Heart rate increase causes anxiety

In 1884, the psychologist William James argued that contrary to prevailing wisdom, our emotional reaction to a situation is a result of our physical reactions. “We feel sorry because we cry, angry because we strike, afraid because we tremble,” he wrote. If he was writing today, having read a paper out this week by scientists at Stanford University, he would possibly also have said, “we feel anxious because our hearts are beating too fast.” By using a clever trick that involved making heart cells sensitive to light shone into the body through the skin, Karl Deisseroth can increase the heart rates of lab mice and show that - when their heart rates are higher - the animals display exaggerated signs of anxiety in stressful situations compared with when their heart rates are lower. This is reflected by increased activity in brain areas known to be linked to anxiety symptoms. Critically, it gives us an insight into how interventions like behavioural therapies and even relaxing pursuits like Yoga can help to manage anxiety disorders: by dropping the heart rate, they reduce the drive to the brain’s anxiety pathways…

Karl - There's a surprisingly large co-occurrence of cardiac problems like fast heart rhythms, tachyarrhythmias, and panic disorder, and nobody really had an explanation for this.

Chris - How did you try and probe that?

Karl - With the technology we developed called optogenetics, we can use light to turn on cells and in this case the heart muscle cells themselves. And we do this by introducing a gene, a bit of DNA, into the heart muscle. And this DNA directs the production of a very interesting protein called a channelrhodopsin. And this is a protein that we borrowed from microbes that receive light and opens a little pore, a hole in the membrane of the cell, and lets charged particles or ions flow across. We can put the gene for these proteins into one kind of cell and deliver light, and then we can have a direct, specific, primary effect on just the cell type that we're interested in.

Chris - So let me guess. You did that, you put that genetic construct into heart cells so you can then shine a light on the heart cells and make them beat faster?

Karl - That's correct. Exactly.

Chris - What did you do this in?

Karl - We did this experiment in mice, they have a mammalian heart and a mammalian brain. They have anxiety related circuitry, and they do this using many of the same brain structures as we do. But we still had to advance the technology a little bit because this was a new challenge targeting the heart. We'd done a lot of optogenetics in the brain before. The brain doesn't move that much. It's not a big beating organ, but the heart, there's so much movement to cause a synchronous contraction. We really had to deliver light across the organ itself. We solved that. We fitted the mice with little vests that had LEDs in them, and the mice could run around freely and we could still use the LEDs to pace the heart at the rate we wanted.

Chris - So the mice get a glowing vest that you can turn on - it's like John Travolta, but for mice - and you can turn this on and off and therefore change their heart rate. Does it change by much when you do this?

Karl - Well, we can change it as much as we want. The normal heart rate for a mouse is about 600 to 660 beats per minute, but when they're anxious or fearful, it goes up and we could set the rate at whatever we wanted. We could set it at 700, 800 or 900 beats per minute. And for most of the paper we worked on 900 beats per minute.

Chris - So you've got mice that you can artificially escalate the heart rate by a substantial amount. Does this produce a behavioural change in the mice?

Karl - That's right. We first asked, "Does the mouse seem to care?" And so we started with a very simple test, we let the mouse move freely between two chambers that were not threatening, not anxiety provoking. There was nothing different about the two chambers, except whenever the mouse was in one chamber, we would elevate the heart rate and the mice didn't care. But then we put the mice in anxiety-provoking situations - mice are very averse to being out in the wide open where it would be easy to prey upon them. So what happens when you pace the heart higher? Well, the animals much preferred being protected when their heart was going faster. So they more strongly preferred the enclosed areas and the corners and the walls.

Chris - And do you know where in the nervous system the outcome was centred? Where in the brain were they altering their activity and response to the heart rate change and was that provoking this an anxiety response?

Karl - Well, that was a big open question. And so we tackled that next and we saw a couple areas that did go up in activity. One was the prefrontal cortex, and this is involved in long-term action planning, what we call executive function. Another part of the brain called the insular cortex also was activated by the cardiac pacing. And this was also very interesting because this site is known to be a part of the brain that receives a lot of what we call interceptive information that comes back from the body. So these were two very interesting regions that we saw were activated by cardiac pacing.

Chris - Do you know how the messages get from the heart to places like the brain's insular so that it can respond? Is that through the blood or is there a nerve connection that's doing that?

Karl - There is a nerve connection called the Vagus nerve that comes from the brain, exits the skull, and it innervates all kinds of organs in the thorax and abdomen, including the heart, but also the gut, but also brings information back. And the vagus nerve is just a synapse or two away from the insular cortex. And so that's a very plausible route for information to flow.

Chris - What now are the clinical implications of this?

Karl - We see this all the time clinically, that there are patients with elevated heart rate and altered mood or anxiety states. These patients are typically treated with conventional anxiety medications that target the brain, but they have side effects. They're strong medications and they're not perfect. An implication of this study is that actually there's another opportunity that we could pay some more attention to directly reducing the heart rate as a way of improving psychiatric symptoms. And there are plenty of interesting medications that would be helpful for this that don't affect the brain, would have fewer side effects, and that could well help patients with their anxiety. And it's plausible too because we know that many relaxation methods, cognitive behavioural therapies, many of these focus on having people try to achieve a direct control over their breathing rate. Although we know these help, we've never known these work through an initial primary direct effect on the body. And this might help us treat patients more completely.