Renee Lustenhouwer Recovery in Neuralgic Amytrophy an interplay between peripheral nerve damage motor dysfunc�on and the brain

Recovery in Neuralgic Amyotrophy an interplay between peripheral nerve damage motor dysfunction and the brain Renee Lustenhouwer

ISBN 978-94-6284-313-4 Cover Ayelt van Veen Design/Lay-out Anouk Tosserams & Renee Lustenhouwer Printing Ipskamp Printing The work in this thesis was funded by the Prinses Beatrix Spierfonds [W.OR16–05]. Financial support for the printing of this thesis was kindly provided by the Radboud university medical center, Donders Insitute for Brain Cognition and Behaviour, and the Prinses Beatrix Spierfonds. © Renee Lustenhouwer, 2023 All rights are reserved. No part of this thesis may be reproduced, distributed, stored in a retrievel system, or transmitted in any form or by any means, without prior written permission of the author.

Recovery in Neuralgic Amyotrophy an interplay between peripheral nerve damage motor dysfunction and the brain Proefschrift ter verkrijging van de graad van doctor aan de Radboud Universiteit Nijmegen op gezag van de rector magnificus prof. dr. J.H.J.M. van Krieken, volgens besluit van het college voor promoties in het openbaar te verdedigen op woensdag 8 maart 2023 om 16.30 uur precies door Renee Lustenhouwer geboren op 15 januari 1991 te Rotterdam

Promotor prof. dr. B.G.M. van Engelen Copromotoren dr. J.T. Groothuis dr. I.G.M. Cameron dr. R.C.G. Helmich Manuscriptcommissie prof. dr. R.J.A. van Wezel prof. dr. R.W. Selles (Erasmus MC) dr. J.J. van Eijk (Jeroen Bosch Ziekenhuis)

voor Paul & Lien

Table of Contents BACKGROUND Chapter 1 General Introduction, Aims & Outline 11 Chapter 2 NA-CONTROL: a Study Protocol 21 PART 1 - How the Brain Adapts to Peripheral Nerve Damage in Neuralgic Amyotrophy Chapter 3 Altered Sensorimotor Representations after Recovery from Peripheral Nerve Damage in Neuralgic Amyotrophy 49 Chapter 4 Visuomotor Processing is Altered after Peripheral Nerve Damage in Neuralgic Amyotrophy 65 PART 2 - How Rehabilitation Can Aid Recovery in Neuralgic Amyotrophy Chapter 5 Effectiveness of an Outpatient Rehabilitation Program on Clinical Outcome in Patients with Neuralgic Amyotrophy: a Randomized Controlled Trial 93 Chapter 6 Cerebral Adaptation Associated with Peripheral Nerve Recovery in Neuralgic Amyotrophy: a Randomized Controlled Trial 111 Chapter 7 Summary & General Discussion 137 Chapter 8 Nederlandse Samenvatting 151 APPENDICES List of References 161 Acknowledgements 173 Curriculum Vitae 181 Portfolio 183 List of Publications 187 Research Data Management 189 Donders Graduate School for Cognitive Neuroscience 193 Theses Spierziekten Centrum Radboudumc 195


A CHAPTER 1 General Introduction, Aims & Outline


13 GENERAL INTRODUCTION, AIMS & OUTLINE 1 A General Introduction Imagine you wake up one morning with excruciating pain in your arm and shoulder. No matter what you try, you cannot find any relief for the pain. At first you do not even notice the muscle weakness, but by the end of the next day you can barely lift your arm. While helping you take off your shirt, your partner notices that your shoulder blade is sticking out. When you look in the mirror, you see that your shoulder blade is indeed positioned at a weird angle, as if it is “winging”. Over the coming weeks, the acute pain subsides, but your shoulder and arm remain weak. After some back and forth with your general physician, you are diagnosed with neuralgic amyotrophy. A neurologist explains that you have nerve damage and that recovery will take time. You continue to struggle with daily tasks such as getting dressed and cooking dinner. You miss playing volleyball and picking up your oneyear-old niece. You wonder if you will ever be able to return to your physically demanding job as a nurse in an elderly home. Over time you develop ways to compensate, but that only helps to some extent. Moreover, the extra burden on compensating muscles causes pain and fatigue. You hold out hope that you will regain function of your shoulder and arm as the peripheral nerves recover, but a year and a half later, you are still not anywhere near where you want to be. This fictional scenario reflects the unfortunate reality many patients with neuralgic amyotrophy find themselves in. It was inspired by stories that patients have shared with me, which have been incredible motivators for the work described in this thesis. Neuralgic amyotrophy Neuralgic amyotrophy (NA) is a common (yearly incidence of 1/1000) and disabling peripheral nerve disorder. 3 It is characterized by severe acute pain, caused by an acute auto-immune inflammation of nerves in the brachial plexus territory. The inflammation leads to peripheral nerve damage and subsequent weakness of muscles innervated by the affected nerves. 4-6 The acute phase, in which inflammation is ongoing, typically lasts several weeks, after which affected nerves will show spontaneous recovery over the course of months to years. 5, 6 NA typically affects one upper extremity, but can also occur bilaterally, and may involve nerves outside the brachial plexus, such as lumbar plexus and phrenic nerve. 5-7 To compensate for the initial muscle weakness, many NA patients develop abnormal movement patterns, most notably in the shoulder region. Abnormal positioning of the shoulder blade in rest and during movement is referred to as scapular dyskinesia, and is present in the majority of NA patients. 6-8 While these compensatory movement patterns can be beneficial at first, they often lead to long-term motor dysfunction and subsequent residual complaints such as impaired functional capability, fatigue and pain, which in turn lead to problems with activities of daily living. 6, 8-10 There is no proven effective causative treatment for NA. 6, 9 Standard physical therapy is often ineffective, and can even worsen symptoms. 8 A large proportion of NA patients thus continue to suffer from residual complaints, even when peripheral nerve recovery has taken place and muscle weakness has subsided. 6-8, 10 (Mal)adaptive neuroplasticity The fact that functional problems persist, despite recovery of the peripheral nerves and muscles, “the hardware”, suggests that the problemmay lie within the “software”: the way

