Deep Brain Stimulation and Parkinson’s Disease

Deep brain stimulation (DBS) is a treatment intended for people for which other treatments for Parkinson’s disease have not been effective. The neurostimulator is placed into the chest similar to a pacemaker. The device is connected to the brain via wires and blocks signals that cause involuntary motions and ameliorates symptoms such as stiffness and tremor by supplying constant electrical impulses. During the surgery the recipients of the device are awake (they receive a local anesthetic). DBS was approved by the FDA for the treatment of Parkinson’s disease in 2002. Risks for the surgery include hemorrhage or stroke, infection, and trouble sleeping, among others. For many, the benefits of DBS outweigh the risks

Andrew Johnson is an individual who responds really well to DBS. He takes other treatment in connection with the electrical impulses he receives from his device for an enhanced benefit. He demonstrates how his device works in the video shown below:

                The advances in technology that allow Andrew to complete daily tasks despite his condition are amazing. Hopefully with the breakthroughs seen in heart surgery with non-invasive procedures, there will be non-invasive brain therapies available soon to administer these electrical impulses that improve Parkinson’s symptoms with reduced risk.

Sources:

http://www.nimh.nih.gov/health/topics/brain-stimulation-therapies/brain-stimulation-therapies.shtml

http://www.ninds.nih.gov/disorders/clinical_trials/deep_brain_stimulation.htm

http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/medicaldevices/medicaldevicesadvisorycommittee/neurologicaldevicespanel/ucm209700.pdf

For more about Andrew Johnson: http://youngandshaky.com/

A number of times our class has discussed issues in translating model animal research into human trials and logistical or ethical issues that arise in the process. Sham surgeries are often used to study surgical interventions in animal studies and involve performing all of the experimental procedures except actually administering whatever treatment or drug is being tested. Such a procedure removes bias from the experiment and helps investigators to identify what effect the treatment itself is having since the sham provides information on what the physical effects of the procedure rather than the drug/treatment might be. During our discussion of stroke, the question of sham surgeries in human trials was brought up; understandably some people thought it unnecessary or even cruel to subject a patient to the risks of surgery if they weren’t receiving treatment. Sham surgeries have been used to test a number of Parkinson’s disease treatments (particularly in the US) and have sparked controversy between investigators too. An article from Nature in 2011 talked about this debate over the use of sham surgeries, the nature of the placebo effect (a perceived improvement in a patient who is not receiving the experimental treatment) in Parkinson’s research, and various treatments being pursued. The article brings up a number of interesting considerations for using sham surgeries in Parkinson’s research including the fact that the placebo effect is mediated by dopamine (which Parkinson’s patients do not have enough of) and therefore is not necessarily something undesirable for control patients. Sham surgery is used for the exact reason that the placebo effect can be removed from the results of any study by using a placebo (the sham surgery) to determine the baseline against which the experimental results are compared: however, when group assignments are finally revealed and the placebo effect is removed, this can be physically devastating to patients who did not receive the experimental treatment. Suggestions for alternatives to sham controls include comparing an experimental treatment with an approved therapy like deep brain stimulation, or having all patients receive the experimental treatment and then be assessed by raters who do not know the status of the patient within the study. The reasoning behind replacing sham surgeries in the context of Parkinson’s research is that some people think they may have prematurely stopped investigations into promising therapies. What do you think about the use of sham surgeries in clinical trials for Parkinson’s research? Do you see merit to either side of the debate?

Katsnelson, Alla. "Why Fake It? How 'Sham' Brain Surgery Could Be Killing Off Valuable Therapies for Parkinson's Disease." Nature 476 (2011): 142-44. Web. 19 Nov. 2014.

