The Importance of the Quadruped Animal Model in Functional

iMedPub Journals INTERNATIONAL ARCHIVES OF MEDICINE 2015 http://journals.imed.pub Section: Physical Medicine and Rehabilitation Vol. 8 No. 178 ISSN: 1755-7682 doi: 10.3823/1777

Ângela Martins The importance of the quadruped DVM, CCRP, ESAVS Member of AARV AND IARVT animal model in functional Department of Veterinary Sciences University of Lusófona de Humanidades e Tecnologia neurorehabilitation for human Campo Grande 376 1749 – 024 Lisboa biped Contact information: REVIEW Ângela Martins

 [email protected] Abstract

Keywords Functional neurorehabilitation (FNR) is an alternative approach to Functional neurorehabilitation; improve patient’s quality of life. FNR has neuroanatomical foundations central nervous and is based on two properties of the central nervous system (CNS), system; neuroplasticity; which are present both in human biped and quadruped animal: neuro- neuromodulation; locomotor plasticity and neuromodulation. The dog and cat models, by their very training; fictive locomotion; own characteristics, become an evidence model for the human biped. pyramidal; extrapyramidal; In the human biped we can apply locomotor training according to motor spinal input; central the norms of locomotor training for fictive locomotion in quadruped. pattern generators.

Introduction and semi-automatic activities, such as locomotion (Thomson & Hatin, 2012). The extrapyramidal sys- The spinal cord in human biped is the most cau- tem tract for upper motor neuron (UMN) originates dal division of the central nervous system (CNS). It is in the brainstem and is of the utmost importance a fundamental structure in mediating the execution (Thomson & Hatin, 2012). of voluntary and reflex arc movements. It contains In the human biped, the UMN system originated neural circuits that control some types of movement, by the motor cortex is responsible for the voluntary some of which located exclusively in the spinal cord. movements of the face, carpus and limbs, using the Therefore, the brain only sends command “signals” pyramidal, corticonuclear and corticospinal tracts for modulating, activating, or suspending the mo- (Thomson & Hatin, 2012). vement. The motor gait pattern itself is located in In summary, human bipedal is pyramidal and qua- the spinal cord (Barros & Pinheiro, 2014). druped animal is extrapyramidal (Barros & Pinhei- In the canine quadruped, the extrapyramidal sys- ro, 2014; Solopova et al., 2015; Thomson & Hatin, tem is responsible for maintaining posture, rhythmic 2012). This statement allows interrelating functional