14 CHAPTER 1 thebraincontrolsmovement. 6 Tounderstandhowdamage toperipheral nervesmay lead to changes in the brain, I will first introduce the concept of plasticity before circling back toNA. Our brains are able to adapt to a changing environment, by adjusting their structural or functional organization to meet the new environmental requirements. This plasticity enables us to learn a new skill, or to recover function after injury. 11-13 An example of the latter is how when one brain area is damaged through stroke, patients are able to retain some level of function through compensation in related, uninjured, regions of the brain. 14 Although plasticity is essential to our survival, such reorganization of the system is not always beneficial, and can even have detrimental consequences. 12, 15 A striking example of such consequences is focal hand dystonia. Individuals that frequently perform highly skilled movements, such as musicians and writers, may develop task-specific involuntary muscle contractions, which impair hand use. This phenomenon is related to an excess of plasticity in response to intensive training. 16, 17 While the occurrence of (mal)adaptive cerebral plasticity and its potential down sides are recognized in disorders that directly affect the brain, such as stroke, 15, 18 cerebral (mal)adaptations may also occur in peripheral nerve disorders where cerebral structures are intact, such as NA. As established at the start of this section, the fact that peripheral nerve recovery does not always translate directly into clinical recovery, is a strong indicator that maladaptive cerebral plasticity may be involved in residual complaints and variable recovery in NA. Moreover, some NA patients develop abnormal and involuntary postures and movements that resemble dystonia, 4 which is linked to cerebral maladaptations. 12, 16, 17, 19 Finally, with specific rehabilitation that focusses on relearning correct movement patterns through coordinative training, NA patients can regainmotor function, even after years of persistent scapular dyskinesia following an NA episode. 1 This thesis introduces and examines the interplay between peripheral nerve damage, motor dysfunction, and the brain in recovery in NA. This hypothesized interplay is depicted in Figure 1: A. auto-immune inflammation of nerves in the brachial plexus territory causes peripheral nerve damage in NA, which leads to muscle weakness and subsequent scapular dyskinesia; B. scapular dyskinesia may induce cerebral maladaptations through plasticity; C. these cerebral maladaptations may contribute to perpetuation of scapular dyskinesia, despite peripheral nerve recovery; D. specific rehabilitation, focused on regaining motor control, may alleviate scapular dyskinesia and related residual complaints by influencing these cerebral maladaptations. Figure 1 The hypothesized interplay between peripheral nerve damage, scapular dyskinesia and cerebral mechanisms in neuralgic amyotrophy

15 GENERAL INTRODUCTION, AIMS & OUTLINE 1 A These hypotheses are tested with motor imagery, task-based functional magnetic resonance imaging of the brain, and a specific multidisciplinary rehabilitation program, which are introduced in the following paragraphs. Motor imagery Motor imagery refers to imagined movement. It shows remarkable similarities to motor execution at the cerebral level: when you imagine performing a movement, your brain activates similar processes and brain regions as when you would actually perform that same movement (see Figure 2). 20-23 Motor imagery typically engages a fronto-parietal network, which is involved in planning and preparing movements. Several key motor areas, such as the supplementary motor area and the premotor cortex, are involved, as are parieto-occipital regions, such as the posterior parietal cortex and the extrastriate body area. 20, 21, 24-26 The more posterior associative areas work together with more frontal somatomotor regions to form sensorimotor representations of your body parts (e.g. the arm), both during motor imagery, motor preparation and motor execution. 26-28 As motor imagery does not involve motor execution, it provides a tool to study sensorimotor representations in the brain, without the influence of peripheral disease factors, such as altered afferent feedback. 29-31 Thus, if NA patients would show altered motor imagery, this would provide evidence that they have altered cerebral processes related to motor control. Task-based functional Magnetic Resonance Imaging32, 33 Magnetic Resonance Imaging (MRI) (Figure 3B) enables us to look inside the human brain and study its organization on several levels. Structural MRI provides an image which shows the structural, or anatomical, organization of the brain with high spatial resolution (see Figure 3A, row 1). With functional MRI (fMRI) it is possible to study the brain’s functional organization, by measuring cerebral activity over time. fMRI measures brain activity based on the principle that brain areas that are more active, require more oxygen and thus greater blood flow, and makes use of the oxygen-carrying haemoglobin’s magnetic Figure 2 Motor imagery Imagining a movement engages similar brain processes as executing that same movement.

