Rehabilitation training in neural restitution

CHAPTER

Rehabilitation training in neural restitution

13

Susanne Clinch*,†, Monica Busse*,1, Mate D. D€obr€ossy{, Stephen B. Dunnett† *Centre for Trials Research, College of Biomedical & Life Sciences, Cardiff University, Cardiff, United Kingdom † Brain Repair Group, School of Biosciences, Cardiff University, Cardiff, United Kingdom { University Freiburg—Medical Centre, Freiburg, Germany 1 Corresponding author: Tel.: +44-2920687559, e-mail address: [email protected]

Abstract Over the last decade, neural transplantation has emerged as one of the more promising, albeit highly experimental, potential therapeutics in neurodegenerative disease. Preclinical studies in rat lesion models of Huntington’s disease (HD) and Parkinson’s disease (PD) have shown that transplanted precursor neuronal tissue from a fetus into the lesioned striatum can survive, integrate, and reconnect circuitry. Importantly, specific training on behavioral tasks that target striatal function is required to encourage functional integration of the graft to the host tissue. Indeed, “learning to use the graft” is a concept recently adopted in preclinical studies to account for unpredicted profiles of recovery posttransplantation and is an emerging strategy for improving graft functionality. Clinical transplant studies in HD and PD have resulted in mixed outcomes. Small sample sizes and nonstandardized experimental procedures from trial to trial may explain some of this variability. However, it is becoming increasingly apparent that simply replacing the lost neurons may not be sufficient to ensure the optimal graft effects. The knowledge gained from preclinical grafting and training studies suggests that lifestyle factors, including physical activity and specific cognitive and/or motor training, may be required to drive the functional integration of grafted cells and to facilitate the development of compensatory neural networks. The clear implications of preclinical studies are that physical activity and cognitive training strategies are likely to be crucial components of clinical cell replacement therapies in the future. In this chapter, we evaluate the role of general activity in mediating the physical ability of cells to survive, sprout, and extend processes following transplantation in the adult mammalian brain, and we consider the impact of general and specific activity at the behavioral level on functional integration at the cellular and physiological level. We then highlight specific research questions related to timing, intensity, and specificity of training in preclinical models and synthesize the current state of knowledge in clinical populations to inform the development of a strategy for neural transplantation rehabilitation training.

Progress in Brain Research, Volume 230, ISSN 0079-6123, http://dx.doi.org/10.1016/bs.pbr.2016.12.006 © 2017 Elsevier B.V. All rights reserved.

305

306

CHAPTER 13 Rehabilitation training in neural restitution

Keywords Activity, Environmental enrichment, Physical training, Cognitive training, Learning to use the graft

1 INTRODUCTION Neural transplantation offers a promising avenue for novel therapeutics in neurodegenerative disease, including Parkinson’s Disease (PD) (Kordower and Olanow, 2016) and Huntington’s Disease (HD) (Dunnett and Rosser, 2007; Rosser and Bachoud-Levi, 2012). Whereas a range of therapeutic drugs are available to alleviate some of the symptoms in both diseases, present treatments are essentially symptomatic; so there remains an imperative clinical need for alternative strategies to modify (and ideally reverse) disease progression and to repair established neuronal cell loss and circuit damage. Cell transplantation has become established as an effective experimental strategy to replace neurons lost through damage or disease in the brain. There is now extensive evidence in multiple model systems that early neurons or neuronal precursors (whether taken from the developing embryo or generated in vitro from pluripotent stem cell sources) can survive transplantation into the adult nervous system, mature into appropriate adult phenotypes, integrate into host neuronal circuitry, and function at physiological and functional levels (Dunnett and Bj€ orklund, 1994, 2000, 2012; also see chapter “Mechanisms and use of neural transplants for brain repair” by Dunnett and Bj€orklund). In HD, the most abundant cells in the striatum, namely, the medium spiny projection neurons, are the principal cell loss in early stages of the disease and have emerged as the primary target for cell replacement. The striatum is the largest component of the basal ganglia with projections to and from multiple brain regions. In HD, ongoing degeneration in this region may also trigger neurodegeneration seen in deep layers of the cerebral cortex, the globus pallidus, thalamus, subthalamic nucleus, substantia nigra, and cerebellum (Hadzi et al., 2012). These widespread changes are responsible for the motor, cognitive, and behavioral abnormalities associated with HD, which progressively worsen over time, severely impacting patient quality of life (QOL). For “striatal” transplantation, in both lesion-based and genetic animal models of HD, immature striatal neurons and their precursors are dissected from the whole ganglionic eminence (WGE) of donor embryos, prepared as a dissociated cell suspension, and transplanted by stereotaxic injection into the striatum of recipient animals (Schmidt et al., 1981). In rats, mice, and monkeys, WGE grafts develop a patchy organization comprising zones rich in striatal-like neurons (including the predominant medium spiny projection neurons and all striatal interneuron subtypes) interspersed by zones of other neuronal populations that originate from the ganglionic eminence (including cells expressing cortical and pallidal cell types) (Graybiel

2 The role of general activity in mediating the physical ability of cells

et al., 1989). Importantly, the striatal-like neurons within the grafts establish essential afferent and efferent anatomical connections with the host brain (Chin et al., 1999; Wictorin, 1992), restore synaptic circuitry (Clarke and Dunnett, 1993), exhibit appropriate physiological activity, and can alleviate a broad range of motor and cognitive symptoms associated with the model lesions (for review, see Dunnett et al., 2000; Kendall et al., 2000). Following a broad range of experimental studies, there is now clear proof of principle that similar grafts can survive in patients (Bachoud-Levi et al., 2000; Freeman et al., 2000), along with preliminary evidence that neural transplantation may provide functional benefit in some patients, lasting for up to 6 years (Bachoud-Levi et al., 2000; Rosser and Bachoud-Levi, 2012). However, such reports are still extremely limited and convincing sustained benefit is yet to be demonstrated. Important questions, not least related to optimum donor tissue conditions and host characteristics need to be addressed if reliable benefit is to be achieved in transplant recipients (Dunnett and Rosser, 2014; Freeman et al., 2011). One critical factor that has been largely neglected until recently has been the role of rehabilitation in achieving effective recovery. For many years the emphasis has been on selecting the right cells and getting them to survive and grow, with the assumption that recovery would follow automatically from effective structural repair. More recently, we have a growing realization not only that rehabilitation and physical therapies can enhance compensation and recovery in general, but also that the training and behavioral experience of the host alter the integration, connectivity, and function of the grafted tissues at cellular and circuit levels. Specifically, a wealth of preclinical research has highlighted the need for striatal-specific behavioral training to allow the recipient to “learn to use the graft” so as to promote neurogenesis, synaptogenesis, graft integration, and functionality. Repair and recovery are not one-way causation, but in dynamic interaction. Consequently, we need to understand and develop compensation strategies to better optimize transplantation efficacy in the clinic. Our refocus on the role of rehabilitation has been most developed in studies of striatal transplantation in animals and of exercise, training, and recovery in HD patients, so experimental and clinical studies in HD will constitute our principal discussion in this review. Nevertheless, the discoveries in this particular disease will have clear implications for other reparative strategies and other disease applications also.

2 THE ROLE OF GENERAL ACTIVITY IN MEDIATING THE PHYSICAL ABILITY OF CELLS TO SURVIVE, SPROUT, AND EXTEND PROCESSES Hebb first documented the link between behavioral changes and the environment nearly 60 years ago when he observed that rats taken home as pets with stimulated environmental surroundings had improved behaviors compared to littermates that remained in a basic laboratory setting (Hebb, 1947). These results contributed to

