**2. Motor pathways reorganization after SCI**

To develop key strategies for functional improvement of injured spinal cord, the knowledge of the central nervous system organization under physiologic and pathophysiologic conditions is essential.

Premotor spinal oscillators (alternating flexor and extensor activity in neuronal spinal cord circuits) exhibit neuronal network organization based on their firing patterns and driving afferents. This oscillatory activity is also observed by firing patterns recorded in muscles, thus making possible to follow up therapeutic interventions in patients with SCI based on the activity of the muscles during flexor and extensor phases of locomotion. At the same time, it is possible to assess the abnormal firing patterns and dysfunction in spinal reflexes.

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The concept of re-organization and pattern formation in imbalanced systems is associated to the firing patterns of groups of identified neurons in the spinal motor networks was extensively developed by Schalow and Zach [33]. Human CNS has integrative functions for learning, re-learning, storing and recalling, being all these necessary elements contributing to plasticity following injuries. Thus, understanding the Central Nervous System (CNS) reorganization in the short and the long-term memory process during a therapeutic intervention as an approach for re-learning adequate motor behavior is fundamental to achieve functional motor improvements. This intervention consists in the training of innate automatisms like creeping, crawling, up-righting, walking, and running. Moreover, the training of rhythmic, dynamic, stereotyped and movements could substantially be improved by applying different protocols of coordinate on dynamic therapy [33, 34]. Among therapeutic goals during coordination dynamic therapy are to induce cell proliferation and neurogenesis, so this could contribute to promote structural changes during the reconnection process in the injured tissue. New training paradigms are being created as a tool for retraining the spinal cord looking to engage the innate locomotor circuitry with appropriate afferent input to avoid lasting maladaptive sensory and motor effects, such as central pain and spasticity [35]. For accurate motor control, proprioceptive information from the body and environment has to be integrated and transformed into an appropriate motor command under physiological conditions [36, 37]. The inherent neural transmission and integration for motor output and the perception of limb position activated in the cortical areas during kinesthetic sensations are based on proprioceptive information [38]. This lead the notion that the activation of the propriospinal pathways in its different configurations may help activating supraspinal areas such as cortical regions where senses involved in modulating motor control are processed, and these can be used to take advantage of strategies for motor recovery from a SCI.

Interestingly, depending on the severity of the SCI, humans and animal models in most cases presentsome degree of spontaneous functional recovery during the first months after injury [39–43]. This outcome has been attributed to spared descendent axons bypassing the site of injury, although precise mechanisms underlying this phenomenon are not known. Courtine and collaborators investigated the spontaneous recovery in a spatially and temporally separated lateral hemisections in a mouse model, using kinematic, physiological and anatomical approaches. Their findings suggest that functional recovery can occur after severe SCI facilitated by the reorganization of descending and propriospinal connections [44]. Interventions headed for enhancing the remodeling of spread connections are important to explore in the various novel therapeutic strategies to reconnect spared tissue and restore function after SCI.

Neurorehabilitation must be in accordance with the re-organization of neuronal networks. Movement patterns re-learned by pattern formation and coordination dynamic therapy progress by cooperative and competitive interaction between intrinsic and extrinsic therapeutic inputs (afferent input) [45].

#### **3. Combination of exercise and therapeutic strategies**

Physical exercise provides important benefits after SCI both in clinical studies and in animal models [1, 46]. Specifically, studies in animal models have emphasized the importance of exercise and combined strategies to boost motor recovery. However, the functional recovery of locomotion has so far been limited, preventing its translation into the clinic.

#### *The Role of Supraspinal Structures for Recovery after SCI: From Motor Dysfunction to Mental… DOI: http://dx.doi.org/10.5772/intechopen.96140*

Exercise and physical training demand adaptation in a wide range of movements and locomotion in upper, lower limbs and trunk, promoting interaction between CPG's, propriospinal neurons and supraspinal structures. Plastic changes induced by activity and sensory entry can take place both in the spinal cord and other supraspinal regions in the brain.

Studies have given evidence supporting the notion that exercise produces "motor learning" in the spinal motor circuits. One hypothesis is that the complex network of components of the extracellular matrix, inhibits the remodeling or reconnection [47]. Therefore, exercise induces the plasticity in the SCI circuitry, which could produce an interneuronal network reorganization [48]. For example, training intervention in a treadmill (20-minute protocol, 5 days a week for 3 weeks, after the complete injury) improved locomotion performance with a reversal in the asymmetric alternating movements that had occurred after a hemisection in a cat SCI model. The untrained group maintained the hemisection-induced asymmetry after the recovery period [49]. Increased excitability and the recruitment of motoneuronal populations drive limb coordination during gait and restores symmetry in a hemisection model of adult rats [50].