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rehabilitation in human medicine (HM) with veteri- promotes motor functionality and fine movements nary medicine (VM), leading to the application to function in the thoracic limbs (Garcia et al., 2015). HM of exercises specific to VM. Within FNR, we demonstrate how exercises that Since the spinal cord has activity in itself, we can stimulate the spinal locomotor circuits play a key perform an interchange of functional neurorehabi- role in attaining the locomotion ability both on qua- litation (FNR), considering that dogs are extrapyra- drupeds and bipeds. midal, with the rubrospinal tract (RuST) acting as Neurorehabilitation is fostered by the neuroplasti- corticospinal tract (CST), whereas in HM the CST city of the motor cortex, brainstem and spinal cord is the main downward tract for motor action, as (Thompson & Walpaw, 2014). mentioned above (Lorenz et al., 2011). Over the years, it has been proved that, in mam- FNR is an area of physical medicine which aims mals, the spinal cord has an intrinsic capacity to at utilizing the motor cortex, brainstem and spinal generate rhythmic motor patterns, without sensory cord neuroplasticity property, as to promote inde- or motor supraspinal input (Chang, 2014; Gad et al., pendence functions and quality of life, both for the 2012). Grillner calls this ability of the spinal cord of quadruped animal and biped human (Thompson & spinal neural circuits of central pattern generators. Walpaw, 2014). Supraspinal control is however essential for a coordinated and even conscious locomotion. In quadrupeds, locomotion is characterized by the Neural plasticity in human biped and coordination of forelimbs and hind limbs, which is quadruped animal generated by the same spinal neural control mecha- A comprehensive review study allows us to ascer- nism (Cazalets & Butrand, 2000; Nathan, Smith & tain that when the biped human has the corticospi- Deacor, 1996). This coordination between the two nal paths damaged, it may, through its neuroplas- motor systems (upper motor neuron - UMN; lower ticity property, promote extrapyramidal paths to be motor neuron - LMN) is present in the quadruped the paths of connection and information from the locomotion and preserved in biped locomotion. motor cortex to the spinal cord (Garcia et al., 2015). The neuroplasticity property allows the biped to Indeed, anatomical and functional studies have de- use, for locomotion, the cerebellum and the brains- monstrated that the motor cortex is connected to tem when it exhibits complete or incomplete spinal the spinal cord, not only by the CST, but also, in- cord injury, after receiving the stimulus of a loco- directly, by the motor pathways of the brainstem motor training. Therefore, it is assumed that the (Garcia et al., 2015). two-legged and four-legged supraneural plasticity Through various studies we are able to prove is associated with the plasticity of the neural spinal the neuroplasticity property of the nervous sys- circuits (Tansey, 2010). tem, which is responsible for the success of FNR The above facts seem to indicate that FNR should and of spontaneous or fictive locomotion (Garcia explore the plasticity of neural circuits both at a et al., 2015). Hence the adaptation of rehabilitation supraspinal and spinal level. exercises in quadrupeds to bipeds is explained on a Several studies have demonstrated how repeated neuroanatomical basis, and it may promote faster rehabilitation exercises that stimulate the afferent locomotion, as well as a more accurate performance and efferent sensory-motor pathways allow the (Garcia et al., 2015). spinal neural circuits to memorize the rehabilitation The potential neuroplasticity ability of the reti- exercises which were practiced, and thus the neu- culospinal tract (RST), a brainstem motor tract, rorehabilitation will depend on repetition and qua-

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lity of the locomotor training (Nielsen et al., 2015; locomotion (Lavron et al., 2015; Shah et al., 2013). Zhong et al., 2012). We can say that the central pattern generators Proving that FNR has clinical success are several are involved in locomotion of both biped and quad- experiments in cats and rats where, after a complete ruped, and in both they work depending on the transaction, the spinal cord alone allows the capaci- supraspinatus input and sensory feedback. The lum- ty of a locomotion pattern. The FNR training consis- bosacral spinal cord intumescence has the CPG that ted of daily locomotor training in a treadmill for at promote a rhythmic activity, without supraspinal ac- least 30 minutes, 5 to 6 times a week. Following 2 tion, and thus in human biped it is suggested by to 3 weeks of training, the animals showed fictive evidence that movements produced in locomotion, locomotion (Nielson et al., 2015; Zhong et al., 2012). race, swim, etc. use the rhythmic circuits of CPG Within FNR, neuroplasticity must be used by (Solopova et al., 2015). the rehabilitator as to allow a connection between Currently, it is proven that electromyostimulation o f plasticity and functionality and, thus, rehabilitation peripheral nerves, as well as cyclical movements, exercises that induce plasticity should avoid erro- increase the excitability of the segments of the neous adaptations which cause pain and spasticity spinal cord, thereby facilitating the emergence of (Nielson et al., 2015). a movement similar to locomotion. In the case of On that account, neurorehabilitation must have cyclical movements, cycles of 2 up to 10 are neces- pain management has one of its purposes, hence sary to promote a gear movement similar to volun- stimulating the spinothalamic tract (Nielson et al., tary gait. 2015; Thomson & Hatin, 2012). We can summarize by saying that the stimulation may be, as stated above, by electric epidural Activation of central pattern generators stimulation, but also by transcutaneous stimulation, (CPG) in human biped and quadruped direct electromagnetic stimulation of the spinal cord animal and rhythmic movements in standing posture, de- The CPG activation can be via epidural, as ex- pending on the supraspinal influence and on the plained by Edgerton in several studies. In recent rhythmic capacity of the spinal circuits (Musienko studies, two types of stimulation are indicated, the et al., 2012; Solopova et al., 2015). epidural stimulation (ES) and the intraspinal stimula- Voluntary locomotion allows a voluntary activation (IS), proving that simultaneous ES and IS stimu- tion of the CPG, making it easier to stimulate the lation provide a more consistent performance of the transcortical reflex pathways and increasing the pelvic limbs, compared to ES and IS isolated. ES and depolarization of motoneurons. Therefore, all FNR IS being potentiated together means that they have modalities that activate CPG must be associated to different neural mechanisms: ES promotes stimu- a locomotor training as to attain involuntary and lation of the dorsal lumbosacral spinal cord intu- voluntary locomotion more similar to normal (Har- mescence, and therefore of the reflex arc, allowing kema et al., 2012; Musienko et al., 2012; Solopova a motion gait with the hind limbs on the tread- et al., 2015). mill, although not rhythmically synchronized with For years it has been proven that the ES is a mo- the forelimb; whilst IS promotes the stimulation of dality of FNR with clinical application in quadruped the propriospinal pathways, associated or not with and biped with spinal cord injuries (Nandra & Ed- the locomotor areas of the brainstem. Hence, the gerton, 2011), furthermore, numerous experiments simultaneous activation of ES and IS allows the en- prove that the effect of ES can be complement and gagement of interneural population which regulates enhanced when combined with the prescription of

