Transcutaneous Spinal Cord Stimulation Facilitates Respiratory Functional Performance in Patients with Post-acute COVID-19

1. Introduction

Management of pulmonary dysfunction is one of the most prominent problems in medical practice [1]. A global pandemic of the novel respiratory infection Coronavirus disease (COVID-19) has contributed to the complexity of this problem tremendously [2]. Although the acute phase is the most severe, the long-term consequences of this disease can persist and need to be addressed [3,4]. Most patients who developed COVID-19-induced pneumonia have bilateral lung lesions, respiratory failure, and/or acute respiratory distress syndrome (ARDS) [5] leading to significant changes in lung function, mostly restrictive, which can persist after recovery and are associated with an increased risk of life-threatening comorbidities [6,7]. Therefore, the development of rehabilitation methods to maintain adequate respiratory function are critical in this population [8].

Currently, there are no effective therapeutic strategies to improve respiratory motor function after COVID-19 that are accepted as a standard of care. A fundamental reason for this is that the pathophysiological mechanisms of respiratory motor dysfunction after COVID-19 are not known. Although the primary pathogenic target is the respiratory system, a growing number of studies have reported central nervous system manifestations of COVID-19 [9,10,11,12,13,14]. Increasing reports have shown that COVID-19 infection affecting central and peripheral nervous systems by direct or indirect damage of neurons and respiratory neural networks may lead to long-term respiratory deficits [15]. Respiratory neuroplasticity, defined as a persistent morphological and functional change in neural control based on behavioral experience, is critically dependent on the establishment of necessary preconditions, the stimulus paradigm, and a balance of complementary neuromodulation through hypoxia, hypercapnia, exercise, stress, and/or other factors [16,17,18]. These speculations suggest that neuromodulation through spinal cord stimulation has potential for respiratory rehabilitation in this patient population. Recently, we reported that non-invasive spinal cord transcutaneous stimulation (scTS) may be a viable neuromodulatory approach to affect locomotor behavior [19] and cardiovascular function [20]. The results of these studies as well as our previous observations [21,22,23] and the work of others [24], led us to the idea that the activity of respiratory neural networks affected by COVID-19 can be neuromodulated by scTS with the goal to be utilized for respiratory rehabilitation. We hypothesized that scTS of respiratory neuronal networks results in increased spinal excitability leading to immediate increase in respiratory functional effectiveness. Here, for the first time, we propose that scTS configured for the activation of respiratory neuronal networks will result in increased respiratory functional performance in patients with post-acute COVID-19 respiratory deficits.

2. Materials and Methods

2.1. Study design and participants

The study was approved by the Ethics Committee of the Pavlov’s Institute of Physiology, St. Petersburg, Russian Federation (protocol #20-02 dated December 18^th, 2020) and was conducted in accordance with the requirements of the Ministry of Science and Higher Education of the Russian Federation "On the activities of organizations subordinate to the Ministry of Science and Higher Education of the Russian Federation in the conditions of preventing the spread of the COVID-19 infection in the territory of the Russian Federation" (order #692 dated May 28^th, 2020).

Data collection occurred between December 2020 and March 2022. Data sets were collected in a physiological laboratory environment during a single visit for each participant. The outcome measures were assessed prior to the intervention (“pre-Intervention” time point) and 15 minutes after the twenty-minute exposure (“post-Intervention” time point) to the simultaneous two-channel scTS applied over the T5 and T10 spinal cord segments. Eight healthy controls and ten post-acute COVID-19 participants have been recruited. Five female and five male COVID-19 participants 55 ± 13 years of age previously hospitalized with severe COVID-19 in association with pneumonia were recruited after 59 ± 48 days post-diagnosis (Table 1). Prior to entering this study, all participants were PCR-tested negative for COVID-19. The following inclusion criteria were applied: at least 21 years of age; post-acute COVID-19 syndrome; no ventilatory dependence; respiratory functional deficit defined as a decrease in predicted FVC values at least 20%; no tobacco or drug use; and no cardiovascular or respiratory conditions unrelated to COVID-19. All individuals reported episodes of shortness of breath and fatigue at the time of the study. Besides experimental procedures, all participants maintained their normal daily routines. No participants withdrew from the study.