307

308

CHAPTER 13 Rehabilitation training in neural restitution

the development of his theory that synaptic changes respond following repeated neuronal activations (Hebb, 1949). The seminal discovery (in 1965) that neurons continued to increase in discrete regions of the brain (Altman and Das, 1965) challenged the widely believed assumption that neurons in the brain had no regenerative capacity. The outgrowth of new neuronal processes coupled with synapse formation facilitates learning and memory throughout life is now generally accepted. The remarkable specificity of neurons to branch and form new synapses is dependent upon the process of learning and memory. A tightly regulated series of events occur not only during development but also throughout the course of life, as we interact with new environments or following acute brain injury. Following axonal injury, postmitotic neurones of the CNS do not typically grow back to distant targets. However, there seems to be a previously underestimated endogenous capacity, driven by experience, disease, or brain trauma that promotes reorganization. This is manifested in collateral sprouting, synaptogenesis, neurogenesis, or more substantial structural changes seen in gray or white matter alterations (Bonfanti and Peretto, 2011; Draganski and May, 2008; Draganski et al., 2006; J€ancke, 2009; May, 2011). Furthermore, (rehabilitative) training has also been shown to promote the survival of newly born neurones during a crucial time window postlearning (Curlik et al., 2013; D€ obr€ ossy et al., 2003; Shors, 2014; Shors et al., 2012). “Environmental enrichment” (EE) does not have a precise consensual definition (Toth et al., 2011). The term generally refers to housing conditions that go beyond meeting the fundamental requirements of animal welfare by offering complex and stimulating conditions that are more conducive to natural behavior, play, motor activity, and new learning than animals encounter in the relatively impoverished, standard cages (Bennett et al., 1978). In an experimental setting, enriched housing is generally more complex compared to standard laboratory cages with the addition and regular changing of toys, tunnels, running wheels, nesting material, as well as bigger cages and larger group sizes permitting more frequent and varied social interactions. Contrary to EE, exercise and training are factors that can be relatively well defined and quantified. In an experimental context, the terms refer to activities that result in increased motor output due either to (a) acquisition and continuous training on a task with a significant motor element or to (b) performance on a spontaneous task without a learning aspect that nevertheless results in increased locomotor activity. The term “plasticity” refers to structural and functional adjustments occurring at multiple levels of organization from molecular to behavior changes of the whole organism in the adult brain, in response to changes in the external or internal milieu. Numerous studies have evaluated the influence of EE on brain plasticity in health and disease, establishing the therapeutic potential of the former (Hannan, 2014) and, specifically, with the clear suggestion that EE may counteract deficits in synaptic plasticity known to present in HD. For example, transgenic R6/1 and R6/2 mouse models of HD show delays in the onset of motor and cognitive deficits when provided with enriched objects of varying size and texture, as well as delays in cerebral volume loss (Hockly et al., 2002; Nithianantharajah and Hannan, 2006; van Dellen and Hannan,

3 Training and exercise influence graft development and recovery

2004; van Dellen et al., 2000). In this review, we are, however, particularly interested in external parameters that impact on the morphology, anatomical connections, and functions of transplanted embryonic striatal cells (D€obr€ossy and Dunnett, 2001).

3 TRAINING AND EXERCISE INFLUENCE GRAFT DEVELOPMENT AND RECOVERY The first studies looking at the possibility of modifying graft function with training came from Lund, Coffey, and colleagues when they demonstrated that retinal tissue grafted into the tectum of an enucleated rat can integrate anatomically with the host and reinstate pupillary reflex when the graft was directly exposed to light (Klassen and Lund, 1987). Mayer et al. (1992), followed by others (Brasted et al., 1999a,b, 2000), using the unilateral excitotoxic striatal lesion and embryonic striatal transplant model of HD, introduced the therapeutic strategy referred to as “learning to use the graft”: the training-associated, gradual, graft-mediated functional recovery dependent on specific and targeted retraining, and not “simply” on survival and spontaneous anatomical integration. Specifically, when rats are pretrained over 6 weeks to reach asymptotic level of accuracy on a complex motor discrimination, performance is completely lost following striatal lesions. Rats bearing a striatal transplant perform as badly as lesioned animals when first retested, but they can relearn the discrimination over a similar 6-week time course to a similar level of performance as the controls, whereas lesion rats can never relearn the skill (Brasted et al., 1999a,b, 2000; Mayer et al., 1992). Since the striatum is believed to constitute the neural substrate for learning motor skills and habits (Mishkin et al., 1984; White, 1997), these results then suggest that the grafted striatal cells can replace the lost striatum as a substrate for motor learning, but that once the substrate circuitry is replaced, they still have to relearn de novo the motor skill that is lost to the lesion. These studies were the first to introduce the idea that focussing the training on the impaired (due to experimental lesion) and then repaired limb (via striatal grafts) not only optimizes recovery and functional integration of the grafted neurons but also replaces the essential neural substrate for the de novo reacquisition of the “lost” behavior. Similar to “constraint-induced therapy” as described in the clinical stroke literature (Taub and Uswatte, 2006), “forced-choice” training of the limb controlled by the lesioned/grafted striatum maximizes the limits of graft-associated recovery (D€ obr€ ossy and Dunnett, 2005b). Variability in the outcome of transplantation is an important issue, and the level of graft-mediated recovery can be diverse. Certain physical properties of the striatal grafts, such as their volume, placement, and proportion of DARPP-32-positive striatal-like tissue, have been described to have direct functional relevance (D€ obr€ ossy and Dunnett, 2005a; Fricker et al., 1997a). Nevertheless, it is conceivable that graft function is not solely predicted by graft components, survival, or level of integration. For example, baseline spontaneous forelimb preference for pellet retrieval (or “handedness”) had no direct predictive value with respect to the eventual

309

310

CHAPTER 13 Rehabilitation training in neural restitution

level of graft-mediated recovery in the motor task (D€obr€ossy and Dunnett, 2006). Nevertheless, grafted animals receiving extensive training in the use of the contralateral limb were seen to be more responsive in countering the tendency toward increased ipsilateral bias. Such data further support previous findings that graft-mediated recovery is both experience and use dependent.

4 ENVIRONMENT-MEDIATED MORPHOLOGICAL IMPACT ON STRIATAL GRAFTS Morphological features of embryonic grafts have been shown to be influenced by environmental complexity following transplantation, and indices of plasticity, including dendritic spine densities and cell volumes of the grafted neurons, have been evaluated (D€ obr€ ossy and Dunnett, 2005a,b, 2008). Dendritic spines are specialized structures located on dendrites interfacing with excitatory presynaptic terminals. Both the morphology and the number of spines on a dendrite are thought to reflect the level of synaptic activity of that particular pathway, and context-dependent changes in spine density have been examined in diverse brain structures (Glantz and Lewis, 2000; Kolb et al., 2003; Leggio et al., 2005) including the striatum (Comery et al., 1995, 1996; Deutch et al., 2007; Solis et al., 2007). In the experimental HD grafting models, the data have consistently shown a significant increase in spine density of the grafted neurones in animals housed in EE compared to grafted animals kept in standard cages (D€obr€ossy and Dunnett, 2004, 2008). The results indicate that the grafted striatal neurones retain the capacity for formation, elimination, motility, and stability of dendritic spines (Lippman and Dunaevsky, 2005; Tada and Sheng, 2006; Yoshihara et al., 2009). There is also indirect evidence that excitatory inputs—which previous studies suggest to be glutamatergic afferents from the cortex (Wictorin et al., 1989)—along with the presence of AMPA and NMDA receptors on grafted striatal neurons, underpin the downstream signals inducing morphological changes within the grafts (Tada and Sheng, 2006).

5 IMPORTANCE OF DURATION AND FREQUENCY OF EXPOSURE TO ENRICHED ENVIRONMENT The interaction of parameters such as housing conditions, duration of exposure, and length of time the graft remained in situ is likely to influence the nature of graft plasticity following enrichment. Graft survival time (7 vs 13 weeks) and the differential housing conditions (standard vs EE 1 h/d vs EE/24 h/d) influenced the morphological development of striatal-like neurons within striatal transplants (D€ obr€ ossy and Dunnett, 2008). Importantly, the factors acted either independently (e.g., on graft size), complementarily (e.g., on spine density), or had no distinctive effect (e.g., on lesion size), on graft development. Animals in full-time EE had the

6 Electrophysiological plasticity of graft–host integration

largest grafts, independent of survival time, and both full-time and 1-h daily EE exposure resulted in an increased spine density compared with grafted animals in the standard cages. Furthermore, longer graft survival times resulted in increased spine density compared to shorter survival and correlated with higher brain-derived neurotrophic factor (BDNF) levels in both the striatum and the hippocampus. Within the striatum itself, BDNF levels were superior on the grafted side compared to the intact side. The presence of TrkB receptors on grafted striatal neurones supports the potential for BDNF to provide an effective stimulus for the downstream mechanisms associated with the adaptive changes observed in neurons (Yoshii and Constantine-Paton, 2010).