drugs, such as serotonergic 5HT agonists, and loco- can be activated by intraspinal and epidural routes, motor training (Angeli et al., 2014; Gad et al., 2012; as mentioned above. A spontaneous locomotion Gerasimenko, 2010; Lavron et al., 2014). might be achieved, since there is a specialized re- K. Thompson and R. Walpaw indicate that the gion of the upper portion of the lumbosacral region human biped, after an incomplete spinal cord in- that includes an ample neural circuit for genera- jury, has a motor disability, namely spasticity and ting a spontaneous locomotion in the quadruped poor motor control, making all FNR modalities that (Chang, 2014; Lavron et al., 2014). activate CPG and stimulate neural plasticity relevant The above mentioned is demonstrated by ex- for rehabilitation; furthermore, the authors indicate periments in cats and rats that demonstrate how that movements with higher amplitudes promote neuromodulation of electric stimulation and drugs the diminishment of muscular spasticity and impro- are more effective in promoting an autonomic sen- ve balance (Thompson & Walpaw, 2015). sory-motor function after a spinal cord injury (Gad, Finally, after a 35 year lasting study, a new capa- 2012; Lavron et al., 2014; Musienko et al., 2012). city of the nervous system is addressed, recognizing The same is proven in regards to neuromodulation that most spinal cord injuries are incomplete and fit and voluntary control in a paralyzed biped (Angeli for regeneration, making FNR therapies fundamen- et al., 2014; Lavron et al., 2014). tal for motor success (Thompson & Walpaw, 2014). All FNR protocols are based on neural plasticity Neuromodulation of the Motor Neuron and suggest a complementary therapeutic method Depolarizing currents mediated by sodium and for recovering functionality (Thompson & Walpaw, calcium channels that have the ability to convert 2014; Thompson & Walpaw, 2015). These exercises motor neurons from mere passive pathways to ac- induce plasticity to the neuro-spinal reflexes, after tive precursors of electric signals are designated as severe injury to the spinal cord, leading to the fictive Persistent Inward Currents (PICs). PICs depend on locomotion gait, or “spinal walking” (Harkema et the presence of monoamines, such as serotonin al., 2012; Thompson & Walpaw, 2014). and norepinephrine, produced by groups of cells located in the brainstem that project their axons “Spinal walking” to the spinal cord segments. Thus, serotonin and Since 1966, experiences show that the mesen- norepinephrine work as neuromodulators affecting cephalon nuclei are specific areas, identified as me- the PICs and the motor neurons (Heckman, 2014). sencephalon locomotor region (MLR). Descending In decerebrised cats, the spinal cord transection spinal pathways are originated in the MLR and damages the brainstem monoaminergic pathways, are projected into the medial reticular formation as well as all descending caudal pathways to the and ventral portion of the spinal cord. Ascending spinal cord transection, eliminating the effects of pathways can activate the MLR regions via the PICs and PICs themselves. Likewise, in animals with locomotor pons-medullar route region (LPR). The incomplete spinal cord injuries PICs are still produ- MLR can also be stimulated by dorsolateral funi- ced, however, their amplifying effect is not achie- culus (DLF) fibers, originated between C1 and L1 ved and therefore muscle activation does not occur spinal cord segments. These fibres (DLF and LPR) (Heckman, 2014; Levine et al., 2011; Musienko et can induce a quadruped locomotor gait through al., 2012). the brainstem (Lavron et al., 2014; Harkema et al., PICs amplify the excitation or inhibition of the 2012; Musienko et al., 2012). electrical current in spinal motor neurons, but the- The same experiments also demonstrate that CPG se are lost in the event of acute spinal cord injury.