16 CHAPTER 1 Figure 3 functional Magnetic Resonance Imaging (fMRI) A. an overview of the different types of images at the individual subject level. A high-resolution structural image (1st row) is used to localize the activity derived from the functional images (2nd-3rd rows). About every 1-3 seconds, the fMRI scanner obtains a functional image of the whole brain. The two rows in the figure are functional images from different timepoints. The 4th row is the preprocessed mean of all the functional images that are acquired during the task. The overlayed activation map shows which brain areas were more active when pressing a left compared to a right foot button (family wise error corrected, p < 0.05, data from a healthy volunteer in the study described in chapter 4). B. the MRI scanner used to obtain the images. C. the results at the group level in standard space: where the group as a whole had more activity when pressing the left compared to the right foot button (threshold-free cluster enhancement based permutation testing, familywise error corrected, p < 0.05, reproduced from chapter 4, figure 3).2

17 GENERAL INTRODUCTION, AIMS & OUTLINE 1 A properties. About every 1-3 seconds, a functional image is captured, which covers the entire brain (see Figure 3A, row 2-3), and measures the blood-oxygen level dependent (BOLD) signal. Varying intensity of the BOLD-signal indirectly quantifies cerebral activity. With task-based fMRI, a participant performs a task while functional images are obtained. This can provide insight into how the brain functions during a particular task. In order to discern activity related to a specific aspect of a task, and to prevent unwanted influence of unrelated factors and noise, conditions are usually repeated many times and contrasted against each other. Activity is typically quantified as the intensity of the BOLD signal of one condition relative to that of another condition (e.g. a left vs. a right button press). The resulting activation maps show what brain areas were more active during condition A vs. condition B (see Figure 3A, row 4). Functional images have considerably lower spatial resolution than the structural image. It is therefore common practice to also obtain a structural image, which can be used to localize the activity to specific brain areas. Activation maps of each individual subject will be registered to a standard space, after which they can be used for group level analyses: to identify shared activity (see Figure 3C), or to compare brain function between groups or time points. Specific multidisciplinary out-patient rehabilitation Despite the high incidence of NA, 3 and the fact that many patients suffer from debilitating residual symptoms, 8 there were no randomized controlled trials investigating rehabilitation treatments when we started the work described in this thesis. 6 Experts at the Radboud University Medical Center (Radboudumc) have developed a specific multidisciplinary out-patient rehabilitation program for NA patients with residual motor dysfunction. This approach has rendered promising results in the Radboudumc’ expert clinic, and was able to improve functional capability of the upper extremity, as measured with the Shoulder Rating Questionnaire – Dutch Language Version (SRQ-DLV) 34 and the Disabilities of Arm Shoulder and Hand (DASH) questionnaire35 in 8 patients in a pilot study. 1, 36 The program starts with a visit to the out-patient Plexus Clinic, where the patient is examined by a neurologist, a physical therapist, an occupational therapist, and a rehabilitation physician. At the end of this visit, the multidisciplinary expert team shares their diagnosis and personalized treatment advice with the patient. This treatment advice will be implemented over the following 16 weeks in 8 two-hour sessions (one hour of physical therapy, one hour of occupational therapy each). The treatment advice and subsequent treatment cover the different components in the model depicted in Figure 4. 1, 6 Although the coverage of the different components depends on the individual patient’s needs, there are two central elements. First, occupational therapy focusses on increasing self-management (e.g. through energy conservation strategies) to improve activities of daily life. 37 Second, physical therapy focusses on improving scapular stability and coordination through relearning motor control. 38, 39 We hypothesize that this motor relearning approach might be targeting cerebral sensorimotor processes that may play a role in persistent motor dysfunction after peripheral nerve injury in NA.

18 CHAPTER 1 Aims & Outline This thesis has two main aims: 1. to determine whether cerebral alterations are involved in NA patients with residual complaints after peripheral nerve injury; 2. to determine the effect of specific multidisciplinary rehabilitation on clinical outcome and cerebral mechanisms; The Background of the work described in this thesis is captured in Chapter 1, this General Introduction, and chapter 2. Chapter 2 further elaborates on the rationale, concepts and aims at the centre of this thesis and provides a detailed description of the design, patient population, materials and methods of the subsequent chapters. It describes the NA-CONTROL study: the randomized controlled trial investigating the effects of our specific rehabilitation program on recovery from peripheral nerve injury in NA. Figure 4 Treatment model The treatment model includes the different components that are addressed during the specific rehabilitation program. Occupational therapy focusses on the issues in the two outer rings (External Factors, Activities). The main focus of the physical therapy is on improving body functions. The remaining components are addressed throughout both types of therapy. Where needed, multidisciplinary approaches are employed. *Reproduced, with permission, from IJspeert et al. NeuroRehabilitation 2013; 3;657-66651

19 GENERAL INTRODUCTION, AIMS & OUTLINE 1 A Part 1 of this thesis centres around the question of How the brain adapts to peripheral nerve damage in NA, corresponding with the first aim of this thesis: to determine whether cerebral alterations are involved in NA patients with residual complaints after peripheral nerve injury. Chapter 3 describes a preparatory cross-sectional behavioural study comparing NA patients to healthy volunteers. We investigated whether a hand laterality judgment task, which involves motor imagery, can provide behavioural evidence confirming the clinical suspicion that cerebral sensorimotor representations of the affected upper extremity are altered in NA. At the same time, this study identifies the hand laterality judgment task as a motor imagery tool sensitive to cerebral adaptations in NA. Chapter 4 describes a cross-sectional neuroimaging study, in which we use functional MRI and the motor imagery paradigm identified in chapter 3, to assess and localize cerebral adaptations related to the affected upper extremity in NA patients with persistent motor dysfunction as compared to healthy volunteers. We additionally relate cerebral adaptations to residual complaints. Part 2 centres around the question of How rehabilitation can aid recovery in NA, corresponding with the second aim of this thesis: to determine the effect of specialized multidisciplinary rehabilitation on clinical outcome and cerebral mechanisms. Chapter 5 describes a randomized controlled trial on the clinical effects of specialized, multidisciplinary out-patient rehabilitation. We compare our specialized rehabilitation program to usual care on a range of clinical domains, with functional capability of the upper extremity as the primary outcome measure. We additionally assess retention effects at 4 months follow-up. Chapter 6 describes the neuroimaging part of the randomized controlled trial described in chapter 5. We use the same motor imagery paradigm as in chapters 3 and 4, combined with functional MRI before and after treatment to investigate cerebral adaptations in NA patients in response to treatment and recovery. We compare the effect of our specialized rehabilitation program, which is focused on relearning motor control, to usual care on behavioural and cerebral responses. Chapter 7 summarizes and discusses the main findings of this thesis, and addresses the clinical implications for neuralgic amyotrophy and future directions. Chapter 8 provides a Dutch summary of the work described in this thesis.

