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Figure 2. The subspecialization represented by the term "neurorehabilitation" has followed closely the application to rehabilitation medicine of basic research on neural plasticity and repair, and has closely led evidence-based clinical research. In order to estimate the frequency with which research on neuroplasticity and neural repair is applied to rehabilitation medicine, the best combination of sensitivity and specificity was obtained with the terms "rehabilitation," "neuroplasticity," and "nerve regeneration." Similarly the term "evidence-based medicine" was best paired with "rehabilitation" rather than other terms pairing "rehabilitation" with modifiers.

human injuries and diseases of the CNS have highlighted the need for caution in translating animal studies into human therapies. The most notable example is Parkinson's disease. Based on results in animal models, attempts to replace dopaminergic cells in human patients have been carried out for more than a decade. Yet despite promising results in small-scale studies on special populations (Lindvall, 1998; Chapter 34 of Volume I), larger double-blind, sham operated controlled clinical trials have not suggested major benefits in idiopathic Parkinson's disease (Olanow et al., 2003; Chapter 6 ofVolume II). Despite favorable results in animals, intraventricular infusions of glial cell line-derived neurotrophic factor (GDNF) also failed to provide improvement in human Parkinson's disease. It turns out that because of the large size of the human brain, the GDNF failed to penetrate far enough into the brain parenchyma.

Thus a small-scale clinical trial of intraputamenal GDNF injections has been reported (Gill et al., 2003). A multicenter trial of in vivo gene therapy, using an adeno-associated virus vector containing the gene for neurturin, a GDNF-related peptide that has similar biological activity, is planned. A multicenter clinical trial of autologous macrophages activated by exposure to skin and injected into the spinal cord (Bomstein et al., 2003) is currently under way. The US Food and Drug Administration has approved small-scale clinical trials of intracerebral transplantation of tumor-derived neuronal progenitors for stroke, nerve growth factor-secreting fibroblasts for Alzheimer's disease, and epidural injection of a rho-A antagonist for spinal cord injury. In countries where clinical research is less stringently regulated, many patients have received transplants of stem cells and other highly invasive treatments for a variety of disabling neurological disorders, in the absence of evidence for effectiveness or experimental controls. The technical difficulties of carrying out controlled trials of these novel, highly invasive therapies are matched by ethical concerns. How do you convince patients to undergo a neurosurgical procedure that might be a sham operation? Should a clinical trial be performed on only the most severely disabled patients, who may have less to lose? Or should they be done on less disabled patients, who might have a better chance of responding favorably to an effective treatment, knowing that a failed trial might make it difficult to mount a subsequent one on a more favorable patient population. These and other questions are under intensive discussion and guidelines for the application of these advanced therapies to human patients are needed.

6 Rehabilitation of cognitive functions

Although rehabilitation is commonly thought of as relating primarily to motor retraining, the most disabling aspects of injury to the nervous system often relate to impairments in other domains, such as autonomic, sensory, and especially cognitive functions. Most major neuropsychological syndromes,

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