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Neuromuscular electrical stimulation for stroke rehabilitation: Is spinal plasticity a possible mechanism associated with diminished spasticity?
Medical Hypotheses 81 (2013) 784–788
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Neuromuscular electrical stimulation for stroke rehabilitation: Is spinal plasticity a possible mechanism associated with diminished spasticity? Anna Amélia P. Motta-Oishi a, Fernando Henrique Magalhães b,c, Fábio Mícolis de Azevedo a,⇑ a Universidade Estadual Paulista, School of Science and Technology, Physical Therapy Department, Biomechanics and Motor Control Laboratory, Rua Roberto Simonsen 305, Presidente Prudente, SP, Brazil b School of Arts, Sciences and Humanities, Universidade de São Paulo, EACH, Avenida Arlindo Bettio 1000 SP, Brazil c Neuroscience Program and Biomedical Engineering Laboratory, Universidade de São Paulo, EPUSP, PTC, Brazil
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Article history: Received 13 April 2013 Accepted 13 August 2013
a b s t r a c t Although the specific pathophysiological mechanisms underlying the development of spasticity are not fully understood, a large amount of evidence suggests that abnormalities in spinal pathways regulating the stretch reflex may contribute to the hypertonia and hyperreflexia that characterize spasticity. It is quite interesting that neuromuscular electrical stimulation (NMES) has been reported as an efficient treatment for reducing spasticity after stroke while other reports have shown that it promotes neuroplasticity in healthy subjects. The hypothesis addressed in this paper is that plastic effects within some spinal cord pathways may be a possible mechanism associated with the NMES-induced improvements in spasticity. If the hypothesis is proven corrected, the association between plasticity within specific spinal pathways and NMES-induced improvements in spasticity may be used to guide the choice of stimulation parameters to be used in NMES-based stroke rehabilitation protocols. Ó 2013 Elsevier Ltd. All rights reserved.
Introduction Stroke is the leading cause of long-term adult disability and spasticity is one of the sensorimotor impairments that are often observed in the paretic limbs of patients after stroke [1]. Spasticity may be defined as a motor disorder characterized by a velocity and acceleration-dependent increased resistance to passive muscle stretch and hyperactivity of stretch reflexes [2,3]. Although the exact pathophysiological mechanisms underlying spasticity remain unknown, it is highly likely that it is not caused by a single mechanism, but rather by an intricate chain of alterations in different interdependent networks [4], which may include: (1) spinal mechanism concerning abnormalities in the functioning of the spinal neurons and spinal subsystems; (2) supraspinal and suprasegmental mechanisms; and (3) abnormality in mechanical properties of muscles. Specifically to the interest of this paper, many studies have associated the exaggerated stretch reflex with altered transmission in a variety of spinal cord pathways [5–21]; thereby suggesting that a malfunction in some spinal pathways responsible for controlling the excitability of the stretch reflex might be partially responsible for (or at least correlated with) spasticity [5,11]. Neuromuscular electrical stimulation (NMES) has been shown to be effective in improving function of subjects with central
⇑ Corresponding author. Tel.: +55 18 9639152; fax: +55 18 32295820. E-mail address: [email protected] (F. Mícolis de Azevedo). 0306-9877/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.mehy.2013.08.013
nervous system (CNS) lesions, such as in patients after stroke [22]. Such a stimulation modality may improve neuromuscular functional condition not only by strengthening muscles, decreasing pain and increasing range of motion, but also by reducing spasticity [22–27]. Although some studies have pointed to central neuroplasticity as a potential mechanism of action for the therapeutic effect of electrical stimulation in CNS lesions [24,28–31], most of the experimental researches have focused on supraspinal mechanisms associated with superior brain areas, probably by taking advantage of measurement techniques that allow the evaluation of brain function with a reasonable resolution (e.g., functional magnetic resonance imaging and transcranial magnetic stimulation). However, no direct experimentation has been conducted in order to explore whether neuroplastic effects within specific spinal cord pathways might be associated with NEMS-induced diminished spasticity in patients after stroke (which is likely due to the more challenging task of obtaining objective measures associated with spinal mechanisms). Given the correlation that has been found between spasticity and altered excitability in some spinal pathways (as commented earlier), the hypothesis addressed in this paper is that plastic effects within specific spinal cord circuitries may be among the possible mechanisms behind the reduced spasticity that has been achieved by NMES-based treatments. The text ahead explores in detail each point involved in the formulation of the hypothesis. Additionally, directions for future research and possible clinical implications are discussed.
