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Kobeissy FH, editor. Brain Neurotrauma: Molecular, Neuropsychological, and Rehabilitation Aspects. Boca Raton (FL): CRC Press/Taylor & Francis; 2015.

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Brain Neurotrauma: Molecular, Neuropsychological, and Rehabilitation Aspects.

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Chapter 14Traumatic Brain Injury (TBI)-Induced Spasticity

Neurobiology, Treatment, and Rehabilitation

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14.1. INTRODUCTION

Traumatic brain injury (TBI) impacts the lives of 1.5 to 2 million new individuals each year; 75,000 to 100,000 of these are classified as severe, and will suffer enduring severe spasticity in addition to cognitive, vestibulomotor (balance), and other motor impairments. Following TBI, the onset of spasticity and associated orthopedic sequellae is rapid, beginning as early as one week following injury. The progressively developing spasticity and other disabilities often represent the most significant barriers for practical re-entry of TBI patients into the community. The lack of sufficient data regarding the neurobiology of TBI-induced spasticity and safety, feasibility and efficacy of early intervention therapy direct the current treatment guidelines to a conservative level. This chapter focuses on several quantitative physiological measures of spasticity, some recent findings regarding a neurobiological basis of spasticity, and finally, a section describing present treatments and the experimental treatments and rehabilitation of TBI-induced spasticity.

Clinically spasticity has been defined as an increased velocity-dependent lengthening resistance of skeletal muscles to passive movement. It is a secondary neurological condition induced by neurological hyperreflexia associated with TBI and spinal cord injury (SCI), stroke, multiple sclerosis (MS), cerebral palsy, amyotrophic lateral sclerosis (ALS), and few other disorders (e.g., anoxic brain damage; some metabolic disorders, such as adrenoleukodystrophy, phenylketonuria). Spasticity is often one of the most troublesome components of upper motor neuron injury (Katz and Rymer, 1989; Ordia et al., 1996) that greatly complicates daily living in individuals with these disorders. Its hallmark feature is altered skeletal muscle tone and spasm, and it is aptly named “spasticity.” The word spasm comes from the Greek word “σπασμµό” (spasmos), meaning “drawing, pulling.” Spasticity symptoms include increased muscle tone (hypertonicity), muscle spasms, increased deep tendon reflexes, clonus, scissoring, and fixed joints. The degree of spasticity varies from mild muscle stiffness to painful, severe uncontrollable muscle spasms. In addition to spasticity symptoms, muscles affected in this way have many other potential features of altered performance, including muscle weakness, decreased movement control, and decreased endurance.

Spasticity is associated with hyperreflexia of the muscle stretch reflexes (Ashby and Verrier, 1980; Bose et al., 2002b; Herman, 1968; Machta and Kuhn, 1948; Thilmann et al., 1991; Toft et al., 1993) that induce velocity-sensitive increased resistance of skeletal muscle lengthening. This dynamic stiffness differentiates spasticity from the changes in passive muscle properties, which are not velocity-sensitive and often seen in patients with spasticity. Although some insights have been made regarding the fundamental neurobiology of spasticity, many aspects of the specific pathophysiology still remain unclear. Therefore, experimental animal models of spasticity have been developed to increase scientific understanding of this clinically troublesome condition. The authors’ previous research works have provided evidence of neurophysiological changes in the tibial monosynaptic reflexes that use the neural pathways that subserve hindlimb muscle stretch reflexes (Thompson et al., 1992, 1993, 1998, 1999). These alterations included significant changes in rate-dependent processes that regulate sensory transmission to motoneurons (Thompson et al., 1992, 1998). More recent animal studies have shown that these physiological changes in the muscle stretch reflexes were accompanied by progressive and enduring spastic hypertonia (Bose et al., 2002b, 2012, 2013; Hou et al., 2014). These changes were severe in magnitude and highly relevant to features observed clinically in humans (Schindler-Ivens and Shields, 2000). Human studies have reported that neurophysiological changes in rate-dependent processes that regulate reflex excitability of the stretch reflex pathways also accompany spasticity (Boorman et al., 1992; Brown, 1994; Calancie et al., 1993; Lance, 1981; Nielsen et al., 1993; Schindler-Ivens and Shields, 2000; Thompson et al., 2001a, 2001b).

Rodent spasticity models for SCIs (Bose et al., 2002b, 2012; Hou et al., 2014), TBIs (Bose et al., 2013), experimental allergic encephalitis (EAE) Lewis rat model of MS (Bose et al., 2009), and a rodent white matter stroke model (Thompson et al., 2013) have been developed and studied in the authors’ laboratory to increase our scientific understanding about this condition and to find ways to prevent, treat, and diminish disabilities of this condition. There are some distinct differences in the pattern, time course of development, and severity of spasticity that is induced by these different injuries or disease processes. These different patterns of spasticity are presumed to be derived according to the manner in which the central nervous system (CNS) trauma or disease has induced alterations in supraspinal drive, their substrate systems (e.g., serotonergic and noradrenergic innervation of the motoneurons), and associated secondary changes at the cellular level in the spinal cord (e.g., both motor neuron and interneurons) below the lesion. Accordingly, an increased understanding of the mechanisms responsible for these injury/disease-induced neuroplastic changes at supraspinal and spinal levels may be of great importance in relation to the design of the most effective treatment and rehabilitation of spasticity.