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However, they can be recovered after a period of 1 contraction of the stretched muscles (Thomson & to 5 months after spinal cord injury, despite losing Hatin, 2012). normal specificity. Somatic Motor System Musculoskeletal system The UMN system is classified anatomically in The musculoskeletal system, in mammals, allows pyramidal and extrapyramidal system (Thomson & postural control and movement patterns with diver- Hatin, 2012). se intensity (Baldwin et al., 2013). The CST represents between 20 to 30% of the The motor unit, in the human biped and quadru- white matter of the spinal cord in primates, while in ped animals, comprises all the muscle fibres inner- carnivores it represents only 10% (Ropper, Samuels vated by a single motor neuron (Ropper, Samuels & Klein, 2014; Thomson & Hatin, 2012). & Klein, 2014). The red nucleus of the brainstem receives, ipsi- In the human biped, locomotion requires the laterally, nerve fibres from the motor cortex, pro- standard postural extensor reflex to be inhibited jecting it to the spinal cord under the form of the and the coordination pattern of the walking move- RuST, this being the most important tract for the ment to be implemented, with the complicity of the control of voluntary movement in the dog and cat. multisegmental spinal reflexes and of the brainstem In human biped, this tract is involved in activities locomotor centres (Ropper, Samuels & Klein, 2014). such as swimming with the superior limbs. The control of the musculature of the proximal In dogs, only 10 to 20% of descendant UMN limb muscles is mediated by the RST and vestibu- tract needs to be intact, after severe spinal cord lospinal tract (VST), while the control of the distal injury, for there to be limb movement (Thomson & musculature is mediated by the RuST and CTS tracts Hatin, 2012). (Ropper, Samuels & Klein, 2014). The VST tract stimulates the extensor muscles The muscle tone depends on the alpha and gam- ipsilaterally and inhibits extensor muscular tonus ma motor neurons. The gamma motor is actively contralaterally (Thomson & Hatin, 2012). tonic at rest, making the intrafusal fibres taut and The medullar RST is responsible for the inhibition sensitive to active or passive muscle length changes of the gamma motor neuron. (Ropper, Samuels & Klein, 2014). This phenomenon, In the biped human, pure pyramidal lesions do not in quadruped animals, is called alpha and gamma result in spasticity, because a large portion of volun- co-activation (Thomson & Hatin, 2012). tary movement relies on extrapyramidal pathways The excitability of the alpha and gamma motor (Ropper, Samuels & Klein, 2014), among which are neurons defines the level of activity of the reflexes the spinal corticoreticular pathways. and muscle tone, yet it is affected by the descen- The UMN lesions in the human biped usually cau- ding fibre system (Ropper, Samuels & Klein, 2014). se flexed like postures and pronated superior limbs The Golgi tendon organ receptors can monitor postures, as well as extended and abducted inferior the strength of contraction and the length of the limbs. Spasticity depends on the increase of resis- muscle fibres (Ropper, Samuels & Klein, 2014). tance to the passive stretching of the muscles. If a The flexion of the limb will cause stretching of the lesion involves the CST, the RST is usually involved as extensor muscles and the extension of the muscles well (Ropper, Samuels & Klein, 2014). The greatest will cause stretching of the flexor muscles. The two indicator of upper UMN in the human biped is the will induce the myotatic reflex, which leads to the Babinski sign, described in 1896.