A.A.P. Motta-Oishi et al. / Medical Hypotheses 81 (2013) 784–788
The association between the excitability of spinal pathways and spasticity As commented in the Introduction section, it seems highly likely that more than one pathophysiological abnormality contributes to development of spasticity [4], including mechanisms associated with spinal and/or supraspinal dysfunctions as well as changes in the mechanical properties of muscles. In this line of reasoning, the excitability of the stretch reflex is regulated by many spinal cord pathways, and hence a dysfunction in any of these pathways may theoretically be associated with the stretch reflex exaggeration observed in spasticity following stroke [32]. From a methodological standpoint, the excitability of the stretch reflex pathway (or parts of it) can be assessed by means of either electrical stimulation of peripheral nerves (e.g., H-reflexes) or mechanical stimulation of the tendons (T-reflexes) [33]. Specifically, the technique of H-reflex has been widely used to assess the excitability of the stretch reflex pathway and to infer the current state of spinal cord mechanisms associated with different conditions of healthy and disease [33–36]. Besides the primary excitability of the motoneurons due to their membrane properties and the obvious influences from supraspinal centers, there are preand post-synaptic influences that affect H-reflex amplitude from a variety of sources [33]. For instance, presynaptic inhibition of Ia afferent terminals, homosynaptic depression (or post-activation depression), disynaptic reciprocal inhibition from Ia afferents of the antagonist muscles, recurrent inhibition via Renshaw cells and short-latency autogenic inhibition (associated with Ib afferents from Golgi tendon organs) are perhaps the most important mechanisms of reflex modulation [33–36]. Fig. 1 illustrates some of these spinal reflex circuits responsible for the stretch reflex modulation that may also be involved in the mechanisms underlying the development of spasticity (see text below for further discussion on this point). By means of these mechanisms, the CNS can regulate the excitability of the stretch reflex pathway in different conditions. In an attempt to better describe the mechanisms responsible for reflex modulation, protocols based on conditioning stimulation have been developed. For example, it is possible to evaluate the level of presynaptic inhibition or disynaptic reciprocal inhibition under different conditions by means of H-reflex assessments [37,38]. One of the techniques consists in applying a conditioning electrical stimulus (1 ms rectangular pulse) to the nerve of the antagonist muscle and a test stimulus to the nerve of the agonist muscle with a conditioning-to-test interval of appropriate latency, depending on the muscle groups and on the specific spinal mechanism under assessment [35,39]. Due to the inhibitory effect associated with the presynaptic or reciprocal inhibition mechanism, the reflex response conditioned by the antagonist nerve stimulation will have a lower amplitude as compared to the reflex elicited without conditioning. This procedure has been widely used in many research laboratories to investigate changes in the degree of excitability of different spinal pathways among different conditions [33]. Another example of a presynaptic mechanism that affects H-reflex amplitude is postactivation depression (or homosynaptic depression), which consists in a frequency-dependent reduction of reflex amplitude. For instance, when the stimulation is applied with frequencies higher than 0.1 Hz, a depression in H-reflex amplitude is observed, supposedly because repetitive activation would lead to a reduced release of neurotransmitter in the Ia terminals [40,41]. Consequently, assessing the amount of reduction in the H-reflex amplitude after repetitive activation (i.e., at frequencies higher than 0.1 Hz) as compared to a control condition (i.e., H-reflex elicited by a single stimulus) has been used as a means to evaluate the amount of homosynaptic depression during different conditions.
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Therefore, thanks to the development of the electrophysiological techniques briefly exemplified above (such as the assessment of H-reflex through a paired-pulse stimulation paradigm, also known as conditioning-test pulse paradigm [33]), several studies could selectively explore the transmission within a variety of human spinal cord pathways so as investigate the possible role of different spinal mechanisms in the pathophysiology of spasticity [5–21]. Although some contradictory results have been reported in the literature [11,42], transmission throughout these spinal reflex circuitries has been found to be modified in spastic patients. For instance, reduced in short-latency autogenic inhibition (Ib inhibition) [12], decreased recurrent inhibition from Renshaw cells [13,14], abnormalities in disynaptic reciprocal Ia inhibition [6– 8,15,20], reduced presynaptic inhibition of Ia terminals [5,11,16 ,21] and decreased post-activation depression [5,11,17–19,43] have been found to be associated with spasticity. Therefore, although the specific pathophysiological mechanisms underlying the development of spasticity are not fully understood, a large amount of evidence suggests that abnormalities in spinal pathways regulating the stretch reflex may contribute to the hypertonia and hyperreflexia that characterize spasticity. NEMS and neuroplasticity NMES is a rehabilitation treatment and exercise training modality that consists in delivering electrical pulses through the skin to repeatedly activate muscles [44]. A growing body of evidence suggests that neuroplastic mechanisms may be activated in response to different modalities of electrical stimulation such as NEMS [22,45]. For instance, substantial increases have been described in the myoelectrical activity of various muscles after 4–5 weeks of training by NEMS, a time not sufficient to induce muscle hypertrophy [46,47]. This has led to the suggestion that certain types of NMES may induce adaptations within the neural systems [48], a hypothesis strengthened by the observation that short NMES training programs may cause changes in the motor activity of the non-exercised contralateral limb [49]. In a rehabilitation context, the postulated mechanism underlying the therapeutic effect of electrical stimulation in CNS lesions is through neuroplasticity of the CNS [22]. The premise is that preexisting functional and non-utilized neuronal connections are activated and/or their inhibition is suspended [28,50]. In this regard, it has been demonstrated that the regular use of a foot-drop stimulator not only increases walking speed in people with CNS disorders but also strengthens activation of motor cortical areas and their residual descending connections, even when the stimulator is off [31]. A treatment of NMES in subjects after stroke showed improvement in the functional use of the hand and changes in cortical activation as measured by functional magnetic resonance imaging [29]. In other study, Shin and colleagues demonstrated that a 10 week use of an electromyography-triggered neuromuscular stimulation led to functional recovery while also changing cortical activation patterns associated with the hemiparetic hand of chronic stroke patients [30]. Similarly, it has also been shown that cutaneous stimulation improves motor performance and limb sensation with concurrent changes in somatosensory evoked potentials of the paretic limb in chronic stroke patients [24]. However, although the effects of NMES in promoting neuroplasticity in superior brain areas have been well established [28], less attention has been given to possible neuroplastic mechanisms within specific spinal cord pathways, such as those responsible for controlling the excitability of the stretch reflex. This is probably linked to the easy of obtaining high-resolution measures associated with brain function by using the various techniques that are currently available to either map regional blood flow and
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Fig. 1. Schematic representation of some spinal cord pathways responsible for regulating the excitability of the stretch reflex (which may also be involved in the mechanisms underlying the development of spasticity). Black filled circles represent inhibitory connections and open triangles represents excitatory connections. Hexagons with interrogation symbols indicate that the number of interconnections within the pathway is variable/unknown. The text in the rectangles indicates the specific mechanisms involved, which are also under influences of supraspinal centers (as represented by the connections from ‘‘descending drive’’). Gray squares depict connections from supraspinal centers that might be either of excitatory or inhibitory origin. Also note the representation of test and conditioning stimuli that might be applied to the nerves of agonist and antagonist muscles so as to probe the state of some of the spinal pathways by means of H-reflex assessment. Gamma motor system is omitted in this figure.