14.2. MEASUREMENT OF SPASTICITY

14.2.1. Velocity-Dependent Ankle Torque and Electromyogram: A Measure of Spasticity

Although the clinical symptoms typically categorized as spasticity present as multiple clinical phenomena (Roy and Edgerton, 2012) derived from complex disease processes (Young, 1992), the dynamic features of velocity-dependent exaggeration of lengthening resistance to the skeletal muscle remains a useful defining criteria (Lance, 1981; Nielsen et al., 2007). Because spasticity diminishes the coordination of voluntary movement and gait, it poses significant limitations to motor recovery after CNS injury or disease. Recent studies used a velocity-dependent ankle torque protocol to chart the time course of spasticity development induced by SCI and TBI, and multiple CNS lesions of the EAE MS model (Bose et al., 2002b, 2009, 2012, 2013; Hou et al., 2014). These studies revealed differences in the pattern and severity of spastic hypertonia that was specific to the type of CNS injury or disorder. For example, mid-thoracic spinal cord contusion injury revealed an initial transient pattern of “tonic” spasticity (i.e., a significantly increased resting tone–induced stiffness that was further increased by muscle lengthening velocity). This tonic pattern progressed to a dynamic pattern of velocity-dependent spasticity. This dynamic pattern revealed elevated electromyogram (EMG) amplitudes and associated increased ankle torques only when tested at ankle rotation velocities that were above the threshold velocity of the stretch reflex (in rat, it is 272° per second). This dynamic patterned spasticity was progressive in onset, and once developed, became permanent. The ankle torques recorded at the lower test velocities (49–272° per second) (see Bose et al., 2002b) were not significantly greater than observed in normal controls, nor were these correlated with synchronized EMG activity in the ankle extensor muscles. These low-velocity ankle torques were, therefore, interpreted to be contributed by the passive properties of the muscle and joint tissues.

By contrast, test rotations at the upper test velocities revealed increased stiffness of ankle rotation that was time-locked to the stretch-evoked EMGs recorded from the ankle extensor muscles, indicating resistance contributions from activated ankle extensor muscle stretch reflexes (see also Bose et al., 2002b). In contrast, cervical spinal cord contusion injuries induced a severe pattern of tonic and dynamic spasticity (i.e., a large resting tone with superimposed velocity-dependent spasticity). The elevated EMG amplitudes and ankle torques appeared at the lowest (tonic) range of ankle rotation velocities and were enhanced as a function of velocity throughout the upper (dynamic) range (Bose et al., 2009; Hou et al., 2014). Tonic and superimposed dynamic patterns of spasticity and proportionally elevated EMG amplitudes have been recorded after TBI (Bose et al., 2013), EAE (Bose et al., 2009), and rodent white matter stroke model (Thompson et al., 2013). Because these velocity-dependent changes were quantifiable, robust in magnitude, and of enduring character, they provide a useful and clinically relevant method of measuring spasticity relative to injury, and provide a quantitative outcome measure to assess the influence of experimental treatments on this condition.

14.2.2. Rate-Dependent Inhibition/Depression

During the course of reflex testing, reflex test protocols were developed that revealed quantifiable features of fundamental inhibitory processes that regulate sensory transmission to hindlimb muscle stretch reflexes; this process was reported to be significantly decreased after contusion SCI (Bose et al., 2012; Thompson et al., 1992, 1993, 1998, 2001a). These studies revealed that spasticity developed over a time course that was mirrored by the loss of rate-dependent depression in the reflex pathways that serve the spastic muscles in rats (Bose et al., 2002b; Thompson et al., 1992, 1993, 1998, 2001a) and in humans (Calancie et al., 1993; Ishikawa et al., 1966; Schindler-Ivens and Shields, 2000). It has been proposed that the progressive loss of presynaptic inhibition contributes significantly to the progressive development of hyperreflexia of stretch reflex pathways. Rate-depression is one of three fundamental processes that controls reflex magnitude elicited by repetitive input; facilitation and potentiation are the other two (Mendell, 1984). Rate-sensitive depression has been tested in animal models of SCI to quantify changes in spinal cord reflex excitability and to measure plasticity by experimental interventions.

