Article In Brief
In a study using mice, researchers found that vagus nerve stimulation, which the US Food and Drug Administration approved to help stroke patients with motor recovery, can reinforce adaptive motor behavior by triggering cholinergic signaling in the basal forebrain.
Vagus nerve stimulation (VNS) can reinforce adaptive motor behavior in mice and does so by triggering cholinergic signaling in the basal forebrain, according to a study published online July 19 in Neuron.
The finding strengthens the rationale for the use of VNS for motor recovery in stroke, which was recently approved by the US Food and Drug Administration for patients who have reached a plateau in their rehabilitation.
“One of the gaps in development of VNS for post-stroke recovery is that the exact mechanistic basis of improvement is unclear,” said Jesse Dawson, MD, professor of stroke medicine in the College of Medical, Veterinary and Life Sciences of the University of Glasgow. Dr. Dawson was the lead investigator in the clinical trial of VNS in The Lancet that led to its approval for stroke and was not involved in the Neuron study.
“This new study consolidates what has been the leading hypothesis of the effect of VNS on neuroplasticity, that it is mediated through activation of cholinergic neuromodulatory networks.”
VNS is used for treating epilepsy and depression; in both conditions, stimulation is constant, said the lead study investigator, Cristin Welle, PhD, associate professor and vice chair for research in the departments of neurosurgery and physiology & biophysics at the University of Colorado School of Medicine in Aurora.
While the stimulation device was essentially the same in her study (though 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 acquisition of new behaviors.
“We applied stimulation in a temporally precise manner, paired with specific behaviors,” she said. “We were interested in at what point in the learning process VNS was effective in healthy animals, and seeing what specific circuits were engaged by stimulation.”
Mice with VNS devices in place were trained to reach through a slit to grab a food pellet from a post where it was balanced, a task requiring precise movements. Dr. Welle and her team delivered stimulation to the vagus nerve at one of three different time points: randomly during the 20-minute training session, during reaching, or after successful retrieval of the pellet.
“When the animal grabbed the pellet and brought it back to the mouth, then we would stimulate the vagus nerve,” she said. “That was the only time that we found that stimulation augmented motor learning.”
With sham VNS, with the stimulator implanted but not turned on, mice achieved success 46 percent of the time. After training with VNS delivered after a retrieval, they were successful 59 percent of the time.
In another experiment, designed to show that VNS itself was neither intrinsically rewarding nor aversive, Dr. Welle found that the mice did not prefer to revisit a room where the stimulation was initially applied, nor did they preferentially avoid it. Instead, she said, “We think we are tapping into the brain's reinforcement system. It is making the animal more receptive to feedback about whether their 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 tied to reinforcement of a desired outcome.
To determine the mechanism of reinforcement, Dr. Welle's team placed electrodes in the basal forebrain, which is the source for cortically projecting cholinergic neurons. Reinforcement in motor learning has been shown to depend on cholinergic neuromodulation, and the team showed that VNS modulated the rate of firing of these neurons. When these cholinergic neurons were optogenetically inhibited, that is, they used light to modulate the activity of the cells, VNS could no longer enhance learning.
VNS also activates other types of neuromodulatory systems, Dr. Welle noted, including the noradrenaline system, which is thought to be partly responsible for the antiseizure effects of VNS.
“We know that when we stimulate the vagus, we're activating that system as well, along with other centers in the brain. What we don't know is if there are other parts of the brain that are also contributing to the learning effect, and if they are also required, in addition to the cholinergic system,” important details that will need to be worked out in future experiments.
It is also not yet clear whether VNS is mimicking some endogenous reinforcement normally carried out by the vagus nerve. “I would say the science is still out on this question,” Dr. Welle said, “but there is promising work being done by other groups, suggesting that the vagus may be required for things like spatial learning, and also for reward representation from the gut, so there are hints.”
“This is a very elegant set of experiments as they provide very clear evidence that VNS, operating through an effect on cholinergic networks, can cause reorganization of the motor cortex and neuroplasticity,” Dr. Dawson said.
“We know from our study that VNS has a modest but important effect on improving upper limb function in people after stroke, above and beyond what we would see with physical therapy alone.”
In their randomized, sham-controlled study of 106 stroke patients with moderate to severe upper limb weakness, Dr. Dawson and colleagues showed that six weeks of VNS paired with rehabilitation led to a clinically meaningful improvement on the Fugl-Meyer upper extremity score in 47 percent of VNS patients, versus 24 percent in controls.
“This study sheds important light on a mechanism for VNS in the brain,” said David M. Labiner, MD, professor and head of neurology at the University of Arizona College of Medicine in Tucson.
“We know stimulation of the vagus nerve does many things, including changing blood flow and affecting neurotransmitters in the brain,” none of which, he pointed out, correlate with seizure control. “So, it doesn't surprise me that VNS also has the effect seen in this paper” of cholinergic neuromodulation. The benefit seen on motor learning “is a fairly exciting advance, if it holds up and can be shown to be useful in a meaningful amount of people.”
Cost may be an issue, he added, suggesting that external stimulation may be a more practical treatment for the large number of stroke patients who might benefit.
“Despite the number of years that it's been used clinically, how vagus nerve stimulation works in the brain has been difficult to figure out,” noted Steven Schachter, MD, professor of neurology at Harvard Medical School. “This study brings us much closer to understanding at least one way in which it works in the brain.”
While the relevance of the cholinergic facilitation uncovered in this study to effects beyond motor learning is uncertain, “it clearly gives researchers a direction in which to pursue new hypotheses.”
If VNS can facilitate non-motor learning as well, he added, it could become attractive both for treatment of other types of learning deficits, such as poor reading skills, and for cognitive enhancement. Both for post-stroke rehabilitation and other, more speculative applications, a non-invasive way to stimulate the vagus nerve may be preferable, especially because the need for the requisite stimulation is likely to be short-term rather than chronic.
Dr. Welle had no disclosures. Dr. Dawson disclosed that MicroTransponder Inc. paid conference expenses to present VNS-related study results in early 2020.