Electrostimulation to facilitate locomotion The primate rehabilitation program consists of: and autonomous rise 30 minutes of assisted ground locomotion, 5 times per week; 20 minutes of treadmill training, 2 times In the human biped there is evidence that, after per week; and 30 minutes of rehabilitation wheel- spinal cord injury leading to paraplegia, electrosti- chair training, during a 24 week period. All patients mulation, in order to stimulate the sensory input of show voluntary movement after 15 days of spinal limbs, associated with a locomotor training of seve- cord transection, with significant evolution after 3 ral weeks, is enough to achieve an active standing to 8 weeks. posture, enabling the patients to support 100% of In primates, 87% of CST descends dorsolaterally their body weight. The presentation of voluntary by the spinal cord and contralaterally to the cerebral movements may occur, but only when the electro- hemisphere of origin; the remaining 11% descend miostimulation is applied. The position of the elec- ipsilaterally to the hemisphere of origin. In the rat, trodes is important and should always be in anode however, 96-98% of the descendant axons of the - cathode orientation. CST decussate at medullar pyramids level, a very important fact concerning neural plasticity (Nout et Human biped with quadruped animals al., 2012). study comparison The remodelling of neural circuits is the result The quadruped animal model most used in experi- of neuronal plasticity, and it may occur at different mental studies is the rat, in which it is caused transec- sites of the central nervous system, allowing the tion of the spinal cord, leading to paralysis. Unilateral restoration of movement after locomotor training, lesions of the cervical spinal cord are preferentially and is therefore indicative of neural reorganization, used as spinal cord injury model in the human biped occurring simultaneously in supraspinal and spinal (Nout et al., 2012). This is due to the fact that the cord circuitry. most common clinical lesions in the human are cer- The CST is a pathway between the motor cor- vical, being of primary interest for the study of the tex and the spinal cord, and even if their neurons superior limbs and hands, due to the anatomical and are not necessary for there to be locomotion, they behaviour resemblance that the rat and the human have an important modulator role in the cat’s lo- share (Nout et al., 2012, Gad et al., 2013). comotion. This modulation combines inputs origi- Although anatomically similar, there are differen- nated from CPG and the afferent feedback reflex, ces in the number, location and termination of the allowing coordination between the limbs (Harkema motor pathways. The fine motor control present in et al., 2012; Knikou, 2012). the human and primates is achieved through the The modulation of the CST allows adjusting mo- CST, whilst in the rat, the same fine motor control vement when an obstacle emerges in the place- is achieved by the RuST, which is vestigial in the ment of the limbs in the correct position. human biped (Nout et al., 2012). Other important differences are the effects of the secondary lesion Relation between degenerative and the nerve regeneration capability, that in the intervertebral disc disease (DIVDD) in the rat is millimetres and in the primate is centimetres. dog and in the human Considering the above data, several studies look The thoracolumbar discal hernias in dogs occur for the Macaca mullata as a preferential animal mo- spontaneously, similar to acute injuries of the spinal del, to which is induced, experimentally, spinal cord cord in humans. transection at C7 level (Nout et al., 2012). Most histopathological lesions observed in dog’s