Reflex repetition at 1.0 Hz elicited by electrical stimulation of the dorsal roots of the L5 and L6 lumbar segments (which included Ia’s from ankle extensor muscles) in the intact rodent produced a 35% decrease in the reflex amplitude (relative to the 0.3-Hz control). Further increases in frequency were accompanied by additional marked reductions in reflex amplitude (Skinner, 1998; Skinner et al., 1996; Thompson et al., 1992, 1993, 1998). After spinal cord contusion in the adult rat, a progressive reduction in rate-sensitive depression was observed that was permanent once established (Thompson et al., 1992, 1998). Recordings in rodents at 2 months after T8 contusion injury exhibited significantly less attenuation at each of the test frequencies from 1.0 through 20 Hz (see detail, Thompson et al., 1992, 1998). Rate-sensitive depression has also been tested in humans with CNS lesions (Calancie et al., 1993; Ishikawa et al., 1966; Nielsen and Sinkjaer, 1997; Schindler-Ivens and Shields, 2000; Thompson et al., 2001b; Trimble et al., 1998). This index has distinguished between control subjects, subjects with acute SCI, and subjects with chronic SCI (Calancie et al., 1993; Ishikawa et al., 1966; Schindler-Ivens and Shields, 2000; Trimble et al., 1998). Reduced rate-sensitive depression function after SCI is attributed, in part, to a decrease in presynaptic inhibition on Ia afferents. This reduction in presynaptic inhibition may be due to the injury associated loss of descending paths and alterations in segmental influences converging on inhibitory interneurons that regulate the probability of transmitter release from the Ia afferents (Cardona and Rudomin, 1983; Delwaide, 1973; Nielsen et al., 1995). If depression is reduced, a larger portion of repetitive afferent signals reach spinal reflex paths and contribute to exaggerated levels of reflex activation (Nielsen et al., 1995; Thompson et al., 1993). Accordingly, analysis of rate-depression has provided a sensitive, quantitative probe of segmental reflex excitability of spinal reflex pathways used for locomotion.

Spastic hyperexcitability has been reported to develop over several months after the primary lesion and includes progressive adaptation in the spinal neuronal circuitries caudal to the lesion (Bose et al., 2002; Nielsen et al., 2007; Roy and Edgerton, 2012; Thompson et al., 1998; Thompson et al., 2001a; Thompson et al., 1993). Accordingly, physiological measures of changes in cellular properties have been used to explore mechanisms underlying spastic hyperreflexia. Recently, studies of dendritic potentials called “plateau potentials” have revealed new insights into changes in cellular properties that contribute to hyperreflexia (Bennett et al., 2001), although the relevance of the changes in plateau potentials to human spasticity has not been described clearly because of the difficulty in demonstrating the existence of such intrinsic membrane properties in the intact organism (Nielsen et al., 2007). Plateau potentials are depolarizing potentials recorded in spinal cord motoneurons produced by dendritic persistent inward currents (PICs). Plateau potentials have also been reported in recordings from cortical and hippocampal pyramidal neurons. Spinal cord motoneurons’ PICs are normally regulated by descending monoaminergic and reticulospinal pathways, especially through 5-HT and norepinephrine projections. These descending projections modulate the activity of dendritic L-type voltage-dependent calcium channels that elicit the sustained, positive, inward currents that produce the long-lasting depolarization. Once long-lasting depolarization is achieved, the cell fires action potentials independent of synaptic input. There are several reports that argued about a possible contribution of plateau potentials to the development of spasticity in human subjects (Gorassini et al., 2004; Nickolls et al., 2004). The contribution of plateau potentials to the clinical manifestations of the spasticity is based on the fact that plateau potentials were activated during the spasm and appeared to contribute to the occurrence of the spasms in SCI patients (Gorassini et al., 2004)

Moreover, measures of disynaptic reciprocal inhibition, have been suggested as an index of changes in inhibitory processes related to spasticity (Crone et al., 2003). However, the intersubject variability of these mechanisms, and the lack of objective quantitative measures of spasticity has impeded disclosure of a clear causal relationship between the alterations in the inhibitory mechanisms and the stretch reflex hyperexcitability (Nielsen et al., 2007). Therefore, the search continues for physiological measures that can quantitate longitudinal changes in inhibitory mechanism correlated with the development of altered reflex excitability.

14.3. PATHOPHYSIOLOGY OF SPASTICITY

Although some insights have appeared in our understanding of the complex neurobiology of spasticity, the etiology of spasticity remains largely unknown. Because spasticity is a multidimensional and dynamic syndrome (Roy and Edgerton, 2012), there are multiple possible mechanisms for the development of spasticity. Studies in animals and humans suggested that alterations in the biochemical and morphological properties of spinal motor neurons after CNS injury or disease lead to cellular and biochemical dysfunctions as a basis for the development of spasticity. Therefore, multiple processes that contribute to spasticity have been identified and include (1) pre- and postsynaptic changes (loss of presynaptic inhibition of Ia afferents) (Calancie et al., 1993; Faist et al., 1994; Nielsen et al., 1995; Schindler-Ivens and Shields, 2000), alterations in rate-dependent processes that regulate sensory transmission to motoneurons (Bose et al., 2012; Thompson et al., 1992, 1993, 1998), and increase in postsynaptic receptor excitability and upregulation of postsynaptic receptors (Little et al., 1999); (2) changes in neural network (decrease in postactivation depression of the H-reflex) (Nielsen et al., 1995), augmented synaptic inputs and terminal sprouting (Jankowska and Hammar, 2002; Little et al., 1999), and decrease in reciprocal Ia inhibition (Crone et al., 1994, 2003); (3) changes in the motor neurons (alteration in the intrinsic properties of spinal cord motoneurons) (Bennett et al., 2001; Li et al., 2004), and gap junctions between motoneurons (Yates et al., 2008, 2009), increased excitability of motoneurons (Cope et al., 1986; Heckmann et al., 2005), increased excitability of motoneurons from a decrease in the number of dendritic branches after SCI (Bose et al., 2005; Kitzman, 2005); and (4) alteration in spinal neurotransmission (an increase in excitatory and a decrease in inhibitory spinal neurotransmission) (Shapiro, 1997) mechanisms play an important role in the development of spasticity. Changes in neural networks and their cellular and subcellular substrate systems may take place over a period of months after CNS injury or disease, and thus development of spasticity also follows that time line. The authors view spasticity as the product of unselective, maladaptive changes in the motor and sensory projection systems as part of an unguided attempt for recovery of function. Damage to the CNS (e.g., SCI, TBI, stoke, MS, ALS) alters the regulation of sensory transmission from peripheral nerves.

