A conversation about the discovery of ancient neurons in mice with Johns Hopkins University researchers, Ninad Kothari, Ph.D., and Shreesh Mysore, Ph.D.

Attention-deficit/hyperactivity disorder (ADHD) is a lifelong neurodevelopment disorder that affects approximately 15.5 million adults in the United States. Depending on the type of ADHD, patients may find it difficult to complete tasks or follow conversations if they have Inattentive Presentation or if they have Hyperactive-Impulsive Presentation, to sit still or they may speak out at inappropriate times. If a patient shows symptoms from both types, they may have Combined Presentation.

It’s long been thought that executive dysfunction within the brain’s prefrontal cortex was to blame for this disorder, but a new discovery from researchers at Johns Hopkins University shows that might only tell part of the story.

The study, called 'Evolutionarily old brainstem neurons are required for the control of selective spatial attention,’ was recently published in Nature Communications.

Lead author Ninad Kothari, Ph.D., is an assistant research scientist and postdoctoral fellow within the university’s Department of Psychological and Brain Sciences.

His colleague and the paper's senior author, Shreesh Mysore, Ph.D., is an associate professor in the Department of Psychological and Brain Sciences.

Kothari and Mysore recently sat down with Managed Healthcare Executive to discuss the study results and what they could mean for the future of ADHD treatment.

This conversation had been edited for length and clarity.

MHE: What neurons did you discover?

Mysore: These are neurons that are called parvalbumin-positive inhibitory neurons. That is, if they are activated, they suppress the activity of the partners that they connected to.

Number two, they live in the brainstem, which is an evolutionarily old part of the brain, and these neurons are thought to exist in all vertebrate animal species. We know they exist in birds. We know they exist in turtles. We know they exist in fish and frogs. There is evidence suggesting that they are also found in primates and in humans.

The third, which is perhaps the most interesting one, is that Ninad, in this lovely study, discovered that these neurons appear to be critical for selective spatial attention control.

Kothari: If we were to put this in the context of, let's say, our conversation here. I am sitting in a room with windows all around, and there are birds flying by and undergrads walking behind me, but we can ignore them — I can select Shreesh as the target of my attention while he talks. This is where the neurons that we found become important, where they can suppress competing information.

MHE: How could this study of mice apply to humans with ADHD?

Mysore: Hyper-distractibility is a hallmark behavioral signature in ADHD patients.

This study is inferring a link between what these neurons do in the brainstem of mice and a human condition, which is ADHD. In future work we hope to then expand upon this discovery and ultimately perform experiments in humans using the information we now have from this mouse study.

MHE: Can you provide an overview of the study?

Mysore: Ninad, in his study, discovered that these neurons appear to be critical for the control of selective spatial attention. He showed this in freely behaving mice that are performing a human-like attention task that we designed in the lab a few years ago.

In this task, the animals need to attend to information from one location while ignoring information from another location. By scoring whether they correctly report the information at the attended location versus the unattended location, we can infer where the mice are paying attention on each trial. That is how we measure what they are paying attention to.

When we have these freely moving mice performing this complex attention task, Ninad uses a genetically based technique to selectively turn off only these parvalbumin-positive inhibitory neurons in the brainstem. Momentarily, it is as if these mice no longer have these neurons.

We then bring the same mice back the next day, once we know the manipulation has worn off — in other words, these neurons are back in function — the same animals go back to behaving normally. They are again able to pay attention to what they are supposed to attend to and ignore what they are supposed to ignore.

One of the issues we had to contend with in Ninad’s study is that historically, the view in the field has been that the prefrontal cortex, or generally forebrain circuits, are either the most important or even the exclusive seat of attention control. That’s where all the “interesting stuff” happens in terms of deciding what to pay attention to.

Part of that notion comes from the idea that having goals, voluntarily deciding to do something, and using that to drive your attention and behavior is something that happens in a more sophisticated way in animals with a more elaborated frontal-parietal network. There’s a standard notion that as kids grow up, there is a point when the prefrontal cortex develops. Until then, little kids find it hard, if you tell them, to stop doing this,” to inhibit those impulses. They have trouble saying, “No, my parents told me I shouldn’t do this; I need to sit in class and pay attention.” It takes time for that goal-driven capability to develop, and that development has been associated with the prefrontal cortex, which has therefore been thought of as a major seat of attention control.

I just want to be clear: we're not saying that the prefrontal cortex is not involved. We do believe that it is heavily involved, but the point that Ninad makes is it's not just the prefrontal cortex.

MHE: What are the next steps for this research?

Mysore: There are a few. The first is to understand how these neurons do what they do. The second is to try and understand how they interact with the rest of the brain to produce attention control. The third is to try and understand what and how they impact the control of attentional behavior in human populations.

MHE: What is one thing you’d like readers to take away from this study?

Kothari: We often put humans on a kind of pedestal, which is understandable. Humans have done a lot; we are extremely smart. But the idea that the abilities humans have evolved entirely independently is something we need to question.

In this study, as Shreesh mentioned, we asked: “Is attention a brain process or a behavior that only humans need to solve?” The answer is a resounding “No.” Fish have to solve the same problem of identifying the most important stimulus. Frogs, salamanders, birds, monkeys and humans all have to solve this same fundamental problem.

Another question is, could these species all be solving that problem in completely different ways?

That question is what drove our work, and it builds on decades of work that Shreesh and others have done in the lab and that we have continued to do. If fish can solve this problem — and fish don’t even have a cortex — then there has to be a subcortical mechanism. Fortunately, we were able to find and discover such a mechanism in mammals as well.

It is very important to do comparative work across species. To think that only human studies will be able to solve all of our issues today is, I would say, at least at this point in time, a slightly flawed way of thinking. We do need animal studies across many species, using all the techniques that have been developed with taxpayer support over many decades. We should continue that work — and, of course, also add human work on top of it.