metabolic changes in the brain (e.g., positron emission tomography and functional magnetic resonance imaging) or to analyze electromagnetic brain activity (e.g., electroencephalography, magnetoencephalography, and transcranial magnetic stimulation). On the other hand, the currently available non-invasive techniques for obtaining measures associated with the state of specific spinal cord pathways in humans are more limited and require specific protocols involving a refined control of stimulation and recording paradigms.1 In this context, Perez and colleagues [45] showed that patterned sensory stimulation applied during 30 min could enhance the strength of the short-latency reciprocal inhibition from ankle flexor to extensor muscles as measured by conditioning the soleus H-reflex with a preceding stimulation of the common peroneal nerve. However, no similar studies have been performed so as to explore the possible role of a NEMS rehabilitation protocol (e.g., for stroke rehabilitation) in promoting neuroplastic effects within spinal cord pathways. 1 A brief review on the current available methods for assessing the state of different spinal cord pathways is provided in the section named ‘‘The association between the excitability of spinal pathways and spasticity’’ (for a more detailed explanation, the reader if referred to the reviews in [33,35,36]).
NEMS and stroke-related spasticity NMES is a widespread tool used in a large diversity of rehabilitation protocols [51] and has been shown to facilitate motor recovery in acute and chronic stroke [24,30,44,50,52–57]. Additionally, reduction of spasticity by the use of neuromuscular electrical stimulation has been reported in a multitude of studies [22,23,25–27]. However, even though changes in transmission within spinal pathways associated with reciprocal inhibition, recurrent inhibition and large sensory fiber activation have been suggested as possible mechanisms for the spasticity reduction, only empirical findings based on well-known neurophysiological pathways have been put forward to substantiate these putative mechanisms [28]. More specifically, no direct experimentation has been conducted in order to investigate a possible association between the NEMS-induced improvements in spasticity and direct evidences for neuroplastic changes within specific spinal cord pathways. The rationale for such investigation relies on the role of spinal pathways in regulating the excitability of the monosynaptic reflex, thereby being a putative mechanism behind the stretch reflex exaggeration that characterizes spasticity and consequently behind the NMESinduced diminished spasticity.
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Hypothesis: Is spinal plasticity associated with NMES-induced diminished spasticity? As briefly reviewed in the previous sections, many studies have associated stroke-related spasticity with altered transmission in a variety of spinal cord pathways responsible for controlling the excitability of the stretch reflex. Additionally, the effect of NMES in promoting CNS neuroplasticity has been well reported and NMES has also been largely used as an efficient treatment for reducing spasticity after stroke. However, no previous study has addressed whether a neuroplastic effect within specific spinal cord pathways may be associated with NEMS-induced reductions in spasticity. Therefore, the hypothesis addressed in this paper is that plastic effects within specific spinal cord circuitries (i.e., shortlatency autogenic inhibition (Ib inhibition), recurrent inhibition from Renshaw cells, disynaptic reciprocal Ia inhibition, presynaptic inhibition of Ia terminals and post-activation depression) may be associated with the reduced spasticity induced by treatments with NEMS. It shall be noted that even thought other pathologies such as spinal cord injuries/infarction, cerebral palsy, multiple sclerosis, etc. may also be associated with spasticity, the pathophysiological mechanisms may be considerably variable among the different conditions, so that the hypothesis presented here is limited to stroke-related brain injuries only. However, we must bear in mind that abnormalities in spinal pathways regulating the stretch reflex may be involved in spasticity related to a variety of causes other than brain stroke and consequently to the changes in the levels of spasticity achieved by different protocols. The protocol to test the above hypothesis involves experimental and clinical studies designed to assess the level of excitability in different spinal pathways.1 Neural transmission within these spinal circuitries shall then be evaluated both before and after the delivery of a protocol with NEMS. The parameters of NMES stimulation (waveforms, frequency, sites of application, short-term or long-term stimulation, etc.) would be left for exploration, i.e., the changes in the state of specific spinal cord pathways may be explored in response to a large variety of rehabilitation protocols (i.e., by changing NMES parameters), for instance, under different frequencies and/or intensities of NMES stimulation. Similarly, different specific spinal pathways might be evaluated: for instance, experimental paradigms in humans would involve the quantification of the reduction in H-reflex amplitude in response to different conditioning-test intervals (the conditioning stimulus being, for example, a stimulus applied to the antagonist muscle), thereby allowing the evaluation of a variety of spinal pathways such as those associated with presynaptic inhibition and reciprocal inhibition (for reviews see [33,35,36]). Protocols involving H-reflex assessments would be applicable to both impaired lower (e.g., soleus H-reflex) and upper limbs (e.g., flexor carpi radialis H-reflex) after stroke [11]. Additionally, it is worth mentioning that previous studies using H-reflex measurements to evaluate spinal cord pathways in humans have shown satisfactory reliability [58,59], and some studies needed to evaluate no more than 10–15 [17,60,61] patients to unveil differences in the modulation of spinal pathways in comparison to control subjects (although other studies have used as much as 87 [11] patients post-stroke). Besides human experiments, the hypothesis presented here may also benefit from data obtained by studies with animal models, in which similar protocols to those commonly performed in humans may be conducted, besides in vitro recording techniques (e.g., in the isolated spinal cord) [62,63]. If the hypothesis is proven corrected, the association between plasticity within specific spinal pathways and NMES-induced improvements in spasticity may be used to guide the choice of the stimulation parameters to be used in rehabilitation protocols.