2.2. Research procedures

Multi-site scTS was delivered by a Biostim-5 device (Cosyma Inc., Denver, CO) over the midline between the third and fourth and between the eighth and nineth thoracic spinous processes (Th3-Th4 and Th8-Th9) corresponding to the T5 and T10 spinal cord segments via self-adhesive electrodes (cathodes) with a diameter of 32 mm (ValueTrode, Axelgaard Manufacturing Co., LTD, Fallbrook, CA) [24]. Two 5×9 cm interconnected self-adhesive rectangular electrodes (ValueTrode, Axelgaard Manufacturing Co., LTD, Fallbrook, CA) served as anodes, were placed bilaterally along the rectus abdominus muscles centered at the umbilical level (Figure 1). Stimulation consisted of 5 kHz-modulated, monophasic, 1-ms pulses delivered with a frequency of 30 Hz to activate dorsal roots as reported previously [25], providing afferent input to the spinal cord segments involved in the activation of the accessory respiratory muscles. During the stimulation intensity mapping phase, starting at 10 mA, the current was gradually increased up to 40.1 ± 11.9 mA at Th3/Th4 and up to 40.3 ± 13.7 mA at Th8/Th9 until twitching of intercostal or abdominal muscles were noted indicating the motor threshold. For interventional stimulation, these values were decreased -10 mA to the sub-motor threshold levels. Brachial arterial blood pressure (BP), heart rate (HR), oxygen saturation, and pain sensation using a visual analogue scale of pain (VASp) were monitored 20 min before, during, and 20 min after the intervention.

2.3. Outcome measures and statistical analysis

Respiratory function outcome measures: Forced Vital Capacity (FVC, L), Peak Forced Inspiratory Flow (PIF, L/min), Peak Expiratory Flow (PEF, L/min), Time-To-Peak of Inspiratory Flow (tPIF, sec), and Time-To-Peak of Expiratory Flow (tPEF, sec), were obtained from flow-volume curves recorded in the seated position during standard spirometry using a Powerlab 16/35 data acquisition system with Human Respiratory Kit (AD Instruments, Denver, CO) [26].

Data values were analyzed in R (R Foundation for Statistical Computing, Vienna, Austria) and represented by descriptive statistics (Mean ± Standard Deviation). Pre- to post-intervention changes for each outcome measure were tested for normality using the Kolmogorov-Smirnov and the Shapiro-Wilk tests. A paired t-test and Signed Rank test were used to assess normally and non-normally distributed outcomes, respectively. The statistical significance threshold was set to α = .05.

3. Results

In the COVID-19 group, application of scTS led to significantly increased PIF (93.99 ± 38.26 vs. 133.67 ± 84.54 L/min, Mean ± SD; p= .040) and PEF (87.84 ± 45.05 vs 108.85 ± 57.31 L/min; p= .049) in association with significantly decreased tPIF (1.13 ± .69 vs .86 ± .49 sec; p= .035) and tPEF (.46 ± .32 vs .35 ± .24 sec; p= .013). In the Control group, exposure to the scTS resulted in significantly increased PIF (475.80 ± 80.79 vs. 553.76 ± 77.76 L/min, p= .010) and significantly decreased tPIF (.17 ± .06 vs .13 ± .04 sec; p= .031). In contrast to the results for the COVID group, there were significant decrease in PEF (717.75 ± 82.76 vs 622.76 ± 58.53 L/min; p= .028) in association with significantly increased tPEF (.06 ± .02 vs .08 ± .03 sec; p= .036) (Figure 2 and Figure 3). There were no changes for FVC after scTS in both groups (2.31 ± .83 vs 2.42 ± .89 L; p= .67 /COVID group/ and 5.25 ± .54 vs 5.33 ± .62 L; p= .503 /Control group/) (Figure 4).

4. Discussion

This is the first publication demonstrating the implementation of scTS as a neuromodulation technique in patients with COVID-19 respiratory deficits. The significant scTS-induced changes in PIF and PEF indicate increased respiratory neuromuscular network activity for both inspiration and expiration in individuals with post-COVID-19 respiratory deficits. In addition, a significant decrease in tPIF and tPEF in these patients indicates improved inter-neuronal activity of the respiratory networks. There were no changes for FVC after scTS in both groups indicating that pulmonary component was not affected by scTS. This report is aimed to present the initial finding regarding the potential of spinal neuromodulation in post-acute COVID-19 population using simple “pre-/post- acute effect” study design where baseline data sets served as self-controls in combination with evaluation of the healthy controls underwent the same intervention. The results of this study suggest that non-invasive scTS targeting respiratory neuronal networks [27] can be a valuable element of a successful respiratory rehabilitation strategy for these patients.

