The team, led by Chi-Sang Poon, a research scientist at the Harvard-MIT Division of Health Sciences and Technology (HST), suggests that this innate ability to adapt, called nonassociative learning, could be leveraged to design more effective and less costly artificial respirators.
In work described in the September 12 issue of PLoS ONE, the online, open-access journal from the Public Library of Science, Poon examined rats under mechanical ventilation to see how they applied different forms of nonassociative learning to adapt to the rhythm imposed by the respirator.
Existing designs of respirators do not consider the adaptive nature of breathing in their design. Some respirators ignore the patient’s natural rhythm and pump air in and out of the lungs on set intervals. Doctors often must sedate or paralyze patients to prevent them from fighting this unfamiliar rhythm. Other designs rely entirely on the patient to trigger the airflow. These systems, however, are costly and tend to be unreliable for weak patients such as newborns or those in critical care.
Poon’s experiment suggests, however, that if a doctor takes the patient’s natural breathing rhythm into account and sets the ventilator’s rhythm in that same range, the patient will adapt and synchronize with the ventilator. This new approach could minimize the need for induced sedation or paralysis.
“We have intrinsic nonassociative learning capabilities, called habituation and desensitization, that make up for changes in the spontaneous rhythm due to artificial lung inflation,” says Poon.
Nonassociative learning is a basic and familiar animal behavior. For instance, roses smell heady and intense at first, but minutes later they lose their affect due to habituation. “The body learns to tune it out if it’s not going to kill you,” says Poon.
In mammals, nonassociative learning also involves a secondary form of habituation, called desensitization. Desensitization engages memory to record the habituation and then apply it more generally using a different, “surrogate” pathway, says Poon.
A study of respiratory rhythms first exposed desensitization as a type of nonassociative learning. “If you take a deep breath,” says Poon, filling his lungs, “the Hering-Breuer reflex tells you not to breathe in anymore. It’s time to relax and expire.” But if a mechanical respirator is keeping a patient’s lungs artificially inflated with continual air pressure, a common therapy for patients with sleep apnea or in critical care to keep their lungs and airways open, it is also preventing the patient from breathing out. Meanwhile, the brain is keeping the patient from inhaling. The result of this deadlock is respiratory arrest.
After a moment, however, habituation and desensitization kick in. The vagus nerve, which detects when the lungs are full, habituates to the full signal. At the same time, says Poon, the pneumotaxic center of the pons, the region of the brain that controls rhythmic breathing, counterbalances the Hering-Breuer reflex by “zeroing out” its relevant neural receptors. As a result, breathing resumes and begins to synchronize with the imposed rhythm of the respirator.
In tests of rats under artificial respiration, Poon found that, if using a suitable rhythm, rats adapted to the mechanical ventilation. Severing the vagus nerve, the nerve supporting habituation, eliminated their ability to adapt. Lesions in the pons, the region supporting desensitization, impaired adaptation.
Poon also found that this learning capability enabled mice to adapt to an artificial rhythm even when the mechanical respirators applied constant air pressure. The rats effectively “tuned out” this extra pressure, filtering it out as background noise.
This filter, according to Poon, is part of a “brain calculus” in which different brain circuits employ integration and differentiation—types of mathematical calculations—to process and filter information. Poon is currently working on a project to map the neural circuits responsible for the calculus involved in habituation and desensitization.
Though nonassociative learning is familiar and commonly applied to smelling roses and adjusting to sunlight after emerging from a dark movie theater, it is not usually applied in a clinical scenario. Because of their focus on stabilizing patients, clinicians often discount the power of learning. "Many ventilators are designed as if the patient were never in the equation,” says Poon. “But it turns out, our vital functions can learn to adapt in order to survive.”
This work was supported by the National Heart, Lung and Blood Institute of the National Institutes of Health.
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