A CHAPTER 2 NA-CONTROL: a study protocol Published as: Renee Lustenhouwer, Nens van Alfen, Ian G.M. Cameron, Ivan Toni, Alexander C.H. Geurts, Rick C. Helmich, Baziel G.M. van Engelen,* Jan T. Groothuis* NA-CONTROL: a study protocol for a randomised controlled trial to compare specific outpatient rehabilitation that targets cerebral mechanisms through relearning motor control and uses self-management strategies to improve functional capability of the upper extremity, to usual care in patients with neuralgic amyotrophy Trials, 2019;20(1):482 *contributed equally

22 CHAPTER 2 Abstract Background: Neuralgic amyotrophy (NA) is a distinct peripheral neurological disorder of the brachial plexus with a yearly incidence of 1/1000, which is characterised by acute severe upper extremity pain. Weakness of the stabilising shoulder muscles in the acute phase leads to compensatory strategies and abnormal motor control of the shoulder - scapular dyskinesia. Despite peripheral nerve recovery, scapular dyskinesia often persists, leading to debilitating residual complaints including pain and fatigue. Evidence suggests that persistent scapular dyskinesia in NA may result from maladaptive cerebral neuroplasticity, altering motor planning. Currently there is no proven effective causative treatment for the residual symptoms in NA. Moreover, the role of cerebral mechanisms in persistent scapular dyskinesia remains unclear. Methods: NA-CONTROL is a single-centre, randomised controlled trial comparing specific rehabilitation to usual care in NA. The rehabilitation programme combines relearning of motor control, targeting cerebral mechanisms, with self-management strategies. Fifty patients will be included. Patients are recruited through the Radboud university medical center Nijmegen, the Netherlands. Patients with a (suspected) diagnosis of NA, with lateralized symptoms and scapular dyskinesia in the right upper extremity, who are 18years or older and not in the acute phase can be included. The primary outcome is the Shoulder Rating Questionnaire score, which measures functional capability of the upper extremity. Secondary clinical outcomes include measures of pain, fatigue, participation, reachable workspace, muscle strength and quality of life. In addition, motor planning is assessed with first-person motor imagery and functional magnetic resonance imaging. In a sub-study the patients are compared to 25 healthy participants, to determine the involvement of cerebral mechanisms. This will enable interpretation of cerebral changes associated with the rehabilitation programme and functional impairments in NA. Discussion: NA-CONTROL is the first randomised trial to investigate the effect of specific rehabilitation on residual complaints in NA. It also is the first study into the cerebral mechanisms that might underlie persistent scapular dyskinesia in NA. It thus may aid the further development of mechanism-based interventions for disturbed motor control in NA and in other peripheral neurological disorders. Trial registration: ClinicalTrials.gov, NCT03441347. Registered on 20 February 2018.

23 NA-CONTROL STUDY PROTOCOL 2 Background Plasticity is a feature of the central motor system that allows change in the system organisation. It enables the development of new motor strategies in a changing environment, which can be advantageous when learning a new skill, or when recovering from injury by adapting with a compensatory strategy. When elements of the motor system are damaged, for example in neurological disorders, neuroplasticity enables patients to regain (part of their) motor function. 40, 41 However, the plasticity is maladaptive when changes in the central motor system are not beneficial to functioning. Maladaptive neuroplasticity can have detrimental consequences, resulting in impaired motor function. There are indications that maladaptive motor strategies can occur not only in central, but also in peripheral nervous system disorders. 42-45 Neuralgic amyotrophy (NA) is a peripheral nervous system disorder in which (mal) adaptive central neuroplasticity might be important. There are several indications from clinical experience that (mal)adaptive central neuroplasticity is involved in this disorder. 6 However, little is currently known about the central mechanisms in this peripheral nervous system disorder. NA is a distinct peripheral nervous system disorder of the brachial plexus, with a yearly incidence ratio of 1/1000. 3, 6 It can also be described as an asymmetric, autoimmune inflammation of the brachial plexus and peripheral nerves. In the acute phase, the inflammation causes damage to the affected nerves, leading to the characteristic acute severe upper extremity pain, multifocal paresis (i.e. muscle weakness) with functional impairments, and patchy areas of sensory loss. The long thoracic nerve that innervates the serratus anterior muscle, is affected in about 70% of patients with NA. 7 In a substantial subset of patients (>50%), weakness of the serratus anterior muscle in the acute phase leads to compensatory, abnormal positioning and movement patterns of the scapula in the chronic phase. These patients develop chronic musculoskeletal pain in the paretic and compensating muscles, which leads to residual complaints of decreased functional capability of the affected upper extremity. 8 Many patients additionally suffer from impairment of activities of daily living, fatigue and decreased participation in daily occupations. 6, 8 The abnormal posture and movement patterns of the scapula are referred to as scapular dyskinesia. The concept of persisting shoulder complaints in NA is that through its plasticity, the motor system adapts to retain motor control of the shoulder region by forming compensatory movement patterns in the acute phase. After the acute phase, most of the damaged nerves recover over time and with this recovery, the strength of affected muscles, including the stabilising serratus anterior muscle, can return. However, recovery often does not lead to improved function because of dysfunctional coordination and instability of the scapula. Although some patients with NA recover well after 2–3 years, recovery is complicated in many. 5-8, 10 Residual complaints in NA are strongly correlated with persisting scapular dyskinesia. 8 There is currently no proven effective causative treatment for NA9 and the usual care given, mostly standard physical therapy, is ineffective and may even worsen complaints in more than half of patients with NA. 8 The fact that scapular dyskinesia persists even when the peripheral nerves and strength of the stabilising scapula muscle recover implies that other, cerebral factors may play a role in explaining the residual symptoms and variable recovery in patients with NA. We introduce the concept that peripheral nerve damage in NA may lead to adaptations in motor planning and representations that are compensatory in the acute phase, but lead