In other study in rats, a combination of Tamoxifen and treadmill exercise had a notorious improvement in the angular displacement kinematics after a hemisection SCI model. The untreated subjects remained considerable discrepancy in the hip and ankle joints. The drug tamoxifen presented neuroprotective effects as well as increased tissue integrity and inflammation reduction [51, 52] and the exercise exerted beneficial effects ameliorating the damage [48].

Complex network of the extracellular matrix components, which includes CSPGs, inhibits the axonal reconnection that exercise can induce, limiting plasticity in the damaged spinal circuitry. A Chondroitinase ABC treatment study was performed to see if it could enable plasticity in adult mice, combined with voluntary physical training on a rotating wheel. The results have not been positively conclusive [47]. It is necessary identifying an adequate protocol for pharmacological interventions as well as the type and amount of exercise. In 2016, another study with Chondroitinase ABC combined with intensive treadmill rehabilitation had a slight recovery, suggesting a beneficial role for chronic SCI in adult rats [32].

Physical training and elements such as the density of functional synapses, and the neurotrophic factors (NF) provide important clues to optimize recovery after injury [53]. Motoneurons and other ventral horn cells in sectioned rats synthesize BDNF in response to treadmill training, suggesting a support mechanism by which postsynaptic release of BDNF from motoneurons contribute to synaptic plasticity [54]. Moreover, BDNF levels had a significantly increase in the lumbar SC region in injured rats with training compared to the non-trained injured rats [55].

Exercise raise the levels of NT-3 and BDNF in the spinal cord, causing modulation of the NMDA receptor, which generates greater activation of the hindlimb muscles [53]. Neurotrophic factors, which include NT-3, NGF, and IGF, modulate neuronal growth, differentiation, and survival [56]. Endogenous NF higher levels can be better than exogenous administration. Exercise is also involved in the nervous system gene regulation, associated to apoptosis and cellular growth signaling pathways (PTEN, PDCD4, RAS mRNA and Bcl-2/Bax). This can produce axonal growth and reconnection improving injured SC morphology [57, 58].

Neurotrophic factors are fundamental for the normalization of spinal reflexes [59]. Limb spasms are phenomena of hyperreflexia that occur after SCI. AAV-NT3 gene therapy, exercise, and combination therapy all attenuated the frequency of spasms in the swimming test conducted at 6 weeks after SCI and increased

rate-dependent depression of H-reflex in rats. Combination therapy was significantly superior to AAV-NT3 alone in protecting motoneurons and remodeling spinal cord circuits. Gene therapy and exercise can alleviate muscle spasm after spinal cord injury by altering the excitability of spinal interneurons and motoneurons, but adjusting the combined strategy is needed to get better results [60].

Exercise produces benefits such as improving strength and conduction to adaptations in skeletal muscle and nervous system [61]. In humans, with almost total loss of voluntary muscle activity in one or both lower extremities, free field gait rehabilitation can be performed [62]. Based on this, the improvement can be achieved by appropriate treadmill training due to the activity of the voluntary muscle [63].

The effectiveness of physiotherapy in people with SCI studied in randomized controlled trials give evidence that a small number of this interventions increase voluntary strength in muscles directly affected by SCI, comparing sham or no intervention, and different physiotherapy interventions [64]. Other randomized control trials studies provide outcomes of specific features of training interventions to improve both sitting and standing balance function in SCI indicate negligible effect sizes [65–70]. Given the importance of balance control underpinning all aspects of daily activities, there is a need for further research [71].

Passive cycling can be an alternative rehabilitation for patients who are too weak or medically unstable to repeatedly practice active movements. Experimental animal studies [72] revealed that passive cycling modulated spinal reflex, reduced spasticity and autonomic dysreflexia as well as elicited cardio-protective effects [73–76]. Also, increased BDNF mRNA levels, GDNF and NT-4 [77]. In contrast, human studies did not show an effect on spasticity reduction nor prevention of cardiovascular diseaserelated secondary complications [78, 79]. However, it is possible that passive cycling could provoke sensory inputs to induce cortical plasticity to improve lower limb motor performance, further wide perspectives are necessary in this direction [72].

In patients with chronic incomplete SCI, targeted physical exercises are designed to simultaneously stimulate cortical, and spared subcortical neural circuits. Participants of a study underwent 48 sessions each of weight-supported roboticassisted treadmill training and a combination of balance and fine hand exercises. Multimodal training tended to increase short-interval H-reflex facilitation, whereas treadmill training tended to improve dynamic seated balance. The low number of participants who completed both phases was a limitation. However, it is important to address engagement of lower extremity motor cortex using skilled upper extremity exercises; and skill transfer from upright postural stability during multimodal training to seated dynamic balance. These multimodal approaches incorporating balance with skilled upper extremity exercises showed no benefit compared to an active control program of body weight-supported treadmill training. Thus, it is necessary to improve participant retention in long-term rehabilitation studies [19].

