Secondary Logo

Journal Logo

Research Article

Neurorehabilitation using a voluntary driven exoskeletal robot improves trunk function in patients with chronic spinal cord injury

a single-arm study

Okawara, Hiroki1; Tashiro, Syoichi2; Sawada, Tomonori1; Sugai, Keiko1; Matsubayashi, Kohei3; Kawakami, Michiyuki2; Nori, Satoshi1; Tsuji, Osahiko1; Nagoshi, Narihito1; Matsumoto, Morio1; Nakamura, Masaya MD, PhD1,*

Author Information
doi: 10.4103/1673-5374.317983
  • Open

Abstract

Chinese Library Classification No. R496; R741

Introduction

Most patients who experience spinal cord injury (SCI) achieve recovery of motor function (Fawcett et al., 2007). Although improvements in acute treatment have reduced mortality rates following SCI (Strauss et al., 2006), many SCI survivors experience severe chronic sequelae. While a number of animal studies have investigated the molecular mechanism of neural regeneration, it is important to delineate the phenotype in clinical studies (Brown and Martinez, 2019; Filipp et al., 2019). There is strong evidence that SCI can be improved by various types of locomotion training (Donenberg et al., 2019; Yu et al., 2019; Zhang et al., 2019). Particularly, body weight-supported locomotion training and robot-assisted gait training (RAGT) have improved gait function during the chronic phase in patients who experience incomplete SCI (Lam et al., 2007; Esquenazi et al., 2012; Bach Baunsgaard et al., 2018; Loy and Bareyre, 2019), as well as in post-stroke patients (Bruni et al., 2018). Voluntary driven exoskeletons (VDEs) have advantages over other rehabilitation robots in that assistive motion is triggered by a subject's voluntary contractions (Grasmucke et al., 2017). VDE training is known to immediately improve parameters of lower limb kinematics (Matsuda et al., 2018) and muscle activity (Shimizu et al., 2017), to correct synergy control of the lower limb muscles during gait (Tan et al., 2018), and increase excitability in the primary somatosensory cortex (Sczesny-Kaiser et al., 2015). In addition, gait training on treadmill or overground using the combination of VDE with a body weight-supported device improves gait ability, even in the chronic phase (Sczesny-Kaiser et al., 2015; Grasmucke et al., 2017; Jansen et al., 2018). Taken together, these findings indicate that VDE can improve residual neural functions by activating impaired spinal cord pathways.

Although few VDEs are commercially available, hybrid assistive limbs (HALs, Cyberdyne Inc., Ibaraki, Japan) of robot suits are attracting wide attention, as they can apply an electromyographical signal to trigger motion. HAL have been certified by the CE as a medical device in the European market, and gait training for SCI patients using HAL is covered by industrial accident compensation insurance in Germany (Matsuda et al., 2018). In addition, Japanese public health insurance recently started to cover HAL for rare progressive neuromuscular diseases, including HTLV-1 associated myelopathy, in which motor dysfunction is similar to that observed in SCI (Matsuda et al., 2018).

Despite technical progress, the functional prognosis of these patients is not favorable, especially for those with more severe impairment. It has been shown difficult to re-establish gait ability, even with RAGT, in SCI patients with poor lower limb strength (Yang et al., 2011; Yang and Musselman, 2012; Piira et al., 2019). Although a few studies have shown that patients with chronic complete SCI can recover balance or trunk muscle activity (Bjerkefors et al., 2009; Sylos-Labini et al., 2014; Squair et al., 2016), no studies to date have investigated the effects of VDE neurorehabilitation on recovery. This study therefore assessed the effectiveness of body weight-supported treadmill training (BWSTT) with VDE (VDE-BWSTT) on trunk function in patients with chronic SCI.

Subjects and Methods

Study design

This open-label, single-arm study enrolled nine outpatients who received treatment in Keio University Hospital, Tokyo, Japan from September 2017 to March 2019. Participants were recruited individually, regardless of neural level and severity of injury. The sample size was calculated as nine according to a previous study describing trunk muscular strength changes after inpatient rehabilitation in patients with non-traumatic SCI (Gabison et al., 2014). Therefore, 10 participants with chronic SCI were enrolled, with the expectancy that there would be exclusions or drop-outs. The study protocol was fully compliant with ethical guidelines for medical and health research involving human subjects, including the Declaration of Helsinki, and was approved by the Ethics Committee of Keio University School of Medicine (IRB No. 20150355-3) on September 26, 2017. Written informed consent was obtained from all study participants before enrollment. No insentive was given to the study participants. This study was registered in UMIN Clinical Trials Registry (UMIN-CTR; UMIN000021907) (https://www.umin.ac.jp/ctr/).

