**4. Electrical and magnetic stimulation strategies for evaluation of spinal and supraspinal circuits after SCI**

Electrical and magnetic stimulation can be used to evaluate supraspinal and spinal structures and promote restoration of the motor function. These approaches consist of electrical or magnetic stimulation delivery into neural structures as therapy in motor, sensory and behavioral disorders such as chronic pain, Parkinson's disease, essential tremor, among others. Electrical stimulation can be invasive or noninvasive and complemented with imaging and electrophysiology to assess therapeutic strategies in subjects. At the same time, studying the mechanisms underlying electrical stimulation is essential to understand short- and long-term effects on neural tissue, explore novel approaches, and guarantee biosafety on implementation.

Electrical epidural stimulation (ES) was originally implemented for chronic pain in 1967 [93]. Later, it was evidenced that ES produced passive rhythmic activity in lower limbs in paraplegic subjects [13], initiating this seminal study a series of clinical investigations with the exploration of specific ES parameters in combination with physical therapy and locomotor training [94–97].

ES consist of the delivery of electrical current (typically square pulses) at different frequencies depending on the designed protocol (see below). An electrode composed of several contact leads (commonly 16) is placed on the dorsal midline of dura spanning the lumbar enlargement (T11-L1 vertebrae). Adequate positioning is monitored through electromyographic responses evoked by electrical pulses delivered at low frequencies (0.2 Hz). Implantation surgery and electrophysiology testing during surgery are described by Calvert et al. [98]. Once the subjects recovered from surgery, initial testing consists of monitoring motor activities (electromyography, EMG) produced by simple tasks during ES, including voluntary contractions on selected muscles and passive movements with suspended limbs [94, 95]. First sessions are essential to optimize parameters individually, for instance, intensities and frequencies to enable motor function in the upper [99, 100] and lower extremities [94–97]. After a couple of weeks, depending on the level and severity of SCI, subjects can be suspended on a treadmill using body weight support devices, allowing them to walk at low speeds (< 2 km/h). Even some subjects AIS-ASIA A can regain some steeping capabilities without using body weight support [94, 95]. The fact that ES enables voluntary motor activation even in subjects classified as AIS-ASIA A, suggests that some spare descending fibers can still be activated even at chronic SCI stages after several years [95, 96, 101, 102]. It is noteworthy to mention that in the absence of ES, the capacity to perform voluntary motor activities is somewhat limited, concluding that facilitation provided by ES should be continually administered in otherwise "dormant" spinal circuits. ES has shown improvements in motor function, and unexpectedly also in sensory and autonomic function [103–105]; however, a small number of highly selected subjects have been enrolled to date, making difficult to extrapolate results to general SCI population.

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

From animal [106–109] and human [110–113] studies, it is assumed that ES excites low threshold afferent fibers (posterior roots). Depending on the intensity of stimulation, anterior roots can also be activated, hence producing potentials (Motor Evoked Potentials, MEP) identified by their latencies. By producing MEP with known latencies, combination of other approaches such as Transcranial Magnetic Stimulation (TMS) and peripheral functional stimulation (FENS) allows the study of spinal and cortical plasticity as discussed below.

Transcranial magnetic stimulation (TMS) has also been used to stimulate muscles below the injury level in SCI subjects. Differences in latencies and thresholds of activation between controls and are widely described as well as emerging protocols to study plasticity in the spinal cord and cortex using TMS [65]. Changes in the motor cortex excitability have also been described [114–116].

Similarly, changes in cortical representations and events involving neural reorganization in rostral and caudal structures to lesion have been described after SCI [117–119]. Although precise mechanisms involving plasticity in cortices after trauma or SCI remains unanswered, animal models have provided valuable information [120].

In humans, targeting upper and lower limb muscles along with FENS has shown to promote spinal and cortical plasticity as partially explained by long-term potentiation mechanisms (LTP) [121]. Together, TMS and FENS are termed Paired Corticospinal-Motor Neuronal Stimulation (PCMS). For example, Jo and Perez [67] hypothesized that exercise promotes cortical plasticity in incomplete lesions. In the same study, the authors found that PCMS produced higher voltage amplitudes recorded in selected muscles. Performance during motor tests in upper and lower limbs also improved, although subjects not included in the "exercise plus PCMS group" also showed advancements. A conclusion is that TMS combined with other methods such as FENS and exercise, produces plasticity in spinal and supraspinal circuits (i.e., motor cortex), which benefits people suffering from SCI. Moreover, the effects on motor performance can last several months [67].

Yet some caveats remain unsolved. For instance, TMS technical aspects are not homogeneous across studies, for example, coils, motor tasks, and the number of muscles recorded [122]. Additionally, results obtained in small samples will be sustained in the heterogenous SCI spectrum, and potentially undesirable side effects should be discarded, as headaches are commonly reported during TMS [123]. Finally, technology advancements must overcome the high cost of TMS nowadays and to offer devices that can be used by patients and caregivers at home.