6 ELECTROPHYSIOLOGICAL PLASTICITY OF GRAFT–HOST INTEGRATION Preclinical data are strong concerning graft-mediated behavioral recovery and graft–host anatomical integration. However, little is known about their physiological integration and if striatal grafts retain the molecular and cellular mechanisms required to act as the neural substrate for relearning of lost functions. In a series of experiments, Mazzocchi-Jones and colleagues used an electrophysiological setup with rat brain slices containing striatal grafts to determine the level of physiological integration between the host and the transplant. Specifically, Calabresi and colleagues have developed an oblique corticostriatal slice model to demonstrate the presence of long-term plasticity at the corticostriatal synapse, as a plausible cellular model for the striatal substrates from motor learning observed at the behavioral level (Calabresi et al., 1997). In particular, long-term plasticity at the corticostriatal synapse is exhibited as long-term depression (LTD) or long-term potentiation (LTP) dependent on the presence or absence of Mg2+ in the culture medium. Whereas striatal lesions abolish all corticostriatal transmission, Mazzocchi-Jones et al. (2009, 2011) showed a restitution of both LTP and LTD at the synaptic connection between host cortical afferents and medium spiny neurons within the grafts, and with exactly the same parameters and sensitivity to pharmacological modulation as observed in the intact corticostriatal circuitry (see Fig. 1). Consequently, they concluded that striatal grafts exhibit the synaptic plasticity at a cellular level thought to correspond to the restitution of motor learning at a behavioral level—the grafted cells thus truly provide a replacement substrate for the relearning of new skills and habits lost to the lesion—true “brain repair”—over and above a simple reactivation of a capacity to relearn. This initial study elegantly supported the idea: (i) that the grafted embryonic striatal neurons reconnect with the host brain both anatomically and physiologically; (ii) that grafted striatal neurones have similar physiological capacities akin to endogenous striatal neurones to establish synaptic contacts with the host circuitry which can conduct neuronal transmission; and, most importantly, (iii) that the embryonic striatal graft neurons can provide the neural substrate for associative

311

312

CHAPTER 13 Rehabilitation training in neural restitution

FIG. 1 The corticostriatal “in vitro” graft preparation and the effect of enriched environment on synaptic plasticity within the grafted striatum. (A) Schematic representation of electrode positions within the striatal graft in vitro slice preparation. (B) Photomicrograph demonstrating the endogenous GFP fluorescence of the transplanted tissue within the striatum. The effect of environmental enrichment on synaptic plasticity within the grafted striatum. (C) Input/output curve generated during enriched and standard recordings (bold line, standard recording; dashed line, enriched recording). (D) Expression of LTD in standard graft and enriched graft recordings. (E) Expression of LTP in standard graft and enriched graft recordings. CC, corpus callosum; CTX, cortex; ENR, enriched housing; fEPSP, field excitatory postsynaptic potential; HFS, high-frequency stimulation; LTD, long-term depression; LTP, long-term potentiation; STD, standard housing; STR, striatum. Adapted from Mazzocchi et al. (2009, 2011), with permission.

plasticity at the reformed host–graft corticostriatal synapses thought to underlie the restoration of motor learning at the behavioral level. Furthermore, they found these utilized similar neural processes (LTD and LTP) that are employed within the neuronal circuitry of the intact striatum (Fig. 1A–E). The results indicate that striatal grafts retain the physiological plasticity of a type, which, at the synaptic level, is required to enable new learning, and thereby provide direct evidence of functional neuronal circuit repair. In a follow-up study, we have looked at these mechanisms of plasticity in the context of BDNF. BDNF has been implicated in HD etiology (Zuccato and

7 Do the experimental data have clinical relevance?

Cattaneo, 2007; Zuccato et al., 2001, 2011), striatal neuronal survival (Ventimiglia et al., 1995), striatal differentiation (Mizuno et al., 1994), synaptic function (Alonso et al., 2005), and responsiveness to both exercise (Vaynman and Gomez-Pinilla, 2005) and EE (D€ obr€ ossy and Dunnett, 2004, 2008). Similar to the previous findings, Mazzocchi-Jones and colleagues recorded LTD and LTP from brain slices containing grafted striatal neurons following high-frequency stimulation of host cortical afferents. Interestingly, however, LTP evoked from the graft region of animals housed in EE was of a higher magnitude than those housed in standard environments. Furthermore, there was a higher chance of induction of LTP in “enriched” grafts, compared to standard-housed controls. Interestingly, facilitation of LTP was not observed in the endogenous striatum even among the enriched animals, suggesting that embryonic striatal grafts retain the plasticity and the capacity to react to environmental cues with greater likelihood than more mature endogenous medial spiny striatal neurones. Importantly, BDNF levels under EE were significantly higher in the striatum and other regions examined. The study confirmed that enrichment can increase the chance of induction, as well as the level of LTP expressed in striatal grafts, and that BDNF is a potential candidate molecule that facilitates the graft–host functional integration.

7 DO THE EXPERIMENTAL DATA HAVE CLINICAL RELEVANCE? There is ample experimental evidence that both the environmental context and specifically designed training protocols have the potential to modify the functional plasticity of striatal transplants. Equally, the literature is supportive that scientifically based neurorehabilitative approaches can limit the deficit and optimize the functional recovery following brain damage or neurodegeneration, e.g., in patients with HD (Busse and Rosser, 2007; Dobkin, 2004; Quinn et al., 2010; Robertson and Murre, 1999; Seel and Cifu, 2005; Taub et al., 2002; Warraich and Kleim, 2010; Zinzi et al., 2007). However, whether targeted posttransplantation care in conjunction with neurorehabilitation can improve functional outcome for the patient has not yet been critically assessed in patients with neurodegenerative diseases (D€ obr€ ossy et al., 2010). Two clinical studies with cell therapy have been undertaken in subcortical motor stroke (Kondziolka et al., 2005) and spinal cord injury (Lima et al., 2010). Although there are good biological arguments that the experimental findings would be transferable to the clinical arena, neither of these previous studies demonstrated that graft-mediated functional recovery could be modulated posttransplantation. Thus, in practical terms, the difficulties of converting the concept of “enriched environment” or “learning to use the graft” into the clinic need to be acknowledged (Dobkin, 2004, 2007). Currently the main issue is the inability to precisely control the patient’s exercise and environmental parameters, as is the case in the preclinical investigations (D€ obr€ ossy et al., 2010).

313

314

CHAPTER 13 Rehabilitation training in neural restitution

8 CURRENT STATE OF KNOWLEDGE IN CLINICAL POPULATIONS The between-subject variability in disease onset and progression of HD attributed to genetic and lifestyle factors creates a challenge in designing robust clinical trials of cell transplantation (Wijeyekoon and Barker, 2011). In HD, WGE is transplanted into the striatum to replace degenerating medium spiny neurons, with the expectation of reestablishing degenerated anatomical circuitry over time. Typically participants return 6–12 months postsurgery and are assessed on a wide range of outcome measures including neuroimaging (Bachoud-Levi et al., 2000; Hauser et al., 2002; Kopyov et al., 1998; Rosser et al., 2002) as a way of tracking and assessing early functional improvements as a sign of graft integration and circuit reconstruction. The minimum follow-up time to allow the graft to mature to the point of exhibiting functional signs that can be attributable to grafted connections is estimated as 12–24 months (Rosser and Bachoud-Levi, 2012), and studies in PD patients have exhibited ongoing improvements over at least 18 years (Kefalopoulou et al., 2014). This is significantly longer than rodent WGE maturation, which was reported as little as 3 weeks posttransplantation (Wictorin, 1992), but certainly does not reach asymptote until 10–14 months posttransplantation (Fricker et al., 1997b). In the first French clinical trial, improvement was detected at 18 months and gradually increased until 4 years posttransplantation (Bachoud-Levi et al., 2006). In the light of clear evidence of the role of EE in preclinical populations (Harrison et al., 2013; Laviola et al., 2008; Nithianantharajah and Hannan, 2006; Spires and Hannan, 2005; van Dellen et al., 2000), alongside knowledge of the role of training in graft integration (D€ obr€ ossy and Dunnett, 2005a), it is somewhat surprising that there has been, as yet, little attempt to evaluate a potential role for physical activity or lifestyle factors in any clinical trial to date (Rosser and Bachoud-Levi, 2012; Wijeyekoon and Barker, 2011).

8.1 CLINICAL OUTCOME MEASURES Well-designed, sensitive outcome measures and clinical tools are required to track graft function alongside changes in disease status. Selecting the most sensitive outcome measures to best match the hypothesis of any study is fundamental. Furthermore, outcome measures are particularly important when validating and developing new interventions. In transplantation trials, it is critical not only to assess graft integration but also to include outcome measures representative of a variety of domains in relation to function. Brain imaging is routinely used to assess graft placement, graft volume, and quantify morphological and metabolic changes over a set period. This includes techniques such as magnetic resonance imaging (MRI), positron emission tomography (PET), and single-photon emission CT (SPECT) (Quinn et al., 1996; Rosser and Bachoud-Levi, 2012). Although neuroimaging is beneficial to demonstrate graft survival, graft placement, and elements of function, it is however

