Study offers new clues to how Rett syndrome affects sound processing

Stimulating the vagus nerve — a large nerve that helps control unconscious bodily functions — partly normalized some measures of sound-related brain activity in a rat model of Rett syndrome, a new study reports.

Although vagus nerve stimulation, or VNS, improved some measures of sound-related brain activity, including how consistently the rats’ brains responded to repeated sounds, it had little or no effect on several other measures. The findings suggest that VNS affects some aspects of auditory processing but does not broadly restore brain activity in the Rett model.

The study, “Variability-dominated auditory cortical dysfunction and targeted VNS modulation in a Mecp2+/− model of Rett syndrome,” was published in Experimental Neurology.

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Rett syndrome disrupts how the brain processes sound

Rett syndrome is a genetic disorder that disrupts brain activity and communication between nerve cells. It is mainly caused by mutations in the MECP2 gene. Previous research has indicated that Rett syndrome is associated with abnormalities in how the brain processes sound. Broadly, studies in Rett syndrome models suggest that sound signals can reach the brainstem normally, but the brain regions responsible for processing and interpreting those signals are disrupted. This may make speech and other sounds harder to distinguish.

The body has two vagus nerves, one on each side, that help regulate automatic functions such as breathing, heart rate, and digestion. VNS involves delivering small electrical pulses to one of these nerves. This is thought to promote brain plasticity, the brain’s ability to reorganize its connections and adapt to new information.

A study published in 2020 suggested that VNS may help normalize auditory processing in a rat model of Rett syndrome. That study focused on spiking activity, brief bursts of neuronal signaling. Spiking provides one way to measure how the brain responds to sounds, but it does not capture the broader, coordinated activity occurring across groups of nerve cells.

Here, one of the scientists from that study, along with two collaborators, conducted further analyses using data from the original rat experiment. In that experiment, rats’ brain responses to different types of sounds were recorded after some Rett-model rats had received VNS paired with tones. Instead of analyzing spiking activity, the researchers examined measurements called local field potentials, which capture broader, coordinated activity across groups of nerve cells.

Reused data offer a broader look at brain activity

By reanalyzing data from the same group of rats used in the earlier study, the researchers were able to investigate additional aspects of brain activity without using more animals. Minimizing animal use is an important ethical goal in research.

In line with prior data, results indicated that the brain’s ability to process sound is substantially disrupted in the rat model of Rett syndrome. Rett-model rats showed abnormally low amplitude, or weaker responses, in several measures of brain activity. They also showed changes in latency, meaning the time between a sound and the brain’s response. Their responses varied more from one presentation of the same sound to the next than those of wild-type rats.

“Our findings showed that the rat model of Rett syndrome is associated with pronounced abnormalities in auditory-evoked responses compared with wild-type controls,” the researchers wrote. Taken together, these abnormalities suggest that the auditory cortex — the brain region that processes sound — is “noisy, poorly timed, and inefficient at filtering and encoding sounds,” the researchers said.

The researchers found that VNS partially normalized some, but not all, of these abnormalities. In particular, VNS reduced variability in some responses, so the rats’ brains responded more consistently each time they heard the same sound. However, VNS had comparatively little effect on response amplitude and latency, and its benefits were most apparent with more complex, speech-like sounds.

“Critically, the primary effect of VNS was a selective reduction in trial-to-trial response variability rather than a change in mean amplitude or latency. This variability-selective normalization … suggests VNS stabilizes [brain signaling] dynamics rather than uniformly shifting response gain,” the researchers concluded. They highlighted the need for further studies into how VNS may affect other aspects of Rett syndrome.