Study participants

Participants were included if they were aged 20–75 years, had self-reported disturbed motor function, and had achieved motor function recovery from paralysis symptoms. Subjects were excluded if they (1) had a disease or skin disorder that would make training impossible or be worsened by training, (2) had received interferon-alpha or botulinum toxin injections within the 6 months prior to enrollment, (3) had participated in another neurorehabilitation training program (such as other BWSTT or functional electrical stimulation) within the previous 3 months, (4) had undergone walking training with VDE within the previous 12 months, or (5) had any orthostatic hypotension that could impair VDE-BWSTT training or evaluation thereof.

Treadmill training with VDE

All participants underwent 20 VDE-BWSTT training sessions, at a rate of 2–5 sessions per week, as referenced to a previous report (Jansen et al., 2017) and investigator-initiated clinical research in Japan. HAL was used as VDE in this intervention study. Motion assistance was controlled by weak bio-electrical signals generated by active muscle contractions, which were captured by electrodes on the skin surface (Grasmucke et al., 2017). VDE training was performed on a treadmill with half of each individual's body weight supported (excluding the weight of the VDE device) by a weight-supported device (PneuWeight, Pneumex, ID, USA), as described previously (Okawara et al., 2020). The velocity of the treadmill was set to each participant's comfortable walking speed (0.5–2.5 km/h), with no incline within each session. The duration of each training session was 60 minutes, which included time to rest that did not exceed 20 minutes. All outcomes were measured at baseline and after 10 and 20 training sessions.

Trunk muscle strength

Trunk muscle strength was defined as the ability to maintain a seated posture in four directions (anterior, posterior, left lateral and right lateral) (Larson et al., 2010). Initially, participants sat on a table with their feet flat on the floor and their hips and knees at 90 degrees. Subjects were instructed to maintain an erect seated posture without back support, but were allowed to put their hands on the table next to them. An examiner placed a hand-held dynamometer (Mobie MT-100, Minato Medical Science Co., Osaka, Japan) onto the participant's body and measured the peak force while pushing the participant's trunk perpendicularly until the participant could no longer maintain a seated posture (Figure 1). The force was applied at the mid-sternum to measure anterior trunk muscle strength, at the thoracic spine midway between the superior and inferior angles of the scapula to measure posterior trunk muscle strength, and at the left and right lateral aspects of the acromial process to measure right and left lateral trunk muscle strength, respectively. All measurements were taken by a single physical therapist, with another physical therapist engaged in support for safety measurements. All tests were performed three times after two practice trials, and the mean value of the three tests were applied to the assessments. Right and left lateral trunk muscle strengths were also averaged.

F1-40
Figure 1:
Evaluation of trunk muscle strength.The picture showing the method used to evaluate trunk muscle strength. Patients were instructed to maintain a sitting posture when pressing against a horizontal hand-held dynamometer for 5 seconds.

10 Meter walk test

Gait speed needed to walk 10 meters was assessed using the 10 meter walk test (10MWT) without VDE and with any aids if needed. These data were obtained from only five patients because of their severe paralysis and because they had been reported previously (Okawara et al., 2020).

Narrative statement

Participants’ subjective feelings about their body and activities of daily living (ADL) function were determined at the end of the intervention by an interviewer who did not otherwise participate in this study. The open-question was “Have you noticed any changes in your body or your daily life ?”.

Statistical analysis

Data were expressed as mean ± SD. Trunk muscle strengths in the nine subjects before and after 10 and 20 training sessions were compared by repeated-measures analysis of variance (ANOVA), followed by Tukey's post hoc multiple comparison analysis test. Correlations between changes in trunk muscle strength and previously measured 10MWT speed (Okawara et al., 2020) were nonparametrically assessed using Spearman's rank correlation coefficient, whereas correlations between changes in trunk muscle strength and subject age at baseline were parametrically assessed using Pearson's correlation coefficient. A P-value < 0.05 was considered statistically significant. Data were analyzed using IBM SPSS statistics version 25.0 (IBM Japan, Tokyo, Japan).

Results

Characteristics of the study subjects

Of the 10 patients, nine patients with chronic SCI, consisting of six men and three women, aged 37.8 ± 15.6 years, and mean time from injury of 51.1 ± 31.8 months completed the study. One patient withdrew from the study because of his own convenience. Their baseline characteristics are shown in Table 1. None of the patients had a medical history other than spinal cord injury. Of the nine participants, three were categorized as having American Spinal Injury Association Impairment Scale (AIS) grade B and two each as AIS grades A, C, and D. The neurological level of injury was cervical in six participants and thoracic in three. All participants completed 20 training sessions with HAL. There were no adverse events. The subjective training intensity in Borg scale of each 20 training session is shown in Additional Table 1.