Yet another reason to exercise, Improving your brain health

As we have seen in nearly all subjects that we have discussed during semester, there has been shown to be inverse relationship between exercise and neuroegeneration. I stumbled upon this topic as I was reading Runners World magazine titled “How Running keeps your brain humming” and this article reported to the running community the results of a study done at Beckman Institute for Advanced Science and Technology at the University of Illinois. This study claimed that after the age of 20 you begin to lose about 1% of your hippocampus annualy, which is a part of your brain that is essential for learning and memory. This study aimed to look at the effects of enrichment and aerobic exercise on the hippocamous and mental function. The was conducted with a mouse model of four different habitats each varying in enrichment. The first cage included toys for the mouse described as a “mouse carnival” and an abundance of rich food, the second included this with also a running wheel, the third was an empty cage with kibble an water, and the fourth was the same as three but included a running wheel.

After studying these mice for several months, they measured brain function with a series of cognitive tests an also measured brain structure. Their findings revealed that the amount of “enrichment” did not make any difference in the mice’s brains, but the mice with running wheels performed significantly better on cognitive tests and had overall healthier brains. Upon further looking up the exact study the results stated that running in these mice lead to a two fold increase in the number of  BRD-U positive cells, which was a technique to mark cells that were dividing, and total number of new neurons, indicating overall hippocampal neurogenesis.

 I found this to be very exciting and encouraging for those of us that are physically active, and it gave me another nudge of encouragement to get out of bed this morning to go running.  While we all know there are countless reasons to exercise to improve our overall health, I belief that this data is overall very promising as a way of implementing overall mental health. While many challenges present in getting the population to all partake in aerobic exercise, this is a promising method for prevention of neuro-degeneration for those at are actively seeking preventative measured.

Mustroph ML, Chen S, Desai SC, Cay EB, DeYoung EK, Rhodes JS. Aerobic exercise is the critical variable in an enriched environment that increases hippocampal neurogenesis and water maze learning in male C57BL/6J mice. Neuroscience.2012;219:62–71. 

Parent, Marc. "How Running Keeps Your Brain Humming." Runner's World & Running Times. Rondale Inc, 22 Oct. 2014. Web. 18 Nov. 2014.

Sick Genes - Huntington's Disease and Genetic Anticipation

The image above shows how widespread the death of brain tissue can be in Huntington's disease patients. Image Credit: the University of Alberta

Huntington's disease is a heritable condition with onset of dementia (cognitive decline) and chorea (jerky and involuntary movements) occurring around middle age. The passing of Huntington's disease from one generation to the next follows the rules of autosomal dominance which means everyone with the Huntington's gene will have the disease and if their partner is healthy then their children have a 50% chance of having the gene passed onto them. The gene itself codes for a protein that is mutated in Huntington's patients such that there an abnormally large number of repetitions of a particular sequence of nucleotides (DNA building blocks): CAD. This repetition leads to the creation of a huge protein called "huntingtin" which will accumulate in the brain and slowly cause damage. What can be so striking and heartbreaking about this disease is the young age that symptoms begin and how early most patients will die. In the video below Daniel Mundy can be seen struggling with chorea while going through daily activities like walking, shaving, and describing his daughter.

Because of Daniel's affliction his daughter is at risk of developing his disease. But there is more than that: if she does get sick she will likely develop symptoms earlier and they will be more severe. This is due to a phenomenon in genetics called "anticipation" where the number of pathogenic repeats increases with each generation. One finds anticipation in many disorders that stem from trinucleotide repeats (CAD in Huntington's) including Myotonic Dystrophy and maybe even Crohn's disease. Integrating the concept of genetic anticipation into a physician's assessment and history-taking could lead to a more accurate and effective diagnosis, prognosis, and treatment plan.