This change in the regulation of sensory transmission to motor reflex pathways appears to favor excitation and therefore an increased reflex excitability. CNS damage/disease also causes nerve cell membranes (such as changes in dendritic PICs) to have a higher probability of a depolarized state. The combination of decreased regulation of sensory transmission and increased cellular excitability collectively contribute to the increased probability for motoneuron discharge that underlies the resulting spasticity. The majority of the previously mentioned possible mechanisms, however, have only been tested in the setting of SCI. Therefore, it is noteworthy that the contribution of these mechanisms to spasticity resulting from TBI, stroke, and other neurological diseases (e.g., MS, ALS) is yet to be confirmed. In our experience, closed-head TBI (Marmarou et al., 1994) or cortical control impact (Dixon et al., 1991) TBI produces more severe spasticity in the rodents than the magnitude of spasticity after SCI, particularly injury to the thoracic spinal cord (the setting in which most SCI research has been done). Moreover, our preliminary physiological data in our experimental TBI models revealed a different pattern, time course, and neurophysiological mechanisms from that observed following midthoracic SCI. For example, rate-dependent inhibition, an index of a long-acting presynaptic inhibition, was minimally altered in these TBI models. Moreover, a robust permanent tonic and dynamic pattern of spasticity was observed in these TBI models.

Immunocytochemical studies in these animals revealed decreased dopamine beta hydroxylase (DβH), positive norepinephrine (NE) fibers (a surrogate marker for norepinephrine) combined with greatly increased density of serotonin positive fibers in the gray matter of the lumbar spinal cords (Bose et al., 2001; 2002). These observations provoke specific hypotheses regarding monoamine mechanisms that are known to be critically involved in the regulation of stretch reflex excitability. In particular, it has been shown that iontophoretic application of 5-HT enhanced the resting activity of fusimotor (gamma) motoneurons and facilitated the transmission of group II afferent input to these neurons (Jankowska et al., 1998). Sites of noradrenergic and serotonergic modulation may also include intermediate zone interneurons that are pre-motor to gamma motoneurons (Jankowska et al., 2000). In addition, apposition of noradrenergic and serotonergic immunoreactive varicosities is localized to the proximal dendrites and soma of physiologically identified and rhodamine-dextran–labeled gastrocnemius gamma-motoneurons suggesting that they are synapses (Gladden et al., 2000). The number of serotonergic contacts with alpha-motoneurons, themselves, has been estimated to be in excess of the number of synapses from Ia afferents (Alvarez et al., 1998). Serotonin is a metabotrophic neurotransmitter that influences intrinsic membrane conductances and, collectively, these changes increase the excitability of motoneurons by several mechanisms stated previously. In this regard, elegant work by Bennett et al. (2001) showed that the influence of plateau potentials on the firing frequency of the motoneuron was linear with respect to the amplitude of the PIC both during recruitment and derecruitment. Serotonin is known to decrease the threshold and increase the duration of plateau potentials (i.e., eliciting a sustained period of motoneuron firing that greatly outlasts the period of stimulation) (Conway et al., 1988; Hounsgaard et al., 1988). This change has been correlated with a decrease in the slow potassium current and a decrease in the threshold for activation of L-type Ca++ channels (Svirskis and Hounsgaard, 1998). Serotonin has also been shown to increase the inward rectifier current (Ih) producing a depolarization that can lead to a strong firing of motoneurons (Takahashi and Berger, 1990). This is a particularly effective mechanism because the Ih operates in a range close to the resting potential. Therefore, the modulation of Ih by serotonin could have a major facilitatory effect on the integration of synaptic potentials as well as on the shaping of spike after potentials (Russo and Hounsgaard, 1999). Therefore, collectively, a robust increase in serotonin expression in the lumbar spinal cord should be correlated with robust increases in motoneuron excitability that can be quantitated by significant changes in the current/frequency curves for tibial motoneurons in TBI-spastic rats.