Noninvasive electrical stimulation techniques called transcutaneous electrical stimulation (tSCS) and transcranial or trans-spinal direct current stimulation (tDCS) have also been implemented as therapy for SCI. Both procedures include delivery of electrical current by surface electrodes placed on the back (as the cathode) and a pair of electrodes located over the iliac crest (as anodes). Like with ES, tSCS activates low threshold afferents, although higher stimulation intensities must be delivered as current must overcome high-resistance structures (skin, muscle, ligaments, and bones). For this reason, high intensities usually produce discomfort in subjects, perceived as painful abdominal muscle contractions. Recently, a strategy was proposed to mitigate pain and reduce current administered transpinally: a carrier frequency (10 KHz) and a lower frequency (40 Hz, for example) [124].

tSCS has shown that delivered electrical current excites large diameter fibers, thus evoking motor potentials with same characteristics (i.e., latencies) as previously demonstrated during ES [111, 125–128]. For this reason, research has explored this noninvasive technique recently as therapy for SCI subjects.

Spasticity appears after an insult to the central motor system compromises descending monoaminergic modulation of spinal circuitry [129]. Unfortunately, this sensory and motor disorder commonly develops in SCI subjects. In chronic, incomplete SCI subjects, Hofstoetter and colleagues applied tSCS over the T11 and T12 showed improvements in spasticity as measured by the Watenberg pendulum test, electromyography and 10 minutes walking. tSCS consisted of a single session of 30 min of stimulation at 50 Hz with subjects lying in supine position. The intensity of stimulation is an important parameter to consider. For example, tSCS is delivered at levels that produce paresthesia but below motor activation [130]. The involvement of brainstem inhibition seems to play a role in the activation of neural circuits through long-loop mechanisms, although the whole picture is not clear for now, as remaining fibers depending on the severity of the lesion may take part on results [131].

Additionally, spinal inhibitory circuitry could be transiently modified, decreasing exaggerated reflexes, such as during cutaneous stimulation on the foot's surface. Interestingly, motor incomplete SCI subjects increased their walking speed and voluntary control, making it less likely that reduced spasticity occurred as a diminished motor output [130, 132]. tSCS delivered tonically at 30 Hz, showed an immediate change in spinal circuitry, i.e., enabling motor output measured by EMG and kinematics [132] similarly as previously shown during ES (see above). At the same time, supraspinal and propriospinal circuitry could participate during steeping in incomplete injuries. For example, ES and tSCS are supposed to increase the excitatory drive necessary to activate central pattern generators [13]. However, tSCS is not feasible as a home-based therapy and carry-over effects are not easy to study. It was recently found in one subject with chronic SCI (AIS-D) that tSCS self-applied during 6 months improved spasticity as measured by several scales and functional tests and that beneficial effects lasted for seven days after cessation of tSCS [133].

Combining TMS and tSCS is possible to explore changes in cortical excitability before and after low frequency (0.2 Hz), continuous (52 m) tSCS after SCI. After 14 sessions of tSCS, paired TMS pulses on the left motor cortex delivered at different interstimulus intervals (ISI) in a range of 1–30 ms, evoked motor potentials that exhibited intracortical facilitation and inhibition that was related to a decrease in latencies and an increase in amplitudes recorded in right wrist flexor and extensor muscles [134]. Authors interpreted these results as changes in cortical map representations, bilateral connection strengthening, and increase in cortical drive, although plasticity in the spinal cord may also play an important role. Importantly, the subject enrolled in this study also reported improvements in autonomic and sensory functions below the lesion, as reported for ES (see above).

Few studies have used the transcutaneous spinal Direct Current Stimulation (tsDCS) technique to study motor activation in complete and incomplete SCI. Cathodal or anodal stimulation can be applied, and corticospinal excitability evaluated in recorded muscles by TMS [135] or spinal reflexes [136]. Although nonsignificant results have been reported, modifications in MEPs suggest differences in cathodal versus anodal stimulation, meaning lateralization in responses depending on the location of the reference electrode [135]. Cathodal tsDCS stimulation did not show differences in spinal reflexes compared to sham stimulation [136]. Overall, results with tsDCS must be taken cautiously as few SCI subjects have been enrolled, and motor outcomes are not readily comparable with healthy population.

#### **4.1 Limitations**

Although these findings may represent a new alternative to invasive methods to restore lost functions, limitations impede translation into the clinic. Research must

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

be extended into the heterogeneity of injuries (extension, level, time after lesion, age, etc.). To date, a small sample of subjects have been included in trials, and carry-over effects have not been fully explored. It is important to mention that beneficial results during neurostimulation are immediate, observable, quantifiable, and self-perceived; however, after cessation of electrical stimulation, there is a notable reduction in the effects, being voluntary muscle contraction the most evident, although some improvements remain as described consistently, especially in incomplete SCI. In this context, evaluation of daily activities should be included in trials to assess patients' quality of life. Finally, long-term effects, especially adverse effects, must be appropriately assessed, being one of the barriers the difficulty of self-applied home-based therapy.

Spinal cord injury is a severe clinical issue that affects in the acute stage the body of the patient and in a chronic stage the mental health. As above mentioned, a cascade of phenomena occurs after a SCI such as: inflammatory response that lead to neurons and axon degeneration, muscular damage, cardiopathy process, etc. If a group of health practitioners give a proper clinical and or surgical management, its patient preserves his life but not his sensitivity and motor control (depending on the degree and location of the injury).

Therefore, patients tend to develop an important state of mental health problems that includes depression [137], chronic sadness states and mood changes [138], delirium [139], and suicidal thoughts [140]. Therefore, is important to address mental health management after SCI in a proper way to ensure an integral patient recovery.