T1-40
Table 1:
Baseline characteristics of the nine participants with chronic spinal cord injury
T2-40
Additional Table 1 Subjective training intensity in 20 training sessions

Trunk muscle strengths

Trunk muscle strengths in three directions improved from baseline after 20 training sessions, although the ANOVA test showed that only lateral muscle strength improved significantly (F(2, 16) = 8.90, P = 0.003, η2= 0.53), whereas anterior (F(1.21, 9.72) = 2.86, P = 0.119, η2= 0.26) and posterior (F(2, 16) = 3.56, P = 0.053, η2= 0.31) trunk muscle strengths did not (Figure 2). Post hoc tests, however, showed significant improvements in lateral (from 3.4 ± 2.8 to 6.9 ± 3.6, P = 0.002) and posterior (from 3.5 ± 2.9 to 6.9 ± 4.4, P = 0.044) trunk muscle strengths after 20 training sessions relative to baseline. Figure 3 shows changes in trunk muscle strengths after 20 training sessions relative to baseline in each AIS grade subgroup. Whereas anterior trunk muscle strength improved only in the AIS-D subgroup, and posterior trunk muscle strength improved in both the AIS-C and AIS-D subgroups. Individual data are shown in Additional Table 2.

F2-40
Figure 2:
Trunk muscle strengths after body weight-supported treadmill training of chronic spinal cord injury participants equipped with a voluntary driven exoskeletal robot.Trunk muscle strengths at baseline and after 10 (post-10) and 20 (post-20)training sessions in nine participants are shown. Although trunk muscle strengths improved in all directions after 20 training sessions relative to baseline, repeated measures analysis of variance (ANOVA) showed statistical significance only in the change of lateral trunk muscle strength (**P= 0.003). Data were expressed as mean ± SD. 1 kgf = 9.80665 N.
F3-40
Figure 3:
The changes of trunk muscle strength (Tr-strength) subgrouped by AIS grade following body weight-supported treadmill training in patients equipped with a voluntary driven exoskeletal robot.Trunk muscle strengths from baseline to after 20 training sessions in nine participants subgrouped by AIS grade are shown. In general, trunk muscle strength showed greater improvement in patients graded as AIS-C and AIS-D than in patients graded as AIS-A and AIS-B. Data were expressed as mean ± SD. 1 kgf = 9.80665 N. AIS: American Spinal Injury Association Impairment Scale.
T3-40
Additional Table 2 Trunk muscular strength (kgf) before and after 10 and 20 sessions of body weight-supported treadmill training with the hybrid assistive limbs

Correlation between the changes of 10MWT speed and trunk muscle strengths

Improvements in lateral trunk muscle strength after 20 training sessions showed a significant positive correlation with the changes in 10MWT speed in the five participants who could perform 10MWT (rs = 1.00, P < 0.01) Figure 4 and Additional Figure 1).

F4-40
Figure 4:
Correlation between change in lateral trunk muscle strength (Tr-strength) and 10 meter walk test (10 MWT) speed.A significant positive correlation was observed between change in lateral Tr-strength and 10MWT speed in the five participants able to perform 10MWT using Spearman's rank correlation coefficient (r s = 1.000, P< 0.001). 1 kgf = 9.80665 N.

Correlation between age and changes in trunk muscle strengths

Figure 5 shows that the correlations between age at baseline and changes in anterior (rs = 0.82, P = 0.01), posterior (rs = 0.85, P < 0.01), and lateral (rs = 0.67, P = 0.01) trunk muscle strengths in the nine participants were statistically significant. These findings indicate that older adult participants with chronic SCI achieved greater improvement in trunk muscle strength following BWSTT using HAL than younger participants.

F5-40
Figure 5:
Correlations between changes in Tr-strength and age.Significant positive correlations were observed between changes in (A) anterior, (B) posterior, and (C) lateral Tr- strengths and patient age using Pearson's correlation coefficient (anterior, r s = 0.787, P= 0.012: posterior, r s = 0.958, P< 0.001: lateral, r s = 0.790, P= 0.011). The dotted lines show the regression line for each scatter plot. 1 kgf = 9.80665 N. Ex: Extension; Fx: flexion.

Subjective improvements

Of the nine participants, six reported improvements in activities of daily life, including work and sports, after 20 training sessions, with all of these improvements being associated with improvements in trunk muscle strength (Additional Table 3).