In this regard, several other recent physiological published reports related to the mechanism of spasticity will be described below. Several studies have been conducted to understand changes in pre- and postsynaptic factors that regulate motoneuron excitability in the normal and the hyperreflexic state following SCI. Accompanying progress in understanding changes in presynaptic mechanisms, substantial progress has occurred in the understanding of postsynaptic mechanisms that regulate the input/output gain of motoneuron discharge (Bennett et al., 1998; Hounsgaard et al., 1988; Kernell, 1979; Lee et al., 2003; Lee and Heckman, 1998a, 1998b, 2000; Schwindt and Crill, 1980a, 1980b). These studies have revealed that the gain of synaptic inputs can be amplified up to a factor of five by brainstem/monoaminergic inputs that regulate dendritic PICs using sodium and calcium channels. The higher the persistent inward current, the higher the synaptic gain and consequent burst rate of the motoneurons. Segmental regulation of PICs occurs through inhibitory mechanisms that regulate afferent inputs. It has been proposed that the acute period of hyporeflexia that follows SCI can be attributed to a reduction in dendritic PICs. Subsequently, after several weeks, recordings have shown that motoneurons reacquired PICs that were indiscriminately initiated by segmental inputs. These unregulated PICs were proposed as a mechanism that significantly contributes to clonus and spasms, and associated amplified bistable properties of motoneurons (Lee and Heckman, 2000).

Furthermore, after a complete transection of the sacral spinal cord (Kitzman, 2005) and after a mid-thoracic spinal cord contusion injury (Bose et al., 2005), a decrease in the number of dendritic branches in the sacrocaudal or soleus motoneurons was reported. These reports suggested that a decrease in the dendritic arborization without a compensatory increase in voltage-gated channels could lead to an increase in motoneuronal excitability that may result spasticity. In this context, segmental inhibitory processes, such as presynaptic inhibition, have an even more important role in the regulation of sensory transmission. Rate-dependent inhibition provides a protocol for testing a type of long-acting presynaptic inhibition that is normally used to regulate the excitability of the muscle stretch reflexes relative to the phase of stepping. Three neurotransmitter systems (serotonergic, GABA, and noradrenergic systems), are known to play critical roles in the modulation of segmental reflex modulation. The authors have observed that the rate-dependent inhibition and velocity-dependent ankle torque are profoundly influenced by GABAb-specific agents (Thompson et al., 2005; Wang et al., 2002) and NE-specific lesions (Bose et al., 2001; Thompson et al., 1999). Specifically, L-baclofen (which acts on GABAb segmental circuitry) increased rate-dependent inhibition and decreased velocity-dependent ankle torque, whereas selective neurotoxic lesions of NE fibers produced nonspecific increase in reflex excitability. Segmental GABAergic system play an important role in this rate-dependent long-acting presynaptic inhibition. However, there are significant and clear differences between GABAa- and GABAb-mediated presynaptic inhibitions. The findings related to GABAa in spinal complete transected animals (work from Edgerton’s group [Edgerton and Roy, 2010; Khristy et al., 2009; Tillakaratne et al., 2002]) and the recent works from the authors of this chapter (that are related to GABAb in moderate contusion SCI) provide insight into the differences in mechanism of action. The presynaptic inhibitory (primary afferent depolarization) mechanism related to GABAa is the action of the GABAa ionotrophic receptor, which when activated, selectively conducts Cl− through its pore resulting in hypopolarization of the axon terminals.

This unusual presynaptic hypopolarization (instead of hyperpolarization) in axon terminals is due to the increased Cl− concentration in axon terminals that is maintained by the NKCC1 Cl− transporter at a concentration gradient that is greater than that produced by the equilibrium potential (Alvarez-Leefmans, 2007). The issue at odds is related to the reporting of a spinal cord transection–induced downregulation in the potassium-chloride cotransporter-2 (KCC2) in motoneuron membranes; this results in a positive shift in the membrane potential for chloride (Boulenguez et al., 2010). Accordingly, a paradoxical effect could occur at GABAa receptors on membranes with downregulated KCC2. Presynaptic inhibition associated with GABAa-mediated primary afferent depolarization is a significantly important inhibitory control of afferent transmission to lumbar interneurons and motoneurons. GABAa receptors, located on presynaptic terminals, are activated by GABAergic interneurons. Although elevated GABAa and glycine receptors could result in more inhibition, the low KCC2 levels and elevated chloride equilibrium potentials could contribute to the increased excitability leading to spasticity (Roy and Edgerton, 2012). Further, Dr. David Lloyd, Sir John Eccles, Dr. David Curtis, and Dr. P. Rudomin showed that the time course for GABAa-mediated presynaptic inhibition has a rapid onset and a duration (elicited by single shock) of <300 msec. By contrast, GABAb metabotrophic receptors are also located on presynaptic terminals, adjacent to voltage-gated calcium channels. GABAergic interneurons terminate on, release GABA, and excite these GABAb receptors. Second messengers released subsequent to GABAb receptor activation act to decrease the Ca++ conductance of the voltage gated Ca++ channels. This decrease in Ca++ influx, an essential part of the depolarization—Ca influx—staging and adhesion of presynaptic vesicles to the presynaptic membrane, results in a significant decrease in excitatory transmitter release from primary afferents. The time course for these metabotrophic inhibitory processes is slow to activate (i.e., >100 msec) but have the unique signature of long duration (i.e., 1000s of msec). Inhibition associated with these two types of presynaptic inhibition can be selectively tested using afferent volleys initiated at different frequencies. For example, 1 Hz (1000-msec interval between stimulus pulse) induced inhibition is, therefore, primarily GABAb, because GABAa has a time course <300 msec. GABAb receptors can be selectively activated by L-baclofen or selectively blocked by specific antagonists such as CGP35348. The authors reported that intrathecal administration of GABAb agonists and antagonists can profoundly alter rate-dependent depression in normal and contusion SCI animals (Thompson et al., 1992, 1993, 1998, 2001a; Wang et al., 2002). These studies reported significant decreases in the magnitude and time course for GABAb-associated rate-dependent depression after contusion SCI (Thompson et al., 1992, 1993, 1998, 2001a; Wang et al., 2002). Moreover, several authors have shown that a similar change occurs in low-frequency (1-Hz) rate-depression–associated changes in spinal reflex excitability after human SCI (Phadke et al., 2009, 2010a, 2010b, 2010c; Thompson et al., 2001a; Trimble et al., 2001) and others (Schindler-Ivens and Shields, 2000). Collectively, these findings contribute to the evidence base for the use of GABAb-specific antispastic medication, intrathecal L-baclofen (ITB) for the treatment of spasticity.

