noises. An extremely complex protocol ensures that no one outside the surgical team knows who got what treatment. “It’s very complicated, there are a lot of moving parts,” Siffert says. All that ratchets up the cost of a trial; Siffert estimates that between operating-theatre costs, follow-up and the unwieldy infrastructure required for data management, a 50-patient study would cost more than $10 million.

Still, at least in North America, Parkinson’s disease investigators overwhelmingly support the use of sham surgery — at a rate of 94%, according to a 2004 survey10. Around 20% said that penetrating the brain is justifiable. And proponents say the procedure is relatively safe. Although sham brain surgery has definite risks, most notably those associated with general anaesthesia, supporters note that adverse events are almost unheard of, unlike the risks of the actual treatments. And participants in the sham groups are generally promised the treatment if it is ultimately approved; in that event, they will already have the burr holes in their skulls through which it would be administered.

Sham treatments help to tease out the placebo effect and biases. In Parkinson’s disease, the placebo effect is especially strong. One reason is that patients’ expectations that they will benefit from a treatment induce the release of dopamine11, the neurotransmitter that is lacking in the disease. “The placebo effect is real, it’s huge and it’s got a physiological basis,” says Jon Stoessl, a neurologist at the University of British Columbia in Vancouver, Canada, who studies Parkinson’s and the placebo effect. In one double-blind study of fetal nerve-cell transplants, patient improvement correlated with whether they believed they had received the treatment, irrespective of whether they actually had12. And the effect can last as long as two years, Stoessl says, citing an unpublished study by his colleagues.

“There’s a historical precedent for using placebo controls, but it may not apply to neurosurgical trials.”

Many regard bias as a more significant confounder. “Investigators have a tremendous vested interest in seeing that their treatment is effective,” says Anthony Lang, a neurologist at the University of Toronto in Canada who has participated in several neurosurgical trials for experimental Parkinson’s therapies. In any trial, bias can affect how researchers assess patient responses and may inflate the patients’ expectations, further enhancing the placebo effect. Compounding the problem for Parkinsons’ research is the fact that there are no objective measures for how well a patient is doing. “It’s just a sort of perfect storm conspiring against our ability to see definitive changes in the underlying disease,” says Steven Piantadosi, a clinical-trials methodologist at Cedars-Sinai Medical Center in Los Angeles, California. “Sham surgery, properly done, can control for that.”

Barker counters that it is possible to control for investigator bias in an open-label trial by taking steps such as having blinded raters assess patients. His position is in some ways unsurprising; in Europe, sham surgery is deemed much less acceptable than it is in the United States. It has never been used in the United Kingdom. Barker is categorical about his belief that transplantation of fetal tissue works, at least for some people. “I don’t need sham surgery to show that,” he says, pointing instead to a paper13 published last year describing two patients treated 13 and 16 years previously who were still benefiting from the treatment, and whose brains showed functional dopamine-producing neurons at the transplant site. He attributes the mixed results in past studies to variation in the patients selected for treatment, the characteristics of the tissue being implanted and the methods used to implant it. His trial will have to demonstrate efficacy without eliciting some of the side effects found in the two sham-controlled studies. That will require some type of control study, he says, but it might take the form of comparison to an approved therapy that is known to work, such as deep brain stimulation.

But time, says Barker, will best establish efficacy. In most trials the end point is no more than a year after the treatment. That may not be long enough: implanted cells or injected growth factors might take longer than this to become fully functional, and the placebo e

effect may not have had time to dissipate. “We want a 3–5-year endpoint,” says Barker.

There are hints from some of the failed phase II trials that patients followed up beyond study endpoints might tell a more positive story4. Some say, therefore, that sham controls are sinking the prospects of valuable drugs. Anders Björklund, a neuroscientist at Lund University in Sweden who is collaborating with Barker, says that sham surgery can lead researchers to throw out a strategy prematurely if the trial fails because of technical or methodological glitches rather than a true lack of efficacy.

Advocacy and frustration

According to Perry Cohen, who leads a network of patient activists called the Parkinson Pipeline Project, that’s exactly what is happening. He had always questioned the need for sham surgery, he says, but after the string of phase II failures, “We started saying, ‘Hey, this is a problem. These trials failed, but we know they are working for some people.'”

For researchers, it is easy to dismiss patients’ concerns as being driven by emotion. “Patients want cures,” says Lang, “and they will often be convinced that the more aggressive, surgical therapies are more likely to be curative.” But Cohen counters that patients have different priorities and that researchers must take these into account. Researchers use placebo controls to weed out false positives. But for patients, the real ogre is the false negatives — which can sink a therapy before it has been optimized. The better a trial is at stamping out the former, the higher the rate of the latter — which means at best delays, and at worst dead ends. Spheramine, for example, “is still on a shelf somewhere”, Cohen says. Then there’s Amgen’s phase II trial of GDNF. The trial was halted in 2004 amid lacklustre results and potential safety concerns, which some have attributed to Amgen’s procedure, rather than to the therapy itself. Now researchers are taking a renewed interest in the molecule, but although Cohen is glad it is getting a second chance, “we lost 6 years on it”, he says.

