For focal neurodegenerative diseases or brain tumors, localized delivery of protein or genetic vectors may be sufficient to alleviate symptoms, halt disease progression, or even cure the disease. One may circumvent the limitation imposed by the blood-brain barrier by transplantation of genetically altered cell grafts or focal inoculation of virus or protein. However, permanent gene replacement therapy for diseases affecting the entire brain will require global delivery of genetic vectors. The neurotoxicity of currently available viral vectors and the transient nature (...) of transgene expression invivomust be overcome before their use in human gene therapy becomes clinically applicable. (shrink)

This commentary reviews data supporting circuitry reconstruction, replacement neurotransmitters, and trophic action as mechanisms whereby transplants promote recovery of function. Issue is taken with the thesis of Sinden et al. that adequate data exist to indicate that reconstruction of hippocampal circuitry damaged by hypoxia with CA1 transplants is a confirmed mechanism whereby these transplants produce recovery. Sinden et al.'s and Stein & Glasier's proposal that there is definitive evidence showing that all transplants produce trophic effects is also questioned.

It is well established that neural grafts can exert functional effects on the host animal by a multiplicity of different mechanisms – by diffuse release of trophic molecules, neurohormones, and deficient neurotransmitters, as well as by growth and reformation of neural circuits. Our challenge is to understand how these different mechanisms complement each other.

Neural transplantation as a recovery strategy for neuro-degenerative diseases in humans has used mainly grafting following acute denervation strategies in young adult hosts. Our work in aged mice and rats demonstrates an age-related increase in susceptibility to oxidative damage from neurotoxins, a remarkably poor recovery of C57BL/6 mice from MPTP insult with transplantation and growth factors, even at 12 months of age, and diminished plasticity of host neurons. We believe that extrapolation of data from young adult animal models to aged (...) humans without thorough investigation of transplantation and host response in aged recipients is scientifically and ethically inappropriate. (shrink)

Neural cell transplants have been introduced in clinical practice during the last decade with mixed results, encouraged by success with simple animal models. This commentary is a reminder that although the ideas and techniques of transplantation appear simple, the variables involved in host-transplant integration still require further study. The field may benefit from a concerted, multidisciplinary approach.

It is often presumed that effects of neural tissue transplants are due to release of neurotransmitter. In many cases, however, effects attributed to transplants may be related to phenomena such as trophic effects mediated by glial cells or even tissue reactions to injury. Any conclusion regarding causation of graft effects must be based on the control groups or other comparisons used. In human clinical studies, for example, comparing the same subject before and after transplantation allows for many interpretations of the (...) causes of clinical changes. (shrink)

We concur that basic research on the use of CNS grafts is needed. Two important model systems for functional studies of grafts are ignored by Stein & Glasier. In the first, reproductive function is restored in hypogonadal mice by transplantation of GnRH-synthesizing neurons. In the second, circadian rhythmicity is restored by transplantation of the suprachiasmatic nucleus.

Grafting embryonic brain tissue into the brain of patients with visual field loss due to cerebral lesions may become a method to restore visual function. This method is not without risk, however, and will only be considered in cases of complete blindness after bilateral occipital lesions, when other, risk-free neuropsychological methods fail.

The neural transplantation research described by Sinden and colleagues provides part of the rationale for the clinical application of neural transplantation. The authors are asked to clarify their view of the role of the cholinergic system in cognition, to address extrahippocampal damage caused by transient forebrain ischemia, and to consider the effects of delayed neural degeneration in their structure-function analysis.

Cholinergic-rich grafts have been shown to be effective in restoring maze-learning deficits in rats with lesions of the forebrain cholinergic projection system. However, the relevance of those studies to developing novel therapies for Alzheimer's disease is questioned.

Research on neural transplantation has great potential societal importance in part because of the expanding proportion of the population that is elderly. Transplantation studies can benefit from the guidance of research on cognitive aging, especially in connection with the assessment of behavioral outcomes. Speech for example, might be explored using avian models.