24 CHAPTER 2 to impaired and dysfunctional motor control in the chronic phase (see Figure 1). This suggested involvement of maladaptive motor planning is illustrated by the promising results of specific rehabilitation after NA. 1 Through rehabilitation focused on relearning motor control, which thus targets cerebral mechanisms, patients with NA can relearn how to correctly position and move their shoulder and arm, which normalises scapular coordination and stability and improves functional capability of the upper extremity. A specific multidisciplinary and personalised rehabilitation programme, consisting of a visit to a specialised outpatient clinic that is followed by 8 sessions of physical and occupational therapy over a period of 16 weeks, has been developed at the Radboud University Medical Center (Radboudumc) in Nijmegen, the Netherlands. This programme combines relearning of motor control with self-management strategies. A clinical pilot study in eight participants showed that this rehabilitation programme can substantially relieve complaints and improve daily function at the level of activities, performance and participation. The programme was feasible, as all patients with NA were able to complete the entire programme. The number needed to treat was low, with 75% of the participants improving on the primary outcome measures. 1 Figure 1 Cerebral reorganisation and rehabilitation after peripheral dysfunction in neuralgic amyotrophy Schematic presentation of the concept that peripheral nerve damage leads to adaptations in motor planning that are compensatory in the acute phase, but lead to impaired motor control in the chronic phase. Neuralgic amyotrophy (NA) is an acute autoimmune inflammation of the brachial plexus, characterised by acute severe upper extremity pain and multifocal paresis. Many patients with NA develop abnormal motor control of the scapular region, scapular dyskinesia, which persists even after peripheral nerve recovery. This suggests that persistent scapular dyskinesia in NA may result frommaladaptive neuroplasticity. Rehabilitation focused on relearning motor control, targeting cerebral mechanisms, can improve scapular movement and positioning, indicating that the impaired motor planning can be restored. This figure includes images that are adapted from Nervous system diagram licensed under the Creative Commons Attribution-Share Alike 4.0 International license, authored by Jordi March i Nogué and William Crochot

25 NA-CONTROL STUDY PROTOCOL 2 Taken together, the available evidence strongly suggests that maladaptive motor planning plays a role in long-term symptoms and disability in NA. Indirect evidence includes the presence of persistent scapular dyskinesia despite peripheral nerve recovery and muscle strength, and the fact that rehabilitation focused on relearning motor control can normalise scapular movements and positioning. However, at this time, there is no direct evidence for (mal)adaptive cerebral neuroplasticity in NA. Despite the high incidence of NA (1/1000 a year) 3 and the presence of debilitating residual complaints, 8 there are no randomised controlled trials (RCTs) investigating rehabilitation therapies targeting the residual complaints in NA. The NA-CONTROL study is an RCT designed to fill this gap; it compares the effect of a rehabilitation programme specifically designed for the residual complaints in this disorder to usual care in patients with NA. Additionally, the trial will combine clinical measures with measures derived to assess motor planning and representations in the central motor system, to provide mechanistic insights into how the rehabilitation program could change central motor system plasticity. Objectives Primary objectives The primary objective of this study is to determine the effect of a specific rehabilitation programme that combines relearning of motor control by targeting cerebral mechanisms with strategies to improve self-management, on functional capability of the upper extremity compared to usual care in patients with NA. Secondary objectives The secondary objectives of this study are: • To evaluate whether this rehabilitation program results in improvements in a range of domains, including but not limited to scapular dyskinesia, participation, quality of life and personal factors such as pain and fatigue, compared to usual care in patients with NA. • To assess the longer term (17 weeks post treatment) effects of the rehabilitation program on a variety of outcomes, including but not limited to functional capability of the upper extremity, participation, quality of life and personal factors such as pain and fatigue. • To determine the effect of this rehabilitation program on cortical motor planning and representations compared to usual care in patients with NA. Methods Study description The NA-CONTROL study is the first RCT to investigate treatment for residual complaints in neuralgic amyotrophy. It additionally investigates a relatively unexplored concept (i.e. the role of (mal)adaptive cerebral neuroplasticity in a disorder of the peripheral nervous system) and employs techniques (including functional magnetic resonance imaging (fMRI)) that have not yet been used to study the underlying cerebral mechanisms in NA. This study is conducted at the Donders Institute for Brain Cognition and Behaviour and the departments of Rehabilitation and Neurology of the Radboudumc in Nijmegen, the

