Totally effective, side-effect free treatment of Parkinson's continues to elude physicians, but a study by Deuschl et al in the NEJM shows that we are definitely making progress.
Deuschl et al performed a randomized study that assigned patients into one of two groups. The control group recieved the standard treatment for Parkinson's -- which right now is pharmaceuticals like the drug L-dopa. The experimental group had stimulating electrodes implanted into the subthalamic nuclei (STN) of their brain in addition to treatment with L-dopa. The study shows that the individuals in the experimental group showed dramatically more improvements in function by quality of life indicators than the control group -- even though the experimental group did have more serious complications.
This is going to be a long post, so I thought I would break it up into three blocks. First, I want to talk about the background of how the part of the brain affected by Parkinson's disease -- the basal ganglia -- works. Second, I want to talk about treatments for Parkinson's as they exist now. Finally, I want to talk about how this study improved on those treatments.
The Basal Ganglia and You
Before, I talk about the results of the study, I want to give you some background. Parkinson's disease is a progressive motor disorder resulting from the selective death of a very tiny group of neurons in the brain called the substantia nigra. These neurons may be few in number, but they do something very important. They secrete a neurotransmitter called dopamine into a part of the brain called the basal ganglia.
The basal ganglia works kind of like a switch that is involved in choosing to initiate motion. When you brain is considering initiating motion, a signal goes to the basal ganglia. The basal ganglia make a computation, and then a signal is sent back either encouraging or discouraging the activation of that motion. The computation is performed by the ratio of the activity through two parallel pathways. (Below is a diagram that I use to teach the medical students this material -- I TA the neurology course at Sinai. The diagram is explained more below.)
- The so-called direct pathway runs directly from input in the striatum to the output at the globus pallidus interna (GPi)/substantia nigra pars reticulata (SNr) -- two areas which are anatomically distinct but functionally the same. (The substantia nigra here is is different from the one that actually degenerates in Parkinson's. That is part is called the substantia nigra pars compacta (SNc). They do different things.) By inhibiting the output, activity through the direct pathway disinhibits the ventral anterior and ventral lateral (VA/VL) portions of the thalamus that activate the cortex. This makes the cortex more likely to initiate motion. Thus, activity in the direct pathway increases the likelihood of initiating motion.
- The so-called indirect pathway runs through the globus pallidus externa (GPe) to the subthalamic nucleus (STN) to the output in GPi/SNr. Because the indirect pathway activates the output, it inhibits the activity in VA/VL, inhibiting activity in the cortex, and making initiation of motion less likely. The activity in the indirect pathway decreases the likelihood of initiating motion.
Where does the substantia nigra come into it (remember we are talking about the pars compacta)? The SNc releases dopamine onto the striatum -- the input. Remember that there are two pathways through the basal ganglia. It turns out that each is associated with a particular type of neuron in the striatum. The neurons that feed into the direct pathway can be stained with substance P (SP). The neurons that feed into the indirect pathway can be stained with enkephalin (Enk). It turns out that each of them possess a different dopamine receptor. The SP neurons (direct pathway) have D1 receptors. These receptors are activated by dopamine. The Enk neurons (indirect pathway) have D2 receptors. These receptors are inhibited by dopamine. The net result is that dopamine in the striatum increases activity through the direct pathway and decreases it through the indirect pathway. Thus, dopamine in the striatum leads to a net
loss increase in the ability to initiate conscious motion.
Everybody coming with me still? Good.
In Parkinson's disease, because of the death of neurons in the SNc, there is a loss of dopaminergic input to the striatum. This explains the clinical presentation of Parkinson's patients. Parkinson's patients have a lot of trouble with motion because they have trouble initiating motions. Here is a diagram that I give to my class that illustrates what happens to the pathways we just talked about:
Current Treatments for Parkinson's and Their Side Effects (And You)
If we wanted to remedy the Parkinson's symptomatology, how would we go about it? Well one way is to add dopamine back into the system. This is what Parkinson's drugs do. The most common is called L-dopa -- which is a precursor of dopamine. L-dopa is changed into dopamine in the brain, allowing for an alleviation of the symptoms. However, as the more and more neurons in the SNc die, more and more L-dopa is often required. This can have some very unpleasant side effects such as what is called L-dopa induced dyskinesia (LID). LID is what happens when you overshoot the amount of dopamine you need to initiate motion, and start initiating way to many.