Sources:

Merck Manual Professional Edition: Huntington Disease

University of Alberta: Huntington breakthrough

The Lancet: Preliminary evidence for genetic anticipation in Crohn's disease

National Institutes of Health Genetics Home Reference: Anticipation

Wikipedia: Anticipation (genetics)

Youtube: Daniel My Brother (Huntington's Disease)

Mmmmm....brains

Multiple sclerosis (MS) is considered an autoimmune disease because it is known to be T-cell mediated—a t least in part (B cells may also contribute to the pathogenesis). The myelin antigen is the target of T cells. Myelin is not recognized as self by the body’s immune system because it is part of the central nervous system (CNS) which possesses its own glia that act as immune cells. From PSIO 201 we learned the blood brain barrier (BBB) separates the central nervous system from the rest of the body and is the interface between blood and cerebrospinal fluid (CSF). The purpose of the BBB is to protect the brain and spinal cord from pathogens while still allowing nutrients and molecules such as oxygen to pass freely.  When the BBB is compromised, the CNS becomes exposed to the immune system for the first time and might be misjudged as foreign. Myelin is a shield that protects and insulates axons to permit nerve signals to be conducted to their destination properly. When myelin is damaged, the signal cannot reach its target. Because the location of nerve and myelin damage varies, so do the symptoms of MS.

The trigger of MS is not known. Genetic and environmental factors have been implicated. MS in itself is not a fatal disease, though those who have been diagnosed may experience challenges and loss of control of body parts. Below is a video from the European Multiple Sclerosis Platform. I think it is very well done and the interviews from the people with MS are enlightening:

One thing I noticed from these people is they experienced something such as blindness or sensations of pain that motivated them to get to a doctor to discover their diagnosis. One of the men attributed his symptoms to stress. I appreciate the hope and awareness that these people express for medical advances to help people who share their condition.

                Something interesting is a map of the prevalence of MS worldwide. The link below is not up to date but the map it shows is sufficient.

http://www.mult-sclerosis.org/ms_world.html

It seems MS is localized to more developed or richer countries. I wonder if it could be related to the “Hygiene Hypothesis” expressed earlier this semester with Inflammatory Bowel Diseases, or if it could be connected to some other factor. There is no scientific evidence I know of that supports this idea, but I contemplate whether culture may play a role. Poorer countries are more likely to eat things such as spinal cords and brains of an animal because it is meat and fat and shouldn’t be wasted. Exposure to these CNS antigens may give T regulatory cells an opportunity to calm down T helper 1 cells and let them know the antigen is foreign, but not dangerous. I am not suggesting we should all eat brains, but I thought it was a point of interest that was worth mentioning.

Sources:

http://www.ninds.nih.gov/disorders/multiple_sclerosis/detail_multiple_sclerosis.htm

Musical Awakenings

The movie “Awakenings” is based on the work and memoir of a neurologist Dr. Oliver Sacks. In the film, catatonic (immobile and often unresponsive) patients respond to surprising stimulation like a ball hurtling towards them, being touched, and even hearing familiar music. Despite the fact that music was an unconventional therapy, this seemed to have real potential for some of Dr. Sacks’ patients and the scene from “Awakenings” that shows the response patients had has stuck with me. Familiar music is being researched and brought to practice now for something entirely different: dementia. It seems that familiar music has a calming effect on those suffering from Alzheimer’s and dementia which has made caring for these patients easier. One particular study (Clark) found that familiar music decreased aggressive behaviors directed towards caregivers as they helped patients bathe. This and other research has provided the foundation for the Music & Memory Program, which is working to bring personalized music to patients and to educate caregivers on how to create therapeutic playlists (Napoletan). There are believers within the healthcare field too; medical protocols utilizing music are being developed and refined as the mechanisms underlying their benefit are being investigated (Gerdner). More information and research is still needed to determine how music affects patients physiologically, but the changes seen in patients are obvious. Gerdner proposes that memory may be accessed which redirects the patient’s attention from confusing stimulation that distresses them and provides stimulation that the patient can interpret using their prior experience. Not surprisingly, at least one physiologic measure of stress has been found to decrease in response to individualized music. Individualized music provides an interesting and innovative approach to dementia treatment which caregivers can easily utilize.

"Awakenings." Wikipedia. Wikimedia Foundation, 5 Nov. 2014. Web. 14 Nov. 2014.

Clark, ME, AW Lipe, and M. Bilbrey. "Use of Music to Decrease Aggressive Behaviors in People with Dementia." Journal of Gerontological Nursing 24.7 (1998): 10-17. PubMed.gov. U.S. National Library of Medicine. Web. 14 Nov. 2014.