26 CHAPTER 2 Netherlands. The effect of a rehabilitation programme on functional capability and motor planning of the upper extremity will be compared to that of usual care in this two-arm, single-centre, open-label RCT. The intervention group will receive a specific 17-week multidisciplinary rehabilitation programme at the Radboudumc outpatient clinic, focused on relearning motor control and self-management (see Intervention for more information). The usual care group will first receive usual care for a 17-week period, before entering the rehabilitation programme. Patients in both groups will be assessed in a single session at baseline. At the end of the baseline measurement, patients will be randomised into the intervention or usual care group (see Randomisation for more information). After the first 17 weeks of treatment (i.e. rehabilitation programme or usual care), both groups will be assessed in a second session (at 18 weeks post baseline). After this second assessment, the group that initially received usual care will then follow the specific rehabilitation programme. After completing the 17-week rehabilitation programme, the usual care group will be assessed a third time (at 36 weeks post baseline). All patients will be asked to fill out several questionnaires by e-mail 17 weeks after completing the rehabilitation programme. This follow up will be at either 36 weeks (intervention group) or 54 weeks (usual care group) post baseline. Figure 2 provides a flow chart of the study design. Sub-study The baseline measurements of all patients with NA who are assessed for the randomised controlled trial described in this publication (see Figure 2) will be used for a sub-study. Patients with NA will be compared to 25 age-matched and sex-matched healthy controls in this sub-study. The healthy controls are assessed in a single session. The primary objective of this sub-study will be to determine if patients with NA have altered cerebral activity related to motor planning of their affected arm, compared to healthy controls and compared to their non-affected arm. This sub-study is important for the interpretation of the secondary objective (the effect of this rehabilitation program on cortical motor planning and representations), to provide information about which cerebral changes from the rehabilitation program are associated with functional impairments in NA. Study population NA is more prevalent in men than in women, with an incidence ratio of 2:1, and can affect people of all ages. NA has an idiopathic form with a median age of onset around 40 years and a hereditary form with a median age of onset of about 28 years. 6, 7 Patients 18 years or older, with either form of NA can participate in the study. Number of participants and sample size calculation In total, 50 patients with NA will be recruited for participation in this study. The required sample size was calculated from the results from the pilot study on the effect of the rehabilitation program. 1 The improvement in functional capability of the upper extremity measured with the Shoulder Rating Questionnaire, Dutch Language Version (SRQ-DLV) was used for this sample size calculation. With a conservative standardised effect size of 0.29 (improvement in SRQ-DLV1), power of 0.90 and two-tailed testing (α = 0.05),

27 NA-CONTROL STUDY PROTOCOL 2 we calculated a required sample size of 42 patients. Assuming 20% dropout or noncompliance, we need to include 50 patients with NA. The Radboudumc hosts the national referral centre and the only expert multidisciplinary outpatient clinic for patients with NA in the Netherlands. Each year around 400 new patients with NA are seen, most referred by Dutch neurologists or general physicians. Of these 400 patients, about 40% are estimated to be eligible for inclusion (see Inclusion criteria). We therefore expect to be able to recruit sufficient patients with NA for this study within the 2-year inclusion period. Figure 2 Flowchart of the study design 50 neuralgic amyotrophy patients will be included. After the baseline measurement, participants are randomised into either the intervention group or the usual care group (1:1 ratio). After the first 17-week treatment period, both groups will undergo the first outcome measurement. The usual care group will then receive the 17-week rehabilitation program, after which they will undergo the second outcome measurement. Participants in both groups will complete a follow up from home 17 weeks after completing the rehabilitation program. Wks= weeks

28 CHAPTER 2 Inclusion criteria The treating rehabilitation physician or his/her physician assistant will judge whether a potential participant meets the inclusion criteria. In order to be eligible to participate in this study, a participant must meet all of the following criteria: 1. Diagnosis (suspected) of NA 2. Initially, the (suspected) diagnosis of NA will be deduced from the information in the referral letter from the patient’s referring general physician or neurologist. If any uncertainty about the diagnosis remains, the rehabilitation physician or his/ her physician assistant will contact the referring physician and/or patient. All patients will visit the specialised outpatient clinic, where the diagnosis will be either confirmed or discarded. 3. NA predominantly present in the right upper extremity 4. Being in the subacute or chronic phase of NA (i.e. no inflammation of the plexus, in practice, > 8weeks after attack onset) 5. Presenting with scapular dyskinesia 6. Age ≥18 years 7. Right-hand dominance (as indicated with an Edinburgh Handedness Inventory (EHI) score > + 40) 8. Able to provide informed consent Exclusion criteria For the patients with NA, the treating rehabilitation physician or his/her physician assistant will judge whether a potential participant meets one or more of the exclusion criteria. A potential participant who meets any of the following criteria will be excluded: 1. Prior NA attacks of the lumbosacral plexus or the left upper extremity 2. Previous participation in the specific rehabilitation programme offered at the Radboudumc or the rehabilitation centre KINOS 3. Other neuromuscular disease affecting the shoulder girdle 4. Central nervous system disorder or neurological disorder (e.g. Parkinson disease, stroke etc.) 5. Pre-existing (bio)mechanical constraints of the shoulder girdle 6. A history of or recent periarticular fractures of the shoulder 7. Past surgery of the shoulder 8. Depressive mood disorder, as indicated by a score > 5 on the Beck Depression Inventory Fast Screen (BDI-FS) 9. Severe comorbidity 10. Ongoing participation in another scientific study that might interfere with the current study Exclusion criteria for undergoing MRI are: 1. Pregnancy (current or planned within the study period) 2. The presence of metal parts that cannot be removed, in or on the upper body (including plates, screws, aneurysm clips, metal splinters, piercings, medical plasters or ossicle prosthesis but with the exception of dental fillings or crowns) 3. The presence of an electric implant (e.g. pacemaker, neurostimulator, insulin pump)