T4-40
Additional Table 3 Subjective comments made by participants after 20 training sessions

Discussion

To our knowledge, this study is the first to report that VDE-BWSTT effectively improved trunk function in patients with chronic SCI. Following 20 training sessions, these patients showed a significant improvement in lateral trunk muscle strength, with a post hoc analysis also showing that posterior trunk muscle strength was improved. This study also showed that changes in lateral trunk muscle strength after 20 training sessions relative to baseline correlated significantly with great gait speed. Surprisingly, the changes in anterior, posterior and lateral trunk muscle strength showed significant positive correlations with age at baseline, indicating that older adult subjects with chronic SCI experienced greater improvements in trunk muscle strength following VDE-BWSTT.

Although VDE-BWSTT did not improve gait function among non-ambulatory SCI patients, the present results indicate that VDE-BWSTT effectively increases trunk muscle strength. Trunk function plays an important role in postural control and motion strategies in humans, and is associated with gait speed in able-bodied persons (Callaghan et al., 1999). Trunk function is also associated with postural control in post-stroke patients who are trying to sit (Pereira et al., 2014). In addition, trunk function has been associated with multidirectional reaching ability (Gabison et al., 2017), wheelchair handling ability (Yang et al., 2006), and ADL including urination control (Chen et al., 2003; Lovegrove Jones et al., 2010). Each SCI patient develops a specific strategy of postural and motion control to maintain sitting balance after their injury, stabilizing their basic activities and performance of upper limb tasks, strategies associated with the severity of neural injury. These individual strategies include both the activation of healthy non-postural muscles and inactivation of abdominal muscles, especially those that are impaired (Seelen et al., 1998). This can result in the weakening through disuse of impaired trunk muscles, leading to a gap between preserved potential motor function and voluntary motor function in trunk muscles (Squair et al., 2016). By contrast, the abdominal and back muscles are activated during gait in able-bodied individuals (Waters and Morris, 1972; Callaghan et al., 1999). Because VDE-BWSTT reproduces a normal gait pattern in patients with SCI, training will also induce trunk muscle activity, including muscles that had atrophied due to disuse, as in normal gait. Consequently, our participants were able to achieve recovery of trunk muscle function, which may contribute to increased gait speed. That is an important effect because spinal cord injury often reduces gait speed (Yuan et al., 2019). This effect was illustrated by the comments made by the participants at the end of the intervention, with six of the nine participants reporting subjective improvements in trunk function while working and while participating in hobbies and other ADL. Thus, it will be important that detailed indices related to ADL, instrumental ADL, and quality of life be investigated in future studies.

With regard to the directionality of trunk muscle strength, only the lateral side resistance showed a significant improvement. Trunk muscle strength along the anterior-posterior axis showed better recovery in participants with milder impairment. Remarkably, posterior resistance showed a greater improvement than anterior resistance in patients with AIS grade B and C injury. These results indicate that different mechanisms underlie the condition of muscles and the effects of training. First, differences in the spinal levels of muscles responsible for maintaining trunk muscular strength in each direction will affect the response to training. The resistant muscles that participate in the lateral and posterior direction are partly dominated by muscles at the higher spinal level, i.e., Trapezius (accessory nerve) or serratus anterior (C5) for lateral movement, and longissimus (C1–L5) for posterior directions, while those that participate in the anterior direction are not. Second, although the participants were equipped with a harness and a body-weight supporting apparatus, vertebral muscles should have been activated to keep the trunk in an upright position during the session (Water et al., 1972). Third, the participants might have applied a gait strategy that involves excursion and rotation of the trunk to swing the lower extremities (Adair et al., 2016). Besides, it is possible that muscle condition differed between participants due to the different adaptation mechanisms they employed and muscle disuse after SCI. Overall, lateral and dorsal muscles might be more susceptible to training. Unusually, we observed that two participants, No. 2 and No. 3, showed a more than 50% reduction in anterior resistant after sessions (Additional Table 2). This might be because the increase in the strength of the dorsal muscles was higher than the increase in strength of the anterior muscles. i.e., the anterior resistant force might decrease with co-contraction of the stronger dorsal muscles. Further investigations to uncover mechanisms behind the different training effects are required.

