Patients with Duchenne muscular dystrophy (DMD) show increased unconditioned startle responses to threat in a similar way to the mouse model of the disease, a new study published in Brain found.
“Our study provides new insights into the neurobiology underlying the complex neuropsychiatric co-morbidities in Duchenne muscular dystrophy,” the researchers wrote.
It is known that DMD can also affect patients’ intellectual abilities. Unlike in the muscles where there is a single full-length dystrophin isoform, there are multiple isoforms of the protein in the brain.
The mdx mouse, a popular model for studying DMD, lacks the full-length dystrophin isoform both in the muscles and central nervous system. These animals have exaggerated startle responses to threats, but these startle responses normalize following the restoration of dystrophin expression in the brain.
“A pathological startle response is not a recognised feature of DMD,” the researchers wrote. They set out on a quest to investigate these responses in patients with the disease and conducted an observational study where they used a novel fear-conditioning task in 31 boys with DMD and 25 controls, aged 7 to 12 years.
Read more about DMD comorbidities
The researchers presented 2 neutral visual stimuli to the participants in a trial phase. One of these was a safe cue that was presented on its own while the other was a threat presented together with an aversive noise. The aim here was to enable the conditioning of physiological startle responses such as increased skin conductance and heart rate. In an extension phase, participants were presented with both cues but without the aversive noise to test whether the conditioned physiological responses were retained.
The results showed that the mean unconditioned skin conductance response was higher in patients with DMD compared to those without the disease. This was associated with significant threat-induced bradycardia seen only in patients with DMD. Participants with the disease also found the task “more aversive” compared to controls.
Moreover, 26% of patients terminated the extension phase of the study early, while none of the participants in the control group did. This study defines an objective measure of unconditioned startle responses, which would be valuable for future dystrophin-restoration therapies targeting the central nervous system.
Maresh K, Papageorgiou A, Ridout D, et al. Startle responses in Duchenne muscular dystrophy: a novel biomarker of brain dystrophin deficiency. Brain. 2022;8:awac048. doi:10.1093/brain/awac048