Improving Stroke Care by Improving the Understanding of Subcortical Structures

Asher J. Alberston, MD, PhD, a neurocritical care fellow at Washington University School of Medicine in St. Louis

Asher J. Alberston, MD, PhD

When it comes to stroke care, there are a number of challenges plaguing physicians and patients. One of the biggest of these is the need to better understand the mechanisms of stroke recovery in order to improve outcomes.

At the American Neurological Association’s 143^rd Annual Meeting in Atlanta, Georgia, a session covered some of the work being done to better understand these biologic workings. One of the presentations was given by Asher J. Alberston, MD, PhD, a neurocritical care fellow at Washington University School of Medicine in St. Louis.

To gain some insight into the research he and colleagues are doing and how it could improve or impact clinical care, NeurologyLive spoke with Albertson on-site at the conference. He shared his experience in building models of the thalamus, as well as what’s next for his research.

NeurologyLive: What prompted your research, and could you explain it further?

Asher J. Alberston, MD, PhD: I would say that, broadly, the thing I'm most interested is in understanding the way individuals recover from stroke, and more specifically, I'm really interested in understanding some of the presumed plasticity that might underlie some of that recovery. There are a lot of people at the American Neurological Association’s annual meeting, a lot of people across the country, in the world, that are doing incredible research to try to get at these mechanisms, but broadly, we have a huge amount to still understand about it. Some of that understanding is going to be absolutely key to, hopefully, eventually improving that trajectory. Using those discoveries to improve the trajectory of patients after a stroke.

That's kind of broadly what I'm interested in. Specifically, the type of stroke I study is subcortical stroke—so strokes that happen in deep brain structures. It's where most strokes occur, and if you're interested in recovery from strokes, a lot of these people do have some recovery. I have a broad hypothesis that when a stroke occurs in a subcortical structure, and in my case specifically, the thalamus, that there is a disconnection of that subcortical region—the thalamus—from connected brain regions and from local networks. A lot of work by other people suggested that probably also global brain networks. Recovery is in my hypothesis thought to be associated with reconnection of those networks, and specifically that new axons actually sprout and mediate some of those reconnections and that some of this may be an underlying mechanism of structural plasticity that underlies that recovery.

To get at that what I've done is developed a model of subcortical injury. In this model, we injured the thalamus and at the same time image the brain volt in a healthy state immediately after an injury, and then a few weeks later. In our model, we're able to image the cortex and animals, we're able to injure the thalamus, and we see that. We see an injury and somatosensory signaling through the thalamus that recovers over time. Then, to get at my hypothesis that this recovery is mediated by new axon sprouting, I knocked down a gene and the thalamus called GAP43, which I think is necessary. A lot of people have done some amazing work showing how essential this gene may be to axon sprouting. When we knock down this gene in the thalamus, the animals that receive this injury fail to recover over time. We think that this is because they're failing to sprout new axons and reconnect to the sensory cortex over time, and we're hoping to obviously expand that research to a pretty large degree.

What’s the next step with this research?

We're very much at a pilot stage with understanding this. We have data to suggest that this is the case, like I explained, but we've got a lot more work to do. Finding this sort of opens the door for a lot more studies, so we'd like to look at more time points, we'd like to look at the specific dynamics of this gene and the axons, we'd like to look at axons themselves, structurally, and we'd like to look at it in different stroke situations not—just thalamic stroke. The thalamus is a really nice model to study because it lets us look at one connection—thalamus to somatosensory cortex—but, of course, there are many more connections than that, there are many more networks than that, even the thalamus is far more complex than that. Piecing that into the broader brain itself in some of these more complex networks, and really trying to figure out how this particular piece of the broad stroke recovery and plasticity after stroke hypothesis fits in will be key.

What’s the potential impact on clinical practice of advancing this understanding?

There's been this huge push of research over time to try to find interventions in the acute stroke period that are either a neuroprotective and prevent strokes from being so bad or enhance recovery, and a lot of that just hasn't taken off. That's for a lot of reasons, many of which we probably don't understand yet. So, we're left with interventions that either act directly to stop a stroke while it's happening through thrombolysis or thrombectomy, and long-term rehab strategies—and those strategies are getting better and better.

If we can take steps like this to identify specific proteins, specific genes, and, most importantly, specific synaptic and neuroscientific mechanisms that explain the way the brain may respond to an injury like that, that would lead to the potential to broaden the window for both potential therapeutic intervention and to find brand-new, more high-yield targets that one could go after. As well, it could enhance what's happening during that window beyond just a better understanding of mechanisms of plasticity in the brain itself.

In these models, have you found anything that was surprising or unexpected?

Our suspicion, and it's still within our hypothesis, was that new axon sprouting was one piece of the pie, and that, likely, there are multiple mechanisms at play here and all of them have the potential to be major impactors in our understanding of stroke recovery and, hopefully, someday in the way we take care of patients with stroke. But we did find a robust effect, and we were a little bit but surprised by how robust that effect was. I don't think it means that it's the only effect—we're still big believers that there are multiple things at play here and understanding all of that will be important. But we were most surprised by how robust the effect was.

Transcript edited for clarity.