To test the physiological effects of coeruleo-spinal noradrenergic modulation to velocity-dependent ankle torque in hindlimb extensor muscles, the authors injected anti-DβH-saporin, an immunospecific ribosomal toxin to lumbar spinal cerebrospinal fluid. Because DβH is specific to noradrenergic fibers, it produced a selective lesion of noradrenergic neurons via inactivating the ribosomes (Wiley and Kline, 2000). The injected normal animals exhibited a spastic hypertonia that resembled the pattern of TBI-spastic hypertonia observed at one week after TBI. These studies indicated involvement of NE neurobiology in TBI-induced spastic hypertonia and have increased the authors’ interest in the possibilities for the therapeutic potential of NE pharmacotherapy in spasticity.

14.4. TREATMENT AND REHABILITATION OF TBI-INDUCED SPASTICITY

Spasticity is one of the most significant challenges associated with treatment and rehabilitation after moderate/severe TBI. Treatment development is hindered by the lack of an understanding of neurobiology of TBI-induced spasticity. As mentioned previously, most of the physiological studies related to the neurobiology of spasticity have focused on thoracic SCI, which has revealed alterations of several physiological parameters of motoneuron firing patterns and associated pre-and postsynaptic inhibition-related mechanisms. However, the lack of fundamental neurobiology that underlies the development and persistence of TBI spasticity prevents focused application of antispasticity medication to specific therapeutic targets. In addition, because data from controlled studies quantifying specific interactions between antispastic medications and cognitive recovery are not available, guidelines regarding initiation of antispastic medications after injury are conservative. Typically, post-injury delay before initiating the most effective antispastic measures (e.g., intrathecal baclofen) is 1 year after injury, although it has been shown that the use of antispastic medications (baclofen), particularly intrathecal baclofen, can decrease the severity of spasticity produced by acquired brain injury (Francisco et al., 2005; Meythaler et al., 1997, 1999, 2001; Saltuari et al., 1989). Therefore, early windows of opportunity to diminish debilitating orthopedic problems induced by hypertonia are usually missed. Current data indicate that of the 75,000–100,000 severe TBIs (total all TBI, 1.5–2.0 million) that occur annually (TBI Model Systems National Database), the incidence of contracture (muscular deformity induced by spasticity) is projected to be as high as 85% (Corrigan et al., 2010; Gottshall, 2011; McGuire, 2011; Thurman et al., 1999). Therefore, current treatment strategies for TBI spasticity include a host of orthopedic and surgical procedures to address musculoskeletal deformities that typically gain a substantial foothold before treatment is initiated. A mild form of spasticity can have beneficial effects, such as improving ambulation and maintaining muscle bulk However, moderate to severe TBI-induced spasticity often interferes with the individual’s general functioning, including limitations in rotation of movement, mobility, dysarthria, and dysphagia. In these cases, treatment is often needed.

The currently available treatments for spasticity include (1) oral medications: baclofen, tizanidine, diazepam, and dantrolene sodium, alone or in combination; (2) intrathecal baclofen drug delivery (ITB); (3) orthopedic surgery: such as tendon transfers, tendon lengthening, osteotomy, and bony fusions; (4) neurosurgery: such as percutaneous and open selective dorsal rhizotomy, neurectomy, or myelotomy; (5) injection therapy: such as neurolytic nerve blocks using phenol; anesthetic nerve blocks using procaine and lidocaine, and botulinum toxin (Botox) injections; and (6) rehabilitation therapy: casting, splinting, positioning, electrical stimulation, and rotary movements, etc.