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DIVDD may be observed in the traumatic myelo- al., 2012; Garcia et al., 2015). In one hand, the line pathy of the human. Typically, these lesions translate that holds that supraspinal inputs are needed to into intraparenchymal haemorrhage on the surface generate involuntary movement, and on the other of marrow necrosis with cystic massive evolution hand the line that claims that the spinal cord con- and compression, representing 79% of spinal cord tains internal circuitry of CPG that allows a fictive injuries present in the human biped (Nout et al., locomotion (Chang, 2014). 2012). Regardless of the line of thought, there must be Neural injury and demyelination are common in coordination between the forelimbs and hind limbs both human and dog, as well as neural necrosis and (Cazalets & Butrand, 2000; Nathan, Smith & Deacor, neutrophilic infiltration, and it can be observed after 1996), as well as memorization of this coordination weeks to months. (Nielsen, et al., 2015; Zhong et al., 2012). In human, 61.2% of hernias occur in the cervical Thus, neurorehabilitation must take into account region, followed by hernias in the thoracic (25.2%) the intrinsic properties of the nervous system, neu- and lumbosacral region (13.6%), while in the dog, roplasticity and functionality, with the latter com- 83.6% of hernias occur in the thoracolumbar region prising the management of pain, thereby turning (Nout et al., 2012). neurorehabilitation into FNR. The primary lesion in both species occurs under The importance of FNR surpasses the properties the form of compression/contusion to the ventral of the nervous system, by the fact that neuroplas- area of the spinal cord (Levine et al., 2011). ticity depends on the accomplishment of the reha- In 2001, Olby and colleagues created a locomotor bilitation methods described throughout the article, rating scale for dogs with spinal cord injury, the these being epidural, transcutaneous or intraspinal BBB, and used it in rats. More recently, the modified electrical stimulation, pharmacological means and Frankel scale has arisen, which is based on the evo- locomotor training, which, when combined, have lution of gait, postural reactions and nociception. greater results regarding voluntary or fictive loco- The presence of hyperintensity on T2 in a pre- motion (Gad et al., 2012; Harkema et al., 2012; La- surgical status results in a poor prognosis regarding vron et al., 2015; Musienko et al., 2012; Nandra et functional recovery after surgery. al., 2011; Roy & Edgerton, 2012; Roy, Harkema & The CST is far more important to ambulatory Edgerton, 2012; Solopova et al., 2015; Thompson function in the human than it is in the dog, due & Walpaw, 2015). to this fact, spinal shock is transient in dogs with The FNR should also be based on neuromodula- DIVDD, when compared to the human. tion, exploiting all circuits of interneurons and motor neurons, and increasing their depolarization. It would be important to clarify the descending Discussion spinal tracts that stimulate excitatory post-synaptic potential (Knikou, 2012) in all animal models used During the study, it was found that the result of for comparative study with the human. neurorehabilitation is potentiated by neuroplasticity, It is known that the primate is the animal model both supraspinal and medullar (Thompson & Wal- with most resemblance to the human. In the pri- paw, 2014). mate, 11% of axons of the descending pathways of Following a constant discussion about the origin the CST descend the spinal cord ipsilaterally to the of the movement, it can be stated that there are hemisphere of origin, which may be compared with two main lines of thought (Chang, 2014; Gad et the 10% that the dog exhibits (Ropper, Samuels &

