New Insights into the Effects of Acute Intermittent Hypoxia on Neural Plasticity in the Human Motor System

SOURCE: Experimental Physiology. 107(6):560-561, 2022 06.

AUTHORS: Behrens M

ABSTRACT: Plasticity is a fundamental property of neural systems and includes changes in its function and morphology in response to different interventions (e.g., exercise, training, and electrical or magnetic stimulation) and with the onset and progression of various diseases. Acute intermittent hypoxia (AIH), which is characterized by brief exposures to short, alternating periods of hypoxia and normoxia, has also been shown to promote neural plasticity. The results of animal studies indicated that AIH was capable of triggering phrenic motor facilitation, which was strongly associated with an enhanced synthesis of the serotonin-dependent brain-derived neurotrophic factor in respiratory motoneurons (Baker-Herman et al., 2004). However, given that sympathetic nerve activity and functional connectivity of spinal interneurons were also increased after AIH in rats, its effect seems not to be confined solely to respiratory motoneurons. This was further corroborated by the observations that an AIH session increased strength and muscle activity of the plantar flexors as well as walking velocity in humans with incomplete spinal cord injury (Hayes et al., 2014; Trumbower et al., 2012), suggesting that this interventional approach also promotes neural plasticity in the human motor system.

In order to investigate the underlying mechanisms, Christiansen et al. (2018) have exposed young, healthy adults to 30 min of AIH consisting of 15 cycles of 1 min inspiring hypoxic air [fraction of inspired oxygen (FiO2) = 0.09] and normoxic air (FiO2 ??0.21). The authors used transcranial magnetic stimulation and electrical stimulation to elicit cortical and cervicomedullary motor evoked potentials (MEPs and CMEPs, respectively) in the first dorsal interosseous muscle, which were enhanced at 15 min up to 75 min after AIH in comparison to the sham intervention. Given that spike timing-dependent plasticity was increased, while measures of intracortical inhibition and facilitation as well as motoneuron excitability (F-wave) were unchanged, the authors suggested that AIH induced corticospinal??otoneuronal synaptic plasticity. These data provided first insights into the potential mechanisms of the motor performance enhancements observed after the application of AIH in patients with incomplete spinal cord injury (i.e., increased plantar flexor strength and walking velocity; Hayes et al., 2014; Trumbower et al., 2012). Therefore, the impressive results of Christiansen et al. (2018) were very promising, given that acute interventions for promoting plasticity at the corticospinal??otoneuronal synapses in healthy people and patients with CNS damage are limited.

However, in a study published in this issue of Experimental Physiology, Finn et al. (2022) failed to replicate the distinct and time-stable effect of the same AIH protocol on transcranial magnetic stimulation-induced MEPs in the first dorsal interosseous muscle observed by Christiansen et al. (2018). The authors have found that corticospinal excitability was increased only at 40 min, but not at 20 or 60 min after AIH in healthy young adults. Interestingly, Finn et al. (2022) have revealed that the Hoffmann reflex (H reflex) recruitment curve of the soleus muscle, evoked by electrical stimulation of the posterior tibial nerve, was shifted to the left at 40 and 60 min after AIH. Lower stimulation intensities were, accordingly, required to produce an H reflex of similar magnitude, indicating an increased efficiency of the Ia afferent??otoneuronal synapses. However, AIH had no effect on the maximal H reflex of the soleus muscle. Given that AIH did not affect homosynaptic postactivation depression of the H reflex, a phenomenon attributed to presynaptic mechanisms, the authors concluded that AIH probably induced the leftward shift of the H reflex recruitment curve via changes in the postsynaptic membrane of the soleus motoneurons.

In summary, although Finn et al. (2022) have also shown that AIH promoted neural plasticity in the motor system, these changes were observable only at discrete time points, which is in contrast to the recently found unequivocal and time-stable effect of AIH on MEPs and CMEPs of the first dorsal interosseous muscle (Christiansen et al., 2018). These inconsistent findings might be related to differences in the internal response (e.g., decrease in peripheral oxygen saturation) of the subjects to the same external hypoxic stimuli (i.e., the same FiO2) between studies. Nevertheless, Finn et al. (2022) have shown, for the first time, that AIH shifted the H reflex recruitment curve of the soleus muscle to the left, indicating an increased efficiency of the Ia afferent??otoneuronal synapses.

Given that the effects of AIH on motor system plasticity in healthy humans have so far been investigated only in resting subjects, future studies should thoroughly examine its influence on motor performance (e.g., strength performance, endurance performance, and motor learning) and the neural adjustments during exercise in healthy individuals and patients (e.g., people with neurological disorders). In this regard, the dose??esponse relationship should be taken into account to find the ??ptimal??combination of variables for promoting neural plasticity and improving motor performance. These variables include the external and internal intensity of hypoxia (frequently reported as FiO2 and peripheral oxygen saturation, respectively), the duration of the hypoxic and normoxic periods, and the number of hypoxia??ormoxia cycles within a single session. Given that the internal response (e.g., peripheral oxygen saturation) to hypoxia determines the physiological strain of the subjects, the AIH dose (i.e., especially the intensity of hypoxia) should be tailored individually. Moreover, the term ??cute intermittent hypoxic exposure??(abbreviated acute IHE) should be used instead of AIH to adopt the terminology used in the current literature for the passive application of hypoxia.