Tagged: parkinsons disease

Parkinson’s Disease: Current and Future Treatments

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This week’s question comes from Alex. She asks, “I saw a video on YouTube where a guy with Parkinson’s disease is able to use a machine implanted in his brain to control his shaking. Please explain this!”

The video Alex is referring to can be seen here and shows a man with the severe shaking most of us associate with Parkinson’s controlled by a device he had implanted in his brain. The effects are dramatic between when the machine is on or off; in fact, it seems that his symptoms are so severe with it off that he has moderate difficulty turning the machine back on after he had switched it off. But, before we go into detail about how that machine and other treatments for Parkinson’s work, we should first understand the disease itself and what exactly is going on in the body to cause its symptoms.

The disease itself is caused when the dopamine producing neurons in an area of the brain known as the substantia nigra begin to die. Past posts and some sources below detail the role of dopamine in the brain, so please refer back to those if you are not familiar (here). The exact reason(s) for this premature death is unknown, but evidence supports excessive oxidative stress and the inappropriate collection of certain proteins (alpha-synulcein bundles known as Lewy bodies, for the curious) in these neurons and to a lesser extent throughout the brain. In certain cases there is also a genetic cause, but for a majority of people the cause is idiopathic (without a known source).

Regardless of the reason(s) behind it, damage to the dopamine producing cells in the substantia nigra has a wide ranging effect on the body. Chief among them is parkinsonism, which is the specific name for the motor (movement) issues most visible in Parkinson’s patients. The motor issues are mainly divided into tremor, rigidity, slowness, and postural issues. Tremor is the familiar shakiness, which more often happens when not moving (resting tremor). Rigidity can come in multiple forms, but basically means the muscle is hyperactive, making it harder to move fluidly or with normal ease. Slowness is what it sounds like, preventing rapid execution of movements. Slowness is especially visible in fine motor movements, making these activities difficult since they often require multiple actions to be executed quickly and successively. Postural issues are present in more advanced stages of the disease, resulting in balance issues and frequent falls.

Beyond the motor issues, Parkinson’s can result in a whole host of issues that vary from person to person. The most common issues associated with advanced Parkinson’s are cognitive issues (ie. slowed thought, speech issues, memory issues), psychiatric issues (ie. depression, anxiety, hallucinations), and dementia. It is thought that the accumulation of the Lewy bodies mentioned earlier contribute to this loss of function. As such, these issues tend to present much later in Parkinson’s patients because it takes time for these elements to accumulate and interfere with function.

Because the symptoms of Parkinson’s are generated largely by loss of dopamine production, the logical treatment would be to try to replace that dopamine. In fact, that is exactly what the main treatment for Parkinson’s does. Known as Levodopa, this drug is converted to dopamine in the body and can increase the concentration of available dopamine in the brain. It can have significant side effects because it can also be converted to dopamine outside the brain. This peripheral dopamine can have a whole host of effects on nerves, leading to inappropriate nerve activity. To combat this, it is usually administered alongside a drug that prevents this conversion outside the brain but allows it to occur within the brain (by not being able to cross the blood-brain barrier). Even with this concurrent drugs,  levodopa can still cause disabling side effects. Ironically, the most common are dyskinesias, or involuntary movements. Other drugs exist, but with varying degrees of effectiveness and still largely have a poor side effect profile. However, on the whole these drugs only mask the symptoms. As of now, no drug in clinical use has been shown to stop progression, though some recent compounds and genetic targets (1, 2, 3) have shown promise by a variety of mechanisms.

But, what if the symptom controlling drugs cause too many side effects, don’t last long enough, or otherwise don’t work? What if a more permanent solution is needed? Enter deep brain stimulation (DBS). As you saw in the video, deep brain stimulation can be tremendously effective in regulating the motor symptoms of Parkinson’s. DBS does this by using electrical signals to block out the errant motor signals generated in the Parkinson’s affected brain. Electrodes are placed in certain parts of the brain (specifically ventral intermediate nucleus, globus pallidus, and subthalamic nucleus) and transmit their signal directly into these areas. All of these areas are involved with some portion of motor control, though the specifics are not important in this context. Despite blocking the erroneous Parkinson’s motor signals in these areas, normal motor signals can still be processed. Think of it like a freeway where a drunk driver is swerving across the road, disrupting all of the normal traffic. Once that driver is removed from the road, traffic can resume as normal. The result of DBS is a much smoother overall motor control and significant reduction of the tremors, slowness, rigidity, and posture control issues. The drawback is that DBS involves open brain surgery and implantation of foreign bodies deep into the brain. Thus it is not considered the primary treatment for Parkinson’s patients. Hopefully in the future a similar technology can be created that involves a much less invasive procedure, allowing it to be a primary treatment option for those with progressive symptoms. Until then, drug therapy continues to be the most widely used treatment for the symptoms of Parkinson’s disease.