Gerdner, Linda A. "Individualized Music for Dementia: Evolution and Application of Evidence-based Protocol." World Journal of Psychiatry2.2 (2012): 26-32. PubMed.gov. US National Library of Medicine, 22 Apr. 2012. Web. 14 Nov. 2014.

Napoletan, Ann. "Music Therapy For Dementia: Awakening Memories in Alzheimer's Patients." Alzheimers.net. A Place for Mom, Inc, 4 June 2013. Web. 14 Nov. 2014.

Diving into Multiple Sclerosis

While briefly what Multiple Sclerosis was discussed in class, I thought it would be good do dive deeper into what MS really is.

Multiple Sclerosis is an autoimmune disease in which our immune system attacks you myelin, the protective sheath of protein and phospholipids around a nerve fiber, leaving the nerve fiber to be scarred and damaged. This damage causes interruptions in signaling and overall decline in function, leaving the person with problems walking, vision problems, numbness and dizziness just to name a few symptoms that can gradually worsen over time.

Multiple Sclerosis can be broken down into four major types:

Relapsing Remitting MS (RRMS): This is the most common type of MS which is characterized by clearly defined times of flare ups which can then be followed by times of recovery.

Secondary-Progressive MS (SPMS): this type of MS is characterized by a relapse, then a steadier worsening after the relapse. Nearly half of the people diagnosed with Relapsing MS will reach a point of Secondary- Progressing MS within 10 years.

Primary-Progressive Relapse MS (PPMS):  This type of MS accounts for 10% of patients diagnosed and is an overall neurological worsening over time.

Progressive-Relapsing MS (PRMS): this is a more rare form of MS where there is a steady decline of neurological function with attacks of clear worsening along throughout its progression.

There is no cure for this neurodegenerative disease; there are pharmacological methods to help recovery from attacks, manage symptoms and slow the diseases progression.

Treatments for MS attacks include: Corticosteroids and plasma exchange, a procedure in which a portion of your plasma is removed where it is mixed with protein albumin and then replaced.

Treatments that modify progression of the disease include a list of drugs that can be administered as oral medications of injection that work to reduce relapses of the disease and work to block the movement of the damaging immune cells.

Treatments of symptoms include medications for fatigue, pain, bowel and bladder control, muscle relaxants to help control muscle stiffness and spams and physical therapy.  Physical therapy can be a useful tool in patients with MS in aiding with issues of balance, coordination, stretching to prevent muscle spasms, exercise to increase range of motion, an skills to prevent falling

Something that is not often explained to those who don’t have multiple sclerosis is what exactly a MS relapse, also refereed to as a attack, exacerbation, or episode is. While the relapse is never the same for any person, it tends to be an acute flare up of that causes new symptoms or worsening of other symptoms. These relapses could occur in an episode of balance issues, severe fatigue, or optic neuritis, which causes impairment of vision.  An relapse or attack is defined as something that lasts at least 24 hours.

While there is still no cure to MS there is much research targeting three different approaches into treating MS, topping the disease progression all together, restoring what has already been lost to MS and the finally ending the disease all together. There is current research looking for genes of associated with MS, finding triggering factors for MS, restoring tissue damage due to MS, and into the immune system and understanding the cascade of events within this autoimmune disease

"About Multiple Sclerosis (MS)." Understanding Multiple Sclerosis. Genzym, 2013. Web. 12 Nov. 2014.

"Managing Relapses." National Multiple Sclerosis Society. N.p., n.d. Web. 12 Nov. 2014.

"Multiple Sclerosis." Treatments and Drugs. The Mayo Clinic, 10 July 2014. Web. 10 Nov. 2014.

"Research on the Immune System." National Multiple Sclerosis Society. N.p., n.d. Web. 12 Nov. 2014.

Senelick, Richard. "Benefits of Physical Therapy for MS." WebMD. WebMD, 25 Oct. 2014. Web. 12 Nov. 2014.