WWTF - Vienna Science and Technology fund - Project Nr. LS11-057:

Augmentation of residual neural control by non-invasive spinal cord stimulation to modify spasticity in spinal cord injured people
Funding period: 2011-2015
Spasticity is a feature of the upper motor neuron syndrome. As a major cause of disability after spinal cord injury (SCI), spasticity involves muscle hypertonus, hyperreflexia, clonus, and involuntary muscle contractions. Irradiation of voluntarily initiated movement can diminish the functional utility of residual voluntary motor control. The pathophysiology of spasticity following SCI results from alterations of supraspinal drive, leading to reorganization of spinal cord circuitries and abnormal intraspinal processing of primary afferent input.
Despite its prevalence, spasticity is not always managed effectively. Physiotherapy predominantly acts on the biomechanical component of spasticity. Pharmacological agents block spinal neural activity in the individuals who already have a reduced voluntary drive. Surgical procedures with potential loss of function are irreversible.
Neuromodulation techniques, modifying altered input-output relations of neural circuitries by stimulation, appear as favourable alternatives. Epidural spinal cord stimulation (SCS) reduces severe lower limb spasticity in SCI persons, when targeting the upper lumbar cord. Over the last decade epidural stimulation of the lumbar spinal cord has been increasingly recognized to facilitate locomotion after SCI. 
The development of a non-invasive, transcutaneous SCS technique motivated the current research. We will explore whether it can be used as a neuro-augmentative rehabilitation tool for spasticity control in SCI. We hypothesize that applying a tonic drive to the lumbar cord can transform neural circuits involved in the control of muscle tone and movement into more functional states and that beneficial post-stimulus effects will persist for some time.
We will study the interaction of tonic transcutaneous SCS with different SCI profiles of participants with motor complete and incomplete lesions. Clinical, functional and neurophysiological methods will assess different manifestations of spasticity and residual motor control capacities before and their modifications after continuous transcutaneous SCS (applied for 30 minutes). The persistence of the therapeutic effects will be investigated, both carry-over effects after single application as well as plasticity with repetitive exposure to the intervention. In parallel, novel electrophysiological methods based on the non-invasive elicitation of multi-segmental spinal reflexes shall be explored to assess spasticity and uncover its underlying integrated mechanisms.
Having all advantages of a non-invasive, simple and cost-effective technique, transcutaneous SCS has great potential to be widely applied for modification of spasticity and residual motor control after SCI as well as in neurophysiological motor control studies. The proposed co-operation of partners with complementary expertise will encourage new approaches and open a new field for students in Vienna to be trained in human neurosciences integrated into patient-relevant programmes.

Wings for Life - Project Nr. WFL-AT-007/11:

Non-invasive spinal cord stimulation and assisted treadmill stepping to generate rhythmic activities in motor complete spinal cord injured people: Control of produced motor patterns 
Funding period: 2011-2013 
Severe injury can functionally separate the lumbosacral spinal cord from higher levels of the central nervous system. Such motor complete spinal cord injury (SCI) results in the loss of voluntary control of muscles below the lesion level, including the ability to walk. One approach to recover motor function after SCI is body-weight supported and assisted treadmill stepping repetitively applied for an extended period of time (locomotor training). This method evolved from experimental animal studies and was considered a promising rehabilitation strategy. However, recovery of motor function was found to be variable depending on the severity of injury and it is now understood that functional improvement cannot be achieved after severe SCI. The low state of excitability of infra-injury lumbar cord circuits due to the absence of descending drive is believed to be one reason for the inefficacy of locomotor training in motor complete SCI. In regards to locomotor recovery specifically, combinations of interventions could be one solution and the synergistic effects of treadmill stepping, pharmacological interventions and spinal cord stimulation have been demonstrated in animal experiments.
In a previous Wings for Life-funded project, we studied the capacity of non-invasive, surface electrode-based spinal cord stimulation (SCS) to provide for a tonic drive to the lumbosacral spinal cord and to facilitate treadmill stepping in wheelchair-dependent SCI people. We found that tonic transcutaneous lumbar SCS increased and modulated lower limb muscle activities produced during (manually assisted) treadmill stepping in motor complete and incomplete SCI participants. Functional motor patterns and changes in kinematics were produced only in incomplete SCI subjects with residual voluntary locomotor capabilities.  
Here, we propose to improve the rhythmic motor outputs in motor complete SCI people. We assume that the effect of tonic transcutaneous SCS is causative in the generation of the motor patterns, while proprioceptive feedback associated with guided stepping has a regulative role. We will study changes of the motor output by variation of the applied tonic drive (SCS site, strength, frequency) and will examine the regulative impact of different proprioceptive cues (load, speed, range of hip joint angle). This knowledge shall enable us to control parameters critical for the generation of functional motor patterns.
The significance of the proposal lies, scientifically, in the unique study design allowing for a better understanding of the interplay of tonic signals, that are characteristic for (missing) descending drive, and patterned feedback signals associated with stepping in the generation of rhythmic locomotor-like outputs. Therapeutically, after our earlier feasibility study, this thrust is a necessary step towards the application of this method in clinical practice. This study will contribute to extend the population of SCI patients to include people concerned who do not benefit from contemporary activity-based therapies.
WTZ Austria/Slovenja I 14/2011:
Electrophysiological Study Hoffmann-Reflex/Posterior Root Reflex
Funding period: 2011-2012
Background information
Originally described by Paul Hoffmann in the early 20th century (Hoffmann 1910, 1918), the Hoffmann reflex (H reflex) is the electrical analogue of the stretch reflex. It is evoked by electrical stimulation of Group Ia muscle spindle afferents within a mixed (i.e., containing both motor and sensory axons) peripheral nerve trunk that subsequently affect depolarization of motoneurons through monosynaptic connections in the spinal cord. This will result in depolarization and contraction of the muscle fibers, electromyographically recorded as an H reflex in the muscle under study.
Due to the direct, monosynaptic connection of Ia afferents and motoneurons, the H reflex provides a non-invasive method for testing the average synaptic excitability of the motoneurons in the pool supplied by the stimulated nerve (Renshaw, 1940). Interpreting changes in H reflex size under various, experimentally controlled influences as changes in motoneuron excitability allowed studies on excitatory and inhibitory convergence onto motoneurons in humans (Schieppati, 1987). Consequently, the H reflex has been extensively applied in the fields of clinical neurophysiology, applied physiology, adaptive plasticity of the nervous system, sensory-motor integration and neural control of posture and movement in humans for some decades (Magladery et al., 1951, 1952; Hugon, 1973; Zehr, 2002; Knikou, 2008).
The H reflex of the soleus muscle is the one most commonly studied in the human lower limb due to methodological, anatomical as well as physiological reasons. Classically, it is evoked by transcutaneous electrical stimulation of the posterior tibial nerve in the popliteal fossa and recorded electromyographically from the surface of the calf muscle (soleus or triceps surae) as compound muscle action potential (CMAP). Equivalents of the soleus H reflex can be evoked in some other lower limb muscles by stimulation of the respective peripheral nerves, but require special conditions (Burke et al., 1989). The rate of occurrence of H reflexes in tibialis anterior in response to deep peroneal nerve stimulation, for instance, amounts to 0-11 %, while the subject is at rest (Zehr, 2002).
While in the lower limbs, peripheral nerves are separated in numerous branches, sensory axons from all muscles enter the lumbosacral cord via the posterior roots/rootlets within a small longitudinal extent of approximately 5 cm in humans (Lang, 1984). Thus, stimulation at that site would simultaneously elicit reflex responses in several flexor, extensor and bifunctional lower limb muscles. Such stimulation would allow novel studies of sensory- motor control at multiple levels of the human spinal cord from the L2 to S2 cord segments, bilaterally.
Rationale of the planned collaboration
Members of the Vienna group have recently described a novel, non-invasive technique of lumbosacral posterior root-stimulation in humans (Dimitrijevic et al., 2004; Minassian et al., 2007). Single stimuli applied via surface electrodes placed over the lower back and abdomen evoke short-latency reflexes in virtually all lower limb muscles, so-called posterior root- muscle reflexes (PRM reflexes).
PRM reflexes were described as CMAPs by using pairs of surface electrodes located over the bellies of quadriceps, hamstrings, tibialis anterior, and triceps surae (Minassian et al., 2007; Hofstoetter et al., 2008). PRM reflexes to single stimuli were hypothesized to be monosynaptic reflexes according to the following electrophysiological characteristics: (i) short and constant onset latencies of CMAPs; (ii) attenuation of CMAP amplitude when a conditioning stimulus was given 50 ms prior to the test stimulus; (iii) attenuation of CMAP amplitudes during Achilles tendon vibration; and (iv) CMAPs of the triceps surae muscle group were significantly increased by slight plantar flexion and suppressed during voluntary contraction of the antagonistic tibialis anterior, with characteristic modifications of responses also in the other muscles.
The hypothesis of the Vienna group members is that the PRM reflexes have similar electrophysiological characteristics like the classical H reflex and can be thus equally applied in various clinical and scientific studies. Their application in studies of human neural control of posture and locomotion is of particular interest.
However, a meticulous electrophysiological description of the PRM reflexes along with a comparison to the classical H reflex will be required as a solid basis for further applications. The necessity of such verification studies lies mainly in the diffuse nature of stimulation applied from the surface of the body to neuronal structures within the vertebral canal. There is also potential of some physiological differences between the PRM reflex and the H reflex.
An obvious dissimilarity is given by the different distances of the stimulation sites with respect to the spinal cord when afferent volleys are evoked either in the periphery or within the posterior roots, with associated differences in the degree of temporal dispersion of the afferent volley. More importantly, peripheral stimulation can be controlled to stimulating primary afferents originating in a single muscle or muscle group. Stimulation applied to the posterior aspect of the lumbosacral spinal cord, on the other hand, usually stimulates afferents involved in the myotatic reflex arcs of agonists and antagonists simultaneously. Short-latency effects like facilitation from close synergists, disynaptic inhibition from antagonists, or influences from the contralateral side could therefore potentially affect the PRM reflexes.
Such effects are difficult to assess by electromyographic (EMG) recordings of populations of motoneurons from the surface of the muscle belly. Limitations of this method are due to the interference of the effects and responses of different motoneurons. Furthermore, temporal resolution of compound EMG responses is limited (Pierrot-Deseilligny & Burke, 2005). These limits can be overcome by selective recordings from single muscle fibers.
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