The effect of mechanical or electrical stimulation on apnea length in mice

Abstract

Premature birth is a leading cause of infant mortality which is often attributed to irregular breathing and apnea of prematurity. A common treatment for apnea is caffeine to stimulate the brain's respiratory center. However, caffeine's long term effect on infant development is not fully comprehended. We hypothesized that noninvasive localized body stimulation regularizes breathing pattern. We investigated the impact of electrical or mechanical stimulation on breathing in mice. After the mice were ventilated for 28 s to induce apnea, mice were taken off the ventilator while receiving mechanical, electrical, or no stimulation in a randomized order. Both stimuli targeted the diaphragm area through a custom-built belt with vibrating motors or adhesive electrodes. After each apnea cycle, the time to take the first breath (T) was recorded. The electrical stimulation given at 4.5, 8.3, 16.7 V (pulse rate = 3 Hz, pulse width = 120 μs) showed no reduction in T. Electrical stimulation at pulse rates of 10 or 20 Hz (16.7 V, pulse width 260 μs) showed a detrimental effect increasing T by ~ 7% compared to control values (p = 0.005, p = 0.038 respectively). High and medium intensity mechanical stimulations significantly reduced T by 11.74 (p < 10^-13) and by 17.08% (p < 10^-8), respectively. Further reducing the amplitude of vibrations did not affect T. When the probe was attached to the ankles, only the high intensity vibrations resulted in a decrease in T (p < 10^-13). Mechanical vibrations, applied at various intensities and locations, could be used to treat irregular breathing and apnea in infants.

Keywords: Apnea of prematurity; Breathing regulation; Electrical stimulation; Mechanical vibrations; Noninvasive.

Fig. 1

Cartoon of a mouse with a vibrating bracelet around abdomen and ankle (dark gray)

Fig. 2

Ventilation cycle and breath detection. a A ventilation cycle consists of a 20-s default period of controlled ventilation (8 ml/kg) followed by a 6-s deep inhalation before stopping ventilation. b The time to take a breath T is determined by the time interval between the end of the deep inhalation and the first breath that has an apex exceeding the threshold defined as 0.128 cmH₂O + mean + standard deviation of the values immediately following the end of the ventilation cycle without breathing

Fig. 3

Probability density distribution functions for the median normalized T values (Tn) for the three stimulation types in Table 2. a High intensity abdomen mechanical stimulation and control (n = 6, 216 ventilation cycles per group). b Medium intensity abdomen mechanical stimulation and control (n = 4, 84 ventilation cycles per group). c High intensity ankle mechanical stimulation and control (n = 4, 151 ventilation cycles per group). For all stimulations, it was observed that the distribution of Tn for the mechanical stimulus had a higher density on the left of the graph representing more frequent lower Tn values (see arrow with “A”). The graph of the control had a longer tail to the right (see arrow with “B”), showing a wider distribution and the presence of larger Tn values