Improvements in truck muscle strength showed a significant positive correlation with subject age. Older adult patients with chronic SCI showed greater improvement following VDE-BWSTT, regardless of the time interval from the initial injury or its severity. Although some previous reports demonstrated improvement of trunk function (Bjerkefors et al., 2007; Bergmann et al., 2019), there has been no report showing a correlation between trunk function and age. In general, the magnitude of functional recovery was lower in older adult patients, with older adult SCI patients having lower degrees of neurological recovery, independence in activities of daily life (Scivoletto et al., 2003) and achievement of gait (van Middendorp et al., 2011) than younger patients during the acute phase of SCI. Moreover, VDE-BWSTT induced a lower level of improvement in gait function in older adult patients than in younger patients during the chronic phase of SCI (Grasmucke et al., 2017). Older adult patients may show much stronger adaptation of motion due to their relative weakness in muscular power at intact spinal levels, which can lead to more severe disuse of paretic trunk muscles. By contrast, younger SCI patients may be able to utilize their impaired trunk muscles because of their stronger residual muscular function. Medical costs for older adult SCI patients have markedly increased, reflecting improvements in acute treatment and chronic care (Barbara-Bataller et al., 2018; Furusawa, 2019). Our results suggest that trunk function in older adult persons with SCI may be more responsive to RAGT, which may enhance precision patient-centered neurorehabilitation, or the appropriate selection of advanced neurorehabilitation for each patient. Furthermore, we consider that this specific feature of RAGT could be used as part of a combination therapy for regenerative treatment, especially for severe cases (Tashiro et al., 2017). While the present study was not designed to perform age and AIS grade subgroup analysis, further analysis can provide more specific and precise insights into the effect of RAGT on patients’ background.

This study had several limitations. First, the number of patients was small and heterogeneous with respect to neurologic levels and the severity of injury. While the sample size was calculated based on the results of a study by Gabison et al. (2014), nine participants are insufficient for subgroup analysis, which is important for the evaluation of participants with heterogenous statuses. The statistical power of ANOVA for evaluating changes in trunk strength in each of the three directions, i.e., anterior, posterior, and lateral, was 0.56, 0.64, and 0.94, respectively, while that of Pearson's correlation coefficient between age and the changes in anterior, posterior, and lateral trunk strength was 0.79, 0.99, 0.80, respectively. While most of the values were around 0.8 as recommended by Cohen (1992), some were lower than 0.8. Therefore, the possibility of a type II error could not be excluded. In addition, the present study was an interventional study without internal and external control groups; thus, the possibility of selection bias cannot be excluded. Second, the present study applied only behavioral assessments and lacked observational data, such as those of electromyography. Third, the present study did not address the long-term effects of the therapy. Although there have been no reports investigating the long-term effects of RAGT, to the best of our knowledge, Kapadia et al. (2014) reported the long-term effects after FES rehabilitation of chronic SCI patients. The key to obtaining a long-term effect is to exercise the achieved functions by training continuously in daily life. While a long-term effect is relatively easy to obtain in ambulatory patients, such as in Kapadia's study, it might be difficult to obtain in non-ambulatory cases, such as those in the present study. After VDE-BWSTT, physiotherapy could help convert newly acquired trunk function into basic motion and daily activities and thereby, enhance the long-term effect. Fourth, we could not determine the effect of sensory function during intervention on changes in trunk muscle strength because we did not perform a detailed evaluation of sensory function, although the balance function has been shown previously to be related to sensory function (Kars et al., 2009). Finally, we could not distinguish the effects of VDE from those of BWSTT.

In conclusion, the present study showed that VDE-BWSTT could improve trunk function in patients with chronic SCI. Older adult patients, who show a greater increase in trunk function than younger patients, may be more suited for VDE-BWSTT. These results may contribute to the establishment of a precision rehabilitation strategy utilizing RAGT for patients with chronic SCI.

We thank Mr. Ikuma Sato (Shonan Robo Care Center, Japan) for his excellent technical support in the use of VDE.

