Imaging Functional Recovery in a Monkey Model of Spinal Injury

In neuroscience, we spend a lot of time studying the normal function of the nervous system, and we spend a lot of time studying disease processes that can impair this function. What we don't typically do is study how functional recovery can happen. Functional recovery is how an neurological impaired individual uses existing pathways to compensate for the injury -- thereby improving overall function. The lack of study in this area is unfortunate, particularly because in some cases the brain can show an amazing ability to compensate for injuries.

(Just as an aside, I want to distinguish compensation from regeneration. Functional recovery is the use of existing pathways to compensate for an injury. It differs from regeneration which involves the regrowth the damaged pathway. Regeneration is an interesting and important matter in itself, but it is not what we are discussing here.)

To this end, Nishimura et al, publishing in Science, use a monkey model to study the functional recovery of fine motor skills in the hand after spine hemi-section. Their study is excellent, so I want to spend a lot of time discussing the background.

Background

To understand how this paper studied functional recovery, you first need to know a little neuroanatomy, particularly neuroanatomy of the pathways that control movement.

The primary tract -- meaning a projection of axons carrying information from one part of the brain to another -- that carries motor information to the distal extremities in humans (and primates) is called the corticospinal tract. (There are many other tracts that activate the other muscles. We are just talking about the one that innervates the muscles at the ends of your arms and legs.)

The corticospinal tract originates in an area of the brain called the primary motor cortex or M1. M1 is responsible for coordinating fine motor movements, and it is the last area that information signaling motion goes to before it leaves the cerebral cortex. Here the first motor neuron (often called the primary motor neuron or upper motor neuron) sends its axon down from the cerebral cortex into the spine.

Here is an important note, however. Your brain is crossed at many points, meaning that the information that goes to the right side of your body comes from the left hemisphere of your brain. In this case, the information from the left M1 must cross the midline -- in neurological jargon it decussates -- to the other side. The corticospinal tract does this in a part of the brainstem in the medulla called the decussation of the pyramids. (Actually it is slightly more complicated because the decussation happens for about 90% of the fibers, leaving some fibers on the same side but this doesn't really matter for our discussion.)

After decussating, the tract continues in the spine down to the level where the nerve to the particular muscles that neuron activates originate. Say the neuron from M1 activates muscles in the hand; then this neuron will stop at a level in the upper spine where the nerves to the hand originate.

At this point the primary neuron synapses on a secondary neuron in the spine. The secondary motor neuron or lower motor neuron then leaves the spine to join a nerve that goes to the target muscle, in our example the hand. (Below is a diagram of this anatomy. Do you like it? I drawed it meself. As should be obvious, I was not an art major. Or an English major for that matter...)

Note that the corticospinal tract crosses the midline (indicated by the dotted line in the diagram) in the brainstem. This means that if I were to cut the spine on just one side of the midline -- called hemisection in our jargon -- this would paralyze the same side of the body as the side I cut on. (The little scissors indicate the point of hemisection.) The jargon here is that the paralysis is ipselateral, meaning on the same side as the lesion. However, those fibers that I cut would have originated on the M1 of the opposite side of the midline in the brain -- we call this contralateral or opposite to the side of the lesion.

Is everyone coming with me on this because it is sort of important to understand this paper? (This stuff confuses medical students every year, so don't feel bad if you have to read it a couple times to get the gist of it.)

Nishimura et al.

Nishimura et al. wanted to study functional recovery in monkeys. They noticed that when the spinal cord of macaques is hemisected (as the example in the background) fine motor function returns to the fingers within 3 weeks. This is in many ways surprising. We discussed how the information gets from the brain to the spine to the muscles. If the fingers are becoming functional again, the information must be taking some alternative route. What is that route?

To figure out this route, the authors hemisected the spines of several monkeys. Then they subjected the monkeys to a task that required fine motor skills -- in this case they had to get a little piece of food out of a tiny hole.

The authors then imaged the brains of the monkeys during the performance of this fine motor task during the period immediately before, immediately after, and long-after the lesion. The do this using a technique called PET scanning which is a way to measure the metabolic activity in a particular brain area.