8 Current state of knowledge in clinical populations

not an informative method to determine neuronal type (proportion of striatal to nonstriatal neurons) or the functional impact of the graft on behavior. Furthermore, it is not an appropriate tool to track performance-based improvement or stabilization over time. The lack of validated clinical outcome measures to assess graft functionality in relation to general function is a critical concern. In particular, disease-specific, quantitative outcome measures are required to understand the extent to which the transplant may have had an impact on independent physical constructs required to perform daily life activities, while also giving an understanding on how this may have affected QOL. The Core Assessment Protocol for Intrastriatal Transplantation in Huntington’s disease (CAPIT-HD) includes a wide range of assessments used to measure any behavioral changes in disease state posttransplantation (Quinn et al., 1996). This was originally developed as a group of assessments covering motor, cognitive, psychiatric function, functional performance, as well as neuropsychological and neuropsychiatric tests, MRI and PET imaging. Although the development of CAPIT-HD represented the standard baseline of current knowledge, there is now greater emphasis on quantitative assessments as opposed to subjective tests rated on an ordinal scale. Ordinal and categorical scales are used for many of the commonly used outcome measures for HD including the Berg Balance Scale (Berg et al., 1992), the Tinetti Mobility Test (Tinetti et al., 1986), the Physical Performance Test (Reuben and Siu, 1990), and the Mini-Balance Evaluation System Test (Leddy et al., 2011). Each of these tests was originally developed for other patient populations, such as stroke or the elderly, so that many of the items are not relevant to, nor reflect, the symptoms of most importance to HD patients and their families, resulting in floor and ceiling effects in the test measures (Busse et al., 2014). In addition, the fact that these tests utilize ordinal ratings increases the objectivity and reliability of the measures and makes it difficult to undertake parametric analyses required to evaluate interactions and to track quantitative change over time. Currently, the gold standard assessment used to determine disease stage in people with HD is the Unified Huntington’s Disease Rating Scale (UHDRS; Huntington’s Study Group, 1996). The UHDRS comprises six broad assessments, including disease-specific self-evaluation questionnaires and clinically rated assessments. The scales were originally developed to provide a core assessment tool to monitor disease progression and impairment in HD and now the UHDRS-total motor score is the most commonly used outcome measure for this population (Bilney et al., 2003). Although it is designed specifically for the core symptoms associated with HD, both intra- and interrater variability as well as the ordinal scaling limit both the objectivity and sensitivity for tracking change over time (Reilmann et al., 2011). Furthermore, since individual UHDRS items do not directly test known striatal functions, using UHDRS assessment(s) as primary outcome measures in a transplantation trial risks rating functions reliant on compensatory neural networks that bypass the striatum, rather than testing directly the influence of the transplanted tissues on their primary target, the striatal circuitry itself.

315

316

CHAPTER 13 Rehabilitation training in neural restitution

8.2 DEVELOPING NOVEL MEASURES FOR CELL TRANSPLANTATION The ultimate aim of cell replacement therapy is to improve QOL. QOL generally deteriorates as HD progresses and is associated with perceived losses of work, general daily function, social activities, and normal family life (Dawson et al., 2004). Thus, if age of onset can be delayed, or symptoms stabilized or slowed through therapeutic interventions, this will also have a positive impact on QOL. As previously described in preclinical models of HD, EE and lifestyle factors can also determine age of onset in people with HD (Wexler et al., 2004). This highlights the importance in understanding general activity levels and daily life activity from one individual waiting to receive cell replacement therapy to the next. One way of achieving this is for the patient to complete a daily diary for a number of weeks prior to and postsurgery. Level of activity could then be determined and a standard rehabilitation program adapted to personalize the intervention for that individual. This would also help clinicians monitor and control for physical exercise that a patient has done following transplantation and correlate this with graft morphology and function obtained from the neuroimaging. Our preclinical knowledge for HD also indicates that training known to depend on the function of the striatum is required for optimal graft functionality. Therefore it is fundamental that rehabilitation programs also include training strategies known to involve striatal function. This will ensure that general activity recommended in the programs does not strengthen alternative circuitry, bypassing the striatum and leaving the graft redundant. Although completing diaries and questionnaires will give clinicians and researchers an idea of day-to-day activity levels, people with HD can lack awareness when referring to the extent of their cognitive and motor symptoms in self-reported questionnaires (Sitek et al., 2013; Vitale et al., 2001). Therefore, although these will be informative, performance-based, quantitative outcome measures that are quick to assess are also required to accurately rate an individual’s functional ability and QOL. Furthermore, the limited space in clinical assessment suites can add important practical considerations when developing suitable outcome measures. An ideal outcome measure should reflect the range of improvements that may be attributed to the graft function when performing activities of daily living (ADL). Many complex and high-level ADL tasks require the ability to carry out multiple tasks at the same time (i.e., “dual-” or “triple-tasking”). This requires various levels of attention depending on the complexity and type of tasks (motor and/or cognitive) to be performed, as well as a capacity to shift attention efficiently from one task to another, in order to prioritize behaviors appropriately. An inability to do this can result in performance deterioration in one or both tasks carried out and may be dangerous under certain conditions. A recent study examined the relationship between dual tasking and risk of falling in people with HD and found a correlation between the number of falls reported in the last 3 months and the motor–cognitive dual task (walking while talking) (Fritz et al., 2016). Participants tended to either prioritize gait or show mutual interference with both gait and the cognitive task.

8 Current state of knowledge in clinical populations

The ability to automate tasks such as walking or balance deteriorates as HD progresses, so “simple” automated tasks may become increasingly demanding on attentional capacity (Yogev-Seligmann et al., 2008), as evident when people with HD are asked to walk while either counting backward or carrying a tray (Delval et al., 2008b). Results showed that walking is more affected when the secondary task is cognitive (counting backward) than when it is motor (carrying four glasses on a tray), suggesting that cognitively demanding tasks may require more attentional processes than motor–motor dual tasks. Additional studies have confirmed that people with HD have limited attentional resources when presented with a dual-task scenario (Delval et al., 2008a,b; Fritz et al., 2016; Vaportzis et al., 2015). The basal ganglia are not typically implicated in automatic movements (Wu et al., 2004), rather they are involved in both goal-directed and habitual behavior (Yin et al., 2004). It is however likely that this region may mediate the shift from learned behavior to more automatic movement (Yogev-Seligmann et al., 2008), gradually easing the ability to perform multiple tasks concurrently if this involves a regularly performed motor/ cognitive task, such as walking. Furthermore, degeneration of corticofrontal circuitry as HD progresses may exacerbate secondary task performance that requires a cognitive input. Importantly, in the context of cell transplantation in HD, the combination of motor–cognitive tasks may be valuable when assessing graft functionality over time. The combination of the voluntary and involuntary symptoms associated with HD means that HD patients are generally impaired when carrying tasks that require accurate and fine-tuned movement required for upper limb dexterity. This ultimately impacts on daily activities such as eating (Klein et al., 2011). In order to develop a quantitative test of multitask performance more sensitive to HD progression, we have developed the Clinch Token Transfer Test (C3T). The C3T provides an objective quantitative assessment of performance sensitive to progression in basal ganglia disease, designed for use as a powerful new outcome measure for clinical trial use (unpublished data; see Fig. 2A and B). It is a multitask grasping and dexterity assessment that comprises three stages with increasing task difficulty and directly relates to upper limb function required for performance of common daily tasks. Participants are required to pick up and transfer tokens of varying size between hands before releasing them into a moneybox as quickly as they can for the baseline task. The harder stages require participants to transfer tokens in order of value with and without reciting the alphabet. Performance of the C3T tasks requires efficient information processing within the frontostriatal circuits of the brain. Optimal C3T performance involves multiple functional components, including attention, motor coordination, fine motor dexterity, oculomotor function, working memory, and goal-directed behavior. Furthermore, in the triple task stage of testing, the subject is required to simultaneously recite the alphabet which for many would be a fairly automatic recitation (Ashby et al., 2010; Turner and Desmurget, 2010), adding another cognitive component to the dual task and loading extra stress to the frontostriatal circuitry. The C3T is assessed using time as a primary measure, combined with the number of errors committed, to generate an overall C3T total score. An optional

317

CHAPTER 13 Rehabilitation training in neural restitution

A

B 1.0

Performance

318

0.8

*** *** *

0.6

**

** ** **

** *** **

** *

0.4

Controls Stage 1 Stage 2 Stages 3 and 4

0.2

0.0

Baseline

Dual task

Triple task

FIG. 2 (A) Tasks required during performance of the C3T. Participants are asked to pick up the token with their nondominant hand, transfer to their dominant hand, and release it into the moneybox. Participants wear accelerometers on each wrist and their chest to quantify involuntary movement and movement signatures throughout the test. (B) Preliminary data highlighting the C3T score based on disease stage where a higher score is indicative of better performance. Values show means  standard error of the mean (SEM); *P < 0.05; **P < 0.01; ***P < 0.001.

component is to ask the subject to wear accelerometers on the wrists while performing the C3T. Individuals with early HD display subtle impairments, which would typically be undetectable using current clinical measures. However, they do reflect underlying disease processes and structural changes in the brain, which are highly important to capture in longitudinal studies, before and after an intervention. Preliminary data (Fig. 2B) have shown that C3T total scores can clearly distinguish between stage of disease, while also significantly correlating with gold standard measures such as the UHDRS-total motor score and total functional capacity (unpublished data). Current work is underway to characterize accelerometer data during C3T performance, as a source of movement signatures allowing classification of the

9 Rehabilitation training strategies for neural transplantation

successive core stages of HD. Although a greater sample size is required to validate the largely diverse HD population, the C3T is emerging as a novel, accurate, objective measure with heightened validity to track longitudinally the core behavioral symptoms of progressive HD, and with potential applicability to other frontostriatal neurological disorders also.