Klein, 2014). These 11% of axons of the CST that biped and quadruped can be similar, and its adap- descend the spinal cord ipsilaterally in primate and tation may be reciprocal. We know that, for both, 10% in the dog, are extremely important in FNR, locomotor training should begin as soon as possible as it is through them that neuromodulation and and with the greatest intensity within the limitations neuroplasticity are achieved. Apart from that, when of the disease (Ditunno et al., 2012; Duffell & Mir- the CST is damaged in the human, it has to resort bagheri, 2015; Hettlich & Levine, 2012; Kim et al., to extrapyramidal tracts, which are vestigial in the 2014; Oosterhuis et al., 2013; Takao et al., 2015). human, to recover, making studies in the dog and The article suggests utilizing the cat and dog cat essential for the study of the human. as an animal model, because in both, if the spinal In relation to the dog, it presents a uniqueness: injury is complete, after a few days of locomotor the dog only requires 10 to 20% of UMN pathways training applied after spinal cord section, the fictive to achieve a normal locomotion (Thomson & Hatin, locomotion is achieved and therefore also a possi- 2012), making its FNR a reference to the human. bility of independence (Gad et al., 2012; Musienko The cat also presents an interesting particulari- et al., 2012; Siegel et al., 1979), in addition to the ty, it is considered an extrapyramidal animal mo- similarities among the degenerative diseases of man del, but it needs the integrity of some of the CST and dog. pathways so that modulation and coordination may The UMN descending pathways can be correla- occur, one aspect that is similar to human (Duysens ted between human, dog and cat, and hence also & Crommert, 1998; Knikou, 2012). the locomotor training exercises. In the rat, since As for the rat, the control of fine motor move- it presents a spinal cord of millimetres in diameter, ment is achieved through the RuST, while in man the power for regeneration is enhanced, potentially this is achieved through the CST. facilitating the onset of coordinated locomotion or A relation exists between the DIVDD in the hu- fictive locomotion. man and the dog. DIVDD in human and dogs pre- We can conclude that, to attain quality of life, sent similarities as to clinical presentation, diagnosis, locomotor training is essential, as is the timing of surgical approach (Bergknut et al., 2011) and FNR. its beginning, and that future studies can be per- formed with dog and cat model as research model. Further studies will be required, perhaps even the Conclusion formation of a robotic model for these animals, in order to understand, by evidence, the human biped With this article we can conclude that, due to and apply this model to him. neurophysiology and neuroanatomy, FNR in human

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32. Takao, T., Tanaka, N., Yanagi, H., et al. (2015). Improvement Comment on this article: of gait ability with a short term intensive gait rehabilitation program using body weight support treadmill training community dwelling chronic post stroke survivors . Journal of Physical Therapy Science. 33. Tansey. (2010). Neural plasticity and Locomotor recovery after spinal cord injury. PM&R. 34. Thompson, & Walpaw. (2014). Operant conditioning of spinal reflexes: from basic science to clinical therapy. Front Integr Neuroscience. http://medicalia.org/ 35. Thompson, & Walpaw. (2014). The simplest motor skill: Where Doctors exchange clinical experiences, Mechanisms and applications of reflex operant conditioning. review their cases and share clinical knowledge. Exercise Sport Science review. You can also access lots of medical publications for 36. Thompson, & Walpaw. (2015). Targeted neuroplasticity for free. Join Now! rehabilitation. Prog Brain Research. 37. Thompson, K., & Walpaw, R. (2015). Restoring walking after spinal cord injury operant conditioning of spinal reflexes can help. J. Clinical Neurology. Publish with iMedPub 38. Thomson, C., & Hatin, C. (2012). Reflexes and motor systems. http://www.imed.pub In: Veterinary Neuroanatomy - A Clinical Approach. Saunders Elsevier. International Archives of Medicine is an open access journal 39. Zhong, H., Roy, R., Leon, R. D., & Edgerton, R. (2012). publishing articles encompassing all aspects of medical scien- Acommodation of the spinal cat to a tripping perturbation. ce and clinical practice. IAM is considered a megajournal with Frontiers in physiology. independent sections on all areas of medicine. IAM is a really international journal with authors and board members from all around the world. The journal is widely indexed and classified Q1 in category Medicine.

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