Grafts of embryonic neural tissue into the brains of adult patients are currently being used to treat Parkinson's disease and are under serious consideration as therapy for a variety of other degenerative and traumatic disorders. This target article evaluates the use of transplants to promote recovery from brain injury and highlights the kinds of questions and problems that must be addressed before this form of therapy is routinely applied. It has been argued that neural transplantation can promote functional recovery through (...) the replacement of damaged nerve cells, the reestablishment of specific nerve pathways lost as a result of injury, the release of specific neurotransmitters, or the production of factors that promote neuronal growth. The latter two mechanisms, which need not rely on anatomical connections to the host brain, are open to examination for nonsurgical, less intrusive therapeutic use. Certain subjective judgments used to select patients who will receive grafts and in assessment of the outcome of graft therapy make it difficult to evaluate the procedure. In addition, little long-term assessment of transplant efficacy and effect has been done in nonhuman primates. Carefully controlled human studies, with multiple testing paradigms, are also needed to establish the efficacy of transplant therapy. (shrink)

Many people have argued that the evolution of the human language faculty cannot be explained by Darwinian natural selection. Chomsky and Gould have suggested that language may have evolved as the by-product of selection for other abilities or as a consequence of as-yet unknown laws of growth and form. Others have argued that a biological specialization for grammar is incompatible with every tenet of Darwinian theory – that it shows no genetic variation, could not exist in any intermediate forms, confers (...) no selective advantage, and would require more evolutionary time and genomic space than is available. We examine these arguments and show that they depend on inaccurate assumptions about biology or language or both. Evolutionary theory offers clear criteria for when a trait should be attributed to natural selection: complex design for some function, and the absence of alternative processes capable of explaining such complexity. Human language meets these criteria: Grammar is a complex mechanism tailored to the transmission of propositional structures through a serial interface. Autonomous and arbitrary grammatical phenomena have been offered as counterexamples to the position that language is an adaptation, but this reasoning is unsound: Communication protocols depend on arbitrary conventions that are adaptive as long as they are shared. Consequently, language acquisition in the child should systematically differ from language evolution in the species, and attempts to analogize them are misleading. Reviewing other arguments and data, we conclude that there is every reason to believe that a specialization for grammar evolved by a conventional neo-Darwinian process. (shrink)

I argue that academic psychology’s quest to achieve scientific respectability by reliance on quantification and objectification is deeply flawed. Specifically, psychological theory typically cannot support prognostication beyond the binary opposition of “effect present/effect absent”. Accordingly, the “numbers” assigned to experimental results amount to little more than affixing names (e.g., more than, less than) to the members of an ordered sequence of outcomes. This, in conjunction with the conceptual under-specification characterizing the targets of experimental inquiry, is, I contend, a primary reason (...) why psychologists find it difficult to discriminate between competing, explanations of the effects of mind on behavior. Absent well-specified theory capable of enabling precise and detailed quantitative prediction, inferring underlying mental mechanisms from experimental outcomes becomes a difficult, if not impossible, task. (shrink)

Neuwelt et al. have proposed gene-transfer experiments utilizing an animal model that offers many important advantages for investigating the feasibility of gene therapy in the human brain. A variety of tissues concerning the viral vector and mode of delivery of the corrective genes need to be resolved, however, before such therapy is scientifically supportable.

The transplantation of cholinergic neurons into the hippocampal formation has been well characterized. We describe our studies on the effects of cholinergic transplants in the retrosplenial cortex. These transplants were capable of ameliorating spatial navigation deficits in rats with septohippocampal lesions. In addition, we provide evidence for the modulation of transplanted neurons by the host brain.

Complementation and correction of a genetic defect with CNS manifestations lags behind gene therapy for inherited disorders affecting other organ systems because of shortcomings in delivery vehicles and access to the CNS. The effects of improvements in viral and nonviral vectors, coupled with the development of delivery strategies designed to transfer genetic material thoughout the CNS are being investigated by a number of laboratories in efforts to overcome these problems.

