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Chapter 1: Introduction and background Spasticity is generally reported to occur frequently following lesions of central motor pathways in neurological disorders such as stroke (in 20-30%) (Malhotra et al., 2009; Sommerfeld et al., 2012), spinal cord injury (in 65-78%) (Sheean, 2002; Adams & Hicks, 2005), multiple sclerosis (in 4784%)(Sinkjaer et al., 1993; Mayer, 1997; Barnes et al., 2003; Rizzo et al., 2004; Oreja-Guevara et al., 2013) and cerebral palsy (Gracies, 2005b; Odding et al., 2006). One problem with such reports is that there is no general agreement regarding the exact definition of spasticity and that many of the studies do not report how they defined spasticity (Pandyan et al., 2005; Malhotra et al., 2009). Spasticity has been defined as “a velocity dependent increase in muscle tone with exaggeration of the stretch reflex circuitry” (Lance, 1980) and it is this definition which is used in most research studies (Pandyan et al., 2005; Malhotra et al., 2009). In 2003 the North American Task Force for Childhood Motor Disorders redefined spasticity as “a velocity dependent increase in hypertonia with a catch when a threshold is exceeded” (Sanger et al., 2003). The SPASM consortium suggested a broader and more clinically relevant understanding of spasticity to be “disordered sensori-motor control, resulting from an Upper Motor Neuron lesion, presenting as intermittent or sustained involuntary activation of muscles” (Pandyan et al., 2005). Such diverse definitions makes it difficult to determine from the literature not only the frequency of spasticity, but also its functional and clinical importance. This problem has been emphasized by findings in a number of recent studies that it is not easy to distinguish between alterations in passive elastic muscle properties and reflex mediated muscle stiffness (Mirbagheri et al., 2008; Alhusaini et al., 2010b; Lorentzen et al., 2010). The resistance against slow passive movements at velocities below stretch reflex threshold, which is caused by the passive elastic properties of the muscle, connective tissue, tendon and joint, is usually called passive muscle stiffness (Toft et al., 1989a; Toft et al., 1991; Mirbagheri et al., 2004; Lorentzen et al., 2010). Even trained neurologists may often falsely attribute increased muscle tone to exaggerated reflex activity rather than changes in passive muscle properties (Dietz & Sinkjaer, 2007; Malhotra et al., 2009; Lorentzen et al., 2010; Dietz & Sinkjaer, 2012; WillerslevOlsen et al., 2013). This was noted three decades ago when Volker Dietz and his co-workers suggested, based on a combination of biomechanical and electrophysiological techniques, that changes in passive muscle stiffness may be the dominant cause of gait impairment in subjects diagnosed with spasticity (Dietz et al., 1981; Berger et al., 1982; Dietz & Berger, 1983). The importance of increased passive muscle stiffness for gait impairment in spastic subjects has been confirmed by recent studies (Lamontagne et al., 2000; Marsden et al., 2012; Roy et al., 2013). Appropriate anti-spastic treatment also requires that the different symptoms are adequately distinguished from each other, since for instance alterations in muscle properties are unlikely to respond to medication that diminishes the neural activation of the muscle (Alhusaini et al., 2011). The different symptoms may also contribute differently to the functional disability of the individual subject with CP. At present, the clinical evaluation of spasticity and the consequent therapeutic decision is usually based on a manual evaluation of muscle tone, presence of clonus and reflex hyper-excitability as part of the neurological examination. The quantification of 11 spasticity is mostly based on clinical scales derived from the neurological examination such as the Modified Ashworth Score (MAS) (Bohannon & Smith, 1987; Alhusaini et al., 2010b) or the Tardieu scale (Ansari et al., 2013). These tests have been shown to have varying reproducibility and reliability in a number of studies and there is growing consensus that more reliable and reproducible tests of spasticity are desirable in the clinic (Alibiglou et al., 2008; Alhusaini et al., 2010b; Lorentzen et al., 2010). For several decades, biomechanical methods using stationary dynamometers coupled with electrophysiological methods have been used in research to quantify spasticity and to some extent distinguish between reflex-mediated muscle stiffness and passive muscle stiffness in different patient groups (Dietz et al., 1981; Berger et al., 1982; Dietz & Berger, 1983; Toft et al., 1991; Sinkjaer et al., 1993; Knutsson et al., 1997; Mirbagheri et al., 2008; Willerslev-Olsen et al., 2013). In 1954 Tardieu and his co-workers introduced the