29 NA-CONTROL STUDY PROTOCOL 2 4. History of brain surgery 5. Claustrophobia 6. Epilepsy Participant selection and enrolment Figure 3 provides a flow-chart of the recruitment, consent and other procedures of patients in the NA-CONTROL study. Identifying potential participants All patients with NA that are newly referred to the Muscle Center of the Radboudumc during the study inclusion period will be checked for eligibility (i.e. meeting inclusion criteria 1–5) by a member of the treatment team through evaluation of the referral information. Eligible patients are informed about the NA-CONTROL study and their eligibility by post. At least a week after this notification letter is sent, a member of the treatment team will contact the patient to ask for his/her consent to be contacted by the coordinating researcher. Patients who express interest and provide consent will receive the extensive trial information package by e-mail. Consenting participants The coordinating researcher will contact patients who consent 7–14 days after the extensive trial information has been sent. After providing further clarification if needed, the coordinating researcher will state the inclusion and exclusion criteria. If the patient meets the inclusion and exclusion criteria, the researcher will ask the patient for oral consent and the baseline measurement will be scheduled. Written informed consent will be obtained by the coordinating researcher at the research location. prior to the start of the baseline measurement. All participants will receive a copy of the signed informed consent form. The original signed informed consent forms will be kept at the study site. After written informed consent is obtained, the patient’s hand dominance will be determined using the Edinburgh Handedness Inventory (EHI) 46 and the patient will be screened for signs of depressive mood disorder using the Beck Depression Inventory-Fast Screen (see Inclusion criteria 6 and Exclusion criteria 8, respectively). Patients’ participation will be noted in their medical chart. As per national regulations, all participants’ general practitioners will be notified of their participation. Ineligible and non-recruited patients A patient’s decision to decline participation will in no way affect their treatment at the Radboudumc. This is clearly communicated to patients during all contacts. For patients who are not eligible, who express that they are not interested in participation or who do not meet all inclusion and exclusion criteria, the usual procedure is followed; they will be put on the regular waiting list for a consultation at our expert outpatient clinic. The content of the rehabilitation programme is the same for patients that participate in the trial as for those that receive the rehabilitation programme outside the study.

30 CHAPTER 2 Figure 3 Flow-chart of patient recruitment, consent and other procedures of the study. NA = neuralgic amyotrophy

31 NA-CONTROL STUDY PROTOCOL 2 Table 1 SPIRIT figure Schedule of enrolment, intervention and assessments during the trial. t5 is only applicable for patients in the usual care group. Patients in the usual care group start with the rehabilitation program after the outcome measurement at t4. For this group, t1, t2 and t3 take place after t4. Abbreviations: 3D: 3 dimensional; BDI-FS: Beck depression inventory – fast screen; CIS-fatigue: checklist individual strength – fatigue; COPM: Canadian occupational performancemeasure; DASH: disability of arm, should and hand; EHI: Edinburgh handedness inventory; HLJT: hand laterality judgment task; KVIQ-10: kinaesthetic and visual imagery questionnaire-10; MPQ: McGill pain questionnaire; MRI: magnetic resonance imaging; NA: neuralgic amyotrophy; NENS: neuromotor encoding in neuromuscular scapular dyskinesia; PAM: patient activation measure; PSEQ: pain selfefficacy questionnaire; SAE: serious adverse event; SEPECSA: self-efficacy for performing energy conservation strategies assessment; SF-36: short-form 36; SRQ-DLV: shoulder rating questionnaire – Dutch language version; USER-P: Utrecht scale for evaluation of rehabilitation – participation

32 CHAPTER 2 Outcomes See Table 1 for an overview of all outcome measures and their corresponding collection time points. Primary outcome Functional capability of the upper extremity The primary outcome measure for the clinical part of the RCT is the change in SRQDLV score from baseline to post intervention. The SRQ-DLV is a reliable and validated questionnaire measuring functional capability of the shoulder, arm and hand34 and has been shown to be sensitive to (changes in) functional capability of the shoulder in patients with NA. 1 Secondary outcomes Secondary outcome measures are divided into clinical measures and measures related to motor planning (see below). Clinical The secondary clinical outcome measures cover multiple domains of the International Classification of Functioning, Disability and Health: 47 A. Activities and function: these will be assessed by administration of the following additional questionnaire: i. Disability of Arm, Shoulder and Hand (DASH) The DASH questionnaire measures the functional capability of the affected upper extremity and has good clinometric properties. 48 B. Personal factors: fatigue, pain, self-efficacy and patient activation are assessed using the following questionnaires: i. Checklist individual strength- subscale fatigue (CIS-fatigue) The CIS-fatigue measures experienced fatigue. 49 ii. McGill Pain Questionnaire (MPQ) The MPQ measures the pain experienced. It assesses the nature, intensity, location, course and effect of the pain on daily life. 50 iii. Self-efficacy for performing energy conservation strategies assessment (SEPECSA) The SEPECSA assesses how the patients perceive their ability to apply energy conservation strategies to their daily lives. 51 iv. Pain self-efficacy questionnaire (PSEQ) The PSEQ assesses the confidence that people with ongoing pain have in performing activities while being in pain. 52 v. Patient activation measure (PAM) Patient’s activation with regard to their health and disease is assessed using the PAM. The PAMmeasures knowledge, skills and confidence in managing one’s own health and/or disease. 53