A major problem in developing an effective gene therapy for the nervous system lies in understanding the principles that maintain or turn off the expression of genes following their transfer into the CNS.

Gene therapy approaches have great promise in the treatment of neurodegenerative disorders and malignant brain tumors. Neuwelt et al. review available viral-mediated gene therapy methods and their blood-brain-barrier (BBB) disruption delivery technique, briefly mentioning nonviral mediated gene therapy methods. This commentary discussed the BBB disruption delivery technique, viral and nonviral mediated gene therapy approaches to Parkinson's disease, and the potential use of antisense oligo to suppress malignant brain tumors.

The work of Sinden et al. suggests that it may be possible to produce improvement in the areas of brain function by transplanting brain tissue. What appears to be the limiting factor is not the complexity of the mental process under consideration but the discreteness of the lesion which causes the impairment and the appropriateness and accuracy of placement of the grafted tissue.

The responses displayed by an injured or diseased nervous system are complex. Some of the responses may effect a functional reorganization of the affected neural circuitry. Strategies aimed at the restoration of function, whether or not these involve transplantation, need to recognize the innate reactive capacity of the nervous system to damage. More successful strategies will probably incorporate, rather than ignore, the adaptive responses of the compromised neural systems.

The spinal cord provides an alternative model for nerve tissue grafting experiments. Anatomo-functional correlations are easier to make here than in any other region of the CNS because of a direct implication of spinal cord neurons in sensorimotor activities. Lesions can be easily performed to isolate spinal cord neurons from descending inputs. The anatomy of descending monoaminergic systems is well defined and these systems offer a favourable paradigm for lesion-graft experiments.

The transition from research to patient following advances in transplantation research is likely to be disappointing unless it includes a better understanding of critically relevant characteristics of the neurological disorder and improvements in the animal models, particularly the behavioral features. The appropriateness of the model has less to do with the species than with how the species is used.

Challenges the revised standard historiography on Wundt as a psychologist. Considers the concept of psychology as a natural science. Examines the relations between psychology and philosophy before and after 1900. Reflects on the notion of disciplinehood as it affects historical narratives.

The concept of structure, operation, and functionality, as they may be understood by clinicians or researchers using neural transplantation techniques, are briefly defined. Following Stein & Glasier, we emphasize that the question of whether an intracerebral graft is really functional should be addressed not only in terms of what such a graft does in a given brain structure, but also in terms of what it does at the level of the organism.

Gene replacement therapy holds great promise in the treatment of many genetic CNS disorders. This commentary discusses the feasibility of gene replacement therapy in the unique context of the retina, with regard to: (1) the genetics of retinal neoplasia and degeneration, (2) available gene transfer technology, and (3) potential gene delivery vehicles.

Three experiments on neural grafting with adult rat hosts are described. Working memory impairments were produced by lesioning the hippocampus or severing its connections with the septum by ablating the fimbria-fornix. The results suggest that the survival and growth of a neural graft, whether an autograft or a xenograft, is not a necessary condition for functional recovery on a task tapping working memory.

Despite reports of recovery of function after neural transplantation, the biological interactions between transplanted neurons and the host brain that are necessary to mediate recovery are unclear at present. One source of confusion is in the variety of models and protocols used in these studies. It is suggested that multisite experimentation using standard protocols, models, and recovery criteria would be helpful in moving neural transplantation from the laboratory to the clinic.

Studies on the snailMelampusreveal that connectivity is crucial to the survival of transplanted ganglia. Transplanted CNS ganglia can innervate targets or induce supernumerary structures. Neuron survival is optimized by the neural incorporation that occurs when a transplanted ganglion is substituted for an excised ganglion. Better provision for the trophic requirements of neurons will improve the success of mammalian fetal transplants.