Unsurprisingly, the contralateral M1 is active during the performance of the task prior to the lesion. (Remember that contralateral M1 is the origin of the corticospinal pathway.) Here is what the data looks like from PET scanning (Figure 2 of the paper). It is a picture of the activity in the brains of control animals prior to surgery. (Click to enlarge)

The big red blob on the contralateral side indicates activity in M1.

However, after the lesion the authors note interesting changes in the activity during attempted performance of the fine motor task. I will summarize those below.

They divide the after-lesion recovery into two stages.

• During the early stage (~1 month post-operative) the activity in both the contralateral and ipselateral M1 increased. This means that on the side that you would expect activity (contralateral) there is much more activity -- possibly in an attempt to compensate for the injury. Likewise, the M1 on the opposite side of the brain (ispelateral), which is generally not thought to communcate with that hand, has also increased. This is very likely also an effect of compensation. In a general sense, the technique of compensation in the early stage is to increase the volume of the signal by increasing the activity in the original start point (contralateral M1) and related start points (ipselateral M1).
• During the late stage (~3 months post-operative) whole new regions become active. For example, both the contralateral and ipselateral premotor (PM) areas also become active. We discussed earlier the hierarchy of activity of the corticospinal tract. Well, above M1 in that hierarchy is PM. PM anticipates, activates, and regulates the activity in M1. (Shown below is a diagram of where PM is in relation to M1.) The two regions are very close together, and they are part of the general movement pathways, so this isn't entirely surprising. In a general sense, the technique of compensation in the late stage is to recruit additional areas to increase their activity to make sure the signal gets through.


There are a couple of important interpretational notes, so to speak, for the data above. The first is that while region (contralateral M1) is directly connected with the appendage in question, the others are indirectly connected with it. This connection can occur either through spinal interneurons -- in essence, going around the injury in the spine -- or by connections within the brain. The M1s on both sides of the brain are connected (as I think are the PMs, but I have to look that up).

The second note is that increases in activity do not necessarily imply that a region is necessary for compensation. It could be an epiphenomenon, or it could be because the animal is aroused -- it is probably pissed because a previously easy task is now hard.

This second issue is why I am glad the authors continued their experiments. In their second set of experiments, the authors inactivated different regions of the brain during the performance of the task after the lesion. They are trying to determine which of these regions being activate is necessary to compensate for the injury.

During the early phase of recovery, when they inactivated M1 on either the contralateral or ipselateral side, the monkey had much greater trouble getting the food. This indicates that increased activation in M1 on both sides is necessary for the functional recovery during the early stage. However, when they inactivated M1 on either side during the late stage of recovery, there was no deficit for the ipselateral M1 and an attenuated deficit for the contralateral M1. This indicates that something happened during the interim such that M1 activity is required less to compensate for the injury.

Could the mode of compensation be activity in PM? Well, the authors tried inactivating PM, and there was no deficit no matter when you did it, so it appears that the PM activity is not required for compensation. There are other regions that are activated during the process of compensation, and it is certainly possible that these regions are involved.

What to make of this paper?

1) Functional compensation is a long and multi-step process. It involves the recruitment of numerous brain regions, and the brain regions involved can vary over time. We still don't know enough about this incredible process, and we need to learn more.

2) The brain is amazing for a number of reason, but one is definitely its ability to modify existing architecture to compensate for a lesion. The fact that these monkeys can restore motor coordination in 3 weeks is remarkable. While in most cases a dead neuron is not replaced, this research and others suggest that large functional recovery is still possible.

This has huge implications for the treatment of individuals with strokes. Physical therapy works for patients with strokes because it recruits still-functioning pathways to compensate for non-functioning pathways. I would not say that after a stroke all patients have the capacity for unlimited improvement; however, their capacity can sometimes surprise you.

Basically, the take home is that you should never write off a stroke patient's ability to find a way. It is possible for them to get quite noticeably better through functional compensation.