A laboratory TBI-spasticity model recently provided new information relative to the fundamental neurobiology and the treatment of this condition. These new data provided a preclinical platform for safety, feasibility, and efficacy of early ITB intervention after TBI spasticity (Bose et al., 2013). This study was performed in the rodent model to evaluate spasticity, cognitive, vestibulomotor, and locomotor disabilities produced by closed-head TBI and how these disabilities could be modified by Lioresal ITB therapy initiated in an acute setting. The influence of TBI and treatment on the excitability of voluntary motor pathways was assessed using TMS-initiated motor-evoked potentials to activate constituents of the executive motor pathway to lower limb muscles. In addition, spinal cord tissues were studied to assess the expression of immunohistochemical markers for agents known to influence the excitability of neural pathways controlling lower limb motor function, especially spasticity. These data indicated that 1 month of ITB treatment initiated at post-TBI week 1 blocked the early onset of spasticity, significantly attenuated late-onset spasticity, significantly reduced anxiety-like behavior, and produced no significant adverse effects on cognitive and balance performance. More specifically, these data indicated that in the acute treatment group, at 2 weeks posttreatment there was a complete block of spasticity (elevated ankle torques and corresponding EMGs), and at posttreatment week 4, ankle extensor spasticity was reduced by 50% compared with untreated injured controls. By contrast, when ITB was initiated post-TBI 4 weeks, at 2 weeks posttreatment, there was 65% attenuation of spasticity, and at week 4 posttreatment, ankle extensor spasticity was reduced by 42% compared with untreated injured controls. ITB-treated animals in both acute and subchronic treatment groups showed improved scores (trends) for serial learning (probe trail) and improved gait performance compared with untreated injured controls. Although balance performance was not affected in the acute group, a significant deterioration in balance performance was detected in the chronic treatment group. Therefore, acute ITB treatment strategy appeared to be more effective in controlling spasticity (with no impact on balance performance) than observed in the setting of delaying treatment for 1 month (e.g., subchronic ITB treatment). This improved spasticity outcome in acute ITB group was accompanied by marked upregulation of GABA/GABAb, norepinephrine, and BDNF expression in the spinal cord tissues of the treated animals (Bose et al., 2013).

This study was the first to show that early intervention with ITB treatment was safe, feasible, and effective in this closed-head TBI animal model. Collectively, these data provide a strong molecular footprint of the enhanced expression of reflex regulation of factors known to be involved in regulation of sensory transmission (presynaptic inhibition) and postsynaptic excitability. ITB treatment at the acute interval may occur in a setting in which less time has passed postinjury for the progressive development of maladaptive segmental and descending plasticity (Bose et al., 2013). However, in addition to demonstrating that early intervention can be highly effective in reducing TBI spasticity, studies need to be conducted to assess the impact of early ITB versus chronic ITB on cognitive function, balance, sleep, and daily activity, using ITB dosages across a broad range. A comprehensive comparison of acute versus chronic ITB treatments will provide a much needed unequivocal comparison of new versus standard of ITB treatment after TBI.

Although oral baclofen and ITB therapy are partially effective in reducing TBI-induced spasticity in humans, amplification of treatment benefits possibly through the use combination of complementary therapies are needed to produce even more effective treatment benefits for long-term outcomes. The authors’ preliminary work in SCI animals revealed that ITB combined with locomotor training (treadmill) produced a profound amplification of long-term spasticity attenuation compared with either of the treatments tested individually. The strategy of combination therapy has also been strongly recommended in recent consensus conferences held to evaluate the disappointing TBI clinical trial outcomes testing single therapies and to encourage combination therapeutic development (Saatman et al., 2008). Because combination therapy potentially represents a paradigm shift in rehabilitation therapy, early intervention combination therapy (ITB and locomotor training) or a combination of ITB and transcranial magnetic stimulation (TMS) for TBI-induced spasticity may be of high importance. To broaden the scope of potential therapeutic application, these therapies need to be evaluated in selected acute and chronic settings. To provide greater confidence in the translation of any of these combination therapies, physiological measures of treatment safety need to be included. A major requirement for the safe application of any new treatment is the quantitative evidence base for safety and efficacy. Although locomotor training has demonstrated positive benefits, the robustness of the single-therapy paradigm (in the setting of human TBI) was not sufficient to yield results significantly greater than conventional therapy. TMS is proposed as a strategy for individual therapy or as an adjuvant to provide an amplification that could move the combined therapy to the next level of effectiveness. The authors’ recent report (Hou et al., 2014) suggests the potential for TMS therapy to influence SCI-induced spasticity and gait disabilities that are correlated with neurochemical changes that are consistent with the neurobiology of these processes. Amplification of locomotor training is needed and TMS represents a logical next step in the development of effective therapy for spasticity.