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More specifically, if the changes in transmission within spinal cord pathways after the delivery of a NEMS protocol are consistently associated with changes in spasticity severity, the choice of NMES parameters to be used in rehabilitation programs may rely on the assessment of the changes in the state of specific spinal pathways. In this direction, Naghdi and colleagues found no correlation between the Modified Ashworth Scale (the currently most widely used clinical scale to evaluate muscle spasticity) and a neurophysiological evaluation based on motoneuronal excitability, thereby indicating that the Modified Ashworth Scale is not a valid and ordinal level measure of muscle spasticity [64]. Additionally, the simple evaluation of spasticity is not sensitive to the specific mechanisms behind it and hence if specific spinal pathways are found to be associated with NEMS-induced improvements in spasticity (i.e., if the hypothesis presented here is proven correct), future research would focus on the development of rehabilitation protocols designed to induce neuroplasticity in specific spinal pathways. Therefore, besides being a more precise measurement than the subjective evaluation of spasticity [64], the assessment of changes in spinal pathways excitability may also be performed in healthy subjects and/or animal models, which could easy the search for optimal NMES parameters that may potentially promote spinal plasticity and therefore shall be more prone to be effective in reducing spasticity. Conflict of interest statement The authors disclose no conflict of interest. Acknowledgements AAPM thank the Brazilian Coordination for Enhancement of Higher Education Personnel (CAPES) for supporting her studies. FHM was a recipient of a fellowship from FAPESP, Grant #2011/ 13222-6. References [1] Petrea RE, Beiser AS, Seshadri S, Kelly-Hayes M, Kase CS, Wolf PA. Gender differences in stroke incidence and poststroke disability in the Framingham heart study. Stroke 2009;40:1032–7. [2] Lance JW. The control of muscle tone, reflexes, and movement: Robert Wartenberg lecture. Neurology 1980;30:1303–13. [3] Fazekas G, Horvath M, Toth A. A novel robot training system designed to supplement upper limb physiotherapy of patients with spastic hemiparesis. Int J Rehabil Res 2006;29:251–4. [4] Mukherjee A, Chakravarty A. Spasticity mechanisms – for the clinician. Front Neurol 2010;1:149. [5] Aymard C, Katz R, Lafitte C, Lo E, Penicaud A, Pradat-Diehl P, et al. Presynaptic inhibition and homosynaptic depression: a comparison between lower and upper limbs in normal human subjects and patients with hemiplegia. Brain 2000;123(Pt 8):1688–702. [6] Crone C, Johnsen LL, Biering-Sorensen F, Nielsen JB. Appearance of reciprocal facilitation of ankle extensors from ankle flexors in patients with stroke or spinal cord injury. Brain 2003;126:495–507. [7] Crone C, Nielsen J, Petersen N, Ballegaard M, Hultborn H. Disynaptic reciprocal inhibition of ankle extensors in spastic patients. Brain 1994;117(Pt 5):1161–8. [8] Crone C, Petersen NT, Gimenez-Roldan S, Lungholt B, Nyborg K, Nielsen JB. Reduced reciprocal inhibition is seen only in spastic limbs in patients with neurolathyrism. Exp Brain Res 2007;181:193–7. [9] Nielsen J, Petersen N, Crone C. Changes in transmission across synapses of Ia afferents in spastic patients. Brain 1995;118(Pt 4):995–1004. [10] Pierrot-Deseilligny E, Burke DC. The Circuitry of the Human Spinal Cord: Its Role in Motor Control and Movement Disorders. Cambridge: Cambridge University Press; 2005. [11] Lamy JC, Wargon I, Mazevet D, Ghanim Z, Pradat-Diehl P, Katz R. Impaired efficacy of spinal presynaptic mechanisms in spastic stroke patients. Brain 2009;132:734–48. [12] Delwaide PJ, Oliver E. Short-latency autogenic inhibition (Ib inhibition) in human spasticity. J Neurol Neurosurg Psychiatry 1988;51:1546–50. [13] Katz R, Pierrot-Deseilligny E. Recurrent inhibition of alpha-motoneurons in patients with upper motor neuron lesions. Brain 1982;105:103–24. [14] Mazzocchio R, Rossi A. Involvement of spinal recurrent inhibition in spasticity.