Criteria for exercise guidelines represent an important step for developing exercise policies and programs for people with SCI around the world. According to current guidelines, for cardiorespiratory fitness and muscle strength benefits, SCI patients should engage in at least 20 min of moderate to vigorous intensity aerobic exercise and strength exercises for each main functioning muscle group are a strong recommendation. For cardiometabolic health benefits, at least 30 min of moderate to vigorous intensity aerobic exercise 3 times per week are a conditional recommendation [80].

The study and analysis of exercise is a major issue for the developing of synergistic strategies in the SCI treatment with pharmacological treatments and stimulation of the damaged tissue (electrical or magnetic). Different combined treatments produce positive interaction that improve or optimize the results in functional motor recovery, and revealing the knowledge of which parameters work is fundamental, so it can be adjusted to the individual needs of people suffering from SCI.

*The Role of Supraspinal Structures for Recovery after SCI: From Motor Dysfunction to Mental… DOI: http://dx.doi.org/10.5772/intechopen.96140*

#### **3.1 Robotic exoskeletons**

Mobility possibilities of SCI people in a wheelchair, are very limited. They usually adopt a sedentary lifestyle, with progressive physical deterioration and risk of musculoskeletal, cardiovascular and endocrine/metabolic morbidity and mortality increase [81]. Robotic exoskeletons can allow individuals with SCI with varying levels of injury to functionally walk or exercise and mitigate these potential negative health consequences. The aim of these powered exoskeletons devices is to improve the mobility for people with movement deficits by providing mechanical support and facilitate the gait training [82]. All long-term manual wheelchair users who participated in a robotic rehabilitation session, predominantly perceived improvements in their overall health status and felt motivated to engage in a regular physical activity program adapted to their condition [83].

Use of exoskeletons take advantage of spared fibers in incomplete injuries and involve the use of voluntary motor control as well as proprioception to promote recovery. Therapies with exoskeleton comprises 16 to 30 sessions [84, 85], during three 60-minute sessions a week [86]. Results indicate potential benefits on gait function and balance [87]. For example, a study measured walking progression, sitting balance, skin sensation, spasticity, and strength of the corticospinal tracts. Results indicate that about 45 sessions are needed to reach 80% of optimal performance. Functional improvements were reported, especially in people with incomplete injuries. Spasticity had mixed changes, suggesting differences between high versus low spasticity prior to training [88].

The sensory information in SCI subjects is missing below the level of lesion, which made difficult to control body posture and balancing with an exoskeleton making its use difficult according to another research group [89]. It is hypothesized that part of the missing sensory information can be provided to improve the control of an exoskeleton by delivering discrete vibrotactile stimulation [89]. Following a training robotic-based proprioception training protocol in people with chronic incomplete SCI, significant improvements in endpoint and knee joint position sense and in a precision stepping task performance were shown. These results suggest altering proprioceptive sense is possible in people with incomplete SCI using a passive proprioception training [90].

An autonomous wearable robot able to assist ankle during walking, utilizes a Neuromuscular Controller with assistance based on specific residual functional abilities of subjects. According to the study, 5 training sessions were necessary to significantly improve robot-aided gait speed on short paths and consequently to optimize the human-robot interaction [91].

Exoskeletons technology have different settings depending on the needs and requirements of protocols. Existent information and evidence must be integrated to optimize rehabilitation SCI therapies. Also, is important to fulfill main goals of exoskeletons as to define basic elements for restoring movement and sensitive functions in the people living with a SCI. Finally, the refinement of the robotic devices is highly desirable to assess the adjustment to individual cases and the application in conjunction with treatments focused on the spared tissue reconnection, as well as electrostimulation therapies.

#### **3.2 Limitations**

Exoskeleton control can be challenging for users and requires a long period of training [89]. Then, functional interaction subject-exoskeleton is a main factor to produce or increase walking abilities with interlimb coordinated movements [86]. The exoskeleton rehabilitation strategies transferring from laboratories to clinical

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settings and their effects remain uncertain due to the absence of large-scale clinical trials. Some researchers and clinicians call for developing pre-training rehabilitation programs to increase passive lower extremity range of motion and standing tolerance [84]. Future studies with larger sample size are needed to investigate the effectiveness and efficacy of exoskeleton-assisted gait training as single gait training and combined with other gait training strategies [92].