In the present study, to affect the spinal structures responsible for accessory respiratory motor control [28], scTS was delivered using two cathodes placed over the T5 and T10 spinal cord segments and two interconnected anodes positioned at the umbilical level. To exclude respiratory muscle contraction during the intervention, the intensity of scTS was maintained at a sub-motor threshold level. In addition, to exclude the direct effect of scTS, post-intervention testing was performed after a 15-min “wash out” period. Our group has pioneered the use of epidural spinal cord stimulation to activate spinal networks in patients with severe spinal cord injury [29]. In individual with cervical motor-discomplete injury, we observed that intercostal muscles are activated when the respiratory effort was assisted by the epidural stimulation is applied at the lumbar segments [30]. Recently, we demonstrated that a single twenty-minutes session of scTS exposure over the cervical spinal cord resulted in increased excitability of not only spinal but also cortical networks lasting for 75 min after cessation of stimulation [31]. These findings suggest that scTS delivered to T5 and T10 spinal segments may also have a facilitatory effect on supraspinal respiratory structures and further contribute to the increased respiratory activity via descending pathways.

One might expect that scTS could also activate the autonomic network associated with innervation of the airways and subsequently increase lung capacity. Our results showed that FVC was not altered by stimulation. This finding indirectly indicates that there was no autonomic activation component of the intervention. Our previous work showed that scTS can induce autonomic activation in association with increase in BP in individuals with spinal cord injury-induced autonomic deficits [19]. In the present study, we did not observe scTS-induced changes in BP. These effects might be linked to the different pathophysiological mechanisms of these two populations and specific parameters of scTS that were used in the two distinct protocols.

This study revealed that in healthy individuals the scTS differently affects inspiratory and expiratory motor networks. As well as in the COVID-19 group, in the control individuals we observed activation of inspiratory motor circuitry manifested by significantly increased PIF in association with significantly decreased tPIF, however, there were opposite effect on the expiratory circuitry: significant decrease in PEF accompanied by significantly increased tPEF which indicates suppression of expiratory neuromuscular activity. Observed for the first time, these phenomena indicate that intact spinal network uses self-regulatory mechanisms to mountain homeostasis.

The therapeutic potential of non-invasive spinal cord stimulation for patients with respiratory deficits has not yet been studied [23]. Further research is needed to define specific pathophysiological mechanisms related to neural dysfunction in patients with COVID-19, which is a key element for the creation of appropriate rehabilitative strategies for this patient population. It should be noted that respiratory-related data from patients with COVID-19 are currently limited to a single randomized controlled study showing that 6-weeks of general respiratory rehabilitation can improve respiratory function, quality of life, and mental health of elderly patients [32]. A study of respiratory function during clinical recovery and 6 weeks after discharge in COVID-19 -induced pneumonia survivors found that although pulmonary function had improved, some restrictive deficits persisted [33]. Based on the results of our previous work [34], we propose that combined with scTS, a specific use-dependent rehabilitative intervention in the form of respiratory training, could result in the enhanced plasticity of respiratory neuronal networks leading to the improved respiratory motor function needed to overcome the restrictive respiratory deficits developed in individuals with post-acute COVID-19.

Limitations

For the future full-scale clinical trials, matched control groups, including healthy controls, and/or experimental controls, and/or controls with non-specific scTS configuration, will be needed. In addition, based on our experience of using scTS for locomotor rehabilitation [18,31,35], this initial scTS protocol for respiratory neuromodulation can be improved. For example, relocation or addition of the anodes to the anterior upper thoracic region might be more effective due to closer proximity to the cathodes. These questions should be addressed by investigating computational and functional effects of different scTS electrical parameters and electrode positioning.

5. Conclusions

A single session of scTS applied over the thoracic spinal cord in post-COVID-19 patients leads to improved respiratory functional performance via activation of the spinal neural networks. These findings indicate that a specifically configurated non-invasive spinal cord stimulation paradigm could be utilized for rehabilitation to reduce persistent respiratory motor deficits in patients recovering from COVID-19.