Sunday, August 12, 2012

How does Deep Brain Stimulation cure Parkinson's Disease? A Cellular Look

Deep Brain Stimulation (DBS) is one of the miracle cures of our lifetime.  Used to treat Parkinson's Disease, and now being applied to depression, it is a drastic but amazingly effective measure.

EDIT 9/23/12: Just because DBS has been shown to be amazingly effective in treating Parkinson's Disease symptoms, that does not mean that it is right for everyone. There are other effective treatments for PD and DBS involves an invasive surgery. In addition, the long term effects of having a stimulating electrode constantly pulsing electricity in your brain are not yet fully known.  In other words, this blog is not giving medical advice, so please don't take it as such.

Deep Brain Stimulation (DBS)

To apply DBS, an electrode is implanted deep in the brain (the SubThalamic Nucleus for Parkinson's Disease).  An implanted wire under the skin connects the stimulation electrode in the brain to a stimulator implanted on the chest. The stimulation can be turned on and off here. 

Here is a short video showing the effect of DBS on and DBS off.  (The actual demonstration starts at 1 minute in, the rest is some arguing in French)

Once the stimulation is turned off, the man has twitches an tremors that prevent him from functioning normally.  As soon as the stimulation is turned back on, he can walk and talk smoothly. 

This is pretty astounding, right? I mean honestly, if I just saw this video and didn't know anything about it, I might not even believe that it was real.  How can electrical stimulation in the brain completely alter this person's ability to move?

Well, scientists around the world are wondering the exact same thing. One recent study made use of optogenetics to dissect the pathways involved in deep brain stimulation.

They first elicited Parkinson's Disease in mice by destroying the dopaminergic cells (in the substantia nigra which feeds into the striatum) on only one side of the brain. Then they give the mice a stimulant drug which makes them hyper. While normal mice would run all over the place on this stimulant, these hemi-parkinson's mice run in a circle because of the imbalance between the two sides of the brain.

or hemi-parkinson's disease (source)

To test whether the treatment you are giving the mouse 'cures' their Parkinson's Disease, you literally count how many times the mouse runs in a circle.  If it runs in a lot of circles, your 'cure' didn't work.

Implanting an electrode into the STN of the mice and applying the stimulation did reduce their circle running, just like the DBS reduces Parkinson's symptoms in humans.  But here's the thing, the STN has a lot of neurons in it, and a lot of axons passing through it.  Stimulating this brain region could be inhibiting firing, or exciting neurons, or something else entirely. 

So Gradinaru et al. (2009) decided to stimulate specific (genetically identified) classes of neurons to determine which aspect of the electrical stimulation was actually 'curing' the Parkinson's symptoms. 

First they tested the most common hypothesis, that the stimulation inhibited the STN.  However, when they directly inhibited the neurons of the STN, their mice still ran in circles, indicating that the brain was still unbalanced. 

Second they stimulated the glial cells around the STN, but still no luck.

Third they excited the neurons of the STN.... but... still the mouse ran in circles. 

I imagine this was very puzzling to the scientists conducting this research.  If stimulating the STN with a big metal electrode is not exciting, and not inhibiting the STN, what on earth could it be doing?

Finally they tried targeting the axons of the motor cortex which run through the STN.  And! low and behold, the mouse did not run in circles any more. Below, rotations per minute is basically a measure of circle running, and the HFS is the stimulation. You can see that as soon as the stimulation is activated the mice generally stopped running in circles, but when the stimulation was turned off, they ran in circles again. 

Gradinaru et al., 2009

So a new theory has emerged, that the stimulation of the STN might actually be acting on other neurons which are not even located in that brain structure.  It clearly works in mice, but whether this is the way that Deep Brain Stimulation works in humans is still not clear. 

© TheCellularScale

ResearchBlogging.orgGradinaru V, Mogri M, Thompson KR, Henderson JM, & Deisseroth K (2009). Optical deconstruction of parkinsonian neural circuitry. Science (New York, N.Y.), 324 (5925), 354-9 PMID: 19299587


  1. Is it thought that the antidepressant effect of DBS is mechanistically related to the anti-Parkinsonism effect of DBS?

    1. I don't think so. As far as I know, the DBS electrode for depression is usually not placed in the STN, as it is in Parkinson's Disease, but rather the cingulate gyrus (and other locations). This explanation is very specific to DBS in the STN (and in mice), so I am not sure what it can say about the mechanisms underlying DBS depression treatment.

  2. nice article, liked the way you describe the paper in such an easy-to-understand way, always find that difficult to do. One note though, Deep brain stimulation is not that new, it has it routs in the mid 1800 going back to Duchenne de Boulogne. Even before that Giovanni Aldini used 'galvanisation' to treat depression :)