33 NA-CONTROL STUDY PROTOCOL 2 C. Participation: participation is assessed using the following measures: i. Utrecht scale for evaluation of rehabilitation-participation (USER-P) The USER-P is used to evaluate the effect of outpatient rehabilitation on participation. 54 ii. Canadian Occupational Performance Measure (COPM) The COPM is used to evaluate occupational performance and satisfaction with performance of the most important daily occupations identified as problematic by the patient. It thus assesses occupational participation. 55 The COPM is administered during the first and last sessions of the specific rehabilitation program. 1 These assessments will serve as a pre-intervention and post-intervention comparison within patients with NA who underwent the experimental intervention. D. Body functions: within the body functions domain, we will assess the reachable workspace and several muscles/muscle groups i. 3D-reachable workspace Reachable workspace is an objective measure of upper extremity impairment. 56 It is quantified by the relative 3D surface area representing the portion of the unit hemisphere that is covered by the hand movements made during a standardized movement protocol. 56 The movement protocol covers cardinal movements of the shoulder and is performed in front of the Microsoft Kinect sensor-based reachable workspace analysis system. 56 ii. The following strength measurements will be performed to determine maximal force exerted with several muscles/muscle groups on both sides (left and right upper extremity) i. The serratus anterior muscle measured using the MicroFET2®, digital manual muscle dynamometer, with the arm lifted to shoulder level, in the scapular plane while ii. Reaching with the arm extended iii. Reaching with a flexed arm (elbow at 90°). iv. Rotation of the shoulder measured using the MicroFET2®, digital manual muscle dynamometer, with the arm at 0° anteflexion, elbow flexed at 90° and thumb pointing upwards 1. Endorotation 2. Exorotation v. Hand gripmeasured using the Jamar® Hydraulic Hand dynamometer, with the arm at 0° anteflexion, elbow flexed at 90° and straight wrist. vi. Pinch grip measured using the Baseline® LiTE Hydraulic Pinch Gauge with the arm at 0° anteflexion and elbow flexed at 90°. The pinch gauge is held between the index finger (top) and thumb. vii. Key grip measured with Baseline® LiTE Hydraulic Pinch Gauge, with the arm at 0° anteflexion, elbow flexed at 90°. The pinch gauge is held between the thumb (top) and index finger (bottom). E. Quality of life: quality of life will be assessed using the following questionnaire: i. Short-Form 36 (SF-36) The SF-36 assesses experienced health and health-related quality of life. 57

34 CHAPTER 2 Motor planning Motor planning will be assessed using a motor imagery task during which functional MRI signal is recorded. Motor imagery involves mental simulation of a movement, without actual execution of that movement. It can be used as a tool to generate cortical motor states without movement production. As is evident by the presence of scapular dyskinesia, peripheral motor control is altered in NA. With motor imagery, changes in central motor control can be assessed, while controlling for alterations in peripheral factors. Empirical evidence shows that first-person motor imagery tasks are sensitive to motor control variables and use central neural mechanisms involved in action planning: 30, 58, 59 A. Motor imagery task-based functional MRI i. Changes (as the result of rehabilitation and as the result of NA (assessed in the sub-study) in the neural mechanisms underlying motor planning and representations will be quantified by changes in the magnitudes of mean functional MRI signal, blood-oxygen-level-dependent (BOLD) activity associated with motor imagery during the Hand Laterality Judgment task (HLJT) (see B). ii. Analyses of the functionalMRI datawill primarily be focused on the following brain regions: the extrastriate body area, the posterior parietal cortex in the intra-parietal sulcus region, and the precentral and postcentral gyri. These a priori regions of interest for analysis of functional MRI magnitude differences are chosen based on previous research using the same motor imagery task. 24, 40, 58-60 Additionally, we will employ a whole brain exploratory analysis of functional changes in NA outside these canonical motor imagery regions (see also Exploratory outcomes). iii. Participants’ respiration will be recorded during the functional MRI scan to be able to control for noise introduced in the data. B. Performance on the motor imagery task i. The HLJT 29 assesses central representations and planning of movements involving the upper extremity. Participants are asked to judge the laterality of line drawings of hands. The hands vary in laterality (left or right), view (palmar or dorsal) and degree of rotation (rotated −135°, −105°, −75°, −45°, 45°, 75°, 105°, 135° from the upright position). Participants are instructed to use their own hands as reference (i.e. imagine moving their upper extremity to match the hand shown on screen), without actually moving their upper extremity. As participants perform this task in the MRI scanner, they cannot rely on visual information to perform the task. The task consists of 32 blocks of 8 trials. The inter-trial interval ranges from 2000 to 3000 ms. Before each block, participants are instructed to place their hands in one of four positions: both hands with palms facing up, both hands palms facing down, one hand palm up (left/right) and one hand palm down (right/left). With this manipulation, participants use of firstperson motor imagery can be checked through assessment of the posture effect: when using first person motor imagery, participants are faster for stimuli with a view that is congruent with the current posture of their own hand than for stimuli with a view that is incongruent with the posture of