Hope this helps, Alex! As always, thank you for the question. If you want to submit your own, feel free to do so at the top link.

Till next time,

Justin

Sources:

http://www.parkinson.org/Parkinson-s-Disease/Treatment/Surgical-Treatment-Options/Deep-Brain-Stimulation

http://www.sciencemag.org.libproxy.usc.edu/content/302/5646/819.short

http://www.psychologytoday.com/basics/dopamine

http://www.parkinson.org/Parkinson-s-Disease/Treatment/Medications-for-Motor-Symptoms-of-PD/Carbidopa-levodopa

http://www.parkinson.org/Parkinson-s-Disease/Treatment/Surgical-Treatment-Options/Deep-Brain-Stimulation

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

http://www.nlm.nih.gov/medlineplus/ency/imagepages/19515.htm

http://www.mayoclinic.com/health/parkinsons-disease/DS00295

http://www.nejm.org/doi/full/10.1056/NEJMct1208070

http://www.neurology.org/content/61/7/919.abstract

http://www.ncbi.nlm.nih.gov/pubmed/11801431

http://www.ncbi.nlm.nih.gov/pubmed/22772329

http://brain.oxfordjournals.org/content/127/1/4.full.pdf

Study Drugs: Pills to Supercharge The Brain?

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We have officially reached 1500 views! Thank you to everyone who has taken the time to read this blog so far. Truly appreciate the support.

This week’s question comes from Joe, who asks “I’ve heard of certain medications, like Adderall and Provigil, that give people a tremendous boost in focus and work ability. Provigil is especially becoming popular with the Wall Street types. How do these drugs work and are there any major negative side effects?”

I think most people have heard of stimulants becoming popular with the big city finance types, starting with cocaine in the 80’s and moving to more sophisticated pharmaceuticals like these as the years progressed. More recently, these types of drugs have become popular with otherwise normal college and even high school students looking to get more done in less time. The military has been using pills like this to keep pilots and other essential personnel awake for days at a time since the early 20th century.

Before we start, one comment: contrary to what some people may believe, no pills as of yet actually make you “smarter” or otherwise enhance your pre-existing function. What they actually do is alter your perception of reality, directly in the brain and/or by systemically suppressing signals of fatigue. The same ability is present no matter what you take, just the drugs can temporarily ease the natural feelings of fatigue that would ordinarily hold back full function.

So to answer the question generally, we can split the drugs into two basic categories. The first category, which most people are familiar with, are stimulants. Stimulants are defined as any chemical that temporarily increases physiological function. Obviously this is a very wide definition that can apply to a wide variety of things. Some drugs we encounter every day are weaker stimulants, like nicotine, than others, like caffeine. Many stimulants are illegal, like cocaine and methamphetamine. Stimulants can and often do cause addiction. Likely the strongest widely available class of stimulants are amphetamines. Adderall is actually a mix of two different types of amphetamine salts, amphetamine and dextroamphetamine. Lets explore how amphetamines work in more detail.

Amphetamines function by causing a large rise in the levels of dopamine and norepinephrine in the brain and prevent their reuptake, allowing these chemicals to continue to exert influence longer than normal. The specifics of this action are not important to this discussion but are described very well in this article. We have already talked about the function of norepinephrine in the brain (here), so I won’t repeat myself. Take a peek at that other article if you need a refresher.

