Neurotherapy (eBook)

Front cover 1
Neurotherapy: Progress in Restorative Neuroscience and Neurology 4
Copyright page 5
List of Contributors 6
Preface 10
Acknowledgments 12
Contents 14
Section I. Stem Cells 18
Chapter 1. Cell transplantation strategies for retinal repair 20
Therapeutic strategies to restore the neural retina 20
Cell sources for retinal transplantation 23
Optimization of transplanted cell integration 27
Future considerations for retinal cell therapy 31
Abbreviations 32
Acknowledgments 32
References 32
Chapter 2. Strategies for retinal repair: cell replacement and regeneration 40
The retina and its degenerations 40
Retinal developmental biology 41
The ciliary marginal zone 41
Endogenous retinal repair mechanisms: Müller glia as a source of new neurons 42
Cell replacement strategies for retinal repair 44
Concluding remarks 46
References 47
Chapter 3. The rostral migratory stream and olfactory system: smell, disease and slippery cells 50
The purpose and importance of olfaction 50
The rostral migratory stream (RMS) pathway: common anatomical features in vertebrates 52
Polysialylated neural cell adhesion molecule: making the neuroblast slippery 54
The fate determinants for neuroblasts arriving at the olfactory bulb 56
Could the RMS be exploited for treating brain disordersquest 56
References 57
Chapter 4. Identifying and enumerating neural stem cells: application to aging and cancer 60
Neural stem cell discovery 60
Identifying neural stem cells using the neurosphere assay (NSA) 61
Enumeration of neural stem cells using the neural-colony forming cell assay and a mathematical model 61
Neural stem cells: potential treatment for age-related CNS disorders 62
Neural stem cells and brain tumors 64
Conclusion 65
References 66
Chapter 5. Transgenic reporter mice as tools for studies of transplantability and connectivity of dopamine neuron precursors in fetal tissue grafts 70
Introduction 70
Cell therapy for Parkinson’s disease 71
Midbrain dopamine neurons 74
Isolation of transplantable midbrain dopamine neurons from stem cell-derived populations 75
Reporter mice as tools in neural transplantation studies 78
Isolation of midbrain dopamine neuronal precursors from the developing midbrain 78
Graft composition and its relevance for functional impact 82
Reconstruction of the nigro-striatal pathway through intra-nigral grafting 86
Concluding remarks 91
References 91
Section II. Immunotherapy and Vaccination Therapy 98
Chapter 6. Developing novel immunogens for a safe and effective Alzheimer’s disease vaccine 100
Introduction 101
Abeta immunotherapy in rodents, monkeys, and humans 101
Novel short Abeta immunogens for active vaccination 105
Conclusions 107
Acknowedgments 108
References 108
Chapter 7. Innate immunity in the nervous system 112
The complement system 112
Activation and regulation of the complement system 113
The role of complement in inflammation 114
Complement in the central nervous system (CNS) 114
Complement in the peripheral nervous system (PNS) 120
Complement regulation in nerve injury and disease: a therapeutic approach 130
Abbreviations 132
Acknowledgment 133
References 133
Chapter 8. Neuroinflammation in spinal cord injury: therapeutic targets for neuroprotection and regeneration 142
Introduction to spinal cord injury (SCI) pathology: neuroinflammation in the pathogenesis of secondary injury 142
Manipulating neuroinflammation to improve recovery from SCI 143
Consequences of neuroinflammation on neuronal plasticity and regeneration 146
Conclusions 148
Acknowledgments 148
References 148
Chapter 9. Toll-like receptors in the CNS: implications for neurodegeneration and repair 156
Introduction and scope of this chapter 156
General features of TLRs 157
Expression and function of TLRs in microglia 158
Expression and function of TLRs in astrocytes 159
Expression and function of TLRs in neurons 162
Concluding remarks and future perspectives 163
Abbreviations 163
Acknowledgements 163
References 163
Section III. Gene Therapy 166
Chapter 10. Gene therapy and transplantation in the retinofugal pathway 168
Introduction 169
AAV-mediated transduction of retinal ganglion cells 169
Use of LV to genetically modify Schwann cells in chimeric peripheral nerve grafts 171
Transduction and tropic properties of modified AAV vectors in the retina 171