9 REHABILITATION TRAINING STRATEGIES FOR NEURAL TRANSPLANTATION With the emerging evidence of functional benefit to be achieved from physical training and the increasing acceptance that exercise has a positive influence on brain function and health (Cotman and Berchtold, 2002; Cotman et al., 2007), it is highly likely that physical activity and cognitive training strategies will be crucial enablers in regenerative therapies moving forward. Classically, regenerative medicine, patient rehabilitation, and care plans exist in parallel, despite the common goal of improving functional outcome. The emerging view is that regenerative rehabilitation should be multidisciplinary. This will require a collaborative effort from the onset of therapeutic development in order to progress toward the availability of an effective therapeutic intervention (Ambrosio and Russell, 2010). Based on the knowledge that general activity and specific training may achieve somewhat different effects in relation to graft morphology and circuit reconstruction, it is also likely that enhancing general activity, engaging in directed aerobic exercise, and task-specific training will all be important components in any effective postsurgical transplant rehabilitation program. The differential effects of goal-based and aerobic exercise have been extensively considered in through both animal model data and clinical literature in PD (Fig. 3; Petzinger et al., 2013). There is clear evidence that the strengthened circuitry that is achieved through a combination of these modalities leads to improved motor and cognitive function, mood, and motivation. Importantly, these different modalities appear to operate via complementary mechanisms. Increased synaptic strength and dendritic spine formation are achieved through goal-directed practice aligned with motor learning principles. A healthier brain environment as the substrate for graft survival, growth, and integration is associated with the benefits of aerobic exercise including increased blood flow, neurogenesis and metabolism, and improved immune system function. Taken together, it would seem logical that the modality of exercise is critical for optimal benefits. Arguably, to date, trials of physical interventions in HD have surpassed pharmacological interventions in achieving functional benefit. Indeed, numerous small-scale studies conducted over the last decade have delivered varied programs of aerobic, endurance and strength training, task-specific training and multidisciplinary activities across inpatient (Ciancarelli et al., 2013; Piira et al., 2013; Zinzi et al., 2007), outpatient (Thompson et al., 2013), and home and

319

320

CHAPTER 13 Rehabilitation training in neural restitution

FIG. 3 Differential effects of exercise modalities in facilitating improved motor cognition and mood in PD. Reproduced with permission from Petzinger, G.M., Fisher, B.E., McEwen, S., Beeler, J.A., Walsh, J.P., Jakowec, M.W., 2013. Exercise-enhanced neuroplasticity targeting motor and cognitive circuitry in Parkinson’s disease. Lancet. Neurol. 12, 716–726.

community settings (Busse et al., 2013; Khalil et al., 2013; Kloos et al., 2013; Quinn et al., 2016b). While there remains a need for the development of rigorous intervention and evaluation protocols in order to fully realize the exciting potential for exercise therapies, both for symptom management and for disease modification in HD, the balance of evidence provided by these studies suggests very clearly that physical activity and multidisciplinary interventions have an important role to play in regenerative rehabilitation. Exactly how this evidence transfers to clinical application in HD cell transplantation studies remains to be established, but critical to this concept is the need to ensure sufficient intensity of practice and exercise to achieve an aerobic effect. A recently completed trial of aerobic and multimodal exercise has provided an initial indication of the likely composition of an effective approach (Quinn et al., 2016a). Thirty-two participants with HD were recruited and randomized to one of two groups: (i) an exercise group, who participated in a 3-month, 3 times per week

10 Concluding remarks

50-min aerobic and task-specific strengthening exercise program, or (ii) a control group who received usual care (no exercise). Participants were supervised in just over half of the exercise sessions by an exercise trainer. The study achieved 91% retention rate and 93% adherence rate. The exploratory outcomes revealed significant improvements in fitness and motor function following the completion of a 12-week long, 3 times per week training program, despite the presence of sometimes advanced motor impairments (Quinn et al., 2016a). Alongside the importance of sufficiently intense aerobic exercise is the greater focus on risks of sedentary behaviors in the general population. Indeed, the nature of the disease (including both motor and nonmotor features) in HD can exert a negative impact on motivation to initiate and sustain participation in regular physical activity, reinforcing the importance of specific support for exercise programs in the clinical trial context. Another trial, ENGAGE-HD, has now provided the first evidence of safety and feasibility of a purpose-developed physical activity intervention for HD and has shown that it is indeed possible to increase physical activity in people with HD over 14 weeks. The intervention approach included one-to-one coaching, telephone support, and a coaching style that highlighted autonomy, competence, and relatedness (Quinn et al., 2016b). Notwithstanding the complexity of impairments in HD, improvements in self-efficacy for exercise, as well as mobility inside and out of the home, were observed.

10 CONCLUDING REMARKS In this review, we highlight the potential benefits of incorporating an active rehabilitation component in clinical trials of regenerative medicine, within the specific context of cell transplantation in HD. Following experimental animal studies showing that exercise, EE, and task-directed behavioral training can all enhance functional outcomes, the challenge is to identify and design similar strategies for the human clinical situation. Moreover, the animal studies show that recovery is not simply dependent upon achieving effective repair, rather the structural reconstruction and functional integration of transplanted cells into damaged host circuits are modified and enhanced by the behavioral experience and training of the host. One of the greatest barriers restricting bidirectional regenerative rehabilitative knowledge between basic science investigators and clinical research is lack of communication. It is crucial that clinical trials begin to incorporate and adapt the understandings derived from preclinical studies to the clinical setting, including optimal training modality, specific task-specific relearning, timing, dose and intensity of training to promote optimal network connectivity, and integration between the grafted and host tissue with the aim of providing circuit reconstruction and graft functionality. In parallel quantitative, disease-specific outcome measures are urgently required in the clinic to measure change over time in the functional domains beyond simple cell survival and to address relevant dimensions of neuroplasticity

321

322

CHAPTER 13 Rehabilitation training in neural restitution

and striatal network functionality following cell replacement therapy. Selected outcome measures also need to address the symptom domains of most concern to the QOL of patients and their families, for example, using tests related to the functional capacities required for common daily tasks, such as effective distribution of attention required for dual-task performance. Furthermore, for clinical studies in HD, selected outcome measures need to target known striatal functions, testing the integrity of basal ganglionic circuitry and the extent to which this has been reestablished. Building on preclinical knowledge combined with disease sensitive outcome measures will aid the development of multidisciplinary rehabilitation programs, enhance the power and likelihood of success in clinical trials, and ultimately enhance the functional capabilities of the graft and improve QOL.

ACKNOWLEDGMENTS Our own studies have been supported by the UK Medical Research Council, Health and Care Research Wales, Gossweiler Foundation, Wellcome Trust, and the European Union Framework programs.

REFERENCES Alonso, M., Bekinschtein, P., Cammarota, M., Vianna, M.R.M., Izquierdo, I., Medina, J.H., 2005. Endogenous BDNF is required for long-term memory formation in the rat parietal cortex. Learn. Mem. 12, 504–510. Altman, J., Das, G.D., 1965. Post-natal origin of microneurones in the rat brain. Nature 207, 953–956. Ambrosio, F., Russell, A., 2010. Regenerative rehabilitation: a call to action. J. Rehabil. Res. Dev. 47 (3), xi–xv. Ashby, F.G., Turner, B.O., Horvitz, J.C., 2010. Cortical and basal ganglia contributions to habit learning and automaticity. Trends Cogn. Sci. 14, 208–215. Bachoud-Levi, A.-C., Remy, P., Ng´uyen, J.-P., Brugie`res, P., Lefaucheur, J.-P., Bourdet, C., et al., 2000. Motor and cognitive improvements in patients with Huntington’s disease after neural transplantation. Lancet 356, 1975–1979. Bachoud-Levi, A.C., Gaura, V., Brugieres, P., Lefaucheur, J.P., Boisse, M.F., Maison, P., et al., 2006. Effect of fetal neural transplants in patients with Huntington’s disease 6 years after surgery: a long-term follow-up study. Lancet Neurol. 5, 303–309. Bennett, E.L., Hebert, M., Morimoto, H., Rosenzweig, M.R., 1978. Social grouping cannot account for cerebral effects of enriched environments. Brain Res. 153, 563–576. Berg, K.O., Wood-Dauphinee, S.L., Williams, J.I., Maki, B., 1992. Measuring balance in the elderly: validation of an instrument. Can. J. Public Health 83 (Suppl. 2), S7–S11. Bilney, B., Morris, M.E., Perry, A., 2003. Effectiveness of physiotherapy, occupational therapy, and speech pathology for people with Huntington’s disease: a systematic review. Neurorehabil. Neural Repair 17, 12–24. Bonfanti, L., Peretto, P., 2011. Adult neurogenesis in mammals—a theme with many variations. Eur. J. Neurosci. 34, 930–950.