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Neuromuscular electrical stimulation for stroke rehabilitation: Is spinal plasticity a possible mechanism associated with diminished spasticity? Anna Amélia P. Motta-Oishi a, Fernando Henrique Magalhães b,c, Fábio Mícolis de Azevedo a,⇑ a Universidade Estadual Paulista, School of Science and Technology, Physical Therapy Department, Biomechanics and Motor Control Laboratory, Rua Roberto Simonsen 305, Presidente Prudente, SP, Brazil b School of Arts, Sciences and Humanities, Universidade de São Paulo, EACH, Avenida Arlindo Bettio 1000 SP, Brazil c Neuroscience Program and Biomedical Engineering Laboratory, Universidade de São Paulo, EPUSP, PTC, Brazil
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Article history: Received 13 April 2013 Accepted 13 August 2013
a b s t r a c t Although the specific pathophysiological mechanisms underlying the development of spasticity are not fully understood, a large amount of evidence suggests that abnormalities in spinal pathways regulating the stretch reflex may contribute to the hypertonia and hyperreflexia that characterize spasticity. It is quite interesting that neuromuscular electrical stimulation (NMES) has been reported as an efficient treatment for reducing spasticity after stroke while other reports have shown that it promotes neuroplasticity in healthy subjects. The hypothesis addressed in this paper is that plastic effects within some spinal cord pathways may be a possible mechanism associated with the NMES-induced improvements in spasticity. If the hypothesis is proven corrected, the association between plasticity within specific spinal pathways and NMES-induced improvements in spasticity may be used to guide the choice of stimulation parameters to be used in NMES-based stroke rehabilitation protocols. Ó 2013 Elsevier Ltd. All rights reserved.
Introduction Stroke is the leading cause of long-term adult disability and spasticity is one of the sensorimotor impairments that are often observed in the paretic limbs of patients after stroke [1]. Spasticity may be defined as a motor disorder characterized by a velocity and acceleration-dependent increased resistance to passive muscle stretch and hyperactivity of stretch reflexes [2,3]. Although the exact pathophysiological mechanisms underlying spasticity remain unknown, it is highly likely that it is not caused by a single mechanism, but rather by an intricate chain of alterations in different interdependent networks [4], which may include: (1) spinal mechanism concerning abnormalities in the functioning of the spinal neurons and spinal subsystems; (2) supraspinal and suprasegmental mechanisms; and (3) abnormality in mechanical properties of muscles. Specifically to the interest of this paper, many studies have associated the exaggerated stretch reflex with altered transmission in a variety of spinal cord pathways [5–21]; thereby suggesting that a malfunction in some spinal pathways responsible for controlling the excitability of the stretch reflex might be partially responsible for (or at least correlated with) spasticity [5,11]. Neuromuscular electrical stimulation (NMES) has been shown to be effective in improving function of subjects with central
⇑ Corresponding author. Tel.: +55 18 9639152; fax: +55 18 32295820. E-mail address: [email protected] (F. Mícolis de Azevedo). 0306-9877/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.mehy.2013.08.013
nervous system (CNS) lesions, such as in patients after stroke [22]. Such a stimulation modality may improve neuromuscular functional condition not only by strengthening muscles, decreasing pain and increasing range of motion, but also by reducing spasticity [22–27]. Although some studies have pointed to central neuroplasticity as a potential mechanism of action for the therapeutic effect of electrical stimulation in CNS lesions [24,28–31], most of the experimental researches have focused on supraspinal mechanisms associated with superior brain areas, probably by taking advantage of measurement techniques that allow the evaluation of brain function with a reasonable resolution (e.g., functional magnetic resonance imaging and transcranial magnetic stimulation). However, no direct experimentation has been conducted in order to explore whether neuroplastic effects within specific spinal cord pathways might be associated with NEMS-induced diminished spasticity in patients after stroke (which is likely due to the more challenging task of obtaining objective measures associated with spinal mechanisms). Given the correlation that has been found between spasticity and altered excitability in some spinal pathways (as commented earlier), the hypothesis addressed in this paper is that plastic effects within specific spinal cord circuitries may be among the possible mechanisms behind the reduced spasticity that has been achieved by NMES-based treatments. The text ahead explores in detail each point involved in the formulation of the hypothesis. Additionally, directions for future research and possible clinical implications are discussed.