Concluding comments 175
References 175
Chapter 11. Controlled dissemination of AAV vectors in the primate brain 180
Introduction 180
Trafficking of AAV in the brain 181
Real-time imaging 184
Clinical implications 185
Conclusion 187
References 187
Chapter 12. From microsurgery to nanosurgery: how viral vectors may help repair the peripheral nerve 190
Introduction: peripheral nerve repair 190
Molecular mechanisms involved in peripheral nerve regeneration 191
Current challenges in peripheral nerve repair 192
Viral vectors: promising tools to express potentially therapeutic proteins in injured peripheral nerves 194
Lentiviral vector-mediated overexpression of neurotrophic factors to enhance nerve regeneration 195
Enhancing motoneuron survival as an application of neurotrophic factors 198
Failed functional recovery: misrouting of regenerating axons is an important factor 198
Addressing the routing problem at a molecular level 199
Future perspective: the continuing miniaturization of surgical and diagnostic tools 200
References 201
Chapter 13. Gene therapy for neurodegenerative diseases based on lentiviral vectors 204
Lentiviral vector-mediated gene therapy 204
Amyotrophic lateral sclerosis 206
Spinal muscular atrophy 207
Parkinson’s disease 208
Huntington’s disease 210
Clinical prospects and challenges of lentiviral vectors 212
Abbreviations 212
References 213
Chapter 14. Trophic factors therapy in Parkinson’s disease 218
Parkinson’s disease and neurotrophic factors 218
Glial cell line-derived neurotrophic factor 219
Neurturin 227
References 232
Section IV. Pharmacotherapy 234
Chapter 15. Progesterone as a neuroprotective factor in traumatic and ischemic brain injury 236
Introduction 236
Stroke and progesterone 239
Conclusion 249
Abbreviations 250
Acknowledgment 250
References 250
Chapter 16. Estrogen and testosterone therapies in multiple sclerosis 256
Introduction 256
Potential mechanisms of sex hormones 259
Sex hormone treatments in MS 262
Conclusions and future directions 263
Abbreviations 264
Acknowledgments 264
References 264
Chapter 17. Treatment of retinal diseases with VEGF antagonists 270
Introduction 270
Ocular angiogenesis 270
Mechanisms of angiogenesis and wound healing 271
Role of VEGF in ocular pathology and clinical use of VEGF antagonists 274
VEGF antagonists in AMD and other conditions with subretinal neovascularization 279
Side effects of ocular use of VEGF antagonists 280
Conclusion 281
References 281
Chapter 18. Pharmacological modification of the extracellular matrix to promote regeneration of the injured brain and spinal cord 286
Introduction 286
Lesion scarring after CNS injury 287
Differences in axonal growth responses to scar formation 289
Therapies to prevent fibrous scar formation 290
Pharmacological inhibition of scarring with iron chelators 291
Conclusion 295
Abbreviations 295
Acknowledgments 296
References 296
Chapter 19. The placebo response: neurobiological and clinical issues of neurological relevance 300
Introduction 300
Two different meanings of the term ‘‘placebo effect’’ 301
Evolution of the sugar pill 301
The placebo response: reflex or cognitivequest 302
Neurological disorders showing prominent placebo effects 303
From research to clinical practice 307
Conclusions 307
Acknowledgment 308
References 308
Section V. Neuroprostheses 312
Chapter 20. Brain-computer interfaces: an overview of the hardware to record neural signals from the cortex 314
Introduction to neuroprostheses 314
Classification of BCI 317
Epicortical electrodes for class II BCI 319
Intracortical electrodes for class III BCI 323
References 330
Chapter 21. Artificial vision: needs, functioning, and testing of a retinal electronic prosthesis 334
Retinal degenerative diseases: an overview 335
Prospects for therapies available to RD patients 336
Electron prosthetic devices: general considerations 337
Morphological and neuronal bases for implantation of a retinal prosthesis 340
Central connections in retinal degeneration and prosthesis implantation 340
Visual perception: measurements in low vision and brain processing after therapeutic intervention 341
A clinical trial and testing of an epiretinal prosthetic device 343
References 347
Chapter 22. Progress in restoration of hearing with the auditory brainstem implant 350
