Thursday, August 29, 2013

Recipe for a mad scientist – lab coat, rats, electricity


I spent some time as an undergrad in the University of Washington’s Department of Physiology and Biophysics conducting research on rats with incomplete spinal cord injuries.

Before I describe my experience, I’d like to explain some of the background for the study. My PI (principle investigator or “guy who runs the show”) was interested in a concept called Hebbian Plasticity.  This whole concept is a rather simple one, basically stating that the more times you use a certain neural pathway, the more “solid” it becomes. This theory is used to describe a dynamic concept in which neurons can adapt to repeated stimuli and “learn”.  You hear about “the science of neuroplasticity” on those Luminosity commercials, and I find it rather silly because it isn’t necessarily new science, it’s just learning by repetition – a concept we are all familiar with. Maybe some of you will disagree, but I recommend you save the money for something more fun. I digress. An important piece of Hebbian Plasticity is the timing of the signals. It is not enough to simply have neuron B receive a signal from neuron A to induce Hebbian Plasticity. If my memory serves me right, the appropriate window of time is between 20-50 milliseconds, outside of this window, a connection between A and B wouldn’t be any more solidified than if it were some random signal coming in from A two days later.  Keep this information in mind as I describe the research we did in the lab.

The research begins with a rat that is trained to reach through a slit to grab a pellet of food from a block with her arm and eat the pellet like an apple. This is a fun thing to do because we’re so used to seeing rats stuff their faces in to their food, but it does take quite a bit of time to train the rats to learn this behavior. The rats are given a score based on their performance in grabbing these pellets and once the rats are trained sufficiently, they are given a lesion on their spinal cord that considerably limits the use of the arm that was used for reaching.

After the rat is injured, it is allowed to heal and then a second, rather massive surgery is performed. A series of microelectrodes is placed into the spinal cord just below the lesion, wires are inserted into the forearm, biceps, and triceps of the affected arm, and a computer chip is attached to the skull of the rat, like some sort of morbid hat.

The wires in the arm of the rat are for EMG recordings, or recordings that gather electrical information every time the rat is able to use these muscles, indicating the rat is choosing to reach, even though it is severely limited because of the spinal cord injury.  The EMG signal is then sent to the computer chip on the rat’s skull, which relays the signal to a brain computer interface (bigger chip AKA neurochip) that will wait about 20 milliseconds to send a signal to the spinal cord electrodes. The microelectrodes in the spinal cord then send the signal down the normal pathway that the rat uses for reaching motion in efforts to strengthen the remaining neural pathways that weren’t damaged by the lesion. In essence, the neurochip tries to pick up the signal that was interrupted by the lesion on the spinal cord and sends that signal to the remaining pathways that extend past the lesion. Also, the signal that is sent down from the neurochip is not a signal strong enough to actually cause a muscle twitch. We call that being “below threshold.” We did this to make sure that the results we were seeing were not simply due to the magnitude of the electricity and to make sure we weren’t masking any real long-term progress or hindering any opportunities for true plasticity.

According to the theory of Hebbian Plasticity, if this signal is propagated properly in the right time window, we can increase the functional output from these remaining neurons and we can get a net result very similar to the result that would have been the case if the injury had never happened. Of course this is in the ideal theoretical world.

In my experience in the lab, I was lucky to be around long enough to see some preliminary results. The initial results were promising, showing an increase in the rats’ reaching scores when they received stimulation as opposed to the rats that did not receive stimulation.  

Like any study, this study has its limitations, but it was exciting for me because medicine seems to be pretty behind in terms of advancements for people with spinal cord injuries and other central nervous system traumas. People who live with spinal cord injuries have a set of problems that most uninjured people could never truly understand. I’ve heard people who were wheelchair bound just wish to have voluntary control of their bladder again. Or be able to make love. Regardless, if anyone is interested in central nervous system research, I really think it’s an area with plenty of potential for profound breakthroughs. I’m convinced that in ten years we will have some very sophisticated technologies available to us that have academic roots in the type of research I was able to do at UW and that you can be a part of too.

4 comments:

  1. This comment has been removed by the author.

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  2. This is incredibly interesting stuff! When it comes to spinal cord injuries, oftentimes therapies can actually induce pain syndromes. Do you happen to know if the method you described would prevent that? The alternative therapy that I have heard of is at the hands of Stephen Davies, a neurobiologist out at Anschutz Medical Campus; he is actually very close to being able to not only regrow axons for spinal cord injuries, but to be able to prevent the pain syndromes that are often associated with spinal cord trauma! However, his method involves stem cells. Basically, he utilizes human embryonic multi-potent stem cells and pre-differentiates them into a particular class of glial restricted precursor cells: astrocytes and treats them with a particular protein: BMP (bone morphogenetic protein), the cells are then injected into the spinal cord injury site of rats (Davies et al. 2011). The pre-differentiation, for reasons I don’t entirely understand, seems to regrow the axons, reestablish normal movements, and eliminate pain syndromes (Davies et al. 2011). If you’re interested, I highly suggest reading some of his publications – his work is fascinating!
    References:
    Davies SJ, Shih H, Noble M, Mayer-Proschel M, Davies JE, et al. 2011. Transplantation of specific human astrocytes promotes functional recovery after spinal cord injury. PLoS ONE. 6(3): e17328. doi:10.1371/journal.pone.0017328

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  3. Ben,

    That's some pretty awesome research that you got to participate in. It did make me want to look a little further into the subject so I did some sifting in regards to Hebbian plasticity and found an article from the Journal of Neurological Science by Huang S., et al. and learned some interesting things about how even differences in even the types of cells as well as their specific receptors (aka - NDMA vs. mGluR5) can have a significant effect on how "plastic" the synaptic connections become. Worth the read, it's only 6 pages. I wonder, if they were able to pin point specific receptors in the specific area of the spinal lesion and manipulate them in a way to increase the speed or efficiency of the recovery?

    References:
    Huang S, Huganir RL, Kirkwood A. 2013. Adrenergic Gating of Hebbian Spike-Timing-Dependent Plasticity in Cortical Interneuron. The Official Journal of the Society of Neurological Sciences [Internet]. 33 (32):13171-8. Available from: http://www.jneurosci.org.dml.regis.edu/content/33/32/13171.full?sid=2bce8846-0fa7-4d73-bd84-8bae190a2e59

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  4. Garrett,

    As far as the UW study, they didn't target specific types of receptors. The treatment was more along the lines of "how much current" and "how fast". It was a difficult task that had to be individualized to each rat. We would have to observe if the stimulation they were receiving was actually inducing movement or not. Each rat has a unique threshold, which we would aim to stay just slightly below. Interestingly, their thresholds would increase over time, making the current adjustment something we had to keep a close eye on.

    Melissa,

    As far as inducing pain, it's hard to really tell, given the rats can't tell us much about their experience. We did notice that few rats would lick at their injured hand more frequently after surgery, which we thought may be a perceived tingling sensation down the arm due to the spinal cord injury, but we can't be certain. the next step would be applying this sort of therapy to a non-human primate, then we could have considerably more access to that kind of information.

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