concept of a spastic reaction produced by passive stretching in the article “A la recherce d’une technique de measure de la spasticite” (Haugh et al., 2006). They used EMG to determine the stretch reflex activity when the elbow was passively extended from 60-110o at a variety of velocities and thereby assess and compare the muscle response to passive movements (Haugh et al., 2006). Later, Knutsson and Martensson (1980) introduced a dynamometer which allowed assessment of spasticity in the quadriceps muscle. The dynamometer was supplied with a transducer to allow measurement of passive movements and EMG recordings were obtained to indicate the presence of muscle activations and stretch reflexes. However, they did not show how to objectively distinguish between the different components leading to increased resistance to passive movements. This was reported from Sinkjaer et al. (1988), who used torque measurements and synchronized EMG recordings to assess passive, intrinsic and reflex-mediated force increments to passive movement of the ankle joint in healthy subjects. The same method has been used on healthy subjects (Toft et al., 1989b; Toft et al., 1989c; Toft et al., 1991), spastic multiple sclerosis patients (Sinkjaer et al., 1993; Toft et al., 1993) and in hemiparetic stroke patients (Sinkjaer & Magnussen, 1994). Sinkjaer et al. (1993) showed that spastic muscles in multiple sclerosis patients had an increased non-reflex stiffness (passive muscle stiffness) and that the reflex-mediated stiffness during a sustained voluntary contraction did not differ significantly from healthy subjects. Mirbagheri et al. (2000) used a reliable and repeatable method for passive ankle joint movements; while measuring torque, position and EMG to identify intrinsic and reflex contributions to dynamic ankle joint stiffness in healthy subjects. They found that intrinsic stiffness dynamics were a linear pathway having elastic, viscous and inertial properties and a large variation in the velocity-sensitive pathway describing the reflex mediated stiffness dynamics with the largest relative contribution near the neutral position at low levels of voluntary activity (Mirbagheri et al., 2000). Lorentzen et al. (2010) and Willerslev-Olsen et al. (2013) used a method (used in study II, III and IV) similar to Sinkjaer et al. (1993) to quantify spasticity and distinguish between passive muscle stiffness and reflex mediated muscle stiffness in spastic patients with multiple sclerosis, stroke, spinal cord injuries and in children with CP. They obtained measures in 17 different semi-randomized velocities between 8-200 o/sec and concluded 12 that the clinical diagnosis of spasticity includes changes in both active and passive muscle properties and that the two hardly can be distinguished based on routine clinical evaluation. Both emphasized the importance of accurately distinguishing different contributors to pathologically increased muscle stiffness to avoid unnecessary antispasticity treatment (Lorentzen et al., 2010; Willerslev-Olsen et al., 2013). The stationary dynamometers distinguish passive muscle stiffness from reflex mediated stiffness, which is essential to determine how each component relates to functional impairments in subjects with CP and to measure the effect of a chosen treatment. However, the stationary dynamometers used in research are still not useful in a clinical context due to demands of highly specialized expertise, time consumption and economic issues. A number of hand-held devices were introduced in later years. They offer the possibility of measuring the resistance against passive movement of a joint (Boiteau et al., 1995; Malouin et al., 1997; Prochazka et al., 1997; Lamontagne et al., 1998; Lee et al., 2002; Pandyan et al., 2003; Lee et al., 2004; Chen et al., 2005; Benard et al., 2010; Lorentzen et al., 2012). These various handheld dynamometers have shown variable intra- and interrater variability and the methods appear generally to provide reliable measures of muscle stiffness (Benard et al., 2010; Lorentzen et al., 2012). However, none of these devices have been incorporated into an accepted routine clinical technique to objectively distinguish passive muscle stiffness from reflex mediated stiffness, and support the clinical decision-making where treatment is directed to reflex mediated stiffness and passive muscle stiffness accordingly. Reduced walking ability remains a fundamental challenge in subjects with CP. The importance of increased passive muscle stiffness for gait impairment in spastic subjects has been confirmed by several studies (Dietz et al., 1981; Berger et al., 1982; Dietz & Berger, 1983). The development of passive muscle stiffness and contractures in subjects with CP seems to be secondary to reduced neural drive and reduced muscle