VNS Enhances Memory
abstract & commentary
Source: Clark KB, et al. Enhanced recognition memory following vagus nerve stimulation in human subjects. Nature Neuroscience 1999;2(1):94-98.
Stimulation of the vagus nerve by use of a surgically implanted electrical device has gained acceptance as a treatment for medication-refractory epilepsy. Clark and associates from Southern Illinois University tested recognition memory in 10 subjects involved in a double-blind clinical trial of vagus nerve stimulation (VNS) for seizure suppression. In a carefully controlled set of experiments, they found that VNS delivered during the memory consolidation period can enhance the delayed recognition of words, but only if the stimulation is at a lower intensity than is commonly used for seizure suppression.
The 10 subjects were patients with epilepsy who had more than four seizures per month and were receiving no more than two anti-epileptic medications. Other subjects were excluded because their regimen included benzodiazepines or beta blockers. The subjects underwent baseline testing prior to stimulator implantation and were retested four times over the subsequent 24 weeks. The memory task consisted of reading several emotionally neutral paragraphs that contained highlighted nouns. Subjects were asked factual questions about the paragraphs to assess their reading comprehension. Approximately two minutes after completing the paragraphs, actual or sham VNS lasting 30 seconds was delivered. Subjects were then asked if they could recognize the previously viewed nouns from among a long list of distractor words. The stimulation parameters were varied over time, with subjects receiving either 0.5, 0.75, or 1.5 mA of stimulation or sham stimulation in combination with the noun recall task. Clark et al were blinded to the intensity of stimulation and as to whether sham stimulation was being carried out.
VNS of an intensity comparable to that used to suppress seizures (0.75-1.5 mA) actually impaired recognition memory performance slightly, reducing the mean word recognition score by 10% relative to the control state. In contrast, VNS at 0.5 mA facilitated word recognition by more than 35% (which was a statistically significant effect at the P < 0.025 level). There was no correlation between the performance on memory testing and self-reported seizure frequency or duration, leading Clark et al to conclude that the effect of VNS on recognition memory was not likely to be a secondary consequence of seizure suppression by the VNS device.
Commentary
The vagus is a major conduit for visceral sensation, and moderate levels of stimulation of this nerve have been shown to increase levels of arousal and orientation to incoming stimuli. By delivering VNS after exposure to the target words, Clark et al provide intriguing evidence that VNS can alter and potentially enhance the memory consolidation process. The double-blind design and the use of more than one intensity of stimulation across subjects adds to the credibility of the study’s findings. Confidence in the results would have been enhanced if a larger number of subjects had been studied and if additional cognitive tests had been used to distinguish between effects on concentration, learning, recall, and recognition memory. In light of the provocative nature of these findings, we expect additional investigations along these lines will eventually be carried out.
Facilitation of memory by VNS had been previously demonstrated in rodents by the same investigators. As proved to be the case in humans in the present study, only a moderate intensity of VNS (0.5 mA) delivered during the memory consolidation period enhanced memory in rats, with higher intensities abolishing the effect. In animal studies, the memory-enhancing effects of VNS were attenuated by beta blockers, an effect thought to be mediated by antagonism of peripheral catecholamine receptors. Neurologists have long been aware of the potential for peripherally acting catecholaminergic agents to cause confusional states. This investigation provides a plausible explanation of how drugs, surgical interventions or disease states that alter vagal function may affect memory and other aspects of CNS function without necessarily acting directly on the brain.
It is of some concern that higher intensities (0.75-1.5 mA) of VNS had a mildly adverse effect on recognition memory in these subjects, especially since this level of stimulation is comparable to that now being used for seizure suppression in epilepsy patients. Although the magnitude of memory impairment associated with higher intensity stimulation was small, its occurrence creates some concern that there may be other, as yet, undiscovered cognitive side effects related to the use of VNS, which is a relatively new and promising alternative therapy for patients with medication refractory epilepsy. This issue is currently under study. These caveats aside, this innovative investigation provides justification for future studies to address the potential applicability of VNS to the treatment of disorders of memory and other areas of cognition.
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