Patients also have different perspectives on risk from researchers, Cohen says. He offers the story of Tom Intili, who had had Parkinson’s for 10 years when, at the age of 50, he signed on to the double-blind, placebo-controlled trial of neurturin. At first, Intili improved dramatically. But when the results were unblinded, he learned that he had received the sham. His condition plummeted, leaving him more debilitated than he had been before the trial. “We just don’t know what the psychological effects of unblinding are,” Cohen says.

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Moreover, trying to exclude the placebo effect is simply misguided, Cohen argues. “I don’t want to subtract out the placebo effect — I want to keep it, because in real life it’s part of the treatment,” he insists. Because psychological factors are so salient in Parkinson’s, a placebo response might actually potentiate a therapy, he explains. “I want to be convinced that sham surgery is necessary. I’m looking for arguments that might change my mind, but I haven’t found any yet,” he says.

Willocks says that she is living proof that many of the recently shelved therapies are in fact salvageable. Of course from a scientific perspective, her story is an anecdote, not data. In May, the failed phase II study of Spheramine — the therapy she received a decade ago — was finally published2. The paper closes with a warning about the dangers of the placebo effect and stresses the importance of controlling for it with a double-blind design. “That last paragraph bothered me,” Willocks says. “I just don’t see how they can call it a placebo effect after ten years.” 

The worst day of this disease was the day I was diagnosed. The best day was when I understood that I could do something about it. It gave me back a sense of control in my life, and some power.” –Phyllis, 63, five years after diagnosis

If you or someone close to you has recently been diagnosed with Parkinson’s disease (PD), you are likely experiencing many emotions and have many concerns and questions.

Remember that you are not alone. As many as one million people in the US and an estimated seven to 10 million worldwide live with Parkinson’s disease. These estimates do not account for cases of PD that are unreported, undiagnosed or misdiagnosed.

With a diagnosis now in hand and the freedom to learn at your own pace, you can begin to understand PD and its treatments and the role they will play in your life. Your diagnosis can be the first step to taking charge of your life with Parkinson’s disease.  What are some next steps?

Hear Real Stories from People with PD:

It is common for many people to experience a wide range of emotions upon diagnosis from shock, to anger and even to sometimes a sense relief at being able to name symptoms (perhaps a small tremor or weaknesses) that have gone unexplained or misdiagnosed for years. Hear from others who may have had an experience similar to yours.

Inform Yourself about PD:

You will need time to adjust to the new diagnosis, so educate yourself about PD – slowly. PDF provides educational publications and website, a HelpLine, suggestions of local support groups and doctors and online and video resources to help you and your loved ones to cope and become informed.

Get Started with the Secrets, Myths and Misconceptions of Parkinson’s

Browse Basic Information on Parkinson’s

Order PDF Educational Materials 

Related Resources from the PD Resource List

Seeking Out a Specialist

Category: Newly Diagnosed

Resource Type: Publications

Publication Date: 2012

Author: Parkinson’s Disease Foundation

Publisher: Parkinson’s Disease Foundation

Cost: Free

Toll Free: (800) 457-6676

Email: info@pdf.org

Associated URL: www.pdf.org/en/factsheets

Address: 1359 Broadway, Suite 1509

City: New York Zip: 10018

Language: English

State: New York

This fact sheet offers in-depth information and practical tips on choosing the right doctor. It includes facts about why it’s important to see a Parkinson’s specialist. Also offered in: Spanish.

In 2009, Andrew Johnson, 35, was diagnosed with early onset Parkinson’s disease. Last November, and again in February, he underwent a procedure, during which surgeons implanted a device in his brain that controls his tremors. Today, you’d never guess he suffers from Parkinson’s – but watch what happens when he turns his new implant off.

Johnson flips the switch on his device at the 2:00 mark, but for the full effect you’ll want to watch from the beginning. When his hands and head are at rest, you’re witnessing the stunning effects of a procedure known as deep brain stimulation (DBS). The surgery involves the implantation of a brain pacemaker. Like the artifical pacemaker you might find attached to someone’s heart, a brain pacemaker is used to generate electrical impulses, only instead of targeting heart muscles it targets specific regions of the brain. In patients suffering from Parkinson’s disease, DBS is used to treat motor symptoms when other forms of therapy fail.

As Johnson points out on his blog, DBS is not a miracle cure – it’s an FDA-approved surgical procedure that’s been cleared for the treatment of Parkinson’s disease for over a decade now. That being said, Johnson has responded to the treatment extraordinarily well, as you can clearly see in the video above.
http://www.infocreations.org/2015/12/30/vanishing-parkinsons-disease