Do you remember the ad with Michael J. Fox during the election where he was having trouble sitting still (the one that Rush Limbaugh revealed yet again that he is a horse's ass by criticizing Fox)? Here is the ad on YouTube:
In this ad, Michael J. Fox is showing symptoms of LID -- difficulty in controlling motion.
Let's think what else you could do to fix Parkinson's. Well one way theoretically would be to lesion something in the indirect pathway. This would lead to a lot easier initiation of motion.
It turns out that this is a extraordinarily bad plan, as lesions to places like the STN produce uncontrolled ballistic motions -- a disorder that if it results from a lesion to the STN on only one side is called hemiballismus. Patients with hemiballismus throw their arms and legs uncontrollably on one side. It is a horrible disease that can be a symptom of strokes. If you are interested in why STN lesions cause uncontrolled motion, check out the diagram below:
Lesions don't work, but what if you combined manipulation of the basal ganglia by stimulation with drugs. This would allow us to take the best parts of drugs and the best parts of surgery. This is what the experimenters did in this study. They compared drugs alone -- with all the side effects associated with LID -- with drugs PLUS stimulating the STN using an electrode.
However, if lesions of the STN nucleus result in uncontrolled motion, shouldn't STN stimulation lower the amount of motion? Wouldn't the two just cancel each other out?
It turns out that because this system is complicated the addition of the STN electrode significantly lowers the amounts of LID associated side effects but does not affect the benefits of drug treatment. The basal ganglia is not simply an off-on switch. It is involved in degrees in the selection of motions as well as their initiation. This means that stimulation of the STN results in a high level of selectivity -- lowering the side effects of Parkinson's treatment like LID while allowing the effects of the drugs to still manifest themselves.
This Study (And You)
In any case, it does work; in fact it works better than drug treatment. This brings us back to Deuschl et al. Deuschl et al were comparing drug treatment to implanting electrodes in the STN PLUS drug treatment. What they found is really good. The individuals with STN electrode show greater improvement in symptoms as measured by quality of life indicators -- did the patient need help, how did they feel, etc. It is always better to use these indicators in my opinions than direct measures of ability to move. They show whether your patient is really happy.
Here is a chart showing the comparison of one of these indicators (click to enlarge):
What you see is that for a variety of indicators the patients are much more satisfied with the stimulator than with the drugs alone. In fact, the drugs alone were causing little or no improvement in these indicators, and the stimulators are causing improvement. The lower chart shows the amount of time the individuals spend each day doing different activities. Look at the dramatic increase in the amount of time spent being mobile without complications. Those are truly fabulous improvements.
Let's look at the downsides though. Implanting these electrodes requires major surgery. As a consequence, the observed serious side effects in the study -- including hemorrhage into the brain -- are much higher in the stimulator group. Still, I think that for these improvements in symptoms many patients are willing to take that risk.
Conclusions: It looks like we are making real progress helping these patients. Granted we can't cure this disease. Maybe we will be able to eventually with stem cells. But I like that people are being real creative and using some pure science to make these patients better.
THANK YOU VERY MUCH!!With these diagrams the pathognenesis and symptoms of parkinson are very understandable!!
"The net result is that dopamine in the striatum increases activity through the direct pathway and decreases it through the indirect pathway. Thus, dopamine in the striatum leads to a net loss in the ability to initiate conscious motion."
Should this read, "Thus, dopamine in the striatum leads to a net INCREASE in the ability to initiate conscious motion?"
I thought that increased dopa would increase ability to initiate motion as the converse of that (as in Parkinson's) is the loss of dopa leads to decreased ability to initiate motion.
Though this is a breakthrough, you have to realize that most patients are to old for or cant get surgery.
Thanks for noticing that Tom. I fixed it.
Firstly - thank you - diagrams make it easier to understand.
Secondly do you know if the D2 receptor is located at the Putamen and the D1 receptor at the Caudate? Or is this the wrong way round or way off track.
Lastly - any thoughts on gene therapy? Up regulate dopamine production/upregulate dopaminergic neuron growth?
I would be most grateful if you could answer these two questions.
the number of dopaminergic neurons in the Substantia nigra pars compacta.
The locations of the autoreceptors and their role in the substantia nigra pars compacta.
Thank you so much.