New therapeutic possibilities include the progressive addition of convergent therapies. For example, it is anticipated that the potential for therapeutic exercise and TMS would be enhanced in conjunction with pharmacological therapy that could further induce augmentation of central norepinephrine and segmental GABAb. The authors’ recent data suggested that treadmill locomotor training and TMS across the SCI site can be an effective and feasible treatment modality for SCI-induced spasticity and gait impairments, and that the combination of these two therapies was significantly more effective than either treatment tested as individual therapy (Hou et al., 2014). The combination therapy revealed a profound therapeutic reduction of spasticity toward preinjury levels. The therapeutic improvements in spasticity (and gait) with each treatment modality were correlated with significantly amplified expression of the immunohistochemical markers for GABAb receptors, GAD67, DβH, and BDNF. However, the combination therapy produced a greater expression of these markers. Each treatment modality has its own merit. For example, although TMS may enhance upregulation of trophic factors, without behaviorally relevant guided neural signaling (e.g., treadmill locomotor training), little normalization of gait confirmation was produced by TMS alone. On the other hand, six sessions of TMS therapy provided an increased unguided ascending and descending activity related to pre- and postsynaptic inhibition that resulted in significant improvement of spasticity. This improvement in spasticity was similar to the improvement in spasticity seen after a 7-week program of treadmill locomotor therapy. However, treadmill therapy, as standalone therapy, revealed significant improvement in spasticity and normalization of gait parameters. The treadmill locomotor therapy perhaps increased guided segmental, ascending, and descending plasticity. These findings suggest that task-appropriate therapy was essential for recovery of spasticity with gait confirmation. Therefore, the robustness necessary to make significant functional improvements in spasticity and gait may require amplification of therapeutic impact through the successful combination of complementary individual therapies. Although TMS has been used in a broad range of therapeutic applications since its inception in 1985, many questions remain regarding the mechanisms of its beneficial outcome. In this regard, this SCI study indicated that TMS may enhance the trophic environment through BDNF and GAD67 and the upregulation of markers for pre- and postsynaptic inhibition (GABAb receptors, GAD67, and NE). Similar studies need to be done to test if similar beneficial outcome in spasticity and gait can be achieved in TBI spasticity.

14.5. REHABILITATION OF TBI-INDUCED SPASTICITY AND LONG-TERM BENEFICIAL OUTCOME

Rehabilitation of TBI-induced spasticity may also provide protection against long-term progressive inflammatory cell loss. In addition to TBI-induced acute motor disabilities, long-term functional losses are also threatened by the possibility of enduring injury-induced changes that can produce progressive loss of neural tissue and concomitant exacerbation of disability. One of the most damaging sources for continued loss of tissue is chronic inflammation (Ramlackhansingh et al., 2011). This section will briefly outline that the unusual nature of this problem is that, in addition to TBI-induced increase in signaling factors that induce inflammation, this inflammation is exacerbated by a TBI-induced decrease in the NE-associated regulation of inflammation. Accordingly, rehabilitation procedures that upregulate central NE contribute significantly to the potential for decreasing chronic disability.

In addition to the TBI-induced reduction of NE expression in the spinal cord described previously, it has been reported that TBI results in widespread and long-lasting changes in brain NE turnover (Dunn-Meynell et al., 1994; Fujinaka et al., 2003; Robinson and Justice, 1986). After injury, a short-term phase (minutes) of increased turnover is followed by a prolonged phase (>8 weeks) of substantial decrease in NE metabolism (Fujinaka et al., 2003; Levin et al., 1995). Consistent with these findings, our immunohistochemistry studies (Bose et al., 2002a, 2012) and others (Fujinaka et al., 2003) indicated that TBI produced a marked decrease in DβH labeled locus coeruleus neurons. Accordingly, because this nucleus provides significant NE projections to the CNS, and because these projections influence the excitability of multiple neural networks for cognitive function, anxiety, and balance, we have proposed a TBI multiple-morbidity model based on the TBI-induced injury of the central NE system (Bose et al., 2012). In addition to the important role of monoamines in cellular excitability, NE plays a critical role in the regulation of the CNS immune system. It is known that NE regulates immune signaling (e.g., iCAM, iNOS, NOS2) that is critical for the immune privilege of the CNS (Galea et al., 2003). Locally diffusing NE has been proposed to negatively regulate transcription of inflammatory genes in astrocytes and microglia (Feinstein et al., 2002) and has been proposed to serve as an endogenous anti-inflammatory agent (Mori et al., 2002).

Because TBI induces a cascade of inflammatory signaling factors, a prominent inflammatory response is marshaled via astrocytes and microglia (Ramlackhansingh et al., 2011). The concomitant inflammatory responses (including the secretion of cytokines) may significantly increase neuronal cell loss and enlarge the scope of functional disability. Consequently, injury-related downregulation of the central NE system could disinhibit the inflammatory cascades that are freed to attack intact cells and render them more subject to inflammatory damage. Therefore, a chronic condition of progressing inflammation can potentially inflict a continual erosion of the nervous system and an ever progressing functional degradation.

Accordingly, putative treatments that induce upregulation of NE can potentially result in significant neuronal preservation against the progressive loss resulting from inflammation.

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