strength caused by inability to activate the muscles fully due to the primary lesion (Barrett & Lichtwark, 2010; Bland et al., 2011a; Moreau et al., 2011; Barrett & Barber, 2013). However, there is a lack of evidence to support training interventions to diminish passive muscle stiffness, increase ankle joint ROM and improve functional gait abilities in adults with CP. In summary, the combination of biomechanical and neurophysiological measures are useful to objectively quantify and distinguish between reflex mediated stiffness and passive muscle stiffness, which contributes to resistance against passive movements. This is a necessity, when in the clinic we should routinely identify how each component influences motor function in subjects with CP and evaluate the effect of given interventions. I have deliberately avoided using the term ‘spasticity’ further in this thesis, with a few exceptions when I refer to other journal authors who use the term. Instead, I use the more precise and clinical relevant terms ‘reflex mediated stiffness’ and ‘passive muscle stiffness’ to define the resistance to passive movements when the subject is at rest. 13 Objectives and outline of thesis The present Ph.D.-project was initiated to support the development of the Portable Spasticity Assessment Device (PSAD) and ensure a validation of the PSAD as a clinical relevant method for use in the evaluation of passive and reflex-mediated stiffness in subjects with CP. Furthermore, the aim was to use the method to determine how reflex mediated stiffness and passive muscle stiffness influences motor function in subjects diagnosed with spastic CP and investigate the effect of interventions on those impairments. However, the technical development of the device was delayed and therefore, we decided to alter the original Ph.D. plan for a baseline study and intervention study to investigate if passive muscle stiffness could be changed through explosive progressive resistance training. We used a stationary dynamometer combined with electromyography to evaluate passive stiffness in study II and III. Since the PSAD was ready for objective measures in autumn 2014, we decided to use it in a study to investigate the effect of treadmill training with an incline on passive muscle stiffness. Therefore, the PSAD was tested in study I and used to measure changes in study IV. The focus of this thesis is to contribute to the existing literature on the functional importance of the different components leading to pathological increased muscle stiffness and thereby elaborate on the clinical understanding of reflex mediated stiffness and passive muscle stiffness. To achieve this objective, an important contribution was to develop an objective clinical method to distinguish between passive and reflex mediated muscle stiffness and to investigate different methods to treat passive muscle stiffness as a major contributor to impairment in spastic subjects. In chapter 2 (Distinguishing passive and reflex mediated muscle stiffness in the spastic population) the background for the development of the PSAD is described and discussed in relation to the different contributors to muscle stiffness. The clinical relevance of the PSAD is elaborated in relation to other methods to objectively evaluate reflex mediated stiffness and passive muscle stiffness. Chapter 3 (Impaired gait function in adults with cerebral palsy is associated with reduced rapid force generation and increased muscle stiffness) compares baseline measurements of muscle stiffness, muscle strength and functional gait measurements between adults with cerebral palsy and neurologically healthy adults. Chapter 4 is an explorative study (Explosive resistance training increases RFD in ankle dorsiflexors and plantarflexors, and gait function in adults with cerebral palsy) which reports the effect of explosive resistance training three times per week for 12 weeks. This study explores specifically the effect of the intervention on RFD in ankle dorsiflexors and plantarflexors and correlates these measurements to changes in specific gait parameters and changes in passive muscle stiffness. Chapter 5 (Treadmill training with an incline reduces ankle joint stiffness, and improves range of movement during gait in adults with cerebral palsy) reports the effect of a randomized controlled trial where adults with CP were randomized to walk 30 minutes per day for 6 weeks on a treadmill 14 training with an incline. The study explores changes in the ankle joint muscle stiffness and changes in different functional gait parameters. Finally, chapter 6 is a general discussion where findings and methods are integrated and limitations presented. The implications of the scientific work of this thesis for clinical practice are synthesized and further research suggested. 15