Introduction 350
Cochlear implants 351
Brainstem implants 351
Conclusions 359
References 360
Chapter 23. Microstimulation of visual cortex to restore vision 364
Introduction 365
Microstimulation of V1 elicits saccadic eye movements 368
Microstimulation of V1 delays the execution of visually guided saccades 373
Microstimulation of V1 elicits a detection response 376
Can microstimulation of V1 evoke phosphenes exhibiting featuresquest 378
Effects of blindness on phosphene induction 379
Discussion 381
Conclusions 386
Abbreviations 386
Acknowledgment 386
References 386
Section VI. Deep Brain Stimulation, FES and TMS 394
Chapter 24. Functional neurosurgery for movement disorders: a historical perspective 396
Introduction 397
Therapy for movement disorders: a random walk around a logical thread 397
What is the current status of the efficiency of high-frequency stimulation in various nuclei in different diseasesquest 400
Deep brain stimulation: a preferred tool in functional neurosurgeryquest 403
What did we learn from the practice of deep brain stimulation in human patientsquest 404
Conclusions 406
References 406
Chapter 25. Recovery of control of posture and locomotion after a spinal cord injury: solutions staring us in the face 410
Why does spinal cord injury result in a loss of movement controlquest 411
Initiating, sustaining, and stopping movements: sources of control 412
Treatment paradigms for preserving muscle function after a spinal cord injury 414
Significance of the concept of ‘‘physiological state’’ of the spinal circuitry in relearning to step 418
Treatment paradigms for restoring locomotor control after a spinal cord injury 419
Integrating neuroengineering and biological concepts to regain posture and locomotion 427
Acknowledgments 430
References 406
Chapter 26. Deep brain stimulation in obsessive-compulsive disorder 436
Introduction 436
Obsessive-compulsive disorder 438
Clinical efficacy of DBS in OCD 438
Side effects of DBS in OCD 441
Conclusion and future 443
References 444
Chapter 27. The use of repetitive transcranial magnetic stimulation (rTMS) for the treatment of spasticity 446
Introduction 446
Pathophysiology of spasticity 447
Effects of rTMS on cortical excitability 450
Effects of rTMS on spinal excitability 450
Effects of rTMS in patients with spasticity 451
Conclusions 453
Abbreviations 454
References 454
Section VII. Mechanisms of Spontaneous Plasticity and Regeneration 458
Chapter 28. Calcium signaling and the development of specific neuronal connections 460
Introduction 460
Axonal growth cone navigation 461
Conclusion 466
Acknowledgments 468
References 468
Chapter 29. Remyelination in multiple sclerosis 470
Introduction 470
Demyelinated MS lesions with persistence of cells of the oligodendrocyte lineage 472
Lesions with oligodendroglial depopulation 473
Conclusion 478
Acknowledgments 478
References 478
Chapter 30. Magnetic resonance techniques to quantify tissue damage, tissue repair, and functional cortical reorganization in multiple sclerosis 482
Introduction 483
Imaging brain atrophy 483
Intrinsic lesion damage 484
Imaging ‘‘diffuse’’ normal-appearing brain tissue (NABT) and normal-appearing WM (NAWM) damage 485
Imaging ‘‘diffuse’’ GM damage 487
Cortical reorganization 488
Imaging the spinal cord 490
Imaging the optic nerve 492
Conclusions 492
References 493
Chapter 31. MRI of neuronal network structure, function, and plasticity 500
Introduction 500
Diffusion tensor imaging 501
Resting state fMRI 504
Discussion 508
Abbreviations 508
Acknowledgments 509
References 509
Chapter 32. The eighteenth C.U. Ariëns Kappers lecture: an introduction 514
C.U. Ariëns Kappers and the Central Institute for Brain Research in Amsterdam 514
Chapter 33. Molecular control of brain plasticity and repair 518
Mechanisms of recovery after CNS damage 518
Plasticity in recovery of function 519
Plasticity decreases with age 519
Methods of restoring plasticity in the adult CNS 520
Chondroitinase and CSPGs 520
NogoA and plasticity 522
Inosine 522
Promoting plasticity opens a window of opportunity for rehabilitation 523
Do the treatments that restore plasticity also promote axon regenerationquest 524
How might therapies be combined to treat spinal cord injuryquest 524
References 524
Subject Index 528