A.A.P. Motta-Oishi et al. / Medical Hypotheses 81 (2013) 784–788
The association between the excitability of spinal pathways and spasticity As commented in the Introduction section, it seems highly likely that more than one pathophysiological abnormality contributes to development of spasticity [4], including mechanisms associated with spinal and/or supraspinal dysfunctions as well as changes in the mechanical properties of muscles. In this line of reasoning, the excitability of the stretch reflex is regulated by many spinal cord pathways, and hence a dysfunction in any of these pathways may theoretically be associated with the stretch reflex exaggeration observed in spasticity following stroke [32]. From a methodological standpoint, the excitability of the stretch reflex pathway (or parts of it) can be assessed by means of either electrical stimulation of peripheral nerves (e.g., H-reflexes) or mechanical stimulation of the tendons (T-reflexes) [33]. Specifically, the technique of H-reflex has been widely used to assess the excitability of the stretch reflex pathway and to infer the current state of spinal cord mechanisms associated with different conditions of healthy and disease [33–36]. Besides the primary excitability of the motoneurons due to their membrane properties and the obvious influences from supraspinal centers, there are preand post-synaptic influences that affect H-reflex amplitude from a variety of sources [33]. For instance, presynaptic inhibition of Ia afferent terminals, homosynaptic depression (or post-activation depression), disynaptic reciprocal inhibition from Ia afferents of the antagonist muscles, recurrent inhibition via Renshaw cells and short-latency autogenic inhibition (associated with Ib afferents from Golgi tendon organs) are perhaps the most important mechanisms of reflex modulation [33–36]. Fig. 1 illustrates some of these spinal reflex circuits responsible for the stretch reflex modulation that may also be involved in the mechanisms underlying the development of spasticity (see text below for further discussion on this point). By means of these mechanisms, the CNS can regulate the excitability of the stretch reflex pathway in different conditions. In an attempt to better describe the mechanisms responsible for reflex modulation, protocols based on conditioning stimulation have been developed. For example, it is possible to evaluate the level of presynaptic inhibition or disynaptic reciprocal inhibition under different conditions by means of H-reflex assessments [37,38]. One of the techniques consists in applying a conditioning electrical stimulus (1 ms rectangular pulse) to the nerve of the antagonist muscle and a test stimulus to the nerve of the agonist muscle with a conditioning-to-test interval of appropriate latency, depending on the muscle groups and on the specific spinal mechanism under assessment [35,39]. Due to the inhibitory effect associated with the presynaptic or reciprocal inhibition mechanism, the reflex response conditioned by the antagonist nerve stimulation will have a lower amplitude as compared to the reflex elicited without conditioning. This procedure has been widely used in many research laboratories to investigate changes in the degree of excitability of different spinal pathways among different conditions [33]. Another example of a presynaptic mechanism that affects H-reflex amplitude is postactivation depression (or homosynaptic depression), which consists in a frequency-dependent reduction of reflex amplitude. For instance, when the stimulation is applied with frequencies higher than 0.1 Hz, a depression in H-reflex amplitude is observed, supposedly because repetitive activation would lead to a reduced release of neurotransmitter in the Ia terminals [40,41]. Consequently, assessing the amount of reduction in the H-reflex amplitude after repetitive activation (i.e., at frequencies higher than 0.1 Hz) as compared to a control condition (i.e., H-reflex elicited by a single stimulus) has been used as a means to evaluate the amount of homosynaptic depression during different conditions.
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Therefore, thanks to the development of the electrophysiological techniques briefly exemplified above (such as the assessment of H-reflex through a paired-pulse stimulation paradigm, also known as conditioning-test pulse paradigm [33]), several studies could selectively explore the transmission within a variety of human spinal cord pathways so as investigate the possible role of different spinal mechanisms in the pathophysiology of spasticity [5–21]. Although some contradictory results have been reported in the literature [11,42], transmission throughout these spinal reflex circuitries has been found to be modified in spastic patients. For instance, reduced in short-latency autogenic inhibition (Ib inhibition) [12], decreased recurrent inhibition from Renshaw cells [13,14], abnormalities in disynaptic reciprocal Ia inhibition [6– 8,15,20], reduced presynaptic inhibition of Ia terminals [5,11,16 ,21] and decreased post-activation depression [5,11,17–19,43] have been found to be associated with spasticity. Therefore, although the specific pathophysiological mechanisms underlying the development of spasticity are not fully understood, a large amount of evidence suggests that abnormalities in spinal pathways regulating the stretch reflex may contribute to the hypertonia and hyperreflexia that characterize spasticity. NEMS and neuroplasticity NMES is a rehabilitation treatment and exercise training modality that consists in delivering electrical pulses through the skin to repeatedly activate muscles [44]. A growing body of evidence suggests that neuroplastic mechanisms may be activated in response to different modalities of electrical stimulation such as NEMS [22,45]. For instance, substantial increases have been described in the myoelectrical activity of various muscles after 4–5 weeks of training by NEMS, a time not sufficient to induce muscle hypertrophy [46,47]. This has led to the suggestion that certain types of NMES may induce adaptations within the neural systems [48], a hypothesis strengthened by the observation that short NMES training programs may cause changes in the motor activity of the non-exercised contralateral limb [49]. In a rehabilitation context, the postulated mechanism underlying the therapeutic effect of electrical stimulation in CNS lesions is through neuroplasticity of the CNS [22]. The premise is that preexisting functional and non-utilized neuronal connections are activated and/or their inhibition is suspended [28,50]. In this regard, it has been demonstrated that the regular use of a foot-drop stimulator not only increases walking speed in people with CNS disorders but also strengthens activation of motor cortical areas and their residual descending connections, even when the stimulator is off [31]. A treatment of NMES in subjects after stroke showed improvement in the functional use of the hand and changes in cortical activation as measured by functional magnetic resonance imaging [29]. In other study, Shin and colleagues demonstrated that a 10 week use of an electromyography-triggered neuromuscular stimulation led to functional recovery while also changing cortical activation patterns associated with the hemiparetic hand of chronic stroke patients [30]. Similarly, it has also been shown that cutaneous stimulation improves motor performance and limb sensation with concurrent changes in somatosensory evoked potentials of the paretic limb in chronic stroke patients [24]. However, although the effects of NMES in promoting neuroplasticity in superior brain areas have been well established [28], less attention has been given to possible neuroplastic mechanisms within specific spinal cord pathways, such as those responsible for controlling the excitability of the stretch reflex. This is probably linked to the easy of obtaining high-resolution measures associated with brain function by using the various techniques that are currently available to either map regional blood flow and
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Fig. 1. Schematic representation of some spinal cord pathways responsible for regulating the excitability of the stretch reflex (which may also be involved in the mechanisms underlying the development of spasticity). Black filled circles represent inhibitory connections and open triangles represents excitatory connections. Hexagons with interrogation symbols indicate that the number of interconnections within the pathway is variable/unknown. The text in the rectangles indicates the specific mechanisms involved, which are also under influences of supraspinal centers (as represented by the connections from ‘‘descending drive’’). Gray squares depict connections from supraspinal centers that might be either of excitatory or inhibitory origin. Also note the representation of test and conditioning stimuli that might be applied to the nerves of agonist and antagonist muscles so as to probe the state of some of the spinal pathways by means of H-reflex assessment. Gamma motor system is omitted in this figure.