References

Brasted, P.J., Watts, C., Robbins, T.W., Dunnett, S.B., 1999a. Associative plasticity in striatal transplants. Proc. Natl. Acad. Sci. U.S.A. 96, 10524–10529. Brasted, P.J., Watts, C., Torres, E.M., Robbins, T.W., Dunnett, S.B., 1999b. Behavioural recovery following striatal transplantation: effects of postoperative training and P-zone volume. Exp. Brain Res. 128, 535–538. Brasted, P.J., Watts, C., Torres, E.M., Robbins, T.W., Dunnett, S.B., 2000. Behavioral recovery after transplantation into a rat model of Huntington’s disease: dependence on anatomical connectivity and extensive postoperative training. Behav. Neurosci. 114, 431–436. Busse, M.E., Rosser, A.E., 2007. Can directed activity improve mobility in Huntington’s disease? Brain Res. Bull. 72, 172–174. Busse, M.E., Quinn, L., DeBono, K., Jones, K., Collett, J., Playle, R., et al., 2013. A randomized feasibility study of a 12-week community-based exercise program in people with Huntington’s disease. J. Neurol. Phys. Ther. 37, 149–158. Busse, M., Quinn, L., Khalil, H., McEwan, K., 2014. Optimising mobility outcome measures in Huntington’s disease. J. Huntingtons Dis. 3, 175–188. Calabresi, P., Pisani, A., Centonze, D., Bernardi, G., 1997. Synaptic plasticity and physiological interactions between dopamine and glutamate in the striatum. Neurosci. Biobehav. Rev. 21, 519–523. Chin, T., Sawamura, S., Fujita, H., Nakajima, S., Ojima, I., Oyabu, H., et al., 1999. The efficacy of physiological cost index (PCI) measurement of a subject walking with an intelligent prosthesis. Prosthet. Orthot. Int. 23, 45–49. Ciancarelli, I., Tozzi Ciancarelli, M.G., Carolei, A., 2013. Effectiveness of intensive neurorehabilitation in patients with Huntington’s disease. Eur. J. Phys. Rehabil. Med. 49, 189–195. Clarke, D.J., Dunnett, S.B., 1993. Synaptic relationships between cortical and dopaminergic inputs and intrinsic GABAergic systems within intrastriatal striatal grafts. J. Chem. Neuroanat. 6, 147–158. Comery, T.A., Shah, R., Greenough, W.T., 1995. Differential rearing alters spine density on medium-sized spiny neurons in the rat corpus striatum: evidence for association of morphological plasticity with early response gene expression. Neurobiol. Learn. Mem. 63, 217–219. Comery, T.A., Stamoudis, C.X., Irwin, S.A., Greenough, W.T., 1996. Increased density of multiple-head dendritic spines on medium-sized spiny neurons of the striatum in rats reared in a complex environment. Neurobiol. Learn. Mem. 66, 93–96. Cotman, C.W., Berchtold, N.C., 2002. Exercise: a behavioral intervention to enhance brain health and plasticity. Trends Neurosci. 25, 295–301. Cotman, C.W., Berchtold, N.C., Christie, L.A., 2007. Exercise builds brain health: key roles of growth factor cascades and inflammation. Trends Neurosci. 30, 464–472. Curlik, D.M., Maeng, L.Y., Agarwal, P.R., Shors, T.J., 2013. Physical skill training increases the number of surviving new cells in the adult hippocampus. PLoS One 8, e55850. Dawson, S., Kristjanson, L.J., Toye, C.M., Flett, P., 2004. Living with Huntington’s disease: need for supportive care. Nurs. Health Sci. 6, 123–130. Delval, A., Krystkowiak, P., Delliaux, M., Blatt, J.L., Derambure, P., Destee, A., Defebvre, L., 2008a. Effect of external cueing on gait in Huntington’s disease. Mov. Disord. 23, 1446–1452. Delval, A., Krystkowiak, P., Delliaux, M., Dujardin, K., Blatt, J.L., Destee, A., et al., 2008b. Role of attentional resources on gait performance in Huntington’s disease. Mov. Disord. 23, 684–689.

323

324

CHAPTER 13 Rehabilitation training in neural restitution

Deutch, A.Y., Colbran, R.J., Winder, D.J., 2007. Striatal plasticity and medium spiny neuron dendritic remodeling in parkinsonism. Parkinsonism Relat. Disord. 13, S251–S258. Dobkin, B.H., 2004. Neurobiology of rehabilitation. Ann. N. Y. Acad. Sci. 1038, 148–170. Dobkin, B.H., 2007. Confounders in rehabilitation trials of task-oriented training: lessons from the designs of the EXCITE and SCILT multicenter trials. Neurorehabil. Neural Repair 21, 3–13. D€obr€ossy, M.D., Dunnett, S.B., 2001. The influence of environment and experience on neural grafts. Nat. Rev. Neurosci. 2, 871–879. D€obr€ossy, M.D., Dunnett, S.B., 2004. Environmental enrichment affects striatal graft morphology and functional recovery. Eur. J. Neurosci. 19, 159–168. D€obr€ossy, M.D., Dunnett, S.B., 2005a. Training specificity, graft development and graftmediated functional recovery in a rodent model of Huntington’s disease. Neuroscience 132, 543–552. D€obr€ossy, M.D., Dunnett, S.B., 2005b. Optimising plasticity: environmental and training associated factors in transplant-mediated brain repair. Rev. Neurosci. 16, 1–21. D€obr€ossy, M.D., Dunnett, S.B., 2006. The effects of lateralised training on spontaneous forelimb preference, lesion deficits and graft mediated functional recovery after unilateral striatal lesions in rats. Exp. Neurol. 199, 373–383. D€obr€ossy, M.D., Dunnett, S.B., 2008. Environmental housing and duration of exposure affect striatal graft morphology in a rodent model of Huntington’s disease. Cell Transplant. 17, 1125–1134. D€obr€ossy, M.D., Drapeau, E., Aurousseau, C., Le Moal, M., Piazza, P.V., Abrous, D.N., 2003. Differential effects of learning on neurogenesis: learning increases or decreases the number of newly born cells depending on their birth date. Mol. Psychiatry 8, 974–982. D€obr€ossy, M.D., Busse, M., Piroth, T., Rosser, A.E., Dunnett, S.B., Nikkhah, G., 2010. Neurorehabilitation with neural transplantation. Neurorehabil. Neural Repair 24, 692–701. Draganski, B., May, A., 2008. Training-induced structural changes in the adult human brain. Behav. Brain Res. 192, 137–142. Draganski, B., Gaser, C., Kempermann, G., Kuhn, H.G., Winkler, J., B€ uchel, C., May, A., 2006. Temporal and spatial dynamics of brain structure changes during extensive learning. J. Neurosci. 26, 6314–6317. Dunnett, S.B., Bj€orklund, A. (Eds.), 1994. Functional Neural Transplantation. Raven Press, New York. Dunnett, S.B., Bj€orklund, A. (Eds.), 2000. Functional Neural Transplantation II: Novel Cell Therapies for CNS Disorders. Elsevier, Amsterdam, London & New York. Dunnett, S.B., Bj€orklund, A. (Eds.), 2012. In: Functional Neural Transplantation III: Primary and Stem Cell Transplantation for Brain Repair, vols. I and II. Elsevier, Amsterdam. Dunnett, S.B., Rosser, A.E., 2007. Cell transplantation for Huntington’s disease should we continue? Brain Res. Bull. 72, 132–147. Dunnett, S.B., Rosser, A.E., 2014. Challenges for taking primary and stem cells into clinical neurotransplantation trials for neurodegenerative disease. Neurobiol. Dis. 61, 79–89. Dunnett, S.B., Nathwani, F., Bj€orklund, A., 2000. The integration and function of striatal grafts. Prog. Brain Res. 127, 345–380. Freeman, T.B., Cicchetti, F., Hauser, R.A., Deacon, T.W., Li, X.J., Hersch, S.M., et al., 2000. Transplanted fetal striatum in Huntington’s disease: phenotypic development and lack of pathology. Proc. Natl. Acad. Sci. U.S.A. 97, 13877–13882. Freeman, T.B., Cicchetti, F., Bachoud-Levi, A.C., Dunnett, S.B., 2011. Technical factors that influence neural transplant safety in Huntington’s disease. Exp. Neurol. 227, 1–9.