1. Adair B, Rodda J, McGinley JL, Graham HK, Morris ME. Kinematic gait deficits at the trunk and pelvis: characteristic features in children with hereditary spastic paraplegia Dev Med Child Neurol. 2016;58:829–835
2. Bach Baunsgaard C, Vig Nissen U, Katrin Brust A, Frotzler A, Ribeill C, Kalke YB, Leon N, Gomez B, Samuelsson K, Antepohl W, Holmstrom U, Marklund N, Glott T, Opheim A, Benito J, Murillo N, Nachtegaal J, Faber W, Biering-Sorensen F. Gait training after spinal cord injury: safety, feasibility and gait function following 8 weeks of training with the exoskeletons from Ekso Bionics Spinal Cord. 2018;56:106–116
3. Barbara-Bataller E, Mendez-Suarez JL, Aleman-Sanchez C, Sanchez-Enriquez J, Sosa-Henriquez M. Change in the profile of traumatic spinal cord injury over 15 years in Spain Scand J Trauma Resusc Emerg Med. 2018;26:27
    4. Bergmann M, Zahharova A, Reinvee M, Asser T, Gapeyeva H, Vahtrik D. The effect of functional electrical stimulation and therapeutic exercises on trunk muscle tone and dynamic sitting balance in persons with chronic spinal cord injury: a crossover trial Medicina (Kaunas). 2019;55:619
    5. Bjerkefors A, Carpenter MG, Thorstensson A. Dynamic trunk stability is improved in paraplegics following kayak ergometer training Scand J Med Sci Sports. 2007;17:672–679
    6. Bjerkefors A, Carpenter MG, Cresswell AG, Thorstensson A. Trunk muscle activation in a person with clinically complete thoracic spinal cord injury J Rehabil Med. 2009;41:390–392
    7. Brown AR, Martinez M. From cortex to cord: motor circuit plasticity after spinal cord injury Neural Regen Res. 2019;14:2054–2062
      8. Bruni MF, Melegari C, De Cola MC, Bramanti A, Bramanti P, Calabro RS. What does best evidence tell us about robotic gait rehabilitation in stroke patients: a systematic review and meta-analysis J Clin Neurosci. 2018;48:11–17
      9. Callaghan JP, Patla AE, McGill SM. Low back three-dimensional joint forces, kinematics, and kinetics during walking Clin Biomech (Bristol, Avon). 1999;14:203–216
      10. Chen CL, Yeung KT, Bih LI, Wang CH, Chen MI, Chien JC. The relationship between sitting stability and functional performance in patients with paraplegia Arch Phys Med Rehabil. 2003;84:1276–1281
      11. Cohen J. A power primer Psychol Bull. 1992;112:155–159
      12. Donenberg JG, Fetters L, Johnson R. The effects of locomotor training in children with spinal cord injury: a systematic review Dev Neurorehabil. 2019;22:272–287
      13. Esquenazi A, Talaty M, Packel A, Saulino M. The ReWalk powered exoskeleton to restore ambulatory function to individuals with thoracic-level motor-complete spinal cord injury Am J Phys Med Rehabil. 2012;91:911–921
      14. Fawcett JW, Curt A, Steeves JD, Coleman WP, Tuszynski MH, Lammertse D, Bartlett PF, Blight AR, Dietz V, Ditunno J, Dobkin BH, Havton LA, Ellaway PH, Fehlings MG, Privat A, Grossman R, Guest JD, Kleitman N, Nakamura M, Gaviria M, et al Guidelines for the conduct of clinical trials for spinal cord injury as developed by the ICCP panel: spontaneous recovery after spinal cord injury and statistical power needed for therapeutic clinical trials Spinal Cord. 2007;45:190–205
      15. Filipp ME, Travis BJ, Henry SS, Idzikowski EC, Magnuson SA, Loh MY, Hellenbrand DJ, Hanna AS. Differences in neuroplasticity after spinal cord injury in varying animal models and humans Neural Regen Res. 2019;14:7–19
        16. Furusawa K. Rehabilitation medicine for spinal cord injuries in Japan Jpn J Rehabil Med. 2019;56:524–530
          17. Gabison S, Mathur S, Nussbaum EL, Popovic MR, Verrier MC. Trunk function and ischial pressure offloading in individuals with spinal cord injury J Spinal Cord Med. 2017;40:723–732
          18. Gabison S, Verrier MC, Nadeau S, Gagnon DH, Roy A, Flett HM. Trunk strength and function using the multidirectional reach distance in individuals with non-traumatic spinal cord injury J Spinal Cord Med. 2014;37:537–547
          19. Grasmucke D, Zieriacks A, Jansen O, Fisahn C, Sczesny-Kaiser M, Wessling M, Meindl RC, Schildhauer TA, Aach M. Against the odds: what to expect in rehabilitation of chronic spinal cord injury with a neurologically controlled Hybrid Assistive Limb exoskeleton. A subgroup analysis of 55 patients according to age and lesion level Neurosurg Focus. 2017;42:E15
          20. Jansen O, Schildhauer TA, Meindl RC, Tegenthoff M, Schwenkreis P, Sczesny-Kaiser M, Grasmucke D, Fisahn C, Aach M. Functional outcome of neurologic-controlled HAL-exoskeletal neurorehabilitation in chronic spinal cord injury: a pilot with one year treatment and variable treatment frequency Global Spine J. 2017;7:735–743
            21. Jansen O, Grasmuecke D, Meindl RC, Tegenthoff M, Schwenkreis P, Sczesny-Kaiser M, Wessling M, Schildhauer TA, Fisahn C, Aach M. Hybrid assistive limb exoskeleton HAL in the rehabilitation of chronic spinal cord injury: proof of concept; the results in 21 patients World Neurosurg. 2018;110:e73–78
              22. Kapadia N, Masani K, Catharine Craven B, Giangregorio LM, Hitzig SL, Richards K, Popovic MR. A randomized trial of functional electrical stimulation for walking in incomplete spinal cord injury: effects on walking competency J Spinal Cord Med. 2014;37:511–524
              23. Kars HJ, Hijmans JM, Geertzen JH, Zijlstra W. The effect of reduced somatosensation on standing balance: a systematic review J Diabetes Sci Technol. 2009;3:931–943
                24. Lam T, Eng JJ, Wolfe DL, Hsieh JT, Whittaker M. A systematic review of the efficacy of gait rehabilitation strategies for spinal cord injury Top Spinal Cord Inj Rehabil. 2007;13:32–57
                25. Larson CA, Tezak WD, Malley MS, Thornton W. Assessment of postural muscle strength in sitting: reliability of measures obtained with hand-held dynamometry in individuals with spinal cord injury J Neurol Phys Ther. 2010;34:24–31