metabolic changes in the brain (e.g., positron emission tomography and functional magnetic resonance imaging) or to analyze electromagnetic brain activity (e.g., electroencephalography, magnetoencephalography, and transcranial magnetic stimulation). On the other hand, the currently available non-invasive techniques for obtaining measures associated with the state of specific spinal cord pathways in humans are more limited and require specific protocols involving a refined control of stimulation and recording paradigms.1 In this context, Perez and colleagues [45] showed that patterned sensory stimulation applied during 30 min could enhance the strength of the short-latency reciprocal inhibition from ankle flexor to extensor muscles as measured by conditioning the soleus H-reflex with a preceding stimulation of the common peroneal nerve. However, no similar studies have been performed so as to explore the possible role of a NEMS rehabilitation protocol (e.g., for stroke rehabilitation) in promoting neuroplastic effects within spinal cord pathways. 1 A brief review on the current available methods for assessing the state of different spinal cord pathways is provided in the section named ‘‘The association between the excitability of spinal pathways and spasticity’’ (for a more detailed explanation, the reader if referred to the reviews in [33,35,36]).
NEMS and stroke-related spasticity NMES is a widespread tool used in a large diversity of rehabilitation protocols [51] and has been shown to facilitate motor recovery in acute and chronic stroke [24,30,44,50,52–57]. Additionally, reduction of spasticity by the use of neuromuscular electrical stimulation has been reported in a multitude of studies [22,23,25–27]. However, even though changes in transmission within spinal pathways associated with reciprocal inhibition, recurrent inhibition and large sensory fiber activation have been suggested as possible mechanisms for the spasticity reduction, only empirical findings based on well-known neurophysiological pathways have been put forward to substantiate these putative mechanisms [28]. More specifically, no direct experimentation has been conducted in order to investigate a possible association between the NEMS-induced improvements in spasticity and direct evidences for neuroplastic changes within specific spinal cord pathways. The rationale for such investigation relies on the role of spinal pathways in regulating the excitability of the monosynaptic reflex, thereby being a putative mechanism behind the stretch reflex exaggeration that characterizes spasticity and consequently behind the NMESinduced diminished spasticity.
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Hypothesis: Is spinal plasticity associated with NMES-induced diminished spasticity? As briefly reviewed in the previous sections, many studies have associated stroke-related spasticity with altered transmission in a variety of spinal cord pathways responsible for controlling the excitability of the stretch reflex. Additionally, the effect of NMES in promoting CNS neuroplasticity has been well reported and NMES has also been largely used as an efficient treatment for reducing spasticity after stroke. However, no previous study has addressed whether a neuroplastic effect within specific spinal cord pathways may be associated with NEMS-induced reductions in spasticity. Therefore, the hypothesis addressed in this paper is that plastic effects within specific spinal cord circuitries (i.e., shortlatency autogenic inhibition (Ib inhibition), recurrent inhibition from Renshaw cells, disynaptic reciprocal Ia inhibition, presynaptic inhibition of Ia terminals and post-activation depression) may be associated with the reduced spasticity induced by treatments with NEMS. It shall be noted that even thought other pathologies such as spinal cord injuries/infarction, cerebral palsy, multiple sclerosis, etc. may also be associated with spasticity, the pathophysiological mechanisms may be considerably variable among the different conditions, so that the hypothesis presented here is limited to stroke-related brain injuries only. However, we must bear in mind that abnormalities in spinal pathways regulating the stretch reflex may be involved in spasticity related to a variety of causes other than brain stroke and consequently to the changes in the levels of spasticity achieved by different protocols. The protocol to test the above hypothesis involves experimental and clinical studies designed to assess the level of excitability in different spinal pathways.1 Neural transmission within these spinal circuitries shall then be evaluated both before and after the delivery of a protocol with NEMS. The parameters of NMES stimulation (waveforms, frequency, sites of application, short-term or long-term stimulation, etc.) would be left for exploration, i.e., the changes in the state of specific spinal cord pathways may be explored in response to a large variety of rehabilitation protocols (i.e., by changing NMES parameters), for instance, under different frequencies and/or intensities of NMES stimulation. Similarly, different specific spinal pathways might be evaluated: for instance, experimental paradigms in humans would involve the quantification of the reduction in H-reflex amplitude in response to different conditioning-test intervals (the conditioning stimulus being, for example, a stimulus applied to the antagonist muscle), thereby allowing the evaluation of a variety of spinal pathways such as those associated with presynaptic inhibition and reciprocal inhibition (for reviews see [33,35,36]). Protocols involving H-reflex assessments would be applicable to both impaired lower (e.g., soleus H-reflex) and upper limbs (e.g., flexor carpi radialis H-reflex) after stroke [11]. Additionally, it is worth mentioning that previous studies using H-reflex measurements to evaluate spinal cord pathways in humans have shown satisfactory reliability [58,59], and some studies needed to evaluate no more than 10–15 [17,60,61] patients to unveil differences in the modulation of spinal pathways in comparison to control subjects (although other studies have used as much as 87 [11] patients post-stroke). Besides human experiments, the hypothesis presented here may also benefit from data obtained by studies with animal models, in which similar protocols to those commonly performed in humans may be conducted, besides in vitro recording techniques (e.g., in the isolated spinal cord) [62,63]. If the hypothesis is proven corrected, the association between plasticity within specific spinal pathways and NMES-induced improvements in spasticity may be used to guide the choice of the stimulation parameters to be used in rehabilitation protocols.
