Article in brief

In a study using mice, researchers found that vagus nerve stimulation, approved by the US Food and Drug Administration to help stroke patients recover their motor, can enhance adaptive motor behavior by triggering cholinergic signaling in the basal forebrain.

To understand how VNS can modulate specific circuits, the researchers used optogenetics and calcium imaging in mice learning a skilled range task. They found that VNS enhanced skilled motor learning in healthy animals via a cholinergic reinforcement mechanism. Enhanced motor learning depends on cholinergic neuronal activity in the basal forebrain, and in the primary motor cortex, VNS specifically modulates outcome-activated neurons.

According to a study published online July 19 in Neuron.

This finding strengthens the rationale for using VNS for motor recovery in stroke, which was recently approved by the US Food and Drug Administration for patients who have plateaued in their rehabilitation.

“One of the shortcomings in the development of VNS for post-stroke recovery is that the exact mechanistic basis for improvement is unclear,” said Jesse Dawson, MD, professor of stroke medicine at the College. of Medical, Veterinary and Life Sciences from the University of Glasgow. Dr. Dawson was the principal investigator of the VNS clinical trial in The Lancet which led to his approval for a stroke and was not involved in the Neuron study.

“This new study consolidates what has been the main hypothesis for the effect of VNS on neuroplasticity, namely that it is mediated by the activation of cholinergic neuromodulatory networks.”

Study details

VNS is used to treat epilepsy and depression; in both conditions, the stimulation is constant, said the study’s principal investigator, Cristin Welle, PhD, associate professor and vice chair of research in the departments of neurosurgery and physiology and biophysics at the University School of Medicine. the University of Colorado at Aurora.

While the stimulation device was essentially the same in his study (although much smaller) and was similarly implanted on the left side of the cervical vagus nerve, the stimulation protocol was significantly different, based on evidence suggesting that Precisely timed, rather than continuous, stimulation can drive circuit plasticity and enhance the acquisition of new behaviors.

“We applied the stimulation in a temporally precise way associated with specific behaviors,” she said. “We wanted to know when in the learning process VNS was effective in healthy animals, and to see which specific circuits were activated by stimulation.”

Mice with VNS devices in place were trained to reach through a slit to grab a food pellet from a position where it was poised, a task requiring precise movements. Dr. Welle and his team delivered vagus nerve stimulation at one of three different times: randomly during the 20-minute training session, during the reach, or after successful retrieval of the pellet.

“When the animal grabbed the pellet and brought it back to the mouth, we were then stimulating the vagus nerve,” she said. “This is the only time we found that stimulation increased motor learning.”

With the mock VNS, with the stimulator implanted but not turned on, the mice were successful 46% of the time. After training with VNS delivered after a recovery, they were successful 59% of the time.

In another experiment, designed to show that VNS itself was neither inherently rewarding nor aversive, Dr. Welle found that mice neither preferred to revisit a room where stimulation was initially applied, nor preferentially avoided it. . Instead, she says, “we think we’re tapping into the brain’s reinforcement system. This makes the animal more receptive to feedback indicating whether its action was successful or not,” and thus leads to faster learning.

It is not yet clear whether VNS would also accelerate aversive learning, or whether it is specifically related to reinforcement of a desired outcome.

To determine the reinforcement mechanism, Dr. Welle’s team placed electrodes in the basal forebrain, which is the source of cortical projection for cholinergic neurons. Enhancement of motor learning has been shown to be dependent on cholinergic neuromodulation, and the team showed that VNS modulated the firing rate of these neurons. When these cholinergic neurons were optogenetically inhibited, that is, they used light to modulate cell activity, the VNS could no longer enhance learning.

Figure 2

“We know that when we stimulate the vagus nerve, we also activate this system, as well as other centers in the brain. What we don’t know is if there are other parts of the brain that also contribute to the learning effect, and whether they are also necessary, in addition to the cholinergic system.”—DR. CRISTIN WELLE

VNS also activates other types of neuromodulatory systems, Dr. Welle noted, including the norepinephrine system, which is thought to be partly responsible for the anticonvulsant effects of VNS.

“We know that when we stimulate the vagus nerve, we also activate this system, as well as other centers in the brain. What we don’t know is if there are other parts of the brain that also contribute to the learning effect, and if they are also necessary, in addition to the cholinergic system,” important details that will need to be be developed in the future. experiences.

It is also not yet clear whether the VNS mimics endogenous reinforcement normally performed by the vagus nerve. “I would say the science is still not there on this issue,” Dr. Welle said, “but other groups are doing promising work, suggesting that vagueness may be necessary for things like spatial learning, and also for the representation of rewards from the gut, so there are clues.

Expert commentary

“This is a very elegant set of experiments because they provide very clear evidence that VNS, working through an effect on cholinergic networks, can cause motor cortex reorganization and neuroplasticity,” said the Dr Dawson.

“We know from our study that VNS has a small but important effect on improving upper extremity function in people after stroke, beyond what we would see with physical therapy alone.”

In their randomized, simulation-controlled study of 106 stroke patients with moderate to severe upper extremity weakness, Dr. Dawson and colleagues showed that six weeks of VNS combined with rehabilitation led to a clinically significant improvement in upper extremity Fugl-Meyer score in 47 percent of VNS patients compared to 24 percent in controls.

“This study sheds important light on a mechanism of VNS in the brain,” said David M. Labiner, MD, professor and chief of neurology at the University of Arizona College of Medicine in Tucson.

“We know that vagus nerve stimulation does a lot of things, including altering blood flow and affecting neurotransmitters in the brain,” none of which, he pointed out, are correlated with seizure control. “So it doesn’t surprise me that VNS also has the effect seen in this article” of cholinergic neuromodulation. The observed benefit on motor learning “is quite an exciting breakthrough, if it holds up and can prove useful in a significant number of people.”

Cost may be an issue, he added, suggesting that external stimulation could be a more practical treatment for the large number of stroke patients who could benefit from it.

“Despite the number of years of clinical use, it is difficult to understand how vagus nerve stimulation works in the brain,” noted Steven Schachter, MD, professor of neurology at Harvard Medical School. “This study brings us a lot closer to understanding at least one way it works in the brain.”

Although the relevance of the cholinergic facilitation discovered in this study for effects beyond motor learning is uncertain, “it clearly gives researchers a direction in which to pursue new hypotheses.”

If VNS can also facilitate non-motor learning, he added, it could become interesting both for treating other types of learning deficits, such as poor reading skills, and for cognitive enhancement. For both post-stroke rehabilitation and other more speculative applications, a non-invasive way of stimulating the vagus nerve may be preferable, particularly because the need for the required stimulation is likely to be short-term rather than chronic.

Disclosures

Dr. Welle didn’t divulge anything. Dr. Dawson revealed that MicroTransponder Inc. paid the conference fee to present the results of the VNS-related study in early 2020.