The changes in dopamine are also tremendously important. Dopamine is a neurotransmitter in the brain responsible for a wide variety of functions. One major function is control/ heavy influence over the reward and alertness centers of the brain. So when a substance causes a major release of dopamine, one effect is you feel really good, have a very positive mood, and are very alert. MDMA, the active ingredient in the drug ecstasy, exerts its influence largely by this mechanism (it also happens to be an amphetamine). This is also where amphetamines give us the ability to remain awake. High levels of dopamine can also have an impact on higher level brain functions such as motor control, causing abnormally high motor activity and low threshold for movement. This is possibly the source of the “jitters” people get when they take dopamine releasing drugs like amphetamines. It is also the reason movement is so difficult with Parkinson’s Disease, as the dopamine producing center of the brain is damaged and dopamine levels are lower than normal.

As you might imagine, amphetamines are incredibly addictive due largely to their reward center influencing mechanism of action. They also have negative side effects such as appetite suppression that can cause longer term health effects if left unchecked. As such, their use should be limited only to those instances where their value outweighs the cost.

The second category of drugs are non-stimulants. These are drugs that seek to mimic the individual effects of the stimulant drugs without similar side effects, including addiction potential. For the treatment of ADHD, sometimes SNRIs (selection norepinephrine reputake inhibitors) are used as an alternative method to amphetamines. This seeks to produce the increase in norepinephrine found in amphetamine medication without the associated addiction potential from dopamine-related activity.

The drug you mentioned, Provigil, attempts to do a similar thing by influencing dopamine levels without a massive increase all at once. By upticking the dopamine transporters in the brain, the levels are increased more gradually and causes the desired alertness without the dose of euphoria that underlies the addictive nature of amphetamines and other stimulants. Mind you, amphetamines do a similar thing, but they also cause a massive release and prevent reuptake so it is likely that transporter alteration is the least negative of the three effects. It also has an impact on norepinephrine, serotonin, and histamine levels in various areas of the brain through its impact on neurons in the hypothalamus, though this effect is much less well understood. However, unlike amphetamines, it seems to have some potential for real cognitive enhancement. There have been basic studies that show some value to this end, and as such this drugs and future drugs like it may actually start to approach a “brain pill” rather than simply tricking your body into not being fatigued.

On the face of it, Provigil seems to work for its intended purpose and is well tolerated, however its full mechanism of action is not well understood. Based on its known mechanism of action, it is likely much less addictive than amphetamines and other stimulants. However, because it is also much less well understood it is something that should also be treated with caution and used only as indicated/prescribed.

In sum, these different types of drugs often work as marketed, but each has their own positives and negatives. You should only use these drugs under the regular care of a physician who prescribes them to you for a legitimate condition. But, should you decide to obtain them outside of that, I would advise you tread carefully. While they may seem innocent at the time and certainly useful in many contexts, you may be making a deal with the devil in the process. There are much more beneficial methods of increasing alertness (exercise, meditation, etc.) than taking a potentially dangerous pill. I would suggest trying those before jumping to a pharmaceutical solution.

Hope this helps, Joe! Thank you for the question. As always, feel free to submit questions to me directly at the link above.

Till next time, tread lightly.

Justin

Sources:

http://www.sciencedirect.com.libproxy.usc.edu/science/article/pii/S0301008205000432

http://psycnet.apa.org.libproxy.usc.edu/index.cfm?fa=search.displayrecord&uid=1998-10330-005

http://journals.lww.com.libproxy.usc.edu/jonmd/Citation/1961/12000/Amphetamine_Addiction.3.aspx

http://pharmrev.aspetjournals.org.libproxy.usc.edu/content/14/1/1.short

http://www.cnsforum.com/imagebank/item/Drug_amphet_high/default.aspx

http://europepmc.org.libproxy.usc.edu/abstract/MED/10505821

http://psycnet.apa.org.libproxy.usc.edu/index.cfm?fa=search.displayrecord&uid=2004-14364-011

http://www-ncbi-nlm-nih-gov.libproxy.usc.edu/pubmed/0007701191

http://www.sciencedirect.com.libproxy.usc.edu/science/article/pii/0278584688900140

http://www.medscape.org/viewarticle/739491

http://www.pnas.org/content/102/9/3495

http://www.ncbi.nlm.nih.gov/pubmed/7751968

http://www.ncbi.nlm.nih.gov/pubmed/16497598