Non-Invasive Optical Motion Tracking Allows Monitoring of Respiratory Dynamics in Dystrophin-Deficient Mice

Abstract

Duchenne muscular dystrophy (DMD) is the most common x-chromosomal inherited dystrophinopathy which leads to progressive muscle weakness and a premature death due to cardiorespiratory dysfunction. The mdx mouse lacks functional dystrophin protein and has a comparatively human-like diaphragm phenotype. To date, diaphragm function can only be inadequately mapped in preclinical studies and a simple reliable translatable method of tracking the severity of the disease still lacks. We aimed to establish a sensitive, reliable, harmless and easy way to assess the effects of respiratory muscle weakness and subsequent irregularity in breathing pattern. Optical respiratory dynamics tracking (ORDT) was developed utilising a camera to track the movement of paper markers placed on the thoracic-abdominal region of the mouse. ORDT successfully distinguished diseased mdx phenotype from healthy controls by measuring significantly higher expiration constants (k) in mdx mice compared to wildtype (wt), which were also observed in the established X-ray based lung function (XLF). In contrast to XLF, with ORDT we were able to distinguish distinct fast and slow expiratory phases. In mdx mice, a larger part of the expiratory marker displacement was achieved in this initial fast phase as compared to wt mice. This phenomenon could not be observed in the XLF measurements. We further validated the simplicity and reliability of our approach by demonstrating that it can be performed using free-hand smartphone acquisition. We conclude that ORDT has a great preclinical potential to monitor DMD and other neuromuscular diseases based on changes in the breathing patterns with the future possibility to track therapy response.

In vivo low-dose phase-contrast CT for quantification of functional and anatomical alterations in lungs of an experimental allergic airway disease mouse model

“…In comparison, we demonstrated that with a rather simple approach of cinematic planar phase contrast imaging, we derived significant differences in lung function parameters that allowed discriminating between asthmatic and healthy mice. Even more importantly, we were able to demonstrate that with a temporal resolution of 100 fps, the phase of elastic recoil of the lung and the dampening effect of the diaphragm could reliably be detected, a characteristic feature of asthmatic mice (29), that so far we were only able to detect with optical cameras at the same high frame rate of 100 Hz (30). The concept of extraction breathing motion by analyzing the average x-ray transmission in a region of interest typically on top of the lung-diaphragm interface is a well-known approach introduced for instance by Ford and Bartling (31,32).…”

Simultaneous assessment of lung morphology and respiratory motion in retrospectively gated in-vivo microCT of free breathing anesthetized mice

“…The k-value as a constant of a Gaussian function fitted to the expiratory phase is predominately measuring the effect of elastic recoil of the lung in combination with an later onset of a dampening effect of the diaphragm 21 and is therefore especially sensitive for characterizing the mdx mice known for fibrotization of the diaphragm 22 . Clinically the expiratory time constant (RCexp) is a known measure that combines effects of changes in compliance and resistance.…”

Lung function measurements in preclinical research: What has been done and where is it headed?

“…Search for finding a simpler way than WBP and XLF to monitor respiratory dynamics, resulted in introduction of an optical technique by Svetlove et al called optical respiratory dynamics tracking (ORDT) ( Svetlove et al, 2022 ). This technique is especially useful for tracking diaphragm function of mice with neuromuscular diseases such as Duchenne muscular dystrophy (DMD).…”

“…Furthermore, unlike XLF technique, ORDT was also able to show the differences between fast and slow expiratory phases in mdx mice, while healthy controls had almost the same fast and slow phases. Compared to the alternative methods for longitudinal assessment of diaphragm function in mice, e. i. WBP and XLF, ORTD is easier to perform, completely non-invasive (no ionizing radiation), cheaper, and can be performed by commonly available tools and equipment ( Svetlove et al, 2022 ). Furthermore, since this optical technique directly assess the dynamics of the body surface, it has a greater potential in detecting abnormal breathing patterns.…”