                26. Lovegrove Jones RC, Peng Q, Stokes M, Humphrey VF, Payne C, Constantinou CE. Mechanisms of pelvic floor muscle function and the effect on the urethra during a cough Eur Urol. 2010;57:1101–1110
                27. Loy K, Bareyre FM. Rehabilitation following spinal cord injury: how animal models can help our understanding of exercise-induced neuroplasticity Neural Regen Res. 2019;14:405–412
                  28. Matsuda M, Mataki Y, Mutsuzaki H, Yoshikawa K, Takahashi K, Enomoto K, Sano K, Mizukami M, Tomita K, Ohguro H, Iwasaki N. Immediate effects of a single session of robot-assisted gait training using Hybrid Assistive Limb (HAL) for cerebral palsy J Phys Ther Sci. 2018;30:207–212
                  29. Okawara H, Sawada T, Matsubayashi K, Sugai K, Tsuji O, Nagoshi N, Matsumoto M, Nakamura M. Gait ability required to achieve therapeutic effect in gait and balance function with the voluntary driven exoskeleton in patients with chronic spinal cord injury: a clinical study Spinal Cord. 2020;58:520–527
                  30. Pereira S, Silva CC, Ferreira S, Silva C, Oliveira N, Santos R, Vilas-Boas JP, Correia MV. Anticipatory postural adjustments during sitting reach movement in post-stroke subjects J Electromyogr Kinesiol. 2014;24:165–171
                  31. Piira A, Lannem AM, Sørensen M, Glott T, Knutsen R, Jørgensen L, Gjesdal K, Hjeltnes N, Knutsen SF. Manually assisted body-weight supported locomotor training does not re-establish walking in non-walking subjects with chronic incomplete spinal cord injury: a randomized clinical trial J Rehabil Med. 2019;51:113–119
                  32. Scivoletto G, Morganti B, Ditunno P, Ditunno JF, Molinari M. Effects on age on spinal cord lesion patients’ rehabilitation Spinal Cord. 2003;41:457–464
                  33. Sczesny-Kaiser M, Hoffken O, Aach M, Cruciger O, Grasmucke D, Meindl R, Schildhauer TA, Schwenkreis P, Tegenthoff M. HAL(R) exoskeleton training improves walking parameters and normalizes cortical excitability in primary somatosensory cortex in spinal cord injury patients J Neuroeng Rehabil. 2015;12:68
                    34. Seelen HA, Potten YJ, Drukker J, Reulen JP, Pons C. Development of new muscle synergies in postural control in spinal cord injured subjects J Electromyogr Kinesiol. 1998;8:23–34
                    35. Shimizu Y, Kadone H, Kubota S, Suzuki K, Abe T, Ueno T, Soma Y, Sankai Y, Hada Y, Yamazaki M. Voluntary ambulation by upper limb-triggered HAL(R) in patients with complete quadri/paraplegia due to chronic spinal cord injury Front Neurosci. 2017;11:649
                    36. Squair JW, Bjerkefors A, Inglis JT, Lam T, Carpenter MG. Cortical and vestibular stimulation reveal preserved descending motor pathways in individuals with motor-complete spinal cord injury J Rehabil Med. 2016;48:589–596
                    37. Strauss DJ, Devivo MJ, Paculdo DR, Shavelle RM. Trends in life expectancy after spinal cord injury Arch Phys Med Rehabil. 2006;87:1079–1085
                    38. Sylos-Labini F, La Scaleia V, d’Avella A, Pisotta I, Tamburella F, Scivoletto G, Molinari M, Wang S, Wang L, van Asseldonk E, van der Kooij H, Hoellinger T, Cheron G, Thorsteinsson F, Ilzkovitz M, Gancet J, Hauffe R, Zanov F, Lacquaniti F, Ivanenko YP. EMG patterns during assisted walking in the exoskeleton Front Hum Neurosci. 2014;8:423
                      39. Tan CK, Kadone H, Watanabe H, Marushima A, Yamazaki M, Sankai Y, Suzuki K. Lateral symmetry of synergies in lower limb muscles of acute post-stroke patients after robotic intervention Front Neurosci. 2018;12:276
                      40. Tashiro S, Nakamura M, Okano H. The prospects of regenerative medicine combined with rehabilitative approaches for chronic spinal cord injury animal models Neural Regen Res. 2017;12:43–46
                        41. van Middendorp JJ, Hosman AJ, Donders AR, Pouw MH, Ditunno JF Jr, Curt A, Geurts AC, Van de Meent HEM-SCI Study Group. . A clinical prediction rule for ambulation outcomes after traumatic spinal cord injury: a longitudinal cohort study Lancet. 2011;377:1004–1010
                        42. Waters RL, Morris JM. Electrical activity of muscles of the trunk during walking J Anat. 1972;111(Pt 2):191–199
                        43. Yang JF, Musselman KE. Training to achieve over ground walking after spinal cord injury: a review of who, what, when, and how J Spinal Cord Med. 2012;35:293–304
                        44. Yang JF, Norton J, Nevett-Duchcherer J, Roy FD, Gross DP, Gorassini MA. Volitional muscle strength in the legs predicts changes in walking speed following locomotor training in people with chronic spinal cord injury Phys Ther. 2011;91:931–943
                        45. Yang YS, Koontz AM, Triolo RJ, Mercer JL, Boninger ML. Surface electromyography activity of trunk muscles during wheelchair propulsion Clin Biomech (Bristol, Avon). 2006;21:1032–1041
                        46. Yu P, Zhang W, Liu Y, Sheng C, So KF, Zhou L, Zhu H. The effects and potential mechanisms of locomotor training on improvements of functional recovery after spinal cord injury Int Rev Neurobiol. 2019;147:199–217
                        47. Yuan XN, Liang WD, Zhou FH, Li HT, Zhang LX, Zhang ZQ, Li JJ. Comparison of walking quality variables between incomplete spinal cord injury patients and healthy subjects by using a footscan plantar pressure system Neural Regen Res. 2019;14:354–360
                          48. Zhang W, Yang B, Weng H, Liu T, Shi L, Yu P, So KF, Qu Y, Zhou L. Wheel running improves motor function and spinal cord plasticity in mice with genetic absence of the corticospinal tract Front Cell Neurosci. 2019;13:106