References

Fricker, R.A., Torres, E.M., Dunnett, S.B., 1997a. The effects of donor stage on the survival and function of embryonic striatal grafts in the adult rat brain. I. Morphological characteristics. Neuroscience 79, 695–710. Fricker, R.A., Torres, E.M., Hume, S.P., Myers, R., Opacka-Juffry, J., Ashworth, S., et al., 1997b. The effects of donor stage on the survival and function of embryonic striatal grafts in the adult rat brain. II. Correlation between positron emission tomography and reaching behaviour. Neuroscience 79, 711–722. Fritz, N.E., Hamana, K., Kelson, M., Rosser, A., Busse, M., Quinn, L., 2016. Motor-cognitive dual-task deficits in individuals with early-mid stage Huntington disease. Gait Posture 49, 283–289. Glantz, L.A., Lewis, D.A., 2000. Decreased dendritic spine density on prefrontal cortical pyramidal neurons in schizophrenia. Arch. Gen. Psychiatry 57, 65–73. Graybiel, A.M., Liu, F.C., Dunnett, S.B., 1989. Intrastriatal grafts derived from fetal striatal primordia. 1. Phenotype and modular organization. J. Neurosci. 9, 3250–3271. Hadzi, T.C., Hendricks, A.E., Latourelle, J.C., Lunetta, K.L., Cupples, L.A., Gillis, T., et al., 2012. Assessment of cortical and striatal involvement in 523 Huntington disease brains. Neurology 79, 1708–1715. Hannan, A.J., 2014. Environmental enrichment and brain repair: harnessing the therapeutic effects of cognitive stimulation and physical activity to enhance experience-dependent plasticity. Neuropathol. Appl. Neurobiol. 40, 13–25. Harrison, D.J., Busse, M., Openshaw, R., Rosser, A.E., Dunnett, S.B., Brooks, S.P., 2013. Exercise attenuates neuropathology and has greater benefit on cognitive than motor deficits in the R6/1 Huntington’s disease mouse model. Exp. Neurol. 248, 457–469. Hauser, R.A., Furtado, S., Cimino, C.R., Delgado, H., Eichler, S., Schwartz, S., et al., 2002. Bilateral human fetal striatal transplantation in Huntington’s disease. Neurology 58, 687–695. Hebb, D.O., 1947. The effects of early experience on problem solving in maturity. Am. Psychol. 2, 306–307. Hebb, D.O., 1949. The Organisation of Behavior. Wiley, New York. Hockly, E., Cordery, P.M., Woodman, B., Mahal, A., van Dellen, A., Blakemore, C., et al., 2002. Environmental enrichment slows disease progression in R6/2 Huntington’s disease mice. Ann. Neurol. 51, 235–242. Huntington’s Study Group, 1996. Unified Huntington’s disease rating scale: reliability and consistency. Mov. Disord. 11, 136–142. J€ancke, L., 2009. The plastic human brain. Restor. Neurol. Neurosci. 27, 521–538. Kefalopoulou, Z., Politis, M., Piccini, P., Mencacci, N., Bhatia, K., Jahanshahi, M., et al., 2014. Long-term clinical outcome of fetal cell transplantation for Parkinson disease: two case reports. JAMA Neurol. 71, 83–87. Kendall, A.L., Hantraye, P., Palfi, S., 2000. Striatal tissue transplantation in non-human primates. Prog. Brain Res. 127, 381–401. Khalil, H., Quinn, L., van Deursen, R., Dawes, H., Playle, R., Rosser, A., Busse, M., 2013. What effect does a structured home-based exercise programme have on people with Huntington’s disease? A randomized, controlled pilot study. Clin. Rehabil. 27, 646–658. Klassen, H., Lund, R.D., 1987. Retinal transplants can drive a pupillary reflex in host rat brains. Proc. Natl. Acad. Sci. U.S.A. 84, 6958–6960. Klein, A., Sacrey, L.A., Dunnett, S.B., Whishaw, I.Q., Nikkhah, G., 2011. Proximal movements compensate for distal forelimb movement impairments in a reach-to-eat task in Huntington’s disease: new insights into motor impairments in a real-world skill. Neurobiol. Dis. 41, 560–569.

325

326

CHAPTER 13 Rehabilitation training in neural restitution

Kloos, A.D., Fritz, N.E., Kostyk, S.K., Young, G.S., Kegelmeyer, D.A., 2013. Video game play (Dance Dance Revolution) as a potential exercise therapy in Huntington’s disease: a controlled clinical trial. Clin. Rehabil. 27, 972–982. Kolb, B., Gibb, R., Gorny, G., 2003. Experience-dependent changes in dendritic arbor and spine density in neocortex vary qualitatively with age and sex. Neurobiol. Learn. Mem. 79, 1–10. Kondziolka, D., Steinberg, G.K., Wechsler, L., Meltzer, C.C., Elder, E., Gebel, J., et al., 2005. Neurotransplantation for patients with subcortical motor stroke: a phase 2 randomized trial. J. Neurosurg. 103, 38–45. Kopyov, O.V., Jacques, S., Lieberman, A., Duma, C.M., Eagle, K.S., 1998. Safety of intrastriatal neurotransplantation for Huntington’s disease patients. Exp. Neurol. 149, 97–108. Kordower, J.H., Olanow, C.W., 2016. Fetal grafts for Parkinson’s disease: decades in the making. Proc. Natl. Acad. Sci. U.S.A. 113, 6332–6334. Laviola, G., Hannan, A.J., Macrı`, S., Solinas, M., Jaber, M., 2008. Effects of enriched environment on animal models of neurodegenerative diseases and psychiatric disorders. Neurobiol. Dis. 31, 159–168. Leddy, A.L., Crowner, B.E., Earhart, G.M., 2011. Utility of the Mini-BESTest, BESTest, and BESTest sections for balance assessments in individuals with Parkinson disease. J. Neurol. Phys. Ther. 35, 90–97. Leggio, M.G., Mandolesi, L., Federico, F., Spirito, F., Ricci, B., Gelfo, F., Petrosini, L., 2005. Environmental enrichment promotes improved spatial abilities and enhanced dendritic growth in the rat. Behav. Brain Res. 163, 78–90. Lima, C., Escada, P., Pratas-Vital, J., Branco, C., Arcangeli, C.A., Lazzeri, G., et al., 2010. Olfactory mucosal autografts and rehabilitation for chronic traumatic spinal cord injury. Neurorehabil. Neural Repair 24, 10–22. Lippman, J., Dunaevsky, A., 2005. Dendritic spine morphogenesis and plasticity. J. Neurobiol. 64, 47–57. May, A., 2011. Experience-dependent structural plasticity in the adult human brain. Trends Cogn. Sci. 15, 475–482. Mayer, E., Brown, V.J., Dunnett, S.B., Robbins, T.W., 1992. Striatal graft-associated recovery of a lesion-induced performance deficit in the rat requires learning to use the transplant. Eur. J. Neurosci. 4, 119–126. Mazzocchi-Jones, D., D€obr€ossy, M.D., Dunnett, S.B., 2009. Synaptic plasticity in striatal grafts. Eur. J. Neurosci. 30, 2134–2142. Mazzocchi-Jones, D., D€obr€ossy, M.D., Dunnett, S.B., 2011. Environmental enrichment facilitates long-term potentiation in embryonic striatal grafts. Neurorehabil. Neural Rep. 25, 548–557. Mishkin, M., Malamut, B., Bachevalier, J., 1984. Memories and habits: two neural systems. In: Lynch, G., McGaugh, J.L., Weinberger, N.M. (Eds.), The Neurobiology of Learning and Memory. Guilford Press, New York, pp. 65–77. Mizuno, K., Carnahan, J., Nawa, H., 1994. Brain-derived neurotrophic factor promotes differentiation of striatal GABAergic neurons. Dev. Biol. 165, 243–256. Nithianantharajah, J., Hannan, A.J., 2006. Enriched environments, experience-dependent plasticity and disorders of the nervous system. Nat. Rev. Neurosci. 7, 697–709. Petzinger, G.M., Fisher, B.E., McEwen, S., Beeler, J.A., Walsh, J.P., Jakowec, M.W., 2013. Exercise-enhanced neuroplasticity targeting motor and cognitive circuitry in Parkinson’s disease. Lancet Neurol. 12, 716–726.