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More specifically, if the changes in transmission within spinal cord pathways after the delivery of a NEMS protocol are consistently associated with changes in spasticity severity, the choice of NMES parameters to be used in rehabilitation programs may rely on the assessment of the changes in the state of specific spinal pathways. In this direction, Naghdi and colleagues found no correlation between the Modified Ashworth Scale (the currently most widely used clinical scale to evaluate muscle spasticity) and a neurophysiological evaluation based on motoneuronal excitability, thereby indicating that the Modified Ashworth Scale is not a valid and ordinal level measure of muscle spasticity [64]. Additionally, the simple evaluation of spasticity is not sensitive to the specific mechanisms behind it and hence if specific spinal pathways are found to be associated with NEMS-induced improvements in spasticity (i.e., if the hypothesis presented here is proven correct), future research would focus on the development of rehabilitation protocols designed to induce neuroplasticity in specific spinal pathways. Therefore, besides being a more precise measurement than the subjective evaluation of spasticity [64], the assessment of changes in spinal pathways excitability may also be performed in healthy subjects and/or animal models, which could easy the search for optimal NMES parameters that may potentially promote spinal plasticity and therefore shall be more prone to be effective in reducing spasticity. Conflict of interest statement The authors disclose no conflict of interest. Acknowledgements AAPM thank the Brazilian Coordination for Enhancement of Higher Education Personnel (CAPES) for supporting her studies. FHM was a recipient of a fellowship from FAPESP, Grant #2011/ 13222-6. References [1] Petrea RE, Beiser AS, Seshadri S, Kelly-Hayes M, Kase CS, Wolf PA. Gender differences in stroke incidence and poststroke disability in the Framingham heart study. Stroke 2009;40:1032–7. [2] Lance JW. The control of muscle tone, reflexes, and movement: Robert Wartenberg lecture. Neurology 1980;30:1303–13. [3] Fazekas G, Horvath M, Toth A. A novel robot training system designed to supplement upper limb physiotherapy of patients with spastic hemiparesis. Int J Rehabil Res 2006;29:251–4. [4] Mukherjee A, Chakravarty A. Spasticity mechanisms – for the clinician. Front Neurol 2010;1:149. [5] Aymard C, Katz R, Lafitte C, Lo E, Penicaud A, Pradat-Diehl P, et al. Presynaptic inhibition and homosynaptic depression: a comparison between lower and upper limbs in normal human subjects and patients with hemiplegia. Brain 2000;123(Pt 8):1688–702. [6] Crone C, Johnsen LL, Biering-Sorensen F, Nielsen JB. Appearance of reciprocal facilitation of ankle extensors from ankle flexors in patients with stroke or spinal cord injury. Brain 2003;126:495–507. [7] Crone C, Nielsen J, Petersen N, Ballegaard M, Hultborn H. Disynaptic reciprocal inhibition of ankle extensors in spastic patients. Brain 1994;117(Pt 5):1161–8. [8] Crone C, Petersen NT, Gimenez-Roldan S, Lungholt B, Nyborg K, Nielsen JB. Reduced reciprocal inhibition is seen only in spastic limbs in patients with neurolathyrism. Exp Brain Res 2007;181:193–7. [9] Nielsen J, Petersen N, Crone C. Changes in transmission across synapses of Ia afferents in spastic patients. Brain 1995;118(Pt 4):995–1004. [10] Pierrot-Deseilligny E, Burke DC. The Circuitry of the Human Spinal Cord: Its Role in Motor Control and Movement Disorders. Cambridge: Cambridge University Press; 2005. [11] Lamy JC, Wargon I, Mazevet D, Ghanim Z, Pradat-Diehl P, Katz R. Impaired efficacy of spinal presynaptic mechanisms in spastic stroke patients. Brain 2009;132:734–48. [12] Delwaide PJ, Oliver E. Short-latency autogenic inhibition (Ib inhibition) in human spasticity. J Neurol Neurosurg Psychiatry 1988;51:1546–50. [13] Katz R, Pierrot-Deseilligny E. Recurrent inhibition of alpha-motoneurons in patients with upper motor neuron lesions. Brain 1982;105:103–24. [14] Mazzocchio R, Rossi A. Involvement of spinal recurrent inhibition in spasticity.
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