                            C-Editor: Zhao M; S-Editor: Li CH; L-Editor: Song LP; T-Editor: Jia Y

                            Conflicts of interest:The authors have no conflict of interest associated with this study.

                            Financial support:This study was supported by the Uehara Memorial foundation, Japan Science and Technology Agency, No. 05-001-0002, and Japan Agency for Medical Research and Development, No. 19bk0104017h00029 (both to MN). The above funders had no role in study design, data collection and analysis, and decision to publish.

                            Institutional review board statement: The study was approved by the Keio University of Medicine Ethics Committee (IRB No. 20150355-3) on September 26, 2017.

                            Declaration of patient consent: The authors certify that they have obtained all appropriate patient consent forms. In the forms the patients have given their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

                            Reporting statement: This manuscript was prepared in accordance with the Transparent Reporting of Evaluations with Nonrandomized Designs (TREND) statement.

                            Biostatistics statement: The statistical methods of this study were reviewed by the biostatistician of National Hospital Organization, Murayama Medical Center in Japan.

                            Copyright license agreement:The Copyright License Agreement has been signed by all authors before publication.

                            Data sharing statement: All data included in this study are available from the corresponding author on reasonable request.

                            Plagiarism check:Checked twice by iThenticate.

                            Peer review:Externally peer reviewed.

                            Funding:This study was supported by the Uehara Memorial foundation, Japan Science and Technology Agency, No. 05-001-0002, and Japan Agency for Medical Research and Development, No. 19bk0104017h00029 (both to MN).

                            Keywords:

                            body weight-supported treadmill training; gait disorders; hybrid assistive limb; neurologic; neurophysiotherapy; postural balance; precision medicine; robot-assisted gait training; robotics; spinal cord injury; trunk

                            © 2022 Neural Regeneration Research | Published by Wolters Kluwer – Medknow