References

Piira, A., van Walsem, M.R., Mikalsen, G., Nilsen, K.H., Knutsen, S., Frich, J.C., 2013. Effects of a one year intensive multidisciplinary rehabilitation program for patients with Huntington’s disease: a prospective intervention study. PLoS Curr. 5. pii: 9504af71e0d1f87830c25c394be47027. Quinn, N., Brown, R., Craufurd, D., Goldman, S., Hodges, J., Kieburtz, K., et al., 1996. Core assessment program for intracerebral transplantation in Huntington’s disease (CAPITHD). Mov. Disord. 11, 143–150. Quinn, L., Busse, M., Khalil, H., Richardson, S., Rosser, A., Morris, H., 2010. Client and therapist views on exercise programmes for early-mid stage Parkinson’s disease and Huntington’s disease. Disabil. Rehabil. 32, 917–928. Quinn, L., Hamana, K., Kelson, M., Dawes, H., Collett, J., Townson, J., et al., 2016a. A randomized, controlled trial of a multi-modal exercise intervention in Huntington’s disease. Parkinsonism Relat. Disord. 31, 46–52. Quinn, L., Trubey, R., Gobat, N., Dawes, H., Edwards, R.T., Jones, C., et al., 2016b. Development and delivery of a physical activity intervention for people with Huntington disease: facilitating translation to clinical practice. J. Neurol. Phys. Ther. 40, 71–80. Reilmann, R., Bohlen, S., Kirsten, F., Ringelstein, E.B., Lange, H.W., 2011. Assessment of involuntary choreatic movements in Huntington’s disease—toward objective and quantitative measures. Mov. Disord. 26, 2267–2273. Reuben, D.B., Siu, A.L., 1990. An objective measure of physical function of elderly outpatients. The Physical Performance Test. J. Am. Geriatr. Soc. 38, 1105–1112. Robertson, I.H., Murre, J.M., 1999. Rehabilitation of brain damage: brain plasticity and principles of guided recovery. Psychol. Bull. 125, 544–575. Rosser, A.E., Bachoud-Levi, A.C., 2012. Clinical trials of neural transplantation in Huntington’s disease. Prog. Brain Res. 200, 345–371. Rosser, A.E., Barker, R.A., Harrower, T., Watts, C., Farrington, M., Ho, A.K., et al., 2002. Unilateral transplantation of human primary fetal tissue in four patients with Huntington’s disease: NEST-UK safety report ISRCTN no 36485475. J. Neurol. Neurosurg. Psychiatry 73, 678–685. Schmidt, R.H., Bj€orklund, A., Stenevi, U., 1981. Intracerebral grafting of dissociated CNS tissue suspensions: a new approach for neuronal transplantation to deep brain sites. Brain Res. 218, 347–356. Seel, R.T., Cifu, D.X., 2005. Rehabilitation and neurologic repair in Parkinson’s disease. NeuroRehabilitation 20, 151–152. Shors, T.J., 2014. The adult brain makes new neurons, and effortful learning keeps them alive. Curr. Dir. Psychol. Sci. 23, 311–318. Shors, T.J., Anderson, M.L., Curlik, D.M., Nokia, M.S., 2012. Use it or lose it: how neurogenesis keeps the brain fit for learning. Behav. Brain Res. 227, 450–458. Sitek, E.J., Sołtan, W., Wieczorek, D., Schinwelski, M., Robowski, P., Harciarek, M., et al., 2013. Self-awareness of executive dysfunction in Huntington’s disease: comparison with Parkinson’s disease and cervical dystonia. Psychiatry Clin. Neurosci. 67, 59–62. Solis, O., Limo´n, D.I., Flores-Herna´ndez, J., Flores, G., 2007. Alterations in dendritic morphology of the prefrontal cortical and striatum neurons in the unilateral 6-OHDA-rat model of Parkinson’s disease. Synapse 61, 450–458. Spires, T.L., Hannan, A.J., 2005. Nature, nurture and neurology: gene-environment interactions in neurodegenerative disease. FEBS J. 272, 2347–2361.

327

328

CHAPTER 13 Rehabilitation training in neural restitution

Tada, T., Sheng, M., 2006. Molecular mechanisms of dendritic spine morphogenesis. Curr. Opin. Neurobiol. 16, 95–101. Taub, E., Uswatte, G., 2006. Constraint-induced movement therapy: answers and questions after two decades of research. NeuroRehabilitation 21, 93–95. Taub, E., Uswatte, G., Elbert, T., 2002. New treatments in neurorehabilitation founded on basic research. Nat. Rev. Neurosci. 3, 228–236. Thompson, J.A., Cruickshank, T.M., Penailillo, L.E., Lee, J.W., Newton, R.U., Barker, R.A., Ziman, M.R., 2013. The effects of multidisciplinary rehabilitation in patients with earlyto-middle-stage Huntington’s disease: a pilot study. Eur. J. Neurol. 20, 1325–1329. Tinetti, M.E., Franklin Williams, T., Mayewski, R., 1986. Fall risk index for elderly patients based on number of chronic disabilities. Am. J. Med. 80, 429–434. Toth, L.A., Kregel, K., Leon, L., Musch, T.I., 2011. Environmental enrichment of laboratory rodents: the answer depends on the question. Comp. Med. 61, 314–321. Turner, R.S., Desmurget, M., 2010. Basal ganglia contributions to motor control: a vigorous tutor. Curr. Opin. Neurobiol. 20, 704–716. van Dellen, A., Hannan, A.J., 2004. Genetic and environmental factors in the pathogenesis of Huntington’s disease. Neurogenetics 5, 9–17. van Dellen, A., Blakemore, C., Deacon, R., York, D., Hannan, A.J., 2000. Delaying the onset of Huntington’s in mice. Nature 404, 721–722. Vaportzis, E., Georgiou-Karistianis, N., Churchyard, A., Stout, J.C., 2015. Dual task performance may be a better measure of cognitive processing in Huntington’s disease than traditional attention tests. J. Huntingtons Dis. 4, 119–130. Vaynman, S., Gomez-Pinilla, F., 2005. License to run: exercise impacts functional plasticity in the intact and injured central nervous system by using neurotrophins. Neurorehabil. Neural Repair 19, 283–295. Ventimiglia, R., Mather, P.E., Jones, B.E., Lindsay, R.M., 1995. The neurotrophins BDNF, NT-3 and NT-4/5 promote survival and morphological and biochemical differentiation of striatal neurons in vitro. Eur. J. Neurosci. 7, 213–222. Vitale, C., Pellecchia, M.T., Grossi, D., Fragassi, N., Di Maio, L., Barone, P., Cuomo, T., 2001. Unawareness of dyskinesias in Parkinson’s and Huntington’s diseases. Neurol. Sci. 22, 105–106. Warraich, Z., Kleim, J.A., 2010. Neural plasticity: the biological substrate for neurorehabilitation. Phys. Med. Rehabil. 12 (Suppl. 2), S208–S219. Wexler, N.S., Lorimer, J., Porter, J., Gomez, F., Moskowitz, C., Shackell, E., et al., 2004. Venezuelan kindreds reveal that genetic and environmental factors modulate Huntington’s disease age of onset. Proc. Natl. Acad. Sci. U.S.A. 101, 3498–3503. White, N.M., 1997. Mnemonic functions of the basal ganglia. Curr. Opin. Neurobiol. 7, 164–169. Wictorin, K., 1992. Anatomy and connectivity of intrastriatal striatal transplants. Prog. Neurobiol. 38, 611–639. Wictorin, K., Clarke, D.J., Bolam, J.P., Bj€ orklund, A., 1989. Host corticostriatal fibres establish synaptic connections with grafted striatal neurons in the ibotenic acid lesioned striatum. Eur. J. Neurosci. 1, 189–195. Wijeyekoon, R., Barker, R.A., 2011. The current status of neural grafting in the treatment of Huntington’s disease. A review. Front. Integr. Neurosci. 5, 78. Wu, T., Kansaku, K., Hallett, M., 2004. How self-initiated memorized movements become automatic: a functional MRI study. J. Neurophysiol. 91, 1690–1698.

References

Yin, H.H., Knowlton, B.J., Balleine, B.W., 2004. Lesions of dorsolateral striatum preserve outcome expectancy but disrupt habit formation in instrumental learning. Eur. J. Neurosci. 19, 181–189. Yogev-Seligmann, G., Hausdorff, J.M., Giladi, N., 2008. The role of executive function and attention in gait. Mov. Disord. 23, 329–342. Yoshihara, Y., De Roo, M., Muller, D., 2009. Dendritic spine formation and stabilization. Curr. Opin. Neurobiol. 19, 146–153. Yoshii, A., Constantine-Paton, M., 2010. Postsynaptic BDNF-TrkB signaling in synapse maturation, plasticity, and disease. Dev. Neurobiol. 70, 304–322. Zinzi, P., Salmaso, D., De Grandis, R., Graziani, G., Maceroni, S., Bentivoglio, A., et al., 2007. Effects of an intensive rehabilitation programme on patients with Huntington’s disease: a pilot study. Clin. Rehabil. 21, 603–613. Zuccato, C., Cattaneo, E., 2007. Role of brain-derived neurotrophic factor in Huntington’s disease. Prog. Neurobiol. 81, 294–330. Zuccato, C., Ciammola, A., Rigamonti, D., Leavitt, B.R., Goffredo, D., Conti, L., et al., 2001. Loss of huntingtin-mediated BDNF gene transcription in Huntington’s disease. Science 293, 493–498. Zuccato, C., Marullo, M., Vitali, B., Tarditi, A., Mariotti, C., Valenza, M., et al., 2011. Brainderived neurotrophic factor in patients with Huntington’s disease. PLoS One 6, e22966.

329